A TEXT-BOOK 
of 
PATHOLOGY 
By 
w. g. MacCallum 
Professor of Pathology and Bacteriology 
The Johns Hopkins University 
Baltimore 
Third Edition, Thoroughly Revised 
PHILADELPHIA AND LONDON 
W. B. SAUNDERS COMPANY Copyright, 1916, by W. B. Saunders Company. Reprinted March, 
1917, March, 1918, and April, 1919. Revised, reprinted, and 
recopyrighted August, 1920. Reprinted March, 
1921, and February, 1922. Revised, 
reprinted, and recopyrighted 
September, 1924 
Copyright, 1924, by W. B. Saunders Company 
MADE IN U. S. A. 
PRESS OF 
W. B. SAUNDERS COMPANY 
PHILADELPH1 A To 
G. A. MacCallum, M.D. 
My Father 
With Gratitude and Affection PREFACE TO THE THIRD EDITION 
During the four years since this book was last revised many subjects 
in the field of medicine have been studied effectively, and, in a few places, 
a flood of light has come. It is interesting, for example, to find an almost 
completely new set of ideas about rickets. The way has been thrown open 
by the discovery of insulin for a new comprehension of diabetes, and 
perhaps for much new light on metabolism in general. We are not much 
further advanced in our ideas of tumors and infections, but there is at 
least much information about epidemic encephalitis, typhus, etc., and we 
may well feel that the course of the world's search for knowledge has 
been as rapid as in any other four years. 
As to this book, a little has been added, a little taken away or cor- 
rected, and some new pictures replace those which were less satisfactory. 
An attempt has been made in reading it through to add at least a sum- 
mary statement of the important accessions to the literature and to ex- 
press any changes in opinion which we have derived from our own ex- 
perience. 
W. G. MacCallum. 
The Johns Hopkins Hospital, 
September, 1924. 
III PREFACE 
In this book, which represents in its order and contents the course in Pathol- 
ogy given in the second year to the students of the College of Physicians 
and Surgeons, an effort has been made to discuss the general principles of 
Pathology as illustrated by a study of the commoner and more important 
diseases. 
It is therefore in no sense intended as a book of reference. No attempt 
has been made to describe systematically all the diseased conditions which 
may occur in each organ, and for that reason there is no division into general 
and special pathology. Instead the whole is constructed upon the idea 
that all pathological disturbances are the result of some form of injury, or 
of the immediate or more remote reactions of the body to injury. It has 
been found possible to carry out this conception quite logically except when, 
as in the case of tumors, we are quite ignorant of the causes of the disease. 
For that reason, after a few chapters devoted to the general working 
principles with illustrations from the most common conditions, the rest of 
the book is divided into chapters which deal with various types of injury 
and their immediate and remote effects. The discussion of tumors neces- 
sarily forms a separate part, since they seem to be so little controlled by the 
laws which govern other pathological processes. 
The whole book is planned therefore to discuss disease as far as possible 
upon the basis of etiology, and the usual subdivision of the material accord- 
ing to its anatomical distribution has not been employed. Nevertheless 
the index is so arranged as to facilitate reference to lesions of the heart, 
lungs, etc. 
Partly because of lack of space, but chiefly because they are admirably 
treated in great detail in books easily accessible to students, several whole 
sections usually included in books on pathology have been omitted. This 
is true of the relations of heredity to disease, of the biology of bacteria and 
other parasites, of malformations, and of many diseases of the nervous 
system. The whole subject of resistance and immunity is touched upon 
only in the briefest way. Nevertheless, even though such subjects are in- 
tentionally omitted, it is realized that criticism may well be offered when it 
is found that the diseases chosen to illustrate the principles of pathology 
do not include many important affections, such as multiple sclerosis, pro- 
gressive muscular atrophy, rabies, yellow fever, and a host of others. 
In discussing the prominent types of injury an attempt has been made 
to give an impression of the far-reaching interdependence of pathological 
V PREFACE 
VI 
conditions by making a continuous story of the whole with numerous digres- 
sions for the description of special lesions or their causes. Several chap- 
ters are devoted to the results of obstruction of the flow of contents of 
hollow organs, and while it may seem that this is a rather forced arrange- 
ment the type of injury is one whose effects depend in each instance upon 
certain common principles. 
A constant effort has been made to speak of the disturbances of function 
and of chemical interchange in the course of disease, as far as that was 
possible, and even to describe symptoms. If this makes the book seem like 
a treatise on clinical medicine, it is only because pathology and clinical 
medicine are, after all, the same thing viewed from slightly different angles. 
References to the literature given with each chapter have been chosen, as 
far as possible, to direct the student to readable and comprehensive papers 
which review the subject and give further and more complete references. 
The illustrations are almost entirely from specimens which we have 
studied in this laboratory, but I have to thank many friends in other 
laboratories for their kindness in sending me material or for allowing me 
use of photographs. The drawings with very few exceptions have been 
made by Mr. Alfred Feinberg. 
I am indebted to my assistants for much help, and especially to Dr. A. 
M. Pappenheimer, who furnished the material for the section on the thymus 
and aided me in reading the proof, and to Dr. R. A. Lambert who made the 
index. 
w. g. MacCallum. CONTENTS 
CHAPTER I page 
Disturbances of the Fluids of the Body 1 
Relation of Fluids to Tissues; Blood, Lymph, Tissue Fluids. The Blood: Va- 
riations in Quality and Quantity. Readjustment. Plethora and Oligaemia. 
Clotting. Thrombosis. 
CHAPTER II 
Local Disturbances in the Circulation of the Blood 15 
Hyperaemia; Anaemia. Postmortem Changes in Distribution. Active and 
Passive Hyperaemia. Local Anaemia. Embolism. Infarction. Gangrene. 
CHAPTER HI 
Disturbances of Intercellular Fluids and Lymph 43 
Their Movement, Character, and Excessive Accumulation. CEdema, Ascites. 
CHAPTER IV 
The Structure and Metabolism of Cells 48 
Cellular Doctrine; Ultimate Unit of Life. Nucleus and Cytoplasm. Mito- 
chondria, Plasmosomes, Paraplasmic Substances, Intercellular Substances. 
Tissues and Motile Cells. Variations in the Appearance of Cells. Necrosis, 
Coagulation and Autolysis. Death. 
CHAPTER V 
Disturbances in the Nutrition and Metabolism of Cells' 60 
Nature of Metabolism. Disturbances Resulting from Slight Injuries. De- 
generations. Atrophy: Its Causes. Hypertrophy and Hyperplasia. 
CHAPTER VI 
Disturbances of Fat Metabolism 72 
Neutral Fats and Lipoids. Their Source, Absorption, Distribution and 
Functions. Pathological Disturbances. 
CHAPTER VII 
Disturbances of Protein and Carbohydrate Metabolism 87 
General Character of Protein Metabolism. The Purine Bodies. Gout. 
Cloudy Swelling. Hyaline Metamorphosis. Amyloid Infiltration. Carbohy- 
drate Metabolism. Glycogen. 
CHAPTER VIII 
Disturbances of Mineral and Pigment Metabolism 106 
Calcium: Its Source, Distribution, Deposition in Necrotic and Other Tissues; 
Its Relation to Various Functions of the Body. Iron: Its Distribution and 
Functional Importance. Disturbance in Its Quantitative Relations. Chloro- 
sis. Haemochromatosis. Pigment: Function and Distribution. Endogenous 
and Exogenous Pigmentation. Jaundice. Dust Diseases. 
VII VIII 
CONTENTS 
CHAPTER IX page 
Defences of the Body Against Injury 132 
Immediate and Late Reactions to Injury. Inflammation, Fever, Immunity 
Production, and Repair. Inflammation an Elaborate Mechanism to Combat 
Injury. Details of Vascular and Phagocytic Phenomena. The Wandering 
Cells. 
CHAPTER X 
Defences of the Body (Continued) 156 
Fever. Genend Nature of the Reaction. Its Chemical Characters and Rela- 
tion to Immunity. Immunity. Nature of Injurious Agents. Types of 
Resistance. Artificial Immunity. Phagocytosis. Lysins, Agglutinins, Anti- 
toxins, etc. Maintenance of Acid-base Equilibrium. Mechanism of Preserva- 
tion of Neutrality. Acidosis. 
CHAPTER XI 
Defences of the Body (Continued) 174 
New-growth of Tissue. General Characters. Influences of Various Agencies 
on Growth. Growth Stimuli. 
CHAPTER XII 
Defences of the Body (Continued) 189 
Repair. Established Character of Tissues. Their Early Differentiation. 
Metaplasia. Regeneration as Exemplified in the New Formation of Various 
Tissues. 
CHAPTER XIII 
Defences of the Body (Continued) 209 
Transplantation of Tissues and Organs, Its Limitations. Healing of Wounds 
-by Direct Union, Under a Crust, by Granulation Tissue, etc. Healing of 
an Open Ulcer, of Inflamed Wounds and Abscesses. Healing of Special 
Tissues. 
CHAPTER XIV 
Illustrative Examples of Inflammatory Processes 227 
Catarrhal Inflammation. Serofibrinous and Fibrinopurulent Pericarditis, 
Pleuritis, Peritonitis, Appendicitis, Endocarditis, Lobular Pneumonia, Puer- 
peral Infection. Pyaemia, Abscess Formation, Diphtheritic Inflammation. 
CHAPTER XV 
Injury with Inflammatory Reaction and Attempted Repair 267 
Nephritis: General Nature of the Process. Its Diffuse Character. Acute 
and Chronic Glomerulonephritis, Tubular Nephritis, and Interstitial Neph- 
ritis. Arteriosclerotic Disease of the Kidney. Combined Inflammatory and 
Arteriosclerotic Disease. Amyloid Deposit. Summary. Functional Altera- 
tions. Renal Insufficiency. 
CHAPTER XVI 
Injury with Inflammatory Reaction and Attempted Repair (Continued). 
-Injury and Repair of the Liver 308 
Cirrhosis of the Liver. Structure of the Liver in Relation to Disease. Direct CONTENTS 
IX 
Injury to Liver-cells. Acute Yellow Atrophy. Eclampsia, and Infections. 
Repair and Compensatory Hyperplasia. Cirrhosis: Its Various Types. 
The Alterations in Architecture Involved. Obstruction of Portal Circulation. 
Collateral Circulation. Biliary and Hypertrophic Cirrhosis. 
CHAPTER XVII 
Further Illustrative Examples of Destructive and Reparative Processes. 333 
Arteriosclerosis. Structure of Arteries. Anatomical Changes in Arterioscle- 
rosis in Aorta and Other Vessels. Pathogenesis and ^Etiology. Syphilitic Ar- 
teritis in Aorta and Smaller Vessels. Obliterative Endarteritis. Thrombo- 
angeitis Obliterans. Aneurysms, Various Types; Their Effects and Their 
Relation to Syphilis. Apoplexy; Location of Haemorrhage in Brain. 
CHAPTER XVIII 
Types of Injury: Physical and Mechanical Injuries 367 
Mechanical Injuries: Pressure, Direct Violence Affecting Bones, Central 
Nervous System, etc. Gunshot and Other Wounds. Secondary Effects: 
Complication with Infection. Shock. Experimental Study and Various 
Theories. Effects of Heat: Burns, Heat-stroke, Insolation. Effects of Cold: 
Freezing. Effects of Light-rays and Radiant Energy on Skin, Blood-forming 
Organs, etc. Electricity: Effects of Strong Currents. 
CHAPTER XIX 
Types of Injury (Continued).-Chemical Injuries 392 
Nature of Poisons: Their Varying Effects. Reaction of Organism; Elimi- 
nation, Detoxication, Resistance. Auto-intoxication. Poisoning by Illumi- 
nating Gas, Corrosive Substances, Cyanides, Chloroform, Alcohol, Metallic 
Poisons, etc. 
CHAPTER XX 
Types of Injury (Continued).-Effects of Obstruction of the Flow of 
Contents of Hollow Organs. Obstruction in the Alimentary Tract 405 
Salivary Ducts. Bile-ducts (Gall-stones, Cholecystitis, Jaundice). Pan- 
creatic Ducts (Pancreatic Cirrhosis, Acute Pancreatitis). Obstruction of 
Digestive Tract: (Esophagus, Stomach (Gastric Ulcer). Intestine; Varying 
Mechanism of Obstruction (Hernias, Intussusception, Volvulus, Compression 
or Kinking by Adhesions, Paralysis, Stenosis). 
CHAPTER XXI 
Types of Injury-Obstruction (Continued).-Obstruction of Respiratory 
Tract 428 
Nose (Coryza, Adenoids, etc.). Larynx ((Edema, Diphtheria, Foreign Bodies, 
Compression, Stenosis). Bronchi (Foreign Bodies, Stenosis). Atelectasis: 
Its Causes. Mechanism of Bronchial Dilatation. Bronchiectasis. Emphy- 
sema. 
CHAPTER XXII 
Types of Injury-Obstruction (Continued).-Obstruction of the Urinary 
Tract 439 
Urethral Stricture. Prostatic Obstruction; Hypertrophy of Prostate. Cyst- 
itis. Urinary Calculi. Hydronephrosis. Renal Calculi. Ascending Renal 
Infection; Pyelonephritis. X 
CONTENTS 
CHAPTER XXIII PAGE 
Types of Injury-Obstruction (Continued).-General Disturbances of 
Circulation 459 
Mechanism of Circulatory Organs. Pericardial and Pleural Effusions. 
Emphysema. Chemical Influences. Effects of Arterial and Myocardial Dis- 
ease. Myocarditis. Valvular Disease. General Mechanism of the Obstruc- 
tion Thus Produced. Various Valvular Lesions and Their Special Effects. 
Cardiac Hypertrophy and Dilatation. Decompensation; Chronic Passive 
Congestion. Disturbances of Conduction System in Heart. 
CHAPTER XXIV 
Types of Injury (Continued).-Obstruction of the Cerebrospinal Fluid: 
Hydrocephalus 502 
CHAPTER XXV 
Types of Injury (Continued).-Bacterial Disease.-Streptococcus Infec- 
tions 507 
General Character of Bacterial Infection: Nature of Bacterial Action. Pyo- 
genic Micrococci. Streptococcus Infections-of the Throat, the Middle Ear, 
the Digestive Tract. Streptococcus Wound Infection, Erysipelas, Pneu- 
monia, Endocarditis. General Septicaemia (Acute Splenic Tumor). 
CHAPTER XXVI 
Types of Injury.-Bacterial Disease (Continued).-Staphylococcus In- 
fections 531 
General Character. Furunculosis. Paronychia, Impetigo, etc. General Sep- 
ticaemia, Pyaemia, Suppurative Nephritis, Endocarditis, Lobular Pneumonia, 
Osteomyelitis. 
CHAPTER XXVII 
Types of Injury. Bacterial Disease (Continued).-Pneumococcus Infec- 
tions 541 
Character of Organism. Lobar Pneumonia. Consolidation. Resolution. 
Organization, etc. Septicaemia. Endocarditis. 
CHAPTER XXVIII 
Types of Injury.-Bacterial Disease (Continued).-Meningococcus and 
Gonococcus Infections. Rheumatism 554 
Meningococcus Infections: Epidemic Cerebrospinal Meningitis. Endocar- 
ditis. Gonococcus Infections: Urethritis and Sequelae. Salpingitis and 
Sequelae. Arthritis. Ophthalmia. Dermatitis, Endocarditis, Vulvovagini- 
tis in Children. Acute Rheumatism: Tonsillitis, Arthritis, Endocarditis, 
Pericarditis, Myocarditis. 
CHAPTER XXIX 
Types of Injury.-Bacterial Disease (Continued).-Diphtheria. Tetanus. 573 
Diphtherial Infection: Diphtheria of Respiratory Tract. General Effects 
upon the Heart, Kidneys, etc. Paralysis. Tetanus Infection: Mode of Oc- 
currence and Mechanism of Distribution of Toxin. Botulism. 
CHAPTER XXX 
Types of Injury.-Bacterial Disease (Continued).-Cholera. Plague. 
Glanders. Anthrax. Influenzal Infection 581 
Asiatic Cholera: Intestinal Lesions. General Intoxication. Bubonic Plague: 
Transmission. Bubonic Type. Pneumonic Type. Glanders: Acute and CONTENTS 
XI 
Chronic Forms. Anthrax: Infection through Skin, Digestive Tract, Lungs. 
Influenzal Infection: Relation to Epidemic Influenza, Pneumonia, Meningitis. 
CHAPTER XXXI 
Types of Injury.-Bacterial Disease (Continued).-Typhoid and Para- 
typhoid Infections 599 
Typhoid Infection: General Relations. Intestinal, Lymphatic, Splenic, and 
Other Lesions. Necrosis in Various Organs. Affections of Circulatory, Re- 
spiratory, and Nervous System. Paratyphoid Infection: Relation to Typhoid 
and Enteritis Infection. Acute Gastro-enteritis, Accessory Lesions. Dysen- 
tery: Various Organisms Concerned. Intestinal Lesions. 
CHAPTER XXXII 
Types of Injury.-Bacterial Disease (Continued).-Leprosy. Actinomy- 
cosis 621 
Leprosy: Nodular and Anaesthetic Forms. The Bacillus and Transmission. 
Lesions of the Internal Organs. Affections of Nerves and Their Sequelae. Ac- 
tinomycosis: General Character of the Disease and Organism. Related 
Organisms. Mode of Infection. Destructive Lesions. 
CHAPTER XXXIII 
Types of Injury.-Bacterial Disease (Continued).-Tuberculosis 634 
Tuberculosis: ^Etiology. Distribution and Transportation of Bacilli. Modes 
of Infection, Immunity and Hypersensitization. The Tubercle, Tuberculous 
Granulation Tissue, Acute Tuberculous Inflammation, Distribution of the 
Bacilli in the Body. Acute Miliary Tuberculosis. Tuberculosis of Respiratory 
Organs, Digestive Tract, Serous Surfaces, Lymph-glands, Genito-urinary 
Tract, Nervous System, Skin, Bones, and Joints. 
CHAPTER XXXIV 
Types of Injury.-Infections of Uncertain Nature 688 
Typhus: Epidemic Distribution. Anatomical Lesions. Experimental 
Studies, Transmission by Lice. A Bacillus Recently Discovered. Acute 
Poliomyelitis: Infectious Nature. The Organism. Febrile Illness, Subse- 
quent Paralysis. Lesions of Nervous System. Epidemic Encephalitis. 
CHAPTER XXXV 
Types of Injury.-Spirochetal Infection 696 
Syphilis: ^Etiology and Distribution. Course of the Disease. Nature of 
Different Stages. Immunity and Transmission. Primary Stage, Secondary 
Lesions, Tertiary Stage. Lymph-glands, Blood, Digestive Tract, Liver, Re- 
spiratory Tract, Bones and Joints, Heart and Blood-vessels, Nervous System. 
Syphilitic Lesions of Genital Organs. Orchitis. 
CHAPTER XXXVI 
Types of Injury.-Spirochetal Infection (Continued) 730 
Syphilis: Syphilitic Lesions of Nervous System. Syphilitic Meningitis. 
Tabes Dorsalis. General Symptoms. Lesions of the Nervous System. 
Theories Concerning it. Dementia Paralytica, Its Relation to Tabes; Symp- 
toms. Anatomical Changes in Brain and Cord. Congenital Syphilis. Gen- 
eral Relations. Lesions in Respiratory Organs, Liver, Pancreas, Bones, etc. 
Late Forms of Congenital Syphilis. XII 
CONTENTS 
CHAPTER XXXVII page 
Types of Injury.-Exanthematic Diseases 757 
Introduction. Measles: Susceptibility, Etiology, Course of Disease, and 
Pathological Anatomy. Scarlet Fever: Aetiology Complicating Streptococcus 
Infection, Transmission; Course and Pathological Anatomy. Scarlatinal 
Nephritis. Smallpox: Relation to Vaccinia; Vaccination; ^Etiology; Symp- 
toms and Pathological Anatomy. 
CHAPTER XXXVIII 
Types of Injury.-Diseases Due to Animal Parasites 768 
Introduction. General Relation of Parasites to Host. Table of Main Zoo- 
logical Divisions. Amoebic Infections: Types of Parasites and Life-history; 
Intestinal Infection; Abscess of Liver; Abscess of Lung. Pyorrhoea Alveo- 
laris. Malaria: Types and Life-history of Parasites; Symptoms and Patho- 
logical Anatomy; Blackwater Fever. Trypanosome Infections: Biology; 
Sleeping Sickness. 
CHAPTER XXXIX 
Types of Injury.-Diseases Due to Animal Parasites (Continued) 784 
Cestode Infections: Taenia and Bothriocephalus; T. Echinococcus; Echino- 
coccus Cysts in Man. Trematode Infections: Bilharziosis; Paragonimus 
and Clonorchis. Trichiniasis: Biology of the Parasite, Symptomatology, 
Pathological Anatomy. Uncinariasis: Symptomatology; Life History of Para- 
site; Pathological Anatomy. Infections with Ascaris, Oxyuris, Trichoceph- 
alus, and Filaria. Elephantiasis. 
CHAPTER XL 
The Effects of Injuries upon the Blood and Blood-forming Organs 799 
Importance of Changes in Blood-formation. The Bone-marrow: Its Regen- 
erative Changes. The Spleen. The Lymphoid Tissues with the Haemolymph 
Nodes. Injuries of Red Corpuscles and Erythrogenic Tissue: Polycythemia. 
Anaemia or Oligocythemia. Post-haemorrhagic and Other Secondary Anae- 
mias. Pernicious Anaemia. Aplastic Anaemia. Haemochromatosis. Haemo- 
lytic Icterus. Osteosclerotic Anaemia. Banti's Disease. Splenomegaly of 
Gaucher. 
CHAPTER XLI 
Effects of Injuries to the Blood and Blood-forming Organs (Continued) . 826 
Leucocytosis; Leucopenia. Lymphocytosis. Eosinophilia. Corresponding 
Changes of Haematopoietic Organs. Independent Disease of the Blood-forming 
Organs: General Characters; Classification in Lack of Information as to 
^Etiology. Chronic Lymphoid Leukaemia. Acute Lymphoid Leukaemia. 
Leucosarcoma, or Chloroleucosarcoma (Chloroma). Lymphoid Myeloma. 
Pseudoleukaemia. Lymphosarcoma. Status Lymphaticus. 
CHAPTER XLII 
Effects of Injuries to the Blood and Blood-forming Organs (Continued) 849 
Chronic Myeloid Leukaemia. Acute Myeloid Leukaemia. Myeloblastic Leu- 
kaemia. Myeloid Chloroma or Chloromyelosarcoma. Myeloid Myeloma. 
Hodgkin's Disease or Lymphogranulomatosis. 
CHAPTER XLIII 
Diseases Due to Injuries of the Organs of Internal Secretion 864 
Pancreas. Diabetes Mellitus; General Character of Process. Pathological CONTENTS 
XIII 
PAGH 
Anatomy. Nature of Disturbance of Carbohydrate Metabolism. Relation of 
Other Organs. Diabetic Acidosis. Resume. Thyroid: Anatomy and Physi- 
ology. Myxoedema, Effects of Extracts. Cretinism, Goitre. Exophthalmic 
Goitre: General Symptoms, Pathological Nature of Disease. 
CHAPTER XLIV 
Diseases Due to Injuries of the Organs of Internal Secretion (Con- 
tinued) 889 
The Parathyroid: Anatomy, Physiology. Tetany: Hyperexcitability of 
Nerves. Relation to Calcium Metabolism, Pathological Anatomy. Other 
Types of Tetany. Thymus: Anatomy, Evolution and Involution. Hyper- 
plasia. Thymus in Exophthalmic Goitre, in Myasthenia Gravis, in Status 
Thymico-lymphaticus; Accidental Involution. Adrenal: Anatomy. Function 
of Medulla, Functions of Cortex. Addison's Disease. 
CHAPTER XLV 
Diseases Due to Injury to the Organs of Internal Secretion (Continued) 903 
Hypophysis. Structure. Properties of Extracts of Different Lobes. Experi- 
mental Extirpation. Effects of Hyperactivity and Hypoactivity at Different 
Periods of Life. Gigantism. Acromegaly. Frohlich's Syndrome. Adiposity. 
Relation of Genital Function. Diabetes Insipidus. Histological Changes 
in the Hypophysis in Pregnancy, Acromegaly, etc. Hypertrophic Pulmonary 
Osteoarthropathy. 
CHAPTER XLVI 
Injuries Causing Metabolic Disturbances and Consequent Disease of the 
Bones 915 
Chemical Interchanges in Growth of Bone. Importance of Calcium. Rela- 
tion of Internal Secretions to Bone Formation. Normal Ossification. Rick- 
ets. Osteomalacia. Chondrodystrophia Fcetalis. Scurvy and Moller-Bar- 
low's Disease; Osteogenesis Imperfecta; Osteopsathyrosis; Paget's Disease. 
CHAPTER XLVII 
Arthritis Deformans 932 
Confusion as to Classification; Infectious, Traumatic, Neuropathic, and 
Gouty Forms. Terminology: 1. Proliferative Arthritis Deformans or Pro- 
gressive Polyarthritis; Clinical and Gross Pathological Characters; Histology. 
Spondylitis of Bechterew and Marie. 2. Degenerative Arthritis Deformans. 
Clinical and Gross Pathological Changes; Histology. Malum Coxse Senile; 
Spondylitis Deformans. 
CHAPTER XLVIII 
Tumors 942 
General Nature of Tumors; Difficulty of Classification. Fibromata. Neuro- 
fibromata, Keloids. Lipomata. Chondromata. Osteomata. (Xanthomata.) 
Myomata; Leiomyomata, Rhabdomyomata. 
CHAPTER XLIX 
Tumors (Continued) 961 
Tumors Derived from Elements of the Nervous System. General Relations 
to Various Stages in Development of the Nervous System. Neurocytoma, 
Neuroblastoma, Neurinoma, Chromaffine Tumors. Gliomata. Angiomata: 
Haemangiomata, Lymphangiomata. Sarcomata: General Characters. Spin- 
dle-cell, Mixed-cell, Round-cell, and Alveolar Sarcomata. Giant-cell Sarco- 
mata. Osteosarcomata. Myxomata. CONTENTS 
XIV 
CHAPTER L page 
Tumors (Continued) 989 
Pigmented Tumors: Naevi. Their Relation to Epithelium and Connective 
Tissue. Melanomata or Melanotic Sarcomata. Tumors of Adrenal Origin: 
Hypernephromata; Relation to Aberrant Adrenal Tissue. Endotheliomata: 
Difficulty of Establishing Their Relation to Endothelium. Endotheliomata 
from Lymphatic Endothelium. Cylindromata. Pleural and Peritoneal 
Tumors. Endotheliomata of the Meninges. Tumors Derived from Endothe- 
lium of the Blood-vessels. "Perithelial" Tumors. 
CHAPTER LI 
Tumors of Epithelial origin 1005 
Relation of Epithelium to Stroma. Papillomata: Origin from Skin and 
Mucosae, Papillomata of Bladder and Ovary. Adenomata: Origin from 
Skin, Salivary Glands, Gastric and Intestinal Mucosae, Kidney, Liver, Ad- 
renal, Hypophysis, and Prostate. Adenomata of the Breast; Intracanalicular 
Forms. Cystadenomata of Ovary: Their Origin and Form; Papillomatous 
Types. Adenomata of the Uterus. 
CHAPTER LII 
Carcinomata 1025 
General Characters, Grouping. Flat-cell Carcinomata. Epitheliomata of 
Lip, Skin, etc. Mode of Growth and Metastasis. Epitheliomata of Tongue, 
Tonsils, Bronchi, (Esophagus, Gall-Bladder, Urinary Bladder. Epitheliomata 
of the Vaginal Portion of the Cervix Uteri. Their Frequency and Importance. 
Adamantinomata. Basal-cell Carcinomata. Their Relatively Benign Char- 
acter. Distribution, Peculiar Morphology. Relation to Naevi. Other 
Tumors Assigned to This Group. Analogous Tumors of Intestine and 
Appendix. 
CHAPTER LIII 
Carcinomata (Continued) 1042 
Adenocarcinomata: General Characters and Distribution. Carcinomata of 
the Stomach: Polypoid, Solid and Scirrhous Forms. Their Histology and 
Mode of Growth; Metastasis. Colloid Forms, Their Somewhat Different 
Mode of Growth. Carcinomata of the Gall-bladder and Ducts. Carcino- 
mata of the Pancreas, of the Colon, of the Prostate. Metastasis of Prostatic 
Tumors in Bones. Adenocarcinomata of the Uterus and of the Ovary. 
CHAPTER LIV 
Carcinomata (Continued) 1064 
Gland-cell Carcinomata: Carcinomata of the Breast: Epitheliomata, Tu- 
mors Derived from the Acini (General Form, Mode of Extension and Metas- 
tasis, Histology, Relation to Adenomata and Chronic Cystic Mastitis, Scir- 
rhous Forms). Tumors Derived from the Ducts. Colloid Cancers. Carcino- 
mata of the Ovary; Carcinomata of the Thyroid; Primary Carcinomata of 
the Liver with Cirrhosis. Chorionic Epitheliomata: Histogenesis of Cho- 
rionic Epithelium, Its Normal Invasive Growth. Hydatidiform Mole. Cho- 
rionic Epithelioma; Gross Appearance, Metastasis, Histology, and Histo- 
genesis; Relation to Corpus Luteum. 
CHAPTER LV 
Teratomata; Composite Tumors 1081 
Chorionic Epithelium in Tumors of the Male. Teratomata. Early Develop- 
ment of the Ovum. Potency of Blastomeres. Their Inclusion in the Forma- CONTENTS 
XV 
tion of Double Monsters. Formation of Solid Teratomata. Dermoid Cysts. 
Cutaneous and Branchial Cysts. Cholesteatomata. Mixed Tumors of 
Salivary Glands; of the Kidney. Congenital Cystic Kidney. Mixed Tumors 
of the Breast and of the Testicle. Chordoma. 
CHAPTER LVI 
Classification of Tumors 1096 
CHAPTER LVII 
General Discussion of Tumors 1098 
General Character of Tumors; Relation to Tissues of Host. Their Indepen- 
dence of the Laws Governing the Growth of Normal Tissues; Consequent Ab- 
normal Architecture and Metabolism. Distinction Between Tumors and 
Infectious Processes. Nature of Cells of Tumors; Specific Relation to Those 
of Host; Relation to Embryonic Stages of Cell Development; Atypical 
Character. Growth; Implantation, Extension, Metastasis, Recurrence. 
Contributory Causes of Tumor Growth: Injury and Irritation (Physical, 
Chemical, Parasitic; Rous' Filterable Tumor); Internal Secretions; Malfor- 
mations; Disposition; Senility; Heredity. Resistance and Immunity. 
Theories as to the Aetiology of Tumors: Theory of Parasitic Origin of Tumors; 
Theory of Tumor Growth as the Effect of Irritants; Theories Emphasizing a 
Disturbance of Equilibrium of Tissues; Cohnheim's Theory; Ribbert's 
Theory; Theories of Tumor Growth Depending upon Changes in the Cells. 
Index 1123 TEXT-BOOK OF PATHOLOGY 
CHAPTER I 
DISTURBANCES OF THE FLUIDS OF THE BODY 
Relation of fluids to tissues; blood, lymph, tissue fluids. The blood: variations in 
quality and quantity. Readjustment. Plethora and oligcemia. Clotting. Thrombosis. 
Relation of Fluids to Tissues.-The cells of the tissues are, like other living 
beings, dependent for their life and activity upon a constant and abundant 
supply of food and oxygen and an equally adequate removal of their waste- 
products. This service is rendered them by the circulation of the various 
fluids through every part, propelled by a mechanical arrangement, the per- 
fection of which we .shall have frequent occasion to admire. There are 
three main types into which we may divide these circulating fluids, the 
blood, the tissue fluids, and the lymph. 
The blood is practically everywhere separated from actual contact with 
the cells of the tissues by a semi-permeable membrane composed of other 
cells, the endothelium. It flows through the whole body, giving off cer- 
tain substances and withdrawing others, always through this membrane. 
Between the cells outside the blood-vessels there are spaces, or at least 
potential spaces, in which a small amount of fluid collects which directly 
bathes the cells and directly receives their waste. This tissue fluid is 
constantly being changed too, by interaction with the blood. But it also 
stands in exactly the same relation to the lymph, which, like the blood, 
flows inside channels with semi-permeable walls composed of endothelial 
cells and goes to empty into the vein. We do not believe now that there 
are open communications between the lymphatic channels and the tissue 
crevices. That idea, it seems, has been thoroughly disproved by the recent 
work which shows the completeness of the endothelial lining of these 
channels. 
It will be realized, then, that there must be qualitative differences at all 
times between these three fluids, although by processes of diffusion and 
osmosis there is constantly going on an attempt to establish a balance 
between them. Uniformity is never reached, though, on account of the 
metabolic activity of the tissue-cells and the immediate removal of the 
blood and lymph before equilibrium is established. These qualitative 
differences and, indeed, the question of the chemical composition of the 
fluids need not arrest us here. Materials pass from the arterial side of the 
1 TEXT-BOOK OF PATHOLOGY 
2 
capillaries into the tissue spaces, and from there either into the lymphatics 
or into the veins, and it is obvious that, according to the character of the 
cells which make up the tissue, the nature of the lymph and of the venous 
blood produced in this way must vary greatly in different parts of the body. 
The portal blood is filled with materials which could not be found in any 
such quantities in the blood of the femoral vein, and the hepatic vein con- 
tains blood which is altogether changed by passing through the liver. 
The degree of activity of the organs plays a great part also, so that during 
digestion portal blood undoubtedly differs very greatly from the blood of 
the same vein at other times. 
THE QUANTITY OF BLOOD IN THE BODY 
Normally the quantity of blood in the body bears a fairly definite relation 
to the weight of the body. Until recently the determinations of this 
quantity were notoriously inaccurate, and even yet little is known about 
the possible variations. But with the method of Haldane-Smith, which 
consists essentially in administering a known amount of carbon monoxide 
and estimating its concentration in a sample of the blood, the quantity 
has been shown to be from 5 to 5.3 per cent, of the body weight. 
Experimental efforts to increase or decrease the amount of blood in 
proportion to the tissues fail except for very short periods, because the 
excess of fluid introduced is immediately excreted, and that which is re- 
moved from the blood-vessels by bleeding is quickly made up by the filtra- 
tion of fluid from the tissues into the capillaries. Blood-pressure is scarcely 
changed by any such measures because the vasomotor mechanism imme- 
diately adapts the capacity of the stream-bed as nearly as possible to its 
new contents. 
The adjustment is especially rapid and effective when an excess of fluid 
is introduced, and if it does not enter the veins too abruptly and rapidly 
the excretion by the kidneys keeps pace with it almost perfectly. In the 
other case, the removal of blood, there are naturally limits to the power of 
the tissues to give up fluid to restore its bulk. Even under the best cir- 
cumstances this is a slower process than the removal of fluid by excretion. 
The terms plethora and anaemia or oligaemia have long been in use to imply 
an excess of blood, on the one hand, and a poverty of blood, on the other, 
but with this extraordinary compensatory power of the body in view, it 
seems that we must use them with some caution. Nevertheless it is per- 
fectly obvious at autopsy, if not during life, that in some persons the vessels 
are distended with an enormous quantity of blood, while in others not 
only do the vessels seem collapsed, but all the tissues are shrunken and dry 
looking. Especially is the latter true in old persons and those who have 
long suffered from a wasting disease. 
Plethora.-Apparently the existence of actual changes in the amount of 
blood which last for any time is dependent chiefly upon qualitative changes 
in the blood itself and in the tissues. A true plethora, in which the blood CLOTTING, THROMBOSIS, ETC. 
3 
is increased without change in its composition, probably occurs with de- 
fects in the action of the heart which then allows a part of the blood to 
remain practically stagnant in the veins and propels an abnormally small 
part of it into the arteries. The compensation for this diminution of the 
arterial circulation by introduction of more fluid may restore the normal 
amount in active circulation, but increases the total amount in the body. 
Hydrsemic or serous plethora is spoken of as a condition in which the 
quantity of blood is increased by a relative increase in its watery part. 
As has been said, it is impossible to maintain this for any length of time 
experimentally because the kidneys promptly excrete the excess of water, 
but it is conceivable, though not proven, that it may arise when the excre- 
tory power of the kidneys is lowered by disease. 
Oligaemia.-Practically the same things may be said of oligaemia or 
anaemia. The simplest type of general anaemia is undoubtedly that which 
is produced when a considerable amount of blood is lost through the opening 
of a blood-vessel. The person becomes blanched, makes forced respira- 
tions, and may become unconscious on account of the poor supply of nu- 
trition to the brain. He becomes very weak and thirsty, and his pulse is 
low and scarcely perceptible, but often very rapid. An immediate attempt 
is made by the tissues to pour back again into the vessels enough fluid to 
fill them again and to raise the blood-pressure, and consequently, for some 
time, on account of this adding of fluid both from the tissues and from water 
taken in by mouth, the blood becomes dilute. The proportion of red cor- 
puscles, which can be determined by counting, sinks for two or three days, 
at which time the inflow of fluid ceases and the reproduction of corpuscles 
by the blood-forming organs begins to make itself evident. From that 
time onward there is a steady increase in the number of corpuscles to each 
cubic millimetre until the blood reaches its normal state. There seems to 
be also the other form of oligaemia in which the quantity is reduced by loss 
of water. Naturally this will be compensated as quickly as possible, too, 
but in such diseases as cholera the loss is so rapid that the tissues become 
desiccated as well. It is quite possible, therefore, that the decrease in the 
quantity of blood is merely proportional to the desiccation of all the tissues. 
CLOTTING, THROMBOSIS, ETC. 
Clotting.-We are not well informed as to the nature of the process through 
which an injury to a single cell or a unicellular animal is healed. The 
wound is closed very rapidly, and apparently by a process rather more 
complex than the mere flowing together of the protoplasm. We do know, 
however, that in such animals as the Crustacea and in the higher types, 
where there is a circulation of blood and other body juices, these fluids 
possess the peculiar property of clotting, or coagulating as soon as they 
are exposed to contact with anything which has not the character of the 
living vessel-wall. It is through this property that the loss of blood from 
every trifling wound is checked, although otherwise it might well prove 4 
TEXT-BOOK OF PATHOLOGY 
fatal. In this sense the clotting is distinctly a protective process, probably 
developed from the time of the first appearance of animal life as a factor 
indispensable to the preservation of the animal. The same process ap- 
pears again and again under the greatest variety of circumstances in patho- 
logical conditions, but it will be seen that in all-in spite of many imper- 
fections in the mechanism-it has a protective significance. 
Clotting, even in its simplest form, is a complex process which has been 
diligently studied for many years, but even yet there are many important 
parts of it which are not at all well understood. The names of Alexander 
Schmidt, Arthus, Hammarsten, Pekelharing, Loeb, Fuld, Spiro, and 
Morawitz are especially prominent in this connection, and the following 
may be regarded as the most generally accepted results of their work, which 
have been clearly stated by Morawitz. 
When blood and lymph are allowed to escape into a glass dish they 
clot, usually in a very short time. If the blood is continually stirred, 
the clot adheres to the stirring rod, leaving a permanently fluid blood 
(defibrinated blood). If it is not stirred, the clot forms uniformly 
throughout the whole quantity of blood, converting it into a solid, 
rather dry, firm mass, often so tenacious that the dish, if it be not too 
wide and shallow, may be inverted without spilling. Such a clot is of 
a uniform dark-red color. If it be squeezed, a red fluid is forced out 
which is identical with defibrinated blood. If the spongy mass be washed 
in running water, all the red blood-corpuscles may be washed away, leaving 
a stringy, yellowish white, elastic mass of fibrin. If the fresh blood be 
kept very cold, or if it be received into an oiled dish, it will not clot so 
quickly, and since the red corpuscles are heavier than the plasma, there 
may be time for them to sink to the bottom in a very thick layer. The 
leucocytes are lighter and rest in a layer on top of the red corpuscles, while 
above there is some plasma almost free from cells. By this time clotting 
occurs throughout, the clot differing from the uniform red one formed by 
rapid coagulation, in the presence of a grayish-yellow upper layer which 
contains most of the leucocytes and platelets. This was called the "buffy 
coat" by the old bloodletters, and its thickness was, in their hands, an 
mdex of the rapidity with which the blood clotted, and of the number of 
leucocytes contained, although their deductions usually took various other 
turns. 
This slow clotting showing the effects of gravity is seen very commonly 
in the heart at autopsy, for the intact endothelial lining of the heart keeps 
its contents a long time without clotting. There the deep-red portion of the 
clot ("cruor clot") is in the dependent part, while the tough, elastic, 
translucent, yellowish substance (chicken-fat or turtle-fat clot) occupies 
the uppermost part of the heart as the body lies on the table (Fig. 1). 
The homogeneous elasticity of this kind of clot and the fact that it is readily 
removed from the heart-wall, leaving it unaltered, make it quite easy to 
distinguish it from the thrombus formed on injured areas of the heart-wall CLOTTING, THROMBOSIS, ETC. 
5 
during life, although extraordinary mistakes have been made and the post- 
mortem clot held to be the cause of death. 
At first-and especially when it is rapidly formed-the clot is quite dry. 
Indeed, it is this which confers the dryness and firmness upon the lung in 
the early stages of pneumonia, where a fresh clot occupies each air-cell. 
Later, however, through its own elasticity, the clot contracts away from 
the wall of the glass and shrinks together. In this way it expresses from 
its meshes a clear fluid, the serum, in which it is finally bathed. If we 
examine the clot microscopically, we shall find it to be composed of a deli- 
cate network of fine fibrils, among which there are entangled the cells of 
the blood. In the rapidly formed clot these are perfectly homogeneously 
distributed in the proportions in which they existed in the circulating 
Fig. 1.-Postmortem clot in the cavity of the heart. 
blood, but in the layered clot which has slowly formed there are red cor- 
puscles, but fewer leucocytes in the lower red part of the clot, while in 
the upper layer there are numerous leucocytes with platelets, but no red 
cells; there may even be a layer in which there are very few cells of any 
kind (Fig. 2). 
Throughout the clot one may sometimes recognize minute centres about 
which the fibrin radiates, or if the corpuscles are not too much crowded, it 
may be possible to see star-like radiations of filaments of fibrin about single 
cells. One sometimes sees these radial arrangements of fibrin about bac- 
teria in the blood, and this may be especially striking in cases of anthrax 
or other such infection in which the blood contains many foreign cells. 
Besides these, in clots which are formed after death in the heart or large 
blood-vessels, it is generally possible to find in sections pale, pink-staining 6 
TEXT-BOOK OF PATHOLOGY 
clumps to which a number of leucocytes adhere buried deeply and irregu- 
larly among the red corpuscles. These have been described by Rost and 
others and seem to consist chiefly of groups of blood-platelets. Never- 
theless, the distinctive character of the clot formed after death in the stag- 
nant blood is its general homogeneity of structure, in which respect it 
differs so sharply from the clots formed during life in the streaming blood. 
As to the mechanism of the 
clotting, it is generally agreed 
that the fibrin is formed by 
the action of a ferment-like 
substance called by Morawitz 
thrombin, upon a proteid sub- 
stance, fibrinogen, which oc- 
curs in the plasma. The throm- 
bin is in itself, according to this 
theory, a complex result of the 
interaction of two substances. 
The first is a material called 
thrombokinase, which is derived 
from the formed elements of 
the blood (leucocytes or plat- 
elets) or from any tissue with 
which the blood may come 
into contact. It does not 
seem necessary that these cells 
should be actually destroyed, 
but merely altered in some 
particular which we cannot 
recognize. The second con- 
stituent occurs in the plasma 
and is called prothrombin. What 
the character of the union or 
interaction of thrombokinase 
with prothrombin is we do not 
know, but it is known that the 
presence of a soluble salt of 
calcium is required to complete 
it and bring about the forma- 
tion of thrombin. After the 
thrombin is formed, the calcium is no longer necessary to carry out the 
second phase of the clotting, although it accelerates it. This second 
phase consists in the interaction between the thrombin and fibrinogen, 
which is present in the plasma with the formation of a fine fibrillary 
network of fibrin. 
The blood ordinarily remains fluid in the vessels because the leucocytes 
Fig. 2.-Postmortem clot: a, Fibrin; 6, layer 
of leucocytes; c, cruor clot with red corpuscles 
and platelets in clumps. CLOTTING, THROMBOSIS, ETC. 
7 
and other cells are not injured enough to liberate thrombokinase-what- 
ever small amounts are set free are neutralized by the antithrombin which 
has been shown to exist in the plasma. The conversion of fibrinogen to 
fibrin is irreversible, but the nature of the change is not known-possibly 
one is a hydrosol, the other a hydrogel. The recent work of Howell and his 
many students has brought to light several new factors in the process of 
clotting and has explained in a new way their interaction. He has devised 
methods for obtaining prothrombin and thrombin in a state of purity 
sufficient for the exclusion of other related factors, and in the substance 
derived from injured tissue and known as thrombokinase he recognizes a 
phosphorus-containing lipoid or phosphatid, cephalin. This he called a 
thromboplastic substance. He has also discovered another phosphatid in 
extracts from the liver and other organs which he has named heparin, and 
a protein material in the plasma, which is the mother substance of anti- 
thrombin, and called pro-antithrombin. 
Prothrombin, which is normally present in the plasma, is apparently de- 
rived from the bone-marrow, which is also the site of formation of the blood- 
platelets. In the presence of calcium if there were nothing to interfere, 
the prothrombin would be converted into thrombin capable of causing 
the formation of a clot from the fibrinogen. But this is prevented in the 
circulating blood by something which protects the prothrombin from the 
action of the calcium. This may be heparin, which was at first known as 
antiprothrombin. Antithrombin could prevent the clotting by neutralizing 
the formed thrombin, but that would entail the continuous conversion of 
prothrombin into thrombin and the accumulation of neutralized prothrom- 
bin.* 
Heparin is able to neutralize prothrombin and to render the blood quite 
incoagulable. On the other hand, heparin forms a combination of some 
kind with pro-antithrombin to produce antithrombin. Hence, pro-anti- 
thrombin, heparin, and antithrombin are ranged on one side to interfere 
with clotting which would otherwise occur in the series prothrombin, cal- 
cium, thrombin, and fibrinogen on the other side. There remains, however, 
the thromboplastic substance, cephalin, which is powerfully antagonistic 
to heparin and antithrombin, and, by overpowering them in situations 
where blood impinges upon injured tissues, frees the prothrombin to become 
thrombin or allows the activity of the thrombin in. forming the clot. It is 
at this point that Howell's explanation of clotting differs radically from 
the older view, in which it was thought that thrombokinase was necessary in 
the formation of thrombin. 
The clot itself has been watched in process of formation with the aid 
of the ultramicroscope. At first there is a clear field, but as the clotting 
* In vitro the combination of thrombin and antithrombin appears as metathrombin, an 
inert substance which can be activated into thrombin by alkalies or acids, but no meta- 
thrombin is found in the circulating blood, and even if it be injected into the veins it 
disappears at once. 8 
TEXT-BOOK OF PATHOLOGY 
begins, shining needle-shaped crystals appear in great numbers, dancing 
about, and later arranging themselves in strands, which are the fibrils of 
fibrin. Fibrin is thus one of the rare examples of crystalline gels. 
The origin of the thromboplastic substance was long discussed, but it 
seems now to be a matter of less interest than the origin of the prothrombin, 
which Drinker has shown to depend largely on the integrity of the bone- 
marrow. Duke thought that the absence of platelets which also originate 
in the bone-marrow might account for the prolonged bleeding in purpura. 
There are some conditions, particularly such infectious processes as pneu- 
monia, in which clotting occurs very rapidly, and shortly after death com- 
plete moulds of the vessel may be pulled out from the large vascular trunks. 
In such cases the clots are dry and uniformly deep red throughout. On 
the other hand, there are other conditions, such as haemophilia, icterus, etc., 
in which coagulation is greatly delayed, and serious haemorrhage may occur 
during and after the slightest surgical operation. Whipple thinks that 
the delay in clotting of blood in diseases of the liver with jaundice is due 
to an excess of antithrombin in the blood, while Howell thought that in 
haemophilia the blood was deficient in prothrombin, but now suggests 
that the prothrombin may there be rendered inactive by an excess of he- 
parin. 
Spontaneous clotting in the veins during life may be due to a deficiency 
in antithrombin, but other explanations, such as are given in the next 
section, seem more plausible. 
Thrombosis.-On the basis of either theory of clotting it is easy to under- 
stand that a coagulum might form about any mass of cells which, after 
suffering some injury, had become clumped together or agglutinated in 
the blood, and, indeed, Loeb and others have observed that an agglutina- 
tion of formed elements always precedes the formation of the fibrin. The 
part played by the platelets is perhaps important in postmortem or extra- 
corporeal clotting, but it becomes especially prominent in the inception of 
thrombi, which are peculiar clots formed during life in the streaming 
blood. 
The character of these thrombi is very different in some respects from 
that of the postmortem clots, although the principles concerned in their 
formation are the same, except that the single mechanical factor of the 
streaming movement of the blood disturbs the ordinary process of clotting 
and brings into prominence the feature of preliminary agglutination of 
the platelets. 
A thrombus begins by the deposition, on the wall of the blood-channel, 
of a minute, pearly, translucent mass of platelets which grows by the ad- 
hesion of other platelets as they come by. These produce curious upstand- 
ing laminae or walls running transversely to the blood-stream and anasto- 
mosing freely with one another; the platelets are so welded together that 
their outlines can no longer be seen, and in section these laminae appear as 
faintly pink-staining, finely granular bands in the substance of the throm- CLOTTING, THROMBOSIS, ETC. 
9 
bus (Fig. 3). However, it must not be supposed that they rise up alone and 
unsupported in the current. Instead of that, they quickly catch the passing 
leucocytes and hold them all along their surfaces (borders in the section), 
like flies on sheets of sticky fly-paper; and at the same time they seem to 
liberate thromboplastic substance, so that filaments of fibrin spread out 
from them on all sides, and, meeting with filaments from the next lamella, 
hang in festoons between them. In this way the branching and anastomos- 
ing lamellee are guyed and braced together by fibrin, which, needless to 
say, entangles quantities of red corpuscles, so that finally the whole is a 
solid mass of peculiarly constructed clot. At first, of course, this thrombus 
Fig. 3.-Thrombus: coral-like laminae of platelets with marginal leucocytes and inter- 
vening red corpuscles and fibrin. 
is predominantly a red mass, although the grayish-white lamellae of plate- 
lets can be seen in a cross-section forming a web all through the red. On 
the free surface of the thrombus these same lamellae project slightly above 
the red part of the clot, and these corrugations are known as the "lines of 
Zahn" (Fig. 4). Red corpuscles, under such circumstances, soon die, lose 
their haemoglobin, and finally disappear into a formless debris which in 
time assumes a semitranslucent appearance. A thrombus, therefore, 
which is largely red at first, becomes yellowish gray after a time, and the 
contrasting color of the platelet sheets is lost in the homogeneous mass. 10 
TEXT-BOOK OF PATHOLOGY 
Fig. 4.-Thrombus: the strands of platelets form superficial corrugations. 
Nevertheless, since a thrombus continually tends to grow by accretion, 
the parts of different ages show differences in color. Indeed, when a 
Fig. 5.-Thrombus in auricular appendage. CLOTTING, THROMBOSIS, ETC. 
11 
thrombus forms in a vein, occluding it, there is left a perfectly stagnant 
column of blood reaching to the next affluent of the vein, and in this an 
ordinary homogeneous clot is formed, just as it would be in a test-tube- 
not exactly, however, for there is some motion communicated to this column 
of blood and clumps of platelets are formed. At the inflow of the next 
Fig. 6.-Thrombus in vena cava. 
branch the clotting may stop or begin once more to assume the character 
of the thrombus. Thus, as Aschoff says, a thrombus has a head, and then, 
perhaps, extending both ways in the vein, a propagated part or tail, which 
differs from it, being more like a postmortem clot. 
Thrombi may be formed anywhere in the blood-stream, even on the walls 12 
TEXT-BOOK OF PATHOLOGY 
of the aorta, where it might seem that the pulsating torrent of blood would 
allow no chance for the deposition of the pioneer platelets. But most 
commonly they appear in the veins or in the auricular appendages or inter- 
trabecular spaces of the heart or upon the valves of the heart. In the veins 
they seem to start from the region of a valve, where the slight obstruction 
gives rise to eddies. In the heart (Fig. 5) they bulge forward from the 
recess as pinkish yellow, distinctly corrugated masses, generally coated with 
an adherent red clot-sometimes they are quite smooth and globular, and 
these, which seem to be old ones, are frequently found to be softened into a 
semifluid or fluid material in their central parts. In the veins (Fig. 6) the 
lumen is usually, though not always, obliterated, and at the lower end the 
vein is plugged for a long way with a soft red clot. The thrombus itself 
differs from a postmortem clot in being inelastic, friable, and granular, and 
in adhering to the wall of the vein so that when it is removed the lining 
of the vein is left roughened and dull looking. In the propagated clot 
one may find for some distance indications of the general characters of the 
thrombus, and such freshly formed thrombi are hard to tell from post- 
mortem clots. Any part of the thrombus may break off and be swept 
along in the blood-stream to plug some distant vessel. 
It may be difficult to avoid looking upon thrombosis as a process harm- 
ful to the body, since it causes the obstruction of blood-vessels, and through 
the dislocation of part of the material of the thrombus frequently gives 
rise to embolism of distant organs, with death of some part of their tissue 
or even death of the individual. 
But it might be argued that this is only a form of the very useful and 
protective clotting of the blood, and that these inconveniences represent 
the usual imperfection in a mechanism of defence. Indeed, there are in- 
numerable instances in which thrombosis has the character of a life-saving 
process. Even the final cessation of bleeding from a cut vessel is really 
due to a form of thrombosis, since the clot is produced in streaming blood. 
The covering of bacteria lodged in a heart valve or on any part of the wall 
of +he circulatory system by a thrombus is a distinct protection inasmuch 
as it prevents the bacteria from being spread through the whole body. 
When thrombosis occurs in a blood-vessel on account of injury and weak- 
ening of its wall, either from within or from the advance of an infectious or 
other destructive process from the outside, it prevents haemorrhage by 
obstructing the vessel and withdrawing it from the pressure of the blood. 
This is well illustrated in the blood-vessels about ulcerative processes of 
all sorts, whether in the intestinal walls, lungs, or elsewhere. It must be 
said, however, that thickening of the walls of the vessels usually plays a 
large part in shutting off the current of blood, especially when the erosion 
of tissue proceeds slowly, so that it may be agreed that were it not for 
thrombosis more serious consequences might follow the injury of the walls 
of the blood-channels. Less can be said for the advantages conferred by 
embolism. CLOTTING, THROMBOSIS, ETC. 
13 
The question as to the cause of the formation of thrombi has been answered in various 
ways. The wall of the vessel underlying them is always injured, but whether by the 
presence of the thrombus or by something which in that way provoked the formation of 
the thrombus is hard to say. Most of the older writers assumed a primary injury of the 
wall (Eberth and Schimmelbusch, Welch) which allowed the production of thrombokinase 
or thromboplastin. This seems especially true of those instances in which thrombi are 
formed in the aorta upon ragged, arteriosclerotic patches or in the venous sinus of the 
dura at a point where an abscess extending from the middle ear encroaches upon it. 
For a time there was great enthusiasm over the idea that thrombi occurring in general 
infections and after surgical operations were due to the presence of bacteria which injured 
the vessel-wall. Perhaps this was going too far, but now the pendulum has swung the 
other way, and Aschoff and his colleagues contend that thrombi are essentially produced 
by some mechanical obstruction or slowing of the stream, and that the bacteria which are 
found in them are brought to the thrombus after it is well formed. Aschoff has made 
elaborate studies to show that, in a stream of water with obstructions of various forms, 
sawdust or sand floating in the stream will accumulate according to definite laws in a 
certain relation to the obstructions, and especially where eddies are formed and where 
consequently the stream is slowed. The distribution of little sand-banks in the course 
of a crooked stream with many obstructions is familiar enough to every one, and it is 
easily credible that such mechanical factors are of great importance in determining where 
the thrombus shall start and how the deposition shall proceed. Indeed, the difficulty is 
confined to the explanation of the first deposit of platelets-after that the growth of the 
thrombus is easily explained by the ordinary principles of clotting and by the obstruction 
produced by the thrombus itself. Schwalbe has shown that if the wall of the vein be 
scraped from within after the blood is rendered incoagulable with hirudin, platelets 
accumulate on the injured area in quantity, but no fibrin is formed and no red corpus- 
cles entangled. But I must still believe that many thrombi arise because an injured 
or dead surface is exposed to the coagulable circulating blood, as in the sclerotic patches 
of the aorta, the infected cranial sinus in otitis media, the uterine veins in puerperal 
sepsis, or the portal branches leading away from an appendix abscess. No one thinks 
of the thrombus formed upon a heart valve as caused by mechanical slowing of the 
stream with secondary deposit of bacteria. Why, therefore, is there any difficulty in be- 
lieving that bacteria may lodge on the endothelium of a valve in a vein where the current 
is vastly slower, and there, by injuring the endothelium, make possible the first step in 
the formation of the thrombus? As a predisposing and later as a guiding factor controlling 
the architecture of the thrombus, modifications of the velocity and direction of the 
current are undoubtedly of great importance, but for the first step in the lodgment of 
platelets injury to the endothelium seems to me to be of prime significance. Me- 
chanical injury to the vessel quite naturally brings about thrombus formation. If a 
vessel be ligated very gently in two places, so that the endothelium is not injured, but 
merely gently pressed together, clotting of the contained blood will not occur for a long 
time, but if the vessel walls are crushed and torn, it ensues almost at once. Cut vessels 
of small size close themselves partly by contraction and partly by the formation of a 
thrombus at the bleeding end. 
Aschoff, in his classification, describes three other forms of thrombi: Agglutination 
thrombi, which occur in capillaries such as those of the glomeruli of the kidney and are 
really formless masses of agglutinated red corpuscles (Flexner). Precipitation thrombi, 
which are produced in the capillaries of exposed tissue, like the mucosa of the stomach, 
by strong chemical poisons which coagulate or precipitate the whole protein-rich blood, 
and, third, thrombi which are composed of the debris of red corpuscles and other cells 
which may appear in quantities after some haemolytic process. 14 
TEXT-BOOK OF PATHOLOGY 
LITERATURE 
Welch: Allbutt's System of Medicine, 1899, vi, 155. 
Eberth and Schimmelbusch: Thrombose, Stuttgart, 1888. 
Aschoff, Beck, de la Camp, and Kronig: Beitrage zur Thrombosefrage, Leipzig, 1912. 
Howell: Amer. Jour. Physiol., 1910, xxvi, 453; Arch. Int. Med., 1914, xiii, 76; Amer. 
Jour. Physiol., 1912, xxxi, 1; 1913, xxxii, 264; 1918, xlvii, 328; Harvey Lectures, 
1916-17, 273. 
Howell's classical work on the coagulation of the blood is brought together in his 
Harvey Lecture. 
Welch's review of thrombosis and embolism should be read by every student. CHAPTER II 
LOCAL DISTURBANCES IN THE CIRCULATION OF THE BLOOD 
Hypercemia; anaemia. Postmortem changes in distribution; active and passive hypercemia. 
Local anaemia. Embolism. Infarction. Gangrene. 
The circulation through a tissue is modified by three main factors: the 
activity of the heart, the changes in the calibre of the blood-vessels, 
and the amount of blood. Of these, the changes in the calibre of the blood- 
vessels are of special importance as far as the local conditions are con- 
cerned. The muscular walls of the arteries, and to a less extent the veins, 
are controlled, as is well known, by the vasomotor nerves, so that the 
amount of blood which passes through any given tissue depends largely 
on the activity of these nerves. Quite aside, therefore, from any patho- 
logical conditions, there are remarkable changes from time to time in the 
amount of blood which passes through the different tissues, the arterial 
blood supply generally increasing with the activity of that particular tissue.* 
* Postmortem Changes.-During life the distribution of the blood in any organ or 
tissue is a very uniform one, as a rule, but on the cessation of the action of the heart 
numerous alterations take place, so that in the tissues, as observed in the dead body, 
the distribution of the blood is very much changed, and it is necessary to be familiar 
with these changes in order to appreciate those which are actually the results of patho- 
logical conditions which have existed during life. The contractility of the arte- 
rial walls is dependent not only upon their muscular structures, which aid, by a 
sort of peristaltic movement, the action of the heart, but also upon the large amount 
of elastic tissue which exists in their walls. The combined effect of the contraction of 
these two tissues, as soon as the heart stops beating, is to drive the blood out of the 
arterial side into the venous side of the circulation in each organ, in that way imme- 
diately producing a change in the appearance of the organ. 
The liver, which is in life of a uniform red color, shows at once on cessation of the 
heart-beat the lobulation with its darker blood-filled central portion and paler periphery, 
a mottling being produced by the collection of blood in the central portion of each lobule, 
while the periphery is left pale. In the same way the great veins in the abdomen become 
filled with blood, whereas the arteries everywhere are found collapsed and nearly empty. 
Other influences are brought to bear also, and especially that of gravity, so that all 
dependent portions, as the body lies, become overfilled with blood and assume a dark 
purplish hue, while the upper portions are relatively pale. This is true even of the differ- 
ent parts of the internal organs, so that the loops of intestine which lie in the pelvis 
and in the lower part of the peritoneal cavity show a great distension of the veins, although 
the upper portions of the loops are pale. When the intestine is opened and stretched out, 
these areas appear as patches of congestion, the nature of which is not always recognized 
by the beginner. 
The purplish discoloration of the skin of the back is not seen in those parts upon which 
the body has lain; thus, for example, the backs of the shoulders, the buttocks, and heels 
usually appear quite white, because, owing to the pressure of the weight of the body, the 
blood has not been allowed to sink into them. Firm pressure of the fingers upon the 
purple area is sufficient to drive the blood out of those veins and to leave white marks. 
This overdistension of the veins through gravity is spoken of as livor mortis, and it must 
be distinguished from accumulations of blood in the tissues themselves-haemorrhage. 
This distinction is readily made because in livor mortis (hypostasis) the blood is still 
15 16 
TEXT-BOOK OF PATHOLOGY 
An increase in the amount of blood to any part is spoken of as hypercemia; 
and such hypersemia may be active, when there is an actual increase in the 
amount of arterial blood, or passive when, through any obstruction, the 
outflow of venous blood is retarded. On the other hand, decrease of the 
supply of blood in any area is known as partial or complete ancemia and 
results from obstruction of the arterial flow. 
HYPEREMIA 
Active hypercemia is usually the result of vasomotor effects upon the vessels, 
and is essentially a physiological process, being concerned so largely with 
the supply of increased nutritive fluid to tissues which are assuming for the 
time a heightened activity. It, however, appears in certain nervous dis- 
turbances, and also may be brought about by the direct application of heat 
and irritants, which cause the blood-vessels to dilate. It is probably in 
just this way that the irritant, which is sufficiently intense to bring about 
an inflammatory reaction, causes the active hyperaemia which forms so 
striking a feature of that process. The tissues through which such a rapid 
stream of arterial blood is passing are usually somewhat swollen and red 
and warmer than the surrounding tissue. 
Passive hypercemia is more commonly a pathological or abnormal process, 
inasmuch as it is the result of interference with the outflow of blood. It is 
usually a very wide-spread obstruction, due to some inability on the part 
of the heart which dams back blood into the whole venous tract, but oc- 
casionally it may be quite local. This is especially due to the fact that the 
veins are more easily compressed than the arteries, so that pressure from 
without which will occlude the veins can still allow the blood to be poured 
in from the more resistant arteries, congesting and distending the tissues 
with stagnant blood. 
It is by no means uncommon to find a loop of intestine pushed through 
an aperture in the abdominal wall, thus constituting a hernia. Such a loop 
may, in most cases, be pushed back into the peritoneum; but sometimes, 
when it has escaped habitually through this newly formed aperture into the 
sac which is formed outside, it may become so enlarged by an increase of its 
within the veins, while in haemorrhage it has escaped from the blood-vessels and can no 
longer be pressed away with the fingers. 
If the body has lain for some time, and especially if the temperature of the surrounding 
air has been high, there may appear other discolorations which are due not particularly 
to the distribution of blood nor to its escape from the vessels, but to the disintegration 
of the red corpuscles by a physico-chemical process which we shall discuss later under 
the name of haemolysis. This sets free into the fluid the red staining matter of the blood 
(haemoglobin), which tinges diffusely all dead tissues with which it comes into contact; 
the lining of the aorta, for example, and of the heart itself may assume a dull red color 
which is in sharp contrast to the normal. Such blood staining of the tissues may appear 
with great rapidity in persons who have died from infection with one of those bacteria 
which have the property of destroying the red corpuscles rapidly by the poison which 
they produce. In such infections, notably the streptococcus infections, the blood in the 
vessels stains the surrounding tissues to such an extent that the course of the subcu- 
taneous veins may be seen through the skin in the form of a network of purplish lines. HYPEREMIA 
17 
contents that it can no longer be returned, and indeed so large that its 
blood-vessels, which, of course, stretch through the aperture, also become 
constricted there, and the circulation is brought to a full stop, not because 
blood cannot get in through the artery, but because it cannot escape 
through the more readily compressed vein. This is a condition which is 
known as "strangulated hernia." 
A local congestion of not quite so extreme a degree may often be seen in 
the liver when a tumor nodule embedded in the liver substance presses on 
the efferent vein and causes that portion of the liver ordinarily drained 
by the vein to become congested. The process is put to therapeutic 
use in Bier's treatment of various local infections in which a stagnation 
of blood is produced for a time in the inflamed area by the applica- 
tion of a tight bandage which obstructs the veins and leaves the arteries 
open. 
Ordinarily, the communications between veins are very abundant, so 
that the obstruction of any one vein is hardly likely to cause such conges- 
tion. Nevertheless, the surgeon must be careful in operating to leave the 
tissues not only with a sufficient arterial supply, but also with an adequate 
venous outflow if they are to remain alive; for the stoppage of the stream 
from the venous side is just as important as the obstruction of the arterial 
side. In the case of mesenteric veins, renal veins, etc., ligation or occlusion 
may readily lead to the death of the tissue which they drain. In other 
places where anastomosis is free there may be no effect, but if the obstruc- 
tion, as in the case of a long thrombus of the femoral vein, is extensive 
enough to plug the communicating branches, the accessory channels are 
also closed and the circulation is greatly disturbed. In such a case great 
pain is experienced, the leg becomes swollen and livid, or later pale, with 
purplish blotches, and, because of the malnutrition and oedema, it can 
scarcely be moved (milk-leg). (Edema or oozing of the fluid of the blood 
into the tissue-spaces is characteristic of all instances of marked passive 
hypersemia, and in extreme cases, with great disturbance of the nutrition 
of tissues, haemorrhage may also occur. 
Passive hypersemia may be the effect also of nervous disturbances which 
render immobile for a long time the muscles of an extremity. The same 
result follows to a slight extent if disease of the joints with ankylosis makes 
them immovable. In both these cases the passive hypersemia is relatively 
slight, and is essentially the effect of gravity. In this respect it resembles 
the condition which is found in the dependent portions of organs in persons 
who are constrained to lie in bed for a long time in one position. It is 
spoken of as hypostasis, and becomes particularly striking in the lungs, 
where it may so lower the nutrition, and consequently the power of 
resistance, of the tissues as to allow bacteria to take root there and produce 
the so-called hypostatic pneumonia. 18 
TEXT-BOOK OF PATHOLOGY 
In a general anaemia, such as has been mentioned, each individual tis- 
sue may, of course, suffer somewhat, but the most intense effects of this 
type may be brought about locally without regard to the general condi- 
tion of the circulation. Such local anaemia must always result from an 
obstruction opposed to the inflow of arterial blood. This may be an 
effect of the active contraction of the blood-vessels through the intermedia- 
tion of the vasomotors, or it may be due to pressure on these vessels from 
without, or to thickening of the walls of the vessels with narrowing of their 
lumen, or, finally, and most commonly, to a complete obstruction or plug- 
ging of the artery by some foreign material which is lodged there. Com- 
binations of all these things very commonly occur. The vasomotor nar- 
rowing of the vessel is ordinarily a normal process, aimed at the withhold- 
ing of blood from a vessel which does not need it at that particular stage of 
its activity, but sometimes it may become pathological, as in the so-called 
Raynaud's disease, which consists in such a constriction of the vessels of 
the fingers and toes as to cause even the death of those tissues. Apparently 
the familiar chilblains depend upon such excessive narrowing of the vessels 
when the hands or feet are exposed to cold. That seems to happen in 
particularly susceptible persons, and probably especially in those whose 
habits are sedentary and in whom the circulation is ordinarily not very 
active. 
Pressure from without might cause the closure of an artery if it were 
directly enough applied. It is difficult, however, to obstruct the arteries 
by pressure from without, because they are so protected by other tissues; 
and it is well known that a ligature tied tightly around an extremity will 
cause rather an increase of blood in the ligated part, because it obstructs 
the outflow through the veins long before it can obstruct the artery. In 
order to render a limb bloodless for the purpose of carrying on an operation 
in a clean field, as in the method of Esmarch, a rubber bandage must be 
applied with great force. 
The pressure of tumor-nodules and of aneurysms upon arteries may 
sometimes cause their obstruction in such a way as to cut off completely 
the supply of blood from the part. The pedicle of a tumor or the long 
mesentery of a loop of intestine may become twisted so as to shut the lumen 
of the artery and cause the death of the tissue supplied by it; but usually, 
as we have stated in speaking of strangulated hernia, this first results in the 
obstruction of the vein, so that the tissue becomes engorged with stagnant 
blood and the final effect of shutting off the artery masked. 
The walls of the arteries themselves may undergo structural changes 
which finally lead to such narrowing of the lumen as to prevent the further 
flow of blood. This usually occurs when an organ has passed its stage of 
usefulness, and such an abundant blood supply is no longer necessary. It 
LOCAL ANEMIA EMBOLISM 
19 
is somewhat difficult to draw a line between this more or less physiological 
process of narrowing the artery and that which comes from actual disease 
of the artery wall. Still, in extreme cases, the pathological character of 
the process is very evident. There are various forms of disease of the 
artery wall, roughly classed under the general name of arteriosclerosis, 
which bring about this effect, and so completely may the vessel be ob- 
structed that all the tissue ordinarily supplied by it dies. When, in the 
legs, for example, this extreme is not reached, the narrowing of the artery 
may be only sufficient so to cut down the blood-supply that the person is 
able to walk perfectly well for a short 
distance, when his muscles fail him 
solely on account of their insufficient 
nutrition. After a rest he is able to 
go on again for a time. This is often 
spoken of as intermittent claudication. 
Harmful in some cases, this shutting- 
off of the blood-stream by thickening 
of the vessel walls is useful in others 
-it is the physiological method by 
which the ductus Botalli is closed; it 
appears in organs such as the senile 
uterus and breast, which have out- 
lived their usefulness, and it forms a 
safeguard against haemorrhage from 
the erosion of arteries in the lung by 
advancing tuberculosis: as the cavity 
extends and cuts across these arteries 
it finds them reduced to bloodless 
cords. Nevertheless in the kidney 
the same sort of narrowing of the 
small vessels produces local anaemia 
and destruction of patches of tissue 
which can only be replaced by scars 
(Fig. 7). Arteries thus narrowed by 
changes in their walls are very often 
finally and completely closed by the formation of a thrombus throughout 
the narrowed portion. 
Fig. 7.-Arteriosclerotic scarring of 
kidney. 
EMBOLISM 
Local anaemia of extreme degree is produced most commonly by some sort 
of plug which obstructs the artery supplying blood to the part. Such a 
plug is known as an embolus, and embolism is defined by W. H. Welch as 
the impaction in some part of the vascular system of any undissolved 
material brought there by the blood-current. Naturally, the number of 20 
TEXT-BOOK OF PATHOLOGY 
kinds of material that can get into the blood-stream is limited, but there is, 
nevertheless, a surprising variety. The commonest are thrombi or frag- 
ments of thrombi, but tumor cells, tissue fragments, clumps of bacteria, 
protozoan and worm parasites, as well as oil-globules and gas-bubbles, 
may play the same role. Of these, only the thrombi are from the first 
within the blood-vessels: the others must gain access to the stream before 
they can act as emboli. 
It has been shown that thrombi form most commonly on the venous side 
of the circulation, although they are occasionally found in the arteries, and 
are common enough upon the heart-valves. Their rather intimate ad- 
hesion to the underlying vessel-wall was mentioned, though not the fact 
that, after they remain in position for a time, they become firmly fixed to the 
wall by blood-vessels and connective-tissue cells which grow into them and 
ultimately replace them completely with fibrous tissue. Before this so- 
called organization begins they can be dislodged by violent movements or by 
manipulation, and then arises at once the condition which makes embolism 
of some distant part of the blood-channel inevitable. A loose mould of the 
vein or a fragment of it caught in the current of the blood-stream must 
move along toward the heart because the vein becomes larger and larger. 
Sometimes the whole thrombus, with its long adherent propagated clot, is 
thus dislodged; sometimes only a fragment, the original situation of which 
might perhaps be recognized by fitting together the surfaces of fracture. 
When the crumbly thrombi which form on the heart-valves are the source 
of such emboli, the dislodged fragments may be large enough to plug the 
aorta, or at the other extreme sifted oft as fine particles which go on to the 
smaller arterioles. It must be remembered that a long narrow thrombus 
may become folded and doubled on itself and thus occlude a much larger 
cavity than that in which it formed. This is the case when dislodged clots 
from the femoral vein are swept into the pulmonary artery, blocking it 
completely. This whole process may occupy only a few seconds after the 
loosening of the thrombus, and death may follow instantly. 
Such an embolus when formed from a part of an old thrombus can usu- 
ally be recognized easily enough by its evident age, although in its new 
lodging-place it is almost at once surrounded by propagated clots. 
Seats of Embolism.-Given its size and its point of origin, the site at 
which the embolus will lodge may be foretold with some accuracy, al- 
though the actual distribution of multiple small emboli has been learned 
only by experiment. It was found, for example, that the great majority of 
a large number of recognizable particles introduced into the blood-stream 
of the aorta were hurried past the mouths of arteries supplying the vis- 
cera into the vessels of the muscles of the legs. After that only came the 
embolism of the brain, liver, kidney, spleen, skin, etc. 
Briefly, one may say that an embolus set free in any of the systemic 
veins, and caught in the current entering from the next branch above the EMBOLISM 
21 
part of the vein which had been completely occluded, is swept through the 
vena cava into the right side of the heart, and thence thrown violently 
into the pulmonary artery. Only the exceptional chance of its passing 
through a wide-open foramen ovale will allow it to reach the systemic 
arteries unless it is a particle so minute that it can pass through the capil- 
laries of the lung. The same course is followed by a thrombus mass origi- 
nating in the right auricle or in the intertrabecular spaces of the right ven- 
tricle, and obviously this holds true also for vegetations dislodged from the 
tricuspid or pulmonary valves. Thrombi set free in any of the veins which 
go to form the portal trunk are caught in the branches of that channel in 
the liver. Those arising in the pulmonary veins, left auricle, or left ven- 
tricle, vegetations from the mitral and aortic valves or thrombi formed on 
the walls of the aorta, are hurried into the aorta and distributed as described 
above. Naturally a thrombus formed in any smaller artery and dislodged 
is merely pushed further into the branches of that artery. Since emboli are 
most easily traced by the effects they produce, the impression is likely to 
arise that they lodge most often in such organs as the brain, the kidneys, 
or the spleen, but from what has been said it will be clear that even though 
no effects become visible, the actual number is greatest for the lungs, the 
body musculature, and perhaps the liver, which is menaced through both 
the portal vein and the hepatic artery. 
With regard to the size of the embolus, a few more words may be said. 
The mass travels until it comes to a pass too narrow to admit it, and there 
it lodges like a cork. Naturally, since the branches are smaller than the 
main trunk in a bifurcating vessel, the plug is often found riding or balanced 
upon the point of bifurcation. Still, most arteries become narrower as 
they advance, and the majority of emboli stick on this account. In a case 
of vegetative endocarditis seen at autopsy recently there were two masses 
of thrombus material successively lodged in the common iliac artery, and 
one much larger mass riding at the bifurcation of the aorta. Each was 
surrounded by a propagated clot formed in the blood rendered stagnant by 
its advent. 
The other things which can act as emboli do so rarely and are of far less 
importance as emboli than are thrombi, although in their other effects they 
may be of great significance. Air-bubbles may act as emboli of a rather 
temporary character, because the gas is so readily dissolved in the circu- 
lating blood. If, however, a great amount of gas is introduced into the 
circulation at any one time, the obstruction may be sufficient to cause 
death either by passing into the vessels of the brain, or, much more com- 
monly, by filling up the heart and yielding to its churning action, so as to 
exclude the inflow of blood. A considerable amount of air or other gas is 
necessary to produce this result-probably much more than is generally 
supposed. It is in operations and injuries which involve the accidental 
opening of the veins of the neck that this is likely to take place. The 
pressure in these veins is so lowered by the inspiratory enlargement of the 22 
TEXT-BOOK OF PATHOLOGY 
chest that the air enters with a hissing sound, and the death of the in- 
dividual may take place very rapidly. Probably its entrance into the 
coronary arteries is of great importance. 
For a time the appearance of gas in bubbles in the organs of the body was regarded 
as evidence of air embolism, especially in the case of women who had died after 
childbirth when it was thought that the air had entered the large open sinuses in the 
uterine wall. Welch has pointed out that these were cases of infection with the Bacillus 
aerogenes capsulatus, which produced after death bubbles of hydrogen gas everywhere 
throughout the organs, so that they became distended like bread that is rising and full 
of holes. The liver assumes the appearance of a red rubber bath sponge, and on incision 
bubbles of gas appear which burn with a blue flame when a match is applied. Similar 
cavities may be formed all through the brain, where they have somewhat the appear- 
ance of the holes in a Swiss cheese. In the intestine or stomach the mucosa may be 
lifted up into blebs. 
At other times emboli may be constituted of droplets of fat which are set 
free into the blood-stream from the adipose tissue. Such globules lodge, 
as a rule, in the capillaries of the lung, and are pressed into a sausage shape 
by the blood of the pulmonary artery. They can be recognized in the 
frozen section of such a lung by their highly refractive character, and also 
by the fact that they readily stain with those stains which are soluble in 
fat, such as Sudan III. They produce no obvious change in the appear- 
ance of the lung, and indeed must be searched for in this way. They are 
commonly introduced by some mechanical injury to the bones, such as 
fracture; but even a severe blow seems sufficient to cause such a commo- 
tion in the marrow as to introduce some of the abundant fat into the venous 
channels. Fat embolism also occurs in a number of convulsive diseases, 
and particularly in such conditions as delirium tremens, in which prob- 
ably the violent exertions of the individual play a part in the process. 
Injury or crushing of the tissues of cellular organs sometimes introduces 
fragments or groups of cells into the blood-stream, where they act as emboli. 
Most commonly this is observed in connection with the cells of the bone- 
marrow and the syncytial structures which arise in pregnancy. There is 
little evidence, however, of their producing any mechanical effect where 
they lodge in the capillaries. 
Bacteria may enter the blood-stream by growing through the walls of 
capillaries or by being discharged from infected thrombi, and can, as is 
well known, circulate with the corpuscles of the blood through any capil- 
laries. That they often lodge and grow into colonies which produce char- 
acteristic effects on the surrounding tissue is shown in cases of generalized 
miliary tuberculosis and in general pyaemia, but they can be said to act as 
emboli only when they circulate in clumps large enough to obstruct the 
capillaries. Protozoan parasites in the same way usually circulate through 
the capillaries, but certain worms, such as the Schistosomum, can behave 
as actual mechanical emboli, plugging and obstructing the vessels. 
In the case of malignant tumors, the transportation of cells foreign to the EMBOLISM 
23 
blood is of particular importance, although these cells rarely act as gross 
emboli. It is perfectly clear, from a study of the gross anatomy of such 
invading tumors, that they frequently extend their growth through the 
wall of a vein and hang loosely in the blood-stream, so that fragments can 
be broken off and swept on by the stream. It is, however, by no means 
always possible to recognize the mode of entrance, and it seems likely that 
in many cases individual cells gain entrance into the thin-walled veins 
of the tumor itself, possibly as a result of mechanical trauma. The cultiva- 
tion of these cells on the glass slide, however, has shown them to be en- 
dowed with a remarkable power of amoeboid movement, so that Hanes 
and Lambert have advanced the idea that the separate cells of the tumor 
may actively push their way through the endothelial lining of the vein 
and thus enter the venous blood-stream. The cells appear to be able to 
pass through such capillaries as those of the lung, and to set up their 
growth in more distant organs, where they find a suitable environment. 
Results of Embolism.-The degree of anaemia produced by the occlusion 
of any artery will depend upon the relation of its branches to those of the 
surrounding arteries and to the other branches of its own trunk, because, 
just as in the case of the veins, such connections dilate to accommodate 
blood whenever it finds its way blocked through its ordinary channel. If 
these branches anastomose widely with the terminal twigs of the adjacent 
artery, a sufficient supply of blood may be maintained in its area of tissue. 
Indeed, this communication between the end-twigs of the arterial branches 
is so wide in some tissues, such as the muscles, skin, lungs, etc., that even 
a large artery can be closed off without causing a moment's delay or dimi- 
nution in the supply of blood to the tissue. It can be seen, then, that the 
advent of an embolus in one of these arterial branches will cause no par- 
ticular disturbance in such tissue as muscle or lung, or even in the stomach- 
wall. 
This compensation for lost arterial supply can be seen most vividly if one 
injects a quantity of ultramarine blue in suspension into one of the gastric 
arteries. This fills the artery, with all its branches, with blue fluid, but the 
moment the stream of blue fluid is interrupted or its pressure lowered, the 
inflow of blood from the neighboring vessels replaces the blue material in 
that artery. In this case, however, the connections are between the larger 
branches and it is found that the minute twigs of the gastric artery thus 
injected remain permanently plugged with the blue granules and the tissue 
which they supply suffers. 
In other places the communications are not nearly so free, so that if it 
becomes impossible for the blood to go through one branch, the connections 
with the adjacent branches may indeed be sufficient to keep the tissue living 
by furnishing blood to the terminal twigs, but they can do this only by 
actually increasing their own calibre; so that in such a case the ana- 
tomical development of a collateral circulation is much more plainly seen. 
Sometimes these connections are so minute as to be invisible under ordinary 24 
TEXT-BOOK OF PATHOLOGY 
circumstances, but become quite conspicuous after they are dilated in this 
way. 
Extraordinary examples of the development of such a collateral circula- 
tion are seen in connection with the larger arteries of the body. So when 
the aorta is tied, as in the experiments of Halsted and Porta, there appears 
Fig. 8.-Collateral circulation after obstruction of vena cava superior (Osler). 
after a time a whole brush of vessels which anastomose with branches 
below the point at which the ligature is applied and which reestablish the 
circulation. I have recently seen two cases in which there had occurred 
obstruction of the large abdominal arteries. In one instance it was the 
trunk of the coeliac axis which had been gradually obstructed by an EMBOLISM 
25 
arteriosclerotic thickening of its wall, supplemented finally by the formation 
of a thrombus; and in the other it was the superior mesenteric artery 
which had been gradually but completely pressed together by the growth 
of a small aneurysm developed from a point very near its orifice in the wall 
of the aorta. In neither of these cases was there the slightest disturbance 
in the appearance of the abdominal organs, for in both the pancreatico- 
duodenal artery had dilated and had assumed the burden of transmitting 
the whole supply of blood for those organs which would otherwise have 
been deprived of it-in one case in one direction and in the other case in the 
other. It is not merely in the case of the arteries that such a collateral 
circulation can be developed, for the same thing may be observed in the 
case of an obstruction of one of the great veins. In one case studied not 
long ago the superior vena cava had been completely occluded, and the 
venous circulation from the head took place through the enormously dilated 
veins of the abdomen* (Fig. 8). 
In certain situations the tissues are entirely dependent upon receiving 
their supply of blood from a single artery. In these cases there is prac- 
tically no chance for compensation through the pouring-in of blood from 
adjacent arteries, for there are no adequate anastomoses, and such arteries 
have been referred to by Cohnheim as "end arteries," and such a circula- 
tion as "terminal" circulation. The propulsion of an embolus into such an 
artery as this will inevitably cause complete anaemia of the portion of tissue 
which had hitherto been supplied by that artery (Fig. 9). 
The effect of the diminution of the supply of blood to any part by way of 
the artery thus depends upon the degree to which the function of that 
artery can be replaced by the formation of channels connecting its region of 
distribution with other arterial supplies. The time which is occupied in 
this reestablishment of the blood-stream is of the greatest importance, for 
if the obstruction be gradually produced, it may reach a very advanced 
degree without there having appeared at any time an insufficiency in the 
blood supply to the tissues; whereas if the cut-off be sudden, the tissue is 
likely to suffer. 
Finally, there are some organs, such as the liver and lung, which enjoy a 
double circulation, both arterial and venous blood being poured into the 
tissues and escaping by way of a common efferent channel. In both these 
instances the flood of venous blood is far more profuse than the small 
stream of arterial blood, and doubtless contributes very largely to the 
nutrition of the tissues, although that is perhaps the main function of the 
arterial supply. In such cases the life of the tissue is somewhat more se- 
cure as far as its food supply is concerned than in the case of those organs 
which are supplied solely from the artery; and, indeed, it is actually found 
that a very much more extensive disturbance is necessary to produce ana- 
tomical changes in these organs than in many others. 
* Osler: Johns Hopkins Hospital Bulletin, July, 1903, xiv, 172. Fig. 9.-Diagram showing circulation after plugging of arteries: A, Terminal circula- 
tion; B, circulation with rich anastomoses; C, double blood supply, as in the Ever; D, 
circulation of the stomach with abundant large anastomoses. 
26 INFARCTION 
27 
Quite aside from the patency of the arteries themselves or of the veins, a 
condition of local anaemia which is very effective in disturbing the nutri- 
tion of the tissues can be brought about by muscular contraction in those 
tissues which are largely made up of smooth muscle. Welch and Mall have 
pointed out that this violent spasmodic contraction of the intestinal wall 
which arises from a sufficient interference with the entrance of the blood, 
results in the complete exclusion of the blood from that part of the in- 
testine, and in that way takes a great part in the final destruction of the 
tissue. It is really this which renders the circulation of the mesentery and 
of the intestine, which is, from an anatomical point of view, so rich in anas- 
tomoses, comparable to a terminal circulation. 
The effect of local anaemia upon the tissue is found to vary with the degree 
of deprivation to which the tissue is subjected and with the nature of the 
tissue itself. As has already been indicated, the more complex the struc- 
ture of the cell, and the more highly developed its specialization of func- 
tion, the more delicate and susceptible to injury it becomes. This is well 
seen in the case of the nerve-cell, whose function becomes impossible if its 
nutritive supply is withheld even for a few moments, and is irremediably 
destroyed in a very short time. 
On the other hand, there is a long series of tissues with gradually de- 
creasing susceptibility until we reach the least highly organized and con- 
sequently the most resistant among the connective-tissue structures which 
can withstand removal from any connection with the circulation for hours 
or even days, and still resume their functions as soon as they are placed in 
proper surroundings or grow again when transplanted into another animal 
of the same kind. 
The injurious effects of anaemia become more severe the more complete 
it is and the longer it lasts, and they reach their climax in the death of the 
tissues. Slighter grades of anaemia may become evident in their effect 
only when great effort is demanded of the organ involved, as, for example, 
in the intermittent claudication spoken of above. 
More complete anaemia, whether caused by the inability of the blood to 
reach the tissues or to give place to new blood, commonly causes the death 
of the affected part, and this is the all-important feature in the production 
of the so-called infarction. Other changes subsequent to this may alter 
very strikingly the appearance of the tissues, but they are of secondary 
importance. As in the clotting of blood and the formation of a thrombus, 
the death, or even the severe injury, of the cells is immediately followed by 
the setting free of some sort of ferment which causes the coagulation of 
the blood, and the intracellular as well as the intercellular fluids. The 
nuclei either fade or break up into small, deeply staining fragments, and in 
every other respect the cells lose the aspect which they possessed during 
life. They are dead cells entangled and held in a coagulum which in- 
INFARCTION 28 
TEXT-BOOK OF PATHOLOGY 
volves the whole area of tissue, and the process is described by Weigert 
and called by Cohnheim "coagulative necrosis." 
The area occupied by these changes is that to which the blood supply 
becomes insufficient. It need not correspond exactly, therefore, with the 
distribution of the plugged artery, because there is almost always some 
compensation from the branches of adjacent arteries. Its form is generally 
stated to be pyramidal, but is not really so in most cases, although it may 
approach that traditional form. This is because the vessels in most organs 
really assume a rather fan-shaped arrangement, as is almost inevitable in 
any vessel which branches out regularly. Still in some, such as the kidney, 
there are blood-vessels which spring up almost at right angles from the 
main trunk, and which reach through the organ, so that we may readily 
Fig. 10.-Ansemic infarction of kidney. 
find an infarct of a more or less cubical form in its cortex (Fig. 10). There 
is nothing typical about the form of the infarct in the intestine which merely 
occupies the whole wall of a certain length of the intestine. So, too, in the 
heart, the area of infarction is irregular in form. The pyramidal form is 
most nearly approached by the infarct of the lung, but even this is fre- 
quently quite irregular in its shape. 
In all instances the infarcted area seems at first swollen and firm, and 
projects above the surrounding surface of the tissue. This is true even 
in the brain in the beginning, although after a short time has elapsed 
the infarcts of the brain become soft and are commonly spoken of as areas 
of softening. Their resemblance to other infarcts in the early stages 
was pointed out by Marchand, who appreciated the fact that they too 
at the beginning present the appearance of a firm coagulum, although 
later the liquefaction of the myeline substance proves more than sufficient INFARCTION 
29 
to overcome the firmness contributed by the fibrin and to make the whole 
area soft. The swelling and firmness of an infarct are due to the accumu- 
lation of a coagulum produced from the coagulable fluids which diffuse 
into the dead area from the surrounding tissue. In a short time the mass 
becomes dense and hard and may be appreciated immediately by the finger 
passed over the surface of the organ. There is no other disturbance in the 
architecture of the tissue at this stage, and the outlines of the cells may still 
be seen quite clearly. Even the outlines of the nuclei may still be seen, 
and as for the supporting structural framework, it is usually quite well 
preserved, at least in its outlines; but the whole area is dead and reminds 
one, on viewing it through the microscope, of the appearance of charcoal 
as contrasted with that of living wood, or of the streets of Pompeii as con- 
trasted with those of a modern town. 
The death with coagulation of the tissues converts them into a white or 
yellowish white, perfectly opaque, dull-looking mass so long as there is no 
infiltration of red corpuscles. We must recognize, however, two kinds of 
infarcts, in both of which the principles just described affect the result in 
an identical manner, but one is spoken of as a haemorrhagic infarct because, 
on account of the laxity of the tissue and the richness of the adjacent capil- 
lary circulation, red corpuscles ooze into the dead area. The other kind, 
which remains pale and opaque, is commonly spoken of as an ancemic in- 
farct, although it is plain enough that anaemia is the cause of the death of the 
tissue in both. The arrangement of the circulation and the density of the 
tissue seem to be the deciding factors as to whether an infarct shall remain 
anaemic looking and white, or, by being flooded with stagnating red cor- 
puscles, assume a deep red color. So, in the kidney, we practically never 
observe a haemorrhagic infarction, whereas in the lung and in the intestine 
the reverse is the case, and it is only with the greatest difficulty that we can 
produce experimentally an infarction which remains anaemic looking. In 
other organs, such as the heart, the spleen, the liver, we may have some- 
times anaemic, sometimes haemorrhagic, types. 
Kidney.-In the kidney, infarctions are likely to be quite small. They 
seem to arise as the result of the entrance of the embolus into one of the 
arcuate arteries, or even into one of the branches, passing thence into the 
cortex. One can nearly always find this plug on careful search and observe 
that the propagated thrombus extends both ways from it. The infarcts 
commonly occupy especially the cortex, but they may sometimes extend 
down into the pyramid of the kidney. One occasionally sees a ramifying, 
anastomosing area of infarction which occupies a great portion of the kid- 
ney, and such, indeed, was the result in a peculiar instance observed re- 
cently. In this case a stab wound had passed through a branch of the 
renal artery which happened to begin its branching outside of the kid- 
ney, and a haemorrhage occurred, which continued slowly for two or three 
days, being restrained apparently in part by the surrounding tissue. At 
the end of that time the kidney was removed at operation, together 30 
TEXT-BOOK OF PATHOLOGY 
with the mass of blood which had been extravasated. It was found that 
there was an extensive infarction occupying a portion of the kidney 
which should have been supplied by the injured artery. This was an 
instance of local anaemia, but not caused by the presence of a plug in the 
vessel. 
On inspection of such a kidney containing infarcts it is possible to deter- 
mine readily enough the position of the infarct even through the capsule, 
Fig. 11.-Margin of renal infarction showing necrosis of tissue with zones of haemor- 
rhage and leucocytic invasion. 
for the opaque yellow color shines through, but this opacity does not quite 
reach the surface, being covered by a layer of living and very hypersemic 
kidney tissue, which receives its blood supply from the capillaries which 
extend to it from the capsule. On incision one finds the infarct sur- 
rounded by at least two distinct zones, which differ in color from the opaque 
yellowish-white central portion. These zones are first a translucent gray 
line of varying thickness, and then an irregular band of deep red which 
borders the infarct and marks it out from the surrounding normal tissue. INFARCTION 
31 
the gray zone is found, on careful examination, to be produced by an 
accumulation of the white cells of the blood which have wandered in there 
and have become more or less broken up. The zone of haemorrhage is 
partly within the necrotic area and partly in the living area, and although 
it may, like the accumulation of leucocytes, be explained in part as due to 
the inflammatory reaction about the dead tissue, it seems probable that 
the anaemic changes in the endothelium of the capillaries play a part too in 
allowing the escape of red cells (Fig. 11). 
Spleen.-Almost the same descriptions might be applied to the anaemic 
infarctions in the spleen, except that they are usually much larger and 
more irregular in form (Fig. 12). They, however, differ from the infarctions 
in the kidney inasmuch as there is no capsular circulation, which is neces- 
sary to keep alive any superficial layer of the spleen, so that the death of 
the tissue extends quite out to the peritoneal surface. There the dead 
tissue exerts the same influence upon the peritoneal fluid as it does upon 
Fig. 12.-Infarction of spleen. 
the passing lymph, and there is deposited over the surface of an infarct in 
the spleen a layer of fibrin which roughens the surface. Sometimes one 
can make the diagnosis of the existence of an infarct of the spleen from 
pain which comes from the rubbing of this roughened surface against that 
of the adjacent peritoneum when a deep breath is taken. 
Heart.-Exactly the same thing is true of infarcts of the lung, and even 
those of the heart wall; but in the kidney there is no opportunity for such 
an occurrence. The infarcts of the heart are particularly interesting be- 
cause of their great importance with regard to the function of the heart. 
The coronary arteries present some anastomoses one with the other, but, 
as has been pointed out recently by Spalteholz, these are insufficient to 
supply the really enormously active circulation which is necessary for such 
an organ as the heart. So, therefore, the arteriosclerotic narrowing of the 
coronaries often leaves traces of malnutrition of the tissues when even there 
is no actual infarct formed; but when to this there is added a thrombus 
formation, or when a vegetation from the valve sweeps into the mouth of 32 
TEXT-BOOK OF PATHOLOGY 
the coronary artery, as has happened so frequently, the nutrition of the 
heart muscle is intolerably limited and the muscle dies. In one such in- 
stance recently Observed there had been an aortic endocarditis with vege- 
tations, and a plug, like a cork, still projected from the mouth of the left 
coronary artery. The whole of the septum between the ventricles, to- 
gether with the anterior portion of the walls of the right and left ventricles, 
formed a necrotic mass. The heart had become abnormally slowed from 
involvement of the auriculoventricular bundle, but still continued to beat 
until a sudden effort caused the rupture of the wall of the left ventricle with 
a fatal haemorrhage. 
Other instances, however, have not so immediately led to death, but 
rather to recovery, with replacement of the dead tissue by scar. In that 
case a patch in the heart wall may be markedly thinned and comes to be 
composed of a fibrous tissue which has by no means the power of resistance 
or the strength of the muscular wall, and one frequently sees such an area 
bulged out into a sac which in time may rupture. Such an event is, how- 
ever, by no means always the outcome of an infarction, but may depend on 
the gradual loss of the muscle substance from a partial ansemia. 
Liver.-In the liver infarcts are very rare because of the extremely 
abundant blood supply from two sources. It is stated that complete 
closure of the main trunk of the hepatic artery will produce complete ne- 
crosis of the liver, whereas closure of any of its branches has no special 
result. Obstruction to the main portal vein is said to diminish the produc- 
tion of bile, asOias been shown recently by Voegtlin and Bernheim, but it 
does not interfere with the nutrition of the tissue. This is especially well 
seen in the numerous instances in which experimentally the whole of the 
blood of the portal vein has been diverted into the inferior vena cava by the 
so-called Eek's fistula. In that case undoubtedly the whole of the tissue 
of the liver must be supplied by the hepatic artery, but the animals live, 
and after a time show no very obvious change in the tissue of the liver, 
although it is stated that sometimes the liver decreases in bulk. Obstruc- 
tion of the whole portal vein is not very uncommon, arising from the throm- 
bosis of the branches from some point of infection or injury in the alimen- 
tary tract, and extending into the main trunk; or as the result of compres- 
sion from without by gall-stones or tumor masses in the vicinity or in con- 
nection with cirrhosis of the liver. Closure of branches of the portal vein 
may be followed by the formation of haemorrhagic infarctions when there 
is some disturbance or enfeeblement of the general circulation, so that the 
hepatic artery does not succeed in making up the nutrition which is lost 
by the shutting off of the portal. 
Lung.-In the lung also there is a double vascular supply, the whole 
current of venous blood rushing through the pulmonary arteries, while the 
bronchial arteries bring arterial blood to the tissue and anastomose with 
the pulmonary capillaries, thus returning their blood by the pulmonary 
veins. It appears from the work of Schlaepfer that when the pulmonary 
artery is ligated the bronchial arterial stream is sufficient to keep the INFARCTION 
33 
tissue alive, although it contracts and becomes scarred. The pulmonary 
arteries anastomose with extraordinary freedom in the lung, probably 
largely by means of the extremely wide capillaries. On this account it 
proves to be almost impossible to produce an infarction in the lung of 
a healthy animal by throwing emboli into the pulmonary stream, because 
the nutrition of the obstructed area is immediately assumed by adjacent 
branches. Virchow did succeed in producing such infarctions, and this 
was the basis of his great work on embolism. But apparently he succeeded 
because the emboli which he used carried bacteria, and he caused, in that 
way, a far more extensive injury to the lung tissue than could be produced 
by sterile plugs. In general, it is only when there is some other circum- 
stance which causes a general slowing of the circulation in the lungs, a 
high pressure in the pulmonary veins, and such malnutrition of the lung 
tissue as leaves it susceptible to injury, that a plug in a branch of the 
pulmonary artery will cause the formation of an infarct. This is the con- 
Fig. 13.-Haemorrhagic infarction in lung, the seat of chronic passive congestion, 
dition which we find in the so-called chronic passive congestion which 
results from the obstruction of the mitral valve or from the regurgitation 
of blood through the mitral valve backward into the lung. Other causes 
may, of course, produce the damming back of blood into the lungs and 
slowing of their circulation, but the changes in the heart, and especially 
those which we have just mentioned, are the most prominent. Under 
such circumstances, when emboli are dislodged from some point on the 
venous side of the circulation and thrown into the branches of the pul- 
monary artery, there arise hsemorrhagic infarctions in the lungs (Fig. 13). 
Sometimes one can recognize by symptoms the beginnings of such infarcts 
from the sudden pain and the spitting-up of blood, and possibly even from 
the change in the percussion-note, which becomes dull over the region of 
the infarct. When the lung is inspected, it is found possible to recognize 
these infarcts at once because they are solid, hard masses, often present 
in numbers and extending to the surface of the lung. The pleura over TEXT-BOOK OF PATHOLOGY 
34 
them is roughened by a layer of fibrin which destroys its gloss, and causes 
the pain of which we have spoken by scratching against the opposite 
pleural surface in respiratory movement. The infarcts vary greatly in 
size, from a diameter of about 1 cm. to such a size as to occupy almost 
the whole of the lobe. They have a tendency to a somewhat triangular 
or pyramidal form, but their margins are usually round, and they bulge 
out on the surface of the lung. They are very dark red-almost black-in 
color, and on cutting through them this is found to be true also of their 
interior portion. They are dry and sometimes of a remarkable hardness. 
It is nearly always quite easy to see the embolus which has caused their 
formation lying in the pulmonary artery which forms the apex of the 
triangle. Usually such a plug is prolonged both ways by the clot which is 
formed about it, but sometimes this may not have happened, and cases are 
even recorded in which the embolus lay at a point somewhat separated 
from the actual region of infarction by an empty stretch of vessel. This is 
important because there has been so much dispute as to whether these 
infarctions were really caused by emboli or whether the clot in the vessel 
was the result of the infarction. It seems perfectly clear, however, that 
the weight of evidence is entirely in favor of the embolic origin of the in- 
farcts. Von Recklinghausen lays a great deal of stress upon the formation 
of hyaline thrombi in the smaller branches of the pulmonary artery, but 
these, it seems to me, might be secondary. There is often a question as to 
whether we are dealing with a real infarction or with a mere haemorrhage 
into the lung substance. Such haemorrhages occur frequently from all 
kinds of causes, but they are never really comparable in appearance to in- 
farctions-first of all, because they are almost never hard and dry, but 
rather soft and loose, and usually very irregular in outline, occupying 
any part of the lung without regard to any special arrangement and with- 
out necessarily approaching the surface of ,the lung. From such haemor- 
rhages absorption of the blood takes place with extreme rapidity, and this 
may possibly account for their remaining so soft. On the other hand, it is 
quite difficult to understand why the haemorrhagic infarction should be so 
extremely hard unless it be that the coagulation of the red corpuscles is also 
brought about in the general coagulation of the necrotic lung tissue; 
Close examination of the area involved in the infarction shows that it is 
overfilled in every part with blood. Not only are the alveoli themselves 
full of red corpuscles in even greater concentration than in the circulating 
blood, but these corpuscles are found also in the substance of the tissue. 
The epithelial cells which line the alveoli disappear rather rapidly, but 
the framework of the lung is very resistant, and it may not appear to have 
been injured very markedly by the local anaemia. There are those who 
speak of resolution of infarctions of the lung, stating that there is no real 
necrosis, but that later the contents of the alveoli may be absorbed as in 
a simple haemorrhage, and the lung resume its function. This, however, 
seems very doubtful, and one may feel sure that when the effect of the 
anaemia is such as has been described, much more complicated changes INFARCTION 
35 
than a mere resolution or restoration to normal will take place. The dif- 
ficulty in deciding this consists chiefly in the fact that when haemorrhagic 
infarctions are formed in the lungs the person is so ill as to die before any 
great length of time has been allowed for alterations to take place in the 
Fig. 14.-Extensive old infarction of brain. 
infarctions, and so it is that we commonly see at autopsy fresh haemorrhagic 
infarctions and only rarely find areas of infarction which have lasted for a 
long time. When we do there is no evidence of resolution, but rather of a 
great shrinkage of the tissue, a loss of the red color, a deep yellow pigmen- 
tation from the debris of the red corpuscle, and the formation of dense. 36 
TEXT-BOOK OF PATHOLOGY 
hard scar tissue in the place once occupied by the infarct. In this respect 
the haemorrhagic infarctions of the lung are quite similar to the anaemic 
and other infarctions in the spleen and in the kidney. Even in the fresh 
infarctions of the lung one finds always a good deal of the yellow pigment 
which comes from the disintegration of red corpuscles. This is not a part 
of the fresh process, but rather a result of the long-continued stagnation of 
blood in the capillaries of the lung, which is the essential feature of a chronic 
passive congestion, and which, as we have said, constitutes the requisite 
basis for the formation of an infarct there. 
Brain.-The formation of infarctions in the brain is an extremely com- 
mon occurrence, and leads to more or less serious results. It is naturally 
most likely to occur when thrombi are formed in the left side of the heart 
in such a way as to be dislodged and thrown into the cerebral circulation. 
The mechanical results of such embolism will again depend upon the posi- 
tion reached by the embolus, and if the obstruction produced is in the 
meninges, it may happen that no obvious result will follow. If, however, 
the plug enters one of the arteries actually on its way to supply the 
brain, there is inevitably an infarct formed because they are terminal 
arteries. 
The symptoms will depend upon the particular tissue thus destroyed, 
but if a large branch is occluded, there may be general symptoms in many 
respects like those of apoplexy; that is, the patient becomes unconscious. 
There may be a flaccid paralysis from which, however, he recovers later 
with the exception of some limited paralysis, which corresponds with the 
portion of the brain destroyed. 
The writer has recently seen an instance in which practically a whole 
cerebral hemisphere was thus converted into a necrotic mass through 
rather extensive embolism of the arteries at the base of the brain. In 
other instances where smaller plugs reached this circulation there may be 
only temporary lapses from consciousness, or not even that. There may 
or may not be narrowly localized paralysis. Indeed, it is not infrequent to 
discover at the autopsy, in a person who has long suffered from a cardiac 
affection, very numerous yellowish patches scattered all over the surface 
of the brain and sunken below its surface. These are merely the pigmented 
scars which have resulted from the formation of the infarcts time after 
time without any history of symptoms (fig. 14). When the infarcts are 
perfectly fresh they are, as stated above, swollen, project above the surface, 
and are somewhat firm, but they very quickly soften into a semifluid mass 
because the greater portion of the brain is composed of lipoid substances 
(myelines) which become converted into a more fluid form in the process 
leading to necrosis of the tissue. At this stage of softening phagocytic 
cells wander in to such an area and load themselves with fat-globules, 
which they carry away (Fig. 15). 
Intestine.-The infarctions of the intestine are usually hsemorrhagic. 
They are perhaps most commonly produced, as in strangulated hernias, INFARCTION 
37 
where the blood supply is impeded by the crowding into the aperture, of 
the mesentery as well as the intestine itself. Other instances are seen in 
the so-called volvulus, in which a lobe of intestine with long loose mesen- 
tery becomes twisted completely round on itself so that the blood-vessels 
in the mesentery are closed. Almost the same effect can be produced by 
bands of fibrous tissue such as arise in the form of adhesions between 
various abdominal organs and can be pulled tight over the vessels running 
to some portion of the intestine. The other type of artificial obstruction 
Fig. 15.-Margin of fresher infarct of brain showing fat-laden phagocytes. Several 
of these are shown enlarged below. 
is, as in the infarction just described, produced by an embolus or thrombus. 
As has been pointed out, the intestines are peculiarly susceptible to with- 
drawal of their blood supply because they add to the anaemia by their vio- 
lent contractions. The intestinal wall at first becomes absolutely pale 
with this contraction, but later on, with the death and relaxation of the 
tissue, it swells enormously and is infiltrated with blood. The swelling is 
particularly intense in the submucosa, which may attain the thickness of 
a centimetre, and the blood oozes through the mucosa into the lumen of the 38 
TEXT-BOOK OF PATHOLOGY 
intestine and is passed in great quantities, giving the diagnostic sign of 
intestinal infarction. 
The surgeon sometimes meets with this condition of swelling and haem- 
orrhage before the complete death of the cells has occurred, and occasion- 
ally he may replace the enlarged loop from the hernial sac or liberate it 
from its constriction and see restoration to normal condition follow his 
operation. It is a matter for his judgment, however, to determine whether 
the injury has passed the point at which this is still possible. Welch and 
Mall, in their experiments, have found that there is relatively little com- 
pensation for the cutting-off of the arterial supply through the mesenteric 
Fig. 16.-Intussusception in a child's intestine showing infarction of the inclosed 
portion. The mesentery is seen constricted in the neck of the receiving portion. 
arteries, so that if even such a short length of intestine as 5 cm. be sepa- 
rated from its blood-vessels, it will undergo necrosis because the supply 
from the adjacent portion is insufficient. 
One of the commonest causes of infarctions is the so-called intussusception, 
which occurs most commonly in children (Fig. 16). It may apparently be 
spontaneous, and, indeed, it seems to be produced by irregular peristalsis 
in the intestine, so that one portion not answering to the peristaltic wave is 
dragged by it into the next portion, to which the wave has actually leaped.* 
At any rate, such intussusceptions are found very commonly in the in- 
testine of infants, where they have been produced postmortem, by the 
peristaltic action of the partially quiescent intestine. The portion which 
is telescoped into a receiving part below draws with it, of course, its mesen- 
teric blood supply. If the intestine be pulled out again at this moment, 
*Albrecht v. Haller in his Pathological Observations, London, 1756, says, "I have 
learned how to produce an introsusception in frogs at pleasure. In these animals if 
you touch any part of the intestine with anything corrosive, it is immediately con- 
stricted, and soon after the part next adjoining to it gradually ascends and folds itself 
over the other so as in a manner to sheath it." INFARCTION 
39 
no harm is done; but if it remain thus imprisoned for any considerable 
time, there arises a moderate interference with the outflow of the venous 
blood from the enfolded part, which soon makes it swell to such an extent as 
to cause a very much more intense interference with the blood supply. This 
circle of events continues to intensify itself, so that very soon the intestine 
acts as a constricting band to prevent the inflow or outflow of blood, and 
brings about the haemorrhagic infarction of the interior portion. 
The question as to whether an infarct shall become haemorrhagic or not 
seems to depend upon a variety of things. Experimental studies have 
been made with regard to the infarction in the intestine, particularly by 
Welch and Mall, by Niederstein and Marek. The results of these experi- 
ments may be summed up in the following conclusions: 
If a branch of the mesenteric artery or the mesenteric vein alone be ob- 
structed, a haemorrhagic infarction results. If, however, the arterial chan- 
nels leading to any portion of the intestine be absolutely blocked by plug- 
ging or tying every possible anastomosis, an anaemic infarction appears, 
even though the veins be left widely open. It is evident, therefore, that 
the haemorrhagic infiltration of the tissue which forms the peculiar feature 
of haemorrhagic infarction does not come, as Cohnheim thought, from re- 
gurgitation of the blood from the veins, but is the result of the oozing of 
blood through the walls of the enlarged capillaries and from the adjacent 
arterioles. 
The laxity of the tissue which is found in the lungs and in the intestines 
aids in this, whereas the sudden complete consolidation of the infarcted 
areas of the kidney and spleen makes it almost impossible. It is for this 
reason that the infarcts in the last-named places are commonly pale. 
This is true in the case of the spleen, particularly when the intervascular 
and vascular spaces are densely filled with foreign cells, as in the case of 
acute splenic tumor and leucaemic changes in the spleen. 
Infected Emboli.-Secondary changes are produced in infarctions by 
the invasion of bacteria. Thus an embolus may carry with it a quan- 
tity of bacteria when it originates from an already infected source, and is 
spoken of then as a septic embolus. It gives rise at first to the ordinary 
mechanical effects of plugging the blood-stream, but later there become 
evident the effects of the poisons produced by the bacteria, and the infarcted 
area becomes the seat of an intense acute inflammatory process, with all 
the softening and disintegration which follow upon the development of 
liquefying ferments both from the bacteria and from the leucocytes, which 
hurry to the spot as a part of the inflammatory reaction. The infarct 
may actually assume the appearance of an abscess, and it is sometimes 
difficult to say whether it started as an infarct or not. In most cases, 
though one sees distinctly the form and general character of the infarct, 
he finds that its central part is softened down into a grayish pulp while the 
periphery still retains something of its firmness. This softening is quite 
different from that which we have mentioned in the case of the infarcts of 
the brain, and probably seldom ends in healing and scar formation. 40 
TEXT-BOOK OF PATHOLOGY 
Healing.-Healing of the uninfected infarcts is by no means uncommon 
in such organs as the spleen and kidney, and it has been described already 
in the heart and brain. It consists in the replacement of the dead tissue by 
a scar tissue which constantly tends to contract, so that finally, in either 
the spleen or in the kidney, one finds, as a sign of where the infarct was, a 
sunken, hard, scar-like area, usually rather opaque and colored yellow here 
and there from the remains of pigment derived from the dead cells. In 
such a scar there may remain some traces of the most resistant of the 
structures previously occupying that place, such as obliterated glomeruli 
in the kidney; but usually these are scarcely recognizable, although, on 
account of the contraction of the scar, they may be concentrated together 
in considerable numbers. 
GANGRENE 
All of these instances of anaemic necrosis which we have described under 
the name of infarcts have been in tissues somewhere in the interior of 
the body, completely surrounded by other tissues from which there could 
be derived by infiltration the ever-increasing supply of fluid which might 
undergo coagulation. This it was which formed the basis of the so-called 
coagulative necrosis. If, however, the anaemia affects an extremity or any 
such tissue as is not thus accessible to the adjacent coagulable fluids, a dif- 
ferent appearance results. The necrosis of the tissue is effected in just the 
same way, but there is no opportunity for it to assume the character of a 
coagulative necrosis. At least the amount of fluid which undergoes coagu- 
lation is relatively small, and the extremity does not become rigid and hard 
as the result of this process. Such death of an extremity is called gangrene, 
and it is commonly brought about in the same way as is the death of the 
tissue in infarctions, that is, by any one of the various processes which lead 
to diminution in the blood supply of the part, often aided by more general 
disturbances of circulation or by decreased vitality of the tissues from other 
causes, as, for example, in the case of diabetes, where gangrene of the feet is 
so common. It may assume one of two forms-the so-called "moist" gan- 
grene or " dry " gangrene. In the former case the tissues remain moist, infil- 
trated with blood. They become opaque, dull looking, and livid in color. 
But the color does not remain as it is in the beginning, but rapidly changes 
through a series of shades to deep purple or greenish black (Fig. 17). The 
epidermis becomes loosened when rubbed, often leaving a raw, damp sur- 
face, which may readily become infected and undergo putrefaction. Such 
death of the tissues usually occupies a portion of the extremity which is 
sharply demarcated from the remainder by a line which separates the dead 
from the living tissue; but commonly this line moves upward with the 
advance of the necrosis until it reaches the point at which the blood-supply 
becomes sufficient to maintain constantly the life of the part above. Unless 
the leg be amputated at some point conveniently above this line, there 
may be a good deal of absorption of the poisonous products of putrefaction, 
and the tissue itself may fall away so as to expose the bone. GANGRENE 
41 
The other kind, the dry gangrene, occurs when all possible advent of fluid 
is shut off from the living tissue and mummification or gradual drying up of 
the extremity takes place. The writer studied one instance in an old man 
in whom some infection of the axillary glands had led to their scarring and 
calcification in such a way as to constrict the axillary artery and adjacent 
nerves. The pain from this constriction was such that an operation was 
performed in which the artery was ligated and removed with the constrict- 
ing mass. Almost immediately there began the evidence of death of the 
Fig. 17.-Gangrene of foot. Case of diabetes with arteriosclerosis. 
fingers and of the hand and wrist, which assumed the dry form, and resulted 
in a few days in almost complete desiccation, so that his hand came to look 
like horn or some such transparent material, covering the bones. 
Gangrene of the extremities occurs in connection with diabetes, as has 42 
TEXT-BOOK OF PATHOLOGY 
been mentioned, very commonly as the result of arteriosclerotic and 
infectious processes which lead to the narrowing and thrombotic occlusion 
of the blood-vessels, and also with certain infectious and toxic processes. 
Perhaps the most striking is that which has been observed in epidemic 
form as a result of ergot poisoning. It was known in the middle ages as 
St. Anthony's fire, and relief was sought for it in a pilgrimage to Paris, 
which at least acted as a preventive. The truth of the matter was, al- 
though it was by no means recognized, that the peasants of France ate 
bread which was contaminated with the ergot smut, and consequently 
suffered from that peculiar poisoning which brings about an intense con- 
striction of the arterioles. Death of the extremities was not infrequent, 
and in those pre-surgical days, from the ninth to the fourteenth century, 
it was no uncommon thing to have part of a hand or a foot torn off, after 
such necrosis, with a glove or boot. At the church in Paris the pilgrims 
were fed with bread from the monks' kitchen and most of them recovered. 
There is one other important instance of the production of gangrene 
through anaemia, which is extremely common and which occurs in those 
persons whose general powers of resistance have been lowered and who have 
been constrained to lie in one position in bed for a long time. This is the 
so-called bed-sore or decubitus ulcer, to which we have referred before. 
The term gangrene is used most loosely in referring to the death of tissues 
produced by bacteria or by other means when associated with putrefaction. 
Thus we shall meet with gangrene of the lungs, which is by no means neces- 
sarily caused by mechanically produced anaemia, but is dependent upon the 
destruction of the pulmonary tissue by various forms of bacteria associated 
later with the ordinary bacteria of putrefaction. Another instance is seen 
in the so-called noma, or cancrum oris, and in the hospital gangrene, which 
used to cause such mortality in the wards of the larger hospitals. In all 
these cases it appears, from recent studies, that a combination of fusiform 
bacilli and spirilla plays an important part. 
LITERATURE 
Karsner: Jour. Med. Research, 1912, xxvii, 205. (Literature.) Jour. Amer. Med. 
Assoc., 1911, Ivii, 951. (Infarctions.) 
Welch: Allbutt's System of Medicine, 1899, vi, 228. (Literature.) Trans. Assoc. 
Amer. Phys., 1887, ii, 211. CHAPTER III 
DISTURBANCES OF INTERCELLULAR FLUIDS AND LYMPH 
Their movement, character, and excessive accumulation. (Edema, ascites, etc. 
It is apparent from what has been said that the well-being of the tissues 
is dependent upon the continuous and unobstructed circulation of the 
blood through them from the arteries and the veins; but the conditions 
are even more complicated, for there is a constant circulation of fluids with 
dissolved materials from the blood, from the arterioles and capillaries, out 
into the crevices of the tissue and into a position where they can come into 
immediate contact with the cells. In this process almost all the cells are 
left behind, but a certain number of them undoubtedly take part in this 
wandering-out from the blood-vessels. This type of circulation is com- 
pleted by the reentrance of the transuded fluid into the veins or into the 
lymphatic channels, and in every case the fluid must pass again a complete, 
continuous, and semipermeable membrane composed of endothelial cells. 
The idea formerly held that these tissue spaces are in open communica- 
tion with the lumen of the lymphatics must be abandoned in the light of 
recent anatomical work (MacCallum, Sabin), and it becomes necessary 
to regard the tissue fluid as having its own peculiar characteristics. It is 
with the tissue fluid that the cells have immediate relations, and this cir- 
culation must be quite active. Up to the present no method has been found 
by which this particular fluid can be drained away and studied, so that the 
statements are, to a certain extent, based on hypothesis. 
The distribution of the fluids of the blood into the tissues, and the drain- 
age of these tissues, proceed in such a way that no matter how rapid the 
circulation may be, there is at no time an excessive quantity of fluid among 
the cells. There are conditions, though, in which a disproportion in the 
rate of inflow and outflow occurs, and there arises an accumulation in the 
crevices of the tissue (oedema) or in the body cavities which are in a sense 
analogous to the tissue spaces. When this concerns the peritoneal cavity, 
we speak of it as ascites; collections of fluid in the pleural cavity constitute 
hydrothorax; in the pericardial cavity, hydropericardium. 
(Edematous tissues are swollen, ooze fluid on incision, and are inelastic 
on account of the spreading apart of the cells so that they retain the im- 
press of one's fingers on pressure. Any organ may become so, but the most 
striking examples are seen in the subcutaneous tissues, especially in the 
extremities, and in such places as the external genitalia or in the soft parts 
below the eyes, where the tissues are loose. When the water-logged 
(EDEMA, ASCITES, ETC. 
43 44 
TEXT-BOOK OF PATHOLOGY 
condition of the subcutaneous tissue is very general, it is spoken of as 
anasarca. 
In those cases which generally result from diseases of the heart or kid- 
neys the accumulation of fluid is often such that the skin becomes tense 
and shiny, and may even crack and allow the escape of some of the fluid. 
The tissues lose much of their opacity, and become almost agate-like in ap- 
pearance, because the opaque cells are widely separated by the clear yel- 
lowish fluid. This is especially true of the lungs, and of such fibrous and 
muscular tissues as make up the wall of the intestine and gall-bladder. 
Causes.-There are many things which seem capable of causing such 
damming-up in tissues, and, indeed, in spite of long study and experi- 
mentation we are not yet precisely informed as to the part played by each. 
Pathologists have proposed a great many widely different theories to ex- 
plain this occurrence, and probably all of them contain some part of the 
truth. Ludwig's school contented itself chiefly with the mechanical in- 
crease in infiltrative pressure which seemed to them sufficient explanation, 
although it is obvious that there are many instances of oedema which can 
by no means be explained in this way. For that reason Heidenhain, Ham- 
burger, and others introduced the conception of the vital secretory activi- 
ties of the endothelial cells which were thought to pour the fluid from the 
vessels into the tissues. This idea involves a mystery which may, of course, 
be unavoidable, but which does not seem to help us further toward a 
satisfactory understanding of the condition. This is true, in fact, of all 
the theories which attempt to bridge over the difficult places by resorting 
to such vague terms as "vital activity," which, while they may express a 
present conception of the process, shed no new light upon it. In general, 
stress is laid upon the mechanical obstruction to the outflow of fluids, 
malnutrition, and poisoning of the tissues and endothelial cells which in- 
crease their permeability, disturbances of trophic, vasomotor, and motor 
nerves, and, more recently, alterations in the metabolism and in the state 
of nutrition of the tissues themselves, which may change their power of 
actively attracting and retaining water within themselves. 
The first of these four general factors, the obstruction to the outflow of 
fluids, concerns both lymphatic and venous outflow, which are apparently 
in a sense compensatory to each other, for it has been observed that if the 
veins of an extremity are tied, the flow of lymph from the lymphatic trunk 
becomes greatly increased. No such observations appear to have been 
made upon the venous outflow when the lymphatics are obstructed. 
Mechanical obstruction of the flow in both veins and lymphatics arises when 
the heart fails in its duty of propelling the blood, and it becomes difficult 
for more blood to enter it. But such venous stagnation is felt by all the 
tissues, not only through the obstruction to the escape of fluids, but through 
the consequent obstruction to the entrance of new nutritive arterial blood. 
Consequently there arise at once several factors which might favor oedema. 
Filtration pressure, increased permeability of the endothelium from mal- (EDEMA, ASCITES, ETC. 
45 
nutrition, and, for the same reason, heightened osmotic pressure on the 
part of the tissues occur, and it is difficult to determine which of these is 
the most important. All are removed if the heart is supported to increased 
activity, when, with the improved circulation, the oedema disappears. 
Local venous obstruction may bring about the same chain of events as 
in the so-called milk-leg, which is an oedema produced by the obstruction 
of the femoral vein by a clot. This kind of local oedema seems to be based 
on precisely the same principles as exist in the case of the general disable- 
ment of the circulation. It depends, to a certain extent, upon the sudden- 
ness with which the obstruction has been produced, and in any case dis- 
appears later if there be established a collateral circulation which allows 
the proper drainage. 
Those types of oedema which are ascribed to alterations in nervous activity 
rest on a very vague and indefinite foundation, and even such so-called 
angioneurotic oedemas as have been long known and quite helplessly as- 
cribed to nervous interferences are gradually revealing themselves as effects 
of chemical disturbances of a complicated character. Naturally, those 
diseases of the nervous system which are followed by prolonged inactivity 
of the limbs result in oedema of these immovable extremities in just the 
same way as ankylosis of the joint or contractures of the tendons might 
produce it. In all such cases the circulation is impaired, the kneading 
action of the muscles which ordinarily propels the fluids in the limb is 
lost, and the tissues are badly nourished. Almost exactly the same factors 
exist in the various forms of anaemia and cachexia with oedema. 
The deterioration in the nutritive qualities of the blood in general 
anaemias, and the absorption of some indefinite poisonous material in the 
so-called cachexias, bring about the important factor of tissue malnutri- 
tion regardless of pressure relations. Poisonous substances, indeed, are 
very commonly responsible for the appearance of oedema, and certain things 
seem especially capable of producing it. Such substances as morphine, 
the juice of grapes and of various fruits, etc., are always spoken of in the 
text-books as capable of producing such cedema, possibly by injuring the 
endothelial wall of the vessel, and the same explanation is offered for the 
cedema which arises as a response to all the manifold effects of injury which 
give rise to the complex inflammation. In every case we probably do 
have just such an injury to the vessel-walls, but we can never exclude an 
injury of the surrounding tissues, which may be an equally important 
factor. 
It is only because the fluid which exudes in the course of an inflammation 
differs quite markedly in its chemical composition from that which we find 
in other instances of oedema that we seem to have especially good proof of 
the existence of an injury to the endothelial walls which makes them more 
permeable for the albuminous material of the blood. 
(Edema of the Lungs.-In spite of much study the mechanism of cedema 
of the lungs is not yet clear. Welch, who produced it experimentally by 46 
TEXT-BOOK OF PATHOLOGY 
compressing the left ventricle and thus producing an enormous dispropor- 
tion in the work of the two sides of the heart, thought that it might result 
from such a disproportion arising spontaneously. It can be produced by 
adrenalin injections, and some have thought it of toxic origin. The fluid 
of the blood exudes into the alveolar walls, and especially into the alveoli, 
so that the air is expelled by the coagulable liquid. In the extreme exam- 
ples of this agonal condition frothy fluid may run away from the nostrils 
and the patient die practically drowned (Fig. 18). 
Fig. 18.-(Edema of the lung. Alveoli filled with fluid coagulated by fixing agent. 
The oedema which so frequently accompanies nephritis of various types 
is apparently clearly shown to be due to the inability of the kidney to ex- 
crete water and salt. It appears that in most instances the power to ex- 
crete salt is at fault, its retention causing the retention of water in order 
to maintain the normal tonicity of the tissue fluids. Withdrawal of salt 
from the diet has generally the remarkable effect of increasing for a time the 
excretion of salt, and consequently the excretion of water, so that the 
oedema disappears as though by magic, and the swollen patient shrinks CEDEMA, ASCITES, ETC. 
47 
visibly day by day. At a certain point the relations of salt and water ex- 
cretion approach the normal in proportion to the intake and the patient 
remains oedema free, but an indiscretion in the consumption of salt may 
again suddenly close the exit, so that, with its retention, water again ac- 
cumulates in the tissues. 
Loeb's review of the recent literature shows that the interrelation of the 
causative factors in the production of oedema is probably even more 
complex than we thought, and that such simple explanations as, for 
example, that which ascribes renal oedema to the inability of the kidney 
to excrete salt, are probably insufficient. There are mechanisms for 
maintaining the amount of water and the concentration of salt in the 
blood at an approximately constant level; both may be excreted through 
the kidney or escape into the tissues. The muscles especially can store 
water; the skin, salt. It is possible that the tissues actively retain the 
water and salt and allow their return to the blood only when the kidney 
becomes able to excrete them. Various substances, such as potassium 
and calcium, play specific roles in the control of the permeability of 
membranes and, consequently, in the distribution of water in the body. 
LITERATURE 
Cohnheim and Lichtheim: Virchow's Arch., 1876, Ixix, 106. 
Meltzer: "(Edema," American Medicine, 1904, viii, 19, 59, 151, 191. 
Muller, F.: Verh. Dtsch. Path. Gesellsch., 1905, ix, 64. 
Welch: Virchow's Archiv, 1878, Ixxii, 375. 
Loeb, Leo: Edema, Medicine, 1923, ii, 171. (An analytical review with full reference 
to literature.) CHAPTER IV 
THE STRUCTURE AND METABOLISM OF CELLS 
Cellular doctrine; ultimate unit of life. Nucleus and cytoplasm. Mitochondria, plas- 
mosomes, paraplasmic substances, intercellular substances. Tissues and motile cells. 
Variations in the appearance of cell. Necrosis, coagulation, and autolysis. Death. 
With the establishment of the cellular nature of the tissues, and Virchow's 
epochal revelation that disease may be referred to alterations in the cell, 
it may well have seemed that the ultimate unit of life had been reached 
and that no minuter element need be considered. Indeed, our doctrine 
of pathology is essentially a cellular one, although we realize that the 
cell is in all cases a vastly complicated structure, within which there are 
elaborate mechanisms developed in almost infinite variety, and within 
which, too, we can discern evidences of the accomplishment of chemical 
processes which, in complexity and ingenuity of combination, surpass any- 
thing which can be carried out in the best of chemical laboratories. Within 
one cell there may occur at once and side by side synthetic processes and 
decompositions which, in the laboratory, would require, if they were pos- 
sible at all, the most elaborate apparatus and the most extravagant ex- 
penditure of energy. Therefore it is not surprising that many have sought 
for a still simpler unit of living matter. 
But even though we can recognize minuter organ-like structures within 
the cells, we realize that they are merely coordinate parts in building up the 
cell, which is the ultimate mechanism which seems complete enough to live 
independently. The smaller parts may be specialized instruments for 
some particular function, but they cannot exist or carry on this work apart 
from the cell. Indeed, it seems that it is upon the nice adjustment and co- 
ordination of all the parts of the mechanism in the cell that life depends; 
when food and temperature conditions are favorable, the precisely adjusted 
mechanism begins to move as though by spontaneous combustion under the 
boiler of an engine all prepared. 
While the modern studies of immunity seem to ascribe wonderful proper- 
ties to the fluids of the body, and changes almost intelligent in their pur- 
posefulness in these fluids in response to noxious substances, all the chem- 
ical characters are controlled by the cells and there is little prospect of a 
return to the humoral theories of long ago. 
It would serve no good purpose here to enter into the details of the va- 
rious conflicting theories as to the nature of the substances which make up 
the body of the cell and its nucleus-all this may be read in the work of 
M. Heidenhain, the recent review of Benda and Ernst, and in other places- 
48 THE STRUCTURE OF CELLS 
49 
So little is firmly established that it will suffice here to mention those points 
which we seem to know most surely. 
THE STRUCTURE OF CELLS 
In spite of the great variety in form and size and in special modifications 
of the cell-body for different functions, we may recognize the following 
parts: 
(1) The nucleus. 
(2) The centrioles or centrosomes. 
(3) Golgi's reticular apparatus. 
(4) The cytoplasm, in which are found- 
(5) The mitochondria. 
(6) The plasmosomes. 
(7) Various paraplasmic substances. 
(1) The nucleus differs from the general protoplasm in its density, its 
chemical nature, and its inner structure. 
How it is separated from the rest of the cell is a matter still disputed, but 
it is clear than an active interchange of materials goes on between the nu- 
cleus and the protoplasm, and that the nucleus presides over the activities 
of the cell, and especially over its reproduction by division, in which it is 
itself so intimately concerned. In the absence of a nucleus the protoplasm 
can remain alive a short time and carry on sluggish assimilation, but it 
soon dies. The minute structure of the nucleus is as much disputed as 
that of the cytoplasm. In most cases there is a homogeneous nucleolus, 
and in our fixed preparations there are various condensations of deeply 
staining chromatin material. Kite states that, from dissection of the liv- 
ing nucleus, he can show that the chromatin is not in definite masses in 
the resting cell, and that only the nucleolus is recognizable as a colloid 
material of different density from the rest. In the process of mitosis, 
however, the clumping of the chromatin into tangible masses, the chro- 
mosomes, is familiar to every one. Their longitudinal division into equal 
parts, and the separation of these parts by the action of the fibrils of the 
achromatic spindle into the so-called daughter stars, which later form two 
separate nuclei, is abundantly described in all books on histology.* 
(2) The centrioles or centrosomes are minute bodies, occurring in pairs 
outside the nucleus, and surrounded by modified protoplasm. They oc- 
cupy varying positions in the resting cell, being often at the roots of the 
cilia in ciliated epithelium, in other cells often embedded in a dell in the 
nucleus. In mitosis they become active, separating to opposite poles of the 
cell and surrounding themselves with radiating, contractile fibrillae (achro- 
matic spindle), which exercise a mechanical influence upon the chromosomes. 
* For a discussion of the peculiar extra chromosomes which have to do with the de- 
termination of sex the reader is referred to Morgan's book, Heredity and Sex, 1913. 50 
TEXT-BOOK OF PATHOLOGY 
(3) Golgi's reticular apparatus appears to be a network or basket-like 
arrangement of canaliculi filled with a peculiar lipoid material which is invis- 
ible by ordinary methods of observation, and only brought to view by im- 
pregnation with silver or by the blackening effect of osmic acid. The net- 
work is usually close to the centrioles, although it sometimes surrounds the 
nucleus. It varies greatly in the details of its form and arrangement in the 
cells of different tissues. During mitosis it disintegrates and the fragments 
separate to the two halves of the cell, arranging themselves roughly in 
relation to the radiations of the achromatic substance. Its function is 
quite unknown and its relation to pathological changes in the cells has been 
very little studied. It is present in what appears to be the usual form 
in tumor cells, it becomes multiple in relation to the numerous centrioles 
in multinucleated giant cells, and it is suggested that its lipoid constituents 
may furnish the material for the hyaline globules in the degenerating epi- 
thelial cells of the kidney in acute nephritis. But it is clear from such 
fragmentary information that the matter demands much further study. 
(4) The Cytoplasm.-The divergent theories as to the nature of the pro- 
toplasm may be read elsewhere. It seems that the more recent study of 
the granular structures which are embedded in it has removed much of the 
support for the earlier theories, and the outcome seems to be that the cyto- 
plasm is essentially colloid in its composition, obeying the physical laws 
which govern colloids in their various phases. Possibly a mixture of col- 
loids of various densities, it has varying powers of water absorption and 
swelling. The admixture of fat-like substances alters its physical char- 
acter somewhat. With regard to the surface of the cell, it has been sug- 
gested that some such condensation through the aid of cholesterin or leci- 
thin admixture may exist. Overton's theory that there is an actual thin 
lipoid membrane which acts as a semipermeable sheath to each cell is 
well known, and has served in the explanation of the action of anaesthetics, 
but it still admits of criticism, as pointed out by Bayliss (Principles of 
General Physiology, 1918, page 138). 
(5) The Mitochondria.-Altmann, in 1894, devised staining methods 
which made visible certain granules in the cell protoplasm which he re- 
garded as elementary organisms, or the only living constituents of the cyto- 
plasm. While this view cannot be maintained, there is much that is exact 
in his observations. Benda recognized by other stains granules, rods, and 
threads in the protoplasm which he called mitochondria, and which have 
been shown by many workers (Meves, Duesberg, and others) to be a very 
constant constituent of the cell-body. 
Many names have been proposed indicating differences in form, such as 
chondriocont for the longer filamentous forms, chondriomita for those re- 
sembling a string of beads, etc., but the original term, mitochondria, may 
well be used in a collective sense. The greatest variety of functions has 
been ascribed to them by different writers. Meves claims that they fur- 
nish the connective-tissue fibrillae, that they transmit the hereditary char- THE STRUCTURE OF CELLS 
51 
acters of the cell-body, etc. Champy, in studying absorption and secre- 
tion in the intestinal epithelium, states that they accumulate at both poles 
of the cell and are converted into secretory granules. 
It is clear that we must as yet be careful in interpreting their function, 
and while it seems probable that they play some important role, it is possible 
that already too many different duties have been assigned to them. 
(6) The Plasmosomes.-Benda distinguishes sharply from the mito- 
chondria these granules, which he speaks of as concerned with the house- 
keeping of the cell, with the assimilation of nutritive materials, with the 
formation of secretory products as the result of their specific metabolism, 
and with the excretion of waste. 
They are not to be recognized in themselves by any of the staining meth- 
ods which we know now, but are readily enough made visible by the sub- 
stances which they store or secrete or by their power to store vital stains. 
That they are really distinct from the mitochondria is shown by their 
different position in the cell, by the fact that the mitochondria are recog- 
nizable as thin filaments in a cell in which, side by side with them, the plas- 
mosomes are swollen with some absorbed material, or with a stainable se- 
cretion, and by the fact that in mitosis, mitochondria, and plasmosomes 
separately divide and continue their existence in the daughter-cells. 
It is in connection with these that fats and carbohydrates are stored in 
the cell. It is probably they that swell and become conspicuous in " cloudy 
swelling" or "parenchymatous degeneration." They in their varieties 
constitute the specific granulations of the leucocytes and other cells. To 
this class too belong, no doubt, the zymogen granules in many glands, even 
though in such a gland as the pancreas we can distinguish so easily the 
coarse, deeply staining zymogen granules in the acinar cells from the 
very minute granules of two types in the cells of the islands of Lan- 
gerhans. 
Lewis has shown recently that in young connective-tissue cells 
cultivated in vitro granules appear in vacuoles, especially about the 
centriole when the culture grows old and becomes ill-nourished. These 
stain with neutral red, while the mitochondria stain with Janus black. 
He regards them as degeneration products composed of non-living 
material. 
It is clear that the construction of the cell is highly specialized in most 
cases for the function which it is to carry out, and that it is supplied with 
the most perfect mechanisms for these purposes. Some of these are evi- 
dent in the form of contractile bands in the protoplasm, or in long nerve 
processes like electric wires carefully insulated by sheaths of fatty ma- 
terial, or in mobile cilia which mechanically perform duties in the trans- 
portation of foreign particles,. In others the tools of their trade are recog- 
nizable in the form of the granules which seem to prepare ferments by which 
the chemical processes which the cells effect are carried out. While these 
are visible in many cases, there are others in which, even when we know 52 
TEXT-BOOK OF PATHOLOGY 
that the most multifarious chemical reactions are being carried on, nothing 
of the mechanism is recognizable to our eyes. 
(7) Paraplasmic Substances.-While the actual instruments of metab- 
olism are thus often invisible, the materials which are being worked up by 
the cells, and more especially those which the cell is unable to dispose of, 
often remain conspicuous in the cell-body. Such "paraplasmic" particles, 
which may consist of fat-globules (Fig. 19), glycogen granules (Fig. 20), 
vacuoles filled with fluid, granules of pigment or calcium, often form an in- 
dex of the activity of the metabolism of the cell, and are useful in determin- 
Fig. 19.-Fat-globules in the epithelium of the renal tubules. Sudan stain. 
ing its condition, although it must be remembered that there are doubtless 
many other substances equally burdensome to the cell, and accumulated in 
its protoplasm, because its metabolism is so sluggish as to make it unable 
to dispose of them, and these, because of their solubility or because they 
are inaccessible to our stains, are invisible. Certainly these substances 
are not to be thought of as alive, at any rate until they become, through 
assimilation, integral constituents of the chemical structure of the proto- 
plasm. TISSUES AND MOTILE CELLS 
53 
TISSUES AND MOTILE CELLS 
It is, of course, clear in connection with this that the higher animals, at 
least, exist as communities of cells in which each district is made up of 
individuals which have specialized in some form of activity which is con- 
tributed to the good of the whole, and that in such a community there are 
many things in common, such as the blood-supply, the gaseous interchange, 
and the removal of waste. Just as in a town the water-supply, the air, 
and the sewerage are of common interest, so we have seen that in the body 
Fig. 20.-Liver of a normal well-fed dog showing glycogen in cells. Best's carmine stain. 
whole districts may suffer from the failure of one of these common necessi- 
ties. 
Communities of this character, inasmuch as they hold together in a 
coherent grouping, we easily recognize as "tissues." It is not so easy to 
think of a constantly moving and changing group of cells like the blood as a 
tissue, although in every other respect it deserves the same dignity as the 
community of liver-cells or kidney-cells. And so it is with those free lances, 
the wandering phagocytic cells, which straggle about in the tissues every- 
where, but are ready on call to assemble at a point where they are needed. 54 
TEXT-BOOK OF PATHOLOGY 
Intimately related to the mobile cells of the blood, they have the same claim 
to the honors of a community, although it must be remembered that they 
differ from the "fixed tissue" elements in refusing to hold together into a 
solid structure or to adopt any particular place as a permanent site. 
The whole body is not composed of cells. Were the cells all removed, 
there would still remain a framework so complete that although we might 
see through it as through a basket, the whole form of the body in all its 
parts would be represented and much of its solidity would remain. This 
is the intercellular substance, which varies greatly in character in different 
places, being almost the whole of the skeleton and the bulkier part of all 
the connective tissues which permeate all tissues and organs. Whether 
this material is alive has been long discussed. Certainly the fibres of 
connective tissue, the matrix of cartilage, and the calcified substance of 
bone could not remain alive alone; but in the body all these things 
undergo constant change, being broken down and reconstructed, and there 
seems no doubt that they carry on a sluggish interchange of chemical mate- 
rials-a slow metabolism. 
Alterations in the appearance of the cell arise constantly from variations in 
its activity, and one must be familiar with such physiological transforma- 
tion in order to interpret correctly what might otherwise be looked upon 
as the effects of pathological processes. This presupposes that we are able 
to view the cells as they are in the height of their activity, but in truth this 
is seldom the case, since most studies of human tissue are made after the 
individual has been dead for some time, or after the tissue has been re- 
moved from the body at operation. Naturally, changes must be expected 
to occur in this interval, and it is easily realized that the more quickly the 
cells can be studied after their removal from the living body, the more 
nearly they will approach to their living condition. Naturally, too, there 
are great advantages to be gained by studying such cells at once without the 
application of any chemical reagent, a method once universal, but now far 
too little used. But it is realized that while much may be learned in this 
way, such tissues change rapidly, and we, therefore, preserve them by sud- 
denly stopping all ferment action and coagulating the protein substances 
by the application of some fluid, such as alcohol or formalin. Advantage 
is taken of the fact that nuclei, protoplasm, etc., react differently to various 
stains, and in the end our microscopical preparations show us the cells 
sharply brought into relief by being coagulated, and by having each of its 
elements differently colored. We are accustomed to the appearance in the 
stained preparations of what was a normal cell and interpret diseased con- 
ditions of the cell by its divergence from this standard, but at the same 
time we know that the cell is really greatly changed from its appearance 
while alive. It resembles the living cell about as a boiled egg resembles a 
fresh laid one. In an autopsy upon a man who had swallowed a large 
VARIATIONS IN APPEARANCE OF CELLS 55 
amount of pure carbolic acid, which is an excellent "fixing fluid," the gas- 
tric mucosa was obviously dead and coagulated into a white layer long 
before the man died, but although it looked so abnormal, the microscopical 
section showed the most perfectly preserved normal gastric mucosa. 
If, then, these are all dead cells which constitute our standard of the 
appearance of live cells, how shall we recognize injured or dead cells among 
living ones? It is very easy, because what we recognize is not the death of 
the cell, but the changes to which it is exposed, after death, while still sur- 
rounded by living tissues and their fluids, and which result partly from the 
action of ferments and partly from the formation of a clot in the sub- 
stance of the dead cell and the coagulable fluids which may permeate it. 
NECROSIS AND NECROBIOTIC CHANGES 
Fig. 21.-Renal epithelium showing pyknosis in several nuclei, with disappearance of 
others. 
If only a portion of the gastric mucosa had been killed, so that the man 
remained alive for a time, it would soon have been liquefied by the gastric 
juice. Exactly so a dead cell in the substance of the liver becomes the seat 
of clotting, and then is liquefied by the ferments of the passing fluids and 
mobile cells, and it is in some stage of this process that we recognize the 
necrotic cell. A cell which had just died would look quite like its living 
neighbor. 
NECROSIS AND NECROBIOTIC CHANGES 
It is important, then, to consider briefly these evidences of the effects of 
necrobiotic changes, a matter which is simplified since they are the same 56 
TEXT-BOOK OF PATHOLOGY 
throughout, whether the injury be caused by a poison, by starvation, or 
in any other way, unless, of course, the poison or mechanical injury should 
in itself produce some peculiar change in the cell. With the cessation of 
life in the cell there is a short pause, during which the dead cell has every 
appearance of being alive, and then its protoplasm sets in a clot. The 
thromboplastic substance, or thrombokinase, which the dead cell radiates 
causes the coagulation of the fibrinogen in the blood plasma which filters 
into it, and in the end the body of the dead cell becomes a swollen mass, 
much denser and heavier than the body of the original live cell. All this is 
not done without changes in the appearance of the cell-changes which 
probably begin before the actual death and continue after clotting has 
Fig. 22.-Karyorrhexis. Edge of infarct of kidney. 
occurred. The most conspicuous are alterations in the nucleus which may 
cause it to shrink and stain more deeply (pyknosis) (Fig. 21). Portions of 
its substance may be extruded beyond its original outline in bizarre forms, 
or it may break up into several irregular, solid-looking, and deeply stained 
fragments, or even into a fine dust of black grains (J^aryorrhexis) (Fig. 22). 
On the other hand, it sometimes retains its form for a long time, but gradu- 
ally fades until only the faintest rim takes the stain and in turn finally dis- 
appears (karyolysis) (Figs. 23 and 24). At the same time the structural 57 
NECROSIS AND NECROBIOTIC CHANGES 
Fig. 23.-Karyolysis in renal epithelium. 
Fig. 24.-Death of renal epithelium with fading nuclei. 58 
TEXT-BOOK OF PATIJOLOGY 
details of the cytoplasm are lost, and merge into a dense, granular or vitre- 
ous mass, which assumes a deep pink stain with eosin. Later changes 
caused by proteolytic ferments lead to the erosion, disintegration, and final 
liquefaction and disappearance of the whole cell remnant. Frequently 
the boundaries of many adjacent necrotic cells are lost before liquefaction 
occurs, and a granular mass remains in which nuclear fragments or the fine 
dust of them is scattered, but even then it is often possible to make out the 
positions of the original cells because the more resistant connective-tissue 
framework of the tissue persists. 
Much of the disintegration and removal of the debris of such dead cells 
is effected mechanically by phagocytic cells, usually of the mononuclear 
type, which engulf particles in their protoplasm in addition to their activ- 
ity in furnishing the proteolytic ferment. They in the end wander away 
with these partly digested fragments, the liquefied material is absorbed, 
and the area of cell death collapses or is partly filled by a growth of scar 
tissue. Sometimes, as in large infarctions or in tuberculous foci, the dead 
material may remain undissolved for a long time, and is walled off by a 
capsule of fibrous tissue. 
Autolysis.-This liquefaction by means of a proteolytic ferment is 
exactly the process known as autolysis, except that it is recognized in that 
process that all tissues can liberate in varying degrees of intensity the pro- 
teolytic ferment necessary to dissolve their own cell-bodies. Even a piece 
of lung or liver kept sterile in a warm place will soften and finally liquefy, 
while tissues, such as spleen, which contain large numbers of specialized 
phagocytic cells which are particularly active in producing such ferments 
will dissolve into a turbid fluid rich in amino-acids far more quicky. 
Bradley and Morse emphasize the importance of a slightly acid reaction 
in accelerating this process. Dernby shows that in all tissues studied 
there are both pepsin-like and trypsin-like enzymes, so that autolysis 
would proceed most rapidly if the reaction were first slightly acid and 
then alkaline. Undoubtedly this mechanism is well adapted to rid the 
body of useless dead and crippled cell material, and it will be seen that it 
plays a great part in the restoration, to an untrammeled working condition, 
of all injured organs, and throughout life is the constantly active method 
of housecleaning which keeps the machinery in order. 
Death.-Death of cells is thus a relatively complicated matter, but the 
whole body is a community of tissues which is not entirely disabled, even 
by the loss of many cells. As in the cell where the controlling nucleus is 
destroyed the protoplasm also dies, so in the body life is the expression 
of the working of a delicate machine which works because it is marvelously 
attuned to the environment. Because it has elaborate regulators, control- 
lers, and safety-valves, it can compensate for many injuries, but when the 
limit of the influence of these is passed, the machine stops. Therefore there 
are many ways in which the balance can be made impossible at one point 
or another-points important enough to involve finally the all-important NECROSIS AND NECROBIOTIC CHANGES 
59 
circulation and respiration. When they cease, all the tissues soon die, 
although for some time after the main machine has stopped working the 
various accessory machines are still in good working order, and need only 
the current of clean blood through their vessels to make them begin once 
more to work. Of course, the central nervous system is the great regulator, 
and one might say the master engineer, but life can go on without it if 
only some one will assume its role and arrange that the circulation should 
continue properly. So, though it is so familiar, it is difficult to define 
precisely what a person's death means or to say at just what moment the 
most important part of death occurred. 
LITERATURE 
Benda: Ergebn. d. Anat. u. Entwickl., 1903, xii, 743. Verh. Dtsch. Path. Gesell., 1914. 
xvii, 5. 
Bradley, Morse: Jour. Biol. Chemistry, 1915, xxi, 113; 1916, xxiv, 27. 
Champy: Arch, d'anat. Microsc., 1911, xiii, 55. 
Cowdry: Amer. Jour, of Anat., 1916, xix, 423, and other papers. 
Dernby: Jour. Biol. Chemistry, 1918, xxxv, 179. 
Duesberg: Biological Bulletin, 1919, xxxvi, 71, and other papers. 
Ernst: Verh. Dtsch. Path. Gesell., 1914, xvii, 43. 
Heidenhain, M.: Plasma u. Zelle, 1907, i. 
Lewis: Johns Hopkins Hospital Bulletin, 1919, xxx, 81. 
Meves: Arch. f. mikr. Anat., Ixxi, Ixxii, Ixxv, Ixxvi, etc. Anat. Anzeiger, xxxi, xxxiv. 
Morgan, T. H.: Heredity and Sex, Columbia University Press, 1913. 
Pappenheimer: Anatomical Record, 1916, xi, 107. CHAPTER V 
DISTURBANCES IN THE NUTRITION AND METABOLISM OF 
CELLS 
Nature of metabolism. Disturbances resulting from slight injuries. Degenerations. 
Atrophy: its causes. 
Ordinarily the normal and abnormal metabolism of animals is studied 
by chemical investigation of the materials taken into the body in compari- 
son with those excreted, taking into account the energy liberated in the 
form of heat, and the changes in the weight of the body. This gives a 
fairly accurate idea of the whole material interchange in the body, and when 
the normal balance is much disturbed, it is usually easy to recognize the 
effects anatomically. 
It is known to every one that in early life the anabolic, or building-up, 
processes should be in excess of the katabolic, or destructive, processes, 
so that growth proceeds through the assimilation and permanent retention 
of much of the food materials in the form of body tissue. In mature life 
such an exquisite balance is maintained that little change in the body weight 
occurs, while in the declining years the organs waste and the body shrinks 
because the katabolic outstrip the anabolic processes. 
Substances taken in as food may be used directly for the building up of 
tissue, whereupon they become a relatively stable part of the body struc- 
ture, or they may be burnt to produce energy, or stored for future burning. 
Such stores are essentially labile constituents of the body, ready at any 
time to be moved about or to undergo rapid chemical change. They thus 
constitute the ready fuel, and it is only after they are exhausted that the 
actual cell substance is consumed. It is like Palissy's furnace, into which, 
when the supreme effort was being made and fuel was finally exhausted, he 
cast his furniture. 
Naturally, if the activities of the cells are restricted, the fuel will tend to 
accumulate-even if the cell is slightly injured, so that it can no longer 
make use of all the materials brought to it, we may expect them to collect 
in its body. 
Under these circumstances we can often see the accumulated materials, 
although we can detect no evidence of injury to the structure of the cell, 
and it must be a matter of long experience to ascertain how much real in- 
jury corresponds with the heaping-up of such materials. 
This is the basis of the so-called " degenerations," of which so much has 
been written. When it was thought that the globules of fat in a cell were 
the direct product of the decomposition of its protoplasm, this naturally 
60 DISTURBANCES IN THE NUTRITION AND METABOLISM OF CELLS 
61 
indicated a great injury, but now if we think the fat merely a part of that 
which is transported from place to place, finally sidetracked in these cells, 
we cannot be so readily convinced of the injury to the cell, especially since 
we know that the same appearances can arise in perfectly normal persons. 
It is almost as though we were to attempt to tell the condition of a flour 
mill which we suspect of being out of order by estimating the amount of 
wheat in its hopper at any given moment. It might be better to estimate 
the flour it has ground or to look for broken wheels in its machinery. 
The situation is difficult for the following reasons: Of all the substances 
which enter into the material interchange of the cells, we can see only a few, 
such as fat. As shown by chemical studies, great disturbances of metabolic 
activity may occur without our being able to see the substances concerned, 
and, on the other hand, great variations in the quantity of the visible 
materials in the cell need not indicate an injury to the cell. Functional 
disability of the cell may exist without any obvious anatomical alteration, 
and yet cause this stagnation of food materials, while perfectly obvious 
anatomical demolition of the cell machinery may occur in such a way that 
no heap of fuel material collects to indicate the change. So we must in- 
terpret what we find with extreme care. 
It is the aim of this chapter to discuss the anatomical changes in the 
tissues produced by injuries, which are accompanied by disturbances of 
metabolism. These changes may be so slight as to be invisible, and indi- 
cated only by the accumulation of materials which should have been used 
up, or they may be so intense as to have destroyed the structure of the cell. 
The term degeneration is usually employed to indicate the effect of an 
injury sufficient not to cause the death of the cell, but to disturb its metab- 
olism to such a degree that the raw materials or the products of its activi- 
ties accumulate in it. It is loosely used in other senses, as in the case of 
hyaline degeneration, in which the cells die and are merged into a homo- 
geneous mass, or amyloid degeneration, in which an abnormal substance 
is deposited in the crevices of the tissue. 
It would seem desirable, if possible, to abandon the term degeneration 
entirely and to use others which refer more accurately to the disturbances 
of metabolism or to the actual injury of the cell. But even if we at- 
tempted this, it would probably be unsuccessful, for the words are so 
deeply rooted and express so concisely a complex and obscure idea. 
It must be observed that a rather limited number of raw materials 
are normally concerned in the chemical processes of the body, although 
they are presented in an almost infinite number of combinations, and pass 
through many further changes in the cells, but the body can deal with other 
things which are not good food or drink or air to breathe, in ways which 
are sometimes surprising and always more or less definitely adapted to its 
protection. 
Normally we take in water, air, protein, carbohydrates, and fats, to- 
gether with smaller but continuous supplies of the salts of sodium, potas- 62 
TEXT-BOOK OF PATHOLOGY 
sium, magnesium, and calcium, combinations of iron, phosphorus, sulphur, 
iodine, chlorine, and minimal amounts of various other substances. The 
lack of any one of these will be severely felt, and may produce an astound- 
ing upset of the whole machinery of the body. 
At other times, when the facilities for dealing with one or other of these 
substances are disarranged, it may become necessary to eliminate them 
from the food if life is to be prolonged-carbohydrates are withheld from 
the diabetic and salt from the waterlogged sufferer from Bright's disease. 
ATROPHY 
In order that growth should occur, or even that the tissue should maintain 
its status, the machinery of the cell must be in working order. We may 
imagine that, by reason of age, this machinery might deteriorate or that 
in other ways it might be incapacitated. 
Evidently when this deterioration appears, the oxidizing or katabolic 
processes go on, although the more difficult building up proceeds but 
haltingly until the cell is hopelessly in arrears and wastes away. 
The cell laboratory does not start up into activity merely because food is 
presented-rather it is controlled in its synthetic and analytic processes 
by influences from without-from the nervous system, perhaps indirectly 
through the organs of internal secretion. They set the pace and determine 
the rate of work. Without them tissue-cells will grow a little in such a 
culture as has lately become possible, but this growth is so meagre that 
their importance has become more than ever clear. When the cell does 
nothing, we might perhaps, at first thought, expect it to remain unchanged, 
and so it would if we assured its complete inactivity by putting it in forma- 
lin, but the inactivity of a cell is more like a household in which the bread- 
winner stops work. 
Of course, grosser influences may have the same effect-hunger may de- 
prive the tissues of nutrition, pressure may so constrict the cell that 
nourishment is impeded, or poisons may wreck the machinery. The 
atrophy of tissues is, therefore, not a simple matter, and perhaps were the 
effects as different in appearance as the causes, we might have many words 
to describe it. And even though we may discover the primary reason for 
the great change, we cannot always be sure of the immediate cause because 
a vicious circle is started each time, any part of which may be responsible 
for the end result. Can we be sure, when the muscles of a limb atrophy 
from disuse, whether the inactivity of the muscle-cell directly halts its 
metabolism, or whether the cell wastes because but little blood comes to it 
now, either because it fails to assist the circulation, or because the vaso- 
motors adjust the supply to its needs as an inactive rather than an active 
cell? 
Wasting of the tissue may be caused by starvation, by old age, by mental 
disease, by derangement of the internal secretions, by infections and in- 
toxications, especially when associated with fever, by inactivity, especially 
when caused by paralysis, by mechanical pressure, and by various other 
causes. ATROPHY 
63 
Hunger.-According to the state of nourishment with which it starts, 
the animal body can survive the complete withdrawal of food for varying 
periods. If water is available, the length of time that elapses before serious 
symptoms or death results may be several weeks, especially in certain per- 
sons who have trained themselves to fast. It is even longer in dogs. 
Aside from the sensations of hunger (which soon decrease) and weakness, 
there are usually no particular symptoms until rather late, when phenomena 
of intoxication with nervous symptoms arise on account of the irregular 
decomposition of fats into /3-oxybutyric acid and acetone, with related 
substances. This acid intoxication, which may bring on coma, is not, as 
a rule, seen in fasting dogs. 
In a starving person the absorption of oxygen and exhalation of carbon 
dioxide continue, the excretion of urine goes on, although the fseces disap- 
pear. Wasting occurs first in the stored substances, such as fat, glycogen, 
etc., then in the tissues themselves, beginning with those which are least 
called into use. Of the muscles, the active ones retain their bulk longer 
than the idle ones. The liver shrinks, and the parts which retain their full 
size for a long time are the central nervous system, the heart, and the 
bones, although the last probably become rarefied. 
While complete deprivation in this way brings about the rapid wasting 
of the body, there are many mechanical and other conditions which lead 
to the same result more slowly. Any obstruction to the passage of food 
through the mouth and oesophagus to the stomach may gradually starve 
the sufferer, and so may an obstruction at the pylorus, since nourishment 
is not sufficiently absorbed from the stomach and is usually vomited after 
a long stay there. Beside this, there are various nervous disturbances, 
which result in inability to take food (anorexia nervosa) or to retain and 
digest it, and lead to extreme emaciation. 
Senility.-With the advance of age, wasting becomes evident in many 
organs, if not in all, although the inconstancy with which it appears leads 
one to wonder whether other factors do not also play a part. The skin be- 
comes thin and satiny, and the disappearance of fat and muscle tissue 
beneath it throws it into wrinkles. The hair, after becoming white, falls 
out, the teeth loosen and decay and fall out. The muscles waste away and 
grow weak, and the ligaments which bind together the bones stretch and 
weaken. Deprived of its strong muscular and ligamentous support, the 
back bends forward. The bones become rarefied, so that they break more 
easily and heal with greater difficulty than in a young person. 
The internal organs decrease in size and turn brown, and every cell, 
through its shrinkage and the accumulation of pigment, can be recognized 
as that of a senile organ. The liver becomes a flabby, shrunken organ, of a 
dark-brown color, made up of lobules far smaller than the normal; often 
whole layers of liver tissue disappear, so that on the surface of the organ 
blood-vessels, bile-ducts, and the fibrous skeleton of the liver lie exposed 
(Fig. 25). The heart becomes small and brown, with tortuous coronary 64 
TEXT-BOOK OF PATHOLOGY 
arteries showing through the watery, brownish fat. The fat of the epi- 
cardium has disappeared, and its cells are separated by fluid which gives the 
gelatinous appearance to the tissue. The heart decreasing in size is too 
small for the coronary vessels, which must take a tortuous course. Each 
heart muscle cell greatly reduced in thickness shows at the poles of its nu- 
cleus great quantities of a yellowish 
brown, granular pigment, which stains 
a little with Sudan III (brown atrophy] 
(Fig. 26). This is one of the little 
known group of lipochrome pigments 
which seem to arise everywhere with 
the wasting of the cell-body. The 
formation of a pigmented ring about 
the margin of the cornea (arcus senilis) 
Fig. 25.-Superficial atrophy in a 
senile liver, exposing the vessels and 
the framework of the organ. 
Fig. 26.-Brown atrophy of the heart. Pig- 
ment-granules at the poles of the nuclei of the 
wasted fibres. 
is another analogous process-there, too, the pigment is probably of the 
group of lipochromes. The brain withstands this shrinkage for a long time- 
at least so far as its external appearance goes, though in the end the con- 
volutions become narrower and separated by wide sulci in which fluid col- 
lects. Long before this the mental deterioration may have given an index 
of the disappearance of association-tracts and the disabling of the cells. ATROPHY 
65 
In the skeleton, aside from the general rarefaction of bony tissue, con- 
spicuous deformities may occur, such as the gradual erosion or hollowing 
away of the outer table of the skull over the parietal regions until deep 
grooves are formed over these regions-sometimes so deep as to penetrate 
the inner table and leave the brain covered only by a soft tissue. 
Mental Disease.-We know very little about the control of metabolism 
from the central nervous system, but every one is familiar enough with the 
lean and hungry looks of the fanatic and the sleek plumpness of such as 
are content and sleep "o'nights." Possibly it is the constant activity of 
the one and the folding of the hands of the other that cause these differ- 
ences, but mere muscular activity seems not quite sufficient to account for 
it all. 
In some mental diseases the influence of excitation or apathy is very 
striking--in the manic depressive insanity, or folie circulaire, the patients 
pass through periods of the wildest maniacal excitement, which alternate 
with others of apathy and depression. In the maniacal periods they be- 
come emaciated in the extreme, only to grow fat when they pass into the 
state of depression. 
Deranged Internal Secretions.-These are intimately related with the 
mental condition, and it is possible that it is in some way through them that 
the mental disturbance acts to affect metabolism. Psychic disturbances 
change the secretion of the adrenal (Cannon), and possibly they do the 
same with the thyroid in such a disease as exophthalmic' goitre. Wast- 
ing characterizes that disease, while in the absence of the thyroid, in de- 
ficiency of the hypophysis or of the ovary or testis, fat accumulates. 
Evidently these organs have the most intimate relations with the general 
metabolism, and are in most direct control of it, for their integrity affects 
not only the disposition that is made of the labile substances, but also the 
growth of the tissues. 
Febrile Disease and Tumors.-In infections and intoxications accom- 
panied by fever the whole metabolism is so adjusted that the katabolic 
processes are in excess, and it is thought that in time the tissues themselves 
are attacked and oxidized. It is, therefore, not surprising that extreme 
degrees of emaciation are found in cases of protracted infections with 
fever-the long-standing cases of pulmonary and bone tuberculosis or 
typhoid fever are examples. 
But the same appearances sometimes accompany the ravages of certain 
tumors, even when there is no bacterial infection, no ulceration, and no 
fever. Not all tumors can do it, nor are the emaciation and evidence of 
poisoning dependent altogether upon the size of the new-growth-instead, 
such symptoms as weakness, pallor, loss of weight, lowered resistance to 
infection, and all the other signs of what has long been called "cachexia" 
may be the first indication of the existence of any tumor. For this reason, 
although one might imagine that much food and body substance would be 
used up or diverted to the formation of a large new-growth, it is necessary 66 
TEXT-BOOK OF PATHOLOGY 
to believe, when the tumor is very small, that it disturbs metabolism 
through some poison which it distils or whose formation it favors. 
In such emaciated people the fat from the wasted subcutaneous tissue 
seems to be lodged in the liver and other internal organs whose cells are 
unable to dispose of it. 
Inactivity.-More local in its effects, and scarcely capable of causing 
anything resembling the general emaciation which is seen under the fore- 
going conditions, inactivity may stop the growth of the tissues of the young 
and lead to the wasting of those of adults. In such organs as muscles the 
forced repose which follows the rigid splinting of an extremity or the un- 
bending fixation of a joint is quickly followed by a decrease in the size of 
the muscle which can be seen to be the effect of wasting of the separate 
Fig. 27.-Atrophy of muscle with pigmentation and concentration of sarcolemma 
nuclei. 
fibres until, with the loss of fibril after fibril, they are reduced to remnants 
of thread-like thinness or disappear entirely (Fig. 27). Generally, the 
sarcolemma nuclei remain and collect together until they form long beaded 
rows in the collapsed sheath. But they disappear also in time, and their 
place is taken by a little fat or by fibrous tissue which contracts so as to 
pull the joint into a fixed position. 
When the inaction follows the cutting of the nerves or destruction of the 
motor nerve-cell in the anterior horn of the spinal cord (as in the so-called 
progressive muscular atrophy), the wasting is even more rapid and com- 
plete. It seems that even when the normal muscle is perfectly quiescent 
there are impulses reaching it constantly through the nerve which main- 
tain its tension or tone. A kind of tremulous, tuned-up state is kept up ATROPHY 
67 
which prevents its complete inertness, and this involves a certain metabolic 
activity. 
When the nerve is cut, all these impulses cease and the muscle sags down 
quite flaccid-compared with the oxygen and carbon dioxide exchange of 
the intact resting muscle the metabolism of this paralyzed muscle is almost 
nothing, and hence, no doubt, its rapid wasting. Doubtless, as was sug- 
gested before, the decreased blood supply to a paralyzed limb adds to the 
tendency to waste, although it cannot be regarded as the most important 
factor. 
Fig. 27A.-Atrophy of muscle-fibres. Juvenile muscular dystrophy. 
Other things than muscle waste in these same circumstances-the bone, 
the ligaments, even the skin, become atrophic in a paralyzed extremity. 
We have little experience with changes that might occur in internal 
organs deprived of their nerve supply, but they are rendered inactive in 
other ways, and chiefly, perhaps, by the occlusion of their ducts or by com- 
pression. Examples of the former are discussed elsewhere (hydronephrosis, 
pancreatic duct occlusion, etc.). 
The secretion accumulates and distends the duct, finally compressing 
the gland tissue so that the nutrition of the cells is interfered with. The 68 
TEXT-BOOK OF PATHOLOGY 
whole gland may be converted into a thin-walled sac containing the secre- 
tion under high tension. The other factors which play a part in completing 
the destruction of the tissue are no doubt the compression of the blood- 
vessels, which now run in the tense wall of the sac, and the stoppage of the 
function of the secreting cells. 
We know little about the actual mechanism of secretion, but it seems probable that 
if the concentration of any element of the secretion in the sac becomes very high, it will 
be impossible for the cell to continue to pour more of that substance into the solution. 
That part of the cell's metabolism will come to a standstill, although it is shown that if 
the sac be emptied, secretion will begin again at once. It is possibly somewhat as though 
two salts were in solution. If from these a new salt can be formed which alone of the 
four possible combinations is capable of escaping by osmosis from the solution, that salt 
will be formed and escape until all its constituents are gone. Not so if it cannot be re- 
moved-it will be formed until a balance is reached and then all interaction will cease. 
This is different from the cessation of metabolism which follows section of the nerve, 
but it is equally capable of exposing the cell to continued, if gradual, breaking-down 
processes. 
Pressure.-Continuous pressure, if applied to sensitive tissues firmly 
enough, may cut off the entrance of blood completely so that the tissue 
dies. This is the fate of the skin and underlying tissues in the formation 
of bedsores or "decubitus ulcers" in bedridden and emaciated persons 
whose tissues are already poorly nourished. Where their prominent bones 
touch the bed, the skin is kept pressed bloodless and quickly dies. But 
if the pressure is less violent, the cells of the tissue dwindle away slowly. 
This is once more a question of inadequate nourishment, for not only are 
the blood-vessels partly closed, but the cells themselves are compressed, 
so that absorption of nutriment and the carrying on of their functions sink 
to a low ebb. 
This is seen particularly well about a tumor-nodule growing in such an 
organ as the liver-all the surrounding cells and capillaries are flattened 
and gradually disappear. 
One might expect the accumulated food-stuffs, such as fat-globules, to disappear first, 
and after that the cell-body itself, but it appears that if the cell is caught with fat- 
globules in it, it may be unable to use them up before it itself is quite disabled, perhaps 
by lack of oxygen. Therefore the liver-cells immediately next to the advancing tumor- 
nodule may be loaded with fat, though most exposed to pressure (Fig. 28). 
The effect of pressure in distorting and perverting the growth of tissue 
is seen in the misshapen heads of some French peasants and certain In- 
dians, in the crippled feet of the Chinese women, and the constricted livers 
of the fashionable white women of past generations. Numerous other 
instances are found in the compressed and distorted organs, and limbs 
found in malformed infants as the result of amniotic adhesions in intra- 
uterine life. 
Another example commonly adduced is the effect of aneurysms upon 
the tissues upon which they impinge. Soft tissues yield in front of them- 69 
ATROPHY 
hard tissues, like bone, are hollowed out before them. But I cannot be- 
lieve that this is merely a pressure atrophy, for one finds the bone actually 
comminuted, as though with a hammer, and the fragments bathed in blood 
and attacked by great phagocytic giant-cells (osteoclasts). In the ver- 
tebral column the centra of the vertebrae are thus excavated, while the 
intervertebral discs project unchanged (Fig. 29). 
Decreased blood supply is commonly held to be a prominent cause of 
Fig. 28.-Compression of liver-cells about a metastatic tumor-nodule. 
atrophy without questioning more closely the nature of the examples that 
are always presented. Decreased blood supply does occur in regions or 
organs which we find in a state of atrophy, but it must be asked whether 
it is cause or effect. The blood supply may be decreased by pressure on 
the supplying artery, or by contraction of the vessel or the narrowing of 
its lumen by abnormal thickening of its wall. 
If effective occlusion of the vessels occurs rapidly, the tissue dies-if 70 
TEXT-BOOK OF PATHOLOGY 
gradually, a collateral or roundabout circulation is developed and no 
effect is produced. 
Probably such a situation as is found in the kidney in which arterio- 
sclerotic narrowing of the blood-vessels limits the blood supply without 
recourse, could be most satisfactorily given as an example of atrophy of 
Fig. 29.-Destruction of vertebrae by aneurysm. Dried specimen with aneurysmal sac 
in situ. 
the tissue from this cause, although, as in the senile ovary or uterus, in 
which the arteries become gradually obliterated, the wasting of the kidney 
might be explained otherwise. 
In a kidney recently observed there were two supplying arteries, one of 
which had long been occluded by a thrombus. That half of the kidney 
was shrunken, in sharp contrast with the other half. 
Hypertrophy and Hyperplasia.-Both terms imply an increase in the 
bulk of a tissue, but hypertrophy is used to indicate an enlargement and 
strengthening of an organ brought about by increase in the size of its ele- 
ments. Hyperplasia, on the contrary, is the result of an increase in the num- 
ber of these elements or cells. Nevertheless it is sometimes difficult to 
determine except by exact enumeration of the cells, as in the case of hyper- 
trophy of the heart wall, whether the increase in the bulk does not represent 
both processes. 
Hypertrophy has often the character of physiological growth in response ATROPHY 
71 
to the free functioning of an organ and its consequently improved metab- 
olism. One might look in this way upon the muscles of the practised 
athlete. In a different sense there is hypertrophy in the uterine wall in 
the course of pregnancy. 
But from the point of view of the pathologist, hypertrophy is usually 
the response to some abnormal strain, as in the case of the great thickening 
of the heart wall when its function is made difficult by obstruction or by 
whatever causes heightening of the blood-pressure. In all these cases it 
seems to be a work hypertrophy. No sharp distinction should be drawn be- 
tween hypertrophy and hyperplasia, because the same causes, usually the 
demand for extra work, give rise to the enlargement of organs through 
the increase in the number of their constituent cells. The distinction is a 
futile one at any rate, since, as a rule, both are involved. A compensatory 
enlargement of the kidney when the other is destroyed is due to an enlarge- 
ment of the tubules and glomeruli, but that is only possible through an in- 
crease in the number of lining cells. 
Numerous instances will be given later in which the destruction or dis- 
abling of portions of the tissue of organs is followed by a new formation of 
equivalent tissue somewhere else in the organ. This is compensatory 
hyperplasia; it is also regeneration. The organ in a broad sense under- 
goes, as far as its units go, a compensatory hypertrophy, and becomes once 
more able to perform its full function. It is seen from this that the terms 
must continue to be used rather loosely, and it must be realized that in at- 
tempting to understand the processes themselves we are brought face to 
face with the problems of the causation of tissue growth in general. 
Whether other impulses than the demand for functional activity can initi- 
ate growth is still unknown. The long-standing dispute between the fol- 
lowers of Weigert, who declared that the new formation of tissue might 
occur only when injury or the production of some defect had disturbed the 
normal equilibrium, and those who maintained that external stimuli of the 
most various sorts could occasion new growth of tissue, still persists. In 
practically every case arguments can be brought to prove one side or the 
other, and, indeed, it seems that it is chiefly owing to our lack of precision in 
defining the nature of the stimuli that we find difficulty in arriving at a con- 
clusion. To say that disturbance of equilibrium is a cause of new growth 
is to employ a vague expression which may indicate a condition many 
steps removed from that which is actually at work. So, too, the analysis 
of the action of chemical or physical stimuli is generally incomplete and 
stops far short of the point at which they actually influence the cell. When, 
for example, we say that an extensive haemorrhage stirs the bone-marrow 
cells to reproduction of red corpuscles, it is easy to say that equilibrium be- 
tween the blood and blood-forming tissue is disturbed, but it is quite as 
possible that chemical substances formed somewhere because of inadequate 
transportation of oxygen or disturbances in the relation of acids and bases 
from incomplete removal of carbon dioxide directly affect the bone-marrow 
and stimulate it to new formation of cells. CHAPTER VI 
DISTURBANCES OF FAT METABOLISM 
Neutral fats and lipoids. Their source, absorption, distribution, and functions. Patho- 
logical disturbances. 
If we attempt to discuss the disturbances of metabolism in their relation 
to pathology, we must remember that the methods of pathological anatomy 
which show alterations in the tissues consisting of destructive changes of 
the cell structure, on the one hand, and accumulation of the materials 
concerned in metabolism, on the other, must give us only the most in- 
complete and even misleading idea of what is taking place. Many of the 
protein or albuminous materials are in solution and invisible, and even when 
we make them visible by coagulation, it is impossible to recognize them 
definitely. The same thing is true of the carbohydrates, since glycogen 
is the only form that we can demonstrate histologically. Sometimes we 
can see fats and lipoid substances, but rarely when they are in the form in 
which they take part in the actual function of the cell-rather it is when 
they are stored and inactive, or when they are thrown out of the current 
of the life of the cell as stagnant material, that they can be seen. Indeed, 
we are doubtless wrong even in trying to consider proteins, fats, and car- 
bohydrates separately, for in their relation to the processes of life they 
seem to combine into the really important substances with which we are 
only indirectly acquainted. Fat we know as it appears in adipose tissue 
or in globules in other cells, but fat in what may be a lipoid proteid com- 
bination as it exists invisible in the cell and recoverable from it only after 
the cell is reduced to debris by digestion, we scarcely know, although it is 
probably in that form that it is most important. 
It seems that in these combinations, varied as they are, we may find 
the agents of many of the extraordinarily efficient chemical processes that 
go on in the body. This should be the ground for discussion in pathology. 
It should form one of the principal chapters, if we only knew enough to 
bring it into the field; on the other hand, it seems hardly worth while to 
describe in detail the various places where abnormal accumulations of some 
of the inert separated constituents of these specialized expert bodies are 
laid up so that we can see them. 
If we could do more than guess at the nature of most of the disturbances 
that wreck the machinery and heap up the raw material or the slag, it 
would be something, but even that is commonly obscure. Nevertheless, 
we must tell what we can with our surmises about the true inwardness of 
the actions which have left these traces. 
Of all these substances, as long as we have been in the habit of separating 
them into three great classes it has been the custom to regard the proteins 
72 FATS AND LIPOID SUBSTANCES 
73 
as the most important, the real basis of life, the substance of protoplasm, 
while the fats and lipoids or fat-like materials were looked upon as fuel and 
as useful in other vaguely understood ways, possibly as insulating materials 
in the nervous system or even as padding underneath the skin to keep the 
body warm. Carbohydrates seemed essentially fuel for rapid burning; 
now, however, in Ivar Bang's phrase, the lipoids are beginning to be recog- 
nized as actors of extreme importance, with roles of unsuspected delicacy 
and complexity. Even yet the carbohydrates have not met with what 
may be a deserved recognition, but it is becoming clearer that it is the 
ensemble action, and not the part played by the isolated fragments, 
which we salt out or extract with ether, that brings about the wonders of 
life. 
FATS AND LIPOID SUBSTANCES 
The fat-like bodies soluble in organic solvents, such as ether, alcohol, chloroform, or 
benzol, are defined by Bang as lipoids. It is perhaps common, however, to speak of the 
neutral fats as fats, and of the rest as lipoids, since that must have been the origin of the 
word. 
Of this great group there are almost innumerable examples, and the series may per- 
haps be extended to forms as yet unsuspected, but in human physiology and pathology 
comparatively few concern us. 
These are as follows, according to Bang: 
1. Fats-lipoids of the aliphatic series containing only C, H, and O, without N or 
P. 
2. Cholesterines-lipoids of the aromatic series containing only C, H, and O, 
without N or P. 
3. Phosphatides-lipoids containing N and P in addition to C, H, and O. 
4. Cerebrosides-lipoids containing N but not P, together with C, H, and O. 
5. Other important but little understood lipoid substances, which include the 
lipochromes. 
The details of what is known chemically of these substances must be read in such works 
as those of Leathes, Bang, Jolies, and others, and only the barest outline can be given 
here. 
Fats.-These, which form the great bulk of the subcutaneous and other depot fat, 
are esters of glycerin with fatty acids. For the most part those which occur in the animal 
body are triglycerides of stearic, palmitic, and oleic acids, but in certain secretions, 
as in milk, butyric, caproic, and other fatty acids occur. 
A typical formula is as follows: 
CH2-O-OC-C17H33 
CH -O-OC-C17H33 
I 
CH2-O-OC-C17H33 
which is triolein. 
The difference in their melting-points and other characters, and in the proportions in 
which they occur in the fat of different animals, are all well known, and one realizes that 
if sheep-fat is more solid at room temperature than human or dog fat, it is because it 
contains more tristearin and tripalmitin and less triolein. 
Such fats may be saponified or broken up by the action of alkalies into glycerol and 
soaps, or combinations of the alkalies with the fatty acids. In another way they may 
be separated into their constituents, glycerol and fatty acid, by the action of a ferment 
(lipase), and this action is reversible. 74 
TEXT-BOOK OF PATHOLOGY 
The cholesterines occur in wide distribution throughout the body as constant con- 
stituents of the cells and body fluid, either free or in combination with fatty acids (cho- 
lesterine esters), often in solution, but sometimes, as in the adrenal cortex, in the form of 
globules. Crystals of free cholesterine are found under pathological conditions. The 
formula for the cholesterine found in the human body is given as C27H46O. It is a com- 
plex terpene, bearing no relation to fats, carbohydrates, or proteins, but consisting 
probably of a saturated cyclic system with the character of a secondary alcohol, since it 
can form ketones, and also with fatty acids, esters. It crystallizes in flat, rhombic 
plates which often show broken or reentrant angles. 
The phosphatides are of the very greatest biological importance, and enter extensively 
into the structure and function of many organs. They fall into the following groups 
(Bang, Thudichum, Aschoff): 
1. Monoaminomonophosphatides (lecithines, kephaline) (glycerophosphoric acid 
esters of two fatty acids and choline). 
2. Monoaminodiphosphatides (cuorine, etc.). 
3. Triaminodiphosphatides (sahidine, etc.). 
All of these contain unsaturated acids. Of the phosphatides containing saturated fatty 
acids we have: 
4. Diaminomonophosphatides (sphingomyeline, etc.). 
5. Triaminomonophosphatides. 
Of these substances, the knowledge is essentially vague, since practically none of them 
can be obtained in a pure state, partly on account of their labile character. The best 
known are probably the lecithines and kephalines, although they too are enveloped in a 
haze of uncertainty, and one cannot say whether these fragile substances which are 
strained out of the brain and other organs ever existed there in the form in which they 
come to light. 
Lecithine, which forms sticky, waxy white or orange masses, is given the formula: 
OH 
I 
CH2O-PO-O-C2H4x 
CH2OR 
That is a glycerophosphoric acid ester of two fatty acid radicles (one of which is unsat- 
urated) in combination with choline. It is soluble in alcohol and other lipoid solvents 
except cold acetone; it unites with acids and bases, with carbohydrates and with pro- 
teins (vitelline, lecithoalbumin). 
Kephaline is a resin-like, crumbling, hygroscopic substance, soluble in ether, etc., but 
not in alcohol or acetone. It is the chief phosphatide of the brain, and is otherwise 
widely distributed. Bang gives the following probable constitution: 
OH 
CH2O-PO-O-C2H4 
CH O-Ci8H36O CH3-N 
CH2O-Ci3H3iO OH^ 
which is a glycerophosphoric ester of stearic and linoleic acids with a monomethyl- 
choline. 
The Cerebrosides.-These are glucosides, and being disintegrated, yield a sugar, galac- 
tose, fatty acids, and a nitrogenous substance, but no phosphoric acid. They occur in 
the white substance of the brain, the blood, spermatozoa, etc. The most important 
are perhaps the phrenosin and kerasin of Thudichum. SOURCE, ABSORPTION, TRANSFORMATION, DEPOSITION OF FATS 
75 
The other little understood lipoid substances, which include the pigmented fatty 
granules found in wasting cells (lipochromes), and probably various substances con- 
cerned in immunity, remain to be investigated. 
It has been said that these substances are sometimes recognizable as 
such (neutral fats, cholesterine esters, etc.), but most of them are extracted 
from the organs by the aid of various solvents, and freed from impurities 
by different chemical manoeuvres. It is, therefore, hard to feel sure that 
in the living organs they exist in the form in which they are finally studied 
and not rather in some easily disturbed combination with proteins or other 
substances. Some of them are readily dissolved out of the cells, in which 
they can be seen as globules of pure fat; others appear to be loosely ad- 
herent or adsorbed in fine, invisible layers about other substances in the 
cells. They can be extracted too without great difficulty, although they 
cannot be seen with the microscope in the cell. Still others are so firmly 
held that they seem to be in chemical combination with the materials of 
the cell, and these, naturally invisible in the cell, can be extracted only 
after the tissue is digested or hydrolyzed so that its chemical compounds 
are disintegrated. That there is constant change in their relations is in- 
dicated by the way in which the simpler fats undergo lipolytic decomposi- 
tion into glycerin and fatty acids, followed by the formation of soaps, 
their decomposition, and the reconstruction of fats. 
As Aschoff says, the pathological anatomist is most interested in determin- 
ing in what form these lipoid substances become morphologically visible, and 
by what means their specific composition can be recognized. The chemist, on 
the contrary, must be content with analyzing the lipoids which remain to him 
after his tortuous methods of extraction, separated thus by a gulf from their 
original relations, and perhaps even entirely changed in their characters. 
It is the biologist who must try to combine these two sets of information 
and attempt to learn the functional role which the lipoids play in the body. 
The anatomist applies with success certain methods to the study of fats 
in the tissues. There are stains which color all lipoids, such as Sudan, 
others which stain neutral fats red, phosphatides blue, such as Nile-blue 
sulphate; osmic acid is blackened by fats of unsaturated acids; cholesterine 
esters are doubly refractive. Phosphatides and soaps form bizarre myeline 
figures, and so on. Great ingenuity has been applied to the recognition 
and distinction of fatty bodies by these methods (which must be read in the 
works of Aschoff, Kawamura, Verse, and others), but they are still very 
imperfect and unreliable, except in the simplest situations. 
SOURCE, ABSORPTION, TRANSFORMATION, AND DEPOSITION OF FATS 
Since similar substances occur in the tissues of other animals, it is probable 
that a great source of the fats in the human body is to be found in animal 
food. Some are derived from vegetable foods, and others are produced in 
the body from carbohydrates, and since carbohydrates can be formed 
from the decomposition products (amino-acids) of proteins, no doubt fats 
.are thus indirectly derived from proteins. Cholesterine comes to us in 76 
TEXT-BOOK OF PATHOLOGY 
animal food-how it is produced in the bodies of herbivorous animals is 
not perfectly clear, but it probably arises from the phytosterines which are 
found in plants. 
Taken into the intestine, the absorption of fats occurs by the action of 
lipolytic ferments, which produce glycerin and soluble soaps, which are 
reconstituted into fats in the intestinal wall, or by direct passage of un- 
changed fats, perhaps with the aid of the bile. Whether in the reconstitu- 
tion in the intestinal wall the foreign fats are remoulded into human fats 
is uncertain. Undoubtedly, some foreign fats go through unchanged to 
the tissues, but since the fats of animals are characteristic, the remoulding 
must take place somewhere, possibly in the course of numerous decomposi- 
tions and reconstitutions which accompany the wanderings of fat in the 
body. How cholesterine and its esters enter is not investigated. Choles- 
terine fed to rabbits is lodged in the tissues largely in the form of choles- 
terine esters, and a great deal of work has been done upon the distribution 
of such esters. They are stored in the cortex of the adrenal, the corpus 
luteum, etc., and are found abundantly present in the endothelial cells of 
the spleen, liver, etc. Aschoff and Landau assume that there is thus a 
"reticulo-endothelial apparatus" controlling their intermediary metab- 
olism. The advent and transformation of phosphatides and cerebrosides 
are even more obscure. 
Distribution in the Body.-Neutral fats are, as every one knows, lodged, 
sometimes in enormous quantities, in what are roughly known as fat de- 
pots, among which the subcutaneous and intermuscular tissues, the bone- 
marrow, the mesentery, omentum, and retroperitoneal tissues, the epi- 
cardium, the tissue about the kidneys, and the tissues of the orbit furnish 
examples. In very obese persons the fat, after filling these places to their 
utmost, seems to overflow into the most unexpected localities-adipose 
tissue extends through the wall of the heart and appears under the endo- 
cardium; it pushes apart the lobules of the pancreas, and even spreads 
round to the free surface of the intestines. In every case the fat is inclosed 
in cells. In the infant one may readily observe that the adipose tissue 
falls into lobules which are easily separated. These are seen to be sharply 
outlined, gland-like structures, provided with an extremely rich capillary 
circulation, and composed of polygonal cells with very granular protoplasm 
which contains only the beginnings of the accumulation of oil-globules 
which will ultimately distend them (Fig. 30). Such lobules are quite dis- 
tinct from the surrounding loose connective tissue, which contains no fat, 
and are very conspicuous in any section which passes through adrenal or 
thyroid since a comparison with those glands is at once suggested. They 
have even been described by Pende as organs of internal secretion, and 
perhaps the specificity of the adipose tissue is almost sufficient to justify 
him in such an idea. In later life they disappear because so much fat 
gathers in their cells that the protoplasm becomes a mere film about the 
great oil-globule-the separate lobules of this tissue swell until they touch SOURCE, ABSORPTION, TRANSFORMATION, DEPOSITION OF FATS 
77 
one another, the intervening fibrous tissue is lost to view, and we seem 
to have a homogeneous adipose tissue. 
It would be interesting to be able to show that all adipose tissue is of this 
nature, but probably in obesity fat accumulates in other connective-tissue 
cells which have no specific relation to its metabolism. 
Cramer recognizes as brown fat certain lobules of adipose tissue, espe- 
cially readily seen in rodents, which contain a preponderant amount of 
lipoid materials as contrasted with the ordinary neutral fats. These he 
Fig. 30.-Adipose tissue of foetus. Lobule of specialized connective tissue in which 
fat accumulates. 
thinks have a more specific importance than the general adipose tissue 
and retain their fat when in hunger the neutral fats waste. 
Neutral fat occurs in the blood plasma and in the lymph and chyle, and 
thus indicates the mode of transport from one part of the body to another, 
and from the digestive tract to the tissues. It is found in the cells of many 
parenchymatous organs, such as the liver, adrenals, and others, where it 
may be merely stored, or where its presence may be explained in other 
ways which will be discussed later. 78 
TEXT-BOOK OF PATHOLOGY 
There seems to be little evidence to show that such neutral fats, aside 
from being foods and the source of energy, play any very complex part in 
the life of the cell. On the contrary, although we do not know exactly 
how they are distributed in the tissues, we cannot escape the impression 
that the phosphatides, the cholesterine compounds, and cerebrosides are 
absolutely essential elements in most of the important functions of the 
cells. Each new investigation reveals their silent and unsuspected par- 
ticipation in the most fundamental processes. 
It is known that even when the microscope, aided by the most effective 
staining methods, reveals no trace of fat in the tissues, a large quantity 
can be extracted by chemical methods. A perfectly normal human kidney 
which shows no recognizable fat yields 10 to 20 per cent, of its weight upon 
digestion and extraction. This fat must have been in some extremely 
fine state of division, or else in chemical combination, such that it failed to 
give the usual staining reactions. 
None of the hypotheses about this disposition of lipoids in the cell has 
up to now been satisfactorily proved, and they are the subject of much 
dispute. It is Overton's idea that each cell is bounded by a very thin 
lipoid membrane which controls the entrance and exit of the substances 
which reach the cell. According to this idea, drugs like narcotics, which 
are usually soluble in fats, gain easy access to the cell, although it does not 
appear quite easy to understand how these substances leave the lipoid 
membrane to enter the watery cell-body. On the other hand, the passage 
of salts in and out becomes difficult, and the theory is forced to resort to 
the vital activity of the cell to explain these things. Nevertheless, the idea 
of a lipoid enveloping membrane for cell and nucleus is very generally held. 
Within the cell similar lipoid membranes are supposed to line vacuoles 
and perhaps to cover some of the specific granules-at any rate, there 
is much to show that the fine globules of fat which appear in the cell pro- 
toplasm do so in relation with mitochondria, or, as Benda claims, rather 
with the vegetative granules, the plasmosomes. These granules accumu- 
lating fat about them finally take on the form of globules. But even with 
these explanations it is evident that there must be much lipoid material 
in the cell in an invisible form. 
FUNCTIONS OF FATS AND LIPOIDS 
The most obvious and best known function of the fats lies in their acting 
as food-stuffs. In their oxidation to set free energy in the form of heat or 
work, they require more oxygen than do carbohydrates, so that the res- 
CO 
piratory quotient or ratio, is about .795. They form, of course, since 
they can be conveniently stored, the ideal material for the accumulation of 
a source of energy. Nevertheless, we must suppose that they also take 
part in aiding the growth of the tissues through furnishing material for 
their constructive processes. 
If it be true that they form lipoid membranes about each cell, each nu- FUNCTIONS OF FATS AND LIPOIDS 
79 
cleus, and each vacuole, it must be agreed that they are primarily instru- 
mental in regulating the assimilation of the cell and in permitting it to 
control in a way the substances which present themselves for absorption. 
The part played by lipoid substances, especially the phosphatides and 
cerebrosides, in the construction of the nervous system, must be of prime 
importance, although we approach its contemplation so awkwardly by 
extracting them from the ground-up brain. From their arrangement in 
the myeline sheaths of the nerve-fibres it would appear that they may act 
as insulating substances which insure the passage of the nervous impulse 
to the correct end-organ; in other words, that they serve a purpose analo- 
gous to that of the rubber and shellac in a complex electric cable, or even 
in the brain, to that of the more elaborate insulation in the interior of 
the dynamo. 
In their relation to enzyme action the neutral fats are played upon by 
lipases which occur everywhere in the organs and fluids of the body, as 
well as in the digestive juices. Anti-lipases which inhibit this reversible 
action exist also. The lipases which must exist to control the decomposi- 
tion of cholesterine esters and of the phosphatides (lecithinase, choles- 
terase, etc.) are not yet even certainly demonstrated. Bang objects that 
experiments carried out to show that such lipoid substances may influence 
the action of other ferments are inconclusive, but Jobling has shown that 
the decomposition products of some fats-unsaturated fatty acids and 
their soaps-have the most decisive inhibiting action upon proteolytic 
ferments, their power being in a sense proportional to the degree of un- 
saturation of the fatty acid. So universally is it true that such unsatu- 
rated fatty acids can impede the action of proteolytic ferments that many 
pathological conditions (such as the persistence of caseous tuberculous 
material in its solid form) can be shown to be due to their presence. If 
they are rendered impotent by saturation of their unsaturated group with 
iodine, the proteolysis goes on rapidly and the caseous tubercle or gumma 
rapidly softens. 
In the complex process which occurs in the clotting of blood Howell 
has shown that the thromboplastic substance derived from the tissue is a 
lipoid, kephaline. It has been shown that certain lipoid substances, 
especially cholesterine, can act as inhibiting or neutralizing agents toward 
such haemolytic poisons as saponin, cobra poison, etc., through forming 
with them an innocuous compound. Hanes showed that the relative 
immunity of puppies from chloroform poisoning is due to the large amount 
of cholesterin esters in their tissues. When artificially introduced into the 
tissues of adult animals a similar protection is conferred. By some (Takaki) 
it was thought that lipoids of the nervous system, phrenosin, cerebron, etc., 
could neutralize the tetanus toxin, but this is contradicted by others and 
is uncertain. In the so-called "Wassermann reaction" lipoid substances 
act in a somewhat similar way to combine with or absorb the complement 
and withdraw it from combination with the blood-corpuscles. 
Our knowledge in this direction is very slight; nevertheless it is enough 80 
TEXT-BOOK OF PATHOLOGY 
to suggest the possibility that lipoid substances may sometimes accumulate 
in an organ for the protection of the cells of that organ from toxic injury. 
On the other hand, lipoids may act as toxic substances or as activators of 
toxins. Of these, the toxic ones are foreign lipoids, such as may be ex- 
tracted from bacteria. The fats from the tubercle bacillus may produce 
lesions somewhat resembling those caused by the organisms themselves. 
It is in connection with haemolytic poisons, such as cobra venom, that 
lipoids (lecithin) are found to behave as activators. Regarded at first as 
representing the complement according to Ehrlich's theory (Kyes), it now 
seems more probable that the lipoids may aid in transferring the poison to 
the cell, since the "lecithid" is apparently only a solution of the venom in 
lecithin (Bang). The direct production of immunity against lipoid sub- 
stances used as antigens has given some vague results, but the matter still 
remains to be investigated. 
Undoubtedly the lipoids fill an important position in many ways, in re- 
lation to the processes of immunity, but for the further discussion of the 
matter reference must be made to works upon that subject (Jobling). 
Cholesterine compounds are known to exist in the circulating blood and 
in the adrenal cortex, as well as in other tissues. What must be a significant 
index of their importance is found in the course of pregnancy, when there 
comes a gradual but great increase in the quantity found in the blood, a 
great storing in the corpora lutea, and, with the end of pregnancy and be- 
ginning of lactation, an outpouring of cholesterine esters with the first 
milk. After that the proportion decreases in the milk, and in the blood 
sinks back to normal. Why this should be is not known, but the flooding 
with cholesterine esters seems to have a protective influence of some kind, 
since under those circumstances animals will survive the loss of the adrenal 
gland far longer than non-pregnant controls, and, indeed, the injection of 
cholesterine esters seems to have the same influence (Stewart). 
So far we have attempted to review the normal relations of the lipoid sub- 
stances in the body, and finding our knowledge so woefully incomplete 
there, we turn not very hopefully to their study under pathological con- 
ditions. 
Obesity.-From what was said of the normal use of fats as food we may 
judge that a certain balance is maintained in the storehouse of the body. 
Nevertheless, the consumption of a great excess, especially an excess of 
fats and oils and of carbohydrates, tends, in persons who lead an inactive, 
sedentary life, to cause the accumulation of excessive fat in all possible 
depots in the body. Even the secreting cells of parenchymatous organs, 
such as the liver, become somewhat richer in fat than normal, although it 
is by no means in obese people that one finds the great collection of fat in 
the liver-cells. The storing-up of fat can be prevented and the fat made 
to disappear by active exercise, massage, etc., or even by hot baths, which 
seem to hasten its consumption. But every one has noticed that the 
PATHOLOGICAL DISTURBANCES OF FAT PATHOLOGICAL DISTURBANCES OF FAT 
81 
obesity which comes from mere sedentary habits and overeating; is in most 
persons a mild kind of disability; other people, even with the greatest 
abuse of these things, remain quite thin, while there are certain unfortu- 
nates who, in spite of efforts to limit their diet strictly and to take abundant 
exercise, grow enormously fat. It seems possible that in these cases there 
may exist some defect in such organs of internal secretion as the thyroid 
or the hypophysis, whose secretion appears to enhance the activity of 
metabolism in general. In known cases of hypophysis defect in young 
persons great obesity arises with retardation of sexual development, and in 
cases in which the thyroid has been destroyed a similar, if less extreme, 
obesity may arise. 
Diabetes.-In pancreatic diabetes another disturbance of internal 
secretion in which the consumption of carbohydrates is made difficult, an 
abnormally violent attack is made upon the fats, which are turned into the 
blood-stream for transportation in such a way as to give the serum a milky 
appearance (diabetic lipaemia). The irregular consumption of these fats 
leads to the production of the poisonous acetone bodies. (See Diabetes.) 
Degeneration of Nerves.-It has been pointed out that lipoid bodies 
form the coatings of nerve-fibres, as though to insulate the axis-cylinders 
within these myeline sheaths. When the nerve dies through being cut 
through or from the destruction of its cell-body, the lipoids of the myeline 
sheath about the dead axis-cylinder disintegrate, leaving globules of the 
decomposition products which now blacken with osmic acid in a way foreign 
to the myeline itself (Figs. 31A and 31B). Saponine attacks and combines 
with the lipoid sheath of the nerve and causes paralysis. Many other sub- 
stances, most of which have certain affinities for lipoid materials, cause in- 
juries to the nerves, followed by inflammation or by paralysis. Lead palsy, 
arsenical and alcoholic neuritis, the neuritis occurring in the intoxication 
associated with pregnancy and in diabetes, are examples of this vague con- 
nection. Beriberi, a form of multiple neuritis, is supposed to result from 
the lack of a lipoid constituent belonging to the covering of the rice grain, 
since it occurs in persons fed on polished rice. This is not yet satisfactorily 
proven, but all these things point to the possibility of a common character 
in the affection of nerves due to disturbances in their medullary sheaths. 
Anaemias.-The same vagueness and uncertainty prevail with regard to 
the part played by the lipoids in the production of some forms of anaemia. 
Faust and Tallquist thought that the pernicious type of anaemia caused by 
the bothriocephalus was due to a lipoid which they later stated to be oleic 
acid, but this is scarcely probable. On the other hand, many of the toxic 
materials which produce anaemia, such as benzole, are solvents of lipoids or 
soluble in them, and it may be through this relation that the lipoid constitu- 
ents of the red cells are attacked. The whole question of haemolysis has 
intimate dependence upon the lipoid content of the cells. 
Abnormal Accumulations of Fats and Lipoids in Organ Cells.-One type 
of evidence as to the role of the lipoids in pathological conditions which has 
scarcely been touched upon is found in the anatomical recognition of ab- 82 
TEXT-BOOK OF PATHOLOGY 
normal accumulations of these bodies in the cells of the organs. This, 
which has always formed the chief interest of pathological anatomists, is, 
after all, at most only an indication of the disability or injury of those cells, 
and has relatively little bearing upon those functions of the lipoids which 
are beginning to show themselves as of fundamental importance. 
Both neutral fats and globules or granules of other lipoids, especially the 
Fig. 31A.-Normal nerve. Osmic acid (Marchi) tinges the myeline sheaths gray 
Fig. 3IB.-Degenerated nerve (Marchi). Lipoid medullary sheath reduced to fat-like 
globules which stain black with osmic acid. 
cholesterine esters, and probably also the phosphatides, may appear in ab- 
normal situations. Since they are normally present in some organs, we 
recognize their abnormal character by their unwonted situation or some- 
times by their quantity. 
The source of these fats has long been the subject of dispute, the main PATHOLOGICAL DISTURBANCES OF FAT 
83 
question being whether they are derived from the substance of the cell in 
which they are found, or transported th'ther from some depot of fat or 
other source. This problem has lost much of its interest, since we have 
learned that much of the fat is transported, while some is made visible (fat 
phanerosis) by being liberated from its invisible combinations in the cell. 
The old question as to the production of the fat-globules at the expense of 
the protoplasm of the cell is now hardly discussed in that form. 
A few examples of such fat accumulation may be mentioned before con- 
sidering further the nature of the process. 
In the heart one may find, in cases of long-standing anaemia, or chronic 
infection, or intoxication, or in dis- 
turbances of the coronary circula- 
tion, especially in the inner layers 
of its muscle, a yellowish pallor 
which, on close inspection, is found 
to be due to innumerable minute 
streaks and patches of opaque yel- 
low which shine through the endo- 
cardium and give the checkered ap- 
pearance which has long been called 
tigering or the faded-leaf appearance 
(Fig. 32). Ribbert thinks that the 
patches correspond with minute ir- 
regularities in the distribution of the 
capillary blood supply, and that 
local anaemia produces them. Mi- 
croscopically it is found that the 
yellow patches show heart muscle- 
fibres in which myriads of minute 
globules, ranged in transverse and 
longitudinal rows, lie in the sarco- 
plasmic discs (Fig. 33). 
In the liver, where there is nor- 
mally some fat in the cells, various 
conditions can arise. The whole or- 
gan may be enormously enlarged, yel- 
lowish white, with swollen round edges, and on section greasy to the touch, 
rigid, and inelastic. In such a liver almost every cell is found stretched with 
one or more globules of fat, so that the nucleus is flattened to one side and 
only a thin film of protoplasm remains. In others fat is found about the 
efferent vein, in the middle zone, or about the portal veins, but not with 
such sharp consistency that one can well associate these forms of distribu- 
tion with different aetiological factors. Whenever there is a destructive 
lesion of the liver-cell, as in chronic passive congestion or focal necrosis 
involving part of each lobule, fat generally accumulates in the cells just 
Fig. 32.-Fatty heart, showing mottling 
of myocardium. 84 
TEXT-BOOK OF PATHOLOGY 
adjacent to the injured cell, and therefore usually between them and the 
portal vein radicle. Sometimes the fat is in large droplets, sometimes in 
small ones or granule-like particles. Probably these arise differently, but 
they can surely not be made the basis for declaring, as Virchow did, that 
the first indicate a physiological infiltration, the second a " fatty degenera- 
tion," in which the fat is produced at the expense of the cell-body. 
In the kidney fat-globules collect in the epithelium of the tubules, most 
often in the convoluted portions and in the glomerular epithelium, but 
Fig. 33.-Fatty heart muscle. Fat-globules in fibres stained with osmic acid. 
appearing also in the conducting tubules (c/. Fig. 19). They lie usually 
near the base of the epithelial cells at first, but later, when the quantity is 
greater, they may occupy most of the protoplasm. Such fat is sufficient 
to give a very opaque yellow color to the labyrinthine portions of the renal 
cortex, and in much scarred and distorted kidneys it is seen in patches where 
the tubular tissue is best preserved. 
In the aorta and smaller arteries which are the seat of arteriosclerotic 
processes fats accumulate in the intimal thickenings and give them their 
opaque yellow color. PATHOLOGICAL DISTURBANCES OF FAT 
85 
But it is impossible to refer to all the situations in which the cells may 
thus be the lodging-place of abnormal fats. Somewhat different in prin- 
ciple are those collections of fat which form in the living tissues around foci 
of necrosis in the brain, in which multitudes of phagocytic cells are found 
loaded with globules of fat derived from the disintegrating brain substance. 
These are analogous to the fat-laden zones of tissue about infarctions or 
abscesses or in the neighborhood of tuberculous lesions which have de- 
stroyed much tissue. The cells bordering upon a growing tumor are laden 
with fat, and so are those whose nutrition is affected in any other mechan- 
ical way by the cutting off of the blood supply. Even the malnutrition 
which comes in company with general anaemia, such as pernicious anaemia, 
brings with it extensive stagnation of fat in all the organs. 
Not all this fat is alike chemically or physically. Nearly always there 
are globules of neutral fats, but in the kidney the sclerotic plaques of the 
aorta, in the desquamated epithelial cells of the alveoli adjoining tubercu- 
lous lesions in the lungs, in the phagocytic cells about infarcts of the brain, 
and in a thousand other places, many of the globules have a different na- 
ture. They shine dully; under the polarizing microscope they show a 
brilliant outline; on heating they disappear; on cooling again they start 
back into view suddenly as brilliant, round, doubly refractive globules, 
showing a Maltese cross of light. These are cholesterine esters and have 
the characters of the my eline bodies described by Virchow (Adami). Cho- 
lesterine crystals are often associated with them, and probably various 
soaps, although these must be of a rather evanescent character. Whether 
combinations of phosphatides and cerebrosides occur in these places too, 
our present technical methods do not reveal clearly, but it seems inevitable 
that they should be there especially when the lesion affects nervous tissue. 
But without paying too much attention to that probability, Aschoff and 
others emphasize the occurrence of degenerative changes in the cells, 
accompanied by the lodgment of two distinct types of fatty substances, 
glycerin esters and cholesterine esters. 
What explanation can we offer for the accumulation of these fatty bodies 
in the cells? Briefly, the results of the long discussion are about as fol- 
lows: Virchow's idea that the fat might reach the cell from elsewhere and 
appear there as an infiltration in the case of normal cells, or be produced at 
the expense of the protoplasm, when it was to be spoken of as a fatty de- 
generation, held sway for long years. These two types were distinguished 
by the large size of the globules of fat in the infiltration, their very small 
size in degeneration. But Rosenfeld showed, in a long series of investiga- 
tions, that the cells of the liver received fat from distant depots when the 
animal was poisoned with phosphorus. He starved dogs and then fed 
them on mutton fat until it was stored in quantities in their subcutaneous 
tissues-phosphorus poisoning then loaded the liver with mutton fat. If 
the dog was so starved as to have no subcutaneous fat, none appeared in 
the liver after phosphorus. It seemed to Rosenfeld that all the fat came 86 
TEXT-BOOK OF PATHOLOGY 
from outside. But an organ with abundant fat-globules in the cells need 
contain no more fat on chemical analysis than one which shows none mi- 
croscopically-the production of a fatty degeneration need not increase the 
total quantity of fat in the organ. Beside the fats found, there are often 
cholesterine esters which are not to be obtained from the subcutaneous 
tissue, although they may well be transported from other sources, such 
as the adrenal, where they have been stored. 
In view of these and other facts the following explanations of the appear- 
ance of fat in the tissue-cell seem possible: 
1. An excess of fat may be brought to the normal cell. 
2. A normal amount of fat may be brought to a cell which is injured, and 
therefore incapable of using up its fat with normal rapidity. Such injury 
may or may not be anatomically obvious. Impaired circulation, impaired 
oxygen supply from general anaemia, or toxic injury to the cell in the course 
of infection are among the causes which might give occasion for the con- 
dition. Fat would accumulate because it was not properly consumed. 
3. Injury of many types might disintegrate the physical or chemical 
combinations of lipoids which are known to exist in invisible form in the 
cells, and thus make the lipoids visible as such in the cell-body (fat phanero- 
sis). 
4. Tissues in the neighborhood of areas of cell destruction may absorb 
or engulf by phagocytic activity the fats set free from those disintegrating 
tissues, as in the case of an infarct of the brain or other organ. 
That fats are redistributed in the body in cases of infection and intoxica- 
tion is shown not only by the demonstration of the fats in transit in the 
blood, but by the enormous accumulation of fat in the liver in certain cases 
in which the rest of the body is greatly emaciated. 
LITERATURE 
Anitschkow: Ziegler's Beitrage, 1913, Ivi, 379; 1914, Ivii, 201. 
Aschoff: Ziegler's Beitrage, 1910, xlvii, 1. 
Bang, Ivar: Ergebn. d. innere Med., 1909, iii, 447. Chemie u. Biochemie der Lipoide 
Wiesbaden, 1911. XVII. Internal. Cong, of Med., London, 1913, Sect. Ill, i, 151 
Kraus, Ribbert, Albrecht, Rosenfeld: Verh. Dtsch. Path. Gesellsch., 1904, vi, 37-73. 
Kawamura: Cholesterinesterverfettung, Jena, 1911. 
Leathes: The Fats, Monographs on Biochemistry, 1910. 
Lubarsch: Ergebn. d. allg. Path., 1897, iiii, 631. 
Leathes and Bang review the whole chemistry and metabolism of fats. Kraus, Ribbert, 
and others review its pathological aspects, and the paper of Aschoff is especially use- 
ful. Anitschkow and his pupils are especially concerned with the part played by 
cholesterin in pathological conditions. CHAPTER VII 
DISTURBANCES OF PROTEIN AND CARBOHYDRATE METAB- 
OLISM 
General character of protein metabolism. The purine bodies. Gout. Cloudy swelling. 
Hyaline metamorphosis. Amyloid infiltration. Carbohydrate metabolism. Glycogen. 
Protein Metabolism.--It is somewhat surprising, in view of the great im- 
portance of protein materials in the constitution of the body and in the 
composition of our food, to find ourselves able to say so little with regard to 
the pathological anatomy of alterations of the metabolism of these sub- 
stances. 
Doubtless it is altogether the result of our inability to see or make recog- 
nizable the abnormalities that may arise. We cannot tell, as we can in the 
case of fats and carbohydrates, whether a tissue is loaded with an excess of 
protein material. Indeed, we know rather little about the relation of 
labile or food protein to tissue protein. But one may recognize the ab- 
normal loss of protein in the urine in renal disease, the passage of albumoses 
into the urine in disease of the bones (myeloma, etc.), and the occurrence 
of various amino-acids there when the liver has been extensively destroyed 
(leucine and tyrosine in acute yellow atrophy of the liver). Under other 
circumstances there occur cystinuria and alkaptonuria, both resulting from 
disturbances of protein metabolism, and producing, in the one case, urinary 
concretions of yellow crystals, in the other, a pigmentation of the cartilage. 
Disturbances in Purine Metabolism.-Variations occur also in the quan- 
tities of urea, uric acid, ammonia compounds, etc., in the urine, and these 
naturally have a direct relation to the protein metabolism. Nevertheless, 
it is rarely possible to gather any real clue as to the protein metabolism 
from their variations. The disproportion in this regard is seen especially 
well in the case of uric acid, a substance playing an important role in gout. 
From the variations in its reaction it would never be possible to diagnose 
gout, because even greater variations occur in a healthy person. 
GOUT 
This is a disease the cause of which is unknown. It may even be said that 
the essential nature of the disease is quite unknown, since the disturbance 
of a part of the protein metabolism, which is accompanied by striking symp- 
toms, is evidently only the effect of some underlying disarrangement of 
the machinery of intermediary metabolism, which is obscure. 
Profound alterations arise in the metabolism of the purine substances, 
such that uric acid, the common end-product of fermentative decomposi- 
tions and oxidations of these complex bodies, is retained in the tissues in 
the form of salts of soda and calcium, and lodges itself in cartilages and 
elsewhere, causing great pain to the sufferer. 
Chemistry of Purine Bodies.-The investigation of the chemical nature of the complex 
bodies which finally yield uric acid has been made by Kossel, Fischer, Brugsch and Schitt- 
87 88 
TEXT-BOOK OF PATHOLOGY 
enhelm, Burian, Jones, Levene, and others, and may be read in Jones' monograph 
(Nucleic Acids). 
It appears that compounds containing nitrogen and phosphorus, which have long been 
known as nucleins or nucleoproteins, can be extracted from the tissues, and in special 
abundance from those such as thymus, lymph-glands, or materials like pus or sperma- 
tozoa, in which cell nuclei form a large proportion of the mass. These names are 
being abandoned since it has been shown that they mean nothing definite, and that the 
characteristic constituent is a nucleic acid. It is from the nucleic acids that the peculiar 
and important alloxuric bodies are derived by the action of ferments. These, in so far 
as they interest us, are guanine, adenine, hypoxanthine, xanthine, and uric acid. All 
are chemical derivatives of purine. 
N = CH (6) 
(2) HC^ C - NHX 
J| /CH (8) 
N-C - N/ 
Representing the purine ring, with its three replaceable hydrogen atoms, by the abbre- 
/H (2) 
viated expression, P/H (6), the relation of the five purine compounds to one another is 
/fi (8) 
seen in the following diagram (Jones): 
/NH2 
P/OH 
\h 
Guanine 
(2-amino-6-oxy-purine) 
H 
P/NH2 
H 
Adenine 
(6-ami no-purine) 
/OH 
P/OH 
/oh 
Uric acid 
(2-6-8-trioxy-purine) 
/OH 
P/OH 
\H 
Xanthine 
(2-6-dioxy-purine) 
/H 
P/OH 
XH 
Hypoxanthine 
(6-oxy-purine) 
Uric acid can be formed from the amino-purine by deaminization and subsequent 
oxidation-from the oxypurines by oxidation. The deaminization is brought about by 
special ferments, guanase and adenase, which are distinct and vary greatly in their 
localization with animal species. The lack of guanase in the pig's tissue seems to be the 
explanation of the deposition of guanine which sometimes occurs there (guanine gout). 
As a brief indication of what precedes this, the following may be quoted from Jones' 
monograph: 
Thymus nucleic acid, according to Levene, is a combination of four mononucleotides, 
each of which is a nucleoside united with phosphoric acid. Hexose, joined to the nitro- 
genous ring compound or purine group, is a nucleoside. From this point of view the 
nucleic acid is a tetranucleoside, made up of four mononucleotides. Levene and Jacobs 
give the following formula for animal nucleic acid: 
HO\ 
O=PO-C6Hio04-C6H4N6O 
I 
O Guanine group 
HO\ | 
O=PO-C6H8O2-C5H5N2O2 
ho/ 
O Thymine group 
HO\ | 
o/po-C6HsO2-c4h4n3o 
ho/ 
Cytosine group 
O^PO-C6H10O4-C6H4N5 
ho/ 
Adenine group GOUT 
89 
The disruption of this complex takes place by the action of two ferments, which first 
split the tetranucleotide into two dinucleotides, after which they in turn are split into 
mononucleotides. These ferments are phosphonuclease and purine nuclease. Levene 
and Medigreceanu find that nucleotidases split the nucleotides to nucleosides, which 
further separate into carbohydrate and purine base under the action of a nucleosidase. 
The liberation of the guanine and adenine is well in the line of uric-acid formation; 
the fate of the pyrimidine groups, thymine and cytosine, is still uncertain. Dr. Levene 
tells me that he has been unable to find an enzyme which will decompose the nucleoside 
in which they occur, and that since they cannot form uric acid, they are possibly excreted 
as urea or in other forms. Only 50 per cent, of the nucleic acid nitrogen can be counted 
on for the production of uric acid, namely, that in the guanine and adenine groups. 
The tissues of the lower animals contain a ferment, uricase, which can decompose 
uric acid, but no such ferment exists in human tissues, and uric acid is excreted as such. 
Uric acid is derived from the food or from the waste of the tissues. It occurs in the 
blood in small amounts, and is excreted in the urine in quantities up to one gram daily. 
The amount excreted is increased by the feeding of substances rich in nucleic acid. The 
solubilities of uric acid are interesting and important, since it has been stated by Gudzent 
that the monosodium urate exists in the blood in two forms-one, the easily soluble, 
unstable lactam form, the other the isomeric, stable, relatively insoluble lactim urate. 
The change from one of these forms to the other may, according to him, account for the 
precipitation of the urates in the tissues. More important seems the more recent work 
of Schade, who shows that uric acid or its salts may, through the influence of alkalies 
(hydrates), pass into a condition in which it is far more soluble than usual, and that, in 
reaching the crystalline form from this oversaturated solution, it passes through a colloid 
stage in which it is relatively stable. Materials which protect this colloid stage and 
antagonize precipitation occur, such as glycerin, urea, albumen of the serum, nucleic 
acids, etc. The application of this knowledge has not yet been made. 
Gout is a hereditary affection most common in men, often transmitted 
by women who have themselves shown no symptoms. It is common in 
those who overeat, and yet it occurs as well in the poor. It is often as- 
sociated with lead-poisoning, on which account a type, "saturnine gout," 
has been spoken of. Renal disease is a frequent but not constant accom- 
paniment or sequel, and some writers, thinking that the gout might depend 
on renal disease, have specified another form, "renal gout." But for these 
separate forms there is little good evidence. 
There seems to be an underlying hereditary tendency to develop the 
actual disease in these persons, although much may be done to ward off 
its appearance by careful avoidance of foods rich in purine. Whether it 
can be prevented in this way remains uncertain. Alcohol has always 
been thought an important cause of gout, although its actual influence is 
not clearly defined. 
Acute attacks are characteristic, with remissions in which the condition 
is fairly good. Chronic forms also occur in which acute attacks appear as 
exacerbations of the more continuous process. The acute attack begins 
with violent nocturnal pain in a joint, followed by fever and chills and 
evidences of inflammation in the joint. 
Before the attack the excretion of uric acid in the urine is diminished; 
during the attack it is much increased. It is clear from this that there is 
no real inability on the part of the kidneys to excrete uric acid. Between 
attacks it is about normal, although it may be diminished (Garrod). 90 
There is generally an increased amount of uric acid in the circulating 
blood, both in the intervals and during the attacks. The average amount 
in Pratt's cases was 3.7 mg. per 100 grams of blood contrasted with 1.7 mg. 
in the non-gouty cases studied by Adler and Ragle. 
Although Garrod and others held that the decreased excretion was due 
to the disability of the kidneys, Umber puts forward the more plausible 
suggestion that the uric acid is actively retained by the tissues. 
Anatomically, the most prominent feature of the disease is the extra- 
ordinary deposition of needle-shaped crystals of monosodium urate in the 
substance of the cartilages. Such opaque, white, chalky deposits are very 
conspicuous when an affected toe-joint or knee-joint is opened (Fig. 34); 
they lie a little beneath the free surface, and extend only about one-third 
of the way through the cartilage, rarely entering the bone. Microscopic- 
ally in sections of the joint, sheaves of these fine crystals are found em- 
TEXT-BOOK OF PATHOLOGY 
Fig. 34.-Knee-joint with white deposits of urates. Gout. 
bedded in the matrix of the cartilage, often surrounded by an area of hya- 
line, pink-staining altered cartilage. Ebstein thinks that necrosis of the 
cartilage is the necessary forerunner of their deposit, but in this he is not 
supported by the other writers, who feel that the changes in the cartilage 
may be secondary to the crystalline deposit. 
Besides the joint cartilages, the neighboring ligaments, tendons, and 
synovial membranes may occasionally be subjected to the precipitation. 
Olecranon, prepatellar, and other bursae are especially likely to be affected. 
Other sites are the edges of the cartilages of the ear, the eyelids, the larynx, 
the kidneys, especially the pyramidal portion, where masses of crystals 
may form in or between the tubules, and many other situations. But 
the cartilages of the joints, especially of the great toe, the fingers, and the 
knees, form the site of predilection. Such accumulations of crystals, when 
they become bulky, are called tophi, and in the course of chronic gout tophi GOUT 
91 
of great size may form in and about the joints, causing their great defor- 
mity and disability (Fig. 35). They become encapsulated, cause a persistent 
mild inflammation, and may sometimes, through stretching the skin to 
atrophy, break through and appear as chalky concretions exposed to the air. 
Digestive and nervous disturbances, arteriosclerosis with myocardial 
disease, and circulatory disabilities, chronic nephritis with scarring of the 
kidney are common accompaniments of the disease. The patients finally 
die from some intercurrent affection. 
From the present knowledge no clear idea of the underlying fault is to 
Fig. 35.-Gout. Uratic tophi about the finger-joints. 
be gained, but it seems as though it might be elucidated by further study of 
the ferments concerned in the production of uric acid and in the influences 
which modify the solubilities of that substance. It seems a mere evasion 
to say that it may perhaps be controlled by some organ of internal secretion. 
LITERATURE 
Ebstein: Gicht, Wiesbaden, 1906, II. Aufl. 
Jones: Nucleic Acids, Longmans, Green & Co., 1914. 
Levene and Jacobs: Jour. Biol. Chem., 1912, xii, 411. 
Magnus Levy: Harvey lectures, 1909-10, 251. 
Minkowski: "Gicht," Nothnagel's Handb., vii, 2. 
Schade: Zeitsch. f. phys. Chem., 1913, Ixxxiii, 347; Ixxxvi, 238. 
Umber: Ernahrung u. Stoffwechselkrankheiten, 1914, 335. 
Joel: Klinische Wochenschrift, 1923, ii, 2212. 
Garrod: Nature and Treatment of Gout and Rheumatic Gout, London, 1859. 
The student will find the lecture of Magnus Levy particularly useful. 92 
TEXT-BOOK OF PATHOLOGY 
CLOUDY SWELLING OR PARENCHYMATOUS DEGENERATION 
When the liver and kidneys and some other organs are inspected in the 
body of a person who has died of typhoid fever, pneumonia, diphtheria, 
or any one of many other acute infections or intoxications, they are com- 
monly found swollen, inelastic, or pasty, and on section very dull and 
opaque in appearance. It is often said that the liver looks as though it 
had been boiled. In frozen sections the epithelial cells are seen to be much 
enlarged and very granular. In the renal epithelium the free edge of the 
Fig. 36.-Cloudy swelling of epithelium of renal tubules. 
cell is ragged and irregular, projecting far out into the lining of the tubule- 
even far enough, sometimes, to meet the opposite cells and greatly narrow 
the cavity of the tubule (Fig. 36). The same appearance is found in the 
kidney if the work of both is suddenly put upon it by the removal of the 
other. This cloudy opacity of the cells with swelling has long been known, 
but even yet its nature is not clear. Virchow thought it the expression of a 
nutritive stimulus and increased absorption of food material. Cohnheim, 
on the contrary, thought it a kind of localized coagulation process. It is 
known that the altered appearance is not necessarily indicative of an irrev- CLOUDY SWELLING OR PARENCHYMATOUS DEGENERATION 
93 
ocable change in the cell, for after the acute infection is past, the cells 
recover their normal appearance. This was, therefore, regarded as one of 
the mildest forms of "degeneration" of the cell. 
The protein nature of the abundant granules which crowd the body of 
the swollen cell has been generally accepted and proven by their solubility 
in alkalies and acetic acid, and by their positive xanthoprotein reaction, 
as well as by other tests, and the problem remains as to their origin and 
their relation to the essential structures of the cell. 
Fig. 37.-Cloudy swelling of epithelium of liver. 
The confused literature is reviewed by Ernst in his recent paper without 
arriving at any definite conclusion as to the nature of the granules, although 
he raises the question as to their relation to the preexisting granules, and 
states that the weight of evidence is in favor of their being derived from the 
mitochondria and their variations. 
In the renal epithelial cells there are found, especially in the more chronic 
forms of nephritis, but occasionally in the acuter form, globules of much 
larger size than any of the granules ordinarily seen, globules of a density 
and high refractive index to make them at once conspicuous objects (Fig. 94 
TEXT-BOOK OF PATHOLOGY 
38). These, it is true, vary greatly in size, and are thought by some 
writers (Pfister) to show gradual transitions into the ordinary granules. 
Fahr objects to this since, as is well known, the large droplets stain sharply 
with the Weigert fibrin stain. They probably play a prominent part in 
the formation of hyaline casts in the tubules. 
Anitschkoff has tried to determine the relation of the granules in cloudy 
swelling to the mitochondria by experiment, and finds that, by the applica- 
tion of hypotonic solutions to the cells, the mitochondria swell up into 
droplets, which, after a time, take the specific stain only at their margins. 
The production of cloudy swelling is, he thinks, a complex process, con- 
sisting of a series of changes in the mitochondria which begins by their 
decomposition into smaller granules, which then swell into droplets some- 
times large enough to touch one another and give the whole cell a web- 
like appearance. This is analogous to the swelling of colloid, which is 
intensified by acids, as shown by M. Fisher, and corresponds with the ob- 
servation of Orgler upon the increase in the water contents of the altered 
tissues. Naturally, this process is reversible under experimental condi- 
tions, but it is not so easy to assume that this is true in the body, where the 
granules may burst, or, as in the kidney cells, be discharged into the tubule. 
Further, a distinction must be maintained between the increase in the 
mitochondria in cells undergoing hypertrophy, and the swelling and dis- 
organization of those structures in injured cells, where the change can be 
regarded as the effect of excessive function only in the beginning, if at all. 
Dibbelt, in studying the effect of diphtheria toxin in the kidney, finds in 
the same way that the first effect consists in a stimulation of the mito- 
chondria to activity, followed by a molecular disintegration, with the lib- 
eration of lipoid substances. Fahr, on the other hand, in discussing the 
hyaline droplets in the kidney cells, makes a sharp distinction between 
mitochondria and secretory granules. Normally, droplets distinguishable 
from the mitochondria by their staining reaction exist in the epithelium 
of parts of the tubule. Pathological droplets staining intensely by Wei- 
gert's fibrin stain occur, however, in different situations in the tubules, 
and are thought to be not merely evidences of the activity of secretory 
granules, but new formed globules, indicating the disintegration of the cell. 
All this is very contradictory and confused, but at least one may see that 
it is scarcely believed any longer that the granular opacity of the organ 
cells in infections and intoxications is due to the accumulation of protein 
food materials, but that it is intimately related to changes in the specific 
granules of the cell. More study is necessary to make the matter quite 
clear. 
Anitschkoff, Dibbelt, Ernst, Fahr: Verb. Dtsch. Path. Gesellsch., 1914, xvii, 81, 103^ 
114, 119. 
Landsteiner: Ziegler's Beitrage, 1903, xxxiii, 237. 
LITERATURE HYALINE DEGENERATION 
95 
HYALINE DEGENERATION 
This expression is loosely employed to class together, in the present state 
of our ignorance, a great many unrelated substances, usually recognizable 
only with the microscope, which have in common, besides their protein 
nature, only their translucent clear or hyaline appearance and their ten- 
dency to stain brightly with such acid dyes as eosin. 
Naturally, there can be nothing chemically specific about such a hetero- 
Fig. 38.-Colloid or hyaline droplets in the epithelium of renal tubules. 
geneous group, and it is easy to withdraw from it such a constant and 
sharply characterized substance as amyloid, which, although it is hyaline 
and stains with eosin, is easily recognized by special microchemical reac- 
tion as well as by its peculiar distribution. 
Ernst has pointed out the possibility of dividing these substances into 
two groups, according to whether the hyaline material is derived from the 
metamorphosis of epithelial and other cells or from connective tissue. 
This rough subdivision, which is open to many criticisms, is based on the 
reaction to the van Gieson stain with which epithelial hyaline stains yellow- 
ish brown, while connective-tissue hyaline takes the red fuchsin stain. 96 
TEXT-BOOK OF PATHOLOGY 
Since we know so little of the chemical nature of the various substances, 
nothing remains but to describe their appearance. In all cases the death 
of the tissue precedes its conversion into a hyaline material, so that we 
are dealing with necrotic and usually coagulated cells which have under- 
gone even further change in assuming the hyaline aspect. 
Epithelial Hyaline.-In areas of necrosis in such organs as the liver or 
kidney or skeletal or cardiac muscle, the protoplasm of the dead cell coagu- 
lates, of course, with the aid of coagulable fluid, which filters in from ad- 
Fig. 39.-Hyaline changes in muscle. Typhoid fever. 
jacent capillaries and tissue spaces. But it does not at once become glossy 
or hyaline. Instead, it seems to require time and perhaps compression or 
the infiltration of more coagulable fluid before the details of the structure 
of the cells are quite lost and fused into a homogeneous, shining mass. A 
good example is found in the clumps of hyaline material sometimes found 
shrunken in the interior of the sarcolemma sheath of the fibres of the rectus 
abdominis muscles in typhoid fever and the pneumonias following measles 
and influenza (Fig. 39). Many other instances will be referred to in other 
places. 
This, which involves the whole cell, must be very different from the HYALINE DEGENERATION 
97 
process which gives origin to the globules or droplets of hyaline appearance 
so often seen in the renal epithelium (Fig. 38). Other hyaline droplets 
which seem to be formed in some analogous way are the so-called Russel's 
fuchsinophile bodies, which may be found in tumors or in old granulation 
tissue. Perhaps the "corpora amylacea" which occur in the alveoli of 
the lung and in the prostate may be regarded as similarly formed by the 
stratified accretion of the hyaline debris of cells, or the secretion of epi- 
thelial cells around some nucleus which itself may be a dead cell. 
Fig. 40.-Hyaline vessel-walls in a tumor of the uterus. 
The globules of hyaline material seen in diseased renal epithelium are sometimes 
spoken of as colloid droplets, and the condition is called colloid degeneration. This is 
confusing, and it is obviously wrong to speak of the accumulation of the colloid of the 
thyroid even when excessive, as a colloid degeneration, since it is only the normal se- 
cretion of the gland. 
The hyaline casts found in the renal tubules which have in themselves 
the general character of hyaline material must be derived from disin- 
tegrated and amalgamated epithelial cells, together with their secretions, 
and they are found to stain in a corresponding way. 
Connective-tissue Hyaline.-In the framework of lymph-glands draining 98 
TEXT-BOOK OF PATHOLOGY 
malignant tumors or tuberculous lesions, hyaline material was first de- 
scribed. But the same appearance can be found in scar tissue or in 
the compact fibrous tissue which underlies old granulation tissue in the 
walls of thickened and diseased blood-vessels (Fig. 40). Especially in the 
walls of the vessels of the uterus or ovaries when they shrink and become 
obliterated in old age does one see the vitreous or hyaline change take place 
in the connective tissue that narrows the lumen. In the ovary every corpus 
luteum, when it loses its specific cells, is finally reduced to a cell-free, hya- 
line, shining mass, the corpus albicans or candicans. 
We must, one supposes, regard such hyaline fibrous tissue as dead, and 
frequently there are evidences of coagulative processes which have oc- 
curred all through it, after which it has become more compact and glisten- 
ing. Often calcium is deposited in such dead tissue. But while it is hya- 
line, it takes, with greater or less brilliancy, the fuchsin red of van Gieson's 
stain, because its inherent chemical value is not quite lost by its becoming 
melted down into hyaline. 
Thrombi, after long standing, fuse in the same way into a formless, 
homogeneous mass m which fibrin, platelets, nuclei of leucocytes, and red 
corpuscles lose their identity in the uniform hyaline mass. This is espe- 
cially true in the lower strata of the thrombi that occupy old aneurysmal 
sacs, where one may no longer be able to distinguish the hyaline thrombus 
from the hyaline fibrous wall of the sac. 
More rapidly produced are the hyaline thrombi which appear in the 
capillaries, especially in the renal glomeruli in some infectious diseases 
(diphtheria, hog cholera, plague). They fill the capillaries like a homo- 
geneous injection mass, and can usually be stained by the Weigert fibrin 
stain, so that they veritably look like a colored injection. It was thought 
that they too were composed of fibrin, but Flexner has shown that they 
consist largely of agglutinated red blood-corpuscles. 
Unsatisfactory as it is, this general conception of nondescript hyaline 
materials derived by necrobiotic processes from the cells and tissues is 
useful so long as we are quite unable to define their nature any more closely. 
LITERATURE 
Lubarsch: "Hyaline and Amyloid Degeneration," Ergebn. d. allg. Path., 1897, iv, 449. 
There was observed long ago, by Rokitansky and the Viennese school, 
a curious material lodged in the substance of various organs, and this was 
later studied in greater detail by Virchow. This amyloid was so called 
because of its fancied resemblance to starch and its fancied resemblance to 
cellulose. It is a translucent, glistening substance, usually so firm and 
often so abundant as to enlarge and render rigid the organs in which it 
occurs. 
It is in persons who have passed through a long wasting illness that it is 
found. In the organs of those who have died after suffering for months or 
AMYLOID INFILTRATION AMYLOID INFILTRATION 
99 
years from some exhausting suppurative process, such as an old osteo- 
myelitis, some chronic destructive infection, such as tuberculosis or actino- 
mycosis, or from such protracted intoxication as may accompany syphilis, 
chronic nephritis, or cancer, this substance is not uncommonly discovered 
at autopsy. With the improvement in surgical technique, which elim- 
inates much of such chronic suppurative and tuberculous disease, it is 
less common than formerly, but it is still frequent enough in homes for 
the incurable and such places. 
The spleen, liver, and kidneys are perhaps the commonest sites for its 
deposit, but it occurs in every other organ at times, not even excepting the 
brain. 
In the spleen it appears in two forms, in one of which it is confined to the 
Malpighian bodies, and stands out as clear, rounded globules against the 
Fig. 41.-Amyloid infiltration; sago spleen. 
red background of the splenic pulp (Fig. 41). Virchow, recalling a favor- 
ite red-wine soup with sago, named it very appropriately sago spleen. In 
the other form the amyloid is diffusely spread through the splenic pulp, 
and being everywhere mixed with the tissue, it is less translucent and glis- 
tening. 
In the liver it may be very inconspicuous, but if abundant, the liver is 
greatly enlarged and firm, and on section the lobulation is rendered in- 
visible by the diffuse infiltration of translucent amyloid. Minute streaks 
of yellowish, opaque liver tissue stretch through it, and there are usually 
patches of liver which are practically free from any admixture of it. 
The kidneys are often pale, large, smooth, and firm, but on the other 
hand they may show any stage of the distortion which follows the ex- 
treme scarring of the organ and still be found to contain amyloid. This 
is lodged in the glomeruli and in the walls of the arterioles and straight 
conducting tubules, and occasionally one may discern it with the naked 
eye, although usually it is too finely divided for that. 100 
TEXT-BOOK OF PATHOLOGY 
The adrenals may contain much or little. In extreme cases the organ 
is greatly enlarged and composed almost entirely of translucent amyloid, 
almost like an enlarged mould of the normal structure. In the intestinal 
wall it is sometimes possible to recognize its presence by the pallor and 
rigidity of the mucous membrane, but this is rare. 
In lymph-glands it is not commonly abundant, but in a recent case in 
which it was widely distributed the cervical lymph-glands were greatly 
enlarged and were found to be composed of almost solid masses of amyloid. 
While the condition of the spleen, liver, and adrenals is easy to recognize, 
one might overlook its existence in the kidneys and in other organs. In 
its detection great help is afforded by the peculiar microchemical reactions 
which can be applied to the fresh organs. They are as follows: 
1. A solution of iodine stains the tissues in general yellow, but makes the 
amyloid stand out sharply in deep brown. This is especially striking if 
the tissue is made acid in reaction with acetic acid. If strong sulphuric 
acid is used instead, the amyloid turns blue or black with iodine, and hence 
its supposed resemblance to cellulose. 
2. Various aniline dyes, such as methyl-violet, methyl-green, thionin, 
etc., cause the amyloid to show a metachromatic stain; that is, it stains 
red while the tissue takes the obvious blue or green color of the dye. 
These stains can be applied to frozen sections in which the amyloid 
also shows its acidophilic character, staining intensely pink with eosin, 
and brownish with van Gieson's stain. 
When thus brought into distinct relief by specific stains, it becomes 
quite clear that the amyloid substance is merely poured into the crevices 
of the tissue, and not situated in any of the cells. It is a true infiltration, 
as though melted paraffin had been forced into the tissue-spaces and al- 
lowed to solidify. In the spleen it crowds the cells of the Malpighian body, 
between which it lies until most or all of them atrophy and disappear 
(Fig. 42). Everywhere it appears in the substance of the walls of the 
smallest blood-vessels, sometimes between the muscle-cells of the media, 
sometimes in the intima. The vessels of capillary calibre are most com- 
monly chosen for such a coating of amyloid. 
In the liver it is found in only one situation, and that is about the en- 
dothelium of the capillaries, and hence between those cells and the liver- 
cells. The amyloid becomes so bulky in that situation that it presses on 
the capillary and liver-cells, and causes the latter to melt away into thin 
threads of protoplasm and finally to disappear (Fig. 43). 
The same crowding is apparent to an extreme degree in the adrenal, 
where the tissue is practically reduced to nothing in advanced cases. In 
the intestinal mucosa amyloid accompanies the minute blood-vessels in 
the villi. Application of iodine makes each one brown separately, so that 
the mucosa assumes the appearance of brown velvet. 
In the kidney it lodges in the glomerulus, between the endothelium of 
the capillaries and their epithelial covering, and consequently soon nar- 
rows the capillary to a very minute calibre or obliterates it. Elsewhere it AMYLOID INFILTRATION 
101 
is found as a mantle for the tiny arterioles and venules in the cortex and 
pyramids, and also for the conducting tubules. It is easy to understand 
that the application of iodine to the cut surface of such a kidney would 
reveal the glomeruli as brilliant, chestnut-brown points in a tissue every- 
where very finely streaked with brown (Fig. 142). 
Fig. 42.-Amyloid infiltration of Malpighian bodies of spleen. 
It is unnecessary to describe in detail the distribution in other organs, 
where it follows the same principle of infiltrating between capillary en- 
dothelium and the adjacent cells. Wherever it is present in abundance it 
causes atrophy of the pre-existing tissues. Its distribution is usually suf- 
ficient to distinguish it, even if specific stains cannot be applied, from other 
hyaline materials which stain with eosin but have not the peculiar chemical 
character of amyloid. 
Chemical Nature.-Amyloid is a very resistant substance, which ap- 
parently persists, when once formed, although some experiments tend to 
show that when it is produced in animals it will disappear after a time if 
the animal is allowed to recover from the injections of bacteria or toxin 102 
TEXT-BOOK OF PATHOLOGY 
which are used to produce it. It was thought not to be attacked even by 
digestive ferments, but now it has been shown that it can be digested slowly 
by artificial gastric juice. In the attempt to determine its chemical nature 
Fig. 43.-Amyloid infiltration of liver. Compression and atrophy of liver-cells. 
it was first extracted in a fairly pure form by taking advantage of its solu- 
bility in baryta water. Oddi then discovered that while different specimens 
vary widely in composition, all sorts of amyloid contain chondroitin- 
sulphuric acid, a substance found normally in cartilage, but whose struc- 
ture is still unknown. Krawkow thought amyloid to be a compound of 
chondroitin sulphuric acid with a histone. Details of the rather fruitless 
attempts to determine its composition may be read in Neuberg's paper. 
The more recent studies of Hanssen, Eppinger, and others make it seem 
improbable that chondroitin sulphuric acid is a constituent of amyloid, and 
Dresel shows that while this substance is increased in the serum of persons 
with amyloid disease, the same is true of others with advanced renal 
disease without amyloid. He therefore thinks its presence due to the 
inability of the kidneys to continue its normal excretion. CARBOHYDRATE METABOLISM-GLYCOGEN 
103 
Davidsohn has speculated on the way in which it is formed. Since it 
cannot be transported in the blood-stream, it must be formed in situ, and 
this he thinks is accomplished by a ferment formed in the spleen, since amy- 
loid is not to be produced in an animal without a spleen. 
Much has been said of its experimental production. Krawkow succeeded 
in this by repeated injections of bouillon cultures of Staphylococcus aureus, 
but others have found that turpentine or other pus-producing poison or 
cultures of various other bacteria or their toxins will also cause its ap- 
pearance. The horses used for the manufacture of diphtheria antitoxin 
often show amyloid changes in their organs, and so do mice and rats inocu- 
lated with transplantable tumors. 
A point of peculiar interest is that amyloid seems to go through several 
stages in its formation-at first it will not stain with iodine, although giving 
a metachromatic stain with methyl-violet. It is only in the latest stages 
that it will give the blue or black color with sulphuric acid and iodine. 
The early stage of non-stainable amyloid recognized by Davidsohn was 
called achrodamyloid. Quite recently we observed an instance in a young 
man with advanced pulmonary tuberculosis in whom a typical sago spleen, 
enormous, bacon-like liver, and advanced renal amyloid were found. 
Nevertheless, although the diagnosis was unmistakable to the naked eye, 
none of the amyloid would stain with iodine. 
Kuczynski has found it possible to produce amyloid in mice by injecting 
casein or egg-albumen parenterally, that is, somewhere outside the in- 
testinal tract, or by feeding very excessive amounts of these substances. 
He thinks it a decomposition product of protein which, becoming too con- 
centrated in the blood, is deposited in the crevices of the tissue. By 
interrupting the administration of casein he shows that amyloid once 
formed may be reabsorbed by the action of ferments produced by plasma 
cells and other wandering cells and by the phagocytic activities of re- 
ticulo-endothelial cells. Such experimental production of amyloid still 
leaves us without any good explanation of the extraordinary physical and 
chemical peculiarities of this substance. 
Besides the general amyloid infiltration there occur localized amyloid 
deposits, sometimes in the form of tumor-like masses, usually in connec- 
tion with cartilage-containing structures, such as the bronchi (Herxheimer, 
Schilder). 
LITERATURE 
Davidsohn: Ergebn. d. wiss. Medizin, 1910, i, 330; Virch. Arch., 1907, clxxxviii, 395; 
1908, cxcii, 245. 
Schmidt: Verb. Dtsch. Path. Gesellsch., 1904, vii, 2. 
Neuberg: Ibid., 1904, vii, 19. 
Kuczynski: Klinische Wochenschrift, 1923, ii, 2193. 
CARBOHYDRATE METABOLISM-GLYCOGEN 
Carbohydrates as they appear in the body are, for the most part, prac- 
tically inaccessible to our staining methods and do not appear in our micro- 
scopical studies of the tissues except in the form of glycogen, which we can 104 
TEXT-BOOK OF PATHOLOGY 
make evident by certain stains. Nevertheless we can study accurately 
by chemical methods the various phases of the carbohydrate metabolism, 
and recognize quantitatively the presence of sugars, etc., in different fluids 
and tissues. 
It has been shown that carbohydrates can be formed in the liver from 
many of the amino-acids which form the constituents of proteins, and there- 
fore from the proteins themselves. The evidence is, on the whole, against 
their formation from fats. Most of the carbohydrate is, however, ab- 
sorbed in a soluble form in the intestine and conveyed to the liver and to the 
general circulation in turn. In the liver it is probable that, through the 
activities of the cells, the soluble sugar which has already passed the in- 
testinal wall, chiefly in the form of dextrose, is polymerized and becomes 
glycogen (Fig. 20). Apparently the liver-cells are not the only ones which 
can carry out this function, for glycogen is found lodged in many other 
tissues. In the epithelial cells, in cartilage, etc., there is constantly gly- 
cogen present, while it is normally lacking in the nervous system, pancreas, 
salivary glands, breasts, thyroid, hypophysis, adrenals, bone-marrow, etc. 
Its amount varies in the muscles and liver according to the activity of 
those organs, the state of nutrition, etc. In the heart muscle it is usually 
more abundant than in the skeletal muscles. In the embryo it is in general 
more abundant than in the adult, but its presence is by no means charac- 
teristic of embryonic tissue, and we are not justified in speaking of patho- 
logical new-growths as composed of embryonic tissue merely because they 
contain much glycogen. It is, nevertheless, true that many rapidly grow- 
ing tumors are especially rich in this substance. 
For its redistribution glycogen must be again converted into diffusible 
sugar, which may be brought to the muscles to act as a store of energy. 
In the blood-especially in the leucocytes-some glycogen may be demon- 
strated under varying circumstances, but. this cannot be regarded as the 
mode of transport, and the dissolved sugar escapes our microchemical tests. 
In order to bring this about certain diastatic ferments must be brought 
into play-the process of mobilizing the carbohydrate. This is easy enough 
in such organs as the liver and muscles, which, with respect to glycogen, 
act largely as storehouses, but in others, like the cartilages and epithelial 
layers, the glycogen seems to form an integral part of the cell-body and is 
not readily mobilized. 
The diastatic ferment converts the glycogen into the more readily sol- 
uble dextrose, which then enters the blood and is carried to the muscles or 
other places, where it is required to furnish energy or heat, and there, by 
the aid of other ferments, undergoes the process of glycolysis, with final 
oxidation to carbon dioxide and water. This diastatic ferment may con- 
tinue to act after death, so that haste is necessary and proper fixation in 
substances such as strong alcohol, if we wish to demonstrate glycogen in 
the tissues. Solution of the glycogen in the fluids of the cell may also 
occur postmortem, so that estimates of the glycogen content of the cells 
after death become uncertain unless carried out with care. CARBOHYDRATE METABOLISM-GLYCOGEN 
105 
Glycogen may be stained brown with iodine or bright red by Best's 
carmine method, and is usually in rounded masses in the cell protoplasm 
or in the interstitial tissue, but not in the nucleus (Fig. 20); if it has been 
dissolved postmortem in the cell protoplasm, it does not quickly pass the 
cell boundaries, but is precipitated in granular masses by the alcohol or 
other fixing fluid. 
In pathological conditions produced by intoxications, disturbances of 
circulation, inflammation, etc., glycogen may appear in tissues ordinarily 
devoid of it or containing very little. The cells about areas of necrosis or 
inflammation may be especially rich in it. This is due to the impairment 
of their function, which does not readily allow them to get rid of the carbo- 
hydrate mass, exactly as is true in the case of fat accumulations. In 
many rapidly growing tumors, especially those of teratomatous character 
and the more malignant growths, it is likely that glycogen may be found, 
although there are many exceptions to this rule, especially in those derived 
from cells whose functions are directed rather to the production of mucin, 
glycoproteids, milk-sugar, etc., where glycogen is not likely to appear. 
In diabetes mellitus the glycogen content of most of the tissues is found to 
be decreased, although for some reason the cells of part of the convoluted 
tubules of the kidney, the heart muscle, and the leucocytes become loaded 
with it. No good explanation for this is known. It is thought that it 
may be due to their inability to get rid of the glycogen, which is brought 
to them by the sugar-rich blood-or that, in the case of the kidney cells, 
they reabsorb carbohydrate from the urine in the tubule. Diabetes seems 
to rest, in part at least, on such a disturbance in carbohydrate metabolism 
that the dextrose is not stored up as polymerized sugar (glycogen) in the 
liver and elsewhere, or else on the extraordinarily active mobilization of the 
sugar in the organs-in either case proper glycolysis and consumption of 
the sugar thus thrown into the blood are lacking, and the sugar is lost by 
being excreted through the kidney. This disturbance of glycolysis is in 
many instances due to the loss, through disease, of the ferment-like internal 
secretion of the pancreas, which ordinarily takes part in glycolysis. There 
is now little difference of opinion as to this point since the preparation of 
insulin, an alcoholic extract of the pancreas, for the injection of this 
material restores the power of the body to consume sugar. (See further 
discussion under Diabetes.) 
Glycogen, then, must be regarded as a normal constituent of many 
organs-absent in others and present in a third group in both a stabile and 
a labile form, the latter of which is most easily mobilized to furnish soluble 
sugar to the blood. Under pathological conditions where nourishment 
and functional activity of cells are depressed, there may appear unaccus- 
tomed accumulations of glycogen simply because the cell is no longer able 
to make use of this material, and by depolymerization set it free into the 
circulation. Removal of the disabling agency soon leaves such cells free 
to resume their ordinary metabolism, and the glycogen disappears. CHAPTER VIII 
DISTURBANCES OF MINERAL AND PIGMENT METABOLISM 
Calcium. Its source, distribution, deposition in necrotic and other tissues. Its relation 
to various functions of the body. Iron: its distribution and functional importance. Dis- 
turbances in its quantitative relations. Chlorosis. Hemochromatosis. Pigment: func- 
tion and distribution. Endogenous and exogenous pigmentation. Jaundice. Dust 
diseases. 
Calcium, which in various combinations plays many important roles in 
the animal body, is absorbed in the intestinal tract, and in very consider- 
able quantity reexcreted into the intestine, although the excretion is also 
carried on to a less extent in the urine. Its most obvious application in the 
body is in the formation of the rigid tissues of the skeleton, but it seems to 
have a very important influence upon the activity of the heart, the excita- 
bility of nerves, the clotting of blood, etc., and is found to form a constant 
constituent of the blood and tissues. 
The pathological disturbances in calcium metabolism might readily 
fall into two groups: those in which there is an inadequate supply or ex- 
cessive withdrawal of calcium, and those in which the reverse occurs and 
the tissues become the seat of abnormal accumulations of lime salts. 
In both instances the disturbance may be local or general, and indeed it 
seems possible that calcium may be removed from one place, only to be 
deposited again at another place in the body. 
Calcium Deficiency.-Experimentally one may, by feeding a diet poor 
in calcium, reduce the consistence of the bones so that they are easily cut 
or broken. The ordinary process of ossification (Fig. 44) is distorted, and 
new-formed bone is calcified only at the expense of the old. Similarly in 
certain diseased conditions whose causation is obscure (rickets and osteo- 
malacia) we find changes which are in some ways similar to the osteo- 
porosis produced by withdrawal of lime salts from the food; but different 
also in many respects, especially in the production of much osteoid tissue 
-which is bone tissue morphologically, but uncalcified. In rickets and 
probably also in osteomalacia there is some obscure disturbance in metab- 
olism which leaves a disproportion between the available amounts of 
phosphorus and calcium such that the proper deposition of calcium 
phosphate cannot occur. In rickets the phosphorus content of the blood 
is decreased, although the calcium may be normal. Mere increase of 
phosphorus or calcium will not remedy this, but cod-liver oil or sunlight 
will restore the proportions and the function of bone formation to normal. 
The processes of building up and breaking down of bone go on constantly 
through life, and it is apparently the result of a disproportion between these 
that the constructive processes are in old age overshadowed by the other- 
wise normal destructive processes. The osteoclasts or giant-cells, whose 
METABOLISM OF CALCIUM 
106 METABOLISM OF CALCIUM 
107 
function is to erode away and dissolve the old bone, continue their work, 
while the osteoblasts, whose function it is to rebuild, slacken in their new 
bone production. The result is the senile osteoporosis which attenuates 
the bony structures until the bone becomes very much rarefied and easily 
broken. Whether this depends upon changes in the available quantity of 
Fig. 44.-Process of calcification in normal line of ossification in fetal bone. Blood- 
vessels with osteoblasts depositing bone on remaining matrix. 
■calcium it is difficult to say. So, too, in the so-called arthritis deformans, 
which is accompanied by great irregularity in ossification and rarefaction 
in the bones, the excessive excretion of phosphorus seems to point to a 
general chemical disturbance which is associated with the destruction of 
the bone. 
The effects of withdrawal of calcium upon the other tissues are far less 
evident, but it has been shown experimentally that this substance, when 
injected, diminishes the excitability of the nervous system. Conversely, 
it might be supposed that in such conditions of nervous hyperexcitability 
as tetany, a symptom-complex which follows upon the destruction of the 
parathyroid glands, there might be an active withdrawal of calcium from 
the tissues; and, indeed, a great many observations have been made which 108 
TEXT-BOOK OF PATHOLOGY 
support this. Erdheim has shown that the destruction of the parathyroids 
results in an extreme decrease in the process of ossification and in the 
normal calcification of the dentine, so that fractured bones heal very 
poorly and the teeth become so softened as to break. After actual re- 
moval of calcium from the blood by dialysis the nerves of extremities per- 
fused with such blood become electrically hyperexcitable. 
Calcium Excess.-In the other group of conditions, in which the de- 
position of calcium in unusual situations takes place, we meet with many 
difficulties in finding an explanation for each step. Aside from the modi- 
fication in the density and in the quantity of the calcified tissues of the 
bones, we may find gritty or mortar-like, or even compact, hard, stone- 
like concretions of lime salts in various parts of the body in positions where 
they can have no direct relation to the skeleton. Thus nothing is com- 
moner than the finding of necrotic or caseous tubercles in the lung or else- 
where which have become encapsulated with a dense connective tissue, 
and in the central parts of which rough granules of lime have appeared in 
the cheesy substance. These may become so abundant and so com- 
pactly placed that it is impossible to cut through the stony mass. The 
lymph-glands of the mesentery undergo the same changes after tubercu- 
lous infection, and may be finally converted into rough white masses like 
pebbles. The walls of the aorta and other large arteries are found to con- 
tain plaques of calcified material which conform with the curve of the wall, 
and are usually smoothly covered internally with endothelium. Such 
plaques are formed in the necrotic patches of thickened intima in the 
course of the disease arteriosclerosis, and when fully formed resemble bits 
of eggshell embedded in the vessel walls (Fig. 171). In the smaller vessels 
such areas of calcification are found in the muscular coat (Figs. 177, 178). 
With advancing age, and probably in association with such conditions 
as bring about calcification of the blood-vessels, we find the calcification 
of such cartilages as the costal and tracheal, which ordinarily remain free 
from this substance. 
Sublimate poisoning and anaemic necrosis in the kidneys are frequently 
followed by an abundant precipitation of calcium in the form of casts in 
the tubules or in the necrotic cells themselves (Fig. 45), and similarly it 
is extremely common to find calcified plates or spicules or even great, stone- 
like masses developed in tumors whose circulation has become deficient, 
so that necrosis of the tissues has resulted. This is analogous to the de- 
position of such granules in any necrotic tissue or about the bodies of dead 
parasites, such as trichinae, which have been long embedded in the muscles. 
We find no difficulty in understanding that tumors which spring from the 
bone themselves produce actual bone in sheets and spicules, because we 
are accustomed to ascribe to the osteoblasts the power of forming bone. 
In some other tumors, such as the so-called psammomata, tumors which 
often arise from the coats of the brain or the pineal gland, etc., there appear 
small calcified grains which are often closely surrounded by the tumor- 
cells and may even replace groups of them. METABOLISM OF CALCIUM 
109 
Except in the case of the growing bone, the osteosarcomata, and other 
tumors springing from the bone, those tissues which become incrusted or 
Fig. 45.-Calcification of necrotic renal epithelium. Sublimate poisoning. 
impregnated with gritty particles of lime are usually dead. They have 
generally assumed the vitreous, glistening appearance which we are accus- 
tomed to associate with the descriptive term "hyaline." Even in the case 
of elastic fibres and other substances which are homogeneous in the normal 
state, it seems probable that we shall find that those which become cal- 
cified are, after all, dead. We may confidently look for dead tissues as the 
basis for such precipitation when we find, for example, a cuirass-like shell 
of lime about the heart in an old case of pericarditis, or a stony plug in the 
veins of the spleen or of the pelvic plexuses where thrombi have lain for 
weeks or months (phleboliths). 
The reason for this process has been sought with eagerness in recent 
years, because simple explanations which once seemed satisfactory are 
found to be baseless. There seems to be something peculiar about these 110 
TEXT-BOOK OF PATHOLOGY 
tissues, living or dead, which gives them the power to catch up the calcium 
from the circulating fluids and hold it finally in solid form; and the Ger- 
mans have called such tissues "Kalkfanger." But so far no precise and 
satisfactory chemical explanation has been found. It is shown that the 
lime salts deposited in dead tissues are generally the same and in the same 
proportion as those in bone-about 87 per cent, of calcium phosphate and 
10-15 per cent, of calcium carbonate. Some authors, however, have found 
only one of these salts in pathological calcification. Magnesium salts 
seem to play a subordinate part in both situations, and although some ob- 
servers have found them present in the proportions found in the bones, 
we are still imperfectly informed with regard to the precipitation of these 
salts. When calcium is present in great quantities in the blood, as in the 
rabbit, calcification of dead tissue takes place very rapidly, so that the 
rabbit is an especially favorable animal for the study of this process. If 
we ligate the blood-vessels of the rabbit's kidney, the tissue becomes quite 
densely calcified within a few days. 
Necrotic fat tissue seems very prone to calcification, and this has given 
origin to the theory, expressed by Klotz, that, in general, calcification is 
preceded by an accumulation of fat with decomposition of the fat into fatty 
acids and another component. This is followed by the formation, by a 
process of double decomposition, of insoluble calcium soaps, and later 
completed by the conversion of these soaps into calcium phosphate and 
carbonate, with the liberation once more of the fatty acid. Unfortunately, 
although the theory is tempting, it has been shown that Klotz's methods 
were inadequate to prove his point, and it has not been possible to show, 
except perhaps in the necrosis and calcification of fat itself, that there is 
more than a trace of calcium soap in any such area-not sufficient to justify 
us in assuming that it plays an important part. Nevertheless, the in- 
vestigations have been concerned chiefly with finished calcium deposits, 
and it may well prove that the calcium soaps have a transitory existence in 
leading to this result. Later Klotz found that by injecting cholesterin in 
oil so that it became lodged in many phagocytic cells he could produce 
focal deposits of calcium corresponding exactly with the localization of the 
fatty material. Wells, who has offered these criticisms, has no equally 
simple explanation in its place, but finds that certain substances, when 
introduced in the tissue fluids of an animal like the rabbit, have far greater 
powers of absorbing calcium salts and retaining them than have others. 
Thus, while pieces of fat, spleen, thymus, etc., are found to contain, after 
a stay of fourteen weeks in the peritoneum of a rabbit, only about 12 mgm. 
of calcium, a similar piece of cartilage has absorbed 154 mgm. And this is 
true even if the cartilage be boiled, so that there can be no question of vital 
activity. Different forms of cartilage differ in this respect, and while the 
above is true of epiphyseal cartilage, that which ordinarily does not become 
ossified, such as the rings of the trachea, will take up hardly more than the 
spleen. Wells thinks, therefore, that the beginning of calcification is based METABOLISM OF CALCIUM 
111 
upon a simple physical absorption of these hyaline substances; that the 
process in the calcification of pathological or dead tissues is identical with 
that in ossification. Calcium is carried in the blood in amounts not far from 
saturation point, held in solution by the colloids and the carbon dioxide. 
This unstable double salt of calcium bicarbonate and dicalcium phosphate 
is adsorbed in the hyaline matrix and precipitated by a reduction in the 
quantity of carbon dioxide. Calcium deposition, according to him, seems to 
depend, alike in normal and most pathological conditions, rather on physico- 
chemical processes than on chemical reactions. 
Howland shows that the precipitation of tricalcium phosphate which 
forms 90 per cent, of the mineral matter of bone is subject to the laws 
which about determine the precipitation of slightly soluble salts. In the 
serum and intercellular fluid it is subjected to the influence of carbonic 
acid. In artificial solutions containing the same amount of sodium bicar- 
bonate, magnesium, and sodium chloride that normal serum contains, the 
addition of varying amounts of calcium and phosphorus was made with a 
carbon dioxide tension to give any desired hydrogen-ion concentration. 
It is found that when the product of the concentration of calcium and 
phosphorus reaches a certain point a decrease of the carbon dioxide ten- 
sion, which increases the alkalinity, brings about precipitation of the cal- 
cium phosphate. 
Calcification may be visualized as follows: Serum contains calcium and 
inorganic phosphorus in solution in much higher concentration than would 
be possible in water on account of the high carbon dioxide tension and the 
contained protein. This is true in intercellular fluids where the carbon 
dioxide tension is high on account of cellular activity. When the carbon 
dioxide tension is low because the tissue is inactive or dead, conditions 
are favorable for precipitation. 
Another type of calcification has been described in the so-called metas- 
tasis of lime salts, which is said to depend usually upon the saturation of the 
circulating fluids with those salts as the result of extensive breaking down 
and solution of the bony tissues in some part of the body. Then the cal- 
cium is deposited in places where the acid is given off, as in the mucosa 
of the stomach, the tubules of the kidney, the lungs, and sometimes in 
the vessel walls. This precipitation must be due to the relative alkalinity 
of the tissues which have just given off acid, and, as Howland states, it is 
striking that the precipitation occurs on the arterial side of the capillaries 
rather than on the venous side. 
Occasionally, as in the tuberculous lung or in the walls of the sclerotic 
aorta, the stony, calcified material may in time be replaced by a for- 
mation of true bone with Haversian systems, and a marrow cavity in 
which all the characteristic cells of the bone-marrow appear. This seems 
to occur only upon the immediate foundation of a mass of formless calcium 
which has itself occupied the place of the dead tissue, and is perhaps to be 
regarded as a kind of reparative process. 112 
TEXT-BOOK OF PATHOLOGY 
LITERATURE 
Aschoff: Lubarsch-Ostertag Ergeb., 1902, viii, 501. 
Klotz: Jour. Exp. Med., 1906, viii 322. Proc. Soc. Exp. Biol. Med., 1915, xii, 159. 
MacCallum, Lambert, and Vogel: Jour. Exp. Med., 1914, xx, 149. 
Ricker: Lubarsch-Ostertag Ergeb., 1896, iiii, 643. 
Schultze: Ibid., 1910, xivi, 706. 
Wells: "Calcification and Ossification," Archives Internal Med., 1911, vii, 721. Har- 
vey Lectures, New York, 1910-11, 102. 
Howland: Etiology and Pathogenesis of Rickets, Medicine, 1923, ii, 349. 
DISTURBANCES IN THE METABOLISM OF IRON 
Distribution of Iron in the Body.-The whole nature of the interchange of 
iron in the body is very imperfectly understood, although it is known to 
be of profound vital significance. 
Iron exists in the body of an adult in the haemoglobin of the red cor- 
puscles and in all the cells of other tissues. The amount contained in the 
blood is about 3 gm. That contained in invisible form in other cells has 
been estimated roughly at 1 to 3 gm. 
It is similarly a constituent of the blood and tissues of other animals 
and of vegetable cells, being present in chlorophyll in combinations some- 
what allied to that found in haemoglobin. Hence it enters into the human 
body in animal and vegetable food. The complex organic compounds are 
decomposed in the intestine in such a way that the iron is absorbed in the 
ionic form. Bunge's statement that it could be absorbed only when pre- 
sented in the form of the higher organic combination is rendered improb- 
able by this fact, and further disproved by the familiar clinical experience of 
the effect of administering inorganic compounds in anaemias, and by the re- 
sults of direct experiments which show the absorption of these compounds. 
The ingested iron is absorbed in the duodenum and the upper part of 
the small intestine. As has been shown in cases of intestinal fistula, the 
chyme of the lower part of the ileum contains none. On the other hand, 
the excess is excreted into the colon and leaves the body with the faeces. 
By microchemical methods it may be demonstrated in the walls of the 
duodenum, and again in those of the colon, but not in the walls of the 
lower ileum. 
The exact mechanism of absorption is not clearly known. Some is 
directly received by the epithelial cells and transferred later. Some 
appears to be carried into the tissues by leucocytes, or may possibly enter 
in association with lipoid droplets (A. B. Macallum). Part of it is thought 
to pass by way of the thoracic duct, but it may be assumed that the greater 
part enters by way of the portal vein and reaches the liver. We are equally 
ignorant of the exact mechanism of excretion, but in this respect iron seems 
to show analogies with calcium. 
In the blood, iron is found in the hemoglobin, a combination of a very 
complex protein, globin, with haemochromogen or its oxidation product, 
haematin. Haematin (C34H34N4O5Fe, Abderhalden) may be decomposed 
into haematoporphyrin through the loss of its iron, and this in itself is a DISTURBANCES IN THE METABOLISM OF IRON 
113 
complex carbon compound containing pyrrol derivatives, and related to 
an analogous decomposition product of chlorophyll. Abderhalden points 
out that the formation of haemoglobin involves, therefore, the process of 
formation of haematin and its subsequent union with the highly specific 
globin, which, since all must start with the simplest building-stones which 
can pass the intestinal wall, leaves several points at which the production 
of the haemoglobin may be deranged. 
The intermediary exchange of iron is beset with difficulties of interpreta- 
tion. Red blood-corpuscles are destroyed in the body, probably very 
largely by the spleen. The haemoglobin thus set free passes intact or 
partly decomposed from the spleen to the liver. Doubtless most of the iron 
absorbed from the intestine passes in the same way directly to the liver. 
From the haematin separated from the globin iron is liberated in the 
liver, and the iron-free residue constitutes the bile-pigment, bilirubin, 
which is an isomer of haematoidin. 
The fate of the iron thus set free in the liver, and of that brought there 
from the intestines, has not been traced, but it is clear enough that it is 
somehow worked up into haemoglobin. 
The iron of the tissues which is largely a constituent of the chromatin is 
tenaciously held by the cells and shared with the blood only in conditions 
of grave anaemia. 
At birth the foetus is rich in iron which was stored in its body from the 
mother, but during suckling very little iron is absorbed with the milk, 
which is extremely poor in that substance. Therefore, the iron content is 
low at the end of the period of suckling, but rises rapidly when the infant 
begins to take other food than milk. M. B. Schmidt found that if the iron- 
free diet were continued in growing mice after the termination of suckling, 
they gradually became anaemic and were stunted in their growth. The 
offspring of such mice were studied through several generations, through- 
out which the feeding was continuously "iron free." If, now, iron were 
given to one of a litter of such meagre, anaemic mice, it quickly outgrew 
the control brother, and as quickly acquired a high percentage of haemo- 
globin and a nearly normal blood count, showing that the manufacture of 
haemoglobin had been halted by the failure of the tissues to acquire and 
then set free sufficient iron, and that this matter was quickly set aright 
by the supply of inorganic iron. The rapid growth that ensues indicates 
the fundamental importance of iron. The spleen appears to be the organ 
in which blood-corpuscles, destroyed there or elsewhere, give up their iron 
to be carried to the liver. But this idea of the function of the spleen, 
which is regarded by Chevallier also as an organ of assimilation of iron, 
preserving and transferring it for the manufacture of haemoglobin, must be 
made to accord with the fact that the spleen is a great site of blood destruc- 
tion, and the further fact that its extirpation has a beneficial effect in such 
severe anaemias as pernicious anaemia. 
The function of iron in the body is at least to be definitely associated 
with the transfer of oxygen, and probably more generally with the processes 114 
TEXT-BOOK OF PATHOLOGY 
of oxidation of the tissues. Its role in connection with its presence in the 
chromatin of the cells is not so clear, but it seems to affect directly or in- 
directly the process of growth. As in the case of fats and lipoids, it is 
evident that the forms in which iron is active in carrying out its important 
functions are those in which it is invisible even with the aid of most micro- 
chemical reactions. When it becomes visible, it is because it is cast out of 
functional activity and lies scattered in the tissues in pigmented granules. 
Much has been written recently concerning its relation to the process of 
calcification. It appeared from the work of Gierke and others that sub- 
stances about to become the seat of a deposit of lime salts first absorbed a 
quantity of iron. Hueck opposed this on the ground that the microchem- 
ical reactions showing the presence of iron in calcified areas were due to 
impurities of fixing fluids, etc. He even suggested the test for iron in 
tissues soaked in a weak iron solution as a means of demonstrating the 
distribution of calcium. Noesske found that, while perfectly fresh bones 
and calcified tissues showed no iron, it was to be demonstrated in those 
situations if the body had lain for some time. He, therefore, thought that 
in this interval iron had been absorbed from the adjacent tissues. 
Sumita, Eliascheff, and others return to the original idea that iron is 
actually to be found as a forerunner of the deposition of calcium in tissues 
examined when perfectly fresh after every precaution has been observed 
to avoid the objection that calcified material eagerly absorbs iron from the 
most dilute solution. Sprunt found an incrustation of elastic tissue fibres 
with calcium and with iron, while Gigon, in studying a lung supposed to 
contain a similar combination of lime and iron, as shown by microchemical 
methods, found by analysis no calcium, but much iron in association with 
sodium salts. The results are very contradictory, but there is, at least, 
much evidence that iron and calcium are deposited together, although it 
is not so clear as to which is the pioneer. 
Two definite affections may be mentioned here as examples of disturb- 
ances in the metabolism of iron, the others, which appear to be rather 
more incidental processes, leading to local accumulations of iron-containing 
pigment, being discussed elsewhere. 
Chlorosis.-Young girls frequently develop a peculiar greenish pallor 
with great weakness, perversion of appetite, digestive disturbances, and 
constipation. The blood shows a nearly normal number of red corpuscles, 
which, however, are very pale, so that the haemoglobin index may be ex- 
tremely low. The disease is readily cured or even passes away itself with 
improvement in the state of the digestive organs, so that little is known 
with regard to its pathological anatomy. It is influenced by purgatives, 
and in a most remarkable way by the administration of iron in any form. 
Whether the inorganic iron thus given actually forms the material for the 
new production of haemoglobin, or stimulates its production by liberating 
the supply of combined iron from the tissues, remains uncertain. Nor do 
we know whether the defect in the formation of haemoglobin is due to the 
inadequate absorption of iron or to some difficulty in its combination with DISTURBANCES IN THE METABOLISM OF IRON 
115 
Fig. 46.-Haemochromatosis. Pigmentation of liver. 
Fig. 47.-Haemochromatosls. Pigment deposit in tissues of the liver. 116 
TEXT-BOOK OF PATHOLOGY 
haematoporphyrin to form haematin, or finally to lack of the necessary 
globin. One might imagine that if these combinations are formed under the 
influence of ferments, the digestive disturbances could explain their absence. 
Haemochromatosis.-A disease described by Hanot and Chauffard, and 
named by v. Recklinghausen, in which an extraordinary deposition of iron- 
containing pigment (haemosiderin), together with other pigment (haemo- 
fuscin) which contains no iron, is found in practically all the organs, in- 
cluding the skin. It is often associated with cirrhosis of the liver and pan- 
creas and with diabetes, hence the name, "bronzed diabetes," which is 
appropriate in many cases. 
The skin is of a dusky bronze hue, and in sections the pigment may be 
demonstrated by its giving the Prussian-blue reaction. The liver, pan- 
creas, kidneys, lymph-glands, heart muscle, etc., are found to be of a 
bright, chestnut-brown color, and show microscopically astounding col- 
lections of pigment in clumps and granules (Fig. 46). The pigment lies 
chiefly in phagocytic cells, such as Kupffer's cells of the endothelium of the 
liver, but it is also lodged in the connective tissue and in the liver-cells 
themselves (Fig. 47). In the other organs it has a corresponding posi- 
tion-apparently its presence as a foreign body leads to much new- 
growth of encapsulating fibrous tissue. Most of it can be stained blue 
with ferrocyanide and hydrochloric acid, but part of it remains brown and 
responds to no tests for iron (haemofuscin). 
There is no obvious anaemia, no especial evidence of wide-spread blood 
destruction, and no especial activity of the blood-forming organs to repair 
a destruction of blood which would, of course, occur to any one as the 
probable source of so much iron-containing pigment. 
Here the disturbance of iron metabolism must occur at some other point. 
In sharp contrast with chlorosis, in which it appears that absorption of 
iron or its combination into haemoglobin is deranged, there is found an ade- 
quate haemoglobin production, little or no blood destruction, but at the 
same time an overwhelming accumulation of haemosiderin. In lack of 
definite information one may make the surmise that it may prove that the 
normal excretion of the excess of iron through the mucosa of the colon is 
defective, and that the pigment represents a retention. But this is far 
from standing as a satisfactory explanation, and haemochromatosis remains 
a problem. Indeed, the studies of Howard and Stevens and of McClure 
show perhaps a slight negative balance in the case of iron, but no marked 
general disturbance of metabolism. 
LITERATURE 
Abderhalden: Lehrb. d. physiol. Chemie, 1909, 491. 
Gierke: Virch. Arch., 1902, clxvii, 318. 
Howard, C. P., Stevens, F. A.: Archives of Inter. Med., 1917, xx, 897. 
McClure, C. W.: Ibid., 1918, xxii, 610. 
Macallum, A. B.: Jour, of Physiol., 1894, xvi, 268. Proc. Roy. Soc., 1891, 1, 277. 
Opie: Jour. Exp. Med., 1899, iv, 279. 
Schmidt, M. B.: Verh. Dtsch. Path. Gesellsch., 1912, xv, 91. 
Sprunt, T. P.: "Hsemochromatosis," Archives of Inter. Med., 1911, viii, 75. DISTURBANCES OF PIGMENT METABOLISM 
117 
DISTURBANCES OF PIGMENT METABOLISM 
Pathological disturbances of metabolism are by no means limited to pro- 
teins, carbohydrates, and fats, but involve irregularities in the formation 
and distribution of many other substances which ordinarily serve a normal 
function. Were we better informed, it would be most logical to discuss 
each of these according to its chemical nature and relations, but we know 
so little that we can hardly escape from the temptation to group them 
according to some striking peculiar feature. It is for this reason alone 
that we discuss in one chapter pigments which are often hardly related, 
except through the fact that they are colored. 
Most of these pigments serve important purposes, and very little of their 
history concerns pathology except when, like the slag heap that indicates 
the activity of a smelter, they show by their accumulation the presence 
of some unusual activity in the body. Ordinarily, enough of the coloring- 
matter of the skin or hair is produced to confer on the animal those colors 
which are the beauty of the animate world, and which serve so well in the 
protection and even in the propagation of each individual's life. Or they 
are concerned in the interior of the body with the mechanisms for carrying 
oxygen to the tissues and in the production of bile, and an exquisite econ- 
omy is observed in their use and the maintenance of their proper propor- 
tions. Only when something disturbs these mechanisms do we find the 
pigments or disjointed by-products in their formation accumulated some- 
where in excess, or, on the other hand, lost to the body to such a degree 
that it lacks its normal colors. 
Certain colored substances are formed in the body and elaborated to 
typical forms, although we may meet, too, with less complex materials which 
are destined to be built up into these type forms or are the results of their 
decomposition. These are endogenous pigments. Beside these there 
are foreign materials-colored particles breathed into the lungs or taken 
into the stomach or through the skin, or fluids which impregnate the body 
with colored deposits, and these are called exogenous pigments. 
Endogenous Pigments 
Of these, several kinds are met with, the principal ones being those which 
are specially produced to color the skin, and hair and eyes, usually grouped 
as the melanins, those which are directly or indirectly derived from the 
haemoglobin of the blood, and those which are somehow associated with 
fat-like substances and come from the wear and tear and breaking down of 
the tissue-cells. 
Melanins.-The melanins may assume various colors, but are usually 
dark brownish or black. Their enormous variety and the ways in which 
they normally occur more abundantly in those races exposed to sun and 
wind, their abundance largely dependent upon hereditary powers of the 
cells, their rapid appearance in the form of tan and freckles in response to 118 
TEXT-BOOK OF PATHOLOGY 
exposure-all these things are hardly our concern, but belong to the field of 
physiology. Still the study of their abnormal production and distribution 
may throw some light upon their normal origin. Melanins are complex 
substances containing no iron, but rich in sulphur. Much discussion has 
arisen as to their origin and as to their chemical nature, but since no two of 
them seem to have the same composition, the latter point still remains 
obscure. In general, it is found that such substances may be produced 
by the action of oxidizing ferments, such as tyrosinase, upon materials like 
tyrosin, ornithin, etc., which 
contain the groups pyrrol, 
pyridine, skatol, or indol, 
but that it is hardly possi- 
ble that melanin should 
be produced from haematin 
unless some other, sulphur- 
containing substance be 
brought into the reaction. 
The evidence seems to be 
entirely against the origin 
of melanins from the con- 
stituents of the blood. On 
the contrary, it was shown 
by Wieting and Hamdi and 
others that these granules 
are formed in the epithelial 
cells apparently especially 
as products of the nucleus, 
and although they may be 
held for a little in these 
" melanoblasts, " they may 
also be given over to other 
wandering cells of connec- 
tive-tissue origin, the chro- 
matophores. Thus the pig- 
ment of the eye is thought 
to be formed in the retina 
and secondarily transferred 
to the cells of the choroid. 
Except in a few cases, we are not at all well informed with regard to the 
abnormal development of melanins in the skin. There are pigmentations 
which are doubtless only accentuations of the normal, and occur chiefly 
in the most pigmented areas of the body, such as the chloasma of tuber- 
culosis and of pregnancy, in which brownish flecks appear on the face and 
body, and the areolae of the nipples, axillae, etc., become more deeply colored. 
Probably, too, in the healing of many destructive skin diseases, and in the 
Fig. 48.-Melanotic sarcoma. Secondary nodules 
in liver. DISTURBANCES OF PIGMENT METABOLISM 
119 
area about an old healing ulcer, increase of melanin produces part of the 
brown coloration, although, especially in the latter instance, blood-pig- 
ment plays a part. In Addison's disease, which results from the destruc- 
tion of the adrenal glands, the skin gradually assumes a darker hue until 
finally it is like that of old bronze. Whence this pigment comes we do 
not know, nor are we well informed as to its nature. 
Fig. 49.-Pigmented cells of melanotic sarcoma in contrast with others not pigmented. 
Pressure atrophy of the liver. 
The most striking example of the massive production of melanin is seen 
in the so-called melanotic tumors, which usually spring from the skin 
or from the pigmented tissues of the eye. Such tumors, which in their 
early and apparently innocent stages are known as moles or pigmented 
naevi (Fig. 504), seem to be derived from the melanoblasts, inasmuch as 
their metastatic nodules continue to form melanin, which could not be 
expected of mere pigment-carrying cells, the chromatophores. The weight 
of evidence in the prolonged strife as to their sarcomatous or carcinomatous 120 
TEXT-BOOK OF PATHOLOGY 
nature is apparently with those who hold that they are really of epithelial 
origin. Growing with extreme rapidity and invading the most distant 
parts of the body arid of pigment, these tumor-cells continue to manu- 
facture such quantities of coloring-matter that not only is the mass itself 
coal black (Figs. 48, 507), but the pigment is carried away and appears 
in the urine either as such or in a modified, colorless form, which turns 
again on exposure, or when an oxidizing substance is added, to pigment 
which stains the urine black. No one seems to have followed very precisely 
the wandering of this pigment, although it is known that melanins injected 
into the circulation of an animal become decolorized by the reducing action 
of the tissues, only to blacken again when they are oxidized. 
Ochronosis is a rather rare condition in which a brown or blackish 
pigment, probably allied to the melanins, is deposited especially in the 
cartilages and ligaments, but also in the aorta and sometimes in the kid- 
neys. The patient becomes conspicuous on account of the bluish color 
that shimmers through the skin, where, as on the nose and ears, the pig- 
mented cartilages are near the surface. It is due to metabolic disturbances 
often accompanied by alkaptonuria, or to the introduction of small quan- 
tities of such a substance as carbolic acid, as in the prolonged treatment of 
an ulcer with that antiseptic. Poulsen thinks that the pigment is pro- 
duced by the action of such a ferment as tyrosinase upon tyrosin or homo- 
gentisinic acid, or upon derivatives of the phenol introduced by the surgical 
dressings. 
The malarial parasite, while still within the red blood-corpuscle, pro- 
duces particles of a shining, brownish-black pigment at the expense of the 
haemoglobin-containing cell. This is probably derived directly from the 
haemoglobin, although it is iron free and by most authors regarded as a 
form of melanin. The remainder of the haemoglobin dissipated in the 
plasma after the parasite breaks out of the cell forms an iron-containing 
pigment. Spleen, liver, and other organs become so laden with a combina- 
tion of these pigments as to be quite blackened (Figs. 383 and 384). 
Of the second group of endogenous pigments, those derived from the 
blood, we may distinguish several forms. The source of all is haematin, 
which, in combination with a globin, forms haemoglobin, and it is after the 
haemoglobin has been set free from its suspension in the corpuscle that the 
decomposition may take place. Many things, ranging from distilled 
water through a series of organic or inorganic poisons to the most subtly 
modified blood-sera, may act as haemolytic substances capable of dis- 
integrating the red corpuscles and setting free the haemoglobin. If it be 
thus set free in large amounts in the general circulation, it may be excreted 
through the kidneys, producing the so-called haemoglobinuria. This is 
not an uncommon accompaniment of malaria in some countries (black- 
water fever), and there has been much discussion as to whether it is caused 
by the malaria or the quinine given to cure it. 
Another form occurs in paroxysmal attacks in certain predisposed per- DISTURBANCES OF PIGMENT METABOLISM 
121 
sons whose red corpuscles seem very fragile and liberate the haemoglobin 
on the slightest injury. Even the mere exposure to cold produces an excre- 
tion of haemoglobin, and it has been found that this is because the haemolytic 
substances present can combine and act only at a low temperature. The 
kidneys become loaded with clumps of a yellowish material which seems 
to have come through the glomeruli and lodged in the tubules. In a 
similar way poisoning with chlorates produces the excretion of a modified 
haemoglobin, methaemoglobin, and that with sulphonal and allied poisons 
causes the appearance of iron-free haematoporphyrin. 
Some bacteria have the power of causing haemolysis, and in general in- 
fections, where the blood becomes filled with these bacteria, there is much 
destruction of red corpuscles. After death the laked blood stains the tissues 
so that at autopsy the walls of the heart and the linings of the blood- 
vessels are of a dull red color. Through the walls of the superficial veins 
this color may diffuse to such an extent that one sees a network of purplish 
bands shimmering through the skin. Nor is this cadaveric staining 
exclusively the effect of such general infections, for in any body which has 
lain some time after death the tissues which are in contact with large accum- 
ulations of blood are stained deep red. It is not particularly a patho- 
logical phenomenon, but one which might confuse the unwary. 
Pigments Arising From the Decomposition of Haemoglobin.-Ordinarily, 
although, as we know, the red corpuscles circulate intact only a relatively 
short time, so that in every hour millions of them fall to pieces, there is no 
noticeable coloring of the blood-plasma with haemoglobin. Nor is the 
haemoglobin excreted from the body in the urine-instead, it is taken up 
by various cells and converted into different sorts of yellowish-brown pig- 
ment. Just here our knowledge of the process proves somewhat incomplete, 
but it is generally accepted that the liver forms bilirubin from such raw 
material, while if the blood is laked in a mass, as, for example, in some 
cavity of the body, so that it is not, except at its edges, in contact with 
living cells, a reddish-brown pigment, called hematoidin, is formed, which 
most authors think is identical, or at least isomeric, with bilirubin. When, 
however, the haematin or the whole haemoglobin is taken up by living 
cells, there may be formed another yellowish-brown, granular pigment- 
hemosiderin. These are the main types, although there are others of less 
importance. Of bilirubin we shall speak in connection with jaundice. 
Like it, haematoidin is an iron-free substance (C16H18N2O3) which occurs 
in amorphous or crystalline form, or sometimes as a diffuse staining of 
tissue. It is often recognizable in the central portions of large haemor- 
rhagic infarcts, in thrombi or old haemorrhages, sometimes in cysts in 
which haemorrhages have occurred, as in the thyroid, or in the brain in 
healing apoplectic haemorrhages. Rich has shown that this pigment is 
formed within phagocytic cells in crystalline form, both in living animals 
and in tissue cultures. It is therefore probable that at least a part of 
the haematoidin found in the old haemorrhages has been merely left by 
dying cells. 122 
TEXT-BOOK OF PATHOLOGY 
It is probably relatively inconspicuous as contrasted with the third 
of these colored materials, the haemosiderin. To this we can give no 
formula, for it is merely a mixture of pigments in which iron exists in 
a most accessible form, so that its presence may be readily shown by the 
application of the Prussian-blue reaction. Haemosiderin is the common 
blood-pigmerit which results upon any small extravasation of blood into 
the tissues, in so far as that blood is not immediately reabsorbed as such. 
Bilirubin is probably there too, but is not visible except when it occurs in 
crystalline or amorphous form. Thus in every sort of wound and bruise, 
in every sort of inflammation in which red corpuscles escape from the 
vessels, in purpura, in scurvy, and in every other disease where there are 
ecchymoses or more extensive haemorrhages into the tissues, or about the 
Fig. 50.-Haemosiderin in phagocytic cells near an organizing thrombus. 
stings of insects or reptiles, haemosiderin may be found after some days. 
When the poison is of a haemolytic character, and, in fact, in any condi- 
tion in which blood or the coloring-matter of blood escapes into direct 
contact with the tissues, there may be formed in the phagocytic cells yel- 
low or yellowish-brown, shapeless granules of this pigment (Fig. 50). 
A few common examples may illustrate the mode of occurrence of this 
pigment. In old insane persons, especially, perhaps, those forms of insan- 
ity arising from syphilis and chronic alcoholism with arteriosclerosis, one 
may find lining the dura mater a thick, blood-stained membrane which 
will peel off in thin layers and which, on being washed free of blood, proves 
to have an ochre or orange-yellow color. This so-called chronic hcemorrhagic 
pachymeningitis may be the result of a single haemorrhage, but is usually 
produced by something, perhaps itself a small haemorrhage, which causes DISTURBANCES OF PIGMENT METABOLISM 
123 
the formation of a thin layer of vascular granulation tissue from the cap- 
illaries of which new haemorrhages occur and cause the growth of a new 
layer of tissue. In the wandering phagocytic cells which pervade this 
tissue haemosiderin appears in granules which give the yellow color to the 
whole. A quite similar rusty-brown membrane may be found in haemor- 
rhagic hydrocele sacs where the tunica vaginalis testis has long been 
inflamed. Sometimes a haemorrhagic infarction of the lung may heal, and 
the area, once turgid with crumbling red corpuscles, is found shrunken and 
firm with scar tissue and of the color of a mass of iron rust. In the interior 
much of the pigment may be the iron-free haematoidin, but that in the 
more marginal portions is found to stain blue with ferrocyanide and hydro- 
chloric acid, and to be made up of amorphous granules inclosed in cells 
which are often fairly bursting with their load of pigment. Again, when 
the mitral valve is contracted so that blood does not readily escape from 
the lungs, we may find them distinctly brown on section. A piece of such 
a lung washed free of blood and dipped in ferrocyanide of potassium and 
then in weak hydrochloric acid becomes bright blue, and we find that 
Fig. 51.-Heart-failure cells in the lung. Chronic passive congestion. 
this is because blood-corpuscles have for months oozed into the alveolar 
cavities, and have there given up their haemoblobin, to have it converted 
into phagocytes, probably the alveolar epithelial cells, into haemosiderin. 
Microscopically, these cells are seen, swollen with yellow granules, lying in 
the alveoli or in the sputum which has been coughed up from the lung. 
Their dependence upon this chain of events has given them the name 
"heart-failure cells" (Fig. 51). 
Arnold finds that many of the iron-staining granules are due to the 
assimilation of fluid iron-holding material by the specific granules of the 
cell protoplasm, and not to mere engulfing of haemosiderin granules by 
phagocytic cells, and Neumann states, too, that in the heart-failure cells the 124 
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pigment masses often have a coal-black central point and are really formed 
by the incrustation of particles of soot by the iron-containing haemosiderin. 
Not in all cases is the formation of haemosiderin such a local process, 
however, for there are many forms of general anaemia in which the destruc- 
tion of the red corpuscles, usually by some unrecognized agency, sets free 
continuously a great excess of haemoglobin into the circulating blood. 
This may cause the production of an excess of bile-pigment or it may result 
in a wide-spread deposition of haemosiderin in the cells of many organs. 
In the so-called pernicious anaemia, of whose true nature we are ignorant, 
Fig. 52.-Haemosiderin granules in the liver-cells and endothelium. Pernicious anaemia. 
the cells of the liver and often of the cortex of the kidney, spleen, etc., 
become laden with haemosiderin in fine granules (Fig. 52). 
In haemochromatosis, a disease of which mention has already been made, 
there is an even greater deposition of haemosiderin and of another iron-free 
pigment, haemofuscin, without any extensive destruction of red corpuscles. 
We know that such pigment is transported from one part of the body 
to the other, and transferred from cell to cell, and that much of it reaches 
the bone-marrow, where it must be thought of as furnishing, according to DISTURBANCES OF PIGMENT METABOLISM 
125 
the economical scheme, the iron-rich material for the formation of new 
heemoglobin by the erythroblasts, but that step in the process is far from 
clear. When there has arisen in any way a deposit of haemosiderin in the 
tissue of the intestinal wall or in the liver and spleen, decomposition of the 
body after death or even the excessive formation of hydrogen sulphide 
in the intestine or in the infected peritoneum may give rise to the forma- 
tion of black iron sulphide throughout the superficial layers of the tissue. 
This is pseudomelanosis. 
The third group of endogenous pigments may be more briefly dismissed, 
since we know little to tell of them. Nevertheless, we may probably look 
forward to learning some day that their significance is greater than we have 
thought. These are the yellowish granules which are found in many 
organs, such as the seminal vesicles, heart muscle, ganglion-cells, and prob- 
ably also the interstitial cells of the testes and the cells of the corpus luteum 
and adrenal. They give something of the characteristic color to the organ, 
and in some cases this color is intensified when the cells of the organ waste 
away. It seems that the pigments are in some instances produced from the 
cell protoplasm in the process of wasting, wherefore Lubarsch and Sehrt 
call them "wear and tear pigments." Others have loosely called them 
lipochromes, but they do not give the reactions which have been set forth 
for the "true" lipochromes, such as have been found in plants and are 
found in fats, and perhaps in the lutein cells of animals. Their distinctive 
feature is that they are in a sense colored lipoids and stain brightly with 
Sudan and other fat stains. Perhaps the best example of their accumula- 
tion in gross is seen in the wasted, shrunken heart of old or cachectic people 
(brown atrophy of the heart). There the muscle has a chestnut-brown 
color, and microscopically the spaces at the ends of the nucleus in the 
narrow, thread-like muscle-fibre are filled with brown granules which are 
shining and red after staining with sudan. Of course, they are normally 
there, but they are vastly more abundant in the brown, atrophic heart 
(Fig. 26); 
Jaundice.-Jaundice or icterus results from the diffusion of bile-pigment 
throughout the body, with imbibition of the tissues. There has been and 
still exists an active dispute as to whether this pigment is necessarily the 
bilirubin formed by the liver-cells, or whether from the laked blood the 
same pigment can be formed by other tissues. This question appeared to 
be settled by the experiments of Minkowski and Naunyn, Moleschott, 
and others who rather crudely destroyed the liver in geese and were then 
unable to produce jaundice. But recently evidence has appeared in favor 
of the opposite view, and Dr. Whipple even tells me that, after ligating off 
all connection between the thorax and the abdomen in dogs, so that the 
heart pumped blood only through the head and thorax, the introduction 
of laked blood was quickly followed by the staining of the tissues with 
unquestionable bile-pigment. The recent studies of Rich show that the 
ligation as carried out in these experiments did not exclude the liver from 
the circulation, so that the evidence is of no value, and that after real 126 
TEXT-BOOK OF PATHOLOGY 
exclusion of the liver the formation of bile-pigments in the rest of the body 
is definite, but slow, so that only the faintest trace appears after several 
hours. 
Although such an extrahepatic formation of bilirubin can occur, it ap- 
pears probable that the pigment is chiefly produced within the liver under 
normal conditions, and in nearly all cases it is from some disturbance in the 
liver and its ducts that we have jaundice. Since the yellow color appears 
over the whole body, and is easily shown to be due to the presence of bile 
in the circulating blood, the bile must pass into the circulation instead of 
the intestine by way of the ducts. According to most observers this takes 
place by way of the lymphatic channels, but there are those who believe 
that it passes directly into the veins. Bloom has shown that in the early 
stages this transport is entirely by way of the lymphatics to the thoracic 
duct. Later, after disintegration of the liver cells which form the walls 
of the bile canaliculi, the pigment may enter blood capillaries. With the 
appearance of jaundice the patient is usually depressed, his pulse is slowed, 
and his skin itches. The bile-pigments and acids appear in the urine, 
which, when the jaundice is intense enough, becomes brownish green and 
gives a green froth. The coagulation of the blood becomes slowed, and sur- 
geons hesitate to operate upon jaundiced persons lest they bleed to death. 
Minkowski held that jaundice might result from the secretion by the 
liver-cell of its product through the outer side directly into the lymph- 
sheath of the liver-cell cord. Eppinger, in his recent monograph, ascribed 
many forms to the plugging of the bile capillaries by solid, thrombus-like 
masses, which seem to result from the passage into the capillary of an 
albuminous, coagulable substance. Certainly it seems clear enough that 
when a gall-stone lodges in the common duct, or even when several gall- 
stones lodge in branches of the hepatic ducts, we have cause for jaundice 
(not so, of course, when the cystic duct is obstructed nor when the gall- 
bladder is full of gall-stones, for that whole apparatus serves only as a 
reservoir). So, too, when a tumor fills up the common duct or, growing 
outside, compresses it. A tumor of the pancreas or of the stomach may 
do this, and secondary nodules or metastases from such tumors growing 
in the liver may compress the branches of the hepatic ducts (cf. Fig. 
548), and, by producing local areas of obstruction, cause nearly as 
intense jaundice. 
One sometimes sees the most profound jaundice as the result of an ascend- 
ing growth of bacteria along the mucosa of the gall-ducts, with the pro- 
duction of abscesses about their terminations (cholangitic abscesses). 
This seems rather due to the occlusion of the ducts themselves than to 
any pressure on the ducts leading from other parts of the liver, for one 
may have numerous large abscesses produced by amoebae or by bacteria 
brought in through the portal vein without any appreciable jaundice. 
In the cases in which obstruction is produced far down in the common 
duct by the pressure of a tumor, the gall-ducts are found dilated and thinned DISTURBANCES OF PIGMENT METABOLISM 
127 
out, and the gall-bladder is dilated to its extreme capacity with bile. In 
those cases, however, in which the obstruction arises from the impaction 
of gall-stones which have lain in the gall-bladder or in the branches of the 
hepatic ducts, one usually finds the ducts roughened and thickened and the 
gall-bladder likewise contracted and thick walled (Courvoi sier's law). 
Such is the jaundice from obvious mechanical obstruction. Slightly 
different only is the common form, in which an inflammation of the mucosa 
of the gall-duct, with abundant mucus formation, may be sufficient to cause 
transient jaundice. This may reach the deepest bronze if the inflammation 
is intense enough and involves the minuter ducts in the liver, as it is sup- 
posed to do in the so-called biliary cirrhosis. 
Other forms of jaundice are harder to explain. Thus in acute yellow 
atrophy of the liver, which is undoubtedly only a name applied to the wide- 
spread necrosis of the liver which might result from the action of many 
different poisons, there may be the deepest jaundice, although there is no 
obvious obstruction to the gall-ducts. This may fit in with the idea which 
forcibly suggests itself (McNee, Eppinger, Rich, and others) that the bile- 
pigments are really elaborated by the Kupffer cells and turned over to the 
liver cells for excretion into the bile canaliculi. The Kupffer cells need not 
be destroyed in this disease, but the aid of the liver cells in pouring the bile 
into the ducts is lost. So it must be in cirrhosis of the liver, which we may 
look upon as the healing of repeated slight injuries of a similar type, with 
eventual reestablishment of interrupted connections between the liver- 
cell cords and the bile-ducts, or in the cell cords themselves. In those 
cases in which the loss of tissue affects whole lobules we are perhaps 
less likely to find jaundice than in those in which minuter lesions destroy 
merely a few cells here and there, but none the less interrupt the continuity 
of the bile capillary. Still the reestablishment of these connections is very 
rapid and effective, and, after all, jaundice occurs in cirrhosis chiefly in 
those cases in which there are infection and swelling of the mucosa of the 
gall-ducts. 
The jaundice which is produced by toxins and haemolytic substances 
has much in common with that seen in such infectious diseases as pneumonia 
and general septicaemias. Stadelmann produced icterus experimentally 
with injections of toluylene-diamine, arseniuretted hydrogen, etc., and 
found not only haemolysis, but the production of quantities of bile so thick 
that it practically blocked the gall-ducts. In this sense he regards it as 
an obstructive jaundice, and Eppinger supports him by finding his bile 
thrombi plugging in these cases the bile-capillaries. In the infectious 
forms no such obstruction could be found by Eppinger or Abramow, who 
have studied the subject. The pathogenesis in these cases is still in 
question, and they, with the toxic haemolytic forms, constitute the chief 
material for the support of the idea of a true haematogenous jaundice with- 
out the intervention of the liver. 
Jaundice of the newborn is also obscure, although, of course, the types 
caused by syphilis or by congenital atresia of the duct, etc., are clear 128 
TEXT-BOOK OF PATHOLOGY 
enough. The common form, which lasts about two weeks and is peculiar 
in showing no tinting of the sclerae nor any bile in the urine, seems to be 
definitively not an obstructive process. Another type of jaundice has been 
studied recently which shows many peculiarities. This is a congenital 
hereditary affection, thus often occurring in several members of a family, 
and is associated with a marked anaemia and enlargement of the spleen. 
Fig. 53.-Bile-canaliculi in jaundice plugged with bile-pigment (a, a). Phagocytic cells 
in capillaries containing similar plugs of bile-pigment (b, b). 
Iron therapy, which improves the anaemia, seems to cure some of them, 
and in one case which I saw splenectomy produced a complete cure. 
Microscopically, in advanced jaundice, one finds a diffuse staining of the 
tissues, but in the liver especially there are masses of green bile-pigjnent 
forming casts of the bile-canals, and especially branching moulds in the 
intercellular bile canaliculi, which are dilated and distorted and often 
ruptured by these accumulations. It is the denser portions of these moulds 
that Eppinger regards as bile thrombi, formed with the addition of some 
coagulable material, and causing evident obstruction of the canal (Fig^ 
53). DISTURBANCES OF PIGMENT METABOLISM 
129 
The liver tissue is seen to be rather disorganized and broken where this 
occurs, and there is a diffuse staining of the liver-cells about the plugs of 
green material. Beside this one may see that the endothelial cells of 
the blood-capillaries are stained green, and that there are many large 
phagocytic cells with clear cytoplasm, but loaded with fragments of the 
green plugs, lying in the capillaries. These have a single nucleus, although 
they are often accompanied by many leucocytes and are probably to be 
regarded as the phagocytic cells of the endothelium, which in the liver are 
known to be so active. 
Exogenous Pigments 
These are nearly always relatively simple substances, which get into the 
body in some way and color the tissues. Most common are those found in 
Fig. 54.-Anthracosis of bronchial lymph-gland. Hyaline alteration of gland tissue. 
the various dust diseases, or konioses, in which the lungs become loaded 
with the particles which are breathed in by those who ply a dusty trade. 
The miller fills his lungs with flour, the smoker with soot, the coal-miner 
with coal-dust (anthracosis), the grinder with metallic dust (siderosis) or with 
the dust from cut stone (chalicosis), and so on. These should be called 
pneumonokonioses, and their variety is as the variety of dusts. The most 130 
TEXT-BOOK OF PATHOLOGY 
common is the ordinary, practically universal anthracosis, which is found 
in every one and every animal of sufficiently advanced age, especially if 
they live in a city. The pigment is sometimes in discrete patches, collected 
along the interlobular septa, but when it is very abundant, as in the coal- 
miner, it fills almost all the tissues of the lung. Such lungs are often very 
hard on account of the constant attempt at encapsulation of the pigment 
in scar tissue, and some pigments are so irritating and require so dense a 
capsule that the lung tissue becomes almost stony (Fig. 54). 
The nature of the coal-pigment has been disputed, and it probably is a 
mixture of soot and a great variety of insoluble particles, but Traube was 
able to show in some lungs, doubtless those of actual coal-miners, that the 
granules were really fragments of carbonized coniferous plants, as could 
be seen from the characteristic bordered pits of the cells which had per- 
sisted throughout. Engulfed by phagocytic cells in the alveoli, or even in 
the free state, these particles gain entrance to the lymphatics of the lungs, 
and are carried, probably with frequent interruptions and transfers, to 
other phagocytic cells, to the bronchial lymph-glands, which are blackened 
and indurated by their presence. These glands are often found adherent 
to the pulmonary veins in such an intimate way that there may arise an 
actual transfer of pigment to the vein-wall, or even a hole in the wall 
through which pigment is swept into the blood-stream. This may explain 
the occasional presence of coal-pigment in the abdominal lymph-glands or 
in the spleen and liver, for it has been found that little if any of the dirt 
and colored matter taken into the intestine passes through the walls into 
the lymph-glands. 
Metallic dust may be inhaled, and colored substances derived from it 
distributed in the tissues. Most striking is the rusty pigmentation of 
phagocytic cells about a needle or any other iron particle which has long 
been embedded in the tissue. These cells look almost as if they had actually 
gnawed off particles of the metal and carried it away. The same thing is 
true of the silver sutures used by some surgeons and left in the tissues. 
Years afterward they may be recognized by a gray cloud about them, which 
is found to be due to the presence of swarms of branching cells loaded with 
fine particles of blackish silver. The long-continued administration of any 
silver salt by mouth, as was once the habit in the treatment of epilepsy, 
gastric disturbances, etc., often led insidiously to the production of argyria, 
in which the skin, connective tissues, and the framework of various organs 
assumed a leaden color from the fine deposit of what is probably a silver 
albuminate. Any one who has ever seen one of these victims can never 
forget the ghastly gray-blue color of his face and hands. 
The lack of normal pigments is, of course, quite as important a divergence 
from the normal as their unusual accumulation. Hereditarily some persons 
possess very little pigment anywhere in the skin, hair, or eyes. These are 
albinos, who, although their melanins are scant, have a normal store of DISTURBANCES OF PIGMENT METABOLISM 
131 
haemoglobin. They suffer from the dazzling effect of the light in their 
unpigmented eyes, in which the ordinary effect of the camera obscura is 
much impaired. Localized absence of pigment in patches which are often 
surrounded by skin of denser pigmentation is not uncommon (leucoderma, 
vitiligo), and is a characteristic of some deep scars, in the formation of 
which the melanoblasts seem not to have wandered in. 
LITERATURE 
Eppinger: Ergeb. d. inn. Med. u. Kinderh., 1908, i, 107 
Hueck: Ziegler's Beitr., 1912, liv, 68. 
Lubarsch and Sehrt: Virch. Arch., 1904, clxxvii, 248. 
Poulsen: Ziegler's Beitr., 1910, xlviii, 348. 
Rich: Bull. Johns Hopkins Hosp., 1923, xxxiv, 321. 
Stadelmann: Ikterus, Stuttgart, 1891. 
Wieting and Hamdi: Ziegler's Beitr., 1907, xlii, 23. CHAPTER IX 
DEFENCES OF THE BODY AGAINST INJURY 
Immediate and late reactions to injury. Inflammation, fever, immunity production, and 
repair. Inflammation an elaborate mechanism to combat injury. Details of vascular 
and phagocytic phenomena. The wandering cells. 
Reactions to Injury.-We may say without hesitation, except perhaps 
in the case of tumors of whose origin we are ignorant, that the underlying 
cause of every abnormal change in the body is some sort of injury. Often 
we may see the direct effects of such injuries, but in many cases they are 
confused with the efforts of the body to annul or repair the hurt. 
In the course of ages, through the action of external agencies, the human 
body has been elaborated to its present form, which is marvelous in its 
perfect adaptation in every detail to its uses. Variations from this stan- 
dard in some respects are compatible with life so long as they are not too 
extreme, although they may handicap the individual in his struggle for 
existence. Why such a form should have been developed involves broader 
questions than we can consider here. The same questions arise in connec- 
tion with every other species, and it is a matter of interest to the paleeontol- 
ogist and the general biologist that, once established, such creatures should 
go on transmitting through ages all the details of their structure to their 
offspring, and that individuals should possess the inherent tendency to 
maintain that form and to return to it as they recover from maiming and 
distorting injuries. So great is this tendency in the lower orders of animals 
and in plants that if only a fragment of the body is left it can reconstruct 
the whole. Even in man, such is the tenacity with which the standard is 
adhered to that within the life of the individual great strides are made to 
return to the normal when tissues and organs have been disarranged. 
It seems, however, that there are two distinct chains of events, the first 
being the perfection of a structure and form adapted to the environment, 
but subject to extremely slow variations, which maintain this adapta- 
tion and are hereditary and stamp the species. The second group of 
phenomena is subservient or auxiliary to this, and consists in the develop- 
ment of protective mechanisms which guard the life of the individual. 
But one cannot so sharply classify and divide these things, for they over- 
lap. Mechanisms which protect the individual, form some of the char- 
acters of the species, and the repairing of a wound in the individual is in 
great degree guided by the hereditary tendency toward the form charac- 
teristic of the species and independent of the momentary action of the 
environment. 
132 REACTIONS TO INJURY 
133 
It is this group of hereditary and gradually perfected mechanisms for 
defence that we must discuss. Of these, some are quite simple and obvious 
in their character. The body is covered with a relatively impervious skin, 
further protected in places by hair and nails. It is true that, compared 
with a turtle or a rhinoceros, we are defenceless in that regard, but ordi- 
narily our need is perhaps not so great. Our respiratory tract is lined with 
cilia, which keep dust out of the lungs, aided by sneezing or coughing when 
necessary. Irritating substances are ejected from the stomach by vomit- 
ing. Wounds are warded off by all sorts of reflex muscular movements, 
and so on. All these, in so far as they are functional, have become or were 
always involuntary processes tending toward the protection of the body 
from injury. 
But still injuries occur from mechanical, physical, or chemical causes, 
and from the invasion of living plant or animal parasites, and these in- 
juries, which generally imply the destruction of some of the tissue, call into 
activity several kinds of reactions or responses which have been elaborated 
through ages of natural selection and bequeathed to their offspring by 
those whom they have helped to survive. They are of several types, and 
appear to be rather independent of one another, for some injuries call out 
one, some another, but most often they all come in combination or in suc- 
cession. They are: Inflammation, fever, immunity production, repair. 
Inflammation is a complicated vascular and cellular response, which 
follows almost immediately upon the injury, and is adapted, by bringing 
much blood to the spot and pouring out its elements upon the injured 
tissues, to prevent the extension of the injury, hold in check the injurious 
agent, or even destroy it. Through the agency of some of the cells which 
are brought in, and in other more purely mechanical ways, it is also im- 
portant in clearing away the debris of injured or dead tissue and preparing 
the way for the process of repair. 
Fever is another complex response through which, by certain changes in 
the heat-regulating mechanisms, the temperature of the body is raised 
chiefly through the saving of heat. It is thought that this is bound up 
with- 
Immunity production, a response to certain types of injury which quietly 
and slowly forms substances specifically adapted to annul and prevent the 
inroads of that particular injurious agent. Sometimes this power remains 
inherent in the tissues for life. 
Repair is the new formation of tissue to replace that which was de- 
stroyed. It may be local, in which case the repair is often a kind of patch- 
ing with tissue of a different sort. Or it may occur in addition at a dis- 
tance from the point of injury, and consist in the new formation of the sort 
of tissue which was destroyed in such a way as to make up for the defi- 
ciency which its loss occasioned. Then it is often called compensatory 
hyperplasia. 
Repair must, therefore, not be confused with inflammation nor regarded 134 
TEXT-BOOK OF PATHOLOGY 
as a part of it. It is true that the result of the local tissue growth is not 
always what we should regard as the ideal outcome of an attempt at heal- 
ing. Awkward scars or an altogether excessive mass of fibrous tissue may 
be produced which may even interfere seriously with the function of the 
organ and be entirely out of proportion with what would seem necessary 
for the repair of the actual gap first produced by the injury. Usually this 
is because the injurious agent persists and repeatedly frustrates healing 
by injuring the repairing tissue itself, so that layer after layer of this new 
tissue is laid down and consolidated into a firm scar. Possibly this might 
not be so to such an extent were it not for the inflammatory outpouring of 
fibrin which it has become the habit of this mechanism to replace by 
fibrous tissue, rather than to remove in any other way. 
It is a mechanism like the others which seems to have been perfected 
through long generations toward a rather complex end, for not only does 
it repair gaps in the tissue, but it is protective in the sense that it brings 
about the encapsulation of any noxious material and prevents its further 
influence upon the neighboring tissues. While we are familiar with its 
ordinary course, and can even prophesy what will happen in a given case, 
we are not so well informed as to the exact mechanism which impels these 
cells to grow. If, therefore, we speak of the impulse to repair, or dis- 
turbance in the equilibrium of tissues, or, on the other hand, of chemical 
or mechanical stimuli acting directly upon the cell and causing its pro- 
liferation, we are using vague terms, all of which may possibly have the 
same meaning. 
This reaction, like the others, is imperfect, and may produce unsatis- 
factory or even harmful results; but if the person survives, there is set at 
work a remodeling process through which, in time, much is done toward 
restoring the tissues to the normal standard. This involves other mechan- 
isms which obliterate blood-vessels in one place and form them in another, 
rarefy and fret away tissue at one point or strengthen it at another. Sel- 
dom does any one live long enough to have this completed, but we find 
evidence at autopsy that it has been at work. 
INFLAMMATION 
According to the definition of inflammation given above, it seems pref- 
erable to use this name for the immediate protective and defensive reaction 
to an injury. It is a complex phenomenon, elaborated to a certain degree 
of perfection in which the blood-vessels with their contents and the wander- 
ing cells from adjoining regions play the greatest parts. Its aim seems to 
be the prevention of further injury by antagonizing the injurious agent, 
and this must be thought to include the solution and removal of foreign 
materials (which may be the dead cells themselves) because such material 
is in itself a cause of injury. 
The removal of foreign material or of cellular debris may take place, as 
in the desquamation of the epidermis or the bursting of an abscess by me- INFLAMMATION 
135 
chanical means, which hardly form part of the inflammatory reaction, so 
that perhaps this process of cleaning up the field so that repair may occur 
may be regarded as incidental to the main aim of combating the injury. 
At any rate, the reaction seems to be quite distinct from the process of 
repair. It is confusing, however, that inflammation, cleansing of the site 
of injury, and repair commonly overlap and proceed together inextricably 
mingled in the same area. One might construct a simile in which the fire 
department, hurrying to a burning house, represents the inflammation, 
although often long before the fire is extinguished workmen are found carry- 
ing away the charred timbers and enthusiastic carpenters are rebuilding 
wherever they can approach near enough. If this combination of activi- 
ties be carried on for a long time, it is easy to foretell a curious distorted 
building as the result of the carpenters' efforts. But would any one say 
that it was the fire that had directly stirred the carpenters to work? 
We must discriminate between the direct effect of the injurious agent 
upon the tissues and the inflammatory reaction. This direct effect may 
be the killing of some of the cells, with further injury not sufficient to cause 
death, diminishing as one passes away from the point at which the destruc- 
tive agent impinged upon the tissue. Sometimes the injury is hardly 
visible, although it stirs up an intense inflammation, but generally it is 
necessary that at least a few cells be killed, that this may result. Exten- 
sive injuries which cause metabolic disturbances in the cells may arouse no 
inflammatory reaction at all; cells may gradually waste away from disease 
or malnutrition or from pressure, as in a hydronephrotic kidney, and there 
is little or no inflammation; but let a few cells die and coagulate into what 
is virtually a foreign body, or introduce any foreign body, and an inflam- 
matory reaction appears at once. This reaction is not attuned to all sorts of 
injuries, nor even necessarily to the most severe, for a man may have his 
leg cut off by the surgeon and the wound will heal with evidences of an 
inflammation which is directed toward the annihilation of the few dying 
cells which happen to have been cut in two in the line of incision, quite 
regardless of the more serious catastrophe that the man had lost his leg. 
Or a vein may be opened aseptically and an animal bled nearly to death; 
wonderful reparatory processes will occur in the distant bone-marrow to 
restore the blood, and fluid will pqur from the tissues into the blood- 
vessels, but there will be no inflammation. Cauterize the wound, however, 
with a hot iron or with boiling oil, as they did in the time of Pare, and the 
inflammatory reaction will appear in its full force. We are tempted to 
ask whether, after all, inflammation as a reaction responds only to the 
presence of dead cells, and their diffusible decomposition products, and 
whether, in the course of the development and elaboration of the reaction, 
this has evolved itself as the general signal for inflammation, but we know 
that we may greatly intensify the reaction by the use of some other more 
irritating substance to kill the cells. 
Given the adequate injury, the inflammatory reaction begins with a 136 
TEXT-BOOK OF PATHOLOGY 
red flush. It can be followed in any place near the skin, perhaps especially 
well, as Samuel pointed out, in such an object as the rabbit's ear, where the 
blood-vessels can be seen, but for the minute details it is best to study with 
the microscope such transparent tissue as the mesentery or tongue of the 
frog or the wing of the bat. If the tip of the rabbit's ear be painted with 
croton oil or dipped in hot water, the whole process comes on with a rush. 
First, after a momentary contraction, there is the widening of the arteries 
Fig. 55.-Portion of inflamed diaphragm cleared by Spalteholtz's method to show the 
abundant dilated blood-channels. 
and veins, so that the blood courses through them very rapidly, and simul- 
taneously the widening of all the minute arterioles and venules in the af- 
fected area, so that channels come into view which were evidently com- 
pletely collapsed before (Figs. 55 and 56). This much is commonly attained 
if, by compressing the veins or by cutting the sympathetic nerves, we cause 
the dilation of the vessels. But, in addition, in the inflamed ear, all the 
spaces between these visible widened channels become uniformly red. A 
needle passed through one of these spaces in the mechanically congested 137 
INFLAMMATION 
ear will draw no blood; but in the inflamed ear there is free bleeding from 
the puncture. Evidently, then, the capillaries are uniformly distended 
with blood. While this change takes place at first in the actually injured 
area, it soon spreads to the adjacent part of the ear, and finally even to its 
root or over the side of the head. The ear is much warmer than the other, 
because blood rushes through it so fast that it has the temperature of the 
interior of the body, and it is gone again before there is time to cool off. 
Fig. 56.-Portion of a normal diaphragm, showing in contrast relatively few visible 
blood-channels. 
This lasts only a short time before the ear becomes swollen and the skin 
tense. If it be pinched, the impression of the finger remains for a time. 
It becomes so thick and heavy that it hangs down, and its function must 
thereby be interfered with. Besides it is very tender and even spontane- 
ously painful. At the least touch the animal jerks back as if burnt. Two 
or three days later the artery may be found contracted again to something 
near its normal size. In the injured area the redness persists, though it 
may be a darker, more violet color-the ear is cooler-blood seems to be 138 
TEXT-BOOK OF PATHOLOGY 
passing through the vessels very slowly, and the swelling is gradually pass- 
ing away. It may require ten or twelve days for all to become normal 
again-the part which has actually been injured is the last to recover, and 
then usually with the loss of its surface epithelium, but even there the 
circulation finally returns to the normal, the epithelium is repaired, and the 
inflammation is over. 
If a transparent tissue is selected, the whole process can be watched in 
its development. In the region where the tissue has been injured, and for 
Fig. 57.-Inflamed omentum showing outwandered leucocytes about a small vessel. 
some distance around it, the small blood-vessels are seen to widen. All 
the capillaries are stretched by the increased stream of blood, and con- 
tracted channels, which could not be seen before, reopen, and the blood 
courses through areas which were quite pale before. The stream, pulsat- 
ing in the arterioles and steady in the venules, now rushes through with 
vertiginous rapidity. Though we cannot see it, there is probably even at 
this stage some filtering-out of clear fluid from the vessels into the crevices 
of the surrounding tissue. After a time, although the stream-bed remains 
wide, the current slows down until one loses the impression of a homo- INFLAMMATION 
139 
geneous, yellowish-red fluid hurrying along, and it becomes possible to 
catch glimpses of the corpuscles as they pass. Throughout all this one can 
see that in the venules, where there is no pulsation to disturb it, the ar- 
rangement of the corpuscles is peculiar in that they float in the centre of 
the stream, separated everywhere from the vein-wall by the clear plasma. 
With the slowing of the stream leucocytes begin to appear in this mar- 
ginal stream and are rolled along the wall. They even seem to find the 
wall sticky, so that they adhere now and then, only to be turned over and 
dragged along by the rest. Still later some of them refuse to be dislodged, 
and one can see that they have fastened themselves to the wall by piercing 
Fig. 58.-Acute diffuse inflammation. Tissue is cedematous and shows exudate of 
leucocytes and red corpuscles in a network of fibrin. Some mononuclear wandering 
cells are present. 
it with a protoplasmic process which may even project a little way on the 
outside. Such a leucocyte soon becomes dumb-bell shaped, with half its 
body outside the endothelial wall, the nucleus squeezing its way through 
the small hole forced by the protoplasm. It is not long before the whole 
cell escapes through this gap and wanders away among the fibres of the 
surrounding tissue. These are chiefly polymorphonuclear neutrophile 
leucocytes, which are the most numerous in the blood, and this is the process 
of active emigration which formed the crucial feature in Cohnheim's clas- 
sical observation, and which is one of the most significant occurrences in 
the whole process of inflammation (Fig. 57). 140 
TEXT-BOOK OF PATHOLOGY 
Along with the leucocytes, or behind them, red corpuscles escape pas- 
sively to the outside, and during the whole time fluid has filtered through 
unobserved until now the cells and fibres of the tissue around the blood- 
vessel are spread apart widely by its great accumulation-the inflammatory 
oedema. Since this fluid is coagulable like the plasma of the blood, and 
since there are injured cells in the neighborhood to set free thrombokinase, 
there soon appears a delicate coagulum of fibrin stretching in fine filaments 
through the spaces forced open by the fluid (Figs. 58, 59, 60). 
If the injury is extreme, the current of blood may come to a complete 
Fig. 59.-Inflamed rabbit's ear showing blisters in the skin and inflammatory infiltra- 
tion of the subcutaneous tissue. 
stop in some of the vessels, and there emigration of leucocytes ceases. 
But in the others, although the corpuscles pass along very slowly, enough 
fresh blood seems to be brought to nourish the tissues. 
The leucocytes and the fluid press toward the point where the tissues 
are most injured and surround those cells. If bacteria are present, the 
leucocytes may swallow them unless they have diffused around themselves 
too strong a poison. Then it seems impossible for the leucocytes to ap- 
proach without being killed, perhaps because in order to do this they have 
to pass through dead tissue around the bacteria where they receive no 141 
INFLAMMATION 
oxygen. It is almost like firemen who are checked by the smoke, but keep 
on rushing in past the dead bodies of those who preceded them. 
Finally, as a rule, if the injury is not enough to cause the death of the 
animal, the bacteria are overcome. This is effected by the continued 
action of the fluid and the leucocytes in ways which we shall discuss. Or 
if there have been no bacteria, the dead tissue is permeated by the exuded 
fluid and invaded by the leucocytes. 
Fig. 60.-Acute myositis. Diffuse acute inflammation with mononuclear wandering 
cells as well as leucocytes, red corpuscles, and fibrin. 
After this the process becomes an effort to clean up the debris. Partly 
by self-digestion, partly through digestion by the leucocytes, the dead cells 
and fibres are liquefied or reduced to a fine granular fluid and absorbed 
through the walls of the lymphatics. The dead bodies of leucocytes suffer 
the same fate, and those which remain alive aid by carrying particles 
through the walls of the lymphatics, where they are swept along into the 
next lymph-gland. There any such particles or dead cells are exposed to 
the digestive action of the cells of the lymph-gland. 142 
TEXT-BOOK OF PATHOLOGY 
Thus the area is cleared of debris; the blood-vessels gradually return to 
their normal calibre, their walls again become normal and contract, and 
the circulation resumes its normal rate. Naturally gaps are left in the 
tissue where cells have died and been removed, but the repair of these gaps 
will form another chapter. 
It is seen from this that inflammation is really a complex but well- 
rounded mechanism, designed chiefly to pour over injurious substances 
and dead tissue a fluid and cells rich in neutralizing materials and diges- 
tive ferments, which tend to quench the action of the injuring agent and 
to liquefy the debris for removal. From this point of view it seems a 
purposeful and beneficial reaction. 
Probably every inflammation is accompanied by some general disturb- 
ance, such as fever, of which we shall have more to say later. When 
the injury is intense enough, poison may be absorbed from the injurious 
agent or even from the dead tissue to affect the nervous system and other 
organs and to cause disturbance of their functions, and what we know as 
illness. Even the fever itself may bring along with it disturbances in 
function. In all cases, too, there is likely to be a change in the blood in 
general, consisting in a great increase in the number of leucocytes. This 
leucocytosis is a convenient index of the existence of an obscure inflamma- 
tion, and results from the great over-production of the cells of the bone- 
marrow and their liberation into the blood. 
While the inflammatory reaction may thus happily succeed in over- 
coming the injury and restoring the cleansed area to a condition in which 
it is ready for repair, it is not always so. The injurious agent may persist, 
as in the case of bacterial infections, or it may be frequently repeated, in 
the case of physical or chemical injuries, so that a smouldering fire is kept 
up for a long time. The persistent reaction, which is then often spoken of 
as chronic inflammation, comes to differ from that which is quickly finished, 
chiefly in that, among the wandering cells which appear in the tissue, there 
arrive swarms of mononuclear forms which are slow to move, being at- 
tracted chiefly by dead tissue or other substances unlike those which draw 
the neutrophile leucocytes. The congestion of the vessels and the oedema 
may subside, being kept up chiefly along the frontier. Most confusing, 
however, is the fact that, if so much time is occupied, reparatory processes 
appear and are closely interwoven with those of defensive character. 
The mononuclear cells emigrate in small numbers with the polymorphonu- 
clears in the acuter forms, but now they come in such numbers that one 
cannot escape the idea that many of them wander in from the crevices of 
the adjacent tissue or are even formed in situ by multiplication of those 
which first appear. They assume many forms, and many of them grow to 
a great size as they move about, swallowing up particles of dead tissue or 
even whole cells which have been injured. When the area is finally and 
permanently rid of the injurious substance, and when all the debris of dead 
tissue is cleared up, these cells in their turn slip away into the spaces of INFLAMMATION 
143 
the tissue or into the lymphatics and disappear into distant parts of the 
body. 
With this bare outline of the inflammatory process we may pass to the 
discussion of some of the underlying principles. 
The Widening of the Vessels.-The widening of the blood-vessels is 
probably due to complete paralysis of their walls, at any rate in the actu- 
ally inflamed areas. Klemensiewicz, who holds this idea, showed that the 
vessels of the web of the frog's foot could be made to contract by electrical 
stimulation of the medulla or of the vessels themselves, but if the foot were 
inflamed, no such stimulation affected them in the least. Section of the 
sympathetic fibres to a part allows of a temporary great dilatation of the 
vessels. In the rabbit's ear section of the auricular nerves, on the contrary, 
causes their contraction. Sensory stimulation will reflexly cause vascular 
engorgement, but while all these conditions may be produced first, and 
will thereupon modify the course of an inflammation set up in that region, 
they are quite different from the changes in the vessels which inflamma- 
tion entails, and which cannot be greatly altered by section or stimulation 
of nerves when it is once well developed. Inflammation in a rabbit's ear 
flushed by section of the sympathetic proceeds more rapidly and intensely 
than in a normal ear, and inflammation in a rabbit's ear rendered anaemic 
by section of the auricular nerves goes on imperfectly, so that in the end 
the injured ear becomes necrotic and drops off. But, after all, these are 
only superimposed influences, and, as we have shown, inflammation runs 
its course, complete in each detail, in a limb which has been amputated 
and then reunited by vascular suture, so that there can be no possibility 
of the existence of any nervous connection with the central nervous system. 
Bruce confirmed this and ascribed the vascular widening to an "axone 
reflex," by which he meant that sensory stimuli were transferred to efferent 
vasomotor fibers without reaching the cord or brain. He found, however, 
that if the nerves be allowed to degenerate no such arterial hyperaemia 
occurred. Breslauer confirmed this, and stated that local but not general 
anaesthesia abolished the initial hyperaemia ordinarily produced by the 
application of an irritant. Lubarsch and his students find that in limbs 
deprived of their nerves or locally anaesthetized, the early stages of inflam- 
mation are retarded and perhaps diminished in intensity, but that the 
further course is lengthened and more severe. General anaesthesia has 
only a slight effect in delaying oedema, but not the hyperaemia. The 
nervous system has at most a regulating influence, but does not control 
inflammation. 
The experiments of Dale and others on shock have shown that it is prob- 
able that the paralysis of the capillaries, which is responsible for that con- 
dition, is due to poisoning by some substance resembling or identical with 
histamine derived from injured tissue. If the mangling of muscle or the 
bruising of intestines can allow the diffusion of enough of this poison to 
paralyze capillaries over the whole body, it seems probable that the local 144 
TEXT-BOOK OF PATHOLOGY 
injury of tissue may liberate enough of the same material to poison and 
paralyze the capillaries in the area which becomes inflamed. Dr. Abel 
shows that practically every tissue is capable of producing histamine in 
consequence of injury; indeed, that it can be extracted from normal tissue. 
Rich showed that histamine applied to the blood-vessels of the omentum 
does cause their dilatation, but Bloom found that it produced no emigra- 
tion of leukocytes. One may surmise, therefore, that here we deal with 
two quite separate processes. 
The Changes in the Rate of Flow.-The stream in any given stream-bed 
ordinarily runs more slowly when it reaches a widened stretch, but here, 
where there is a choice of channels, it is more influenced by the friction 
against the wall, and consequently runs through these widened vessels at 
a rate more nearly approaching that in the larger vessels than before. It 
is for this reason that the part feels hot-not that there is any appreciable 
amount of heat produced by increased metabolism in the inflamed area, 
but merely because, in a superficial tissue, the blood, when coursing nor- 
mally, has time to cool, while now there is no such opportunity and the 
temperature of the part approaches that of the interior of the body. 
Probably we could determine no difference in temperature between an 
inflamed loop of intestine and a normal one in the same person. 
The slowing of the stream and the passing out of the leucocytes into the 
marginal or plasma zone are much harder to explain. One is practically 
compelled to think that there is a change in the endothelial lining of the 
vessel of such a character that it becomes rough or sticky, and thus offers 
more friction to the passage of the blood-stream. Some have thought that 
the blood itself becomes thickened by the loss of fluid through the vessel 
walls, and that this increased viscosity might explain the sluggish stream, 
but there is no convincing evidence that the venous blood from an in- 
flamed area has any perceptibly greater viscosity than the arterial blood. 
Indeed, the observations upon the slowing of the stream have usually 
been made upon such an object as the exposed mesentery of the frog, where 
the minute vessels could be examined microscopically, and end, as a rule, in 
complete stagnation of the blood from the intensity of the injury, so that 
I have been disposed to question the occurrence of such slowing in a more 
protected tissue. Schlarewsky and others have shown that any suspended 
particles passing in a stream of fluid through a tube are governed by a 
centripetal force which keeps them in the axis of the stream, but that, 
with slowing of the stream, this force is relaxed, and first the lighter, then 
the heavier, particles are allowed to approach the periphery. Apparently 
this would explain the marginal position of the leucocytes as the stream 
slows, but it does not touch upon their adhering to the wall and finally 
penetrating it. Nor does it throw any light upon their increasing abundance 
in the whole circulating blood, for which two things quite different causes 
must be sought. 
Chemiotaxis and Phagocytosis.-It has been observed, in watching free INFLAMMATION 
145 
swimming amcebse and other unicellular or even multinucleated organisms 
which are mobile and jelly-like (myxomycetes), that their movements are 
largely influenced by changes in their surroundings, or even more definitely 
by physical or chemical stimuli. Of special interest is their behavior 
toward soluble substances, some of which attract, while others repel, them. 
One of the myxomycetes, for example, which grows on tanbark, will move 
actively along a moist surface toward a drop of an extract of that bark, 
while it will move just as actively away from a solution of glucose or of 
some salt. Nevertheless, it can be accustomed to these latter things so as 
to be attracted rather than repelled by them. This is an example of 
chemiotaxis, or the stimulation to motion by a chemical substance, in the 
one case positive, in the other negative. Attempts have been made (A. B. 
Macallum and others) to explain this activity as due to alterations in the 
surface tension of the protoplasmic mass, and apparently this is the true 
basis, although it becomes complicated when we come to explain how the 
response changes as the amoeboid organism accustoms itself to a repellent 
substance and is finally attracted by it. Probably a similar explanation 
will hold good for the tactile irritability which is evident in those amoebae 
or other cells which come into contact with some insoluble particle. In 
such a case the protoplasm flows around the particle and encloses it com- 
pletely unless it is too large, when it spreads itself over the mass as far as 
possible. 
This is the process of phagocytosis in its beginning, and both it and chemi- 
otaxis are things which can be closely simulated by non-living substances. 
Thus a drop of chloroform in water will stretch itself along a thread of 
shellac brought against it, and, dissolving it as it goes, keep moving along 
the thread until it is saturated. 
All of this applies equally well to the mobile cells of the body, par- 
ticularly to the leucocytes, and Metchnikoff especially has laid great 
stress upon the fundamental role which it plays in inflammation, for while 
in lower forms these mobile mesenchymal cells form the means of defence, 
arriving at the point of injury by their own motility, in vertebrates there is 
added a convenient blood-vascular system, with its rapid current, which 
brings the leucocytes to the injured area and then slows up so that they 
may emigrate through its walls and reach the spot. Were it not for this 
slowing and the roughening and stickiness of the endothelium in that 
region, the leucocytes would all be swept by without any chance of reach- 
ing the place where the injury occurred. 
Many ideas have been expressed as to the reason for the passage of the 
leucocytes through the wall, but it seems that the weight of evidence is in 
favor of their active penetration between the cells in response to the at- 
traction of some diffusible soluble substance which is either the injurious 
agent itself or produced by its destructive action on the cells of the tissue. 
It is so evident that dead tissue killed by any mechanical means or by being 
deprived of its blood supply, as in the case of an infarction, can act in this 146 
TEXT-BOOK OF PATHOLOGY 
way to attract the leucocytes, that in every case it must play a part. 
Experimentally it has been shown that extracts of dead cells are positively 
chemiotactic. Nevertheless, the leucocytes appear in so much greater 
number when bacteria or some chemical irritant cause the inflammation 
that unquestionably these poisonous substances themselves have a power- 
ful influence. 
All forms of leucocytes are not equally attracted by each substance, 
and indeed some things actually repel one form while attracting another. 
Thus while in most inflammations the polymorphonuclear neutrophile 
cells are prompt to respond in great numbers, cells of the type of the lym- 
phocyte are most abundant in the inflamed areas in typhoid fever and 
even in tuberculosis. So, too, in the lesions produced by many animal 
parasites, such as the trichina, the polymorphonuclear eosinophile cells 
appear in great numbers. It is not clear that any bacteria exercise a 
definitely repellent action on the neutrophile leucocyte, although it seems 
that this may be so in typhoid fever. 
Leucocytosis.-How the impulse is sent to the bone-marrow, when there 
is a localized infection, to call forth the storm-like discharge of new leu- 
cocytes into the blood, is not very clear. Certainly far more are formed 
and liberated than could possibly be accounted for by any dearth in the 
circulating blood caused by their departure from the blood-vessels, and it 
seems necessary to believe that some chemical substance circulating in the 
blood causes this great hyperplasia. If one reflects that a leucocytosis of 
30,000 to 40,000 per cubic millimetre is not unusual, the colossal number 
of new leucocytes quickly formed and thrown into circulation becomes 
a matter of wonder. 
The Wandering Cells.-It is clear that in the adult animal the greater 
number of the cells are intimately and permanently attached to their 
neighbors, and in virtue of this coherence tissues are formed which are 
stable. The rest of the cells are not so fixed, but wander about loosely or 
are driven about with great speed, as in the case of the red corpuscles and 
leucocytes of the circulating blood. Even in the circulating blood the 
leucocytes have the power of moving at their own volition, but this power 
comes to its proper expression only in the crevices of the tissues, where 
they are at leisure and are not hurried along by the force of the heart. 
There it is easy to recognize such free cells by their clear-cut outline, their 
independence of attachment to other cells, and by their bulging or lobose 
pseudopods. If the tissue is allowed to grow cold before fixation, most 
of these cells will be found to have retracted into a round form, but if it is 
dropped in small pieces, perfectly fresh and warm from the living animal, 
into some solution which will fix it instantaneously, the wandering cells are 
seen caught in all sorts of attitudes, and often stretching out long arms or 
twisting their way among the fixed cells. 
It is generally agreed now that these wandering cells take no part in the 
formation of any fixed or stable tissue, but are probably always nomadic INFLAMMATION 
147 
until they perish. But it appears that the fixed tissues do in some way give 
rise to the wandering cells. This is most readily and clearly observed in 
the early embryonic stages of development and perhaps especially in such 
tissues as the blastoderm of the chick, where the whole structure may be 
spread out for microscopic observation and even kept alive and growing 
under the microscope. 
Later, in the growing and adult animal such processes of formation of 
wandering cells become localized in certain blood-forming organs and are 
normally carried out there exclusively, although, under the stress of excep- 
Fig. 61.-Early development of wandering cells in embryonic tissue (Maximow). 
Cross-section of a vessel of the area vasculosa with primitive blood-cells (p. biz) in the 
lumen. Rounding off of endothelial cells (m) and their conversion into blood-cells; 
mz, mesenchyme cells; ed, endothelium. 
tional demands, similar blood-forming functions may be reassumed by 
various organs and tissues not normally concerned in that way. Thus, 
while the bone-marrow normally forms most of the blood-cells in adult 
life, aided by the lymphoid tissues and spleen, the liver, spleen, and the 
most various portions of the connective-tissue framework of the body 
may become conspicuous manufactories of all these cells when for any 
reason the bone-marrow is destroyed or rendered incapable of carrying 
on its usual duties. This is spoken of as a myeloid transformation, and 
something resembling actual bone-marrow may appear in the lung or an 148 
TEXT-BOOK OF PATHOLOGY 
artery wall, or in the tissue about the pelvis of the kidney. That this is 
possible seems to be evidence in favor of the idea of the intimate relation 
of the function of blood formation with the connective tissues in general. 
The cells concerned are about as follows: In the circulating blood there 
are found normally, besides the red corpuscles and platelets (which are 
derivatives of the megalocaryocytes of the bone-marrow), several types of 
leucocytes. Of these, the polymorphonuclear neutrophile leucocytes are 
most numerous and form about 70 per cent, of all the white cells. Similar 
to them are other polymorphonuclear leucocytes which differ in possessing 
larger, shining, eosinophile granules which stain bright red with eosin. 
The remainder consist of cells with rounded nucleus and protoplasm con- 
taining few granules, or none at all. Of these, the smaller, with relatively 
little protoplasm, are the lymphocytes. There are a few larger cells with 
paler, round, or indented nucleus, which are variously known as large 
mononuclears, large lymphocytes, monocytes, etc. Outside the blood- 
vessels there are also to be found many wandering cells even in those 
tissues which are not clearly occupied in their formation. They are 
abundant in all the loose connective tissues, in the skin, in the intestinal 
wall, and in relation with all the mucosae and with the adventitial coats of 
blood-vessels. In general, they are mononuclear cells rather larger than 
lymphocytes and resembling more nearly the large mononuclear cells of 
the blood. Polymorphonuclear neutrophile and eosinophile cells are 
scarcely to be found in these lurking places. In the course of the more 
chronic inflammatory processes in the tissues these cells assemble in great 
numbers and in a great variety of forms and sizes, and the greatest diffi- 
culty has been felt in characterizing them accurately and in classifying 
them or determining their identity and origin. They are phagocytes par 
excellence, and it is especially striking that they have the power of en- 
closing other cells and fragments of cells, whereas most bacteria, when 
taken up by any cells, are to be found in the polymorphonuclear leuco- 
cytes. They are undoubtedly mobile, although not endowed with the 
great activity and speed of the polymorphonuclear leucocyte. 
As to the origin of these cells and of others not yet mentioned, the fol- 
lowing may be said, although our knowledge with regard to all this is still 
in a very fluid state and the conclusions of today may be reversed tomorrow. 
It is agreed that in the embryo certain of the mesenchyme cells, after 
assuming a somewhat different form and consistency from the rest, divide 
and remain connected in such a way as to produce a network of strands 
which then hollow themselves out into anastomosing canals. These are 
the angioblasts and represent the first endothelial cells of blood and 
lymph capillaries. Danchakoff showed that such cells could round them- 
selves off, and after division fall into the lumen of the capillary and become 
red corpuscles. Maximow and many others have confirmed this, although 
Maximow thinks that after the first stages of the embryonic life the forma- 
tion of red corpuscles is extravascular. Nevertheless it seems that the INFLAMMATION 
149 
work of Sabin and Finley brings strong evidence for their continuous 
vascular production both in these stages and later in the bone-marrow 
of the adult. 
With regard to the colorless cells, it may at least be said that less dif- 
ferentiated precursors of each type are to be found. From the angio- 
blasts, or early endothelial cells, certain large mononuclear cells are formed 
which either fall into the vascular lumen or wander away from its outer 
side. These are not the forerunners of the granular leucocytes of the 
blood, nor of the lymphocytes, but appear to constitute a portion of the 
mononuclear, phagocytic, wandering cells of the tissues. Another cell 
outside the primitive blood-vessels seems to give origin to the neutrophile 
and eosinophile leucocytes by way of at least two stages, the so-called 
myeloblast and then the myelocyte. Later this process becomes crys- 
tallized in the bone-marrow where a parent cell produces the non-granular 
myeloblast which develops into either a neutrophile or eosinophile granular 
myelocyte. These, in turn, by alterations in size and in the form of the 
nucleus, produce the corresponding leucocytes and are occasionally swept 
out into the blood with them. As to this there is geneial agreement. 
The lymphocytes are not clearly traced to a parent cell in the early 
embryo and develop late. In the adult they appear to be formed in the 
lymphoid tissues of the lymph-nodes, the spleen, the intestinal mucosa, 
tonsils, skin, bone-marrow, etc., and are lodged in a reticulum which is 
surrounded by the lymph sinuses with their endothelial lining. In the 
reticulum there are many large, pale cells which may be concentrated in 
the middle of each lymph cord or island to form the so-called germinal 
centre (Fig. 62). Although it was stated by Flemming that these large 
cells give rise by mitosis to the lymphocytes, there is still much dispute 
about their actual origin. Marchand, in reviewing the work with its 
divergent results, concludes that large macrophages are certainly formed 
from the reticulum cells and endothelium of the sinuses, but that it is 
difficult to prove the origin of the lymphocytes from the large cells of the 
germinal centre. 
The greatest difficulties arise in the attempt to determine the origin 
and relations of the larger mononuclear, phagocytic wandering cells to 
which many names have been applied. They have been known as macro- 
phages, endothelial leucocytes, monocytes, clasmatocytes, adventitial 
cells, and by many other names. Maximow, by ingenious experiments 
with porous foreign bodies which he embedded in the tissues, thought 
that he could trace their origin directly to lymphocytes which had wandered 
out of the blood-vessels and had penetrated into the crevices of the foreign 
body, as it were, in pure culture. These later were seen to grow and develop 
until in their various stages they became identical with all the forms of 
large, mononuclear, wandering cells with abundant protoplasm and phago- 
cytic activity (Fig. 64). Fusion of several such cells produces giant, syn- 
cytium-like, protoplasmic masses with many nuclei, and these are par- 150 
TEXT-BOOK OF PATHOLOGY 
ticularly able to engulf foreign particles, and are known as foreign body 
giant-cells. This fusion was confirmed by Lambert, who cultivated 
lymphoid cells in vitro with lycopodium grains as foreign bodies (Fig. 65). 
This whole group of wandering cells derived by gradual metamorphosis 
in the new environment from lymphocytes which had emigrated from the 
blood-vessels, he designates as polyblasts, suggesting thereby the variety 
of forms which they may assume. He thinks it possible that they may be- 
come imprisoned between the fibres of connective tissue and then resemble 
closely fixed tissue cells. 
Marchand recognizes the fact that there are normally great numbers 
of large, mononuclear, wandering cells of this character in the crevices of 
the tissue, and from their abundance in the outer walls of blood-vessels 
has named them adventitial cells. 
Besides the adventitial cells there are others in the tissue similar in their 
general form, but distinguished by the possession of basophilic granules. 
These are the mast cells, which are found most abundantly in the walls 
of the bronchi and blood-vessels and in the intestinal mucosa and skin. 
Whereas the adventitial cells show a few metachromatic granules staining 
red with azur dyes, the mast cells are full of large basophilic granules which 
stain purple with dahlia, and red with polychrome methylene-blue. 
Dr. Sabin's recent work, carried out as was that of Goldmann and others, 
with vital dyes, has shown that there are peculiaritie s in these cells with 
regard to their specific staining with these dyes which make it possible to 
recognize them very surely by their finer morphological characters. Al- 
though in her review of the origin of the cells of the blood she regarded all 
of these large mononuclear cells as derived from the endothelium, she is 
now able to distinguish two types, of which one is a mononuclear cell with 
a very distinct centrosphere about which is a rosette of granules which 
stain with neutral red. This cell, which is not very greedily phagocytic, 
she calls a monocyte. It is found in the spleen or in a peritoneal exudate 
provoked by injection of red corpuscles. These cells correspond with the 
large mononuclear and transitional cells of the circulating blood, and are 
not derived from the endothelium, but from a primitive cell which produces 
them by way of an intermediate form which might be called a monoblast. 
The second type is a larger mononuclear cell found in the same places, 
very actively phagocytic, with many granules of large size which stain 
with neutral red, but with no centrosphere or rosette arrangement. This 
cell, which she has traced directly to its origin from the early embryonic 
endothelium, she would call the clasmatocyte, although this name, long ago 
applied by Ranvier to a cell in amphibia which had the power of frag- 
menting itself, has in this connection no descriptive significance. She thus 
recognizes, as derived from the endothelium, red corpuscles and clasmato- 
cytes. From the mesenchyme, by way of a primitive blood-stream cell, 
she would trace three forerunners of the cells which appear in the adult, 
namely, the myeloblast, the monoblast, and the lymphoblast, giving rise INFLAMMATION 
151 
Fig. 62.-Germinal centre in Malpighian body of the spleen. 
Fig. 63.-Lymph-gland showing phagocytic wandering cells in the lymph-sinuses. 152 
TEXT-BOOK OF PATHOLOGY 
respectively to polymorphonuclear leucocytes, monocytes, and lympho- 
cytes. 
Aschoff, Eppinger, and others have recently laid much stress upon the 
so-called reticulo-endothelial system, meaning to indicate a group of 
Fig. 64.-Group of polyblastic or wandering cells of various types: ly., Lymphocytes; 
pl., plasma cells; ph., phagocytic cells of large size, some containing blood-pigment, others, 
l.ph., containing much fat; g., foreign-body giant-cell formed about granules and crystals 
of bismuth; fibr., connective-tissue cell. 
phagocytic cells which probably play an important part in the metabolism 
of blood-pigments and in various other ways. This group would perhaps 
include the Kupffer cells which hang in the liver capillaries and Dr. 
Sabin's clasmatocytes, and the recent work of Rich goes to show that these INFLAMMATION 
153 
cells are intimately related, at least as far as their functional activities 
are concerned. 
The explanations of the interrelations of these cells are so new and so 
little applied in human pathology that it may be excusable for a time to 
speak of all the large, phagocytic, mononuclear cells of the tissues simply 
as mononuclear, wandering cells. 
Among them there occurs one peculiar form which is obviously derived 
from the lymphocyte through a modification of its nucleus and protoplasm. 
This is the so-called plasma cell described by Unna, which occurs normally 
in the intestinal mucosa and elsewhere and appears in great numbers in 
many forms of long-standing subacute 
inflammatory reactions (Fig. 64). Tu- 
berculous granulation tissue and gonor- 
rheal salpingitis afford examples of such 
conditions. The cells are rather larger 
than lymphocytes-somewhat amoeboid, 
but in fixed preparations they usually 
assume a rounded or oval form, with the 
nucleus excentrically placed, generally at 
one end of the cell. The nucleus, whose 
chromatin is in coarse masses, is sur- 
rounded by a pale halo, while the re- 
maining protoplasm takes a bluish stain 
with ordinary nuclear dyes. Such cells, 
which may be regarded as a type slightly 
differentiated from the rest of the tribe 
of mononuclear wandering cells, are con- 
spicuous because they are so constant in 
their form. They are not commonly 
phagocytic, but probably active in pro- 
ducing a digestive ferment. 
The mere fact that these cells take 
up in their nuclei or protoplasm or 
in their granules certain stains in a 
specific way does not, after all, afford 
us much information as to their true character. It would be more impor- 
tant to determine something as to their function. Metchnikoff, in his 
studies of inflammation and immunity, has been at great pains to show 
the analogy between the activites of the wandering cells of the body and 
those of amoebae or other amoeboid, simple, protoplasmic organisms. These 
latter swallow up bacteria and other substances, and by the aid of ferments 
or cytases digest thepi. These ferments, he says, are also present in the 
wandering cells of the body, and differ according to the type of cell, the 
small neutrophile leucocyte possessing a so-called microcytase, while the 
mononuclear cells or macrophages, which eschew bacteria, except such as 
the tubercle and leprosy bacilli, and digest with avidity cell debris, carry 
Fig. 65.-Foreign-body giant- 
cell in tissue culture, enclos- 
ing two lycopodium spores. 154 
TEXT-BOOK OF PATHOLOGY 
out their digestive processes by the aid of another ferment which he calls 
macrocytase. Therefore the plasma of the blood is scarcely bactericidal 
as compared with blood-serum, in which digestive ferments are found, owing 
to the disintegration of leucocytes in the process of clotting. He does not 
distinguish sharply between such ferments and the complement or alexine 
of the serum, but does sharply separate the "fixateurs" or "amboceptors" 
which are produced, he thinks, by the phagocytes, but set free into the 
plasma as specifically adapted substances capable of preparing the bacteria, 
etc., which stirred up their production, for solution by the complement. 
In any case he regards the phagocytes as the great source of these ferments. 
Many writers have recognized the power of certain tissues to digest 
themselves in vitro (autolysis), and have observed that the neutrophile 
leucocytes produce a strong proteolytic ferment capable of digesting fibrin, 
gelatin, etc. Most of them, however, according to Wiens, have denied the 
production of a ferment by lymphoid cells. Opie has cleared the matter 
up very well by finding that the ferments of different cells require for their 
activity different reactions. He states that the polymorphonuclear neu- 
trophile leucocytes and their ancestral granulated cells produce a trypsin- 
like ferment which acts best in an alkaline or neutral medium to digest 
proteins. Its action is often combated by an anti-enzyme, which is 
present in the plasma of the blood and in other body fluids. It is re- 
sistant to heat up to 70° or 75° C., and is therefore quite different from 
the complement of the serum, which is destroyed at 55° C. When formed 
in great concentration in a focal area of inflammation, the enzyme far out- 
strips the neutralizing anti-enzyme, and brings about the liquefaction of 
dead tissue, as in the case of an abscess. When in the presence of a great 
exudation of fluid, as in the pleural cavity, its action may be held in check. 
This proteolytic ferment Opie calls leucoprotease. Contrary to the results 
of other workers, he finds that, if the correctly feeble acid reaction be offered, 
the mononuclear cells also show the formation of a proteolytic ferment 
which is more like pepsin in its character, although it is unable to act in 
so strong an acid as is favorable to pepsin. This ferment, which he calls 
lymphoprotease, is produced in the lymph-glands and in all accumulations 
of lymphoid cells, and of the various types of larger wandering mononu- 
clear phagocytic cells which go to form Metchnikoff's group of macro- 
phages. 
While these ferments are evidently used inside the cell in the case of the 
particles which have been ingested, it seems certain that, in the formation 
of pus, as in the abscess, they are diffused from the bodies of the disin- 
tegrating leucocytes, and in the free fluid effect the solution of the adjacent 
injured and dead tissue. This function of the wandering cells is, of course, 
of immediate importance in connection with their task of cleaning up the 
injured area to prepare it for repair. While the proteases thus produced 
are active in the solution of undesirable material, their unbridled action 
might be detrimental. As a matter of fact, it is shown by Jobling and 
Petersen that the anti-ferment known to be present in the serum and to INFLAMMATION 
155 
restrict the action of the ferment is a recognizable chemical substance, 
usually a soap or other combination of an unsaturated fatty acid. It is 
possible to remove or decompose this substance or to saturate the fatty acid 
with iodine and thus release the ferment to its full activity. The presence 
of excess of such soaps in the tubercle bacilli seems to be the cause of the 
delay of liquefaction of tissue brought to necrosis by those bacilli. It is 
seen from this that we are at the beginning of our knowledge of the activi- 
ties of the wandering cells. What other ferments they produce has been 
as yet only imperfectly studied, although we have evidence that others, 
such as oxydases, are produced by some of them, and there are surely 
more. 
Pain in Inflammation.-Doubtless the cause of pain in inflamed tissues 
is different in various parts of the body, for in certain confined places it is 
not hard to imagine that the accumulation of exudate stretching sensitive 
tissues would cause suffering, which might be relieved, as is so often the 
case, by an incision which allows the exudate to escape. Still it has been 
objected that pressure and tension on the nerve-endings are not sufficient 
to cause pain, since local anaesthesia can generally be produced by injecting 
some indifferent solution into the tissues until they are distended. There- 
fore it has been thought that the poisons which caused the inflammation 
also irritate the nerve-endings. Possibly this is so, but an inflamed area 
following a burn is as painful as one resulting from bacterial infection, and 
in sunburn no pain is felt during the injury, but only when the inflammation 
is at its height. Possibly the hyperaemia itself renders the sensory nerves 
hyperexcitable, as seems to be true in the case of non-inflammatory hy- 
peraemias. 
LITERATURE 
The student should particularly consult the papers of Maximow with regard to the 
cells concerned in inflammation and the repair of tissue, as follows: 
Maximow: Ziegler's Beitrage, Suppl. 5, 1902; 1905, xxxviii; 1907, xli. Arch. f. mikr. 
Anat., 1906, Ixvii; 1909, Ixxiii; 1910, Ixxvi. 
Adami: Inflammation, Macmillan, 1909. 
Danchakoff: Anat. Hefte, 1908, xxxvii, 473. Anat. Record, 1916, x, 397, 483. Amer. 
Jour, of Anat., 1916, xx, 255; 1918, xxiv, 1, 127. 
Jobling and Petersen: Jour. Exp. Med., 1914, xix, 239, etc. 
Lambert: Jour. Exp. Med., 1912, xv, 510. 
Lubarsch, Rossie, and others: Verh. Deutsch, path. Gesellsch., 1923, xix, 3. (Review 
of Inflammation.) 
Marchand: Verh. Deutsch, path. Gesellsch., 1914, xvi, 5. (Lymphocytes.) Virchow's 
Archiv., 1921, ccxxxiv, 245. (This is the best recent article on the whole subject of 
Inflammation.) 
Metchnikoff: Lectures on the Comparative Pathology of Inflammation, 1893. 
Opie: Harvey Lectures, 1910, 192. 
Rich: Jour. Exp. Medicine, 1921, xxxiii, 287. (Capillaries in histamine shock.) 
Sabin: Physiological Reviews, 1922, ii, 38, Bull. John Hopkins Hosp., 1923, xxxiv, 277. 
Samuel: Ergeb. d. allg. Path., 1895, 12, 64. 
Weidenreich: Arch. f. mikr. Anat., 1909, Ixxiii, 793. (Literature.) 
Wiens: Ergeb. d. allg. Path., 1911, xvi, 1. 
Ziegler: Ziegler's Beitr., xii, 152. (Historical and critical.) CHAPTER X 
DEFENCES OF THE BODY (Continued) 
Fever. General nature of the reaction. Its chemical characters and relation to immunity. 
Immunity. Nature of injurious agents. Types of resistance. Artificial immunity. 
Phagocytosis. Lysins, agglutinins, antitoxins, etc. 
Maintenance of the acid-base equilibrium in the body. Mechanism of the preservation 
of neutrality-acidosis. 
FEVER 
General Nature of the Reaction.-It is common knowledge that fever is 
likely to accompany inflammation, and, as in the case of inflammation, 
the efforts of physicians and healers of all sorts have been directed toward 
cutting it short on the idea that it in itself is the harmful process. Only 
in the last decade has it become vaguely appreciated that there is real 
evidence that fever, on the contrary, is a reaction elaborated to a consider- 
able degree of perfection, which aids in the defence of the body against the 
advance of an injurious agent by facilitating the production of the sub- 
stances which are formed in the body to neutralize poisons or kill bacteria. 
From this point of view it would seem, to say the least, short sighted to 
give a patient in fever an antipyretic drug which will cut short the febrile 
reaction. 
Fever is a reaction which seems to be carried out under the control of 
the nervous system, and especially of the vasomotor mechanisms which 
have to do with heat regulation, the most striking feature of which is the 
elevation of the temperature of the body above the normal. This is not 
the result of an excessive heat-production, although there is a moderate 
increase in the production of heat, but rather of the retention of an undue 
proportion of the heat produced. In the course of fever the body gives 
off more heat than it normally would at rest, but not nearly so much as it 
would during active exercise. Indeed, the heat-production during exer- 
cise may be increased 200 or 300 per cent., but such is the accuracy of 
adjustment of heat loss to this increase that the temperature of the body 
remains normal. During fever, on the other hand, the production of 
heat is increased only 20 or 40 per cent., but the dissipation of heat is not 
proportional, and therefore the temperature rises. Heat is given off, but, 
as Liebermeister has said, the regulating mechanism is altered to react 
for a different standard of body temperature. It is tuned up to a higher 
pitch, so that it begins to allow of the escape of heat only at a higher level, 
just as we might screw up the thermoregulator of a thermostat so that its 
temperature would stand at 40° instead of 35°. 
The regulating mechanism is found in the vasomotor apparatus of the 
vessels of the skin, in the secretory activities of the sweat-glands, in the 
156 FEVER 
157 
respiration (especially in the dog, which cools itself by panting), in shiver- 
ing, and partly, in human beings, in conscious changes in the clothing. A 
striking instance of the coordinated working of all these arrangements is 
seen in a chill, which is so frequent an accompaniment of toxic or bacterial 
injuries with inflammation. The superficial vessels of the skin are con- 
tracted so that little blood is carried to that radiating surface. The skin 
is pale or livid. The sweat-glands stop secreting, so that the cooling effect 
of evaporation of the sweat is held in abeyance; the smooth muscles in 
the skin contract and pull it into gooseflesh; the person feels cold, cowers 
together, covers himself heavily with blankets, and shivers violently, thus 
turning stored-up energy into heat. Every available mechanism is brought 
into play to stop the dissipation of heat and to warm up the body, and in 
spite of the sensation of cold, the temperature of the interior is at its highest 
during the chill! 
Later, when chemical processes are under way to produce the moderate 
excess of heat which is observed in fever, these contractions of the cutane- 
ous vessels, etc., are no longer kept up, and the skin may be flushed and 
even moist, but still the balance is so adjusted that a little less heat is 
dissipated than is produced-enough, at least, to keep the temperature 
above the normal. 
Chemical Characters of Fever.-Naturally, since fever is a process 
concerned with heat-production, the most painstaking efforts have been 
made to ascertain its nature by the study of the changes in metabolism 
during febrile diseases, but so varied and complex are the conditions that 
it can hardly be said that the results have brought out any very definite 
and characteristic changes peculiar to fever as such, and independent of the 
direct effect of the underlying cause. It is generally agreed that oxidation 
is increased over that found in the normal individual at rest, but it is not 
so certain that it is qualitatively altered. From a study of the excretion 
of nitrogen, together with a comparison of the amounts of carbon dioxide 
and oxygen in the expired air, it has been thought that the increased 
oxidation affects especially the nitrogenous or protein constituents of the 
body, and indeed not so much the labile or circulating proteins as those 
which actually form part of the living tissue. It is known that the store 
of carbohydrate is rapidly depleted, but it was thought until recently that 
the other ordinary fuel used in the production of heat energy-the fat- 
was relatively little encroached upon. Now May, Grafe, Coleman and 
Shaffer, and others state that in fever, too, the fats form a particularly 
important source of heat, and that if sufficient carbohydrate and fat be 
supplied to the febrile patient the waste of body proteins may be prevented. 
Indeed, Grafe thinks that this attack on the living tissues which was tradi- 
tionally emphasized as the most typical feature of febrile metabolism, is 
due altogether to inanition, and that qualitatively the febrile metabolism 
need not differ greatly from the normal. 
In many fevers, especially in pneumonia, there is a curious retention of 158 
TEXT-BOOK OF PATHOLOGY 
sodium chloride, which is then excreted in great amounts after the fever 
is over. Water may be retained in the same way. The metabolism of 
other inorganic substances may suffer alteration in this way or that as well, 
but, on the whole, it is difficult, if not impossible, to put one's finger on any 
of these changes and say that this is characteristic of the metabolism of 
fever. 
In all these studies little attention has been devoted to the anatomical 
changes in the disease, so that it is not surprising that there are discordant 
results. If there is extensive destruction of tissue produced by the poisons 
of bacteria, or if great quantities of leucocytes appear in the tissues and 
are broken down, digested, and absorbed, as in pneumonia, there must be 
changes in the nitrogen output. It is difficult, too, to estimate what part 
of the increased oxidation is due to the heightened temperature itself, 
quite aside from any other cause, for it has been shown that artificial over- 
heating produces an increased oxidation. 
But aside from the mere existence of dead tissue which can be used as 
fuel and appear in the excreta, and the later result that heightened tem- 
perature facilitates further burning, there must be some original cause for 
the intensification of the oxidation process, even if it prove that it is not 
qualitatively but only quantitatively altered. 
Relation to Immunity.-So closely has attention been concentrated on 
the questions of disturbances in metabolism that the biological significance 
of fever has been somewhat neglected, but recently Rolly and Meltzer, 
Loewy and Richter, Fukuhara, and others have published results which 
show it in a clearer light. They found that if animals were artificially 
kept at a high temperature in a thermostat room, they were able to develop 
a much more effective defence against intoxication and infection than those 
left outside at ordinary temperatures. Briefly, Rolly and Meltzer showed 
that the high temperature itself had probably no injurious influence on the 
growth of bacteria in the body. Further, that if a fatal dose of bacteria 
or of a toxin be given, no special difference could be observed between 
heated and unheated animals. But this sort of infection, by the sudden 
introduction of enormous quantities of bacteria or of a toxin hardly occurs 
in nature. Instead, a few bacteria get into the tissues and then gradually 
increase in number, or in their growth produce an increasing amount of 
toxin, so that time is given for the appearance of a defensive reaction. 
If, now, the experiment be arranged in the same way, small doses of bac- 
teria or toxin being injected at intervals, the heated animals showed a 
great advantage over the controls. They lived longer, and many of them 
survived doses which inevitably killed the control animals. 
When they studied the details of these experiments more carefully, they 
found that it was not that the high temperature merely prevented the 
growth of bacteria-it might do so in test-tubes, but in the body the bac- 
teria grow well enough at febrile temperatures. Phagocytosis proved 
difficult to compare in the two sets of animals, but in vitro they found that IMMUNITY 
159 
it was increased by temperatures ranging even up to 41° C., so that prob- 
ably the conditions for its development are improved by high temperatures 
in animals. When they studied the formation of specific antibodies, how- 
ever, they found a great difference. Antitoxins they did not investigate, 
but agglutinins and bacteriolytic substances were produced far more 
quickly and in much greater amounts than in the control animals. 
New' as these results are, they seem to open the way to a more fruit- 
ful study of fever and to confirm the somewhat vaguely expressed idea 
that it is in a way analogous to the vascular reaction in inflammation in 
that it is the process which facilitates the more essential activities of the 
phagocytes and the production of defensive chemical substances in the 
body. 
But still more recent discussions of fever seem to lay little stress on this 
aspect of the matter. Instead, they are concerned more especially with 
the mechanism of nervous control and with the character of the chemical 
substances which excite this nervous mechanism to the production of the 
disturbance of heat regulation which we have described. In brief, it appears 
that destruction or interruption of the hypothalamic region of the mid- 
brain throws out of function the regulatory mechanism, so that the warm- 
blooded animal becomes poikilothermic and makes no response to the 
usual causes of fever. This merely means that the vasomotor and other 
changes ordinarily set in motion by the "heat-regulating centre" are 
absent because their connection with the brain is interrupted. As to the 
nature of the regulating centres nothing is yet known. 
In anaphylactic shock the temperature falls suddenly, but if the dose 
of antigen is too small to produce this collapse, it results in fever. Fried- 
berger, Leschke, and others show that with minute doses of "anaphylatoxin" 
it is possible to produce a febrile rise in temperature at will, but it remains 
to be seen whether there is one substance responsible for this or many. 
One gains the impression that it is the product of injury of cells and con- 
sequent decomposition of protein which stimulates the heat-controlling 
centres. In this sense the fever may still be purposeful, although it is less 
easy to discover any active character than formerly seemed to be the case. 
Antipyretics and baths may do good, not so much by allaying the fever 
as by calming the excitement of the rest of the brain. 
LITERATURE 
Loewy and Richter: Virch. Arch., 1896, cxlv, 49. 
MacCallum: Archives of Internal Medicine, 1908-09, ii, 569. 
Meyer, H. H., Krehl, Schittenhelm, Friedberger, Grafe, Leschke: Verh. Congr. f. In- 
nere Medizin, xxx, 1913, 15-80. 
Richter: Oppenheimer's.Handb. d. Biochemie, 1910, 1V2, 104. 
Rolly and Meltzer: Dtsch. Arch. f. klin. Med., 1908, xciv, 335. 
Vaughan: Proc. Assoc. Amer. Phys., 1911, xxvi, 191. 
Welch: Cartwright Lectures, Boston Med. and Surg. Jour., 1888, cxviii, 333, 361, 413. TEXT-BOOK OF PATHOLOGY 
160 
IMMUNITY 
Nature of Injurious Agents.-The body may be regarded as a kind of tube 
with thick walls, into which there extend cavities open to the exterior. 
These cavities, as well as the lumen of the digestive tract, with all its di- 
verticula, are outside the body, and poisonous fluids or bacteria can exert 
their influence only when they pass through the lining membranes into the 
real interior. An injury to the lining membrane, often produced by the 
bacteria themselves, exposes thennterior of the body, just as in the case of 
an abrasion of the skin, to invasion, but many poisons can be absorbed 
without such cell destruction. 
These surfaces then constitute the portals of entry of all the injurious 
agencies from the outer world, whether in the form of inanimate poisons 
or live creatures which can live and multiply in the interior of the body, to 
its detriment. Sometimes entry is immediate, but it is well known that 
the outer and lining surfaces of the body may and do swarm with living 
creatures, many of which are permanently innocent, while others are only 
waiting an opportunity when the guard is weakened to force their way 
through the walls and attack the vital organs inside. 
Externally the impermeability of the skin acts as a defence, while in the 
case of the lining membranes, fluid secretions tend to wash away noxious 
materials or annul their effects, in which they are often aided by phagocytic 
cells. So in the conjunctiva bacteria are quickly washed down into the 
tear-duct; in the upper respiratory tract ciliated cells wave back every 
kind of particle, and from all the adenoid apparatus leucocytes are ready 
to emerge on alarm. In the biliary ducts, as in the genito-urinary organs, 
bacteria are kept in check by the stream of fluids, often aided by valvular 
arrangements to close the channels, which wash away the bacteria and dis- 
infect the lining surfaces. Nevertheless, all these defences are often over- 
come. Through the skin the attack may be successful not only by way of 
ordinary wounds, but by the aid of biting insects and other animals, or 
even in the case of some worm larvae by their own penetrating force. 
Through the mucosse entrance is forced by the destructive action of the 
organisms themselves, though this is often aided by mechanical factors 
which protract their contact with these tissues or by the failure of the 
phagocyte guard from the interior. Thus the upper intestine or the 
bladder, which normally keep themselves practically free of bacteria, quickly 
become perfect hotbeds for their growth if an obstruction prevents the 
escape of the intestinal contents or the urine. 
Aside from mechanical or physical injury, then, the body suffers from 
the effects of destructive chemical substances which may be wholly de- 
rived from the inorganic or inanimate world, or may be produced in some 
way by living beings. Indeed, the greatest danger comes from the latter 
when, as is so often the case, these living beings establish themselves in 
the body or on its surface and manufacture their poisons on the spot. 
A word should be said here about the rather obscure question of their IMMUNITY 
161 
interfering with the well-being of their host by the mere abstraction of the 
materials necessary for its nutrition and metabolism. Possibly this may 
occur in the case of some of the larger parasites: they may drain away the 
blood or, as in the case of malaria, eat out the blood-cells, but probably 
even in the most obvious of such cases the greatest harm is done by the 
poisons which these creatures produce. On the other hand, Dibbelt has 
lately maintained that in the fulminant bacterial infections which kill in 
a few hours death is not due to the formation of poisons, but rather to the 
wholesale withdrawal of oxygen from the tissues. Such a result might be 
comparable to that in cyanide poisoning, in which metabolism is brought 
to a standstill by the stoppage of oxidation processes. 
Of all the living parasites which thus insinuate themselves into the body, 
only a few, such as the diphtheria and tetanus bacilli, produce a soluble, 
diffusible poison or toxin which, by itself circulating through the organs, 
can cause the symptoms of the disease. Such bacteria can, therefore, 
live and grow, even in a very small spot in the tissues, and yet diffuse enough 
poison to kill the animal. Practically all the rest, whether animal or vege- 
table, fail to do this, although they cause the most intense and frequently 
fatal diseases. The fluids of animals dying of these diseases will not cause 
the disease in other animals if the parasites are filtered out, and the fluids 
in which they have grown are found not to contain any appreciable amount 
of poison. Still, if their bodies are ground up, a poisonous material or en- 
dotoxin may often be found mixed with their body proteins in the extract 
made from the debris. How they produce the disease is, therefore, very 
difficult to learn, and generally we are content with the idea that they be- 
come harmful only when they die and are broken up in the tissues, liber- 
ating their endotoxin. That their body proteins under the influence of the 
ferments of the host may act as poisons, too, begins to seem probable, and 
will be referred to again. 
It should be observed that the harmful effects of one invader are often 
greatly intensified when it is accompanied by another, and, indeed, some 
bacteria and even protozoan parasites seem hardly able to cause an in- 
fection without the help of others. Such mixed infections are very com- 
mon, and may be simultaneous, or one may thrive in the soil prepared by 
the other. 
Types of Resistance.-Poisons very similar to those produced by bac- 
terial and animal parasites are secreted by venomous animals and plants, 
or may be extracted from them. Indeed, it is quite difficult to draw any 
sharp line of demarcation in the long series of poisons beginning with the 
simple inorganic substances, and passing by way of the complex synthetic 
compounds to the highly intricate combinations, of whose nature we are 
generally ignorant, which we find in the toxins and toxalbumins and other 
protein substances which play such an important role in disease. In 
general, however, it is found, through the biological test, that it is only 
toward the complex, protein-like poisons that the body can elaborate 162 
TEXT-BOOK OF PATHOLOGY 
special defensive substances. Even though the others may finally be 
tolerated, it is through some other mechanism. Thus it is well known that 
through long habit animals or human beings may become able to swallow 
doses of such poisons as arsenic, morphine, etc., which would be far more 
than enough to kill an ordinary being, but our ideas as to how this tolerance 
is produced are very vague. Certainly no substance is produced in the body 
which will neutralize the poison, and it seems that it must be due to some 
change in the metabolism of the cells themselves. 
There is, even without any such gradual case hardening, a natural in- 
susceptibility on the part of some animals to injury from certain poisons; 
thus an almost unlimited quantity of the most intensely active tetanus 
toxin, a milligram of which would kill thousands of mice, can be injected 
into a scorpion or an alligator without producing the slightest malaise, 
and a long time later it may be found still lodged in the tissues. Certain 
animals are equally resistant to invasion by bacteria which can produce 
the most deadly disease in others, apparently because their defensive 
phagocytes are so active that long before the bacteria can gain a proper 
foothold they are all seized upon and devoured. Whether this is an in- 
herited character, resulting from the survival of those thus fitted to resist 
infection, it is difficult to say. The immunity is not absolute, however, 
for influences, like exposure to cold or heat, great fatigue, or other illnesses, 
may so break down the resistance that, after all, the animal succumbs to 
infection. Race immunity is doubtless an example of this kind, and race 
susceptibility illustrates its opposite-the South Sea islanders succumbed 
in thousands to measles because their ancestors had never had to contend 
with it. On the other hand, children in our countries sicken with such so- 
called children's diseases because they alone have not acquired immunity 
by having had the disease themselves. 
In all the ills produced by living invaders there exists a struggle for 
supremacy-even for existence-between the host and the parasite, in 
which the stronger prevails and in which defences are developed not only 
by the host, but by the invader as well. It is doubtless through this that 
the bacteria accustom themselves in passing from the body of one animal 
to another to the action of the defensive reactions of the host, and become 
thereby more virulent. This is made evident in some cases by the appear- 
ance, under these circumstances, of capsules which are formed in the bacillus 
of anthrax, the pneumococcus, etc., as they grow in the animal body but 
not in cultures. The capsulated forms become less susceptible to phago- 
cytosis and it is even stated that infection can occur only when capsules are 
formed. In addition to this protective covering such bacteria are thought 
to become more formidable through the production of more active poi- 
sons which injure the phagocytes ("leucocidins," "aggressins"). Danysz 
found that bacteria in culture may be accustomed gradually to the presence 
of arsenic, so that they finally grow in relatively strong solutions and in the 
course of this adaptation acquire a capsule. Indeed, it is clearly shown that IMMUNITY 
163 
certain protozoa, the trypanosomes, may, like the Styrian arsenic-eaters, 
become so used to arsenic that they live on unhurt in the body through a 
continued bombardment with the new synthetic arsenic compounds, if 
only they have managed to survive the first doses. 
We know so little about the defences of the parasite, however, that at 
present we must exemplify the principles by reference to those of the host. 
We realize that, normally, animals have well-developed powers of defence, 
although these are efficient in such different degrees in different animals 
that we must surmise that they are not conferred in their full perfection 
on all at their creation, but have been gradually acquired through the 
survival of those best provided, who in turn bequeathed them to their 
offspring. These defences may guard against simple poisoning or against 
the inroads of living parasites, and we shall see that they do not lack in 
variety to correspond with these different forms of injury. Already we have 
found that certain general mechanisms, inflammation, and fever have been 
developed alike in all animals, but we have been forced in both instances 
to recognize the fact that these reactions are mere auxiliary mechanisms 
designed to bring into play to the greatest advantage, and in the most 
opportune concentration during sudden emergencies, other more profound 
and more subtle processes, phagocytosis, and the chemical neutralization 
of poisons which we admit as the essential agents of defence. 
For a time there were those who maintained that the activity of the 
phagocytes constituted practically the whole defensive armament, while 
others, enthusiastic over their new discoveries, were just as sure that the 
neutralizing substances in the body fluids were all-important. But now 
a reconciliation of these cellular and humoral doctrines has been effected, 
because it has been shown that they are very largely interdependent, 
phagocytosis depending upon the presence of auxiliary substances in the 
plasma, while in turn the leucocytes are important in producing other 
defensive fluid substances. 
Artificial Immunity.-From time immemorial it has been known that a 
person who has had smallpox, or typhoid fever, or yellow fever, or any 
one of a host of diseases can hardly have another attack of the same dis- 
ease: he is immune. On the other hand, there are certain diseases, such 
as pneumonia, diphtheria, erysipelas, furunculosis, etc., which seem to 
predispose to a repetition. While we are yet far from clear as to the 
reasons for this latter fact, we have learned a great deal about the security 
conferred by the immunizing sort of diseases. It is not necessary that the 
illness should be severe to give this lasting protection, and, recognizing 
this, it was the habit, many years ago, to court mild attacks of such a 
deadly disease as smallpox in order to be safe in the midst of an epidemic 
where the disease was severe. This was the beginning of man's inten- 
tional use of artificial methods of providing immunity, a plan which, under 
the influence of the phenomenally intelligent studies of such men as Pas- 
teur, Ehrlich, and von Behring, has extended until it promises now to be- 164 
TEXT-BOOK OF PATHOLOGY 
come the very most important practical achievement of medicine. It has 
proved possible to devise methods by which security from parasitic dis- 
ease can be attained without risking any serious preparatory illness, and 
to intensify the strength of this defence until it is almost absolutely un- 
assailable. Further, instead of thus producing an active immunity by 
making the person go through an imitation of. the disease himself, it is 
sometimes possible to cause an animal to go through the disease and then 
transfer the fluids of its blood to the body of the person, and with it the 
immunity, so that a passive immunity is conferred which may even stop 
the disease already in progress. 
Several methods are thus in common use: (1) The parasites in full 
virulence, but in very minute doses, are administered so that the person 
finally overcomes and recovers from a mild attack of the real disease; 
(2) the same thing is accomplished by a larger dose of weakened, attenu- 
ated, or non-virulent parasites; (3) dead bacteria are used in place of the 
living, and produce a feebler but similar immunity; (4) the isolated 
poisons of the parasites are injected in gradually increasing doses so that 
the power is developed to neutralize the poisons or (5) from such an animal 
this neutralizing power is transferred to another which thus, without effort, 
becomes immune. 
Space will not allow more than the merest outline of these processes. 
Details may be read with the help of the general references given to the 
literature, which is colossal. 
Phagocytosis.-As has been stated above, bacteria and other parasites 
are in normal animals taken up and digested by the phagocytes, but the 
help of the serum of the animal is most important-without it the leuco- 
cytes engulf very few bacteria. Denys, Wright, and others have shown that 
the serum contains opsonins, which act on the bacteria and prepare them 
to be attacked by the leucocytes. Neufeld found that in the serum of 
animals immunized by repeated introduction of those bacteria, somewhat 
more resistant bodies (bacteriotropins) appear, which exercise the same 
function in making the bacteria more approachable for the leucocytes. 
It appears that cytotropins, or substances which prepare foreign cells for 
phagocytosis, may be produced in the same way by injecting such cells. 
Aided by these substances, which bind themselves to the bacteria or for- 
eign cells, but do not affect the phagocyte itself, the wandering cells exhibit 
a great phagocytic activity. Although the swallowing-up of a bacterium 
does not necessarily kill it, it commonly does so, and at any rate removes it 
for the time from the field of action. 
Cytolytic and Bacteriolytic Reactions.-The introduction of foreign cells 
has other results than those just described. The serum of an animal which 
has received repeated doses of a certain foreign cell acquires the property 
of disintegrating and dissolving those cells. This reaction is highly 
specific, so that if red corpuscles of a dog be introduced into a rabbit there 
appears a hoemolytic serum which will destroy only red corpuscles and only IMMUNITY 
165 
those of the dog. Similarly, with inoculations of liver-cells, kidney cells, 
endothelial cells, etc., more or less specific hepatolytic, nephrolytic, or 
endotheliolytic sera have been produced. Other cells, such as those of 
animal parasites or bacteria, are responded to in the same way, and an 
intense trypanolytic or trypanocidal serum can be produced by injecting 
the bodies of trypanosomes, just as bacteriolytic (consequently bactericidal) 
sera result from the introduction of the dead bodies of bacteria. The 
fresh serum alone, quite free from phagocytic cells, has then the power to 
break up and destroy living bacteria brought into contact with it, whether 
in the body or in a test-tube. In any case it must be sharply distinguished 
from the antitoxic immunity which is referred to later. 
Agglutination.-Another sort of reaction is often produced at the same 
time, the effect of which is to cause the special bacteria or cells which 
caused its production to stick together in clumps if they are brought into 
contact with the serum in a test-tube-and to some extent within the 
animal body. This is the so-called agglutination, which is so specific in its 
relations that it can be used for diagnostic purposes. Thus the serum 
of a person suffering from typhoid fever or one who has had the disease, 
and of such persons alone, will cause the clumping and immobility of 
known typhoid bacilli suspended in a culture. 
Precipitins.-It is not even necessary to inject cells for the production 
of these antibodies, for the repeated injection of any foreign protein is 
responded to in the same way by the formation of a new substance which 
will specifically and exclusively act upon that protein at the first oppor- 
tunity. It may, when a new quantity of the protein and the serum are 
brought together, form a cloudy precipitate, or, and sometimes coinci- 
dentally with this effect, it may break down the protein into simpler but 
still complex substances, some of which are poisonous. 
The first of these phenomena is practically useful as a biological test 
in the recognition of proteins. Thus it may be necessary, for legal pur- 
poses, to say whether a blood-stain is composed of human or ox blood. 
The clear serum of a rabbit which has been treated with human blood- 
serum will become clouded if a trace of the dissolved blood-stain be added 
to it in case it really is human blood, but no precipitate will appear if the 
blood came from an ox. Conversely, the serum of a rabbit treated with 
ox blood would serve to recognize that blood. Another most ingenious 
method of recognizing human or other blood is that known as the fixation 
of complement (see paragraph on the Side-chain Theory). This method, 
developed by Neisser and Sachs, depends upon the fact that complement 
is used up when mixed with a combination of human protein and the in- 
activated serum of a rabbit immunized against human protein, so that the 
subsequent addition of inactivated haemolytic serum of a rabbit immunized 
against the red corpuscles of the sheep finds no complement left and no 
haemolysis occurs in added sheep cells. A principle similar to this is the basis 
of the well-known Wassermann reaction for the recognition of syphilis. 166 
TEXT-BOOK OF PATHOLOGY 
The second phenomenon which is probably intimately related with 
the precipitin reaction has recently come into prominence, because of the 
observation that the sudden introduction of a second dose of a certain 
protein into an animal already immunized to that protein may kill it. This 
effect, which is accompanied by certain characteristic symptoms,-vaso- 
motor paralysis, fall in temperature, inefficient heart action, dyspnoea, urti- 
caria, etc.,-is known as an anaphylactic shock, and the condition of the 
animal as anaphylaxis. Much ingenious experimentation has been carried 
out in the attempt to analyze and explain this phenomenon. In general it 
was thought to be the effect of poisoning by peptone-like bodies or proteoses 
produced by the partial digestion of the protein of the second dose by the 
combined action of the specific antibody developed in response to the first 
dose and the normal alexin or complement of the blood plasma. It 
seemed that all of this might occur in the circulating blood, since it was 
sometimes found possible to mix the antibodies and protein or antigen in 
vitro and to produce the characteristic symptoms by the injection of the 
mixture, and since passive sensitization of a normal animal might be pro- 
duced by injection of the blood of a sensitized animal, after which injec- 
tion of the protein would give anaphylactic shock. But partly because it 
was found to require time after the transfer of the sensitized blood before 
the injection of the antigen or protein could produce a distinct shock, partly 
because sensitized animals completely perfused with normal blood were 
still sensitized, and partly because strips of smooth muscle from sensitized 
animals were observed to contract on exposure to solutions of the antigen 
so dilute as to leave unaffected strips of muscle from a normal animal, it 
has been decided that anaphylactic sensitization is largely an affair of the 
tissue cells (Weil). It seems that the antibody upon which the reaction 
depends is not altogether free and floating in the circulating blood, but that 
much of it remains sessile, attached to the cells. It is for this reason that 
the effect is so intense, since the poison is produced in or on the cells. It is 
even suggested that possibly the presence of abundant antibody in the 
blood might protect the cells by combining with the antigen before it 
reaches them. Such explanations assume that the poison is produced 
from the antigen or injected protein. As a matter of fact, more nitrogen 
is excreted as a sequence of the anaphylactic shock than could be accounted 
for by that much protein, and this with other things has given rise to another 
explanation. Substances such as kaolin, agar, bacterial bodies, etc., mixed 
with normal serum produce poisons like those which cause symptoms 
of anaphylactic shock. In the animal body the increase in nitrogen excre- 
tion shows that a proteolytic ferment must attack the proteins of the 
serum. While Friedberger thought that the poison produced from bac- 
teria injected into sensitized animals was due to cleavage of the bacterial 
proteins, Jobling points out that bacteria as well as kaolin or other inert 
substances can absorb anti-enzymes (unsaturated lipoids, etc.) of the serum IMMUNITY 
167 
and thus release proteolytic ferments which effect cleavage of the proteins 
of the serum into poisonous proteoses. Whatever the nature of the 
mechanism by which they are produced, it seems clear that the poisons are 
the cleavage products of protein. Even if it be true that after the injec- 
tion of cells, bacteria, or such materials as kaolin, the poisons may be 
evolved by the action of proteolytic ferments on the proteins of the serum, 
the evidence in other cases of sensitization in animals, as by foreign serum, 
seems to support the idea of the participation of a specific antibody and 
the complement both in the tissue cells and in the blood. 
Dale has suggested that histamine-like substances may be the poisons 
concerned, and the work of Dr. Abel appears to show that the poison is 
actually histamine or a combination of histamine. This .substance, which 
can be obtained from any tissue by acid cleavage and extraction, has 
precisely the same physiological effects as are seen in the anaphylactic 
shock. 
The reaction depending upon this production of poison, when a special 
protein to which the animal has been spontaneously (through disease) 
or artificially immunized, is directly or parenterally introduced, is made use 
of for diagnostic purposes, as, for example, in the tuberculin and luetin 
tests, in which the proteins of the tubercle bacillus or of the Spirochaeta 
pallida are injected into the skin. Such a small dose, instead of overwhelm- 
ing the nervous system and producing a fall in temperature, affects it only 
to the extent of stirring up a febrile reaction. 
Antitoxins.-In those cases in which bacteria produce a soluble toxin, 
as well as in the case of soluble toxins of animal or vegetable origin, the 
body will respond to the repeated injections of the toxin by the production 
of a soluble antitoxin which circulates freely in the blood and combines 
with and neutralizes quantitatively a fresh injection of the same toxin. 
This will happen quite as well in a test-tube or in the body of another 
animal if the serum of the immunized animal be removed and mixed with 
the toxin in the test-tube or injected into the body of the other animal. 
In the latter case the neutralization of toxin already introduced will take 
place in so far as it is still uncombined. The first animal has acquired an 
active antitoxic immunity, while a passive antitoxic immunity is con- 
ferred on the second one by the injection. This is the basis of the use of 
the well-known diphtheria antitoxin of von Behring. The commercial 
preparation is nothing more than the serum of a horse, which, by repeated 
increasing doses of diphtheria toxin, has been brought into a state of active 
antitoxic immunity. It is quite specific, and the diphtheria antitoxin is 
therefore useless against tetanus, or vice versa. 
When a child has recovered from diphtheria, antitoxin is found circulat- 
ing in the blood. Many children are found to be thus protected by the 
possession of a circulating antitoxin which may have been acquired with- 
out any severe illness. In its presence the intracutaneous injection of a 168 
TEXT-BOOK OF PATHOLOGY 
minute amount of diphtheria toxin produces no result, while in its absence 
such a test leads to the formation of a minute area of necrosis with a rather 
wide zone of reddening and swelling of the skin (Schick reaction). 
The participation of these various phenomena in natural and acquired 
immunity is not always perfectly clear. The simplest is perhaps the anti- 
toxic immunity in which the poison is neutralized, as an acid might be 
neutralized by an alkali, while the bacteria causing the disease are left 
unharmed. The immunity conferred by one attack of the disease is prob- 
ably a combination of bacteriotropic and phagocytic activity with bac- 
teriolytic immunity. So, too, the immunity produced by vaccines of dead 
and attenuated bacteria. Bacteriolytic sera have not been very success- 
fully produced except in the case of a few bacteria, such as cholera, typhoid, 
etc., but even when they are active they seem unable to cut short the 
progress of the infection in the animal, possibly because they lack the 
presence of sufficiently active bacteriotropins. An animal may be able 
to destroy a quantity of bacteria injected into the peritoneum, but still be 
unable to withstand infection by way of the intestinal tract. Local appli- 
cation of these sera is, therefore, often desirable and effective in conditions 
such as meningitis, where the infection itself is essentially a localized one. 
In all cases the intense specificity of the reaction makes itself felt, so that 
a bactericidal serum or bacteriotropic substances which might aid in the 
destruction of one strain of streptococci may fail of all activity in the case 
of another hardly distinguishable except by such a biological test. 
The Side-chain Theory.-To explain all these phenomena, and to further 
the discovery of others, Ehrlich has constructed a hypothesis known as the 
side-chain theory, which, although even yet not proved in all its details, 
is marvelously perfect in its agreement with new facts as they are brought 
out and in its serviceability in showing the direction in which new facts 
may be sought. He conceives of the cells of the body as provided with 
certain molecular arrangements or receptors, by means of which they 
normally anchor and bind to themselves substances which they require 
for their metabolism. Such substances are ordinarily useful, but they may 
be injurious. In that case the cell may be destroyed. If not, those re- 
ceptors are at least thrown out of function and the cell is to that extent 
injured by having anchored to itself the toxin. With its natural powers of 
repair it produces new receptor groups, and since, as Weigert has expressed 
it, the process of regeneration leads to the production of an excess, the 
loss is more than made up. These new receptors have the same facility in 
uniting with toxin groups, and being in excess, they are discharged by the 
cell into the circulating fluids. There they by themselves anchor toxin 
molecules and thus prevent them from reaching the susceptible cells. 
Without such receptors the cell is, of course, insusceptible of being affected 
by the toxin, and hence perhaps the natural immunity of some animals. 
In the case of the opsonins, bacteriolytic substances, and all the cyto- IMMUNITY 
169 
lytic and antiprotein reactions, the specific antibody is produced in a 
similar way by the susceptible cells as a result of the influence of the foreign 
protein or cells (antigens), but in these instances it is found that the specific 
group, or antibody, thus produced cannot act alone to destroy the foreign 
cell or protein, but must call to its aid a ferment-like substance normally 
present in the serum-the so-called alexin or complement. There are many 
of these complements, and they do not all unite equally easily with the 
specific immune bodies. They are easily destroyed by relatively low 
temperatures or by any other injury, such as drying, the action of chemi- 
cals, etc. 'The fact that the specific immune body requires the aid of the 
complement has shown that it itself is merely a link specifically able to 
connect or introduce the non-specific complement into combination with 
the special cell or protein against which it has been developed. It is for 
this reason that Ehrlich has named it the amboceptor or linking body, 
although Bordet and others thought of it as a mere mordant-like material, 
which sensitized the cell to the attack of the alexin. Amboceptors or 
immune bodies are resistant to heat, drying, etc., and may be kept in good 
condition for years. Their characters have been particularly well shown 
in the experiments of Ehrlich and his school on haemolysis, and those of 
Pfeiffer on bacteriolysis. Left in contact with heated immune serum, in 
which all complement has been destroyed, the foreign cells bind to them- 
selves the amboceptor, but no destruction of the cells occurs. The ad- 
dition of fresh unheated normal serum which contains the non-specific 
complement allows haemolysis or bacteriolysis to take place at once. 
Bacteriotropins, agglutinins, and precipitins appear to be simpler sub- 
stances not composed of a specific resistant and a non-specific labile por- 
tion. .Their action is not altogether clear, although there are many in- 
genious theories for which the student is referred to the literature. 
Only general reviews which give further literature references are cited. 
Aschoff: Ehrlich's Seitenketten-Theorie, Jena, 1902. (Zeits. f. allg. Physiol., 1902, i.) 
Besredka: Kraus and Levaditi, Handbuch d. Immunitatsforschung: Anaphylaxie. 
Biedl and Kraus: Ibid., 255. 
Dold: Bakterien Anaphylatoxin, Jena, 1912. 
Ehrlich: Gesammelte Arbeiten, Berlin, 1904. 
Friedberger and many others: Kolle u. Wassermann, Handbuch der Bakteriologie. 
Metchnikoff, E.: Immunite dans les maladies Infectieuses, Paris, 1901. Lubarsch- 
Ostertag Ergeb., 1896, ii, 298. 
Sobernheim: Krehl u. Marchand, Handb. d. allg. Pathol., 1908, i, 417. 
Vaughan: Proc. Assoc. Amer. Phys., 1907, xxii, 268. (Split Products of Proteins.) 
Wassermann, A.: Volkmann's klin. Vortr., 1902, No. 331 (Chir. No. 94). 
Consult especially, 
Zinsser: Infection and Immunity, New York, 1914; Arch. Int. Med., 1915, xvi, 223. 
(Anaphylaxis.) 
LITERATURE 170 
TEXT-BOOK OF PATHOLOGY 
THE MAINTENANCE OF THE ACID-BASE EQUILIBRIUM OF THE BODY 
Mechanism of the Preservation of Neutrality.-It is known that the cir- 
culating fluids and, therefore, the tissues depart very little under normal 
conditions from a neutral reaction. The fact that external secretions, 
such as those of the gastric mucosa and kidney, have an acid reaction 
does not interfere with this, but is in some degree connected with up- 
holding it. It is of extreme importance that this constancy of reaction 
should be maintained, inasmuch as many of the functions of the body, 
and those of the most vital importance, depend on it. Thus the respira- 
tory interchange is quickly affected by the excessive production of acids, 
and the violent gasping for breath or air-hunger seen in such cases is a 
symptom of the disturbance of the normal balance. 
The mechanism of the preservation of this approximate neutrality is by 
no means easy to understand, but it has been analyzed by Lawrence Hen- 
derson, and I quote chiefly from his writings and those of Van Slyke and 
Bayliss in the following: 
The hydrogen ion concentration of the arterial blood is kept at a very 
constant level, 10~ 7-45 (Ph = 7.45), and does not change except in the 
terminal stages of some disease in which great overproduction of acid 
is taking place. It is the expression of the successful functioning of the reg- 
ulating mechanism, the factors of which do not change, although they con- 
tinue to maintain this nearly neutral reaction. 
The regulation is carried on by two groups of substances: carbonic 
acid with various bases, of which the predominant one is sodium, and 
phosphoric acid, in its combinations with sodium or other bases. For 
practical purposes we need only consider carbonic acid and bicarbonates, 
on the one hand, and monosodium and disodium phosphate on the 
other. 
"Free carbonic acid is present in the body fluids in such concentration 
that it automatically converts into bicarbonate all bases not bound by 
other acids. The bicarbonate, therefore, represents the excess of base 
which is left after all the non-volatile acids have been neutralized and is 
available for the immediate neutralization of further acids. In this sense 
it constitutes the alkali reserve of the body. 
Acidosis.-Acidosis is a condition in which through rapid production or 
inadequate elimination of acids the alkaline reserve of the body is reduced 
below the normal level. As stated above, it is only in the most extreme 
examples, in which the overwhelming production of acid has almost 
exhausted the alkali reserve, that the hydrogen ion concentration of the 
blood is changed. 
Until then the organism can by accelerated respiration maintain the 
. H2CO3 
ratio - in the arterial blood at its normal value, and the PH being 
-N aHGOs 
directly proportional to this ratio is thereby also kept normal. Whenever, 
•either by increased rate of CO2 production, or by decomposition of NaHC03 MAINTENANCE OF THE ACID-BASE EQUILIBRIUM OF THE BODY 
171 
H2CO3 
by other acids the ratio -T TT^ZA increases, the PH of the blood is propor- 
J NaHCO3 
tionately increased and stimulates respiration. More rapid ventilation 
H2CO3 
follows until the H2CO3 of the blood is so reduced that the normal ---■ TT^zc 
in aMCOs 
ratio and consequently the normal PH is restored. This respiratory 
response fails when the acids which combine with sodium are in great ex- 
cess and the bicarbonates are almost depleted, and there arises from com- 
pensated acidosis an uncompensated form. 
It is clear from this that the natural method of maintaining this ratio 
is through the continuous discharge of CO2 through the lungs. The amount 
of CO2 in the alveolar air is directly proportional to the concentration of 
free carbonic acid in the blood, and this, under normal respiratory condi- 
tions, with the bicarbonate concentration. 
While this respiratory control acting upon the carbonic acid and bicar- 
bonates is perhaps the most important, it is not the only influence tending 
to maintain neutrality of reaction in the body in the face of abundant pro- 
duction of acid. It is known that blood is able to withstand the addition 
•of considerable amounts of free acid or alkali without much change in its 
reaction. This is chiefly due to the carbonates and phosphates present. 
Henderson has shown that almost any mixture of monosodium phosphate 
and disodium phosphate is neutral to indicators, and will take up strong 
acids or alkalis without apparent change in its reaction. 
This depends upon the fact that strong acids and bases combine quanti- 
tatively with the alkaline or acid phosphate. 
HC1 + Na2HPO4 = NaCl + NaH2PO4 
NaOH + NaH2PO4 = Na2HPO4 + H2O 
Similar properties are found in a mixture of carbonic acid and bicarbonates 
which have much of this ability to absorb alkalis or acids without apparent 
•change of reaction. The systems even interact as follows: 
Na2HPO4 + H2CO3 = NaH2PO4 + NaHCO3 
The addition of acids or alkalis to such mixtures changes the proportions 
of the two phosphate salts or of the carbonic acid and bicarbonates. 
The readjustment of the hydrogen ion concentration in such mixtures 
is an expression of the law of mass action affecting solutions in which electro- 
lytic dissociation may be represented as taking place in stages as follows 
(Bayliss): 
(1) Na2HPO4 Na* + NaHPO4' 
(2) NaH2PO4 Na* + H2PO4' 
(3) NaHPO4' Na* + HPO4" 
(4) H2PO4' H* + HPO4" 
(5) H2O H* + OH' 
(6) HPO" + H2O H2PO4' + OH' 172 
TEXT-BOOK OF PATHOLOGY 
In a solution of NaH2PO4, which has an acid reaction, the only source 
of H' ions is the stage of dissociation numbered (4) in the list above; (2) 
must precede this, so that, combining the two, we have: 
NaH2PO4 = Na* + H* + HPO4" 
In a solution of Na2HPO4 we have also HPO4" ions from (1) and (3): 
Na2HPO4 = Na* + Na* + HPO4" 
If we add Na2HPO4 to a solution of NaH2PO4, we add an excess of 
HPO4" ions. Therefore, since these solutions, as weak acids and bases, 
obey the law of mass action, we reverse the dissociations of equation (4), 
H2PO4' H* + HPO4", 
and the H* ion concentration of the acid phosphate is reduced. 
Similarly, the alkalinity of a solution of Na2HPO4 is due to the OH' 
ions derived from hydrolysis of HPO4" ions, according to equation (6). 
Perhaps it would be more correctly expressed by saying that the HPO4" 
ion combines with H* ions of water to form H2PO4" ions, in a way analogous 
to that in which acetic anions combine with hydrogen ions to form non- 
dissociated acetic acid. In any case the result is an excess of OH' ions. 
If, then, NaH2PO4 is added to Na2HPO4, the excess of H2PO4' ions throws 
back equation (6), and the alkalinity is reduced. 
The monosodium phosphate, as a weak acid, gives off very few H* and 
HPO4" ions by (2) and (4), so that a very small amount of disodium salt, 
which as a sodium salt gives many HPO4" ions by (1) and (3), has con- 
siderable power of diminishing the acidity of the former. Again, the di- 
sodium salt as a weak base gives rise to a very few OH' ions by (1), (3), 
and (6). Hence a very small amount of NaH2PO4, which in its character 
as a sodium salt dissociates with the production of many H2PO4' ions, 
diminishes considerably the hydroxyl ion concentration of the disodium 
salt by throwing back equation (6). 
Similarly in the case of carbonic acid and bicarbonates the equations of 
dissociation may be written to correspond with those of the phosphates: 
(3) NaHCO3 Na* + HCO3' 
(4) H2CO3 H* + HCO3' 
(5) H2O H* + OH' 
(6) HCO3' + H2O H2CO3 + OH' 
Since carbonic acid, HoCCb, is a very weak acid, few hydrogen ions are 
formed by equation (4). Sodium bicarbonate, as a weak base, produces 
few hydroxyl ions, but, as a sodium salt, produces a considerable number 
of HCO3' ions. Suppose that CO2 is added to a mixture of bicarbonate 
and CO2.H2CO3 is formed, and this increases the concentration of HCO3' 
by dissociation. The result of this will be an increase of non-dissociated 
NaHCOs by throwing back equation (3) (Bayliss). MAINTENANCE OF THE ACID-BASE EQUILIBRIUM OF THE BODY 
173 
"The whole physiological equilibrium may be concisely summed up 
(Henderson). The hydrogen ion concentration of the body has been seen 
, . H2CO3 
to depend upon the ratio • Acid reacting with this system causes 
a diminution of the denominator and an increase in the numerator of the 
fraction; the value of the fraction increases and with it the hydrogen ion 
concentration. Hereupon the lung reduces the value of the numerator by 
diminishing the concentration of carbon dioxide in the blood and alveolar 
air; the value of the fraction is restored more or less exactly to its original 
value and with it the concentration of the hydrogen ion. But the denomi- 
nator is still below normal. To offset this there occurs, on the one hand, a 
production of ammonia which takes the place in the urine, of alkali exist- 
ing as salt in the blood. This alkali recombines with carbonic acid, forming 
bicarbonate, and thus increasing the denominator. On the other hand, 
the kidney removes less alkali in combination with phosphates than exists 
in this state in the blood. This alkali, too, helps to regenerate sodium bi- 
carbonate and thus to increase the denominator. Both of these processes 
are so regulated that the ratio returns to normal." 
Excessive production of acids in the body, depleting the alkali reserve 
and calling into activity the compensatory mechanism just described, occurs 
most conspicuously in diabetes where the imperfect oxidation of fats gives 
rise to beta-oxybutyric and other acids. Various infectious diseases with 
extensive destruction of tissue are accompanied by the liberation of acids 
in excess in the tissues. Destruction of the liver, the extensive metabolic 
disturbances which sometimes accompany pregnancy, protracted starva- 
tion, poisoning with acids are among the conditions which bring about an 
acidosis. Chronic nephritis, inasmuch as the excretion of acids is retarded, 
may have the same result, while cardiac disease with decompensation and 
dyspnoea may produce a similar change by the inadequate removal of 
carbon dioxide. 
On the other hand, a condition which might be referred to as alkalosis, 
in which the alkali reserve is greatly increased, arises with pyloric obstruc- 
tion when there is vomiting and continued loss of hydrochloric acid with 
the gastric juice. Details of the untoward results of this are given in 
describing gastric tetany. 
LITERATURE 
Bayliss: Principles of General Physiology, 2d ed., 1918, 195. 
Ewing: Archives Int. Med., Nov. and Dec., 1908. 
Frothingham.: Ibid., 1916, xviii, 717. 
Henderson, L. J.: Science, 1917, xlvi, 73; Ergebn. Physiol., 1909, viii, 254. 
Van Slyke and Cullen: Jour. Biol. Chemistry, 1917, xxx, 289. CHAPTER XI 
DEFENCES OF THE BODY (Continued) 
New-growth of tissue. General characters. Influence of various agencies on growth. 
Growth stimuli. 
NEW-GROWTH OF TISSUE AND REPAIR 
We are very ill informed with regard to the principles which underlie 
the growth of tissues, and any discussion of them soon leads us to a point 
beyond which we cannot go without invoking the deceptive aid of such 
expressions as vital force, inherent vitality, etc. There have been many 
efforts to explain the manifestations of life on a chemical or physical basis, 
but while they explain very well what happens, they leave us with little 
notion of what the real spark is which starts the setting free of energy, 
whether its result be a functioning of the cell as we see in a muscular con- 
traction or the division of one cell into two. 
We do know well enough that new-growth of tissue occurs when tissue 
is destroyed. Much of this compensatory new formation may take place 
somewhere quite far away from the point of injury, but at any rate there 
is a local patching which, when the tissue destroyed is a highly specialized 
one, is usually carried out by the ubiquitous connective tissue. The 
patch is, therefore, not likely to be of the same dignity as the original tissue, 
and serves mainly to reestablish continuity. 
Since injury often excites the inflammatory reaction also, the two may 
become inextricably entangled, so that there has long been confusion with 
regard to "inflammatory new-growth." This is especially true when, on 
account of the persistent repetition of the injury, the inflammatory re- 
action continues for a long time, and attempts at healing are repeatedly 
partly frustrated. But the most intense inflammatory reaction may occur 
with hardly any new-growth of tissue, as in pneumonia, and, on the other 
hand, regeneration and repair sometimes take place with no visible signs 
of inflammation. The two processes seem distinct in their causes, in their 
aims, and in the cells which participate, so that though they occur to- 
gether they should not be confused. If we reflect upon this, even though 
we meet with difficult and questionable cases, we must realize that that 
process which we call inflammation consists essentially in the flooding of 
the injured tissues, by special mechanisms, with an excess of wandering 
cells and the fluids of the blood which tend to neutralize the injurious agent 
and clear away the debris and then to fade away and disappear, having 
taken part in no new formation of tissue. Repair, on the other hand, is 
the new formation, from neighboring cells, of a more or less complex, 
174 NEW-GROWTH OF TISSUE AND REPAIR 
175 
permanent, and coherent tissue which takes the place of that which was 
lost. 
It seems not unreasonable to suppose that the warmth and good blood 
supply which are so characteristic of inflammation might favor this process 
of repair, or even that the irritant itself, when it becomes diluted in its 
extension into the tissue, may act as a stimulant to cell growth. The 
conception of "inflammatory new-growth" or "productive inflammation" 
must depend upon this last possibility, and there will arise occasion to 
discuss it further. For a long time there was doubt as to the role of the 
many kinds of wandering cells which appear in old areas of inflammation, 
and as long as they were thought to be able to give rise to connective tissue, 
the influence of inflammation on new-growth seemed very great. Now, 
however, since Maximow and others have shown their rather specialized 
wandering character, and it is admitted only grudgingly that they have 
any part in tissue formation, the matter becomes clearer and we have to 
deal with wandering cells as concerned with inflammation and fixed tissue 
cells with repair. 
Nowhere, however, could there be a more convincing instance of the 
effect of a chemical stimulant acting to excite a rapid new-growth of tissue 
than in the case of the sudden phenomenal proliferation of leucocytes in 
the bone-marrow, and the flooding of the blood with these cells when some 
bacterial poison is absorbed from an area of inflammation. 
We must ask ourselves what are the causes which lead to the growth of 
tissue in general, and the new-growth of tissue in particular, and we find 
that, while we have some information concerning those things which 
influence growth, we are reduced to theories when we attempt to explain 
the actual causes. Underlying it all we must recognize one essential thing 
which distinguishes a live cell from a dead one, namely, the ability to absorb 
and assimilate nutritive substances, building them up into its own pro- 
toplasm, and then, by the exercise of a certain amount of energy, to divide 
its nucleus and protoplasm in such a way as to form two new cells in place 
of the old one. Given this power, which we cannot explain, we may as 
well go on to discuss the conditions and influences which guide this growth, 
find which are directly chemical or physical in their nature. 
The materials for growth must be supplied, and are precisely selected 
by the cell in quantities to suit its metabolic processes. Water, protein, 
carbohydrate, and fatty substances, inorganic materials, and oxygen are 
absorbed, and carbon dioxide with various other substances, elaborated or 
excreted by the cell, are given off. We realize that growth is inhibited by 
faulty nutrition or by an inadequate blood supply, and that the healing of 
a wound is slow and imperfect in those whose metabolism is impaired by 
old age or illness. The idea that increased activity in growth is brought 
about by an excessively rapid and abundant blood supply has long been 
held, and there is some evidence in its favor. A rabbit's ear kept flushed 
with blood by the section of the sympathetic nerves is said to grow more 176 
TEXT-BOOK OF PATHOLOGY 
rapidly than the other, and to outstrip it, while conversely it is well known 
that rapidly growing tissue makes its appearance with an excessive pro- 
vision for blood supply in the form of numerous wide capillaries which dis- 
appear when the tissue becomes mature. Still, the situations in which we 
may study the effect of an excessive blood supply in comparison with an 
adequate one are generally complicated, and give us little light on the 
subject. 
When tissue is grown artificially in a hanging drop of blood plasma, all 
these influences come most clearly to view, and it is quickly apparent that 
growth stops at once when the supply of nutriment contained in the drop 
of plasma becomes insufficient. The effect of warmth is most apparent 
there also, and it can be shown that, whereas at very low temperatures 
growth does not occur at all, it begins and increases slowly in rate as the 
temperature is raised until, at a certain point, it finds the optimum con- 
ditions. Higher temperatures than this are unfavorable, and growth 
becomes slower and slower until a point is reached at which it is com- 
pletely inhibited. In living animals this can be demonstrated to some 
extent, inasmuch as the ear of a rabbit kept warmer than normal for a 
long time is said to grow so that it becomes larger than the other ear, which 
has not been so treated. 
In this last instance, as in the case of the influence of the nervous system, 
it is difficult to decide which of several things may be the real cause of the 
growth, for in such a rabbit's ear the warmth tends to widen the blood- 
vessels and thus bring increased supplies of nutrition to the part. Indeed, 
it is somewhat doubtful whether the nervous system has any direct in- 
fluence over growth, even though we speak so confidently of trophic nerves. 
For while an extremity which has been paralyzed fails to grow as the nor- 
mal one does, this may well be due to its inactivity and the consequent 
diminution of the blood supply. 
Mechanical influences play a considerable part in determining growth, 
although it is well known that in plants at least a force can be exerted by 
growing tissues far greater than that which might ordinarily be used to 
interfere with their growth. Here again there enter the complicating 
factors of interference with nutrition and light, which are most powerful 
to disturb growth, for while a tree growing in a crevice can split a rock and 
roots can lift up pavements, one may apply a relatively slight pressure so 
as to cut off nutrition and light, and growth will be blocked. 
Continuous pressure applied to organs or extremities in the animal 
body interferes with their growth or causes the cells to atrophy and dis- 
appear, as we see in the deformed livers of those who lace tightly and in 
the misshapen skulls of those Indians who bind the heads of their children. 
But intermittent pressure, as that of a shoe which pinches, tends rather to 
cause an excessive callous growth of epidermis. We might multiply ex- 
amples of the growth of tissue in response to various sorts of mechanical 
tensions and strains, a growth which forms the basis of the wonderful NEW-GROWTH OF TISSUE AND REPAIR 
177 
adaptation to function so generally observed when tissues or organs are 
subjected to changed conditions. Thus the arching lamellae of bone which 
are precisely calculated to meet the strain at the upper end of the femur 
are, after a time, rearranged to suit the new conditions with equal mechani- 
cal perfection when the bone has healed after a fracture. 
Probably few persons who survive an extensive injury, and in whom this 
process of readjustment to new conditions is going on, live long enough to 
allow it to be quite perfected, but there are frequently found in such per- 
sons the most extraordinary adaptations. 
It is only in those tissues which have to do with movement and support, 
however, that the inciting cause of the new-growth of tissue is chiefly 
mechanical, and it must be remembered that in other organs whose func- 
tion is not of a mechanical nature other influences are at work to bring 
about the readjusting new-growth. A good example of the mechanical type 
is seen in the establishment of a collateral circulation when an important 
vein or artery has been obstructed. Numbers of channels which were pre- 
viously insignificant become large, thick-walled vessels and give passage 
to the pressing stream of blood in a roundabout way, so that it may re- 
join the original channel beyond the obstruction. A remarkable instance 
of this which showed a complete obstruction of the superior vena cava is 
described by Osler.* A bulky mass of new vascular channels was so 
formed as to convey the blood from the upper part of the body over a long 
detour to the heart (Fig. 8). 
Obstructions placed before tissues which act mechanically in such a way 
as to make it difficult for them to carry on their function nearly always 
cause a growth of the tissue, so that it becomes stronger and forces the 
barrier. This is seen in the heart and in all those muscular structures, such 
as the intestine and the bladder, whose duty it is to move their contents 
by contraction. Above a tumor which obstructs the colon the wall be- 
comes enormously thick and powerful, and so does the wall of the bladder 
when, through the enlargement of the prostate, urine is evacuated with 
difficulty. 
In the repair that follows a loss of substance these mechanical influences 
are not quite so plain, but they undoubtedly play a part. New tissue is 
formed hurriedly and in great quantities to replace that which was lost, 
and although at first it seems to grow in a somewhat disorderly way, it 
quickly shows an adaptation to its purpose. All this is probably guided, 
at least in part, by the influence of the solid materials with which the cells 
come in contact, for while the young connective-tissue cells and blood- 
vessels can grow by themselves and form an even swelling tissue, the more 
usual and natural way for them is to grow upward into a network of fibrin 
filaments along which they creep and which, in turn, they dissolve and 
destroy (Fig. 66). Epithelium grows and spreads out on a surface when 
* Johns Hopkins Hospital Bulletin, 1903, xiv, 169. 178 
TEXT-BOOK OF PATHOLOGY 
that is offered, but scarcely penetrates into a feltwork of fibrin. These are 
differences in the "inherent vital characters" of these cells, for when iso- 
lated from all connection with the body and growing in the hanging drop 
of plasma, they show the same peculiarities in their growth; connective- 
tissue cells sprout out in every direction so long as they may follow the 
course of a filament of fibrin. Epithelium grows in a sheet, just as it 
tends to do on the surface of a healing wound (Figs. 67, 68, 69). 
Fig. 66.-Fibroblasts growing into a thrombus. 
Even the simplest of these forms of tissue proliferation can hardly be 
ascribed directly to any mechanical influence, but it is clear that the cells 
in their growth are guided and directed to some extent in this way. There 
must be remembered always the underlying tendency of the living cell to 
assimilate food materials, increase its substance, and divide. 
Functional Equilibrium.-Is there then some stimulus from without 
which accentuates this tendency, or is the tendency merely allowed full 
play by the withdrawal of some restraining influence? This has been the NEW-GROWTH OF TISSUE AND REPAIR 
179 
subject of debate for many years, for while Virchow held that there exist 
actual growth stimuli which might indeed act through the injury or de- 
struction of certain cells, Weigert declared that cells grew because the 
mutual resistance of the tissues was set aside, the equilibrium disturbed, 
and, as John Hunter before him had thought, the cells grew impelled by 
the loss of the physiological limitations which one tissue element opposes 
to another. John Hunter had spoken of the stimulus of incompleteness; 
Weigert regarded the tissue growth which occurs with inflammation not as 
Fig. 67.-Characteristic growth of connective tissue cultivated in vitro. There are many 
mitotic figures. 
the result of a stimulus, but only as the consequence of the tissue defect. 
According to him, it was quite unproved that there is any direct idioplastic 
stimulus. 
The existence of a certain equilibrium among tissues, and the remark- 
able effects of its disturbance, have long been recognized, but this equilib- 
rium cannot be looked upon as a merely mechanical one. Nor is it to be 
explained on any simple chemical basis. We are perhaps nearest to the 
truth if we say that it rests chiefly upon a balance between the functional 180 
TEXT-BOOK OF PATHOLOGY 
activities of different tissues. If, in the functioning of a cell, certain ma- 
terial is consumed, the cell makes this up by its assimilative processes. 
If functional activity is maintained at an extreme, so is the assimilation, 
and the cell even increases its size and functional power, or, after accumu- 
lating an excess of cell material, divides into two cells, so that the function 
is better maintained (hypertrophy; hyperplasia). But no mechanical or 
chemical disturbance in the body will give more than a motive for this. 
Fig. 68.-Characteristic growth of epithelium in culture. 
The process itself depends on that inherited power of growth by which the 
cell adjusts itself to the new conditions. 
When they reach maturity, the bodies of any one kind of animal have, 
as we know, a characteristic form and a recognized average size, but a good 
deal of variation from the standard is still compatible with life. Within 
the body the interrelation of organs seems to be much more precisely 
calculated, just as the works of a watch must be calculated throughout, 
although the case may have any form. It seems probable that there may 
even be an actual numerical relationship between the cells of different NEW-GROWTH OF TISSUE AND REPAIR 
181 
organs, so that a disturbance of this balance is felt if cells are destroyed in 
one. It is known, of course, that each organ is able to put forth in an emer- 
gency a vastly greater functional activity, since it has a reserve power 
which constitutes its margin of safety, but this effort is felt at once and 
shortly leads to the multiplication of the cells and the increase of the 
functional power. This is true whether the emergency results from the 
destruction of some of the cells or the increase in the demand upon the 
organ. 
Fig. 69.-Epithelium and connective tissue growing side by side in a culture made from 
the intestine of an embryo. 
This is the functional equilibrium of the tissues which is maintained very 
precisely by the increase and reduction of the various functional units. 
But there is also a mechanical equilibrium. The tissues grow in certain 
arrangements, and the organs assume certain normal forms which are the 
result of the action of various tensions and strains not always easy to recog- 
nize or calculate, and the end-result is the recognized normal body form. 
It requires a very extensive disarrangement of the tissues to obliterate 
the trend of these tensions and strains and allow the body to heal into any 
unusual or inappropriate form. Usually, if time is given, the healing of 182 
TEXT-BOOK OF PATHOLOGY 
any moderate injury goes far toward restoring the normal body form and 
thus the mechanical equilibrium. 
When an injury is such as to unbalance for a time this mechanical 
equilibrium, there occurs a new formation of tissue to replace that which 
was lost, and in time the original mechanical conditions may be well 
restored and the body form reinstated, but it would be rash to state that 
this was carried out solely because the mechanical equilibrium was dis- 
turbed or that the cells grew because pressure relations were altered on one 
side or the other. There is always the other factor to be considered, 
namely, that the loss of tissue, even when it is merely supporting tissue, 
involves an unbalancing of the functional equilibrium, so that the growth 
occurs also to reinstate that. However, even with these two reasons it 
is difficult to explain the purposeful methodical growth of tissue which so 
precisely accomplishes the healing of a wound, but in its detail, in which 
fibrin plays a part, guiding the direction of growth of the new cells so that 
they stretch across from one side of the wound to the other, a plan is 
doubtless being carried out which has become a routine after a long process 
of evolution, and is now merely the common means, regardless of the reason 
for growth. 
That the unbalancing of the mechanical equilibrium can hardly be con- 
sidered the main reason for the new-growth of tissue becomes clear when 
we consider cases in which it can be practically eliminated. When, for 
example, some poison kills a part of the liver-cells in each lobule of that 
organ, multiplication of the remaining cells occurs while the bodies of the 
dead cells are still in position and little change in the pressure relations can 
have arisen. So, too, on the removal of one kidney, or even when its 
function is annulled by obstruction of the ureter so that it becomes atro- 
phied or enlarged into a sac of fluid, growth occurs in the other kidney until 
it is able to do easily the work of both (Fig. 70). These are examples of 
the results of an unbalancing of the functional equilibrium which seems, 
upon due consideration, to be the most important factor in this question 
of new-growth. 
Influence of Nutrition.-In general, growth of tissue is much influenced 
by the character of the food, and in the lack of certain constituents may be 
greatly retarded. This question, obviously of great importance, has been 
the subject of extensive studies in recent years, and has become so complex 
that the original articles of F. G. Hopkins, Osborne and Mendel, and others 
must be consulted. Hopkins showed that certain substances, often vaguely 
referred to as vitamines, which are present in minute quantities, are of 
fundamental importance. The nature of these substances and their varying 
solubility in fats or in water have been much discussed without any definite 
conclusion. It is realized that certain of the constituent amino-acids are 
requisite for the building up of the proteins of the cells and that growth 
is retarded by their absence, but the absence of the vitamines brings with 
it profound pathological changes. Whipple and Hooper have shown that NEW-GROWTH OF TISSUE AND REPAIR 
183 
Fig. 70.-Atrophy of left kidney following obstruction of the ureter. Corresponding 
enlargement of the opposite kidney. 184 
TEXT-BOOK OF PATHOLOGY 
regeneration of blood by the bone-marrow is much influenced by the char- 
acter of the food, and Clark found that the healing of wounds begins more 
promptly upon a protein-rich diet than upon a diet composed chiefly of 
fats and carbohydrates, although when once begun the rate of healing is 
the same. 
Active Stimuli to Growth.-Still the question remains whether there 
exist means by which growth can be directly and actively stimulated. 
The great difficulty in answering this question lies in our being unable to 
eliminate the factors of the unbalancing of the mechanical and the func- 
tional equilibrium by the injury which these stimuli cause in the cells, and 
for this reason we may await with interest the results of systematic experi- 
ments with the application of such supposed stimuli to tissue growing 
in vitro where mechanical conditions can be controlled and functional de- 
mands reduced to a minimum. Further, in those frequent cases in the 
animal body in which the very excess of the new tissue produced seems to 
argue the existence of some special stimulus to growth, we must eliminate 
the possibility that this new tissue may represent the accumulated product 
of repeated attempts at repair, each of which has been partly frustrated 
by a new injury, so that even the repairing tissue is injured and responds 
in an attempt to repair itself. It is readily seen that this process, kept up 
for a long time, would end in the formation of a great quantity of scar tis- 
sue, or, at the margin of a chronic ulcer, of a greatly thickened and irregular 
epithelial growth. 
But in the present state of our knowledge it is impossible to deny the 
existence of direct stimuli to tissue growth, although it seems that this 
facile explanation ought to be used perhaps a little less freely than is done 
in most text-books. There are certain substances, such as the stains 
Sudan III and scarlet red, which, when injected into the tissues, provoke 
an extraordinary growth of epithelium, cartilage, etc., which in some cases 
finally looks almost like a tumor. Similar results have been obtained with 
skatol, indol, etc., and even with ether water. It is not quite clear how 
these substances act nor what part is played by the injury they produce in 
the tissues, but the new-growth is far in excess of what would be needed for 
repair. They are all soluble in lipoid substances, and it is possible that their 
effect is due to their attacking the lipoid membrane, which is supposed to 
envelope each cell, thus exposing the cell to outward influences from which 
it has been protected. This is somewhat allied to Loeb's methods of stir- 
ring up artificial or parthenogenetic development in unfertilized egg-cells, 
for in that process he emphasizes the importance of lipolytic substances 
in their action upon the envelope of the cell. In that case, however, the 
segmentation which is started is rather a process of the development of a 
cell endowed with great energy of growth, while in the mature cell the 
latent potential energy must be converted into an active form and greatly 
intensified. 
Very vague, too, are our notions about the substances which cause the NEW-GROWTH OF TISSUE AND REPAIR 
185 
sudden new-growth of tissue at the onset of puberty, and especially those 
which produce the remarkable changes in the breasts and other organs in 
pregnancy. Doubtless these are chemical substances which circulate in 
the blood, as has been shown in the case of those malformed twins which, 
being fused together, have a common circulation, and in whom preg-. 
nancy in one affects the organs of the 
other (Blazicek sisters, one of whom 
became pregnant, after which the 
breasts of both secreted milk). 
Other instances in which the in- 
creased or perverted activities of the 
organs of internal secretion are followed 
by a great overgrowth of all or a part 
of the tissues are well known (gigan- 
tism, acromegaly), and, on the other 
hand, the extreme stunting of growth 
from the failure of these secretions is 
equally well known (myxcedema, cre- 
tinism, etc.). There are conditions, 
too, such as the pulmonary osteo- 
arthropathy of Marie, in which the 
absorption of poisonous material from 
the widened and infected bronchi pro- 
duces a great overgrowth of the ex- 
tremities-actually a sort of gigantism 
(Fig. 71). 
Infections and Foreign Bodies.-Of 
daily interest in regard to the new- 
growth of tissue is the influence of in- 
fections and of foreign bodies, among 
which may be classed dead tissue and 
fibrin. 
Many infections lead to inflamma- 
tory reaction without necessarily re- 
sulting in any great destruction of 
tissue or any very evident reparatory 
process. But this is doubtless partly 
dependent upon the situation of the 
infection, for while the pneumococcus 
may produce a pneumonia which will 
disappear, leaving only a few gaps in the respiratory epithelium to be filled 
up by the neighboring cells, the same organisms in the pleura or pericar- 
dium are likely to produce an exudate the replacement of which by new 
tissue leads to the permanent binding together of those surfaces. Never- 
theless, even there the adhesions may be slight or absent, and the extent 
Fig. 71.-Secondary hypertrophic 
osteoarthropathy showing enlarge- 
ment of the forearm and hand. 186 
TEXT-BOOK OF PATHOLOGY 
of new formation of tissue appears to depends upon the extent of the 
injury. 
The result of the destruction of tissue by bacteria seems to differ from 
that produced mechanically chiefly in that the bacteria persist after the 
repair has begun and repeat the injury. This is notoriously true of those 
resistant bacteria and animal parasites which remain lodged in the tissue 
for a very long time. It is true of the tubercle bacillus and of the Spiro- 
chaeta pallida, which linger after completing their first injury to the tissue 
until they are encased in a nodule of new tissue, and then still longer, 
until, by their poisons, they cause the necrosis of the cells of that nodule, 
which is then replaced by a wall of cells a little further out. The first 
nodule seems far in excess of what was needed to repair the injury caused 
by the bacilli, and the question arises at once whether its abundant cells 
have not grown in direct response to a stimulus furnished by the bacillus. 
Probably so, but the matter is so complex in the animal body that it seems 
possible to decide it, if at all, only by recourse to experiments with isolated 
tissues growing in vitro. 
All the factors which decide the inception of growth are at work when a 
portion of tissue is left dead and surrounded by living tissues in the organ, 
as in the case of an infarct. Scavenging leucocytes attempt to remove the 
coagulated material, but before they can make much impression on it the 
gap in the organ is patched by a new-growth of tissue and the dead material, 
which blocked and choked this gap, is replaced by the new tissue. The 
functional replacement occurs elsewhere, and at this point there is only a 
growth of fibrous tissue and blood-vessels to restore continuity and remove 
the irritating foreign substance. Perhaps unbalancing of the mechanical 
equilibrium is important, but it seems that the presence of the fibrin-con- 
taining necrotic tissue offers a chemiotactic attraction which guides the 
growth of the invading blood-vessels, and it may be that it is really a chem- 
ical stimulus to growth. An exudate of fibrin on the surface of the peri- 
toneum or pleura, where no unbalancing of mechanical or functional 
equilibrium can be caused by its presence, exerts the same influence on the 
underlying tissue and is quickly replaced by a new tissue. So, too, a clot in 
the course of the blood-stream, whether it obstructs the circulation or only 
lies on the wall of the heart. 
Inert foreign bodies are attacked in the tissues by wandering cells of all 
sorts, just as the fibrin and dead cells are attacked and dissolved or sur- 
rounded; but they too soon find connective tissue and blood-vessels flowing 
in about them, so that they are quickly encapsulated or permeated by these 
cells. Indeed, there is hardly anything which sets up such an extraordinary 
new formation of cellular fibrous tissue as a suspension of foreign par- 
ticles, such as the diatom shells which form the fine dust of silicious earth 
or kieselguhr (Podwyssotzky). Perfectly insoluble, these particles can 
hardly act through any chemical stimulus, nor do they appear to cause any 
great injury to the neighboring cells or disturb the mechanical equilibrium NEW-GROWTH OF TISSUE AND REPAIR 
187 
to any great degree. Perhaps it may be regarded as a tactile stimulus 
which causes cells to grow around them, much as they follow threads of 
fibrin or the surface of the cover-slip in cultures. Indeed, as Lambert has 
shown by the aid of lycopodium spores, the cells in a culture which sur- 
round foreign bodies are not those of the connective tissue, but the wan- 
Fig. 72.-Tubercle-like capsule formed around a lycopodium spore introduced into the 
liver through the portal vein. 
dering cells. Nevertheless, in the body the actual fibroblasts appear 
in time and form an outer capsule (Fig. 72). 
The growth of tumors exemplifies in a singular way the stimulation of 
another tissue to growth. No matter what may eventually prove to be the 
reason for the unbridled growth of the tumor-cells themselves, we know 
that, standing as they do in close relation with connective tissue and 
blood-vessels, they stir up a growth in those structures which leads to the 
production of a most complicated and extensive organized stroma, which 
sometimes assumes forms totally unknown in the body and reaches a bulk 
far greater than that of any new-growth formed in the process of repair. 188 
TEXT-BOOK OF PATHOLOGY 
Analogies Between Embryonic Growth and Pathological New Forma- 
tion of Tissue.-The dividing cells, and more especially the products of 
division which appear in the course of the new formation of tissue, are 
often spoken of loosely as embryonic cells; the tissue has returned to the 
embryonic state, and the ontogenetic phases are being reproduced. This 
seems hardly justified, since these new cells do not really resume the char- 
acter of embryonic cells, which have such a great potential energy push- 
ing them to unfold and develop. On the contrary, they are merely 
young cells of the type which has reached maturity, and whose growth 
energy has been finally reduced to a point which leaves them able to main- 
tain the integrity of the organ, but not to develop further into a still more 
highly specialized and mature tissue. Even in those situations in which 
normally there is a constant active production of cells, as in the Mal- 
pighian layer of the skin or in the bone-marrow, the cells are mature in the 
sense that they do not tend to develop further, but merely produce new 
ones of the same kind. Even the fact that these new cells become much 
modified does not affect this idea. 
LITERATURE 
Various papers of Harrison, Lambert, Hanes, Burrows, and others. Summarized, 
Trans. Cong. Amer. Phys, and Surg., 1913, ix, 63. CHAPTER XII 
DEFENCES OF THE BODY (Continued) 
Repair. Established character of tissues. Their early differentiation. Metaplasia. 
Regeneration as exemplified in the new formation of various tissue. 
REPAIR 
General Phenomena of Repair.-When the body has reached its mature 
form, cells are newly formed only in sufficient quantity to make up for 
those lost each day in the ordinary wear and tear. Since cells are being 
constantly rubbed off the surface of the skin, the lower layers are just as 
constantly occupied in producing new ones. Since the red corpuscles of 
the blood are short-lived cells, they are constantly manufactured anew 
in the bone-marrow. These processes are so gradual and inconspicuous 
that it is hard to be sure that they are going on. But if a piece of skin be 
scraped off, or a few ounces of blood allowed to escape, there suddenly 
occurs a far more vigorous new formation of cells in the skin or in the bone- 
marrow. 
Every obvious new formation of tissue in the grown person seems to occur 
as a result, which we might predict, of some disturbance which impairs or 
renders inadequate the function of that tissue. It is a response so appro- 
priate to the situation and carried out with such moderation and in a man- 
ner so eminently suitable to the supposed purpose of restoring the functional 
equilibrium of the body that it is hardly possible to doubt that- it, like in- 
flammation, must be a plan evolved and elaborated through ages of natural 
selection for the preservation of the species. It is complicated and makes 
use of subsidiary mechanical aids, as we shall see (such as the filling of the 
gap across which tissue is to grow with fibrin); but whatever the details 
may be, the process is nicely adjusted to the purpose, and is so constant that 
we can predict with absolute certainty what will happen in a given case. 
This, as every one will recognize, constitutes a striking difference between 
the regenerative and reparatory growth of normal tissue and the growth 
of tumors, in which one cannot foretell with certainty what will happen or 
where the growth will end. 
The embryo grows according to an inherited plan, almost entirely pro- 
tected from outward influences until the body form is reached. Yet then, 
too, so profound is the impression of this plan, if part of an organ or tissue 
be destroyed, regeneration and repair take place in such a way as to further 
the original plan as much as possible. Indeed, the degree to which this 
repair may proceed is greater in the embryo than it is in mature life. 
189 190 
TEXT-BOOK OF PATHOLOGY 
Specificity of Tissues.-An important factor governing the repair or 
regeneration of tissues lies in the established character of the tissues them- 
selves. According to the plan of development of the animal, the cells of 
each tissue assume at an early stage a specialized character which they 
retain tenaciously. When these cells divide and multiply after that, they 
breed true, as it were, and produce new cells which have the same form and 
function as themselves. This is the well-known specificity of tissues, which 
is pretty rigidly maintained in mature life. In the embryo we may, of 
course, pass back to stages where we can no longer recognize the character 
of the cell, and where we are unable, in the present state of our knowledge, 
to say that this cell is predestined to become a liver-cell and that a smooth 
muscle-fibre, for in reality the cells at that stage have not divided to the 
degree at which one of the daughter-cells takes one path while another 
follows a different one. They have not yet adopted their careers. But it 
is further clear that this is not only because we are unable to recognize 
their tendencies, but because, at a very early stage, these tendencies are 
not absolutely fixed. The original fertilized ovum forms by its segmenta- 
tion the whole body, but after it has undergone its first division, each of 
those two segmentation spheres, if separated from the other, is capable 
of producing a perfect individual, as we so frequently see in those so-called 
single ovum twins which are of the same sex and remarkably alike in ap- 
pearance. At later stages, when the segmentation has progressed much 
farther, the destruction of one or more of the segmentation spheres can be 
compensated by the adjacent cells, which assume their function, but there 
must come a stage, and that quite early, when such compensation can no 
longer be carried out; if, for example, all the formative material destined 
to produce the heart be destroyed, a monstrous foetus would be formed 
without a heart. We cannot say, however, when this specificity is estab- 
lished, nor whether it is at very different epochs in the development, for 
different tissues. In any case it is only when all the cells are destroyed 
that the production of that tissue is made impossible. If any of this 
formative material be left, the processes of cell multiplication in the embryo 
are so efficient that even that remnant may be able to reconstruct as much 
of the tissue as is necessary. 
The most important point is, however, the absence of differentiation at 
a sufficiently early stage, so that from an indifferent type of cell quite a 
variety of mature cells may arise. An example of this is seen in the primi- 
tive amoeboid mesenchymal cells, which may develop into any one of the 
various sorts of connective tissue, or form the endothelium of blood- or 
lymph-vessels; or, on the other hand, remain amoeboid and become special- 
ized in the form of the lymphoid or myeloid cells of the blood, or even the 
red corpuscles. Such a variety of fates is not reached by these cells 
directly, but through a series of subdivisions and metamorphoses, and 
where once entered upon, the destiny of each developing cell is fixed. A con- 
nective-tissue cell can no longer give rise to a red corpuscle, nor the red REPAIR 
191 
corpuscle to a connective-tissue element. Nevertheless the whole scheme of 
the elaboration of such specialized cells as those of the blood, from simple 
amoeboid mesenchymal cells, does not cease to exist when the embryo has 
grown into a mature individual, and amoeboid mesenchymal cells are no 
longer scattered everywhere through the body. Instead, as we know for 
that particular tribe of cells, certain places, such as the bone-marrow and 
lymphoid tissue, are set aside as sites for the continued production of the 
elements of the blood by exactly the same process, and throughout life 
we can find in those places this progressive differentiation of the most 
elaborately specialized cells from undifferentiated forerunners. We are 
not informed as to any particular site in which such a differentiation of 
the other tissues occurs. Rather it seems that they merely repair their 
daily losses through a local multiplication of the differentiated cells. 
While we know that most tissues are so specialized that they can assume 
only one form and one function, and in dividing give rise to no other type 
of cell, we recognize somewhat different degrees in this specialization. We 
cannot imagine the case, for example, in which, through division and mul- 
tiplication of liver-cells, there might be produced pancreas tissue, although 
these organs arise in the beginning in much the same way, but we are quite 
accustomed to observe the alteration of one type of connective tissue into 
another. Here the specificity appears to be less rigid, for while we know 
that ordinarily white fibrous connective tissue produces only that type in 
its growth, it may be greatly , altered in character by metabolic changes or 
by such mechanical influences as oedema or the prolonged action of a ten- 
sion in one direction. Mucoid or mucin-holding tissue apparently arises 
in one way, while loose connective tissue may become tendon-like in the 
other. 
Adipose tissue is specific in its appearance, and especially in infants or 
emaciated persons, in which the tissue is not entirely distended with oil- 
droplets, it can be seen in the form of lobules sharply marked out from the 
surrounding areolar tissue and supplied with a peculiar and abundant 
capillary circulation. Whether all fat, even in the most obese persons, is 
lodged in this special tissue only it is difficult to say with certainty. 
It is in the complicated changes which go to the formation of bone that 
we see the most varied interrelations and modifications of connective-tissue 
structures. Both from cartilage and fibrous tissue, bone may be formed 
by the activities of certain specialized connective-tissue cells, the osteo- 
blasts. In so far as bones are formed in the normal positions, we might 
believe that, at an early stage, this specialization of certain connective- 
tissue cells to the character of osteoblast formed the essential basis upon 
which bone formation is possible, but we are frequently confronted with 
the formation of perfectly typical bone in places, such as the wall of the 
aorta, where no osteoblasts could normally occur, but where areas of 
necrotic tissue had become encrusted with lime salts. It is for this reason 
that we must think that the specialization among connective-tissue cells 192 
TEXT-BOOK OF PATHOLOGY 
is not so rigid as in more highly developed tissues, because it is obvious that 
in those cases some neighboring mesoblastic cells assume the function and 
form of osteoblasts, and then produce bone in the regular way. 
Endothelial cells, both of the blood-vessels and of the lymphatic vessels, 
have a rather high degree of specificity, marking them off from other types 
of mesoblastic cells, and yet it is precisely with regard to these cells that 
the most extraordinary powers of assuming other forms and functions have 
been described. They are known to act as phagocytes, in some organs, 
and Mallory regards them as especially important in giving rise to the 
wandering phagocytic cells found in many infectious processes. In most 
places they act as a mere lining of the channel, but in some organs, as in 
the spleen, they are greatly modified in form, and appear to have more 
complicated functions. There, as in the liver, they are actively phago- 
cytic, and it is said that they do separate themselves from the wall and 
pass in the blood-stream into the liver. (This I have never been able 
to observe.) In the bone-marrow, too, they are concerned closely with 
the formation of the new cells of the blood, just as they were in the 
early stages of embryonic life, when an endothelial cell arose from the 
amoeboid mesenchymal cell merely because it came to be the border of 
a space which contained blood, or in which blood was formed from changes 
in some of the endothelial cells themselves. But while all this was true 
in that early embryonic state and may remain true in the bone-marrow 
and other sites of blood formation, there comes a period in the develop- 
ment of the embryo at which, at any rate, most of the endothelial cells are 
specialized to their function of lining blood- and lymph-channels. They 
grow* as distinct sprouting strands which later become hollow, among the 
other less differentiated cells. In later life this specificity prevails, at 
least for most of the endothelial cells which line the vessels outside of those 
special blood-forming sites, and for them function remains the successful 
lining of the vessels. Even when a thrombus fills the vessel and becomes 
replaced by fibrous tissue, the endothelial cells take no part in the formation 
of that tissue, but confine their growth to the production of a new lining 
membrane which will cover all the surface of the clot and extend into every 
crevice, so that the blood is kept from contact with the fibrin or the new 
fibrous tissue. 
These examples have been cited to show, in a general way, the importance 
of the specificity of tissues and the different degree to which this holds good 
in different tissues. More will be said about it in connection with those 
more highly specialized structures in which it is held to far more strictly. 
Metaplasia.--Metaplasia is a term used rather loosely to express the 
conversion of one tissue into another, but more accurately defined by Orth 
* MacCallum: "Relation of Lymphatics to Connective Tissue," Johns Hopkins 
Hosp. Bull., 1903, xiv, 142. REPAIR 
193 
as the transformation of a well-characterized tissue into another equally 
well characterized, but morphologically and functionally different. For- 
merly such processes were thought to be very wide-spread, and even Virchow 
did not hesitate to derive cancerous or epithelial tumors from a matrix of 
connective tissue, but now different explanations are available for most of 
the puzzling conditions in which a tissue is found in a position totally ab- 
normal for it, and replacing the type which should occupy that place. 
Metaplasia is not meant to include the morphological changes produced 
by mechanical means, such as the keratinization of the mucosa of a pro- 
lapsed vagina. Nor does it include such displaced embryonal tissues as 
develop normally in a wrong situation, islands of gastric mucosa in the 
oesophagus or of squamous epithelium in the stomach, bronchi, or gall- 
bladder, nor those which are mechanically displaced in later life, such as 
traumatic epidermal cysts, bone formation from displaced periosteum, etc. 
Another thing which lies outside the boundaries of this term is the growth 
of one tissue in such a way as to push back the normal and replace it. 
This happens, for example, when the skin about a healing tracheotomy 
wound grows through the opening and extends so as to line the trachea for 
a short way. 
Metaplasia does not include the ordinary processes of differentiation 
which take place in the development of the embryo, nor those quite similar 
processes which continue in certain sites in adult life, such as the con- 
tinuous differentiation of the tissue of the bone-marrow and the continuous 
destruction and new formation of bone by the action of the osteoblastic 
cells. It is difficult, therefore, to say just where the term will apply, for it 
is difficult to show that any well-characterized tissue is produced from an- 
other well-characterized tissue which is already differentiated. The ten- 
dency is rather to assume that when such a transformation does occur, it 
is through the mediation of cells which, like the bone-marrow in other 
cells, are not completely differentiated. 
Such examples as we have to illustrate true metaplasia lead one to this 
opinion, and they are very limited in number and practically confined to 
epithelial and connective tissues. 
Epithelial Metaplasia.-Under pathological conditions, such as the forma- 
tion of an ulcer with subsequent healing, one may find that typical squa- 
mous epithelium appears to cover the gap, although the ulcer may be 
formed in a dilated bronchus or a gall-bladder, or even in the intestine. 
So, too, in eversion of the mucosa of the bladder in the so-called ectopia 
vesicse, the mucosa is altered, sometimes to epidermal tissue, sometimes 
to a high cylindrical form. 
Connective-tissue Metaplasia.-Among mesoblastic tissues there are so 
many examples of the persistence of groups of cells undergoing continuous 
differentiation that the appearance of the results of such differentiation in 
unusual places need cause little surprise. If we ligate the arteries of the 194 
TEXT-BOOK OF PATHOLOGY 
kidney in a rabbit, the organ becomes necrotic and quickly calcified, after 
which true bone may develop about the edges of the mass. In precisely 
the same way the presence of necrotic material which becomes calcified 
may be observed in the sclerotic walls of the blood-vessels, in degenerated 
tumors, especially such as occur in the thyroid and in the uterus, in old 
caseous tubercles in the lung, in old adhesions in the pericardium or pleura, 
and in many other places. Apparently we must assume that undifferen- 
tiated connective-tissue cells exist near by which become specialized in their 
differentiation as osteoblasts, for these calcified necrotic areas become the 
basis upon which true bone is formed. In exactly the same way new sites 
of progressive differentiation are established in cavities left in such bone, 
in the form of a definite bone-marrow producing myelocytes, erythroblasts, 
and all the other characteristic cells. Is this to be defined as metaplasia? 
Certainly one tissue has been replaced by another, but hardly by a direct 
transformation. At most, connective-tissue cells serving some function 
unknown are transformed into osteoblasts. Doubtless the same thing 
occurs in the larynx or bronchi or in the costal cartilages, when in time 
they become ossified. • Whether the bony metaplasia is of this sort in the 
case of tendons and muscles in the so-called myositis ossificans is uncertain. 
REGENERATION 
Regeneration of lost parts occurs with great readiness in the lower and 
simpler animals, and it is well known that their life can continue after the 
most profound mutilations by the simple expedient of forming anew what- 
ever is found to be lacking. Details of the extraordinary experimental 
studies of these phenomena may be read in the books of T. H. Morgan, 
J. Loeb, and many others. As has been stated, something of this power 
of regeneration prevails in the embryo of higher animals and man up to a 
certain stage of its development. It may be expressed once more by say- 
ing that the fertilized ovum and the first segmentation spheres are toti- 
potent. The cells produced in the course of later segmentations are multi- 
potent, but the cells of the differentiated tissue are highly specialized, as a. 
rule, and potent to produce others of the same type only. Quantitatively 
also the power of regeneration diminishes with the advance of develop- 
ment and cell specificity, but even in the mature human individual the 
latent power of these specialized cells for regeneration is often astonishing. 
While we recognize this decrease in the versatility of the cell in so far as its 
offspring are concerned, we must also recognize a very great difference 
among the mature tissues in their power to regenerate themselves, for 
although such slightly specialized tissue elements as those of the ordinary 
connective tissue, the periosteum, the epidermis, etc., regenerate very 
rapidly and extensively, those which are more highly specialized, such as 
the central nervous system, heart muscle, and striated muscle in general, 
regenerate themselves hardly at all, and any gap made in their substance REGENERATION 
195 
must be filled by some inferior tissue which can grow fast and restore the 
continuity quickly. It need hardly be said that the tissue most commonly 
employed is the ordinary fibrous tissue. Over and over again we find this 
principle exemplified. In the heart there may be energy enough to form 
new muscle tissue in time, but when an area is destroyed, it is healed by 
fibrous tissue and not by muscle. In the liver, although the liver-cells can 
divide fast enough, the same thing prevails, and each gap left by their 
destruction is stopped up with fibrous tissue. 
Thus, owing to the different powers of regeneration shown by various 
tissues, local repair is carried out sometimes by the injured organ substance 
itself, but more often by an inferior material, such as connective tissue. 
But even though such patching may occur there is, with few exceptions, 
some attempt made there or elsewhere to restore the original specialized 
Fig. 73.-Growth of epithelium over a granulating surface. Irregular downgrowths 
of epithelium are an index of the delay in the healing. 
tissue unless it has been destroyed to the last cell. Before discussing this 
process of local repair we may pass in review the phenomena which appear 
in the case of each type of tissue. 
Epithelium.-All sorts of epithelium possess a quite remarkable ability 
to grow again and make up for that which was lost. As is so well known to 
every one, the surface epidermis will quickly grow out to cover again any 
abrasion or to heal over the granulating surface of an open wound (Fig. 73). 
This is so clearly visible in the case of a healing ulcer where the thin, pearly 
blue edges of the epidermis advance slowly from the margin toward the 
centre until the whole area is covered, that it seems strange that there could 
ever have been doubt as to the source of the epithelium. Yet for a long 
time it was questioned whether the epithelium might not be produced by 
the granulation tissue. More careful studies have shown, though, that the 
regeneration is strictly specific, and that all new epidermal cells are pro- 196 
TEXT-BOOK OF PATHOLOGY 
duced through division of those still alive about the margin of the wound. 
Apparently many of them move and stretch out to spread themselves over 
the uncovered area before any division occurs, because the karyokinetic 
figures are found a short distance back of the edge, and especially in the 
lower layers of cells. These less specialized cells seem to take a greater 
part in the new formation than those which have progressed some way 
toward the keratinization, and have, therefore, lost to some extent or 
completely their power of division. Groups or masses of new cells are thus 
formed and furnish the material for the further spreading of the whole 
layer, but if, as is so often the case, that spreading is constantly prevented, 
they accumulate and extend downward in rapidly thickening and very 
irregular interpapillary growths (Fig. 73). It is generally stated that direct 
or amitotic division plays a great part in this new formation of epithelium, 
but this statement receives very little support from the direct observation 
of growing epithelium in vitro. 
Since such a conclusion is dependent upon finding distorted or constricted nuclei, 
or upon the failure to find mitotic figures, it seems hardly convincing. No one can fail 
to accept the evidence concerning the growth by mitosis, but there seem to be very few 
instances in which the appearance of a cell with its nucleus constricted in the middle, 
and a corresponding constriction of the protoplasm, must be accepted as showing that 
two new cells of normal capacities are thus being formed. The appearance may so 
readily be due to pathological conditions, and the chance of abnormalities in the amount 
and arrangement of chromatin in the new cells is so great, that I hesitate to accept the 
process of amitotic division as a normal method of reproduction and growth in the organs 
of the higher animals. Of course, we have abundant observations of this sort of division 
in simpler forms, and one may not deny its existence or its importance, but at least it 
seems clear that such a process should be more closely investigated rather than so un- 
questioningly accepted. If there is any truth in the theory of Hansemann that tumor 
growth may be imitated by the unequal or irregular separation of chromosomes in 
dividing cells, then amitotic division, where the separation of chromatin material into 
two nuclei is guided by no such precise mechanical process as in mitosis, may well be the 
source of such inequality. 
The regeneration of surface epidermis produces a smooth layer of cells 
without any reformation of such specialized epidermal structures as sweat- 
and sebaceous glands and hairs. Yet, as Minervini points out, the inter- 
papillary downgrowths and the fine markings of the palm are formed again 
after years. Of course, if the abrasion be so superficial that these glands 
and hair-follicles are not completely destroyed, they may regenerate them- 
selves from the remnants, and may also produce the less specialized sur- 
face epithelium. 
The epithelium of the mucous surfaces behaves in exactly the same way, 
growing out from the edges to cover, with a smooth layer, the denuded area. 
Glands are regenerated from the epithelium which remains in their depths 
if they have not been completely destroyed. This is the common result 
in superficial ulcerations of the intestinal tract, and indeed one receives REGENERATION 
197 
the impression that, even though the whole mucosa be destroyed over a 
small area of the intestine, as in the deep typhoid ulcers, it may be restored 
to a semblance of the original much more rapidly than in the case of the 
skin. After all, the production of crypts or villi is a rather simpler matter 
than the new formation of sweat- and sebaceous glands and hair-follicles 
from the epidermis. 
In the epithelial organs new specialized and perfect gland tissue is pro- 
duced essentially by subdivision and multiplication of the remaining spe- 
Fig. 74.-Formation of new liver-cells at the ends of sprouting bile-ducts in cirrhosis of 
the liver. 
cialized cells. It is true that an elaborate effort toward their regeneration 
is made by the less highly specialized cells which constitute the lining of the 
ducts. From the very fact that they are less highly specialized, and there- 
fore more resistant, these cells survive in places where all the gland epi- 
thelium is destroyed, and remain alone in that area as a possible source for 
new gland tissue. They multiply, and the ducts bud out and ramify in all 
directions, but generally end in forming new connections with the gland 
tissue which remained alive after the injury, and whose duct connections 
may have been disarranged. Occasionally one may find, in a cirrhotic 198 
TEXT-BOOK OF PATHOLOGY 
liver, a definite formation of new specialized liver-cells at the end of a 
growing bile-duct (Fig. 74). The cells are seen to be fresh young liver-cells 
from their characteristic staining and their lack of pigment, but such 
things are rare and can play no very important part in the restitution of 
the functional liver tissue as compared with the profuse multiplication of 
the already differentiated liver-cells which remain in the fragments of the 
liver lobules which have not' been destroyed. 
In the kidney, in the same way, the increase in the specialized secreting 
cells comes from the multiplication of survivors which have reached that 
stage of differentiation, and not from the cells lining the conducting tubules. 
If all the cells of a convoluted tubule are destroyed, that tubule collapses 
and compensation occurs through the enlargement of another tubule. It 
is by no means denied that differentiation of less specialized tissue occurs 
in the course of regeneration in adult life, but it seems that the repair of 
highly specialized tissue is more readily and more commonly assumed by the 
remnants of tissue which has already reached that stage of differentiation. 
Connective Tissues.-These tissues are preeminently capable of regen- 
erating themselves rapidly and in profusion, so that they form the bulk of 
the new material used for local repair. In nearly all their modifications 
they are resistant to injuries, and will survive and grow readily after treat- 
ment which would kill more delicate tissues in a short time. 
The character of their specificity has been discussed already, and it has 
been shown that, although in places undifferentiated cells persist and fur- 
nish the specific differentiated cells of the blood throughout life, most of the 
connective tissues of the body are differentiated, and in their multiplication 
reproduce the same type of cell. Nevertheless, the assumption of osteo- 
blastic functions by connective-tissue cells quite away from the original 
osteoblasts is sometimes seen, and certain other lapses from strict specificity 
may be observed. 
Ordinarily, white fibrous or areolar tissue produces, by the division of its 
cells, other cells of exactly the same character. The elongated cell, poor 
in protoplasm but with prolongations in all directions among the dense 
fibres in which it lies embedded, swells before division and retracts some of 
its processes. It becomes somewhat rounded and denser than the adjacent 
cells, and by division gives rise to two young cells which are temporarily 
rounded, but quickly put forth pseudopods and acquire an elongated form. 
A great variety of forms may be found, but the vesicular nucleus and the 
elongated form generally suffice to distinguish these cells from the more 
rounded mononuclear wandering cells. 
Occasionally, when newly formed connective tissue arises to constitute 
the lining of a cavity in the body or to form a bursa, the superficial cells 
which form the actual lining become flattened and assume the appearance 
of endothelium. This is exemplified in Fig. 75, which is from the granu- 
lation tissue lining an infected space left after an operation, among the REGENERATION 
199 
muscles of a dog's neck. The cavity was filled with turbid fluid full of 
leucocytes. The new tissue is of the ordinary type, with distinct project- 
ing granulations, but everywhere covering this nodular surface, and ex- 
tending down into the crevices between them, there is a layer of cells 
resembling endothelium, although much stouter. These cells are often in 
two layers for a small space, and pass over by insensible gradations into 
the fibroblasts underneath. Evidently this is a mild kind of metaplasia 
analogous to that which occurs in the first formation of endothelium, but 
it is not to be believed that these cells ever play the part of real endothelial 
cells or are to be identified with them. 
Fig. 75.-Granulation tissue lining a cavity showing endothelium-like flattening of the 
innermost cells. 
While at first these new cells lie loosely about so that the spaces between 
them accommodate fluid and wandering cells, they later produce in the 
marginal parts of their cytoplasm the fibrils which stain differently from 
the general protoplasm, and which, increasing in number and in thickness, 
become arranged in roughly parallel form, so as to produce a dense fabric 
in which the cells themselves finally become rather inconspicuous. This 200 
TEXT-BOOK OF PATHOLOGY 
process, so carefully studied by Minervini, Maximow, and many others, 
constitutes the formation of scar tissue. The early stages are seen, how- 
ever, to especial advantage in cultures of connective tissue in which the 
fibroblasts are seen to grow out separately from the margin, showing in the 
most beautiful way their long, sheet-like processes, and dividing actively 
by mitosis beneath the observing eye (Fig. 67). 
Elastic Tissue.-The regeneration of elastic fibers is to be observed after 
the lapse of time in newly formed connective tissue, but perhaps especially 
in those places, as in the lung or in the vessel wall, where those fibers play 
a particularly important part. There has been much discussion of the 
possibility that they may arise in the intercellular substance, but the work 
of Jores, Nakai, and others seems to show clearly that they are formed by 
differentiation of the protoplasmic processes of the cells. Though chemi- 
cally and physically different, they are produced in much the same way 
as the collagenous fibres, and there is no way of distinguishing the mother- 
cells from each other. Nevertheless, although Jores thinks the collagenous 
and elastic-forming cells the same, it seems probable that, with finer meth- 
ods, we may be able to show that they are differentiated from each other 
before they proceed to form their different fibres. Apparently the new 
fibres do not grow in connection with the old ones, but increase in size by 
accretion. Sometimes, however, as in the walls of blood-vessels, we may 
see very plainly that a new distribution of the lamellae or fibres is brought 
about by the splitting and separation of the old ones. 
Fat Tissue.-There is much evidence that the adipose tissue of the body is 
specialized at an early stage, and remains distinct from other forms of 
connective tissue. In the infant it is segregated in lobular masses in 
which, in the beginning, the large, round, isolated cells which are to become 
fat-cells have a deeply stained granular protoplasm, which later becomes 
filled with globules of fat until it is stretched out into a thin film and its 
nucleus pressed to one side. In wasting disease the fat may disappear 
from the cell and be replaced by fluid. In a sense regeneration occurs 
through the refilling of these cells with fat, but if the tissue is destroyed, 
it must probably be regenerated by the methods used in its first formation. 
In the neighborhood of old inflamed areas one may often distinguish, 
within the outline of an empty fat-cell, many polygonal or rounded cells 
with finely vacuolated protoplasm. These Marchand regards as evidences 
of regeneration or new formation of several fat-cells in place of one. Others 
(Maximow) have, however, thought of these cells as invading phagocytes 
which have taken up some remaining globules of fat. 
Cartilage and Bone.-Defects in cartilage are in part healed by the forma- 
tion of fibrous tissue scars, but regeneration of actual cartilage also takes 
place. According to Marchand, this is brought about chiefly by the 
activity of the perichondrium, which produces a callus-like growth of new 
tissue which gradually assumes the characters of cartilage. Borst and REGENERATION 
201 
certain Italian writers maintain, however, that the cartilage itself takes 
part in this new formation, a method which certainly prevails in such ani- 
mals as the salamander; and that the defect is filled largely by the active 
division of its cells. 
Bone is regenerated by methods identical with those concerned in its 
first formation. On account of its easily recognizable arrangement, it can 
be seen building-up is in progress throughout life. By means of osteoblasts 
the well-preserved Haversian systems are irregularly eroded, and new Ha- 
versian systems fitted into the gaps thus left through the activity of the 
osteoblasts. The cells concerned in the regeneration and new formation 
of bone are always the osteoblasts, or at least cells which have assumed 
Fig. 76.-Early stage in the healing of fractured bone, showing periosteal new-bone forma- 
tion, together with fibrous and cartilaginous growth. 
the function of osteoblasts. Therefore bone can be formed by the osteo- 
genetic layer of the periosteum and by the endosteum, but probably not 
by the bone-corpuscles, which are buried in the rigid bone. If all the cortex 
of a bone be removed and the periosteum left intact, a new bone may be 
formed by the activities of that membrane-it can even be transplanted 
into some distant region of the body, where it will begin once more to pro- 
duce bone, provided always that the nutrition be maintained and that 
the actual osteogenetic layer be not destroyed. Membranous bone is 
formed anew in the same way by the production of a mass or sheet of spindle- 
cells, some of which assume the characters of bone-corpuscles and give up 
part of their cell-body to the fibrillar substance, which first becomes hya- 
line and then calcified. 202 
TEXT-BOOK OF PATHOLOGY 
In fractures the broken ends of the bone are at first surrounded by a 
haemorrhage, but after the escape of blood from the bone-marrow is stopped 
by clotting, regeneration and healing begin through the proliferation of 
new tissue from the periosteum and endosteum. These produce a callus 
which flows in between the separated ends of the bone as the intermediary 
callus. It consists at first of cartilage and osteoid tissue, that is, tissue with 
homogeneous ground substance inclosing the newly formed cells, and hav- 
ing the form of bone without being calcified. The osteoid tissue may be 
laid down as a solid layer on the surface of the old bone, or, through the 
guiding action of blood-vessels, assume a spongy form. Solid new formed 
tissue of this kind may be transformed later into spongy bone by the in- 
vasion of blood-vessels, and that in turn become compact by later growth. 
The cartilage which is formed by the activity of the periosteum is similarly 
invaded by osteoblast-carrying blood-vessels and converted into osteoid 
tissue, and finally into bone, exactly as in the intracartilaginous bone forma- 
tion of the embryo. Great defects in the bone produced artificially or by 
disease may thus be made good, although for a time the new bone thus 
formed is very abnormal in its arrangement. Later modifications tend to 
reduce it with wonderful accuracy to the form best adapted to meet the 
strain put upon it. 
Smooth Muscle.-Experimental and other study of the healing of defects 
in smooth muscle seems to show little activity in this regard-sometimes 
mitotic division has been described, sometimes a new formation by amitotic 
division, but more recent studies tend to the idea that there is in higher 
vertebrates very little regeneration of the muscle itself, but that healing 
brought about by scar tissue brings together the muscle edges at the site 
of the defect. 
Striated Muscle.-Two distinct methods of regeneration occur, as pointed 
out by Volkmann, Schminke, and others. In one, new separate cells are 
formed from the remains of the fibre by collection of the protoplasm about 
its nuclei within the sarcolemma (sarcoblasts). These develop, just as the 
embryonic muscle-fibres do, by the gradual appearance of striated fibrils 
in the elongating cell. In the second method a bulbous end is formed in 
continuity with the remains of the muscle-fibre with a great number of 
nuclei, and the elongation and differentiation of this protoplasmic mass give 
rise not to new fibres, but to increase in the mass of the muscle substance. 
Many authors have ascribed all of this to amitotic division of the nuclei, 
but many mitoses have been observed, and doubtless play the usual im- 
portant part in the reproduction of this as in other tissues. 
Heart muscle has been thought to regenerate itself little, if at all, any loss 
of substance being made good by a patch of scar tissue. Indeed, this seems 
to be generally the case, although Heller has recently described clear evi- 
dences of regenerative activity in the heart-muscle fibres, and we have seen 
one case in which a condition resembling closely the formation of the bul- REGENERATION 
203 
bous ends in the skeletal muscles appeared. The fibers could be traced in 
the scarred areas into deeply stained swollen masses of protoplasm, with 
numerous nuclei which seem to represent growing ends. 
Blood- and Lymph-vessels.-In the early stages of embryonic growth 
blood-channels seem to be formed anywhere in the mesenchyme by the 
mere separation of the cells, with later alteration of the innermost cells 
adjoining the cavity thus formed into definite flattened lining or endothelial 
cells, which in turn may produce any of the elements of the blood. Chan- 
nels formed in this way are capable of obliteration by collapse and the ad- 
hesion of their walls, while other new channels are being formed. Thus 
it happens that in a network of such spaces there is finally emphasized one 
passage which, after the collapse of the rest, survives because it is best 
adapted to carry the blood according to the existing needs and pressure rela- 
tions. Thus in early life the whole process is very labile, and the relation 
to the connective tissue extremely intimate. It is maintained by some that 
lymphatic channels are formed in the same way, becoming secondarily 
connected with the blood-vessels, but Sabin has shown that their genesis 
may be traced to an actual sprouting from certain points in the well-formed 
vessel-wall, of blind-ending canals which finally ramify in all directions in 
the tissue and constitute the lymphatic system. At any rate, there comes 
a period, somewhat later in embryonic life, at which the promiscuous for- 
mation of blood-vessels or lymphatics from spaces in the mesenchyme 
seems to be restricted, and thenceforth the endothelial cells become per- 
manently specialized to carry out that function only and to give rise, by 
their division, to all subsequent endothelial cells. After this epoch new 
vessels are formed only by the formation of an endothelial bud from the 
wall of a vessel, which may grow out as a mobile strand of endothelial cells 
moving through the tissue until it meets another such strand. Exactly 
the same process is carried through in the case of the lymphatic channels, 
which are quite as completely walled off from the connective tissue by endo- 
thelial cells as are the blood-vessels.* When such strands of endothelial 
cells, which at first may be no more than whiplash-like protoplasmic fila- 
ments, become united with others so as to form a bridge and become thick- 
ened into a double row of cells by mitotic division, there gradually appears 
a cleft in the middle through winch blood-corpuscles are forced. There 
has been much discussion as to the part played by connective-tissue cells 
in this process, but the evidence seems to be overwhelming in favor of the 
idea that when connective-tissue cells take any part they act merely as 
supporting cells, applying themselves to the outside of the new tube, of 
which the essential lining layer is composed of endothelial cells alone 
(Marchand). Coffin has traced carefully the formation of lymphatic 
vessels in newly forming granulation tissue, and has found that they appear 
in precisely the same way as the new blood-vessels. 
* MacCallum: "Relations Between Lymphatics and Connective Tissue," Johns 
Hopkins Hosp. Bull., 1903, xiv, 142. 204 
TEXT-BOOK OF PATHOLOGY 
Bone-marrow, Lymph-glands, and Blood.-Bone-marrow regenerates 
itself rapidly after destruction through injury, disease, or poisoning, by the 
formation of a new connective tissue rich in vessels, in which there appear 
later fat-cells and the specific blood-forming cells. As to the source of 
these, some authors (Haasler, Enderlen, Marchand) have held to the idea 
that they are derived from the division of those which remained behind or 
are brought to the marrow cavity by the blood-stream or by wandering 
through the tissues. Others (Maximow, Weidenreich) regard them as 
derivatives of the young, undifferentiated connective tissue formed upon 
the invasion of blood-vessels with their periosteal cells into the cartilage. 
This seems well enough established in the case of embryonic marrow forma- 
tion, but is more difficult to accept in the regeneration of marrow in the 
adult, although it is perhaps supported by the observation of the new for- 
mation of marrow in bone produced in such organs as the lung or aorta. 
Lymph-glands and nodules of lymphoid tissue reappear, without doubt, 
in areas where they have been destroyed, but the mode of their regenera- 
tion is not very clearly understood. In the case of an autopsy assistant 
who had suffered repeated infections of the hands, after which infected 
lymph-nodes had been dissected from the axilla, new nodes appeared under 
the skin about the shoulder as well as in the axilla. Similarly, in the 
intestine, after destruction of Peyer's patches and solitary nodules, through 
ulceration in the course of typhoid fever, repair and new formation of these 
structures are in time very complete. Undoubtedly, as Ribbert points 
out, there are many scattered lymph-follicles in the tissues which become 
evident only when they are caused to swell by some inflammatory reaction, 
and it is possible that these, through their enlargement, compensate for the 
loss of the original lymph-nodes in places where the latter have been de- 
stroyed or removed. In the spleen, when the amyloid has occupied the 
whole of each Malpighian body, one may sometimes see, as in Fig. 42, the 
counterpart of this in the new formation of lymphoid nodules all through 
the splenic pulp. Bayer and others state that complete lymph-nodes may 
be newly developed in fat tissue, but it seems probable that this occurs 
rather in connection with preexistent lymph-channels than with relation 
to the fat tissue itself. 
The Blood.-Constant new formation of these cells occurs on account of 
their brief tenure of life in the circulating blood. Lymphocytes are un- 
doubtedly produced in great quantities in the lymph-nodes, wherever they 
may be, and are turned into the blood either by way of the lymphatic 
channels or more directly into the veins. Bone-marrow, spleen, and 
possibly thymus also play a part in their production. When traced to 
their ultimate source in the undifferentiated rounded mesenchymal cell, 
they are seen to have the same origin as the granulated cells and the red 
corpuscles, although for the granulated cells Naegeleand Schridde claim a 
separate ancestor in the non-granular myeloblast. The granular mye- 
locyte, which is formed from a preceding non-granular cell (whether it be REGENERATION 
205 
the specific myeloblast or the common ungranulated ancestor of all), and 
which gives rise to the granular polymorphonuclear leucocyte, is ordinarily 
found in greatest numbers in the bone-marrow, but it may be formed in the 
spleen, in the lymph-glands, in the liver, in the thymus, and in various other 
places, so that the regeneration of the granular polymorphonuclear leucocytes, 
eosinophile as well as neutrophile, may take place almost everywhere. 
Nevertheless, the chief site of this formation, and in normal conditions the 
only site, is the bone-marrow. The forerunner of the red corpuscle, a non- 
granular, non-haemoglobin-holding cell, may shrink as it acquires haemo- 
globin, and thus become the normoblast, which, on losing its nucleus, 
becomes the ordinary red corpuscle. Large haemoglobin-holding nucleated 
cells which are possibly forerunners of the normoblasts are the megalo- 
blasts. They are sometimes swept into the blood when regeneration is 
active in an extreme anaemia. 
Leucocytosis.-Infections of all sorts cause regeneration of the greatest 
intensity in the blood-forming tissues, so as to furnish to the blood the 
necessary phagocytes. Polymorphonuclear leucocytes may be produced 
there with rapidity in a quantity far exceeding that ever called for in 
ordinary regeneration to make good a loss. It is not uncommon, then, to 
find the leucocytes chiefly of this type, numbering 50,000 or 60,000 per 
cubic millimetre, and cases are described in which this outrush, bringing 
with it the myelocytes, has so flooded the blood as to produce the picture 
of an acute myeloid leucaemia. Other infections, such as typhoid fever, 
through exerting another kind of chemiotactic action, attract to the blood 
chiefly the mononuclear cells. It is even difficult to produce a polymor- 
phonuclear leucocytosis in those cases. Similarly in tuberculosis, syphilis, 
and many other infectious processes, most of which progress slowly, and in 
malaria and other protozoan infections, the stimulus produced by the in- 
fective agent calls forth the production not of polymorphonuclear leuco- 
cytes, but of mononuclear forms. 
Thus there is a certain independence among the cell types in their re- 
generation. Red corpuscles are produced in great numbers when those 
normally present have been destroyed, and generally there is a consider- 
able coincident outpouring of leucocytes, but this too is dependent upon 
the nature of the destructive agent and not merely upon the fact that re- 
generative activity is going on in the bone-marrow. 
When blood is suddenly removed, as by an extensive haemorrhage, regen- 
eration begins in the bone-marrow (often very slowly after an extreme 
haemorrhage), and the red-corpuscle content of the circulating blood is 
gradually restored to normal. Naturally, immediately after the haemor- 
rhage the number of red corpuscles in the circulating blood per cubic milli- 
metre is unchanged; then there comes quickly an absorption of fluid from 
the tissues and from the digestive tract to make up the necessary volume of 
blood, and with this dilution the red corpuscle content per cubic millimetre 
rapidly sinks. It is not until after the third or fourth day that the regen- 206 
TEXT-BOOK OF PATHOLOGY 
erative process begins to overtake this diluting process, so that from that 
time on the red-corpuscle content steadily rises. It may be observed that 
this new formation proceeds rather spasmodically, as indicated by the 
periodic "crises" of normoblasts which are swept out into the circulation. 
In the bone-marrow during this process evidences of most active growth of 
these cells can be found, and although they are present in such great num- 
bers, it can often be seen that they are arranged roughly in groups or islands 
among the granular and other cells. 
Chronic ansemias which follow long-continued infection or intoxication, 
or repeated small losses of blood, as from bleeding hsemorrhoids, cause the 
same regenerative processes. The marrow of the long bones, normally 
yellow and composed chiefly of fat, becomes dark red, solid, and granular, 
and is found to be made up of compactly crowded formative cells and their 
products. In many cases, of course, the benefit from this regeneration is as 
promptly frustrated by the continued destruction or loss of the cells as they 
appear in the circulation. There are a few cases in which, in spite of ex- 
treme anaemia, no sign of regenerative processes begins in the bone-marrow 
("aplastic anaemia"), and others in which it is prevented by the extensive 
destruction of that tissue by tumor growths or otherwise. The extreme 
anaemia produced by benzol poisoning seems to depend largely upon its 
coincident destructive effect upon the bone-marrow and blood. 
Nervous Tissue.-If a peripheral nerve be cut, the proximal portion 
remains alive, except for the last two or three Ranvier's segments, but the 
whole peripheral portion degenerates. The myeline sheath loses its homo- 
geneous character and breaks up into globules which now stain with fat 
stains. The axis-cylinder becomes granular and disintegrated. The cells 
of the sheath of Schwann or neurilemma increase greatly in size and num- 
ber, and become actively phagocytic, engulfing and removing the debris of 
the myeline sheath and axis-cylinder. 
Up to this time the degenerating fibres show the presence of black- 
stained globules in the position of the myeline sheath by the method of 
Marchi, but after the phagocytic activity of the cells of the neurilemma is 
completed, nothing is left of the medullary sheath, and such degenerated 
and emptied fibres can now be made out best by their lack of staining, in 
contrast to the neighboring well-preserved medullary sheaths, which be- 
come blue black with Weigert's medullary sheath stain. The proliferated 
cells of the sheath of Schwann now become arranged closely together in 
long, tubular strands-the so-called "band fibres." At this point arises 
the difference of opinion upon which there has been strife for many years, 
v. Bungner, Bethe, and others maintain that, inside these band fibres, 
there are formed new axis-cylinder fibres without any connection with the 
ganglion-cell, and quite independent of the proximal portion of the fibre 
from which they were originally separated. The weight of evidence, how- 
ever, is overwhelmingly on the side of those (Waller, Ranvier, Howell, 
His, Ramon y Cajal, Perroncito, Stroebe, Harrison, and others) who have REGENERATION 
207 
shown that new fibres appear growing along in these tubular band fibres, 
but only as sprouts from the axis-cylinders, which are still in the proximal 
part of the healing nerve and still in connection with the ganglion-cell. 
It is shown that the ends of these axones in the tip of the proximal stump 
become bulbous or branched, or peculiarly altered into a basket-like ar- 
rangement, and that when the peripheral portion is brought into apposi- 
tion with this stump, filaments penetrate into the guiding canals furnished 
by the Schwann's sheath tube, and grow down them until they reach the 
end-organs and reestablish connections there. If there is a large gap 
between the two ends of the nerve, the accomplishing of this process is 
delayed. It is hastened, on the other hand, by the accurate suture of the 
cut ends to one another. The band fibres thus form merely a guide for 
the newly sprouting axone, and in no case give rise to new axone material 
themselves. All this is particularly well shown by Harrison's experiments, 
in which he showed that axones could grow out to a great length if offered 
merely a suitable moist medium upon which to grow, and were not entirely 
dependent upon the facilitating and guiding influence of the band fibre. 
Functional capacity of such nerves is restored in a remarkably short time, 
and seems to depend largely upon the character of the nerve-endings and 
not upon the precise rediscovery by the axones of their proper band fibres. 
Indeed, a nerve accustomed to convey one set of impulses may be arti- 
ficially united to a peripheral stump which had been used to act as the 
mechanism for a quite different sort of activities, but the old impulses will 
now produce the new function characteristic of the new nerve terminations. 
Such a person has to learn to interpret and control his impulses-in other 
words, learn again to do the right thing at will. 
In the central nervous system a similar type of regenerative process is 
attempted, but seldom carried far, because no proper paths seem to be 
prepared for the guidance of new fibres. At the scarred edges of wounds or 
defects, either in the brain or in the spinal cord, the same bulbous or branch- 
ing ends of fibres are to be found, but there is little evidence of their cross- 
ing the scar and reestablishing the original connections. There is also 
little positive evidence of regeneration on the part of ganglion-cells-mitoses 
are sometimes seen, but at best it is only an attempt at new formation. 
Healing of a defect in the brain takes place partly by scar-tissue formation 
and partly later by the production of a rather broad zone of sclerotic neu- 
roglia. The cleansing of the area is carried out by the so-called granule 
cells, large, rounded, mobile cells filled with globules of fat which accumu- 
late in great numbers in areas where destruction of nervous tissue has 
occurred (Fig. 15). These cells, which are especially abundant in areas of 
softening, infarcts, etc., in the brain, resemble the mononuclear phagocytic 
wandering cells very closely, and are regarded as such by Borst and others. 
Although this view seems perfectly plausible, it is contended by others, 
including Fr. Marchand, Morzbacher, and Tanaka, that they are really 
wandering cells of neuroglial origin. 208 
TEXT-BOOK OF PATHOLOGY 
LITERATURE 
Coffin: Johns Hopkins Hosp. Bull., 1906, xvii, 277. 
Goldzieher and Makai: Ergeb. d. allg. Path., 1912, xvi2, 344. 
Jores: Ziegler's Beitr., 1900, xxvii, 381; 1907, xli, 167. (Elastic Tissue.) 
Marchand: Process der Wundheilung, 1901. 
Maximow: Ziegler's Beitr., xxxv; Suppl. v; xxxiv; xxxviii. (Suppuration.) 
Minervini: Virchow's Arch., 1904, clxxv, 238. (Scars.) 
Nakai: Virchow's Arch., 1905, clxxxii, 158. (Elastic Tissue.) CHAPTER XIII 
DEFENCES OF THE BODY (Continued) 
Transplantation of tissues and organs, its limitations. Healing of wounds-by direct 
union, under a crust, by granulation tissue, etc. The healing of an open ulcer, of inflamed 
wounds and abscesses. The healing of special tissues. 
The result of attempts to transplant tissues or whole organs from one 
animal to another, or from one portion to another in the same animal, is a 
matter of great surgical interest, and also of importance in contributing 
to our knowledge of the growth of tissue and the function of the organs 
themselves thus transplanted. It is treated in detail by Marchand, Borst, 
Stich, Makai, and many others, to whose papers the reader is referred. 
To graft tissue or a whole organ into a new situation is a matter of 
technical difficulty, but success depends not only upon the skill with which 
the operation is carried out, but also upon the nature and age of the animal, 
nature of the tissue, the intimacy of relationship of the new host, the 
efficiency of the blood supply (often the restitution of the nerve supply), 
and, finally, in many cases, the functional need for such tissue. 
It seems possible to carry out successfully far more extensive trans- 
plantations in the lower animals, such as worms and coelenterates, than in 
higher forms. Probably this is because of their greater adaptability, and 
is quite like their great power of regenerating tissue and organs. At any 
rate, one may easily transplant half the body of one of these creatures by a 
sort of grafting on to half the body of another. But this can be done in 
embryos of much higher animals also, with the production of remarkable 
monsters. Complex organs, like the eye, may be implanted in unusual 
situations with a certain success which could not be attained in adults. 
The success with which tissues can be transplanted is, to some extent, 
parallel with their degree of specialization and their need of constant and 
abundant blood supply. Little difficulty is experienced in transplanting 
epidermis from one situation to another, or even from one individual to 
another. The so-called Thiersch grafts, which are thin films of epidermis, 
sometimes including the upper layer of the corium, are used daily in surgi- 
cal operating-rooms to cover large denuded areas, and there is seldom any 
question about their success. So, too, bone with its periosteum may be 
made to fill a gap in another bone. With more highly specialized tissues 
transplantation is more difficult, probably because their cells will not 
TRANSPLANTATION OF TISSUES AND ORGANS 
209 210 
TEXT-BOOK OF PATHOLOGY 
survive long enough to allow capillary blood-vessels to grow in from the 
new site. 
Nevertheless, pieces of thyroid, parathyroid, adrenal, etc., have been 
implanted in a cavity made in one tissue or other, and have grown and 
functionated generally only after necrosis of the central part, with survival 
and increase of the marginal layers. It is important to observe that in 
some cases, as in the transplantation of bone or nerves, the graft may sur- 
vive only as a sort of splint which supports and guides the new-growth of 
tissue from the host, which finally absorbs and replaces it entirely. This is 
always true with nerves whose specialized structures invariably degenerate, 
but not always with bone, which may remain active and itself perma- 
nently occupy the new site. 
Transplantation of whole organs by anastomosis of the blood-vessels 
has been carried out in a number of cases, notably by Carrel, and often 
with successful functioning of the transplanted organ. Thus in one animal 
the transplanted kidney was able, after the removal of the other, to main- 
tain the life of the animal for a long time. 
The reimplantation of an organ or tissue into the same animal is an 
autoplastic operation-its transfer to another animal of the same species 
is a homoplastic operation, while a heteroplastic transplantation involves 
its growth in an animal of another species. Transplantation of whole organs 
has succeeded so far, only in autoplastic operations, although homoplastic 
transplantations of extremities or peripheral tissues have been successful. 
Heteroplastic transplantations have been uniformly failures. It is, there- 
fore, necessary to have the most favorable possible conditions for the re- 
newed growth of the more sensitive tissues, although those less dependent 
upon an uninterrupted blood supply may sometimes be transferred to other 
animals of the same species with success. Evidently the foreign biological 
character of the blood of another species makes life impossible for the graft. 
Mechanical conditions, too, are important in the success of a transplant, 
and a piece of skin transplanted into the peritoneum or between the muscles 
is sure to act merely as a foreign body and be encapsulated. 
In the case of some organs, such as the salivary glands, in which we 
know so well the important influence of the nerve supply we must expect 
function to be greatly disturbed by transplantation, although others in 
which the function is governed rather by the chemical composition of the 
blood, as perhaps in the case of the kidney, may possibly be transplanted 
with more hope of the continuance of a function approaching the normal. 
The organs of internal secretion, in so far as they can be transplanted at 
all, seem to fall into this latter group. 
Finally, it has seemed, especially from some experiments of Dr. Halsted, 
that successful implantation and growth of such organs as the parathyroid 
depend upon a need for their functional activity. In animals with a normal 
amount of parathyroid substance he found it impossible to make an extra HEALING OF WOUNDS 
211 
gland grow, while he succeeded in one already deprived of most of its 
parathyroid tissue. This seems a plausible suggestion, and has been 
supported by others, but as yet it is hardly possible to set it down as a 
general law. 
LITERATURE 
Borst: Proceedings XVII. Internal. Congress, London, 1913, Sec. 3, pt. 1, 171. 
Halsted: Jour. Exp. Med., 1912, xv, 205. 
Makai: Ergeb. d. allg. Path., 1912, xvi2, 344. 
Marchand: Process der Wundheilung, 1901. 
Stich: Ergeb. Chir. u. Orthopadie, 1910, 1. 
HEALING OF WOUNDS 
While the principles remain exactly the same, the details in the healing 
or making good of any destructive injury to the tissues vary with cir- 
cumstances, and it forms a great part of the skill of the surgeon to be able 
to leave the tissues upon which he has operated in the most favorable 
possible condition for repair. Neglect of these precautions, which concern 
chiefly the mechanical adjustment of the tissues which should grow to- 
gether, their proper nutrition, and the exclusion of infection, will readily 
defeat his object, no matter how ingeniously he has planned to cure his 
patient. As in the early days of surgery, the wound will in a short time 
break open and discharge a flow of pus and fragments of dead tissue, blood- 
vessels may burst their ligatures, and the secondary haemorrhage, dreaded 
of old, will follow. All this depends upon the malnutrition of tissue from 
crushing or cutting off the blood supply, and the infection which can thrive 
in such dying or dead tissue or in the material accumulating about it. 
But if the tissues be carefully brought together by light pressure, or by 
sutures so arranged as to leave them all very richly supplied with blood 
in rapid circulation, the few bacteria which may gain access to every 
wound, no matter how carefully made, are easily overcome by the living 
tissues, and healing proceeds apace. 
Healing by Direct Union.-It is in wounds treated with this careful 
attention to the condition of the tissues, or in wounds so superficial and 
limited that apposition and good nutrition of the tissues are secure of them- 
selves, that healing occurs with the slightest reaction and with the least 
requirement for new formation of cells. 
If a clean incision be made through the abdominal wall and the tissues 
approximated edge to edge by sutures throughout, they become glued to- 
gether almost at once, and in a short time heal together, with an almost 
imperceptible linear scar, with never any very evident inflammatory reac- 
tion and no sign of actual suppuration. In such an incision only the cells 
along the line of incision are killed,-some bleeding occurs, and between 
the approximated edges a little blood remains,-or if the escape from the 
blood-vessels has been stopped, at least a little coagulable fluid oozes out 212 
TEXT-BOOK OF PATHOLOGY 
between these edges. This clots about the severed cells and cements the 
surfaces together (Fig. 77). A few leucocytes appear from the slightly 
widened adjacent vessels. Mitoses arise in nearby epithelial cells of the 
epidermis, and in the connective-tissue cells close to the wound. Blood- 
vessels sprout from those on either side, and accompanied by fibroblasts 
grow across, absorbing and removing the fibrin and the dead cells which the 
Fig. 77.-Fresh stab wound of the liver. A few cells have been killed and the edges 
glued together by the clot. 
leucocytes help to liquefy, and replacing this material by a more permanent 
bond. Later this new connective tissue matures into a scar. Epithelium 
has by this time been pushed across to cover the outer surface and the 
peritoneal lining cells to close the interior, and the wound is healed. This 
is healing by first intention (Fig. 78). 
Healing Under a Blood-clot or Crust.-In many cases, when apposition 
has not been so exact or when more tissue has been destroyed, a good deal 
of blood and serous fluid oozes out on the surface, clots, and dries, or the 213 
HEALING OF WOUNDS 
cavity of a wound whose edges are not brought together may fill up with 
blood which clots and remains. So good is such a clot as protection against 
infection that, at times, surgeons have intentionally allowed large spaces to 
fill up in this way (Schede, Halsted), and have carefully preserved the clot 
as a covering. Not only is it a protective substance, which, on account of 
Fig. 78.-Scar of healed surgical incision through the abdominal wall. 
its bactericidal power, does not decompose or become further infected, but 
it forms a nutritive material, and at the same time a scaffolding for the 
up-growth of blood-vessels and fibrous tissue. 
When there is only a little blood or inflammatory or serous exudate which 
dries on the surface of the wound, healing proceeds under the protective 214 
TEXT-BOOK OF PATHOLOGY 
crust thus formed, and is found complete when it drops off. Quite the 
same process goes on if the crust is formed by the necrosis and drying up 
of the superficial tissue. The epithelium works its way beneath this dried 
mass and quickly grows over the surface of the underlying living tissue, 
even if it has not been covered by any thick, new-formed granulations. 
This is the peculiarly favorable feature of healing under a crust that, with 
such perfect protection, the new epidermal covering is completed without 
the previous slow and tedious formation of granulation tissue. It is true 
that later much new tissue of that sort is produced beneath, but at least it 
is closed in from the air and goes on unnoticed, the process being essentially 
finished and secured when the epidermal covering is complete. 
Granulation Tissue-Secondary Healing.-When a wound is infected 
with bacteria, it is not apt to heal throughout any great part of its extent. 
Instead, it breaks open and discharges a purulent exudate, and heals 
finally by "second intention," in a way rather different from those just 
described. It builds up from the bottom a new connective-tissue layer 
which, beginning by covering and masking all the exposed structures with 
a thin gray film, heaps itself up in an ever thicker nodular, translucent, 
grayish-red substance, until the whole space may be filled or even until 
the granulation tissue projects in soft, fungus-like masses above the level 
of the skin. This sort of reparatory growth is by no means limited to 
infected wounds-it is the regular method of filling up and repairing any 
and every gap in the tissue. It is inconspicuous and limited in the two sorts 
of healing already described, because in the one case very little of it is 
needed before healing is complete, and in the other because the epidermal 
covering is so soon finished that connective-tissue growth is held in check 
and covered from view. 
If an open wound or ulcer be kept clean and moist and therefore unable 
to cover itself by a crust, it must heal slowly from the bottom. In the same 
way a space among the tissues kept open by the presence of bacteria and 
an accumulation of fluid will close itself gradually by the formation of a 
complete wall of new young connective tissue, which is gradually drawn 
together by the absorption of the fluid (Fig. 79). Any foreign body em- 
bedded in the tissues stirs up the same response. About it on every side, 
as though it were a space to be filled, there develops a wall of new tissue 
(Fig. 80). A portion of tissue itself, killed by any means, becomes a foreign 
body, and is treated in the same way-hence an abscess with its mass of 
bacteria and surrounding dead tissue is in time encapsulated. Any group 
of cells in an organ, such as the liver or kidney, on being killed and absorbed, 
leaves a gap which is filled up by a new-formed connective tissue not limited 
exactly to their site, but extending a little into the neighborhood. 
Other examples of this same tendency are seen when it is not dead tissue, 
but fibrin, that acts as the foreign body, and the replacement of a fibrinous 
exudate on a serous surface (Fig. 81), or of a thrombus in a blood-vessel by 
the growth of granulation tissue (Fig. 82), is perfectly well known. 215 
HEALING OF WOUNDS 
In all cases the mechanism is the same. It is the standard method of 
Fig. 79.-Granulation tissue lining a space left between the muscles in a dog's neck. 
healing adapted to deal with the most varied types of injury, but always 
proceeding on the same principles toward the patching of the injured area. 216 
TEXT-BOOK OF PATHOLOGY 
The degree to which inflammation is mixed with it depends upon the sort 
of injury, and the nature of the wandering cells found in the new tissue 
depends upon the sort of injurious material and debris that must be treated 
and removed. The healing of an open ulcer may serve as one example. 
Even if such a loss of substance is produced by actually cutting out a 
piece of tissue, bleeding soon stops, and the cut surface is found moistened 
by a thin layer of fibrinous exudate. Within an hour, although the surface 
Fig. 80.-Granulation tissue with giant-cells developed around a foreign material (para- 
ffin) injected into the tissues. 
becomes reddened by the widening of the capillaries, it is found, on injecting 
the blood-vessels, that none of the colored mass oozes out on the cut surface. 
The cut ends of the vessels are closed by the fibrinous exudate, and by con- 
traction, many are definitely thrombosed. The exposed surface con- 
tracts somewhat, the skin edges tend to turn inward, and, as healing pro- 
gresses, this contraction plays a considerable part in forwarding the closure 
of the wound. HEALING OF WOUNDS 
217 
The reparatory process begins first, in all probability, by the amoeboid 
stretching out of the adjacent connective-tissue cells, and even of the 
epithelial cells at the skin edge. This is readily observed in tissues grown 
Fig. 81.-Organization of a fibrinopurulent exudate on the pleural surface by new blood- 
vessels and connective tissue from the pleura. 
in vitro, and it seems probable that it occurs here too, since the mitotic 
figures which indicate the new formation of cells are found some dis- 
tance back from the actual margin of the wound. Connective-tissue 218 
TEXT-BOOK OF PATHOLOGY 
cells reaching out their pseudopods from among the intercellular fibres 
find guidance in the filaments of fibrin. Through their multiplication and 
that of the endothelial cells of the blood-vessels a recognizable amount of 
new tissue is formed in the course of a day or two. At the same time an 
acute inflammatory process arises, with all the features described above: 
The vessels widen and pour out their fluid and cellular contents; the tissue 
becomes oedematous and infiltrated with leucocytes and scattered red 
Fig. 82.-Thrombus formed behind a valve in a vein, being invaded by blood-vessels 
and fibroblasts. 
corpuscles-on the surface, more exudate of leucocytes and fluid is poured 
out, and the network of fibrin becomes thicker; mononuclear wandering 
cells appear in numbers from the blood-vessels and from their resting places 
in adjacent tissues; sprouts of endothelial cells spring up from the intact 
capillaries and stretch forward into the fibrin, making way for themselves 
by their mobility and digestive power. Spread open into tubes by the 
pressure of the blood, they become complete capillaries, carrying a current HEALING OF WOUNDS 
219 
of blood. With them there grow upward the fibroblasts, with their long 
branched protoplasmic processes, supporting and surrounding the vessels. 
Growing upward in this way, the capillaries anastomose and form arches, 
and it seems probable that it is this arching forward of the vessels which 
brings about the granular appearance of the surface of the new tissue 
(Fig. 83). Thus an actual new tissue is formed, and continues to be formed 
with the greatest rapidity. It consists, as is evident, of abundant blood- 
vessels and young fresh connective-tissue cells, all spread apart by fluid, 
Fig. 83.-Granulation tissue formed in the healing of an ulcer. 
a large portion of which is an inflammatory exudate. Therefore it is easy 
to understand that this tissue should appear as it does. It is a soft gray 
or grayish-red, gelatinous, translucent layer of irregular nodular surface, 
bleeding at a touch, but quite insensitive to pain. When it is found, as 
it often is, in surroundings abundantly infected with bacteria, the inflam- 
matory reaction becomes more intense, and the purulent secretion oozes 
-out on the surface (Fig. 84). 
Granulation tissue is subject to the same circulatory and other dis- 220 
TEXT-BOOK OF PATHOLOGY 
turbances that affect other tissue-it may be congested with venous blood 
or become very cedematous in patients whose circulation is embarrassed. 
Checked in its growth by some injury, that which remains becomes compact 
and forms the basis for the growth of a new layer. It may. therefore, pre- 
sent very different appearances in different cases, although in its essentials 
it is the same in all. 
Having grown to such an extent that it fills or nearly fills the gap, one 
becomes aware of the fact that a thin, grayish-blue film of epithelium is 
Fig. 84.-Granulation tissue showing acute inflammation. 
spreading out from the edges toward the centre of the wound, to cover the 
granulations, much as ice in its first formation spreads out from the edges of 
a pond. One can also plant a fragment of epithelium in the form of an island 
in the middle of the surface of the granulation tissue, and if successful, 
the spread of new epidermis will take place from there in just the same way, 
meeting that from the margin and completing the covering of the granula- 
tions (Fig. 73). Bluish at first, the new epidermis gradually becomes 
thicker, more opaque, and white. Naturally this process occurs most 
readily when the granulations are clean and oozing only a little serous fluid- 
it is often frustrated by infection and the consequent inflammatory process. HEALING OF WOUNDS 
221 
The influence of different diets upon the rate of healing has been studied 
by Clark and has already been mentioned. Other studies upon the rate 
of healing have shown that it may be expressed by a formula in which 
the original size of the wound and the age of the animal must be taken 
into account (de Noiiy). 
Finished in this way, the site of the original wound is occupied by a 
highly vascular, purplish looking tissue, hidden under a smooth, pearly 
layer of epithelium, which has none of the lines and markings of the normal 
skin-no hairs, no sweat- or sebaceous glands, and no nerves. From this 
time on a process of maturing of this tissue begins, which, as has been said, 
tends to mould it into the form of that which was lost. Much new con- 
Fig. 85.-Margin of abscess in fat tissue with large phagocytic cells containing cell debris. 
nective tissue is formed. The new cells produce abundant new inter- 
cellular fibrillar substance. Many of the too abundant blood-vessels are 
pressed shut and disappear. Since the venous side is first compressed, the 
new scar retains for a time its congested appearance. The purplish healed 
area grows paler and firmer until, in the end, it becomes very white, hard, 
and tendon-like, and that dense connective tissue which is the final product 
of the growth of the granulation tissue we know as a scar. In the first 
healing of the wound and in the course of formation of the granulation tissue 
a good deal of contraction occurs, and if it is an extensive superficial wound, 
such as might be caused by a burn of the skin, this contraction is apt to 
deform the person. After the scar is definitely formed, it tends rather to 222 
TEXT-BOOK OF PATHOLOGY 
stretch out again (Minervini) or relax, and this extension is accompanied 
by a development in which nerves grow in, so that the place again becomes 
sensitive, and new cutaneous papillae arise. The fine lines or wrinkles 
reappear when the scar becomes flexible, and on the palms or soles the 
characteristic fine corrugations develop in time and again cross the scar 
by which they were interrupted. Almost every one may test the truth of 
this in his own hands. 
Abscesses.-In an abscess which has existed for some time we are ac- 
customed to find the dead tissue separated from the living by a wall of 
this same granulation tissue. It forms all around in just the same way, 
but it is peculiar in the extraordinary number of wandering cells that haunt 
the meshes of its connective-tissue network. Inflammation still proceeding 
actively insures this, and such a wall, from this character, has often been 
called a pyogenic or pus-producing membrane. There is nothing peculiar 
about it though, and the point of greatest interest is the extraordinary 
array of very large, highly phagocytic, mononuclear wandering cells which 
crowd into this marginal tissue and aid in the cleaning-up process. They 
are probably free wandering cells, although some writers think them 
derivatives of the fibroblasts, and others, of the endothelium. As shown in 
Fig. 85, they are often loaded with fat and the debris of other cells. (See 
Chapter XIV concerning the formation of abscesses.) 
Sinuses.-Sometimes such an abscess may break through the skin and 
discharge its contents, or if deep seated, it may burrow a long way and 
finally burst through the skin. A long channel or sinus results, and all 
along its course a lining or wall of granulation tissue is formed. As long 
as the infection persists in the original site this sinus may stay open and 
will discharge the products of inflammation. This is especially likely to 
be true if dead tissue, such as a fragment of necrotic bone or a foreign body, 
remains in the depths. Such a process is common with deep tuberculous 
lesions, with actinomycosis, and with various other chronic and tenacious 
infections, and sometimes the granulation tissue itself gives us a clue as to 
the nature of the infection. 
Psoas Abscess.-A good example is seen in the tuberculous destruction of the cen- 
trum of one or more vertebrae, which reduces the bony substance to a soft, creamy, or 
mortar-like fluid. Inclosed as it is, this fluid seeks a way of escape and burrows into 
the psoas muscle and down along its course, to appear as a bulging sac at the femoral 
ring. Bursting out there, a sinus is established which leads from the inner side of 
the thigh far up to the mid-dorsal region. It is only its great extent which makes this 
example peculiar though, for with tuberculous disease of the hip-joint or tuberculous 
osteomyelitis at any point, the same thing may occur. The granulation tissue lining 
the sinus is quite like any other, except in that it is particularly rich in mononuclear 
wandering cells and contains tubercles and tubercle bacilli. It is, therefore, a precarious 
material for healing, since it itself is very prone to become completely necrotic, leaving 
only a basal part alive. On this remnant new granulation tissue forms. It is for this 
reason that there is built up about tuberculous lesions such a great amount of scar 
tissue, and this is true for actinomycosis and other infections of like character and for 
syphilis. HEALING OF SPECIAL TISSUES 
223 
Fistulae or channels leading into openings in hollow organs are lined in 
the same way by granulation tissue, which is often partly covered by epi- 
thelium, which grows inward from the skin or outward from the mucosa. 
Closure of these channels takes place partly by their gradual contraction, 
partly by their being choked with the ever-thickening lining of granulation 
tissue which finally fuses together to obliterate the lumen. 
HEALING OF SPECIAL TISSUES 
The healing of special tissues need not detain us beyond the description of 
one or two illustrative cases, since they are merely examples of the regen- 
erative processes already described. 
Serosae.-The flat lining cells of the serous cavities are peculiarly active 
in their growth, and cover with amazing rapidity any defect in their con- 
tinuity. When, for example, a loop of intestine is brought through the 
abdominal wall and sutured there, its surface, where it passes, is glued to 
the parietal peritoneum by fibrin after the briefest interval, and in a very 
short time the serosa cells become continuous from the abdominal wall 
back over the intestine. 
In peritoneal infections and inflammations these cells are much injured. 
When a fibrinous exudate is poured out upon their surfaces, burying them 
in its depths, they finally disappear, unless, as sometimes happens, the exu- 
date arches up over a group of them-then they grow round to line this 
latter space and form a sort of cyst in which they preserve their characters. 
Many such little cysts may arise in this way, and are common enough in the 
pericardium; between them granulation tissue springs up into the exudate 
and, uniting with that from the opposite layer, finally composes itself into 
a fibrous adhesion or synechia (Fig. 86). 
Exactly the same sort of thing is seen in blood-vessels in which thrombi 
have formed-if there is a point in the wall upon which the thrombus has 
not been laid down, the endothelium persists, and through multiplication of 
its cells, relines the little cavity thus left, while granulation tissue grows in 
and replaces the thrombus from the exposed tissues between these cavities 
(c/. Fig. 87). Mucosce heal in exactly the way described for the skin, 
although the healing seems to take place more rapidly. Regeneration of 
the special features of the mucosa, including lymph-nodules, villi, etc., 
occurs in time, so that the scar may hardly be found. 
Wounds and Injuries of Parenchymatous Organs.-Wounds in such 
organs as the liver heal with the formation of a scar, exactly like wounds in 
any other tissue. More interesting is the healing of the minute, but widely 
diffused foci of destruction of cells which are so common in the course of 
intoxications and infections. Different cells are picked out for destruction 
by different injurious agents, and it is very hard to tell why. Chromic 
salts kill one set of renal epithelial cells, uranium salts another; the poison 
of eclampsia destroys the cells of the liver lobule nearest the portal veins; 224 
TEXT-BOOK OF PATHOLOGY 
that from the streptococcus peritonitis produces a midzonal necrossi (Opie), 
while the circulatory disturbance in chronic passive congestion destroys 
the cells about the efferent vein. The healing processes which follow each 
of these lesions are practically identical, but are modified by the differ- 
ences of their situation. 
Fig. 86.-Chronic adhesive pericarditis showing small spaces in the connective tissue 
which represent the remains of the pericardial cavity. 
They proceed by the gathering of phagocytic cells which dissolve or 
carry away the dead bodies of the specific cells of the organ, whereupon 
the connective-tissue framework in which they had been supported col- 
lapses. As in other places where tissue has been destroyed, a heal- HEALING OF SPECIAL TISSUES 
225 
ing or patching process ensues which consists in a new formation of 
connective tissue and blood-vessels-a granulation tissue bounded on all 
sides by the uninjured organ substance, so that it cannot show any free 
Fig. 87.-Organized thrombus in a blood-vessel canalized by clefts which are relined with 
endothelium. 
nodular surface, but otherwise is quite like that which fills up a healing ulcer. 
In the course of time such tissue settles into a scar. When organ cells are 
destroyed in small groups or singly, there may be a very fine diffusion of 
this scar tissue, and we have the condition known as cirrhosis in the case 226 
TEXT-BOOK OF PATHOLOGY 
of the liver, and often loosely spoken of as chronic interstitial nephritis, 
pancreatitis, or hepatitis, as the case may be. That this latter term is 
practically always misleading may be shown, however, by a study of the 
development of the lesion. The diffuse scarring and shrinkage of the organ 
is not due to an inflammation of the interstitial connective tissue, with the 
development of scars which contract and constrict the epithelial cells be- 
tween them. On the contrary, the highly specialized epithelial cells are 
the first to suffer destruction by the poisonous substance which is the pri- 
mary cause of the disease, and the scar formation is essentially a reparatory 
response to their disappearance. There is practically no evidence that the 
scar tissue causes any further injury to the epithelial cells. Of course, 
it is true that the scar tissue may seem to be in great excess of what was 
necessary to repair or patch the gap produced by the loss of epithelial cells, 
but it must be remembered that in such cases the process of epithelial 
destruction and patching with connective tissue has been repeated fre- 
quently through years, each new scar heaping itself upon the old one near 
by. The constant regeneration of epithelium from remnants makes this 
possible, but there is also the possibility that the new connective tissue 
itself may be injured and later repaired in voluminous fashion. 
LITERATURE 
Berry: Regeneration of Smooth Muscle, Jour, of Medical Research, 1920, xli, 365. 
Clark, A. H.: Johns Hopkins Hosp. Bull., 1919, xxx, 117. 
Davis, J. Staige: Plastic Surgery, Phila., 1919. See also the many papers of L. Loeb on 
Transplantation and Regeneration, Jour, of Medical Research, 1920, xli, 247, etc. 
de Noiiy: Jour. Exp. Med., 1916, xxiv, 451, 461; 1917, xxv, 721; 1919, xxix, 329. 
Schlaepfer: Skin Grafting, Johns Hopkins Hosp. Bull., 1923, xxxiv, 114. CHAPTER XIV 
ILLUSTRATIVE EXAMPLES OF INFLAMMATORY PROCESSES 
Catarrhal inflammation. Serofibrinous and fibrinopurulent pericarditis, pleuritis, peri- 
tonitis, appendicitis, endocarditis, lobular pneumonia, puerperal infection, pycemia, abscess 
formation, diphtheritic inflammation. 
The form assumed by the inflammatory reaction varies somewhat with the 
intensity and concentration of the irritant, and with the kind of tissue in- 
volved, but in principle it is the same throughout. Names are rather 
loosely applied to these different forms which indicate in some degree their 
anatomical characters. Thus a catarrhal inflammation is an affection of 
a mucous surface in which the irritant is not intense enough in its action 
to kill the epithelial cells. The same irritant applied to the peritoneal or 
pleural surfaces might produce an exudation of fluid with few leucocytes 
only. A somewhat more intense injury in these serous cavities or in the 
alveoli of the lungs may occasion the exudation of a layer of fibrin on the 
surface-a croupous inflammation. If the irritant is such as to cause the 
necrosis of the epithelium and the underlying tissue, with an extremely in- 
tense, often haemorrhagic, inflammatory reaction, in which the fibrinous 
exudate infiltrating into the dead tissue binds it together into a membrane- 
like layer, we speak of it as diphtheritic or pseudomembranous inflamma- 
tion. Although the diphtheria bacillus gives rise to a good example of this 
type, it must be remembered that the term merely indicates the anatomical 
condition, so that not every diphtheritic inflammation is caused by the diph- 
theria bacillus. According to the distribution of the inflammatory irritant 
in the tissues the inflammatory reaction may be diffuse or concentrated. 
In the first instance, if it be very intense and accompanied by a fibrino- 
purulent exudate, it is often called phlegmonous; in the second, in which, 
on account of the concentration of irritant and exudate, necrosis of the 
tissue and intense digestive liquefaction ensue, an abscess is formed. Putre- 
faction may be associated with the more extreme necrotizing injuries if 
the tissue is exposed to invasion by putrefactive organisms, and this char- 
acter, often spoken of as gangrenous, is added to the inflammatory reaction. 
Catarrhal inflammation is well represented by the familiar coryza, which 
is an acute inflammatory reaction following the invasion of some unknown 
infectious agent into the upper air-passages. It is probable that the infec- 
tion is favored by exposure to cold, by drafts, and all the other widely 
credited causes of colds, but undoubtedly the main factor is the trans- 
CAT ARRHAL INFLAMMATION 
227 228 
TEXT-BOOK OF PATHOLOGY 
mission of the organism from some infected person. Recurrences may well 
be due to the infection of pockets in which handkerchiefs are carried. 
The infection is quickly followed by dryness and reddening of the mu- 
cosae, which then swell up and secrete a profuse flow of clear, mucoid 
fluid with some desquamated epithelial cells. Later, from the advent 
of leucocytes, the mucus-containing fluid becomes thick and yellow. 
After a time it decreases in amount and dries on the mucous surfaces, 
Fig. 88.-Catarrhal inflammation of a bronchus. 
producing crusts. The mucosa in section shows great hyperaemia and 
oedema, with an excessive production of mucus by the goblet-cells of the 
epithelium. Between these cells there wander leucocytes, but no fibrin 
is formed on the surface (Fig. 88). Catarrhal inflammations appear in 
every mucous surface, with characters similar to those just described. 
When it is the affair of a narrow tube, such as the gall-duct or the Eusta- 
chian tube, the swelling of the tissue may produce obstruction. PERICARDITIS, PLEURITIS, PERITONITIS 
229 
The more intense serofibrinous and fibrinopurulent inflammations are 
well illustrated by the various effects produced by bacteria in the serous 
cavities. 
PERICARDITIS, PLEURITIS, PERITONITIS 
The general characters of these processes are similar, and they differ 
chiefly in their mode of origin, or rather in the portals of entry of the organ- 
isms which cause them. 
The walls of all these cavities are richly supplied with blood-vessels, and in the peri- 
toneal cavity there hangs the peculiar omentum, which is largely composed of such 
vessels, although it may be also laden with fat. In each of the spaces there is normally 
a little clear fluid. Each is lined with flattened cells of mesoblastic origin, which are 
not identical with the endothelium of the blood and lymphatic vessels. These form a 
complete lining without any orifices or stomata, such as have been declared by so many 
authors to exist. The relation of the lymphatic channels to pleura and pericardium is 
very inadequately studied, but in the case of the peritoneum it is better known. In the 
abdominal surface of the diaphragm and in the floor of the pelvis are the two most con- 
spicuous areas, where an absorbent mechanism is presented. There, there project be- 
tween the connective-tissue fibres, which are spread apart in lozenge-shaped spaces, 
thin-walled, sac-like endothelium-lined structures which connect abundantly in the 
depths of the tissue with lymphatic trunks. These are completely lined by the endo- 
thelium, and separated from the peritoneal cavity practically only by this cell layer and 
the overlying layer of serosa cells. Occasional fibres stretch across them when they 
are distended like a rope across a full sail. There is no direct communication with the 
peritoneal cavity, but fluids enter by diffusion, and solid particles are carried through by 
leucocytes between the cells, or are pressed through free along the same lines. Bacteria 
injected into the peritoneum reach the retrosternal lymph-glands or the thoracic duct 
by this route very quickly indeed.* 
Many leucocytes and mononuclear wandering cells lie in the omentum and elsewhere 
in subserous tissues, and the serosa cells themselves are somewhat phagocytic. 
Absorption from the pleura seems to occur, in part at least, through the lung, since, 
when carcinoma cells are scattered in that cavity, they lodge and grow on the surface 
and later invade and actually inject the lymphatic channels running toward the hilum. 
Pericarditis may be caused by a great many organisms, among which the 
most common are the pyogenic micrococci, the unknown cause of rheuma- 
tism, and the tubercle bacillus. They are thought to be brought directly 
to the pericardium by the blood-stream, since it is difficult to trace a direct 
extension from a pleural infection, and such pleurisies occur so often with- 
out pericarditis. It seems, however, that they must sometimes enter in 
this way or from adjacent lymph-glands. Endocardial and myocardial 
infection may also extend to the pericardium. That bacteria may be 
introduced in stab wounds or other forms of traumatism is obvious. 
Rather curious is the frequent occurrence of pericarditis in the terminal 
stages of chronic nephritis, and in those cases it is generally difficult to 
find any bacteria. 
* MacCallum: "Absorption of Granular Materials from Peritoneum," Johns Hop- 
kins Hosp. Bull., 1903, xiv, 105. 230 
TEXT-BOOK OF PATHOLOGY 
Sometimes only a thin film of fibrin is exuded on the pericardial surfaces 
without effusion of fluid (dry pericarditis). In that case a loud creaking 
or rubbing sound is made by each movement of the heart. If, then, fluid 
appears in excess, the surfaces are held apart, and the sound is lost or cut 
short. So, too, when a thick soft layer of fibrin is formed on the surface 
the sounds may be greatly muffled. In this condition (serofibrinous peri- 
carditis), or even when the fluid is pus-like (fibrinopurulent pericarditis), 
one may observe that, through the motion of the heart, the fibrin is beaten 
Fig. 89.-Acute fibrinous pericarditis. The fibrin is moulded into ridges by the move- 
ment of the heart. 
into compact ridges which run, roughly speaking, in certain transverse and 
oblique lines which are fairly constant. The heart is given a very shaggy 
appearance by this process (Fig. 89). 
If a very great deal of fluid be exuded into the pericardial cavity, the sac 
is gradually dilated and will accommodate a large amount-far more than 
could be forced into it suddenly. There comes a time, however, when the 
heart is greatly embarrassed by this fluid because it can no longer expand 
properly to receive the blood. 
This condition is especially well seen when a sudden haemorrhage occurs into the 
pericardial sac, and may be imitated experimentally by distending the sac with oil or 
salt solution under pressure. The arterial pressure falls, the venous pressure rises, and PERICARDITIS, PLEURITIS, PERITONITIS 
231 
the heart collapses and stops beating. If the pressure is removed quickly enough, it 
will recover, with restoration of normal pressure relations. 
In other cases, as so often happens, when little or no fluid is exuded, 
or if, later, the fluid is absorbed, the pericardial layers covered with exudate 
come together and adhere; granulation tissue springs up from each sur- 
face and, replacing the fibrin, binds the pericardial sac to the surface of the 
heart. Blood capillaries arising from opposite layers anastomose with one 
another and complete the organic union of the two surfaces, by forming a 
vascular fibrous tissue. The motion of the heart stretches and keeps loose 
these adhesions, so that practically always the heart can move about a 
little within the sac. Nevertheless, if dense adhesions exist also between 
the outer surface of the pericardium and the lung, the heart in contracting 
will be forced to pull directly upon the lungs and upon the diaphragm. 
This shows itself in each contraction by a drawing in of the diaphragmatic 
insertion, which visibly retracts the chest-wall along that line in children, 
and is followed by a very great hypertrophy of the whole heart. In other 
cases in which the external adhesions are absent there is no such hyper- 
trophy. 
The fresh exudate is composed, of course, of outwandered leucocytes, 
red corpuscles, and fibrin, beside the fluid. Most of the serosa cells persist 
for a time in an indistinct row in their old site (Fig. 90), while, as stated 
above, they remain able to proliferate actively in any place where they are 
not covered by exudate, and quickly reline any part of the pericardial 
cavity which has not been obliterated. In the midst of the fibrous ad- 
hesions one may find spaces lined with such cells which have proliferated 
in this way. The adhesions may be localized in certain areas, where they 
are usually drawn out into bands. If these break through, the stumps 
flatten themselves into opposed plaques which remain for a long time on 
the surface of the heart and the opposite area of the sac-wall as the so-called 
tendinous flecks or milky patches. Other explanations are offered for 
these thickenings of the epicardium, and will be referred to later. 
If very thick, dense layers of fibrous tissue are formed-if the adhesions are firm or 
tunneled with channels filled with yellowish, opaque fluid, or if, with the thickening of 
the sac and epicardium, a haemorrhagic, fibrinous, and fluid .exudate accumulates, the 
tuberculous nature of the affection may be suspected, and close inspection will usually 
show little nodular tubercles in the granulation tissue (cf. under Tuberculosis). 
Pleuritis or pleurisy arises in a similar way, although there are more 
opportunities for the advent of infection into the pleural cavity. Every 
pneumonic process which approaches the surface of the lung causes at least 
a localized pleurisy. The occurrence of a sterile, haemorrhagic infarction 
in the lung is equally productive of a localized pleural exudation or coagu- 
lation of fibrin. The types of exudate and the method and results of its 
organization, with the formation of adhesions, are exactly as in the case 232 
TEXT-BOOK OF PATHOLOGY 
of the pericardium (Fig. 91). Great accumulation of fluid in the pleural 
cavity relieves at once the pain caused by the rubbing together of inflamed 
surfaces, but tends to cause dyspnoea through the compression of the lung. 
There are also direct anatomical changes produced in the lung by this 
Fig. 90.-Acute pericarditis, parietal pericardium. Cross-sections of compact ridges 
of older fibrin are separated by a network of fresher fibrin. The serosa cells are still 
visible. 
pressure, consisting essentially in the collapse of the alveoli, with the ex- 
pulsion of the contained air. 
Slight inflammatory processes in the pleura may heal completely, leav- 
ing no trace behind. More severe alterations with fibrinous exudate usu- 
ally cause the formation of granulation tissue to replace the exudate, which 
finally binds together the pleural surfaces, with adhesions. Repetition of 
the infection may call out a new exudate in the meshes and crevices of PERICARDITIS, PLEURITIS, PERITONITIS 
233 
these fibrous adhesions. In other cases an abundant purulent exudate 
persists for a time and becomes walled off (empyema) and surrounded by 
a dense fibrous capsule which must be cut into and evacuated if recovery 
Fig. 91.-Acute fibrinopurulent pleurisy. The serosa cells are still to be seen covering 
the lung. 
is to be expected in a reasonable time (Fig. 92). Otherwise a long time is 
required for the thickening and gradual removal of the exudate, and in the 
meanwhile the pleural tissues about it become enormously thickened and 
form a dense, tendon-like wall as hard as cartilage and sometimes nearly 
an inch thick. Great deformity of the chest follows such protracted em- 234 
TEXT-BOOK OF PATHOLOGY 
pyemas, for if the accumulation of exudate is large, the lung is generally 
found compressed into a small mass retracted against the vertebral column, 
and fixed in this compressed state by the growth of fibrous tissue through- 
out it. 
Peritonitis.-Little is known of peritoneal inflammation produced with- 
out the agency of bacteria, although in some instances in which bacteria 
Fig. 92.-Empyema with thick fibrinopurulent exudate lining the pleural cavity. 
Compression and atelectasis of the lung caused by the large amount of fluid which 
was in the pleural cavity. 
have not been actually demonstrated the exudate has been ascribed to 
chemical irritants. Bacteria may enter by way of the blood-stream, by 
growth and spreading from an adjacent or contained tissue which is dis- 
eased, or by being directly introduced through a wound in the abdominal 
wall or a perforation of one of the bacteria-laden organs which lie in the PERICARDITIS, PLEURITIS, PERITONITIS 
235 
peritoneal cavity. Naturally, the variety of organisms which may be 
concerned is almost unlimited, but in the ordinary course of events the 
pyogenic micrococci and bacilli of the colon group are most commonly 
found. The tubercle bacillus occupies a special place as a common exci- 
tant of peritoneal inflammation, and the gonococcus is occasionally respon- 
sible. Of other organisms, something will be said elsewhere. 
From an anatomical point of view peritoneal inflammation resembles 
closely that of the pleura and pericardium, except that it is more frequently 
seropurulent in character. Nevertheless, there are many instances, es- 
pecially when the inflammation is not diffuse but confined to a limited 
region, in which it appears as fibrinous or fibrinopurulent exudate, which 
glues together opposing surfaces and is soon replaced by a growth of blood- 
vessels and connective-tissue cells which form fibrous adhesions. This is, 
of course, the most favorable type, for the adhesions prevent the further 
spread of infection and may themselves be mechanically harmless, or later, 
when healing is complete, even become attenuated and finally disappear. 
On the other hand, a general diffusion of bacteria, especially if there be 
injured tissue, foreign material, or a considerable accumulation of fluid to 
favor their growth, leads to hyperaemia of the whole enormous surface of 
the peritoneum, with the pouring-out of quantities of fluid, leucocytes, 
and fibrin, and the absorption of much poisonous material and many 
bacteria into the blood-stream. Naturally, the outcome of such an in- 
fection depends upon the balance between the power of resistance of the 
individual and the virulence of the bacteria, and this balance is greatly 
affected by the presence of injured tissue in the peritoneum. The normal 
peritoneum can annihilate many more bacteria without the appearance of 
any peritonitis. 
Primary or haematogenous peritonitis is often produced by the pneu- 
mococcus, which gains entrance to the body by way of the tonsils or 
some similar portal of entry. In a case recently observed at autopsy 
no distinct lesion which could have played this part was discoverable on 
most careful search, and yet the whole peritoneal surface was covered 
with a thick, greenish-yellow, fibrinopurulent exudate which slipped off 
easily into the turbid fluid which filled the cavity. The Pneumococcus 
Type III was there in pure culture. Secondary forms of peritonitis 
include those which follow gunshot or other wounds of the abdomen, 
among which surgical operation wounds unfortunately hold a high place, 
because they are so frequently concerned with infected tissues and organs 
in the cavity. The seriousness of such injuries as gunshot or stab wounds 
lies chiefly in their opening into the stomach or intestine and allowing the 
escape of food or faecal material loaded with bacteria. The peritonitis 
which follows surgical intervention is usually the result of unskilful attempts 
to anastomose intestinal loops or other infected organs in which tissues 
are left stretched and badly supplied with blood, or sutures passed through 
. an infected area with constriction of too much tissue. 236 
TEXT-BOOK OF PATHOLOGY 
Secondary peritonitis resulting directly from disease of the organs lying 
in the cavity may begin in several ways. Ulceration of stomach or duo- 
denum proceeds often to perforation and discharge of their contents. 
Were it not for the food, the juices of these parts of the digestive tract are 
almost sterile, and prompt surgical operation with closure of the perfora- 
tion usually cures the patient. Typhoid ulcerations in the lower ileum, 
tuberculous ulcers, amoebic and other dysenteric ulcers and the phlegmon- 
ous and gangrenous forms of appendicitis rupture and perforate in the same 
way, with discharge of bacteria of the intestinal contents, as well as those 
which have directly caused the lesion. Of these, the typhoid ulcers are 
perhaps least likely to be guarded by adhesions. Even without actual 
perforation, peritonitis arises when the wall of the intestine becomes necro- 
tic, so that bacteria can wander through, as happens in strangulated hernia, 
intussusception, volvulus, infarction of the intestine through embolism or 
thrombosis of the mesenteric vessels, etc. In intestinal obstruction from 
whatever cause the part of the intestine above the obstruction becomes 
greatly dilated and stretched, and its mucosa ulcerated, so that the passage 
of bacteria through the wall is easy, even if not precipitated by actual rup- 
ture of one of these ulcers. 
Extension of the infective process from inflammatory lesions of the gall- 
bladder and ducts, from renal and perirenal abscesses, from the Fallopian 
tubes, or even through the walls of the uterus in puerperal infections, occurs 
but requires no special explanation here. 
Gonococcal infection by way of the Fallopian tubes may produce diffuse 
peritonitis, with rather dry, tenacious exudate of fibrin. It is not common. 
APPENDICITIS 
The extraordinary frequence of appendicitis, and its extreme seriousness 
in many cases, make its study important. It will serve well as an example 
of bacterial infection, followed by inflammation and generally by healing. 
The wall of the appendix is composed of various tissues which correspond with those 
making up the rest of the intestine. The lumen may be stretched into cylindrical form, 
but in general collapses into a narrow space, which is Y shaped on cross-section, one 
limb of the Y reaching toward the mesenteric attachment. The mucosa sinks into 
crypts, as in the colon, but has no villi. It is peculiarly rich in agminated nodules of 
lymphoid tissue. The appendix most commonly extends inward to the brim of the pel- 
vis from the caecum, but great variations are found in its position, as well as in its size, 
its mesenteric attachment, and in its relation to the folds of the peritoneum. These 
matters of surgical interest may be read of in Kelly's monograph. 
Appendicitis is an acute infectious disease produced by the invasion of 
bacteria from the lumen into the mucosa and other walls. The haema- 
togenous infection of the appendix wall by bacteria transported from in- 
fected tonsils, which Kretz regards as a common origin of appendicitis, has 
not been clearly shown to take place. If it does so, it must be considered an 
exceptional occurrence, and does not explain the majority of cases in which APPENDICITIS 
237 
infection from the lumen can be conclusively demonstrated. Appendicitis 
may heal, leaving characteristic scars which predispose to a renewed at- 
tack, and it is usually in this way, that is, in the occurrence of repeated 
attacks, that one is justified in speaking of a chronic appendicitis. 
Strangely enough, there is still much question as to the bacteria which 
cause it, and probably several sorts are concerned. Aschoff and his stu- 
dents find a Gram-positive diplococcus and Gram-positive bacilli as the 
most characteristic organisms. Apparently, streptococci, perhaps accom- 
Fig. 93.-Acute appendicitis with beginning necrosis of the mucosa. 
panied by the colon bacillus, have been found most often, but a great many 
other forms are also described, even including certain anaerobic bacilli. 
Mechanical factors favor the lodgment of the organisms in the mucosa, 
especially the kinking or sharp bending of the terminal portion or the pres- 
ence of obstruction caused by previous inflammation and scarring. In- 
fected foreign bodies of a sharp angular form may have the same effect, 
but the prevalent idea that foreign bodies are commonly present and the 
ordinary cause of the disease is quite erroneous. Nearly all the "cherry- 238 
TEXT-BOOK OF PATHOLOGY 
stones" and "date-seeds" or "grape-seeds" which are found in the appen- 
dix are really not seeds at all, but concentrically laminated masses of faecal 
material. They are injurious inasmuch as they may cause obstruction and 
allow bacteria to accumulate behind them, but Aschoff insists that they 
do not themselves injure and infect the mucosa, but that they rather pro- 
tect it. 
As may be determined from the study of the very early stages, infection 
Fig. 94.-Acute appendicitis. A portion of Fig. 93 enlarged to show the earliest 
changes. 
begins in the mucosa in the bottom of one of the grooves which form the 
Y- or X-shaped lumen in cross-section. Starting as a tiny break in the 
epithelium, with an underlying accumulation of polymorphonuclear 
leucocytes, the inflammatory reaction spreads outward in a widening area 
toward the outer surface. This diffuse inflammation may be practically 
bacteria free in its outer part, but nevertheless reaches the serosa and ex- 
tends along the walls of the appendix. It is the phlegmonous type of APPENDICITIS 
239 
Aschoff, and may sooner or later show the formation of small abscesses 
anywhere in the affected region. Such abscesses, causing liquefaction 
of the wall, bring about perforation either into the lumen of the organ or 
into the peritoneum. Such rupture to the outside is, of course, the origin 
of an acute spreading peritonitis, unless it is limited by adhesions from a 
previous attack. Even without actual perforation, however, the extension 
of the phlegmonous inflammation sets up an acute fibrinous exudative 
peritonitis over the wall of the appendix itself. The organ is swollen and 
reddened, and roughened by the presence of the fibrin. When an abscess 
approaches the surface, it is recognizable as an opaque yellow spot in the 
congested wall (Fig. 95). 
It is even more common to find that, instead of 
remaining as a minute lesion of the mucosa, the 
infection spreads so as to cause rather extensive 
patches of necrosis, in which the outlines of the 
crypts can still be made out, although a dense fibrin- 
ous exudate welds the dead tissue of the mucosa into 
a sort of false membrane. Numerous haemorrhages 
accompany this, and with the loosening and dis- 
charge of the false membrane deep ulcers are left 
(Fig. 96). Extension into the depth is rapid, and 
may proceed to destruction of the whole thickness 
of the wall and perforation, especially since the 
cavity is often distended to bursting with the exu- 
date. Such extreme lesions are not likely to heal, 
and unless saved by operation, the patient succumbs 
to a general peritonitis. If, however, there have 
been previous attacks of milder character, the ap- 
pendix may have become adherent to the surround- 
ing tissues by the organization of fibrinous exudate 
between its surface and that of adjacent coils of in- 
testine. In that case the material discharged through 
the perforation may not pass into the general peri- 
toneal cavity, but only into contact with these adhesions, where an abscess 
is then formed. Such periappendiceal abscesses are sometimes quite large, 
and may contain the necrotic debris of the appendix, floating in pus. They 
are perhaps not so common now as formerly, nor so common as they 
would be in an age of less prompt and aggressive surgeons. 
Slighter lesions which stop short of destruction of the whole wall may 
heal without intervention, and such a person is then liable to a renewed 
acute attack unless his appendix is removed by operation in the interval. 
The mucosa may not have been very widely destroyed, especially in the 
suppurative form, but even when it is ulcerated away over one side of the 
lumen, it is regenerated from that which remains and the lumen is kept 
open. If it be destroyed all the way round, the cavity usually collapses 
Fig. 95.-Acute ap- 
pendicitis with per- 
forating ulcer. 240 
TEXT-BOOK OF PATHOLOGY 
and becomes obliterated by a continuous growth of granulation tissue 
(Fig. 97). Even when the destruction has been very slight and the inflam- 
Fig. 96.-Acute phlegmonous appendicitis. 
matory reaction in the walls moderate, scars are left which indurate the 
submucosa and which persist in the interstices of the musculature. The APPENDICITIS 
241 
elastic tissue, which has a characteristic arrangement for each layer, is 
partly destroyed, and though regenerated, is left greatly distorted. 
Various complications and sequelae occur, among which is the general 
or localized peritonitis already mentioned. This, if survived, often leaves 
adhesions, which may later cause mechanical obstruction to the intestine, 
either by kinking and constricting loops, or by facilitating the occurrence 
Fig. 97.-Sequel of old healed appendicitis. Obliteration of lumen. 
of internal hernial entanglements. Extension or burrowing of the peri- 
appendiceal abscess may lead to the accumulation of pus in extraordinary 
places, among which the subdiaphragmatic region about the liver, in front 
or behind, and on either side, is conspicuous. These are the so-called sub- 
phrenic abscesses, which may, of course, have other points of origin. 
Thrombosis of the nearby iliac and femoral veins may follow appendi- 242 
TEXT-BOOK OF PATHOLOGY 
citis, but more serious, and even more characteristic, is the formation of an 
Fig. 98.-Suppurative pylephlebitis arising from appendix abscess. Numerous abscesses 
in the liver. 
infected thrombus in the branches of the portal vein which lead away 
from the appendix itself. A case was recently observed in which the 243 
ENDOCARDITIS 
branches of the vein leading from an abscess around the appendix were 
found filled not with blood, but with a purulent, greenish-white ma- 
terial. The main trunk of the vein, greatly dilated and thickened, was 
full of the same material. The splenic vein was plugged at its entrance by a 
firm thrombus, so that the inferior mesenteric vein which joins it before 
that point was reached evidently discharged its blood by way of the splenic 
vein and anastomosing channels to the stomach and oesophagus. In the 
liver every branch of the portal was full of soft, purulent thrombus ma- 
terial, and there were numerous large abscesses and groups of smaller 
ones. This is the so-called suppurative pylephlebitis. In this case the 
infection extended even further, and there were abscesses in lungs and 
spleen (Fig. 98). 
LITERATURE 
Aschoff: Wurmfortsatzentziindung, Jena, 1908. 
Aschoff: Ergeb. d. inn. Med. u. Kinderh., 1912, ix, 1. 
Kelly and Hurdon: Diseases of Vermiform Appendix, 1905. 
Kretz: Mitth. a. d. Grenz, d. Med. u. Chir., 1907, xvii, 1. 
Kretz: Verh. Dtsch. Path. Gesellsch., 1907, x, 229; 1910, xiv, 157. 
Noll: Mitth. a. d. Grenz, d. Med. u. Chir., 1907, xvii, 249. 
Obemdorfer: Ergeb. d. allg. Path., 1909, xiiii, 527. 
Watzold: Ziegler's Beitr., 1907, xlii, 260. 
ENDOCARDITIS 
Bacterial or other injury to the heart valves or to any other part of the 
endocardium is like injury to the endothelium of the blood-vessels, and is 
peculiar in its results inasmuch as any reaction must occur in the streaming 
biood. The common effect, just as in the case of a vein, is the formation 
of a thrombus upon the injured place. This generally occludes the vein, 
but in the wider space of the heart, and especially on the valves, where the 
stream is rapid, it forms an irregular cap of platelets with a little fibrin and 
a few leucocytes and red corpuscles. It is rather important to realize that 
this is primarily a thrombus, and that it is only later, in response to the 
presence of active bacteria, that an acute inflammatory process is added 
with exudation from such capillaries as exist in the valves. Of course, 
when bacteria settle on the endocardium, covering the musculature of the 
heart, the primary thrombus formed by the passing blood is far more 
quickly joined by an acute inflammatory reaction from the heart-wall 
(Fig. 99). 
It seems that all cases of thrombo-endocarditis are really dependent 
upon the invasion of bacteria into the endocardium, although it is not 
always possible to demonstrate their presence. The mild and beginning 
forms that produce very small warty or verrucose vegetations are the ones 
in which it is most difficult to find organisms. They occur very often with 
rheumatism, of which, in spite of the persistently repeated claims that it is 244 
TEXT-BOOK OF PATHOLOGY 
the effect of diplococcus or streptococcus infection, we do not yet know the 
cause. 
Fig. 99.-Acute endocarditis. Vegetations upon the wall of the auricle showing great 
numbers of bacteria and an intense inflammatory reaction. 
It is thought possible that toxins alone might produce destructive lesions of the en- 
dothelium of the valves, and numerous experiments have been made, with some success, 
in producing such endothelial injuries because it seemed possible that they might in turn 
afford a foothold for bacteria. There are thickenings of the valves which occur in old 
people, and which are thought to be gradually produced by mechanical strain, and there 
are thickenings and distortions brought about by a process apparently identical with ENDOCARDITIS 
245 
arteriosclerosis (Beitzke, Martino). But the lesions which we may call endocarditis 
seem to be essentially bacterial in origin. The syphilitic alterations of the valves will be 
discussed separately. 
Many organisms are concerned in the production of endocardial vege- 
tations, but the different forms of streptococci, the Staphylococcus aureus, 
the pneumococcus, and the gonococcus are by far the most important. 
The influenza bacillus has been found several times, and various other 
bacteria in single cases, but such organisms as the typhoid bacillus, the 
diphtheria bacillus, the colon bacillus, etc., are probably not the actual 
cause of the lesion, although they may be found as secondary invaders. 
Clearly, the bacteria reach the valves by way of the circulating blood, 
and from the situation of the vegetations one cannot escape the impression 
that they lodge directly upon the surface of the valve. It is not at any 
indifferent point, but, as is clear from the inspection of any large series of 
affected hearts, upon the so-called line of closure, that they produce their 
first effects. It is easily seen that the valves do not come together only at 
their very edges, but rather along a somewhat thickened or fortified line 
a short way back from the edge, this line being supported in the case of the 
semilunar valves by the corpora Arantii. In these valves the delicate film 
which forms the actual edge accurately completes the closure, even though 
it is often perforated by many fenestrations. So, too, in the tricuspid and 
mitral valves, upon the backs of which the insertions of the chordae ten- 
dinese are spread out in several rows, the filmy edge which is also held tense 
by delicate cords accurately completes the closure. Thus, it is not on this 
complementary film that vegetations first appear, but definitely along the 
main line of closure, from which they extend so as to involve any other part 
of the valve, the heart-wall, or the chordae tendineae. How they happen 
to lodge there has long been discussed, and it has generally been thought 
that the mechanical beating together of the valves at this point catches 
them up from the blood and drives them into close contact with the tissue, 
so that they cannot slip by as they do over the smooth walls of the arteries. 
Nevertheless, one sometimes sees independent lesions of the same kind 
on the endocardium of the auricle or ventricle. Rosenow has recently re- 
vived the old view of Koester that bacteria reach the valve as emboli by 
way of the capillary blood-vessels. This idea was set aside by Coen and 
v. Langer,* who found that the semilunar valves contained no capillaries, 
and the atrioventricular valves were supplied only at their base, so that 
such embolism seemed impossible. Rosenow has shown that, with large 
injections of the Streptococcus viridans, he can produce bacterial colonies 
in the substance of the valves beneath intact endothelium, and surrounded 
by a gross haemorrhage. Such haemorrhages are best seen two or three days 
after the injection, and before any obvious vegetation has appeared on the 
valve. Whether they offer the explanation of the mechanism of the first 
* Arch. f. mikr. Anat., xxvii; Virch. Arch., 109. 246 
TEXT-BOOK OF PATHOLOGY 
appearance of endocardial vegetations is by no means settled, and Rose- 
now himself states that they can be most easily understood in those cases 
in which previous injury of the valves has led to their vascularization. 
In the first edition of this book a paragraph was devoted to the description of injec- 
tions of the dog's heart valves made by introducing India-ink into the circulation after 
obstructing the aorta. The ink penetrated to the bases of the valves, but not to the 
line of closure. Bayne-Jones* explains this as the result of insufficient pressure from 
the dying heart. He himself produced beautiful injections of a network of capillaries 
reaching the extreme edges of the auriculoventricular valves, but in the semilunar valves 
ending like the top of a hedge along the basal part of the valve. These injections give 
Fig. 100.-Verrucose endocarditis of the mitral valve with chronic adhesive pericarditis. 
(From a case of rheumatism.) 
an anatomical basis for Koester's view as far as the auriculoventricular valves are con- 
cerned. 
While cases of endocarditis differ among themselves in detail according 
to the bacteria concerned and their localization, they are alike in principle. 
Those following rheumatism show the smallest thrombi or vegetations 
* Bayne-Jones, S.: Amer. Jour, of Anatomy, 1917, xxi, 449. ENDOCARDITIS 
247 
along the line of closure, although with time these may be added to until a 
considerable size is attained. This is the so-called verrucose endocarditis, 
and the vegetations in which it is often impossible to find any bacteria 
become organized quickly, so that they are firm and gray and no longer 
easily pulled off. Even with fairly complete healing they may be recog- 
nizable by their form, but in other cases the scar leads to thickening and 
shortening of the valve, 
which, with the nodular 
irregularities along the 
edges, make the closure 
inefficient (Fig. 100). 
The streptococcus is 
likely to give rise to 
larger vegetations, which 
grow rapidly and are 
found in a crumbly, soft 
state. Occasionally they 
are so massive as prac- 
tically to occlude the 
whole valvular orifice 
(Fig. 101). This is true, 
too, of those produced by 
the gonococcus, although 
there a hint as to the 
nature of the infection 
may be gained from its 
frequent occurrence in 
the valves of the right 
side of the heart, and 
from the rapid destruc- 
tion of the valves them- 
selves, so that one fre- 
quently sees great throm- 
bus masses flapping back and forth on the end of a thread of tissue, 
which is all that remains of the valve. Naturally, either obstruction or an 
extreme insufficiency follows such events. Naturally, too, emboli of in- 
fected thrombus particles are scattered into the circulation. Such ulcer- 
ative endocarditis may be produced by the Staphylococcus aureus, which is 
rapidly destructive, and also by the pneumococcus. Every position may 
be ultimately assumed by the vegetations; they grow away from the line 
of closure to the edge of the valve, and down into the sinus of Valsalva or 
along the chordae tendineae (S. viridans). These may rupture, since it is 
the advance of bacteria which determines the extension of the vegetations, 
and the necrotic ends of the broken chordae flap loosely in the blood-stream 
Fig. 101.-Large vegetation upon the mitral valve 
obstructing its orifice. There are smaller vegetations 
at other points. 248 
TEXT-BOOK OF PATHOLOGY 
and are capped with thrombus material (Fig. 102). Vegetations extend 
along the auricular wall, covering whole patches of it with a flattened, rough 
mat of thrombus, or, where the broken chordae flap against the endocardium 
there are sown bacteria which rapidly cover themselves with new thrombi. 
Loss of substance through necrosis of the valve itself underneath the vege- 
tation often leads to perforation, so that blood regurgitates through the 
Fig. 102.-Endocarditis involving the mitral valve and causing rupture of the chordae 
tendineae, which are covered with vegetations. Vegetations also extend on the wall 
of the auricle. 
hole thus formed. The edge of such a perforated valve may swing loose 
in time as a thread bearing a thrombus, and we have seen such a thrombus 
still attached driven into the orifice of the coronary artery, blocking it 
completely and causing death. Or if the valve is not at once perforated, it 
may bulge at the weakened part into a sort of aneurysmal sac which pro- 
jects into the ventricle, or in the case of the mitral valve, into the auricle. 
In some cases when the vegetation extends to the base of the valve the 
myocardium may become involved, and a burrowing abscess extend far 
into its substance. 
Libman has studied the subacute form of endocarditis produced by the ENDOCARDITIS 
249 
Streptococcus viridans, and finds that it affects the aortic, and much more 
commonly the mitral, valve, producing large yellow, pink, or greenish 
vegetations, rarely with actual ulceration of the valve. Auricular vegeta- 
tions (Fig. 103) and others involving the chordse are common, and bacterial 
emboli are scattered in numbers, producing characteristic embolic glome- 
rular lesions in the kidney and gross infarcts in other organs. Although, 
as in the other forms, the blood is infected with these bacteria, there may 
come a bacteria-free stage in which the vegetations heal. This is accom- 
plished by the calcification of the thrombus, together with its organization 
and the great distortion of the 
valve. But just as the vege- 
tations in this infection are 
found to have developed upon 
the scars of older lesions, so 
upon these healing vegetations 
new bacteria may be developed 
and begin the process anew. 
Probably in all forms of bac- 
terial endocarditis some such 
healing may occur if the pa- 
tient can live long enough, but 
such roughened valves are 
very susceptible to new locali- 
zation of the bacteria. At best 
such healing is advantageous 
only in that with it the danger 
of succumbing to the bacteria 
is at an end, but the disease 
cannot be said to be healed 
when a large, calcified mass 
still hangs on a valve, or 
when the valves are short- 
ened, thickened, and distorted 
by the scars that replace the 
thrombi. 
The anatomical results are then, as may be gathered from what has been 
said, as follows: Fresh vegetations are produced along the line of closure 
on the face of the valve, more commonly in the case of the mitral and aortic 
than in that of the tricuspid and pulmonary, although these are also fre- 
quently affected. The bacteria may be destroyed before they produce 
any greater injury to the valve than is sufficient to cause the thrombus 
formation, upon which organization of the thrombus occurs exactly as it 
might anywhere else, except that blood-vessels must grow a long way to 
reach it. With the completion of this process the valves are left beaded 
Fig. 103.-Mural vegetations on the left 
auricle accompanying vegetations of the mitral 
valve and chord®. 250 
TEXT-BOOK OF PATHOLOGY 
with nodules of fibrous tissue, which later shrink and flatten themselves, 
and although with the most favorable result the delicacy of the valve is im- 
paired and the smoothness of its closing surface lost, still no great degree 
of insufficiency may result. When the bacteria are not so easily destroyed, 
they grow in the substance of the valve and cause more or less necrosis, 
followed by loss of substance not only from the overlying thrombus, but 
from the valve itself. The ulceration and crumbling of the larger vegeta- 
tions afford a source of emboli, and by eating away the valve give rise to a 
more and more extensive insufficiency with regurgitation of the blood. 
Even without ulceration, large heaped-up thrombi prevent the accurate 
closure of the valves, with the same result. They in their turn may become 
organized, and the eroded 
remnants of valves may 
heal, naturally with the 
production of extraor- 
dinary deformities and 
distortions. 
Large vegetations may 
in themselves block the 
passage of blood through 
the valvular orifice, pro- 
ducing a kind of acute 
stenosis. But beside 
this there is the effect of 
healing, which commonly 
thickens the whole of the 
valves, welding them to- 
gether with dense plaques 
of fibrous tissue, which 
form in the place of the 
vegetations and extend 
up on the valves toward 
their base and toward 
the angles, where they 
adjoin one another. The 
contraction of this tissue brings together into a narrow slit the bound- 
aries of the valvular orifice, producing the well-known stenosis of the valves 
(Fig. 104). In the case of the mitral there is commonly a great thickening 
of the left auricle and of its endocardium, and from the mitral ring down 
to the mitral orifice there is formed a dense, rigid funnel at the bottom of 
which is the small crescentic slit with rough, nodular edges, often discolored 
by yellowish pigment and made rigid by extensive deposits of calcium. 
The edges of this orifice, if brought together, fit pretty well, and appear as 
an irregular line in the bottom of the otherwise smooth and rounded funnel. 
From that line down to the actual edge of the valve is a precipitous surface 
Fig. 104.-Mitral stenosis. Great narrowing and 
scarring of the mitral orifice, which stands open. 
Hypertrophy of the right ventricle and left auricle. 
The heart is viewed from the apex. ENDOCARDITIS 
251 
representing the thickness of the valve and fitting the opposite one. Often, 
however, the valve is so rigid that this orifice stands permanently open, 
causing insufficiency as well as stenosis. The chordae tendineae are very 
much shortened and thickened into dense white cords. Sometimes, as in a 
case studied recently, the stenosis is produced by scars occupying only the 
edges of the valves, so that their basal parts remain delicate and soft, and 
sometimes, though rarely, there remains a delicate edge on each valve 
Fig. 105.-Insufficiency of aortic valve. Hypertrophy and dilatation of left ventricle 
Thickening of endocardium below the incompetent valve. 
capable of completing the closure, so that there is stenosis without insuf- 
ficiency. On the edges of the stenosed valves it is common to find fresh 
vegetations. In the case of the aortic valves exactly the same things 
may arise-the valves are sometimes thickened and stiffened by old scars 
in which lime salts are deposited, or their edges alone may be thickened 
into round cords which interfere with accurate closure (Fig. 105). When 
the valves are greatly thickened, they adhere by their angles and fuse into 
a sort of triangular orifice, bounded on all sides by rigid, jagged, calcified 252 
TEXT-BOOK OF PATHOLOGY 
walls which offer great obstruction to the passage of the blood-stream and 
are useless to prevent its eddying back when systole is over. 
That combinations of these things may arise is often exemplified, as in a 
case just observed, in which there was found tricuspid stenosis with ex- 
quisite minute fresh vegetations, similar fresh vegetations along the line 
of closure of the pulmonary valves, extreme mitral stenosis, again with a 
fringe of minute thrombi, and thickened, insufficient aortic valves with 
thrombotic deposits on their ventricular surfaces. The effects of all these 
changes we shall discuss elsewhere. Here it suffices to show them as 
examples of the processes of inflammation and repair. 
Although it has been said that endocarditis is essentially a bacterial 
disease, distortions of the valves may arise (especially in the case of the 
aortic) through syphilitic infection of the aorta involving the valves, and 
apparently also through the ordinary arteriosclerosis. Syphilitic aortitis, 
involving, as it does, the lodgement of the Spirochaeta in the adventitia and 
media of the vessel, may apparently be reproduced in the aortic valves 
themselves. Its early stages have not been studied, but the healing proc- 
esses, like those in the aorta, result in scars and retractions, and it is shown 
that this course of events, never at any time accompanied by thrombotic 
vegetations, may shorten, thicken, and distort the valves in such a way as 
to produce a marked regurgitation. Indeed, a very large proportion of 
the cases of aortic insufficiency develops on the basis of a syphilitic in- 
fection, and the Wassermann reaction is an indispensable clinical procedure 
in every case. 
Whether the ordinary arteriosclerosis is of as much importance as was 
once thought in encroaching upon these valves and disturbing their func- 
tion is questionable. There are many cases in which, with an old arterio- 
sclerosis, the aortic valves are found united at their angles and thickened, 
but it is impossible to say with certainty that this is the uncomplicated 
effect of the sclerosis. It is true that such fatty and sclerotic plaques are 
found on the back of the mitral valve, but the part they play in actual 
disease of the heart-valves is relatively slight. 
LOBULAR PNEUMONIA OR BRONCHOPNEUMONIA 
Focal or patchy inflammation in the lung due to infection beginning in the 
terminal bronchioles is an exceedingly common condition, of serious import 
in both children and adults. It is not strictly lobular in its distribution, 
since only a part of each lobule may be affected or several lobules at once; 
nor is it in all cases caused by a primary infection of the bronchi, since a 
practically indistinguishable condition may arise through distribution of 
bacteria into the lung by way of the blood-stream. In most of those cases, 
however, the bacteria are carried in emboli of thrombus material, and the 
lesions are apt to assume the form of abscesses in the lung substance. 
In spite of these objections the names bronchopneumonia and lobular 
pneumonia will remain in common use. LOBULAR PNEUMONIA OR BRONCHOPNEUMONIA 
253 
Bacteria exist quite commonly in the respiratory tract in small numbers, causing no 
disturbance, but if the carrier of such bacteria be weakened by another disease, by in- 
jury, exposure to cold, or any of a great variety of things that seem to lower resistance to 
infection, invasion and destruction of the tissue of the bronchioles may occur. It is 
doubtless partly for this reason that lobular pneumonia forms such an extremely common 
terminal event in protracted illness from chronic nephritis, rickets, typhoid fever, chronic 
anaemias, long-standing tumor-growths, etc. It is partly on this account, too, that this 
form of pneumonia is so very common in the course of certain acute diseases, such as 
measles, scarlet fever, influenza, and diphtheria, but there the additional reason exists 
that the whole upper air-passages are usually intensely infected. The coryza of measles, 
the sore throat of scarlet fever, and the membranous exudate of diphtheria which may 
extend into the small bronchi are well known. 
Another well-defined group of cases exists in which foreign material infected with 
bacteria is aspirated into the bronchi because, for some reason, the ordinary protective 
reflexes fail. This is seen in extremely ill, delirious, or unconscious patients, in intoxi- 
cated people, in the insane, and in patients anaesthetized for surgical operations. Vomit- 
ing gives an opportunity for the aspiration of gastric contents, but saliva drawn into the 
bronchioles is also laden with bacteria. 
It is evident that almost every sort of bacteria may be concerned in one or other of 
these forms. Especially when foreign particles reach the bronchi, it is likely that many 
different organisms will accompany them. In the cases which seem to begin spontane- 
ously the pneumococcus is very common. In those associated with exanthematic dis- 
eases and diphtheria the streptococcus is prominent, but other pyogenic microorganisms, 
as well as the influenza bacillus, Friedlander's bacillus, and many others may play im- 
portant parts. 
The lung is commonly quite glossy on its pleural surface, but if any foci 
of consolidation lie very near, the pleura is found covered with a thin, 
fibrinous exudate at least over that region. On section the consolidated 
parts can be felt, and can usually be seen as slightly elevated patches, vary- 
ing in color from a dark red or blackish red through the precise color of the 
remainder of the tissue to paler and paler grayish rose or yellowish gray 
(Fig. 106). It is hard to see them when their color is quite the same as 
that of the surroundings, but they can generally be made evident by gently 
pulling the lung tissue this way and that. The alveoli stretch out into long 
rhombs as though one stretched diagonally a fine silk gauze, but those which 
contain exudate resist this slightly and stand out by contrast. 
They vary in size from the minutest foci, which occupy only a few alveoli 
about the termination of a bronchiole, to large, confluent areas which 
stretch over a considerable portion of a lobe of the lung. The variety in 
their appearance and color is largely due to the fact that the exudate 
changes in color as time passes. Red corpuscles, which give it a dark or 
hsemorrhagic hue at first, fade through being broken up, and the grayish 
color of the increasingly abundant leucocytes comes into view. The exu- 
date is often very loosely arranged-with only a few cells in each alveolus 
and, in many cases, probably most of those in children, it does not form 
such rough projecting plugs as in lobar pneumonia. From the bronchi 
there may usually be expressed a drop of purulent fluid. But in other 254 
TEXT-BOOK OF PATHOLOGY 
cases the consolidated patches are firm, and the alveoli filled with project- 
ing masses that are in every way like those seen in lobar pneumonia. 
When they are very small and arranged in clusters around the ends of 
the bronchial branches, their relation to the bronchi can be easily made out, 
both microscopically and on inspection of the gross organ, but when they 
become confluent, this relation is no longer so clear. 
Microscopically, the condition is equally variegated in appearance. 
At times, when a sudden aspiration of infected foreign material has occurred 
Fig. 106.-Lobular pneumonia in adult lung, showing patchy areas of consolidation. 
shortly before death, these particles can be seen in the bronchioles or alveoli 
loaded with bacteria, and surrounded almost solely by red corpuscles. 
Such foci are soft, impalpable, and deep red. In other cases time is given 
for the growth of enormous numbers of bacteria, which fill the bronchus and 
every alveolus, but which, although they destroy the tissue, seem to kill 
the patient without rousing any inflammatory reaction. Such patches are 
soft and gray, and often surrounded by a zone of haemorrhage. When much LOBULAR PNEUMONIA OR BRONCHOPNEUMONIA 
255 
gastric juice has been drawn into the lung, one may smell it and distinguish 
yellowish, green, opaque discolorations about the bronchi and in patches in 
the lung. The tissue is softened and disintegrated, generally without much 
inflammatory reaction. It is probable that death always follows rapidly, 
and that partial digestion of the injured tissue proceeds after death. 
But ordinarily the infection of the lung is produced by the aspiration or 
wandering of the organisms which are present in the upper respiratory 
Fig. 107.-Bronchopneumonic patch showing infiltration of bronchial and alveolar 
walls with the inflammatory exudate. 
tract. The individual when weakened by disease is infected by bacteria 
of which he is himself the healthy carrier, or by breathing in the bacteria 
from other infected persons his lungs are invaded by some new bacterial 
strain. The occurrence of epidemics of bronchopneumonia owing to the 
rapid spread of some virulent bacterium among persons predisposed by 
measles or influenza became a familiar phenomenon during the mobiliza- 
tion of the troops. The exact nature of the changes both general and local 256 
TEXT-BOOK OF PATHOLOGY 
which are due to the predisposing disease is not well known, since it is 
masked by the supervening bacterial infection. But the character of the 
pneumonia itself is clearly dependent on the nature of the bacterium which 
predominates in the secondary infection, and this becomes much more 
apparent in the epidemic occurrence of the disease than in the daily in- 
stances in which various strains of organisms from every source are con- 
cerned in the production of terminal bronchopneumonia. 
The latter seem never so extensive or intense as those which occur in 
the midst of an epidemic, probably because the accidentally invading organ- 
ism has not acquired the extraordinary virulence developed by passage in 
the course of an epidemic. 
It will be best to consider in detail the anatomy of each specific form of 
lobular or bronchopneumonia in connection with the other effects of those 
particular organisms, and to confine ourselves here to the barest outline 
of what may happen in the non-epidemic forms. 
The bacteria, after producing an intense inflammation of the larynx, 
trachea, and larger bronchi, extend into the terminal bronchioles, where in 
the same way they cause the outpouring of an exudate rich in leucocytes 
and red corpuscles. This, with their further growth, fills the terminal and 
neighboring alveoli. Desquamated epithelial cells and a network of fibrin 
are added, and the alveoli thus come to contain plugs of exudate more or 
less consolidated by the filaments of fibrin. The old distinction between 
catarrhal or bronchopneumonia and croupous or lobar pneumonia has never 
seemed to me accurate, since there is commonly a great deal of fibrin in the 
exudate in bronchopneumonic patches, particularly in their more distal 
portions. The walls of the bronchioles and of the air cells themselves are 
infiltrated with leucocytes and fluid, and the lymphatics in the walls of the 
bronchi and blood-vessels and in the interlobular septa are commonly 
infected and contain an exudate of leucocytes or are even thrombosed. 
The complete occlusion of the bronchioles by the exudate leads quickly 
to the collapse of its air-cells, since the imprisoned air is absorbed or dis- 
solved by the passing blood. This atelectasis is often evident on the sur- 
face of the lung in the form of patches of purplish, pasty tissue sunken 
below the surroundings. On the other hand, if the occlusion is incomplete, 
the alveoli may become overdistended with air, in the manner described in 
another chapter. 
The healing of this type of pneumonia, brought about by the annihila- 
tion of the bacteria and the complete or partial liquefaction of the exudate 
and its absorption, occurs rather more slowly than in lobar pneumonia, 
and its retardation by the organization of the exudate into fibrous strands 
is more common. Occasionally in children in whom bronchopneumonia 
has lasted for some time and is rather mild one finds that the exudate is 
largely composed of desquamated epithelial cells, with leucocytes and fibrin, 
and that these epithelial cells have fused to form syncytial masses of proto- 
plasm, with many nuclei. These "giant-cells" often extend from one 
alveolus to another, or line a whole air-space while inclosing masses of fibrin PUERPERAL INFECTION 
257 
or leucocytes. In severe bronchopneumonia the walls of the bronchi and 
of the air-cells are, as has been said, much infiltrated by the inflammatory 
exudate, and their destruction and the formation of an abscess-like soften- 
ing in place of the focus of pneumonia may take place. On the other hand, 
the introduction of putrefactive bacteria, together with those which injure 
and destroy the tissue, may set up a condition far different from that ordi- 
narily seen. This is the so-called gangrene of the lung, which leads not only 
to the death of the lung tissue, but to its softening into a violently foul- 
smelling, greenish, shreddy mass, semifluid in character, which is usually 
fairly well marked off from the surrounding tissue by a zone of coagulated 
lung substance. Cavities of considerable size, lined with ragged, floating 
shreds of dead tissue, discharge part of their contents into the bronchus, so 
that a foul odor is given off with the breath. Buday and others find in this, 
as in other examples of progressive infectious gangrene, many organisms, 
but especially frequently a combination of fusiform bacilli and spirilla, 
which they regard as the specific cause of the condition, and as being suf- 
ficient to cause the necrosis of the tissue as well as the putrefaction. 
Around such an area the alveoli are found to be filled with a dense 
exudate composed largely of fibrin, with many leucocytes and red corpuscles. 
LITERATURE 
Buday: Ziegler's Beitrage, 1910, xlviii, 70. 
Hecht: Ziegler's Beitrage, 1910, xlviii, 263. 
Karsner and Meyers: Arch. Inter. Med., 1913, xi, 534. 
Ribbert: Bruening u. Schwalbe, Handb. d. Krankh. d. Kindesalters, ii, 465. 
PUERPERAL INFECTION 
Particularly favorable opportunity for the development of a serious in- 
fectious process is offered in the puerperal uterus, not, as is so often stated, 
because in the detachment of the placenta many blood-channels are torn 
open, but because tissue which is no longer permeated by the circulating 
blood is often left adhering to the uterine wall, and because fluid stagnates 
in the cavity. It is the same danger which threatens the patient after an 
unskilful operation upon some internal organ in which a portion of tissue 
is left constricted so as to be deprived of its blood supply. It is practically 
the same danger of infection that exists in a strangulated hernia. 
An example will make this clear: A man whose leg was crushed and torn below the 
knee was treated by a surgeon who washed out the dirt from among the exposed muscles, 
stopped the bleeding, and sewed up all the tears in the skin. Within a few hours the 
sutured skin became tense almost to bursting, and when the stitches were removed, a 
bloody, turbid fluid poured out. Next day the muscles and shreds of tissue were bathed 
in thin pus, the man's temperature was high, and there were evidences of a rather pro- 
found poisoning. In spite of every proper surgical intervention he finally died, and many 
abscesses were found in lungs and elsewhere. Undoubtedly the accumulation of fluid 
within the sutured skin gave a medium for the growth of bacteria from the dirt left 
behind, and at the same time rendered the tissues anaemic through pressure. 258 
TEXT-BOOK OF PATHOLOGY 
Differences of opinion still exist as to the source and nature of the bac- 
teria which are responsible for puerperal infection, and doubt prevails 
still as to whether they may be the bacteria already present in the genital 
tract, or only those introduced by the hand or instrument of the operator. 
Kronig adheres strongly to the latter view. The Streptococcus pyogenes 
in one or other of its modifications (5. v.) is almost always found, although 
the pneumococcus or staphylococcus may be the organism concerned, and 
various bacilli, including the Bacillus aerogenes capsulatus, may play a part. 
Fig. 109.-Puerperal endometritis. In this case there was no thrombophlebitis 
In cases of criminal abortion at any stage in the course of pregnancy 
infection is likely to take place on account of the haste and secrecy with 
which instruments are forced into the uterus at the hands of persons 
ignorant of the conditions of bacterial growth. Fortunately, with the ad- 
vance in the knowledge of bacteriology puerperal infection is no longer the 
dreaded scourge of obstetrical practice that it once was before the time of 
Semmelweiss. Even yet, however, the cases in which, after a complicated 
delivery, infection occurs are not all too rare. It may result only in a 
temporary fever, or, on the other hand, it may advance to general septi- 259. 
PUERPERAL INFECTION 
csemia and death. The uterus is found to be large, relaxed, and soft, with 
the enormously enlarged blood-vessels characteristic of the later stages of 
pregnancy. The external os projects into the vagina as a swollen, greenish- 
black, rough, friable mass. The whole cavity of the uterus is lined with 
the same greenish-black, ragged, necrotic tissue, the walls on section gray- 
ish red and cedematous, the veins open and full of blood. The Fallopian 
tubes contain a turbid fluid, No changes are found in the organs except 
the acute splenic tumor and the cloudy swelling of the liver and kidneys 
which are so regularly seen in acute infections. But everywhere the tissues 
are blood stained, the lining of the heart and aorta are quite red, and over 
thorax, arms, and legs there is a network of broad, brownish purple lines 
which show where the laked blood in the cutaneous veins has stained 
through into the skin. Such is the result of the rapid spread of the hsemo- 
lyzing streptococci into the blood. 
In other cases, when the resistance is not so readily overcome, the process 
is more localized. The dead tissue lining the uterus may remain odorless, 
or, when there is a mixed infection with putrefactive organisms, it softens 
into an extremely foul, putrid mass. In other cases a fibrinous exudate 
rich in leucocytes forms over the superficial necrotic tissue, and blends with 
it so as to form a sort of false membrane (diphtheritic or pseudomembranous 
endometritis) (Fig. 109). Beneath this the wall is densely infiltrated with 
leucocytes, red corpuscles, and fluid, and abscesses with local liquefaction 
of the muscular tissue develop and may extend even to the outer surface. 
Extension in this way or along the Fallopian tubes to their fimbriated ends 
is likely to produce a peritoneal infection which hastens the fatal outcome. 
Otherwise the broad ligament and adjacent pelvic tissues become infected 
and enormously thickened and infiltrated with the spreading inflammatory 
exudate. Great abscesses may develop in these tissues, and at an even 
later date extend and rupture into the peritoneum. 
The infection may be communicated to the rest of the body in two other 
ways-one by the lymphatics, the other by the formation of infected 
thrombi in the veins. In the first case the lymph-channels become swollen 
and distended with pus, adjacent lymph-nodes are enlarged and softened, 
and bacteria finally pass into the thoracic duct and blood. The second 
process is far more striking in its appearance. Section through the wall 
of such a uterus shows numerous great canals, which were the veins, now 
filled with greenish-yellow pus, their walls converted into opaque yellow 
material or destroyed entirely so that the uterine musculature itself, edged 
with yellow, necrotic tissue, forms the wall of the canal. For a long dis- 
tance nothing remains of the more solid thrombus, and one may trace such 
channels far out into the broad ligament and to the walls of the pelvis. 
Aschoff raises the question as to whether this thrombosis is the direct result 
of the infection, but I cannot doubt it. The fluid may partake of the foul 
character of the uterine lining in the putrefactive cases. Fragments of 
such infected thrombi, or even the liquefied material, may be swept into TEXT-BOOK OF PATHOLOGY 
260 
the blood-stream, and emboli are lodged in different organs, while the 
blood is flooded with bacteria. Hence the development of abscesses in 
lungs, kidney, brain, etc., or even in the joints (pysemia). These may be 
foul and gangrenous when the uterine inflammation has that character. 
Hence, too, the production of endocardial vegetations, which assume an 
ulcerative and destructive character and form the source of more infected 
emboli. 
ABSCESS FORMATION, PYEMIA, ETC. 
Certain bacteria, notably the staphylococci, show a marked tendency to 
grow in the tissues in closely packed colonies about which the cells are 
rendered necrotic for varying distances. A violent inflammatory reaction 
ensues, and the immediate neighborhood becomes tumefied, red, and pain- 
ful. Coagulable fluid exuded from the vessels into the necrotic tissue clots 
there, and converts it into a firm mass, rather larger than it originally was. 
Leucocytes in great numbers accumulate outside these neighboring vessels, 
and wander into the necrotic mass, dying and becoming disintegrated as 
they pass beyond the zone of safety into the poisoned area. Such quanti- 
ties of them appear, however, that the proteolytic ferments which they 
produce become sufficiently concentrated to digest the outer portions of the 
coagulum, so that it comes to lie loose in a cavity surrounded by a thick 
yellowish fluid filled with intima and partly disintegrated leucocytes (pus). 
At this stage the remainder of the coagulum, loaded as it is with bacteria, 
constitutes the core or central plug (Fig. 110), often recognizable when an 
abscess is incised or when it bursts through the skin. Later the ferment 
process may succeed in dissolving the whole of it, and the abscess is then 
merely a cavity filled with pus and surrounded by an intensely inflamed 
wall. Further necrosis of this wall may occur, and the abscess increases 
in size, often in the direction of least resistance, so that the pus seems to 
burrow its way along natural lines of division of the tissues. It is reab- 
sorbed only with difficulty, and unless it is evacuated by the surgeon or 
bursts its way to a free surface cr into the lumen of some hollow organ, it 
remains in situ for a long time and is gradually inspissated and thickened. 
In this case, and indeed in all abscesses which persist for a long time, even 
when they have been opened, a thick layer of granulation tissue springs 
up to line the cavity and to encapsulate the remainder of the pus, or more 
frequently to obliterate the cavity. This granulation tissue is exceptionally 
thickly infiltrated with leucocytes, and shows the presence of many large, 
mononuclear wandering cells, which become larger as they approach the 
surface of the granulations. Here they exhibit their voracious phagocytic 
characters, loading themselves with the debris of injured and dead cells, 
and usually containing many large fat-droplets (Fig. 85). 
When bacteria and dead tissue are quite removed, as when an abscess is 
opened and thoroughly cleansed, healing proceeds rapidly and the granu- 
lation tissue later forms a dense scar. ABSCESS FORMATION, PYAEMIA, ETC. 
261 
Abscesses arise at the point where direct introduction of the bacteria 
from without takes place, or else they appear, often in numbers, through the 
transportation of infected emboli from some focus of infection in another 
part of the body. These emboli may consist practically of masses of bac- 
teria, and while the flooding of the circulating blood with organisms of this 
sort is known as septicaemia, the condition which we are discussing is often 
called pyaemia. 
Fig. 110.-Abscess of kidney showing necrosis of tubules, some of which are filled with 
bacteria. 
Abscesses from direct introduction of bacteria are often seen in the skin, 
where they are called boils or furuncles, or, when very large, with several 
communicating centres of infection, carbuncles. Most often the organisms 
are rubbed into a hair-follicle by a chafing collar, or in some similar way, 
hence their great frequency on the back of the neck or on the buttocks. 
Frequently, too, they are seen about the nose or lips. The course of 
such abscesses is modified bv the thickness of the skin and the obstruc- 262 
TEXT-BOOK OF PATHOLOGY 
tion to their breaking through. Thus an abscess within the red line of 
the lip readily ruptures and is cured, while one which arises a few milli- 
metres away, in the thick skin, may be much more extensive and last much 
longer. 
In some persons whose resistance is lowered by any one of the many 
things which seem to have that effect, such as overwork, unsanitary sur- 
roundings, or wasting diseases (among which are other infections, such as 
Fig. 111.-Abscess in the liver. The drawing shows the compression and destruction of 
the liver-cells and a broad layer of leucocytes surrounding the central mass of bacteria. 
typhoid fever), a whole series of boils may make their appearance-one 
is no sooner healed than another appears. In these cases it seems that the 
skin becomes smeared with the bacteria, which readily find the oppor- 
tunity to lodge in hair-follicles or sebaceous glands and to form abscesses. 
From the fact that bacteria of a pyogenic character are normally present 
in the superficial layers of the skin it appears that the matter of resistance 
is of the greatest importance. When a number of hair-follicles become ABSCESS FORMATION, PYEMIA, ETC. 
263 
infected side by side with the staphylococcus, a most extensive necrosis of 
the skin and underlying tissue may occur (carbuncle), and with the lique- 
faction of each focus of dead material a perfect honeycomb of communicat- 
ing passages filled with pus may be formed. 
Such, in brief, are the circumscribed abscesses. As the result of pyaemic 
distribution of emboli or cocci they appear in the lungs, heart, kidneys, or 
any other organ (Fig. 111). In the lung such a focus, at first very haem- 
orrhagic, is soon found to have a gray, solid, or rapidly liquefying centre, 
surrounded on all sides by a barrier zone of haemorrhagic pneumonic con- 
solidation, outside of which the lung is cedematous. Such abscesses seem 
to reach a considerable size before coming into communication with a 
bronchus. Frequently confluent with one another, their origin may 
generally be traced by finding a whole colony of cocci lodged like an in- 
jection mass in the lumen of a central blood-vessel. So, too, the embolus 
may be found in the blood-vessel in the centre of those deeply haemorrhagic 
abscesses sometimes found in the submucosa of the small intestine. Rup- 
ture of such abscesses through the mucosa leaves a ragged ulcer which heals 
by granulation. 
While there is thus a great similarity in the mode of formation of ab- 
scesses wherever they occur, it must be recognized that the feature which 
they have in common is the concentration of the whole effect, which not 
only allows the bacteria to kill tissue which might resist a less concerted 
attack, but also allows the inflammatory exudate (perhaps aided slightly 
by the ferments of the bacteria themselves) to digest and liquefy that 
necrotic tissue. 
Phlegmons.-When the bacteria are spread quickly throughout a con- 
siderable area of tissue, as often happens in the loose tissues of the neck 
after invasion from suppurative processes in teeth, salivary glands, or 
mouth cavity, there is nowhere sufficient concentration to produce the 
effects seen in an abscess. The tissue is not all dead, and the exudate is so 
spread out that no liquefaction takes place. Such an intense diffuse in- 
flammation may be called a phlegmon, and so dense and hard may the 
affected tissue become that the phlegmons of the neck are often called 
ligneous or woody inflammations. 
DIPHTHERITIC INFLAMMATION 
On any mucosa the invasion of bacteria or the destruction produced by a 
chemical irritant may cause a peculiarly intense inflammatory reaction, 
usually haemorrhagic, and different from the milder forms in that the ne- 
crotic surface layer is welded together with the fibrinous exudate into a 
membrane-like film. This is well seen in the mucosa of the intestine when 
bacteria of the dysentery group invade it, or when, at the end of a long 
illness, streptococci or other organisms from the intestinal lumen attack it. 
Perhaps the most striking changes of this sort are produced in cases of 
poisoning with bichloride of mercury, possibly because the corrosive salt 
is excreted again into the colon. TEXT-BOOK OF PATHOLOGY 
264 
In the early stage of any of these cases it is found, on stretching out the 
wall of the intestine, that certain parts of the mucosa are covered with a 
grayish or bile-stained, opaque, rough substance which may be scraped off, 
showing beneath it a raw surface (Fig. 112). Such patches are bordered or 
separated by mucosa, which is soft and velvety, but swollen and deeply 
haemorrhagic. The distribution of the chaff-like exudate in the small 
intestine is primarily along the crests of the transverse folds or valvulae- 
Fig. 112.-Diphtheritic enteritis. The inflamed and partly necrotic mucosa is covered 
with a tenacious layer of exudate. 
in the colon, where it is far more commonly found, it is in patches, inasmuch 
as the intestine, in its contracted state, exposes only a part of its mucosa to 
the lumen. The rest is hidden in the depths of the folds, and less constantly 
exposed to the intestinal contents. Perhaps this is inconsistent with ac- 
cepted ideas of the normal relation between the intestinal mucosa and. 
intestinal contents, but the appearance of the inflamed intestine imposes 
such an explanation upon one, and it is easily conceivable that the presence 
of a sharply irritating substance might keep the walls at their maximum 
contraction. Thus, in addition to transverse or circular bands of exudate, 
there are three longitudinal streaks which correspond with the part of the 
mucosa thrown into relief by the longitudinal muscle-bands. 
Microscopically, it is found that the superficial part of the affected mu- 
cosa is completely necrotic and sharply marked off from the underlying 
tissue, which is intensely inflamed (Fig. 113). Continuous with it, and 
overlying it, is a layer of matted fibrin filaments which can be traced 
continuously through the dead tissue. Through both parts of this dead DIPHTHERITIC INFLAMMATION 
265 
layer of tissue, which constitutes the false membrane, remnants of leu- 
cocytes are to be found, with many signs of haemorrhage, and in the tissue 
beneath and about the site of the pseudomembrane there is an exudate 
extremely rich in red corpuscles, leucocytes, and fibrin. All this is often 
particularly well seen in the stomach after intense corrosive poisons have 
been swallowed. 
Later the cedematous and hyperaemic parts of the mucosa between the 
lines and patches of intensest injury become involved in the same process 
Fig. 113.-Diphtheritic enteritis. The crest of the fold of mucosa is necrotic, heemor- 
rhagic, and intensely inflamed. 
if the condition progresses and does not heal. The older sites of injury 
may then discharge the dead tissue into the intestine, and present them- 
selves as ulcerations which may go deep into the intestinal wall. Such 
ulcers are found especially in the colon, and are characteristic of the more 
chronic forms of dysentery. They may arise, too, when there is an ob- 
struction of the intestine, so that its contents accumulate above and 
remain a long time in the dilated upper part of the loop. Probably this 266 
TEXT-BOOK OF PATHOLOGY 
dilation, with its stretching of the wall and narrowing of the blood sup- 
ply, may be a contributory cause of the ulceration. 
LITERATURE 
Bumm: "Puerperal Infection," Arch. f. Gynak., 1891, xl, 398. 
Korte: Handb. d. prakt. Chir. (Bruns, Garre, Kiittner), 1913, iii, 37. 
Lenhartz: Septische Infektionen, Nothnagel's Handb., 1903, iii4, Abth. 1. 
Nothnagel: "Erkrankungen des Darms und des Peritoneum," Handb. d. spec. Path, 
u. Therap., 1898, xvii. 
Thorel: Endocarditis; extensive literature in Lubarsch and Ostertag, 1907, xi2, 319 
1910, xiv2, 331; 1915, xvii2, 499. CHAPTER XV 
INJURY WITH INFLAMMATORY REACTION AND ATTEMPTED 
REPAIR.-NEPHRITIS 
Nephritis: General nature of the process. Its diffuse character; acute and chronic glomerulo- 
nephritis, tubular nephritis, and interstitial nephritis. Arteriosclerotic disease of the 
kidney. Combined inflammatory and arteriosclerotic disease. Amyloid deposit. Sum- 
mary. Functional alterations. Renal insufficiency. 
NEPHRITIS 
Disease of the kidneys which affects diffusely both organs, and which 
leads to structural alterations and disturbances in the function, recogniz- 
able by abnormalities in the urine and by various other symptoms, such as 
oedema, high blood-pressure, etc., has long been known as Bright's disease, 
or nephritis. Weigert, in his classical paper, pointed out the diffuse char- 
acter of these diseases, which distinguishes them from other more localized 
affections, such as might be caused by an abscess or an infarct in one kidney 
or by a stone in its pelvis or an obstruction in its ureter. Still it must be 
kept in mind that although both kidneys are affected in the same way, 
one element of the kidney structure may suffer more than others. Thus 
the glomeruli may be especially injured, while the tubular epithelium 
escapes almost entirely, or the reverse may happen. So dependent are 
these elements upon one another, however, that in the long run the 
tubules are injured by the destruction of the glomeruli and vice versa. 
Except in a few forms, we are ignorant of the causes of the different types 
■of diffuse renal disease, so that it becomes difficult to repeat their produc- 
tion experimentally, or to classify them satisfactorily. It is hard to trace 
the progress of their anatomical development, since in human beings we 
can study in each case only one stage, and it is even yet uncertain what 
may be the final outcome of some of the alterations which are familiar 
enough in their acute stage. It is true that experimental nephritis will 
probably throw a great deal of light upon this problem, even though up to 
the present the most improbable substances have been used to produce 
nephritis in animals. Such substances as uranium nitrate, cantharidin, 
and rattlesnake venom are not likely to be the cause of nephritis in many 
human cases. Yet they produce changes which are, in principle at least, 
identical with those in human kidneys, and therefore give useful informa- 
tion. 
As in the case of cirrhosis of the liver, we must believe that in the 
kidney the extreme distortions which are so frequently met with are prob- 
ably the result of oft-repeated or constantly acting injuries rather than of 
267 268 
TEXT-BOOK OF PATHOLOGY 
a single one. It is the destruction and disappearance of some portion of the 
kidney substance, with the scar which forms in its place, that cause this 
distortion. The great variety in the appearance of the kidneys found at 
autopsy in persons who have shown the symptoms of diffuse renal disease 
becomes more intelligible when we consider that these appearances must 
vary not only according to the character and severity of the injury, but 
also according to the duration of the disease, since in the course of time the 
injured tissue which is still conspicuous in the acute stage, is removed, and 
its place taken by a scar. This decreases the size of the organ and allows 
the blood-vessels to show through more plainly, but the result is still further 
modified by the fact that whatever secretory tissue remains intact becomes 
hypertrophied, in order to compensate for that which was lost. It is easy 
to see then that, whereas in the acute stages of severe renal disease the 
kidneys may appear swollen, smooth, and translucent, with flecks of opaque 
yellow and of bright red in the cortex, they would look quite different if the 
person survived this attack for months or years. Then there would appear, 
in all probability, a very small, rough, granular organ, in which grayish, 
opaque nodules of the remaining secretory tissue project above sunken areas 
of reddish gray, translucent, scarred tissue, in which the red color is due 
to the visible capillaries. Further, the injury which, like a conflagra- 
tion, suddenly destroys a great part of the secretory substance of the kid- 
ney, may finally, if the person survives, end in the production of a kidney 
which looks almost exactly like another which has gradually reached that 
stage through long years in which its nutrition has suffered through nar- 
rowing of its blood-vessels, and which never, at any time, had shown the 
picture produced by extensive acute injury. In other words, it is dangerous 
to conclude anything as to the real nature of the disease of the kidney from 
the mere outward appearance of the organs at autopsy. Even micro- 
scopical study often leaves us uncertain, although there are generally 
traces left which show the path by which the highly elaborate structures 
have reached this stage of commonplace wreck. 
To have a clear idea of the nature of such disease we must follow the 
symptoms throughout its course, and, above all things, make clear-sighted 
tests of the functional capacity of glomeruli, tubules, etc., under standard- 
ized burdens. Up to the present we have not learned to correlate these 
things precisely with changes which we can see in sections of the kidneys, 
since sometimes blood-capillaries or tubules which seem anatomically intact 
are quite unable to carry out their normal function. Beside this, each of 
these structures has a variety of special functions which may separately 
become defective, without our being able to suspect this from any change 
in their appearance. 
Only the very grossest correspondence then is possible at present between 
the anatomical changes and the functional disturbances. This, however, 
we can say-that when several glomeruli with their tubules are quite 
obliterated and converted into scar tissue, they no longer play any part in NEPHRITIS 
269 
the symptoms of the disease, except in so far as the kidney substance is 
reduced by their loss. It is aside from this, in the better preserved tubules 
and glomeruli, that we must look for changes to correspond to the altered 
secretion. It is perfectly easy to understand, therefore, that since the 
remaining tissue may retain its normal state and hypertrophy to compen- 
sate for the areas which have been lost, such a kidney, sprinkled with 
obsolete scars, might carry on its functions perfectly normally. Doubtless 
that is exactly what happens in many cases in which a single injury- 
say from the ingestion of a poison or from a single attack of some acute 
infectious disease-is entirely healed, by the scarring of the destroyed 
areas and the compensatory enlargement of the tissue that is left. Per- 
haps the majority of the cases in which the pathologist at autopsy writes 
down "slight chronic nephritis" are only instances of such obsolete scars 
in the kidney whose cause it is now impossible to tell. 
From the point of view reached by anatomical study, it seems hardly 
justifiable to classify these cases sharply into groups. If we knew the 
aetiological factors, it would be different. Then we might say with assur- 
ance, this is the acute stage of the renal change produced by a protein in- 
toxication, that the terminal result of a long-past infection with strepto- 
coccus. But it is only in a few cases that we can do this, and even when we 
can definitely assign an acute infection as a cause of the renal change, we 
are generally ignorant of the nature of that infection. So it is in the 
common scarlatinal nephritis. But we do know that streptococcus in- 
fections cause nephritis and are possibly responsible for the scarlatinal 
form, and that corrosive sublimate and a few other substances which 
have a chance of being introduced into the body can do so too. Other 
unusual poisons will in the same way injure the kidney, but they practi- 
cally do not come into consideration except in experimental studies. 
Indeed, in the vast majority of cases we do not know what the injurious 
factor is, so that we cannot yet make our classification on this aetiological 
basis. 
A division founded upon structural alterations is the one in common use, 
and yet it is very unsatisfactory, since, with the lapse of time, the responses 
to injury become so combined that we can never outline perfectly sharply 
which is cause and which is effect. Even a division according to disturb- 
ances in function leaves much to be desired, since totally different condi- 
tions, both renal and extrarenal in nature, may cause the same changes 
in the excretory power of the kidney. 
With this in mind we may consider first the anatomical changes and then 
the defects in function. 
Some of the things which are noxious to the kidney stir up an acute or 
inflammatory reaction, while others seem to destroy tissue and leave the 
gap to be filled up by regenerating cells or by scar tissue without any very 
striking inflammatory response. Especially is this thought to be true in 
those cases in which arteriosclerotic thickening and narrowing of the renal 270 
TEXT-BOOK OF PATHOLOGY 
arterioles diminish the nutrition of small patches of kidney substance, so 
that their place is taken by fibrous tissue in which the remains of obliter- 
ated tubules and glomeruli persist. On this account many authors set this 
group apart as quite separate from the other diffuse renal affections, but 
they seem to me so closely related in principle and marked by such similar 
derangements of function that I prefer to class them with the rest, espe- 
cially since we are not in all cases perfectly sure that the arteriosclerosis 
is not caused by the renal disease rather than the reverse. 
Fig. 114.-Glomerulus with capillaries occluded by hyaline thrombi and adherent to 
capsule. 
In studying any large series of cases one meets with instances (a) in 
which the injury primarily affects the glomeruli; others (6) in which the 
glomeruli are apparently intact, while the tubular epithelium has suffered, 
and still others (c) in which neither of those structures seems much changed, 
although there is an intense inflammatory reaction in the interstitial tissues. 
The results of these things are found in many cases in which extensive scars 
remain to show where the injury was done, and in which there are generally NEPHRITIS 
271 
traces of some sort which indicate what was the character of the action. 
Besides these there are (d) kidneys in all stages advancing toward the con- 
dition of maximal scarring, in which there are not to be found the distinctive 
traces of initial destruction of the glomeruli or tubules proceeding with 
inflammation. In these the arteries are almost closed by sclerotic changes, 
and this offers the easiest explanation of their state; and then there is a 
group (e) in which, in addition to other injuries, the presence of amyloid 
causes extensive changes. 
Fig. 115.-Glomerulus showing formation of capillary thrombus. 
Of course, the healing of isolated local lesions of all sorts may produce 
local conditions closely resembling these, but their explanation follows 
simply from what may be said about the diffuse changes. 
It is obviously unfortunate that such terms as chronic interstitial nephritis, chronic 
parenchymatous nephritis, etc., should be in such common use, since they do not ex- 
press exact ideas. It is possible that there may be a chronic as well as an acute inter- 
stitial nephritis, but this is by no means what is meant by the term chronic interstitial 
nephritis, which is used of the late or contracted condition of a kidney in which the 
injury actually affected chiefly the parenchyma. Upon the complete destruction of 272 
TEXT-BOOK OF PATHOLOGY 
this, of course, the scar tissue which remains in its place becomes the most obvious thing, 
and it is hard to escape the idea, at first sight, that it was the tissue primarily affected. 
So, too, the wide-spread use of the terms large white kidney, small red kidney, etc., is 
deplorable, since, though graphic, they express only the crudest and most misleading 
opinion of the nature of the lesion. As Ponfick complains, we might as well speak of a 
small blue lung or a large red liver. 
(a) Acute and Chronic Glomerulonephritis 
Scarlatina, streptococcus infections, especially the protracted subacute 
infections with the Streptococcus viridans, certain poisons used experi- 
Fig. 116.-Acute glomerulonephritis. Glomerular capsule filled with leucocytes. 
mentally, such as cantharidin, uranium nitrate, etc., and probably many 
other violent toxic agencies attack especially the capillaries of the glomeru- 
lar tufts, finally producing extraordinary complex alterations in the whole 
glomerular structure, which heal with distortion or obliteration. Perhaps 
the simplest are those in which bacteria actually lodge in the capillaries, 
sometimes in clumps large enough to occlude the lumen or when bacteria 
or toxic substances injure the wall of the capillary and cause the formation 
of an occluding thrombus. Generally this happens in only a part of the 273 
NEPHRITIS 
glomerular tuft, while blood circulates still through the rest (Fig. 114). 
Such occluded loops become greatly swollen or distended by a mass of 
hyaline, pink-staining material, which seems to be formed chiefly by the 
agglutination and fusion of red corpuscles (Fig. 115). Ordinarily, it seems, 
we must believe that the pulsation of the arterial stream may be felt in 
the glomerular capillaries, which move a little backward and forward in 
the elastic capsule almost as the lung does in the pleura. But now, while 
the rest of the loops still slide on the parietal wall with their expansion and 
Fig. 117.-Intracapillary glomerulonephritis. 
relaxation, the occluded ones become rigid, and because of their distension 
press continuously against one place in the wall of the capsule. This place 
quickly becomes adherent to the loop, and alterations appear in it like those 
which affect the loop itself. Later, just as in any other place where in- 
jured or dead tissue is left surrounded by the living, connective tissue grows 
through and replaces it, making the adhesion permanent. Interesting in 
this connection is the observation of A. N. Richards that under normal 
conditions not all of the glomeruli are permeable for blood at the same 
time. Such periods of bloodlessness may affect the development of lesions 
in these organs. 274 
TEXT-BOOK OF PATHOLOGY 
In other cases, when the capillaries are not quite blocked, leucocytes may 
come in in numbers to approach the injured walls, so that all the loops seem 
stuffed with them, and even the capsule and the tubule are found to con- 
tain those which have penetrated the capillary walls (Fig. 116). Occa- 
sionally one sees a slightly less tempestuous form in which the glom- 
erular tufts become greatly enlarged through the appearance of quan- 
tities of cells in the lumina of the capillaries, which are not polymorphonu- 
clear leucocytes, but look more like endothelial cells. At least they are 
mononuclear cells with indistinct outline, so fused together that their ori- 
gin can hardly be made out. With them there is always an indefinite 
foamy or spongy mass of protoplasm which completes the occlusion of the 
Fig. 118.-Hyaline clot in the glomerular capsule overgrown by epithelium. 
capillary. Such glomeruli must be entirely impermeable, for practically 
all the capillaries seem to be thus obstructed by the mass of endothelial 
cells (Fig. 117). 
The lumen of the capsule generally contains albuminous material or 
blood, with leucocytes and fibrin. That the lining epithelial cells become 
desquamated into this cavity at times is undoubtedly true, but I at least NEPHRITIS 
275 
have never seen an instance in which they were abundant nor sufficient to 
produce the appearance known as the epithelial crescent. That is rather 
the outcome of a well-ordered proliferation which brings with it a supporting 
framework of connective tissue. When blood exudes into the capsule the 
corpuscles often fuse into a hyaline mass, which lies in contact with the 
epithelium (Fig. 118). This may be one of the stimuli for the prolifera- 
tion of the epithelium, because just as in the case of the endothelium of a 
vessel which grows up to cover a mural thrombus, this hyaline clot soon 
becomes completely encapsulated by epithelial cells. So, too, whenever 
adhesions form between glomerulus and capsule, the epithelium becomes 
Fig. 119.-Glomerulus with blood-clot adherent to capsular wall. 
continuous from wall to tuft (Fig. 119). In this way the cavity of the 
capsule may be divided into several chambers which communicate with one 
another. In more advanced cases, through the aid of still other mechan- 
isms, the most extraordinary growths of the epithelium take place, always 
or nearly always in a simple layer, but in folds which unite with one another 
and thus form a sponge-like tissue all the cavities of which communicate 276 
TEXT-BOOK OF PATHOLOGY 
with one another, with the main cavity of the capsule, and thus with that 
of the tubule (Fig. 120). 
Flattened down in the narrow space of the capsule, this tissue at first 
sight gives the impression of a crescentic mass of desquamated cells, whence 
the term, "epithelial crescent" (Fig. 121). 
All these changes cause the glomerulus to become greatly enlarged, so 
that it is conspicuous on the cut surface of the fresh kidney-all interfere 
greatly with the permeability of the glomerulus, and all are usually associ- 
ated with changes of an inflammatory character in the membrana propria 
and surrounding connective tissue of the capsule. With adhesions and the 
replacement of the hyaline and necrotic capillary loops by connective tissue 
Fig. 120.-Proliferation of capsular epithelium in contiguous folds. 
grown in from outside, the glomerulus may be in large part obliterated by 
being converted into dense fibrous tissue. Nearly always, however, even 
in the latest stages, there remain traces of the less affected capillary loops, 
and abundant indications of the method by which obliteration occurred. 
The epithelium of the tubules is undoubtedly injured also, although for a 
time it shows relatively little change. Later the cells show every sort of 
degeneration, and globules, both of neutral fat and cholesterine esters, 
accumulate in them. With their desquamation and disappearance, or 
even with their shrinkage and atrophy, the tubule belonging to that glom- NEPHRITIS 
277 
erulus tends to collapse and becomes lost to view. Often for a time the 
epithelial cells are greatly swollen through the presence of small and large 
globules of refractive hyaline material, which stains like fibrin (Fig. 122). 
Often, too, the lumen is filled with blood, leucocytes, epithelial cells, and 
granules, or with hyaline moulds or casts to which these various things 
adhere, being swept down into the urine, to appear there as different sorts 
of urinary casts. 
About the glomeruli and about the injured tubules there is generally 
Fig. 121.-Glomerulus with epithelial crescent. The cavities among the epithelial cells 
communicate with one another. 
some inflammatory reaction, shown by the presence of wandering cells 
(Fig. 123), and in the course of time in these somewhat cedematous areas 
new connective tissue forms in ever-increasing amounts until finally the 
obliterated glomeruli and atrophic tubules come to lie in a very dense 
framework of fibrous tissue. Aside from these areas, or intercalated some- 
where among them, there are intact glomeruli with their tubules, which 
now carry on the work of the kidney. Such glomeruli actually enlarge, 
and the tubules increase in size and length through the multiplication, by 278 
TEXT-BOOK OF PATHOLOGY 
mitosis, of their epithelial cells. It is a compensatory hypertrophy on the 
part of the remaining functional tissue. Such groups of tubules, until 
they themselves meet with destruction, form the prominent projecting 
granules which stand up on the rough surface of the contracted kidney in 
relief above the shrunken, scarred areas where the tubules are lost. 
No attempt is made to subdivide types of glomerular lesions, because in 
every instance the whole of the glomerulus is somewhat altered-where 
the change seems to be intracapillary, search will reveal changes in the 
epithelium of the capsule, and, when the striking alteration seems to be in 
Fig. 122.--Colloid or hyaline droplets in the epithelium of renal tubules. 
the epithelium, traces, at least, of occluding thrombi will be found in the 
capillaries. 
Such lesions of the kidney are recognizable in the gross organ, in the early 
stages by the swelling of the glomeruli, which project as pale, translucent 
grains, and by the opacity of the cortex, with its sprinkling of ecchymoses. 
Even much later the swollen kidney is still quite smooth when the capsule 
is pulled off and generally pale, grayish, and translucent, though mottled 
thickly with flecks of yellow opacity and to a less extent with haemorrhages 
(Fig. 124). Occasionally the haemorrhages are very abundant,-almost 279 
NEPHRITIS 
confluent, so that the organ is deep red or almost black,-but that is rare. 
With the gradual removal of the fat-containing, opaque, degenerated epi- 
thelium, the kidney decreases in size, the translucent, gray, fibrous stroma 
sinks together, the hypertrophied intact tubules stand out as gray nodules 
from the intervening tissue, where, now that the epithelium is gone, the 
capillaries begin to show through red-and in the end we have a small, 
Fig. 123.-Acute diffuse nephritis with epithelial degeneration, oedema, and infiltration 
with leucocytes and haemorrhage. 
hard, reddish-gray organ, roughened by granules of gray over which the 
capsule is quite adherent-the so-called secondary contracted kidney 
(Figs. 125 and 126). 
Naturally, the disturbance of function must change as the kidney pro- 
gresses through all these stages of the disease. Very striking, however, in 
the beginning is the diminution of the amount of urine, its high concen- 
tration and admixture with blood, albumin, and casts, and the coincident 280 
TEXT-BOOK OF PATHOLOGY 
oedema. Later the whole clinical picture may change, as shall be described 
later. 
(b) Acute and Chronic Tubular Nephritis 
Destructive lesions, affecting especially the epithelium of the tubules, and 
followed by more or less inflammatory reaction, result from various poisons, 
among which bichloride of mercury, ura- 
nium nitrate, and chromates are more 
familiar. Baehr has recently described 
an exquisite tubular lesion produced by 
iodine. But there are many others of less 
definite nature, since general peritonitis 
and septicaemias are sometimes accom- 
panied by quite analogous changes, and the 
acute nephritis of pregnancy is commonly 
Fig. 124.-Acute and subacute 
nephritis, showing punctiform haem- 
orrhages and opaque yellow flecks 
which are produced by the degen- 
erated epithelium. 
Fig. 125.-Secondary contracted kidney, rep- 
resenting later stage in the development of the 
diffuse glomerulonephritis. 
of this type. In eclampsia, too, one sometimes finds the tubular epithelium 
necrotic. In any series of cases anatomically studied one must be careful 
to rule out possible postmortem autolytic changes, but with this in mind, 
there are still found many instances in which a great proportion of highly NEPHRITIS 
281 
sensitive epithelial cells of the convoluted tubules are necrotic, as shown by 
their disintegration and the loss of their nuclei. Nevertheless, severe altera- 
tions of these cells may occur without proceeding to actual death, and in 
most infectious processes, including typhoid fever and pneumonia, and in 
such nutritional disturbances as result from chronic passive congestion, 
Fig. 126.-Chronic diffuse nephritis following repeated glomerular injuries (secondary 
contracted kidney). 
striking functional derangements, referable at least in part to the tubular 
epithelium, appear, while nothing more than the so-called cloudy swelling 
can be demonstrated anatomically. In glomerulonephritis, in which the 
tubules often seem to be spared, the occurrence of mitoses in their lining 
epithelial cells, which is an indication of their extraordinary power of regen- 282 
TEXT-BOOK OF PATHOLOGY 
eration, may give a clue to their participation in the injury, even when 
actual destruction of the cells is not evident. So, too, the ultimate fate 
of the tubules in an area of atrophy, whether brought about by glomerular 
obstruction, by intoxication, or by malnutrition, gives us convincing evi- 
dence of the fact that their cells suffer very regularly, even though the 
glomerular lesions may be far more conspicuous. 
Pure tubular nephritis is probably not quite so uncommon as is generally 
thought, since recovery with complete compensatory new formation of the 
Fig. 127.-Destruction of tubular epithelium caused by poisoning with mercury 
bichloride. 
cells seems so easily possible, and even when the affected tubules lose all 
their epithelium and collapse, the signs of their downfall, when some time 
later the person dies, are inconspicuous. Apparently when a tubule be- 
comes permanently obliterated its glomerulus soon falls together in a 
bloodless state, and is, some time later, surrounded by a progressively thick- 
ening hyaline and connective-tissue capsule, which accompanies its com- 
plete obliteration. The best example of tubular lesions is that produced by NEPHRITIS 
283 
mercuric bichloride, a condition which has become peculiarly frequent of 
late, and there one finds, side by side in the tubules, living and necrotic 
cells (Fig. 127). Those which have succumbed soon become formless 
masses, often calcified, which may be surrounded and encapsulated by the 
new epithelial cells which quickly grow from the division of those remaining 
intact (Fig. 128). 
The ultimate result of destruction of the epithelium of the tubules must 
Fig. 128.-Later stage of nephritis following bichloride poisoning. The necrotic cells 
are calcified and surrounded by new-formed epithelium. 
depend upon its extent, since if it be partial, the tubule may be perfectly 
relined from the cells which remain, while if it be complete, the collapse 
of the tubule will lead shortly to destruction of the glomerulus and the 
formation of a scar in the place once occupied by the whole structure. 
Doubtless this is the origin of some of the scattered scars which are so 
frequently seen in the kidney, but in its completed form it is almost im- 284 
TEXT-BOOK OF PATHOLOGY 
possible to say whether such a scar was brought about in this or in some 
other way. 
Rarely one encounters renal changes resembling closely those produced by Baehr 
through the injection of iodine, and found in animals which have survived a long time.* 
In a case studied recently the kidneys were found to be smooth, pale, and hard, and on 
section the tubules were uniformly atrophic and shrunken, while the glomeruli remained 
large and conspicuous (Fig. 129). It is true that in this case the capillaries of the 
Fig. 129.-Subacute and chronic nephritis. Glomeruli fairly well preserved in spite of 
universal atrophy and shrinkage of the tubules which are embedded in scar tissue. 
glomeruli appear to be blocked by masses of large cells, so that other interpretations of 
the whole condition are possible, but the general aspect of the cortex points to a primary 
lesion of the tubular epithelium. 
(c) Acute, Subacute, and Chronic Interstitial Nephritis 
By this is meant strictly the injury which seems to affect particularly 
the framework of the kidney, causing an inflammatory reaction there, 
* Ziegler's Beit., 1913, Iv, 572, Fig. 12. NEPHRITIS 
285 
while glomeruli and tubules are left more or less intact, with the resulting 
formation of scars throughout the organ. It does not apply to the several 
varieties of scarred, contracted kidneys, which are clearly the outcome of 
injuries to the specialized secretory mechanism, that is, to the great ma- 
jority of the contracted kidneys, which are so commonly and loosely spoken 
of as chronic interstitial nephritis. It is perfectly recognized that, as 
Weigert pointed out, all forms of nephritis are diffuse in that every element 
of the tissue is somewhat affected, so that, in an instance in which the 
Fig. 130.-Acute interstitial nephritis from a child dying of diphtheria. 
glomeruli show the most striking changes, the connective-tissue framework, 
as well as the epithelium of the tubules, also feels the shock and reacts. 
But it is entirely wrong to conclude, from the fact that in the late stages of 
such a condition, when much of the kidney substance has disappeared 
and is replaced by scar tissue, the connective tissue was the first thing to 
be affected, and that it, in its growth, has constricted and destroyed the 
secreting structures. It is not in this sense that we use the term interstitial 
nephritis, but rather to describe a quite uncommon condition, seen only 286 
TEXT-BOOK OF PATHOLOGY 
once or twice among the last 500 autopsies at the Presbyterian Hospital, 
where the patients are chiefly adults, but much more frequent in hospitals 
for the infectious diseases of children. Councilman found 42 cases in such 
material in the course of two years. 
In its rather focal distribution, the acute interstitial nephritis resembles 
somewhat the forms of acute suppurative nephritis, caused directly by the 
lodging of bacteria in the kidney substance, but the whole course, the type 
of wandering cells involved, and the absence of bacteria serve to distinguish 
it from them. It appears usually in the course of scarlatina or diphtheria, 
or other similar intense infections, perhaps more commonly in mixed in- 
fections than in pure scarlatina or diphtheria. 
The swollen kidney shows on section clouding with grayish areas, which 
are found microscopically to depend upon the accumulation, between the 
tubules, of great numbers of wandering cells of several sorts (Fig. 130). 
Most of these are mononuclear, and vary in form from those resembling 
the lymphocyte to plasma cells and even much larger types. Usually 
there are also some polymorphonuclear leucocytes. There is a spreading 
apart of the interstitial connective tissue, and commonly a new formation 
of fibroblasts. The glomeruli seem to suffer very little or secondarily, as 
shown by the penetration of wandering cells through the capsule into the 
intracapsular space. The epithelium of the tubules may also be relatively 
intact, although wandering cells are sometimes found in the lumen. But 
the same changes are, as found in adults, by no means independent of alter- 
ations of glomeruli and tubules, and most often accompany them. 
The healing, or rather the passing into a stationary, obsolete condition of 
this process, is difficult to follow certainly, but it seems probable that a 
rather diffuse thickening of the interstitial tissue in many areas may repre- 
sent its last stages. No definite symptoms need accompany the acute 
stages, and the urine may be normal. If this be so, there seems no reason 
to suppose that the later stages should be productive of symptoms. This 
will naturally depend upon the extent of the injury to glomeruli and tubules. 
(d) Arteriosclerotic Disease of the Kidney 
It seems incorrect to discuss a disease of the kidney brought about by the 
gradual diminution of its blood supply under the heading nephritis, but 
the main principle is that here, too, an injury leads to the distortion of 
the kidney anatomically and functionally in a way like that produced by 
other injuries, which bring in their train inflammatory reaction. After 
all, the existence of an inflammatory reaction is by no means the most 
important feature, and this arrangement is for convenience, it having 
been said that if there must be a classification, it can be satisfactory and 
logical only when on an setiological basis. 
Long ago it was pointed out by Gull and Sutton that thickening of the 
walls of the renal vessels, causing their narrowing and hence depriving the 
kidney of blood, is found in kidneys which have lost much of their substance, NEPHRITIS 
287 
and have become scarred and contracted. After tang dispute it seems 
probable that the sclerosis of the vessels is actually the cause of these 
changes in the kidney, and not the incidental result of other injuries which 
also affect that organ. The arteriosclerotic thickening of the intima 
associated with an excessive reduplication of the internal elastic membrane 
extends into the smallest vessels, and may completely occlude them and 
narrow them to the minutest channel (Fig. 131). This change, as pointed 
out by Jores, Cash, and others, is often associated with a great deposition 
of fat in the intimal tissue. Usually the effect of this, inasmuch as most 
Fig. 131.-Arteriosclerotic narrowing of the renal vessels, with thickening of the arterial 
coat and reduplication of the elastic lamellae. 
of the branches of the renal artery are thus narrowed, is to produce many 
minute areas of malnutrition, in which the sensitive tissue suffers and 
finally atrophies away, to be replaced by a scar. This is the type of 
arteriosclerotic, contracted kidney or primary contracted kidney which is 
most important and which we wish to describe. 
There are some cases, however, in which, while most of the cortex is 
quite normal and shows itself to be smooth and normally tabulated on the 
removal of the capsule, there are numerous, quite large depressions into 288 
TEXT-BOOK OF PATHOLOGY 
which the capsule dips and becomes adherent (Fig. 132). These corre- 
spond with gross scarred areas sunken below the general surface, in which 
obliterated glomeruli and remains of shrunken tubules persist. Since the 
intervening tubules have collapsed or been reduced to narrow cords of 
cells, the persistent glomeruli concentrate themselves into a small space, 
and are embedded in scar tissue infiltrated with mononuclear wandering 
cells. The explanation usually given is that the sclerotic narrowing of the 
vessels is not uniform in all the branches of the artery, and that these are 
areas which have suffered especially. This explanation does not rest on 
an absolutely firm foundation, and 
since it is obvious that the scarred 
areas are entirely like slowly pro- 
duced infarcts which are organized 
as fast as the cells disappear, it 
seems possible that, after all, they 
Fig. 132.-Atrophic scarred areas in 
renal cortex produced by arteriosclerotic 
narrowing of the vessels. 
Fig. 133.-Arteriosclerotic contracted 
kidney (compare Fig. 136, which repre- 
sents a section of this kidney). 
may have had an embolic origin. The functional disturbances in such 
cases are not especially marked, since there is much normal tissue to carry 
on the work. 
The changes caused by diffuse sclerosis of the small branches is quite a 
different matter. Such kidneys are usually small and hard, and are often 
surrounded by a thick mass of fat. The capsule, which is thickened, is 
adherent to the surface, tearing it somewhat as it strips off, or in other 
instances it peels off easily enough. In any case it leaves a pale, mottled NEPHRITIS 
289 
surface which is roughened by fine projecting nodules of a pale yellowish 
gray or pinkish gray color (Fig. 133). The scar-like tissue between these 
is translucent, grayish red, often allowing small vessels to be seen shining 
through beneath its surface. On section it is usually found that, with the 
decrease in size of the kidney in all directions, the space in which the pelvis 
lies is enlarged and filled with fat (Fig. 134). The blood-vessels are stiff 
and thick-walled, and even the minute ones on the cut surface stand open 
like rigid tubes. The pale cortex is greatly thinned, measuring sometimes 
not more than 2 to 3 mm., and in it one can no longer make out the ordi- 
nary striations in their usual parallel lines. Where they can be seen, they 
are greatly twisted and distorted and interrupted by the presence of opaque 
nodules of tissue which, beside projecting on the surface, are found deeper 
Fig. 134.-Old arteriosclerotic contracted kidney showing the filling of the widened 
space about the pelvis with fat. 
in the cortex. Flecks of opaque yellow or deep red haemorrhage are some- 
times seen. 
The gross appearance of such a kidney differs in no way, therefore, from 
the end result in a protracted glomerulonephritis (the so-called secondary 
contracted kidney), and in all probability something similar may result 
if the destruction be severe enough and time be given in the case of the 
tubular and interstitial forms. As a matter of fact, except perhaps through 
the presence of the strikingly thickened blood-vessels, it is difficult, if not 
impossible, to distinguish macroscopically the types of ultimate contracted 
kidney. The arteriosclerotic (so-called primary contracted kidney) may 
be very pale or quite dark red in color, but this depends in great part first 
on the exposure of the blood-capillaries in the translucent tissue, and then 
upon the degree of congestion of these vessels. The same difference in 
color may be seen in other contracted kidneys. 290 
TEXT-BOOK OF PATHOLOGY 
Small cysts filled with clear or dark-brown fluid are often seen projecting 
from the cortex (Fig. 135), but these seem not to depend entirely upon the 
scarring of the kidney, for they are quite frequently found in kidneys which 
have undergone no such change. 
The microscopic alterations in the diffuse arteriosclerotic kidney are 
about as follows (Fig. 136): The arcuate vessels, the vasa recta, and the 
afferent vessels of the glomeruli show throughout or in patches such a 
thickening of the intima as greatly to encroach upon the lumen, but this 
cannot affect all the branches uniformly, for there are the projecting gran- 
ules in which one finds the glomeruli enlarged and actively functional, and 
the tubules not only well preserved, but greatly hypertrophied, being both 
wider and, as shown by recon- 
struction, actually longer than 
the normal, and lined with cells of 
normal appearance. In every re- 
spect these seem to be magnified 
normal glomeruli and tubules 
which have undergone a work 
hypertrophy to compensate for 
many which have been lost. It 
is true that, with the progress of 
the malnutrition, these epithelial 
cells often show degenerative 
changes and become granular 
and disintegrated, or enormously 
swollen from the presence of 
large and small hyaline droplets. 
In most instances, as in almost 
all destructive renal changes, 
fat accumulates in drops in the 
epithelial cells, and, as in the in- 
flammatory forms, these fats may 
be both glycerin and cholesterine 
esters, showing well all the chem- 
ical and staining peculiarities of 
those two types, as well as their different effect upon polarized light. It 
is the presence of the fats, hyaline droplets, etc., which confers the opacity 
upon the degenerating projecting granules of the kidney surface. In the 
kidneys, in which the process is less active, these granules have practically 
the color of the normal organ. 
The more severe changes in the tubules produce a variety of appearance. 
Many of those which have already become enlarged through the compensa- 
tory hypertrophy become greatly dilated, probably through obstruction at 
some point lower down. These are found to be filled with a homogeneous, 
pink-staining fluid, which is retracted from the wall during fixation, and 
Fig. 135.--Arteriosclerotic contracted kid- 
ney with cortical cysts. NEPHRITIS 
291 
Fig. 136.-Cortex from arteriosclerotic contracted kidney (Fig. 133). Narrowed 
blood-vessels and obliterated glomeruli and tubules are conspicuous. Hypertrophied 
and dilated tubules are present in groups. 292 
TEXT-BOOK OF PATHOLOGY 
lined with extremely low, flat epithelium (Fig. 137). The other tubules in 
the more frankly scarred areas show no epithelium like that which normally 
lines the convoluted tubules. The cells which remain are cubical, slightly 
granular, or with clear protoplasm, and often desquamated or distorted 
and shrunken. There is scarcely a lumen left, and the epithelial cord is 
generally inclosed in a membrana propria, which has become greatly thick- 
Fig. 137.-Projecting nodule of active cortical tissue in arteriosclerotic kidney: a, 
Dilated tubules; b, degenerated tubular epithelium. 
ened by the apposition of a vague, irregular, wrinkled hyaline substance 
which stains blue with Mallory's connective-tissue stain (Fig. 139). 
The glomeruli may be quite intact and enlarged, or they show some stage 
in the complex process leading to their complete obliteration. It seems 
that in this type of renal disease the obliteration of the glomeruli is brought 
about by quite different changes from those seen in acute and chronic 
glomerulonephritis, and it is generally possible, even at a late stage, to NEPHRITIS 
293 
recognize which sort we are dealing with. But it would be hazardous to 
state that the changes about to be described are peculiar to the effects of 
arteriosclerosis. They probably depend on a great variety of injuries to 
blood-vessels and tubules, and doubtless play a part in the end results of 
tubular and of acute and chronic interstitial nephritis as well. Certainly 
they are common in all those very abundant cases in which atrophic and 
scarred areas occur in the kidney, without marked vascular change and in 
which we are left with no definite clue as to the real nature of the injury. 
Fig. 138.-Glomerulus from arteriosclerotic kidney. The capillary tuft is converted 
into a compact mass, smoothly covered with epithelium. 
In all cases the capillary loops become, sooner or later, impermeable to 
blood. This may happen through narrowing of the afferent vessel, or 
through collapse of the capillaries themselves, possibly the result of ob- 
struction of the tubules and a short-lived distension of the capsule with 
urine, or through changes in the glomerular capsule. Here the imper- 
meability is not the result of thrombotic occlusion of the capillaries, as in 
the glomerulonephritis. Nevertheless, unless they collapse completely, 294 
TEXT-BOOK OF PATHOLOGY 
these capillaries are left filled with a formless material which may be de- 
rived partly from the remaining blood-corpuscles or from proliferation of 
the endothelium. In the end it* stains yellow with van Gieson's stain and 
has no recognizable cellular character. Evidently the epithelial cells 
between the loops fuse and disappear, and finally the rather solid tuft is 
smoothly covered with epithelium in a continuous layer (Fig. 138). At 
any rate, the collapsed glomerulus remains visible a long time and is recog- 
Fig. 139.-Late changes in the glomerulus in an arteriosclerotic kidney. Collapse of 
tuft with great thickening of Bowman's capsule. Atrophy of adjacent tubules. 
nizable as such. It may finally adhere to the capsule, but such adhesions 
are not characteristic, as in glomerulonephritis. 
Changes in the capsule are practically constant, and by many thought to 
be the cause of the collapse of the glomerulus either through constriction 
of the vessels at the hilum or through direct compression of the whole 
glomerulus. They consist in hyaline swelling of the membrana propria, 
with masses of hyaline bulging into the capsular lumen, or in new connective- 
tissue formation around the outside, or in a combination of the two. NEPHRITIS 
295 
These things lead to an extraordinary thickening of the capsule surrounding 
the collapsed glomerulus, so that this comes finally to look like a small, 
wrinkled structure in the centre of a great hyaline and fibrillar mass. By 
this time the capsular epithelium has disappeared, and the space of the 
capsule being lost, the hyaline and fibrous material incloses the glomerulus 
tightly (Fig. 139). In later stages the whole becomes fused and reduced to a 
homogeneous, hyaline, scar-like nodule. In other cases hyaline material 
appears in the outer wall of the capsule, in the walls of the afferent vessels. 
Fig. 140.-Hyaline changes in, a glomerulus. 
and even in the walls of the capillaries of the tuft outside the endothelium, 
and it is easy to see that its increase may lead to the collapse of these 
capillaries and the final obliteration of the glomerulus (Fig. 140). 
The connective tissue outside the glomeruli, as well as that between the 
tubules, becomes, in the course of time, remarkably increased in amount 
and very tough and firm. In its meshes the blood-vessels, obliterated 
glomeruli, and traces of tubules become very closely ranged, because of the 
disappearance of so many structures which were there before. This is in 296 
TEXT-BOOK OF PATHOLOGY 
a sense a condensation of the kidney substance, and if the connective 
tissue were stretched out to the original size of the kidney, it would seem 
less abundant. Infiltration with wandering cells of the mononuclear type 
is almost the rule. Doubtless they appear as scavengers in an organ where 
tissue downfall is so constant (Figs. 136, 137). 
Although the supposed effects of the plainly visible, extreme narrowing 
of the arterioles is described in great detail separately from those of toxic 
and bacterial injuries, it is by no means clearly proven that these are the 
effects of primary arteriosclerotic disease, even though this is a belief 
which has prevailed for more than half a century. It is quite as easy to 
believe that, as in the atrophic genital organs of women in old age, the 
narrowing of the arterioles is associated with the wasting of the tissue, 
or that repeated injuries to the tissue of the kidney may also affect the 
blood-vessels. Further, it should be pointed out that the cases in which 
sclerosis of the arterioles is so conspicuous that it seems necessary to 
regard it as the cause of the whole lesion are really rather uncommon. 
The idea is so firmly implanted that it may seem absurd to those who have 
always readily made the diagnosis "arteriosclerotic kidney" to read the 
statement that in order to find one convincing case from which to draw 
the figures in this book a very large series of autopsies had to be searched 
through. 
Indeed, while glomerular and tubular lesions are very commonly found 
without appreciable alterations of the blood-vessels, and predominantly 
vascular changes are so rarely found, it is quite usual to find these lesions 
combined in such a way as to suggest their simultaneous origin rather than 
their complete dependence the one upon the other. 
(e) Combined Inflammatory and Arteriosclerotic Disease 
AMYLOID DEPOSIT 
Amyloid deposit in the kidney has been very generally regarded as consti- 
tuting a special type of nephritis, but it seems that this material may appear 
just as it does elsewhere, in an organ which is otherwise, for a time at least, 
practically normal, so far as one can see, while in other instances its ap- 
pearance is associated with any or all of the changes described in progres- 
sive nephritis. It is clear, then, that in the most extreme degrees of scar- 
ring (Fig. 141), distortion, and contraction of the kidney, we may find 
amyloid, as well as in those acute and subacute stages in which the secre- 
tory elements of the kidney are still present, though often much injured. 
Most commonly amyloid is found in kidneys which are greatly swollen 
and pale, with mottlings of opaque yellowish-white, and sometimes haem- 
orrhages. The capsule is not adherent in this stage, and the surface of the 
kidney is quite smooth or slightly granular. The tissue is often gray and 
translucent, except in the yellow, opaque areas, where fat-globules and dead 
cells are accumulated and the glomeruli are visible and prominent as AMYLOID DEPOSIT 
297 
translucent points. On the application of iodine they flash out into a 
bright brown color, showing very distinctly their arrangement along the 
straight vessels of the cortex. Often, too, there are brown lines in cortex 
and pyramid which indicate the presence of amyloid in tubule or vessel- 
walls. Microscopically, the minuter blood-vessels are surrounded by the 
pink-staining amyloid which lies directly under the endothelium. In the 
glomeruli (Fig. 142) one finds it especially abundant, occupying the same 
Fig. 141.-Extreme scarring of the kidney, with amyloid. The glomeruli approach each 
other, since the tubules have been destroyed. 
position, and thus separating, in the capillaries, the endothelium from the 
epithelial covering. Sometimes it thus forms a tube lined with endothe- 
lium, through which blood may still pass, but if it becomes more abundant, 
the lumen of such a tube is narrowed, and although one or two endothelial 
cells may still persist there, it becomes obstructed, as far as the passage of 
blood goes. In late stages the glomeruli become almost solid masses of 
amyloid. Thickening of the capsule may occur, but there are not usually 
adhesions with the glomerular tuft. The membrana propria of the tubules 298 
TEXT-BOOK OF PATHOLOGY 
may, in the same way, become the point of deposit of the amyloid, espe- 
cially in the pyramids. 
The epithelial cells of the tubules show the most advanced degenerative 
changes, being loaded with fat-globules or becoming desquamated. Hya- 
line droplets with great swelling of the cell are common, too (Fig. 143). 
It is characteristic of such amyloid kidneys that in patches the tubules be- 
come greatly dilated and lined by very flat, low epithelium. In other 
Fig. 142.-Amyloid in glomerulus. The amyloid lies between the endothelium and the- 
capsular epithelium in each capillary. 
areas, with the obstruction of the glomeruli, the tubules atrophy and 
collapse, and the region is involved in scar tissue. The blood-vessels may 
or may not be sclerotic. The further changes in more advanced cases 
differ in no essential from those seen in other contracted kidneys, and it is 
difficult to say whether the presence of the amyloid caused the degeneration 
of the cells. Possibly the destruction of the cells and the presence of 
amyloid were the parallel results of the same long-standing intoxication, 
for, as has been stated before, the source of the amyloid is connected with 
the existence of some protracted intoxication or infection. 299 
AMYLOID DEPOSIT 
It is, perhaps, because of the usual existence of some such disease as 
syphilis, tuberculosis, or malignant growth, with their secondary anaemia, 
that the heart and blood-vessels fail to hypertrophy. Indeed, during the 
life of these patients blood-pressure seldom runs high, though exactly why 
arterial hypertension should fail to appear in amyloid disease is not clear. 
Fig- 143.-Subacute and chronic nephritis with amyloid. Tubules show epithelial 
degeneration and dilatation. 
Probably the amyloid has little to do with this, for in the later stages, when 
renal tissue is largely destroyed, a rise in blood-pressure may occur. It 
has been suggested that the amyloid involvement of the adrenals may 
prevent the rise of pressure. 
The urine is abundant, with low specific gravity, and pale, but rich in 
albumen; hyaline casts and epithelial and other cells appear there. It has 
never been shown, though, that the specifically staining amyloid plays any 
part in forming these casts. 
In general, then, while some of the symptoms of nephritis are changed 
by the amyloid in the kidney, we may regard its presence there as inci- 300 
TEXT-BOOK OF PATHOLOGY 
dental, rather than as the cause of the nephritis or as constituting a new 
form of the disease. 
Fig. 144.-Great hypertrophy of the heart affecting especially the left ventricle, in chronic 
nephritis without valvular lesion. 
SUMMARY 
If, now, we consider together all the anatomical changes found to occur in 
the kidneys, we find that they are the effects of various injuries, with re- 
sponses arising according to clearly defined principles, and ending, if time 
be allowed, in the production of altered organs in which one may recognize 
great destructive effects side by side with strenuous attempts at healing 
and at compensatory hypertrophy. The injuries are of many different 
kinds: they affect one or other part of the kidney predominantly; they 
frequently occur in combination, and they often act repeatedly and per- 
sistently over a long time. No sooner, then, is one injury complete, the 
dead tissue removed, and the place healed, with perhaps some compensa- 
tory growth of functional tissue elsewhere, than a new injury ensues, and 
in another place, or even in the compensatory new tissue, the whole process 
begins again. Nor is this all-the destruction or distortion of one element 
entails the downfall of another-the tubule is dependent on the glomerulus, 
and the glomerulus on the tubule, both on the blood supply, so that an 
injury anywhere has far-reaching results in this complex organ. SUMMARY 
301 
It is difficult to unravel, then, the anatomical effects of such injuries act- 
ing singly, but far more so when they are combined. A still greater dif- 
ficulty arises, however, when we attempt to estimate the importance of 
these anatomical changes, since we know that the function of the kidney is 
affected so profoundly by alterations of the cell which do not show them- 
selves at all to our eyes, even with the best of microscopes, aided only by 
our present technical methods. 
We recognize certain types of change in each element of the kidneys. 
The tubular epithelium may be swollen and granular in various infections 
and intoxications: the cells in all severer injuries usually become clogged 
with droplets of fat, glycerin, and cholesterine esters, or -with peculiar 
hyaline droplets, or they finally pass through even more profound changes 
and lose their structure, becoming necrotic. These things in one form or 
another are common to all sorts of nephritis. In the lumen of the tubules 
we find fluid holding albumen, and therefore coagulable, granular debris, 
epithelial cells, leucocytes, red blood-corpuscles, and finally curious moulds 
or casts which are hyaline, compressed products of the fusion of all these 
things, characterized often by the adhesion of better preserved leucocytes 
or epithelial cells or granules. Slipping down the tubule, they appear in 
the urine. The glomeruli may have their capillaries obstructed, when 
bacteria or poisons injure them, by thrombi formed from the blood, or by 
masses of leucocytes or proliferated cells. Rigid loops adhere to the capsule, 
the capsular epithelium proliferates to cover these adhesions, or to encap- 
sulate exudate which appears in its lumen. Or, on the other hand, the 
blood may be shut off from these capillaries from a point in the afferent 
vessel at some distance, or by the obstruction of the tubule and the con- 
sequent accumulation of secretion in the capsule, or even by the thickening 
of the capsule with hyaline changes. The end result in every case is the 
impermeability and final obliteration of this complex mechanism. 
The blood-vessels may be sclerotic and thickened, so that their stream- 
bed is narrowed, or, as we have just said, they may be occluded or com- 
pressed, but all these changes lead alike to an obstruction of the blood- 
flow. The framework of the kidney responds to the loss of the structures 
which it supports by an attempt to replace and heal the loss, or it itself 
is injured and heals, often with excess of tissue. It probably plays little 
part in embarrassing and trammeling the tissue of more important func- 
tion, although this idea has so long been held to be true. 
Injuries may occur, and renal tissue be destroyed and removed and re- 
placed by a scar, and yet the remaining tissue will grow to compensate for 
this loss until the kidney resumes perfectly the normal function. If too 
much tissue is destroyed, signs of renal insufficiency will arise, but a rela- 
tively small amount of normal renal tissue will suffice to carry on the nor- 
mal function. Diseased renal tissue, however, is at once inefficient in some 
respects, and symptoms arise to show it. So it is that we may have normal 
function in a kidney in which there are many obsolete scars of an old injury, 
because the remaining tissue is normal and equal to its task, while in other 302 
TEXT-BOOK OF PATHOLOGY 
cases, what seems a relatively slight change, may cause great disturbances 
in function. 
From the changes observed anatomically in human kidneys, it is clear that 
the injury may affect the blood-vessels, including the capillaries of the 
glomeruli, the epithelial cells of the glomeruli and tubules, or even the 
connective-tissue framework, and it has already been seen that the func- 
tional disturbances vary with these different lesions. But what we find 
in the injured kidney is usually a combination of these changes, because 
one entails another in course of time, and it is only rarely that we are able 
to study the very beginning of the disease. Besides, what we see is, for 
the greater part, not the direct effect of the injury, but evidence of a reac- 
tion or response on the part of the tissue. It is true that we can see de- 
structive changes in the epithelium after necrobiotic or fermentative proc- 
esses have combined with the accumulation of the materials of metabolism 
to make them evident, but it is important to bear in mind that extreme 
functional disturbances may result from injuries which produce in the cells 
no changes that we can see. The functional activities of the cells go on in a 
mysterious, invisible way that we may appreciate only by the results, and 
to certain cells there seem to be assigned special duties, even in the course 
of a single renal tubule. Thus Aschoff states that uric acid is secreted in 
the first and second division of the convoluted tubule, while sugar passes 
out through its fourth division or is stored in those cells in the form of 
glycogen. Carmine is secreted in solution, but may be stored in the epi- 
thelial cells in granules. Similarly water and salt are specifically secreted 
by certain cells, which may cease their function long before any morpho- 
logical change is visible in them or resume it without having ever shown 
such a change. 
Of course, when cells are obviously injured or killed and disintegrated, 
their function falls away with them, and glomeruli whose capillaries are 
plugged with clots no longer filter out water, but these are very gross 
changes which we may not find at all in a kidney whose disability is, never- 
theless, extreme. And yet we continue to insist on finding them and 
attempting to correlate them with the functional changes in order to estab- 
lish a classification of renal disease. We must know far more about the 
exact site of functions, and we must be able to disentangle extrarenal 
influences from the actual renal changes before we succeed in this. For 
at most such scars represent areas where kidney substance has been com- 
pletely lost, and they give an indication, therefore, of a possible quantita- 
tive insufficiency of that part which remains. But if, as so often happens, 
the remaining tissue is functioning, but in a perverted way, symptoms 
arise. 
Of these symptoms, perhaps the most common is the excretion of al- 
bumen in the urine, sometimes merely a recognizable trace, sometimes such 
a large quantity that a thick coagulum is formed when the acidulated urine 
FUNCTIONAL ALTERATIONS-RENAL INSUFFICIENCY FUNCTIONAL ALTERATIONS RENAL INSUFFICIENCY 
303 
is boiled. This evidently depends upon some injury to the endothelium 
of the glomerular capillaries, or the renal epithelium, and the wonder is 
not so much that the albumen should appear, but that it should be so 
completely retained by the normal kidney. It is most abundantly excreted 
in the acute stages, and in chronic forms of nephritis in which the injury 
to the structures of the kidney is actively progressing or passing through 
an exacerbation. In the more completed conditions, such as are found in 
the old contracted kidneys, where, although there are great distortion and 
loss of substance, the active injury has ceased, there is little or no albumin- 
uria, although evidences of renal deficiency may persist, and at any moment 
with a new poisoning the albumen may reappear in the urine. 
Red blood-corpuscles and leucocytes, as well as epithelial cells, come 
down the tubules when there is acute inflammation, and hyaline casts 
or moulds of the tubules are an almost constant accompaniment of all the 
more active processes. Exactly what goes to form the casts is not certain, 
but it seems that they must arise from the fusion of many things, including 
the debris of cells, hyaline droplets which are found in the epithelium, al- 
buminous materials, and sometimes fibrin. Adhering cells which are 
better preserved are easily recognized. 
Variations in the amount of water excreted are extreme, and do not 
always accord perfectly with what we should expect from the anatomical 
state of the kidney. Schlayer has attempted to establish the idea that 
this depends upon variations in the sensitiveness of the capillary walls- 
that with increasing severity of the injury there may be at first an increase 
in the sensitiveness, and consequent secretory activity or permeability of 
the capillaries, which results in the excretion of an excess of water, while 
later the more injured wall becomes less sensitive, and oliguria or finally 
complete cessation of urine flow (anuria) results. Aschoff objects to this 
that extrarenal conditions of blood-pressure and blood supply are more 
than sufficient to account for these variations; but it may be that these 
extrarenal conditions themselves affect the sensitiveness of the renal 
capillaries. A disturbance of water and salt excretion, or a deficiency in 
the whole renal activity, as shown by injections of phenolsulphonephthalein, 
may be greatly accentuated by chronic passive congestion. When the 
renal substance is greatly reduced, as in the old contracted kidneys, a great 
amount of water is excreted, with relatively little solids, while actual cessa- 
tion of urine or the excretion of only a little, with high specific gravity, 
accompanies the acute destructive stages. The reasons for these differ- 
ences are not known, but it is suggested that the high blood-pressure and 
rapid stream through the kidneys so characteristic of the contracted stage 
may account for the polyuria, while the specific inability of the glomeruli 
to excrete water, or more probably their specific inability to excrete sodium 
chloride and other inorganic substances, may explain the oliguria or anuria 
of the acuter stages. 
Sodium chloride passes into the urine through the quite specific activity 
of some of the epithelial cells, and when these fail, it is retained in the 
tissues. Since the tissue fluids must remain isotonic for the cells, water is 304 
TEXT-BOOK OF PATHOLOGY 
reserved to dilute this concentrated salt solution, and the consequence is 
oedema, hydrothorax, and ascites. Little doubt can exist as to the nature 
of this nephritic oedema, for if such waterlogged patients are deprived of 
salt in their food and given water in restricted amounts, the oedema quickly 
disappears, to reappear at once if a considerable ration of salt be allowed. 
Thus in the case of a man who entered the hospital with enormous swelling 
of arms and legs and great accumulation of fluid in pleura and peritoneum, 
a salt-free diet restored the normal appearance very quickly. In two 
weeks this man lost 35 pounds in weight, and this experience is practically 
of daily occurrence. Volhard thinks this altogether extrarenal in origin 
and due to changes in the permeability of the vessel walls rather than to 
any change in the secretory ability of the kidney. 
But with this it must not be forgotten that there are often mechanical 
reasons also for the lessened excretion of water. Thrombosis of the glom- 
erular capillaries, or their plugging with leucocytes and endothelial cells, 
as well as their compression by exudate in the capsule, or by proliferation of 
the capsular epithelium, makes them impermeable for the blood and 
directly interferes with their function. Similarly it is conceivable that the 
tubules may be obstructed by desquamated cells and casts, but although 
these things have their part, they are probably not so important as the 
disturbances of the specific function of the secreting cells themselves. 
Nitrogenous substances, such as urea, are often retained in the blood in 
the same way, and although urea itself seems to be a relatively harmless 
material, it has always been thought that the retention of some such sub- 
stances, as yet unrecognized, is responsible for certain general conditions 
which are frequently associated with nephritis. Of these, the most im- 
portant are uraemia and vascular hypertension. 
Urcemia is an intoxication of unknown cause which may arise in connec- 
tion with any sort of nephritis, but is commonest in those in which very 
extensive destruction is quickly produced, and in those contracted kidneys 
in which an extreme diminution of the kidney substance is finally reached. 
It may result in all sorts of nervous and mental disturbances, delirium of 
the most violent sort, delusions, etc., ending in coma or convulsions. The 
name, indicating a retention of urea, does not give a true explanation of its 
cause, and we are still in the dark concerning it. 
Arterial hypertension, in which the systolic blood-pressure may reach 
250 mm. of mercury or more, is a characteristic accompaniment of some 
forms of nephritis. It is found beginning in the acute or subacute stages, 
but reaches its maximum in the more advanced conditions of longer stand- 
ing. Jores thinks that it is particularly associated with the so-called pri- 
mary contracted kidney, with arteriosclerosis, but this does not seem to be 
strictly true, for we have found the highest pressures in cases in which there 
had evidently been inflammatory disease of the glomeruli, and in combina- 
tions of the inflammatory and arteriosclerotic processes. The cause of 
this high blood-pressure is again a mystery. It has been thought to be due 
to the narrowing and obliteration of the blood-channels in the kidney, but FUNCTIONAL ALTERATIONS-RENAL INSUFFICIENCY 
305 
it is clear that ligation of the renal arteries does not elevate the general 
blood-pressure. Nevertheless, compression of the kidneys seems to have 
some effect in this direction, and the gradual reduction of the kidneys by 
their piecemeal removal does produce a permanent rise in blood-pressure 
after a certain proportion of the kidney substance has been destroyed. 
These experiments leave us still with the problem, however, as to whether 
obstruction of the circulation or inefficiency of the kidney is the important 
factor. Schur and Wiesel have thought that chronic nephritis is accom- 
panied by hypertrophy and excessive activity of the adrenals, and that 
constriction of the arterioles by the epinephrine thus produced should 
account for the high tension, but evidence for this is very weak. No one 
has found a sufficient quantity of epinephrine in the blood to support this 
idea. Still, the general opinion is that some sort of vasoconstrictor material 
must be retained in the blood to keep up such a high pressure. The heart, 
especially its left ventricle, becomes greatly hypertrophied, and in time 
even the walls of the vessels thicken their muscular coats. Arteriosclerotic 
changes in the vessels are common, and may play some part in producing 
the high pressure if it can be shown that it causes the narrowing of arterioles 
in general. This, however, is so variable that it does not afford a satis- 
factory explanation. The experiments of Cash, not yet published, seem 
to show that the great reduction of functional kidney substance combined 
with the absorption of dead, renal epithelium forms the basis for the origin 
of the hypertension. Thus the removal of one kidney does not cause hy- 
pertension, but if half or more of the other kidney is rendered necrotic by 
an embolus or by ligature of the vessels the blood-pressure rises, although 
such an infarct without the removal of the opposite kidney has no effect. 
Evidently this condition of extreme reduction of functional kidney tissue in 
combination with continuous, diffuse destruction and absorption of renal 
epithelium is exactly what is found in most of those cases of nephritis in 
which hypertension exists. Albuminuric retinitis, which is a change often 
accompanied by arteriosclerotic modifications of the retinal vessels, and 
marked by the presence of haemorrhages and shining deposits of choles- 
terine in the retina, is very frequent in the course of nephritis. Actual 
blindness may be caused in this way. Acute pericarditis and acute diph- 
theritic enteritis are also frequent terminal affections. 
LITERATURE 
Aschoff: Archives of Internal Medicine, 1913, xii, 723. 
Baehr: Jour. Exp. Med., 1912, xv, 330; Ziegler's Beitr., 1913, Iv, 545. 
Fahr: Frankf. Zeits. f. Path., 1912, ix, 15. 
Frey: Dtsch. Arch. f. klin. Med., 1912, cvi. 347. 
Gull and Sutton: Medico-Chir. Trans., 1872, Iv, 273. 
Harvey: Proc. N. Y. Path. Soc., 1912, xii, 154. 
Herxheimer: Ziegler's Beitrage, 1909, xlv, 253. 
Janeway: Amer. Jour. Med. Sci., 1913, cxlv, 625; Trans. Cong. Amer. Phys. & Surg., 
1913, ix, 14. 
Jores: Dent. Arch. f. klin. Med., 1908, xciv. 306 
TEXT-BOOK OF PATHOLOGY 
Lbhlein: Ergebn. d. inn. Med. u. Kinderh., 1910, v, 411; Arb. a. d. Path. Inst. Leipzig, 
1907, Heft 4. 
Muller, Fr.: Verh. Dtsch. Path. Ges., 1906, ix, 64. 
Ponfick: Verh. Dtsch. Path. Ges., 1906, ix, 49. 
Schlayer: Beihefte zur Med. Klinik, 1912, viii, 211; also several papers in Dtsch. Arch. 
f. klin. Med., xcviii, ci, cii, civ, etc. 
Volhard: Handb. d. inn. Medizin, Mohr. u. Stachelin, Berlin, 1918, iii, 1149. 
Volhard and Fahr: Die Brightsche Nierenkrankheit, 1913. 
Weigcrt: Volkmann's Sammi, klin. Vortr., 162, 163. 
Ziegler: D. Arch. f. klin. Med., 1880, xxv, 586. 
After reading the extremely voluminous literature upon renal disease of the last 
three years I have decided to leave the foregoing chapter as it is. Most of the publica- 
tions have been from German authors and have concerned the classification and espe- 
cially the nomenclature of the different types of renal change. The term "nephrosis," in- 
troduced by Muller to denote degenerative changes of the epithelium without promi- 
nent inflammatory reaction in the glomeruli and elsewhere (the tubular nephritis 
referred to above), was adopted at once by clinicians, but later rejected by the German 
pathologists, with few exceptions. Nephropathia, with various adjectives, has been sub- 
stituted. Little has been added to our knowledge of glomerulonephritis, although in the 
war nephritis there was opportunity to study early stages (Herxheimer). 
The discussion has been chiefly over the nature of the arteriosclerotic contracted 
kidney. Various names have been coined to describe it, and the most recent separates 
it as nephrocirrhosis arteriolosclerotica initialis and progressa into early and late stages 
of a condition in which the thickening and consequent narrowing of the afferent arte- 
riolse of the glomeruli is the primary cause of all the progressive changes (Lbhlein). 
These are to be distinguished from those forms in which focal areas of scarring result 
from arteriosclerosis of the rather larger and more distant vessels (atrophia arterio- 
sclerotica). Lohlein's is by far the clearest paper; all appear to attack Volhard and Fahr, 
who recognized clinically the existence of cases in which the prognosis is good, and 
others in which it is very bad, by the names "benign" and "malign" sclerosis, which were 
equivalent to bland hypertonia and hypertonia + functional defect. In attempting to 
base this on the anatomical state of the kidney they decided that the bland hypertonia 
corresponds with a pure arteriosclerotic disease, while the malign form is due to a com- 
bination of atherosclerosis of the minute arteries of the organ with an inflammatory or 
degenerative factor. To this malign form they gave the name "combination form," and it 
is to this that all the other pathologists object. Jores, Lbhlein, and others conclude that the 
glomerular changes are the direct effect of the arteriolar disease. Lbhlein decides that 
the benign forms are the initial stages of the arteriolosclerotic disease, while the malign 
is due to advanced stages of the same process. Still later Fahr, assuming a position in 
opposition to Volhard, declares the arteriolar changes in the malign sclerosis to be of 
syphilitic nature. Herxheimer, Lbhlein, and others agree that glomerulonephritis is 
often found combined with the changes recognized as due to the sclerosis of the arterioles, 
and accept for these cases the term suggested by Aschoff, "complication forms." It 
seems that much of what Volhard and Fahr described as a combination form might fall 
under this heading. 
The studies of renal function have been carried on chiefly by American workers with 
but little serious consideration of the pathological anatomy of the renal changes in the 
cases studied. They have been chiefly efforts to determine the value of various tests 
of renal function in the diagnosis and prognosis of renal disease, and most of the authors 
agree that these tests are of relative value only. They include the study of non-protein 
nitrogen and urea nitrogen in the blood, the coefficient of Ambard (the ratio between 
the urea of the blood and that of the urine), the power of excretion of water, salt, and 
nitrogen after a standard test-meal, the power of excreting phenolsulphonephthalein 
and other test substances when injected into the blood. No single test gives a clear 307 
FUNCTIONAL ALTERATIONS-RENAL INSUFFICIENCY 
idea of all the disturbances of renal function, and although they are useful in determin- 
ing the degree of impairment of these functions, they scarcely permit of an exact diag- 
nosis of the anatomical condition. 
During the war there were many cases of acute nephritis among 
the soldiers, and the name "trench nephritis" tended to convey the 
idea that a new disease had been discovered. It appears, however, 
that there is scarcely evidence enough for this, and, indeed, it is not 
certain that the same condition is present in all. Bradford, Tytler and 
Ryle, and others describe it as characterized by the rapid appearance 
of dropsy and by the associated bronchitis and dyspnoea. There is 
severe and sudden uraemia, with epileptiform seizures, but the mortality 
is very low. 
Dunn and McNee and Stokes describe acute glomerular changes at 
autopsy with intracapillary accumulation of cells, which resemble endo- 
thelium and often merge into a sort of syncytium. There are no cap- 
illary thrombi, and no changes in the epithelium of the glomeruli. 
The degenerative changes in the epithelium of the tubules are slight, 
but casts and occasionally blood are found there. The lungs show 
oedema, bronchitis, and the hyaline layer in the infundibula and ductuli 
alveolares which was so frequently seen in the lungs of those who died 
in the influenza epidemic. Petechial haemorrhages occur also in the 
brain. 
Pathological Anatomy: 
Fahr: Virchow's Arch., 1919, ccxvi, 119. 
Gaskell: Jour, of Path, and Bact., 1911-12, xvi, 287. 
Herxheimer: Ziegler's Beitrage, 1918, Ixiv, 297. 
Jores: Virchow's Arch., 1916, ccxxi. 
Lohlein: Ziegler's Beitr., 1917, Ixiii, 570. 
Ophuls: Leland Stanford University Publications, 1916. 
Oliver: Jour. Exp. Med., 1915, xxi, 425; 1916, xxiii, 301. 
Functional Changes: 
Christian and others: Amer. Jour. Med. Sci., 1915, cl, 655. Jour, of Urology, 1917, i, 
319. Cleveland Med. Jour., April, 1917. Prog. Med., 1918, iv, 135. 
Fitz: Amer. Jour. Med. Sci., 1914, cxlviii, 330. 
Frissell and Vogel: Arch. Int. Med., 1918, xxii, 56. ; 
Frothingham: Amer. Jour. Med. Sci., 1915, cxlix, 808; 1916, cli, 72. Arch. Int. Med., 
1918, xxii, 74. 
Geyelin: Arch. Int. Med., 1914, xiii, 96. , 
Mosenthal and others: Jour. Amer. Med. Assoc., 1916, Ixvii, 933. Arch. Int. Med., 
1917, xix, i, 329; 1915, xvi, 733; 1914, xiv, 844. 
O'Hare: Arch. Int. Med., 1916, xvii, 711. 
Peabody and others: Ibid., 1916, xvii, 980. 
Trench Nephritis: 
Ameuille: Jour. Urology, 1918, ii, 51. 
Bradford: Quart. Jour. Med., 1915-16, ix, 125. 
Dunn and McNee: Brit. Med. Jour., 1917, ii, 745. 
Tytler and Ryle (with Adrian Stokes): Quart. Jour. Med., 1917-18, xi, 112. 
LITERATURE CHAPTER XVI 
INJURY WITH INFLAMMATORY REACTION AND ATTEMPTED 
REPAIR (Continued).-INJURY AND REPAIR OF THE LIVER 
Cirrhosis of the liver. Structure of the liver in relation to disease. Direct injury to liver- 
cells. Acute yellow atrophy, eclampsia, and infections. Repair and compensatory hyper- 
plasia. Cirrhosis: its various types. The alterations in architecture involved. Obstruc- 
tion of portal circulation. Collateral circulation. Biliary and hypertrophic cirrhosis. 
INJURY AND REPAIR OF THE LIVER 
As in other organs, injury is possible in the liver in all sorts of ways, but 
we shall discuss here more especially those changes which are caused by the 
introduction of the destructive agent by way of the blood-stream or bile- 
ducts. Poisons or infections may enter in these ways, and produce all 
degrees of injury to the liver tissue with many types of reaction. On the 
other hand, the lack of some nutritive substance in the blood, or even the 
mere extreme sluggishness of its course, may be sufficient to disable or 
even to kill some of the liver-cells. As in other organs, the elements which 
make up the liver tissue are not all equally resistant, and it is constantly 
evident that the highly specialized liver-cells are injured or killed by poison, 
which leaves the less delicate gall-duct epithelium perfectly intact and 
capable of growth. The connective-tissue framework and blood-vessels 
are even more hardy, and show little effect from injuries that ravage the 
liver-cells. 
Since in many of the cases which we are about to consider, the noxa 
reaches the tissue by way of the blood, it is clear that if there are any 
peculiarities in the way the blood-stream is distributed there may be cor- 
responding variations in the concentration with which the poison reaches 
the liver-cells. 
Structure of Liver.-The surface of the living organ is uniformly red, but on the death 
of the animal, and especially if the blood be allowed to escape from the large veins, a 
distinct fine lobulation becomes visible because the blood is pushed on in every arterio- 
venous communication to the venous end. On this account the portion about the effer- 
ent vein normally looks red, while the rest is paler, showing the brownish color of the 
liver-cells. If all the blood be washed out, the liver is uniformly light brown. 
These lobules are not sharply marked off from one another, but anastomose in such 
a way that, from the arrangement of the cells alone, it is not easy to say where one 
begins and another ends. Naturally, the lobule should be, as suggested by Sabourin, 
the unit mass of tissue which pours its secretion into a terminal branch of the bile-duct, 
but even there it is difficult to determine how much of the bile-duct shall be adopted 
as belonging to one lobule, and the lobule tends to be a branched mass, forming a mantle 
around the end ramifications of the duct. It has exactly the same relation to the portal 
vein and hepatic artery. This relation is made very distinct in chronic passive conges- 
308 INJURY AND REPAIR OF THE LIVER 
309 
tion when the parts of the liver tissue most distant from the portal vein, that is, nearest 
to the efferent vein, are destroyed (c/. Fig. 147). Unfortunately, the efferent veins 
which receive capillaries from adjacent lobules become so conspicuous from the radial 
way in which these capillaries enter into them that they are almost irresistibly attractive 
in a single section, as the centre of each mass which they drain. A purely artificial 
lobule, set up around the central (efferent) vein, has become the time-honored lobule of 
the fiver, and the more so because in the pig that mass is sharply outlined by fibrous 
tissue. Doubtless we should break away from this conception and speak always in 
terms of the true lobule, but it would cause great confusion and add little of great value. 
Wherever greater clearness can be reached by considering the liver on the basis of 
Sabourin's lobule it will be done. 
Fig. 145.--Diagram of the Ever lobule (Mall). 
The great supply of blood is brought in by the portal vein, but from the capillaries of 
the hepatic artery which unite with those of the portal where they enter among the liver- 
cells, blood under higher pressure gives impetus to the venous stream, driving it forward 
toward the efferent vein. The portal vein may be ligated and its blood diverted into the 
vena cava without causing the death of the liver tissue, and so, too, the hepatic artery 
may be obstructed without effect, but if the smaller branches of the portal vein are 
occluded where the hepatic arterioles join them, the blood supply is cut off from the liver- 
cells and they die. Capillaries once formed, after the union of portal and hepatic ter- 
minals, run in part directly to the efferent veins, but some take a more roundabout course, 
so as to supply liver-cells not lying in that direct line (Fig. 145). The disadvantageous 
effect of this longer course becomes apparent in chronic passive congestion. 310 
TEXT-BOOK OF PATHOLOGY 
The bile-ducts branch minutely so as to connect with the end of each complex cord of 
liver-cells, the bile capillary, bounded on all sides by liver-cells, forming the continuation 
of their lumen. The bile-duct epithelium, although of the same origin as the liver-cells 
and presumably endowed with the same potentialities of specialization, has not become 
so differentiated and remains as less highly organized, but more hardy cells, with the 
simpler function of lining the ducts. 
Direct Injury to the Liver-cells.-With such a distribution of the circu- 
lation it is not surprising that injuries to the cells are often zonal in their 
Fig. 146.-Necrosis of liver-cells about the efferent vein in each lobule: case of strepto- 
coccus peritonitis. 
arrangement. It is true that in many infections practically all the cells 
may appear turbid and cloudy, and in extreme accumulations of fat in the 
liver all the cells may contain globules, but usually such alterations are not 
so uniform. The fat may be lodged especially in the cells nearer the portal 
vein, or, on the contrary, especially in those about the efferent vein. When 
there is actual injury sufficient to kill the cell, it may affect the cells of the INJURY AND REPAIR OF THE LIVER 
311 
zone nearest the portal vein, as in eclampsia gravidarum, or the zone 
farthest from the portal vein, and therefore encircling the efferent vein, as in 
chronic passive congestion, chloroform poisoning, many acute infections, 
especially those in which generalized peritonitis (Fig. 146) or other exten- 
sive and intense inflammations occur, and in all that ill-defined group of 
cases known as acute yellow atrophy of the liver. Sometimes, as Opie 
points out, in intense infections, and especially where a toxic injury is 
combined with bacterial infection, a zone midway between portal and 
Fig. 147.-Chronic passive congestion, destruction of liver-cells extending from one 
efferent vein to another and isolating the periportal tissue. 
efferent vein may be picked out for necrosis. One cannot doubt the deter- 
mining influence of the blood-stream in producing these differences of dis- 
tribution, although it is not always easy to understand it. Opie has shown 
that colored materials injected into the hepatic artery or portal vein during 
the normal circulation tend to lodge in the middle zone, and one might 
imagine that a peculiarly acrid poison could destroy the first cells it im- 
pinged upon, as happens in eclampsia, but how is one to explain the exten- 
sive and often sharply limited necrosis of the cells farthest from the entrance 312 
TEXT-BOOK OF PATHOLOGY 
of the blood, which is so frequently seen in the conditions mentioned above? 
In the case of chronic passive congestion it is probable that those cells 
which receive the blood last are poorly nourished by the stagnating stream, 
which becomes less able to supply oxygen as it reaches the neighborhood 
of the efferent vein. It is interesting that, in this case, as in many infectious 
and toxic injuries, the cells along those capillaries which take a long course 
to empty into the efferent vein suffer throughout a region everywhere 
equidistant from the portal vein and artery, but not everywhere equi- 
distant from the efferent vein. Therefore in these cases the necrotic 
tissue does not merely encircle the efferent veins, but extends from one to 
Fig. 148.-Focal necrosis with invasion and fragmentation of wandering cells: typhoid 
fever. 
another. If we accept Sabourin's lobule, the whole periphery of the lobule 
is necrotic; if we regard the efferent vein as the centre of the lobule, the 
necrotic area occupies the centre of each lobule, and stretches across to 
join that about the centre of each adjacent lobule (c/. Fig. 147). 
But although injury and destruction of liver-cells may often be distributed 
in a zone of each lobule, it is very frequently focal. In numbers of infectious 
diseases, such as typhoid fever, diphtheria, malaria, smallpox, and in pois- 
oning with diphtheria toxin, ricin, abrin, and similar things, one discovers 
small groups of cells situated anywhere in the lobule which have been 
killed and coagulated (Fig. 148). Why those cells should have been picked INJURY AND REPAIR OF THE LIVER 
313 
out for destruction it is not easy to say. Some authors, including Mallory, 
believe that emboli of cells or agglutinated red corpuscles, often supple- 
mented by fibrin thrombi, so occlude the capillaries about a tiny group of 
cells as to deprive them of their blood supply and thus produce an anaemic 
necrosis. In spite of the difficulty of finding another satisfactory explana- 
tion, there is much that seems hardly plausible about this. It is true that 
such cell emboli are often found, but it is hard to believe that they could 
so completely surround a group of cells in the liver as to render it anaemic. 
Even then it would seem that such a small mass of tissue might absorb 
enough nutriment by diffusion to keep it alive. On the other hand, if a 
mass of liver-cells did die, one might expect its capillaries to become throm- 
bosed. 
It would seem that injection of granular material into the mesenteric vein ought to 
decide this question at once. In my hands such injection (corn-starch) does rarely pro- 
duce focal changes which will probably lead to necrosis of the liver-cells, but these are 
in the beginning areas of tearing of the tissue by haemorrhage evidently as the result of 
plugging of the capillaries. In those areas stretched and dismembered cords of liver- 
cells are found; the remainder are pressed back and flattened, but none are necrotic. 
This is very different from the familiar appearance of most focal necroses, in which the 
tissue is not in the least disarranged, but each cell has died where it stood. In all the 
rest of the experiments the grains lodged singly or in groups in the capillaries, without 
producing the least change in the liver-cells. (See further discussion under Typhoid Fever.) 
If chloroform be administered to an animal for an hour or two and its 
liver examined after a time, marked changes are to be found in the liver- 
cells nearest the efferent vein. In case the chloroform has acted mildly, 
these are chiefly evident in the great accumulation of fat, but in other 
animals where it has acted longer or more intensely, these cells are quite 
dead, their nuclei failing to stain, while the cell-body is coagulated and 
deeply stained with eosin. This may be ascertained by excision of a small 
piece of the liver tissue shortly after the poisoning, the animal being left alive. 
After three weeks the liver is found restored to practically its normal 
condition, so rapid is the removal of the dead cells and the regeneration 
of new ones from those which remain. By combining bacterial infection 
with chloroform poisoning Opie has produced much more profound 
injuries which are not so readily repaired. In the zonal necroses which 
accompany intense septic infections a similar anatomical condition is 
produced. All the liver-cells most distant from the portal vein, that is, 
encircling the efferent vein and stretching to the region of the next, are 
necrotic. Nevertheless, in these areas of cell death the endothelial cells 
and connective tissues remain alive. Nearer to the portal vein in each 
lobule is a zone of cells distended with fat-globules, and still nearer the liver- 
cells seem intact (Fig. 146). 
Acute Yellow Atrophy.-This name is loosely given to those cases in which some un- 
known agent suddenly produces a destruction of liver-cells so wide-spread that signs of 
acute insufficiency of the hepatic functions appear. It occurs most commonly in young 314 
TEXT-BOOK OF PATHOLOGY 
women or men, and often in pregnant women, but may also affect children. Sudden 
malaise, symptoms of indigestion, nausea, rapidly deepening jaundice, vomiting of 
blood, delirium, mental dulness, and coma lead to death. The urine is deeply jaundiced, 
but contains also amino-acids in crystal form, such as leucin and tyrosin. At autopsy 
the liver is found very much decreased in size, and very soft and mushy, of an opaque 
ochre yellow color, often with areas of red. In each lobule all the liver-cells, often with 
the exception of those nearest the portal veins, are reduced to a necrotic debris. If, 
as rarely happens, the person survives, regeneration takes place to some extent in a way 
that shall be described. 
It is in such extreme injuries, and perhaps only there, that the liver actually shows 
itself insufficient. This is a point which is far too frequently overlooked by clinicians 
who search for tests of hepatic function to apply to cases in which there may be scattered 
focal necroses, or in which regeneration has restored the normal functional strength of 
the organ. As we shall see, in even the most extreme cirrhosis of the liver there need 
be no functional insufficiency. Icterus is present in the most intense form, doubtless 
Fig. 149.-Haemorrhagic necrosis in the liver in puerperal eclampsia. 
because the columns of liver-cells which form the walls of each bile capillary are inter- 
rupted, so that the bile which is still formed escapes into the blood. Haemorrhages into 
the mucosae and elsewhere are abundant, partly on account of the jaundice, but partly, 
perhaps, because the liver, which is so important in the formation of fibrinogen, has 
ceased that function. The amino-acids in the urine and tissues probably appear in 
large part because they are ordinarily brought to the liver in that form from the intesti- 
nal wall, and finding the deamidizing power of the liver in abeyance, they pass on into 
the general circulation. 
Eclampsia gravidarum is a condition appearing before, during, or after childbirth, 
and accompanied by the most violent convulsions and evidence of the most extreme 
disturbances of metabolism, somewhat similar to those found in acute yellow atrophy. 
Nothing certain is known of its cause, although Schmorl at one time thought that syn- 
cytial masses from the placenta swept into the liver produced the necroses found there, 
while others ascribe them to the action of poisons derived from the foetus or from the INJURY AND REPAIR OF THE LIVER 
315 
placenta. At autopsy the liver is found sprinkled with haemorrhages, which may become 
confluent into great patches (Fig. 149). These haemorrhages correspond with areas of 
necrosis of the liver-cells beginning essentially in the periportal region of each lobule, 
but often becoming confluent (Fig. 150). In and about them, it is true, one may 
sometimes find syncytial masses in the capillaries, but it no longer seems probable 
that this explains the condition, since they occur as well in normal pregnancy. 
In the other infectious and toxic processes mentioned, in which scattered 
focal necroses occur (typhoid fever, diphtheria, etc.), one finds anywhere 
Fig. 150.-Eclampsia gravidarum. Peripheral focal necrosis with haemorrhages. 
in the lobule circumscribed areas in which the liver-cells are dead. Here, 
as in the zonal type, delicate hyaline thrombi are common in the capillaries, 
entangling the many wandering cells which hurry there and which are active 
in dissolving and removing the debris of dead cells. 
Repair and Compensatory Hyperplasia in the Liver.-The liver possesses 
very great powers of repairing losses of its substance. Whipple has shown 
that destruction of the liver-cells throughout two-fifths of each lobule in 
the dog can be repaired in a few weeks by the removal of the dead cells, 
and their accurate replacement without any distortion of the lobule. 316 
TEXT-BOOK OF PATHOLOGY 
Thus the necroses so constant in typhoid fever are healed without an 
appreciable scar. This power belongs not only to the highly specialized 
liver-cells, but also to the epithelium of the bile-ducts, which, if they become 
disconnected from their liver-cell strands by the destruction of some of the 
cells, quickly bridge the gap and reestablish the connection. All these 
cells multiply by mitotic division, and are guided in the direction of their 
growth by the persisting liver framework. Thus, when all the liver-cells 
Fig. 151.-Beginning repair of the liver by sprouting bile-ducts after destruction of all 
the liver-cells in a lobule. 
about the efferent vein of the lobule have been destroyed, numerous karyo- 
kinetic figures can be found in the cells of the adjoining zone, where they 
are so loaded with fat-globules, but are rather fewer in the better preserved 
cells immediately about the portal veins (Fig. 146). 
Often recognizable as young cells by their pale, clear protoplasm and 
convex outline, these fresh liver-cells, together with some of the older ones, 
push their way along the spaces formerly occupied by those which were 
killed, unless those spaces are collapsed and obstructed. If all the cells INJURY AND REPAIR OF THE LIVER 
317 
of the lobule are annihilated, the framework remains, and is often held 
open by the rigidity of the tissue about it (Fig. 151). Then there is no 
source for new liver-cells. Broken ends of bile-ducts w'hich formerly con- 
nected, one with each of these strands of liver-cells, remain uninjured in the 
portal spaces and now grow out with bulbous ends into the framework of 
the lobule toward the efferent vein, that is, in the Sabourin lobule they 
sprout out from the central bile-duct. In the lobule in which the efferent 
vein forms the centre these bulbous bile-ducts appear to grow centripetally. 
There has been much dispute as to whether they can actually produce new 
liver-cells. I believe they can to a limited extent, as shown in Fig. 152, 
where the club-shaped masses were unquestionably liver-cells and new, 
since they contained none of the pigment which was so abundant in all the 
Fig. 152.-Formation of liver-cells by bile-ducts. 
older liver-cells. That they can thus become differentiated seems certain, 
but probably they do so but seldom, and then produce very few liver-cells. 
Melchior thinks this process very important, but it seems that he assigns 
to it cells otherwise produced. 
Thus healing or readjustment of breaks in continuity may be easily 
carried out by the liver-cells and the bile-duct epithelium. It must not 
be supposed, however, that the framework of the liver is always left undis- 
turbed, so that repair can proceed so easily and accurately. It may col- 
lapse when the liver-cells are gone, and become consolidated into a scar- 
like band. Then bile-ducts may push their way into it and new liver-cells 
may be formed there, but their arrangement will not be that of the normal 
lobule. 318 
TEXT-BOOK OF PATHOLOGY 
Perhaps the simplest available example of repair m an extensively injured 
liver is furnished by a case studied some years ago, that of a boy who had 
gone through a severe illness, which may have been acute yellow atrophy 
of the liver, six months before his death. In the mean while, up to his 
death from an infection, he had been fairly well. The liver was greatly 
reduced in size, but contained a tumor-like mass in the right lobe, composed 
of dark-green lobules like 
swollen liver lobules. 
Throughout the general 
liver substance every 
liver-cell had been de- 
stroyed; the framework 
had remained intact with 
the bile-ducts and blood- 
vessels, and from every 
bile - duct branching 
sprouts were growing 
into the old framework, 
although nowhere pro- 
ducing definite liver-cells. 
In the right lobe a por- 
tion of liver tissue had 
evidently been left in- 
tact, and this had be- 
come the tumor-like 
mass by the symmetrical 
enlargement of each re- 
maining lobule. This 
mass, which was finally 
about the size of a small 
orange, must have been 
very much smaller at 
first, and yet it sustained 
life and prevented any 
serious symptoms of he- 
patic insufficiency. This 
exactly corresponds with 
Ponfick's experimental 
results, in which he found that, after removal of a large part of the liver, 
the remainder enlarged by a symmetrical growth of each lobule, new liver- 
cells being formed everywhere by division of the old ones. No rearrange- 
ment of liver-cells, bile-ducts, nor blood-vessels was necessary in this case, 
and we have the effects of a single great injury before us. (Similar cases, in 
which many large nodules of liver tissue are found embedded in a scar-like 
organ, are probably also due to a single injury (Fig. 153). ) 
Fig. 153.-Coarse cirrhosis of the liver with large, 
nodules of regenerating liver-cells. CIRRHOSIS OF THE LIVER 
319 
This is a term applied to an extensive diffuse scarring of the liver which has 
followed the destruction of much of the liver substance. It is regularly 
accompanied by wide-spread regeneration of the functional liver tissue, 
usually sufficient to prevent the appearance of any signs of hepatic in- 
sufficiency. 
There are great difficulties in classifying all the different types of cir- 
rhosis, because, except in about three or four, we are ignorant of their causes. 
The rest we have to classify, then, on the basis of the anatomical and func- 
tional disturbances, which is not very satisfactory. We know that syphi- 
litic and tuberculous infection can produce scars throughout the liver, with 
profound distortion of the organ, and that obstruction of the bile-duct will 
in the end set up a peculiar type of scarring about the bile-duct branches, 
with deep jaundice-but with regard to all the other cases of cirrhosis in 
which these things are readily excluded we are still rather at sea. Of 
course, in the lay mind the abuse of alcohol is held responsible for cirrhosis 
of the liver in a quite unprejudiced way, but although it may well play 
some part, its influence is undoubtedly greatly exaggerated.* Long- 
cope's recent experiments, which show that lesions resembling those found 
in cirrhosis may be produced by repeated anaphylactic shocks caused by 
injections of egg-white or other protein, are most suggestive of an origin 
through protein sensitization and intoxication. But the most accurate 
approach to this anatomical condition has been made by those authors 
(Opie and others) who have combined bacterial infection with various 
poisons, such as chloroform, which destroy liver-cells. Probably it is in 
some such protracted and complex injuries that we shall find the actual 
cause of the disease, but undoubtedly, as in any scar, the same common- 
place result may have a great variety of original causes. The anatomical 
condition of the liver, and the occurrence or absence of certain associated 
disturbances, such as jaundice, obstruction of the portal blood flow and 
ascites, enlargement of the spleen, etc., form the further basis for classi- 
fication of the cases, and we find that the following types may be separated: 
1. The Ordinary Nodular Cirrhosis (Laennec's Cirrhosis; Atrophic or 
Portal Cirrhosis; Hobnail Liver; Alcoholic Cirrhosis, etc.).-Liver rough and 
nodular, tends to be smaller than normal, no jaundice, marked portal 
obstruction, with ascites and enlargement of the spleen. ^Etiology obscure. 
2. Obstructive Biliary Cirrhosis.---Liver enlarged, smooth, or granular. 
Jaundice. Clay-colored stools. Scars following bile-canals. Usually no 
portal obstruction nor ascites, but spleen may be enlarged. Etiology: 
Obstruction of bile-ducts, usually accompanied by infection. 
CIRRHOSIS OF THE LIVER 
* It is misleading to try to determine this relation by estimating the percentage of the 
cases of cirrhosis of the liver in which there has been abuse of alcohol. If, instead, we 
study a great number of chronic alcoholics, we find (Simmonds) a relatively small per- 
centage of cases of cirrhosis of the liver. On the other hand, great accumulation of fat 
in the liver is common in alcoholics. Experimental administration of alcohol to animals 
produces no cirrhosis, even when enormous doses are given over a very long time. 320 
TEXT-BOOK OF PATHOLOGY 
3. Hanot's Cirrhosis, or Primary Hypertrophic Biliary Cirrhosis.-Liver 
large, smooth, diffusely and finely scarred. Jaundice, with no gross ob- 
struction of bile-ducts; bile-stained stools; no portal obstruction; splenic 
enlargement. ^Etiology obscure, possibly an infectious process. 
4. Syphilitic Cirrhosis, Congenital or Acquired.-In the congenital form 
the liver may be large, smooth, and diffusely scarred, or it may present 
gummata which later become scarred. In the acquired form gummata 
heal with large scars, producing deep grooves and lobulations in the liver. 
No jaundice; no marked portal obstruction. 
5. Tuberculous Cirrhosis.-Especially with tuberculosis of peritoneum, 
producing thickening of Glisson's capsule, with constriction and distortion 
Fig. 154.-Diffuse nodular cirrhosis of the liver. 
of the organ. In another form with many tubercles in the liver the process 
is somewhat like the syphilitic. 
There are unquestionably many other types, for any injury recovered 
from and healed may leave its trace in the form of a cirrhotic process. 
1. Diffuse Nodular Cirrhosis.-In the ordinary cirrhosis one finds the 
liver hard and stiff-sometimes larger than normal, but generally shrunken 
and deformed and roughened all over by projecting nodules of a yellowish- 
brown or chestnut-brown color (Fig. 154). The capsule is generally thick- 
ened and sometimes finely granular, but through it one can see that the 
shrunken tissue between the nodules is gray and translucent, often showing 
little veins in the depths of the depressed areas. It is hard to cut, and in CIRRHOSIS OF THE LIVER 
321 
extreme cases creaks or cries under the knife. The cut surface shows just 
the same appearance-rounded or irregular nodules of liver tissue of 
variable size projecting as little plateaus from the gray, translucent ground- 
work. Every kind of variation in the appearance of these nodules may 
occur (Fig. 155); sometimes they are all quite small and uniform, more 
often some of them are larger, and these tend to be pigmented or bile 
stained; occasionally they are all very large,-even as large as marbles,- 
and widely separated by a rather loose, vascular connective tissue. In 
Fig. 155.-Irregular nodular cirrhosis with ascites. Half of liver. 
some cases the liver substance forms the great bulk of the organ, so that 
scars can be traced through it with difficulty; in others the whole organ 
seems to be composed of solid elastic fibrous tissue, with only scattered 
pockets of greenish or brown granular liver substance embedded at inter- 
vals through it. The liver tissue itself may be made up of quite normal- 
looking cells, or the cells may be loaded with fat or pigment, or be actually 
on the way to necrosis and disintegration. 322 
TEXT-BOOK OF PATHOLOGY 
All these variations are of subordinate importance though, and further 
study shows that in principle these cases are all very similar. Large iso- 
lated masses of liver appear when only widely separated groups of cells 
have been spared and have been allowed ample time to regenerate as much 
liver tissue as possible. Small, closely packed nodules result when destruc- 
tion has occurred in smaller foci, and some portion of nearly every lobule 
has survived. Even the most casual examination shows that these nodules 
have no longer anything like the normal arrangement of the lobules. They 
are not, as a rule, isolated nodules, for reconstruction of serial sections 
shows that they are almost all connected together into an irregular net- 
work, but they have lost their regular relation to the original portal veins, 
bile-ducts, and hepatic veins. They no longer even approach uniformity 
in size, nor can one find a central vein in each. Instead, they generally 
Fig. 156.-Cut surface of the liver; nodular or Laennec's cirrhosis. 
appear in section as smooth, finely granular, almost velvety, solid masses of 
liver-cells and nothing more. 
Microscopical study confirms all this (Figs. 157, 158). Everywhere in 
the section there are found patches of liver-cells arranged in a most dis- 
orderly fashion. All bear evidence of having been enlarged by the mul- 
tiplication of their cells, so that the arrangement with reference to portal 
and efferent veins is all that will tell us whether we have the enlargement 
of a whole lobule or of an isolated group of cells. In the latter case the 
patch will have no portal and no efferent vein immediately connected with 
it, but is merely a conglomeration of liver-cells with intervening capillaries 
which have grown into a perfect labyrinth, and allow the passage of blood 
with some difficulty. The whole lies surrounded by vascular connective CIRRHOSIS OF THE LIVER 
323 
tissue, in which there are many wandering cells, and in which one can see 
numerous tortuous bile-ducts. Very often one can make out in this tissue 
what must have been the efferent vein which originally drained the lobule 
of which we have just considered the hypertrophied remnant, and, indeed, 
this vein doubtless still drains that overgrown remnant (Fig. 159). Portal 
veins are also visible, but they are commonly in no clearly recognizable 
relation to the liver-cells, but lie quite far away in the intervening tissue. 
So, too, the original bile-ducts can be seen, but there are many other sinu- 
Fig. 157.-Nodular cirrhosis of the liver. The low-power drawing shows the irregular 
arrangement of the remaining liver tissue and the distribution of the newly formed bile- 
ducts. 
ous channels lined with epithelium which branch abundantly and which 
one may trace into connection at one end with the bile-duct, at the other 
with a strand of liver-cells in one of the nodules (Fig. 160). 
There has been much dispute as to their nature, and they have been 
thought by many to be compressed liver-cells, but everything goes to show 
that they are bile-ducts, for the greater part newly formed from the stumps 
of those which were left, and now growing to reestablish connection with 
the liver-cells. The slight part they play in the new formation of liver- 324 
TEXT-BOOK OF PATHOLOGY 
cells has been mentioned. Of course, in any such strand of tissue as we 
find between the nodules of liver-cells a great many bile-ducts, portal 
veins, etc., are concentrated together through the collapse of many lobules 
whose skeleton framework goes to form a large part of the strand, but the 
newly formed ducts can usually be recognized. 
One might trace out the fate of any isolated portion of a lobule which 
remained after the devastation of the rest in this process, but the process of 
reestablishment of relations is the same no matter how much or how little 
of the original lobule remains. It is as though groups of liver-cells were 
transplanted into a vascular tissue rich in bile-ducts. They acquire the 
Fig. 158.-Nodular cirrhosis showing atypical arrangement of liver-cells in each nodule. 
best vascular connections possible for their situation, and the ends of the 
strands unite with the sprouts of bile-ducts which approach them, after 
which the liver-cells multiply as fast as possible to produce a larger nodule, 
which will compensate in function for the cells which were destroyed. 
There is no evidence of the compression of the liver-cells by the fibrous 
tissue in which they are growing-rather one might say the fibrous tissue 
is pushed aside and compressed by them. Nor is there any justification 
for the term lobular cirrhosis, since, as we see, it is by no means a question 
of the enveloping of lobules in fibrous tissue. Although many conflicting CIRRHOSIS OF THE LIVER 
325 
views have been held, it seems clear enough that the injurious agent effects 
the destruction of the liver-cells in the first instance, and that the scarring 
and the hyperplasia of the epithelial remnants are reparatory processes. 
Very commonly the liver-cells are quite normal in appearance and 
function, and doubtless they are so for weeks and months at a time. If 
the attacks of the injurious agent could be stopped, there is no reason why 
compensatory hyperplasia should not go on until the organ had once more 
its full complement of cells in an abnormal arrangement. But they are, 
of course, as always, susceptible to injury, and for that reason they are 
Fig. 159.-Nodular cirrhosis with very great hyperplasia of the liver-cell nodules. Ob- 
serve the distorted relation of portal and efferent veins to the liver tissue. 
often found at the death of the individual, loaded with fat or injured in some 
other way. Some of these injuries may be of the series which is still at 
work, adding to the changes which bring about the cirrhosis, but others 
may be independent, and we might expect to find focal necroses in the 
liver-cells of a man who has long had a cirrhotic liver and who dies of 
typhoid fever. 
The whole condition is brought about in exactly the same way as the 
scarring of the kidney with compensatory hyperplasia. The liver-cells 
are killed in patches-whole lobules and groups of lobules at a time, or 326 
TEXT-BOOK OF PATHOLOGY 
only parts of lobules. There remain irregular masses of liver tissue partly 
disconnected from their bile-ducts. The framework of the rest of the 
tissue collapses and shrinks, and is kept in that position by the growth of 
new fibrous tissues, but through that tissue blood still streams readily. 
The bile-ducts which were interrupted by the death of the liver-cells 
send out sprouts which attempt to connect again with liver-cell strands. 
The masses of liver-cells quickly increase in size by multiplication of their 
cells, new capillaries are formed in every direction, and this labyrinth of 
Fig. 160.-Cirrhosis of the liver showing the reunion of bile-ducts with the liver-cells. 
cells expands, pressing the stroma away on all sides. For a time the liver- 
cells are normal, but then comes another injury, and many of the hyper- 
plastic nodules are partly destroyed. The whole process is repeated, and 
not only once, but many times. It is clear that this must lead to an extra- 
ordinary distortion of the liver's structure. There are no longer lobules, 
but only nodules produced by the hyperplasia of smaller groups of cells 
which were left intact. CIRRHOSIS OF THE LIVER 
327 
Obstruction of the Portal Flow.-With advancing cirrhosis of the liver it becomes 
difficult for the portal blood to pass through, and all the branches of that vein come to be 
distended, sometimes even to the point of bursting. The organs which are drained by 
them are swollen and blue from the stagnation of venous blood, and their function is 
disturbed. Digestion is impaired, and the spleen becomes greatly enlarged. Fluid 
filters through into the peritoneal cavity, and the ascites accompanying cirrhosis may 
be of the most persistent. 
Why so much obstruction should occur is not as simply explained as might appear at 
first sight. With the great reduction in the size of the liver much of the stream-bed is 
doubtless obliterated. The rigidity of the scarred organ may prevent the normal dis- 
tensibility of the blood-vessels, but the capillaries of the scarred bands are still more 
easily injected than those of the regenerated nodules of liver tissue. In the liver nodules, 
on the contrary, the tortuous course of the new capillaries offers an increased resistance 
to the flow of blood. 
Herrick* has offered the explanation that the communications between the hepatic 
artery and the branches of the portal vein become far wider than normal in the cirrhotic 
liver, so that the high arterial pressure is communicated directly and obstructs the out- 
flow from the veins, much as it does in an arteriovenous aneurysm. The long-continued 
overdistension of the portal branches is sometimes partly relieved by the widening of 
certain communications between the portal system and the branches of the vena cava, 
which always exist but are normally too small to be of any use. These are well de- 
scribed by Charcotf and are diagrammatically shown in Fig. 161. They are: 
1. Anastomoses between the left coronary vein of the stomach and the oesophageal 
veins which open into the azygos or intercostals. These communicating channels often 
become enormously enlarged (oesophageal varices), and may burst into the oesophagus, 
with fatal results (Fig. 162). The coronary vein may also anastomose with superior 
or inferior diaphragmatic veins. 
2. Anastomoses exist between branches of the inferior mesenteric vein, the superior 
haemorrhoidals, and branches of the internal iliac veins, the inferior haemorrhoidals. 
These are apparently not especially efficient, and haemorrhoids are said not to be common 
in cirrhosis. 
3. The veins of Retzius, which originate in the walls of the intestines and through a 
little trunk empty into the vena cava or one of its branches. 
4. The veins of Sappey, or accessory portal veins, which originate in some organ other 
than the digestive tract, and, after forming a trunk, reach the liver and ramify in its 
substance. Some of them are quite useless in establishing a collateral circulation, as, 
for example, those which connect the omentum or the gall-bladder with the liver, or 
those which constitute the vasa vasorum of the portal vein, hepatic artery, and bile- 
ducts. But the veins of the suspensory ligament which unite with those of the dia- 
phragm are useful. So, too, are the para-umbilical veins (Umb C, Fig. 161), whose 
roots communicate with the epigastric, the internal mammary, and the subcutaneous 
abdominal veins. They enter the liver along the obliterated umbilical vein, and are dis- 
tributed to the lobules along the longitudinal groove, to the portal vein to the left of 
the umbilical ligament, or to the still permeable part of that ligament. They are im- 
portant channels of communication, and sometimes appear in their swollen state under 
the skin of the abdomen radiating from the navel (caput medusae). 
Of course, other collateral channels arise through the formation of adhesions between 
the abdominal organs and the walls of the abdomen, and they are often intentionally 
produced for this purpose by an operative procedure (Talma's operation). 
At times the collateral circulation reaches an efficiency which allows the patient to 
live on without ascites or symptoms of chronic passive congestion, but usually it is not 
* F. C. Herrick: Jour. Exp. Med., 1907, ix, 93. 
t Charcot: Maladies du Foie, Paris, 1882. 328 
TEXT-BOOK OF PATHOLOGY 
so complete. Jaundice in the type of cirrhosis described above is rare, and when it does 
occur, is probably due to some accessory cause. 
Fig. 161.-Diagrammatic representation of the collateral circulation established in 
cirrhosis of the liver (from Charcot): 1, 2, 3, 4, 5, Accessory portal veins of Sappey; 
7, 7, 7, veins of Retzius. The organs are viewed from behind. 
2. Obstructive Biliary Cirrhosis.-It has been shown experimentally 
(Vaughan Harley, Ogata, and others) that, in certain animals at least, the CIRRHOSIS OF THE LIVER 
329 
occlusion of the bile-ducts results in the destruction of some of the liver- 
cells and in the formation of scar tissue in their place. This is especially 
striking in zones about the portal veins and bile-ducts, and in these zones 
numerous new bile-ducts sprout out. The addition of infection to the 
mechanical stasis of the bile intensifies the process. The same thing is 
Fig. 162.-Collateral circulation in cirrhosis. (Esophageal varices with rupture and 
fatal haemorrhage (liver of this case shown in Fig. 155). 
true in human beings when the hepatic or common duct becomes obstructed 
by a gall-stone or by a tumor-growth. Jaundice results promptly, and 
the liver becomes swollen and deep green in color. After this obstruction 
has lasted some time slight irregularity of its surface arises, and on sec- 
tion delicate scars can be seen. There is rarely time for the development 330 
TEXT-BOOK OF PATHOLOGY 
of any such extreme changes as have been described for the diffuse nodular 
cirrhosis. The spleen becomes enlarged, but there is, except in advanced 
cases of long standing, no obstruction to the flow of portal blood. In a 
man aged fifty-five jaundice appeared and quickly deepened to a dark, 
greenish bronze color. At the autopsy several jack-stone-shaped black 
gall-stones were found in the gall-bladder, at the fundus of which a small 
cancer had developed. A secondary growth from this lay embedded in 
Fig. 163-Biliary cirrhosis. 
the liver in such a way as to surround and compress the hepatic ducts as 
they left the liver-below this the ducts were normal; within the liver 
they were distended to a phenomenal degree. The liver was deep green, 
flabby, and coarsely lobulated, although only slightly wrinkled on the 
surface. Even on section there was no great departure from the regular 
lobulation. Microscopical study showed each larger bile-duct twig and 
portal vein surrounded by a loose scar tissue infiltrated with leucocytes, CIRRHOSIS OF THE LIVER 
331 
and rich in young, sprouting bile-ducts, evidently growing out to join the 
remaining liver-cells after the destruction of many of those nearest the 
portal space (Fig. 163). 
Apparently in the cases of longest duration a great deal more distortion 
of the liver may occur, but it does not approach that seen in the previous 
type. 
3. Primary Biliary Hypertrophic Cirrhosis (Hanot's Cirrhosis).-There 
exists much confusion as to what Hanot actually meant to include in his 
type of hypertrophic cirrhosis with icterus and without ascites, but Heineke 
Fig. 164.-Hanot's cirrhosis. 
describes it as a change resulting from the inflammation of the minuter 
bile-ducts, and producing a fine, almost intercellular, scarring throughout 
the liver, with its enlargement-enlargement of the spleen, fever, but no 
portal obstruction. There are other cases in which there is the same deep 
jaundice but no evident inflammation of the bile-ducts (Kretz), and still 
others in which there is no jaundice. Nevertheless, in these too the liver 
is found greatly enlarged, hard, and smooth, and on section no definite 
lobulation whatever can be made out. Microscopically there is found a TEXT-BOOK OF PATHOLOGY 
332 
finely diffused network of scar tissue all through the tissue, separating the 
lobules into little groups of cells (Fig. 164). 
LITERATURE 
Ackermann: Pathol. Bindegewebsneubild. in der Leber, Berlin, 1894. 
Ford: Amer. Jour. Med. Sci., 1901, cxxi, 60. 
Heineke: Ziegler's Beitrage, 1897, xxii, 259. 
Kretz: Verh. Dtsch. Path. Gesellsch., 1904, viii, 54; 1905, ix, 260. International 
Clinics, 1905, iii, fifteenth series, 289. 
MacCallum: Johns Hopkins Hosp. Reports, 1902, x, 375. Jour. Amer. Med. Assoc., 
1904, xliii, 649. 
Meder and Marchand: Ziegler's Beitrage, 1895, xvii, 143. 
Ogata: Ziegler's Beitrage, 1913, Iv, 236. 
Opie: Jour. Exp. Med., 1910, xii, 367. 
Ponfick: Virch. Arch., cxviii, cxix, cxxxviii. 
Ribbert: Deutsche med. Woch., 1908, xxiv2, 1678. 
Vaughan Harley: Brit. Med. Jour., 1898, ii, 1743, 
Whipple: Jour. Exp. Med., 1911, xiii, 136. CHAPTER XVII 
FURTHER ILLUSTRATIVE EXAMPLES OF DESTRUCTIVE AND 
REPARATIVE PROCESSES 
Arteriosclerosis. Structure of arteries. Anatomical changes in arteriosclerosis in aorta 
and other vessels. Pathogenesis and cetiology. Syphilitic arteritis in aorta and smaller 
vessels. Obliterative endarteritis. Thromboangeitis obliterans. Aneurysms, various types; 
their effects and their relation to syphilis. Apoplexy; location of haimorrhage in brain. 
ARTERIOSCLEROSIS 
Structure of Arteries.-The structure of the arteries changes as we pass from the aorta 
into the branches and finer ramifications. Everywhere, however, there is, as in the 
case of the veins and lymphatics, a lining membrane composed of a single layer of flat- 
tened endothelial cells which offers a smooth surface and acts as a protection for the 
blood against any contact with other tissues. 
In the aorta the outer wall or adventitia is composed of a loose connective tissue carry- 
ing blood-vessels, nerves, etc., and containing a loose network of elastic fibrils. The 
middle coat or media is composed of elastic tissue, smooth muscle, and connective tissue. 
The elastic tissue which forms the most prominent feature is arranged in a complex of 
laminae, with fibrils which run obliquely and connect the laminae. In a cross-section 
one sees the main circular strands of elastic tissue about equidistant from one another, 
running with a somewhat wavy course around the vessel, and connected by numerous 
oblique, bridge-like fibres; but since in a longitudinal section one sees exactly the same 
thing, it seems evident that were the elastic tissue isolated, one might discern something 
roughly approaching the form of a series of imperfect concentric tubes. It seems to be 
about as though one should paste on a sheet of paper, one after another, pieces of gauze 
irregular in size and outline, gluing only their edges where they happen to fall, until a 
uniform thick layer is produced, and then make a tube of the whole, except that each 
piece of gauze, where it stands away from the underlying and overlying pieces, should be 
connected with them by many oblique threads. In a tangential section of the media 
the muscle-fibres, instead of being perfectly circular in their course, form a sort of her- 
ringbone pattern, and are surrounded everywhere in the same meshes by loose white 
fibrous tissue. 
There is a vague outer condensation of the elastic fibres which might be called the 
external elastic lamella, but at the inner margin of the media there is a continuous mem- 
brane, uninterrupted except for certain fenestrations, which would correspond to the 
sheet of paper in the model-the internal elastic lamella. It is difficult to decide whether 
this should be taken as part of the media or part of the intima, but it is more convenient 
to consider it with the latter. Blood-vessels, the vasa vasorum, springing from the 
roots of the intercostal arteries, etc., penetrate the adventitia and extend part way 
through the media. 
The intima of the aorta, which in very early life seems to show little but the endothe- 
lial layer resting upon the internal elastic lamella, develops in later life a much more 
complex structure. Just inside the internal elastic lamella there is a layer composed 
partly of smooth muscle running longitudinally, and partly of fibres and lamellae of 
elastic tissue which are abundantly connected with the fenestrated membrane. This 
is the musculo-elastic layer inside which a second layer may generally be distinguished, 
333 334 
TEXT-BOOK OF PATHOLOGY 
composed of similar elastic structures intermingled with white fibrous connective tissue. 
Within this is a third layer immediately beneath the endothelium, which is made up of 
connective tissue alone, the cells of which show beautiful branching processes. Although 
with the advance of age the intima thus becomes progressively thicker (Jores), it is 
normally a very thin layer as compared with the media. 
The branches of the aorta and smaller vessels differ from this in their structure, 
especially in that the elastic tissue of the media is far less abundant, so that the smooth 
muscle becomes the predominant element of that layer. The elastic tissue is for the 
most part concentrated in a layer between the muscular media and the adventitia, where 
it forms an exaggerated external elastic lamella. The radial fibres of Diirck, which run 
irregularly from the internal elastic lamella to this outer layer, are more clearly seen in 
the arteries of medium size than in the aorta. They can be stained by special methods, 
and probably differ somewhat from the elastic fibres proper. They act apparently as 
dilators of the vessel. 
In the smaller arteries the intima becomes simplified until finally, in the very small 
vessels, the endothelium lies almost directly upon the internal elastic lamella. Never- 
theless, in many small arteries, especially in such organs as the kidney, stomach, etc., 
the internal elastic lamella splits in the third decade into three or four concentric layers, 
between which are connective-tissue elements. It will be seen that much attention has 
been devoted to this reduplication of the elastic lamella; in the discussion of arterio- 
sclerosis. In accord with these differences in structure between the aorta and smaller 
vessels we may expect differences in their pathological alterations. 
Arteriosclerosis is the term in most general use for that disease of the 
arteries which leads to their loss of elasticity, and changes in the appear- 
ance and structure of the intima and other coats which lead to dilatation 
and deformity of the artery. The condition is sometimes spoken of as 
atheroma of the arteries, and there is much in favor of the name athero- 
sclerosis, suggested by Marchand, but the old term, endarteritis deformans, 
of Virchow, is now but little used. 
We may consider in turn: Arteriosclerosis (properly so called), syphilitic 
arteritis, endarteritis obliterans, although doubtless this list is far from 
exhausting the list of related vascular changes. 
ARTERIOSCLEROSIS PROPER 
The earliest changes recognizable in the aorta as the beginning of arterio- 
sclerosis are found in the form of very slightly elevated, flattened yellow 
streaks, which usually run on the posterior wall of the vessel, longitudinally, 
between and about the openings of the intercostal arteries, although they 
are not by any means confined to this position (Fig. 165). With further 
advance of the disease these yellow patches are to be found diffusely dis- 
tributed among the older lesions. Sections passing through them show 
that, while the artery is normal elsewhere, the elevation is due to a distinct 
thickening of the intima produced by a new formation of connective tissue, 
with small and large wandering cells (Fig. 166). Both the original branched 
connective-tissue cells and the wandering cells are found to be loaded with 
fat. Such fat is by no means lodged only in the deeper layers of the in- 
tima, but extends up to the surface, where the fat-laden wandering cells 335 
ARTERIOSCLEROSIS proper 
Fig. 165.-Fatty streaks and patches in the intima of the aorta. 
Fig. 166.-Section through a fatty streak in the aorta. (The fat is stained red with 
Sudan.) 336 
TEXT-BOOK OF PATHOLOGY 
lie free in crevices. If the upper layer of the intima be stripped off and 
laid flat under the microscope, the branched connective-tissue cells with 
their fine fat-droplets can be well seen. 
In a later stage the hillock of thickened intima becomes more extensive 
and thicker, and the tissue becomes hyaline or necrotic about the most 
abundant accumulation of fat. The superficial or innermost layers be- 
come very much thickened, and are now composed of a dense, homogeneous 
connective tissue (Fig. 167). Rarely do the vasa vasorum penetrate from 
Fig. 167.-Margin of a relatively fresh arteriosclerotic plaque. 
the media to take part in this new formation of tissue, and generally they 
can be found only in the later stages, although it is stated that injections 
reveal an increased richness in the vascular supply about the patches of 
disease. Nor is there any invasion of wandering cells at all commensurate 
with the new formation of tissue. The dense connective tissue formed 
over the mass of fat containing tissue is bluish white and translucent. It 
covers the yellow, opaque, fatty material, so that it now appears to lie in 
the depths of the intima, encroaching on the musculo-elastic layer and the ARTERIOSCLEROSIS PROPER 
337 
internal elastic lamella. When such an aorta is opened, the most common 
and characteristic appearance of arteriosclerosis is revealed (Fig. 168). 
Elevated rounded or irregular plaques or patches stand up from the intimal 
surface like solidified drops of paraffin. They are often about the orifices 
of the intercostal arteries, but may occur anywhere. They seem hard and 
homogeneous, but on cutting through them there is always to be found the 
mass of opaque, yellow, fatty material hidden in their depths. From the 
cut edge this yellow mass can be expressed or dug out, and its soft, mushy 
character was the origin of the name atheroma. Often the fat extends 
so as to form a yellow halo about such a 
plaque, the opaque material shining through 
the relatively thin surrounding intima. 
At this stage the internal elastic lamella 
underlying the plaque generally shows frag- 
mentation or interruptions, or it is frayed 
out into several thin laminae which again 
unite at the other edge of the plaque. This 
is best seen in the smaller arteries (Fig. 169), 
but is visible also in the aorta, and is re- 
garded by Jores as the most characteristic 
feature of true arteriosclerosis. Usually the 
longitudinal muscle-fibers of the musculo- 
elastic layer are involved in the necrosis in 
the depths of the plaque, and in great part 
destroyed. Delicate elastic fibrils appear 
in the new tissue which forms inside the 
musculo-elastic layer, and are thought by 
Jores to arise independently of the lamellae 
of that layer. They are, he thinks, more 
characteristic of such changes as occur in 
the obliteration of vessels in inflammatory 
processes or in the organization of thrombi 
than of the true arteriosclerotic changes. 
The media under the plaque, which, for 
the sake of the various theories which have 
been put forward, has been studied with 
especial care, generally shows surprisingly slight alterations. Very definite 
thick plaques may form in the intima, while the underlying media seems 
practically intact, although we realize, of course, that ordinary staining 
methods may well fail to reveal qualitative changes in the elasticity of the 
elastic tissue or the contractility of the muscle. Nevertheless, there are often 
slight accumulations of fat in that layer, and it is generally thinner under 
the plaques than in neighboring regions. Indeed, such thinning out may, 
especially in the smaller vessels, proceed almost to the complete disappear- 
ance of the coat, leaving us to determine whether this is the primary injury 
168.-Arteriosclerotic plaques 
in the aorta about the intercos- 
tal arteries. 338 
TEXT-BOOK OF PATHOLOGY 
to the vessel-wall which is compensated for by the formation of the plaque, 
or the result of pressure from the plaque itself. Again, we have to deter- 
mine whether the necrosis which occurs in the substance of the plaque is 
due to malnutrition of the central part of that mass of tissue or to primary 
injurious processes affecting the newly forming tissue. The time-honored 
explanation has been that nutrition from the vasa vasorum on the one 
side, and from the blood in the main vessel, on the other, kept alive the 
outermost and innermost layers of the plaque, while allowing the centre to 
Fig. 169.-Sclerotic plaque in the mesenteric artery, showing reduplication of elastic 
lamellae. Lipoid substances are stained red with sudan. 
perish (Fig. 170). At any rate, the central mass often becomes very soft, 
so that if the inner wall or roof of this sac gives way, the contents are 
washed out into the blood-stream and the ragged edges and base of such 
an "atheromatous ulcer" are exposed to the circulating blood, often with 
the result that a thrombus forms in that situation. 
The soft material is found to be rich in crystals of cholesterine as well as 
globules of fat, some of which are evidently cholesterine esters, since they ARTERIOSCLEROSIS PROPER 
339 
Fig. 170.-Section of an older sclerotic 
plaque in the aorta, showing cholesterine 
crystals in the necrotic atheromatous sub- 
stance. 
Fig. 171.-Late stage in arterioscle- 
rosis of the aorta: ulceration and cal- 
cification. 340 
TEXT-BOOK OF PATHOLOGY 
are doubly refractive, while others are neutral fats. Granules or little 
spherules or larger, irregular masses of calcium and magnesium phosphates 
also appear, and, indeed, the deposit of calcium salts may be so great that 
the whole plaque becomes converted into a solid plate of stony material 
which will crack with a dry snap, like a scale of oyster-shell (Fig. 171). 
Such plates correspond, of course, fairly well with the contour of the artery, 
although they project awkwardly when the vessel is laid open. Usually 
they are smoothly covered with a delicate layer of intimal tissue and en- 
dothelium; otherwise they form a base for the deposit of thrombi. Actual 
Fig. 172.-Calcified plaque in arterial wall with bone and bone-marrow formation. 
bone formation may occur, with marrow cavity and marrow rich in cells, 
either in calcified plaques in the vessel-wall or in old calcified thrombi which 
adhere to it (Fig. 172). 
The sequence of events which leads to the presence of crystals of cholesterine, granules 
and masses of calcium, etc., has been explained by Klotz and others as follows: Glycerin 
and cholesterine esters are deposited in the tissue of the plaque, but readily split up and 
become saponified, with liberation of the soluble glycerin and crystalline cholesterine. 
Of the soaps formed, with the resultant fatty acids, calcium soaps are insoluble, and 
remain where they are formed until the advent of phosphates in the circulating fluids, 
whereby another reaction occurs which leaves the calcium in the form of hard calcium 
phosphate. ARTERIOSCLEROSIS PROPER 
341 
It must be obvious, from this description, that since all these stages 
may and frequently do occur at one time in the same aorta, the most 
variegated appearance is produced. Smooth, rounded, gray eminences 
scattered along the aorta, and especially about the orifices of the intercostal 
and other arteries, are interspersed with irregular yellow patches of stain- 
ing of the relatively unthickened intima, while atheromatous ulcers and 
Fig. 173.-Arteriosclerosis of the renal artery showing fat-laden wandering cells in the 
thickened intima. 
sunken, calcified remnants of former atheromatous plaques occur side by 
side with them. Sometimes the calcification is so extensive that the aorta 
is converted into a rigid tube. 
In all cases there is very great diminution of the elasticity of the artery 
wall, although its rigidity may be increased. Usually the aorta in ad- 
vanced sclerosis is dilated and lengthened so that it curves from one side 
of the vertebral column to the other, and bulges irregularly at different 342 
TEXT-BOOK OF PATHOLOGY 
points. Distension of such an artery reveals the rigidity and inelas- 
ticity of the affected parts of the wall, while other places may still be quite 
elastic. 
Exactly the same processes in the same sequence are found in the 
branches of the aorta (Figs. 173, 175). In these branches, in comparison 
with the calibre of the vessel, the intimal plaques may be far thicker, so that 
they go far toward obstructing the channel. It is by no means rare that 
the lumen of such an artery as the superior mesenteric or the splenic is 
reduced to a mere slit for a short way as it passes the projecting mass. 
Fig. 174.-Lower layer of the intima from Fig. 173, showing the musculo-elastic layer 
(a) and the fat-holding wandering cells in crevices (b). 
A cross-section at such a point reveals the misshapen lumen crowded over 
to one side of the artery, and bounded on one side by the normal wall of the 
vessel, with its wavy internal elastic lamella, on the other by a great mass 
of tissue over the outer side of which the media stretches as a thinned-out 
layer and the internal elastic lamella as a tense straight line. The blood- 
pressure in the distal part of such a vessel must be greatly reduced, and 
yet one may find a series of plaques of this kind ranged along its course. 
The smaller ramifications of the arteries in the organs often show particu- 
larly well such relatively huge masses of new tissue bulging out one wall, 
and encroaching greatly upon the lumen. The endothelium accommodates ARTERIOSCLEROSIS PROPER 
343 
itself to the decreased surface it must cover, and is seen to be intact until, 
through its injury or otherwise, a thrombus completes the occlusion of the 
vessel. Calcification of the necrotic and fatty plaque occurs, exactly as in 
the aorta. 
This process may occur in the arteries of the extremities, where it seems 
to be especially common in cases of diabetes, and may, by causing the 
narrowing of the vessels and their final occlusion by secondary thrombosis, 
Fig. 175.-Coronary artery encroached upon by a thick arteriosclerotic plaque. 
give rise to the senile and diabetic forms of gangrene. Other changes in 
the peripheral arteries are, however, often concerned in the production of 
gangrene, and we shall describe them later in discussing obliterating end- 
arteritis. 
A special form of sclerosis of the peripheral arteries which gives them the 
appearance of being ringed, like a trachea, with stony concretions, was 
distinguished by Monckeberg, although known long before. In this con- 344 
TEXT-BOOK OF PATHOLOGY 
dition, which is found chiefly in the arteries of the lower extremities, the 
lesion begins in the media, where degenerative and destructive changes in 
the muscle-cells, associated with the deposit of fat-droplets, are followed by 
calcification, which appears first in the form of granules of lime salts, which 
Fig. 176.-Femoral artery 
showing transverse rings of 
medial calcification (Moncke- 
berg's sclerosis). 
Fig. 177.-Medial sclerosis of Monckeberg in a 
femoral artery in longitudinal section. The calcified 
rings are seen in cross-section. 
later become welded together into irregular rings which may even occupy 
the whole thickness of the media. Such zones, which are often beaded by 
further concretions, sink below the level of the adjacent more normal intima 
when the vessel is opened (Fig. 176). The internal elastic lamella is ARTERIOSCLEROSIS PROPER 
345 
stretched straight over them, as though they had solidified while the vessel 
was at its maximum dilatation. In many cases, however, they are by no 
means so regular, but press through and interrupt and distort the elastic 
lamella (Figs. 177, 178). Granulation tissue of a cellular sort arises to sur- 
round them, and extends through the breaches in the lamella into the region 
of the intima. Sometimes actual bone with marrow cavities and red marrow 
forms in these places by a metamorphosis of the calcified material through 
Fig. 178.-Monckeberg's medial calcification in a peripheral artery. 
the production of osteoblasts from the granulation tissue. The intima is 
often, but not always, thickened over the calcified rings, sometimes with 
great fraying out of the internal elastic lamella and loss of the recognized 
relations, but there is rather little evidence of necrosis or the accumulation 
of fat in such a thickened layer. It appears on section rather more like a 
granulation tissue, and often contains blood-vessels or spaces. This 
comparatively common condition does not tend specially toward the 346 
TEXT-BOOK OF PATHOLOGY 
obliteration of the vessel, which is rather dilated and lengthened so as to 
fall into sinuous curves, readily seen in x-ray photographs even through the 
shadows of the bones. 
Monckeberg regards it as independent of true arteriosclerosis, since it 
differs from that condition in the slight changes in the intima and in the 
extreme alterations of the media. Its existence in the peripheral arteries 
does not signify that there are arteriosclerotic changes in the internal 
arteries and aorta. Nevertheless, it is frequently combined with arterio- 
sclerosis in the form of extensive intimal thickening, and it is then difficult 
to separate the two processes if, indeed, they are really different. Occa- 
sionally extraordinary masses of new tissue may be formed inside the in- 
ternal elastic lamella in such a way as almost completely to block the 
lumen. Such obstructing tissue, which converts the artery into an ex- 
tremely thick-walled tube with pin-point lumen, generally extends only a 
short way, so that the vessel opens out again into a wide tube. Several 
such strictures may be found in a single artery, suggesting that they may 
have been due to the organization of thrombi with secondary canalization, 
although they can be equally well explained as arteriosclerotic thickenings 
of the intima. Such changes commonly lead to great reduction of the 
blood supply of the extremity and gangrene of the toes or foot, and it 
is probably this type of change which most frequently occurs in diabetic and 
senile gangrene. 
Pathogenesis and Etiology.-We are at present, in spite of numerous 
theories, practically ignorant of the cause of arteriosclerosis. Rokitansky 
thought the plaques deposited from the blood; Virchow regarded the whole 
process as inflammatory, whence his designation, endarteritis deformans; 
Koster also regarded it as inflammatory, but rather in Cohnheim's sense, 
as an exudative process, because he traced the formation of a cellular exu- 
date in the vessel-walls from the vasa vasorum. Thoma elaborated a 
theory based on the idea that the cutting-off of the placental circulation at 
birth must necessitate an adaptation of the calibre of the blood-vessels to 
the changed amount of blood. This, he thought, was effected by a thick- 
ening of the intima of the vessels, especially those which lay in the course 
of the old umbilical blood-stream. To this process there might be com- 
pared the thickening of the intima in arteriosclerosis, which evidently 
occurs at those points, where, owing to some primary weakening of the 
musculature of the media, there arose a local bulging of the vessel-wall. 
In such a bulging area the passing blood-stream would eddy and be re- 
tarded, whence the intimal growth, which should be just sufficient to 
compensate for the bulging-out of the media and thereby reinstate the 
original level of the intimal lining of the vessel. Naturally, such a patch 
would be thrown into relief by the elasticity of the arterial wall after it is 
laid open. It is evident that many criticisms of this theory may be offered. 
In general there has prevailed insistently the idea that the changes in 
the vessel-wall are due in some way to heightened arterial blood-pressure. ARTERIOSCLEROSIS PROPER 
347 
The favorite situation of the lesions in the arch and about the orifices of 
the branches has been explained on the ground that pressure relations at 
those points constitute a more severe test of the strength of the wall than 
at other points in the aorta. Marchand, Aschoff, and others look upon 
arteriosclerosis as a degenerative process, brought about largely by the 
overworking of the vessel-wall, due to heightened blood-pressure (sudden 
strains, Albrecht). They see in the connective tissue a substance more 
rigid and less distensible than the elastic tissue, which at least maintains 
the strength of the wall. Aschoff finds the weakening due to degenera- 
tive changes in the intima, with its elastic lamella, and not, as Thoma 
supposed, to primary changes in the media. 
Jores described the progressive thickening of the intima with the normal 
advance of age, and declared that such a thick intimal coat is especially 
prone to degenerative changes which occur at the level of the musculo- 
elastic layer. The reformation of the elastic tissue by repeated splitting 
off of lamellae from the internal elastic lamella is characteristic of true 
arteriosclerosis, as contrasted with the obliterative changes in the vessels 
where the elastica is formed in new, delicate, independent fibrils in the 
new tissue of the intima. 
The present state of our knowledge is unsatisfying, but it seems that 
we are far from having proved that the heightening of blood-pressure as 
such has more than a guiding influence upon the development of the lesions, 
just as the structure of cancellous bone and other tissues is adapted in 
growth to the strain put upon it. It is true that Klotz claims to have pro- 
duced arteriosclerosis in rabbits by hanging them head downward for a 
long period, but rabbits are notoriously subject to spontaneous arterial 
lesions, and Lubarsch and others have been unable to confirm his results. 
Arteriosclerosis sometimes occurs in the pulmonary artery in cases of 
mitral stenosis, or in the arch of the aorta in cases of stenosis of the aorta 
at the isthmus, but it is often absent in these cases, and there are other 
explanations than the high pressure to offer when it does occur. It is 
common in cases of nephritis when the pressure is high, but there again we 
are unable to say that it is the high pressure per se which is responsible 
for the disease of the arterial wall, and not some other factor which may 
have caused the nephritis. There are many cases of arteriosclerosis 
without high blood-pressure, even though the walls of the arteries may 
be very much altered. In these it is clear that the cause of the sclerosis 
must be sought in some other factor. 
It seems more probable that, as the French have so long suggested, ar- 
teriosclerosis is the effect of some injurious or poisonous agent acting 
upon the intima of the arteries, as it might upon any other organ, with 
destruction, fat accumulation, and repair. What this agent may be is 
as yet uncertain. Every sort of poisonous substance has been experi- 
mentally administered to animals either by mouth or by injection into the 
blood-stream or tissues, but without any very constant results. The 348 
TEXT-BOOK OF PATHOLOGY 
setiological factors commonly held responsible, alcohol, lead, nicotine, etc., 
have occasionally given rise to changes comparable to those of arteriosclero- 
sis, but not constantly-indeed, with alcohol and lead the experiments 
have generally proved negative. Adrenalin (Josue and others) will pro- 
duce medial lesions and calcification, with corresponding intimal scars in 
rabbits, and various bacterial toxins, especially those extracted from 
staphylococci (Saltykow), give rise to changes even more closely resem- 
bling those of arteriosclerosis. But so far none of these substances can be 
set down as the proved cause of the condition. Recent Russian observers 
-Chalatow, Anitschkoff, etc.-have found that cholesterine and its esters, 
on being fed to rabbits, lodge in the intima of the aorta and produce tissue 
proliferation there, resembling those of arteriosclerosis. On the other 
hand, the idea asserts itself that since repeated anaphylactic shocks may 
produce lesions in liver and kidneys (Longcope), they may also cause 
injuries to the arterial walls. All these things are yet in the experimental 
stage, but it seems probable that long-continued and oft-repeated injuries, 
such as might arise during chronic infections, chronic intoxications, or in 
sensitive animals from repeated absorption of the sensitizing protein, 
may constitute the underlying cause of injury, which is responded to by 
reparatory processes and by an accumulation of fats and fatty acids which 
may be protective. 
Anitschkoff: Ziegler's Beitrage, 1913, Ivi, 379. 
Aschoff: Beihette z. med. Klinik, 1908, 4, 1. 
Faber: Arteriosklerose, Jena, 1912. 
Hubschmann: Ziegler's Beitrage, 1906, xxxix, 119. 
Jores: Wesen der Arteriosklerose, 1908. 
Klotz: Arteriosclerosis, Publ. Univ. Pittsburgh, 1911. 
Longcope: Jour. Exp. Med., 1913, xviii, 678. 
MacCallum: Physiological Reviews, 1922, ii, 70. 
Marchand: Verb. d. XXL Cong. f. inn. Med., 1904. 
Monckeberg: Virchow's Arch., 1903, clxxi, 141; 1914, ccxix, 408. 
Saltykow: Ziegler's Beitrage, 1908, xliii, 147. 
Thoma: Virchow's Arch., xciii, xcv, civ, cv, cvi, cxii, ccxvi. 
Thorel: Ergebnisse der allg. Path., ixi, xia, xiv2. 
LITERATURE 
SYPHILITIC ARTERIAL DISEASE 
For the sake of convenience, and because of the confusion which has existed 
for so long between syphilitic disease of the artery and true arteriosclerosis, 
that condition may be described here. Other infectious agents cause 
disease of the vessels of a more or less specific character, but none lead to 
such important alterations as syphilis. It affects the aorta as well as the 
smaller vessels, and is then apparently the commonest original cause of 
insufficiency of the aortic valves, as well as aneurysm formation. In 
itself, without these ultimate effects, it may often be recognized during 
life by certain clinical phenomena, such as the reflex respiratory disturb- 
ances described by Longcope. 
Since its recognition by Doehle and Heller, and especially since the SYPHILITIC ARTERIAL DISEASE 
349 
papers of Chiari and Benda, syphilitic disease of the aorta has come to be 
quite clearly understood, because the aetiological factor, the Spirochaeta 
pallida, has been found in the lesions, and even made to produce similar 
lesions in animals. Then, too, the anatomical changes are quite comparable 
with those produced by syphilis elsewhere, and are sometimes distinctly 
gummatous in character. They are found in all three coats of the vessel, 
and affect the vasa vasorum as well. In the adventitia, and extending 
into the media or even into the intima, there are found around these vasa 
vasorum collections of wandering cells of the character of lymphoid and 
plasma cells, sometimes with multinucleated giant-cells. The vasa vaso- 
rum are often obliterated in this process. The cellular granulation tissue 
Fig. 179.-Syphilitic aortitis. Gummatous foci about vasa vasorum in the adventitia 
and media. Frequent breaks in the media. 
may occupy considerable space, and may even be evident on the surface 
of the artery as a nodular mass. Such are, clearly enough, gummata, 
for they tend to become necrotic in their centres and present, in general, 
the architecture of gummatous nodules seen elsewhere. Nevertheless, it 
is more common to find mere collections of cells of less characteristic 
arrangement in the adventitia and media. They often surround necrotic 
foci, or are found side by side with quite extensive necrosis of the media. 
One sees sometimes patches of necrotic media in which the arrangement 
of the elastic lamellse and muscle is still visible, as in an anaemic infarction, 
and about these there forms the cellular granulation tissue. Later such 
necrotic patches are absorbed and scarred, a process which adds to the 
distortion of the artery. If the artery be examined at this stage, which is 350 
TEXT-BOOK OF PATHOLOGY 
the one most commonly seen at autopsy, the media will be found to be 
interrupted repeatedly by irregular strands of scar tissue rich in wandering 
cells, and when the elastic tissue alone is stained, one receives the impression 
that that layer is composed of mere fragments or clumps of elastic fibres 
strewn along at intervals. Such interruption of its continuity must greatly 
weaken the aortic wall, and goes far to explain the ready development of 
aneurysms on a syphilitic basis. Over such a tattered media the intima 
is found to have formed a thick, irregular layer of hyaline fibrous tis- 
sue, in which there is relatively 
little fat to be found (Fig. 179). 
Cholesterine crystals and calcium 
deposits are equally rare, unless, 
of course, as frequently happens, 
the syphilitic disease is developed 
in an aorta already the seat of a 
true arteriosclerosis. In the syph- 
ilitic intimal thickenings the in- 
ternal elastic lamella shows no 
such regular fraying up into ac- 
cessory lamellae as is seen in 
arteriosclerosis. It suffers whole- 
sale interruptions and destruction 
with the rest of the elastic coats. 
The gross appearance of the 
aorta is most clearly to be under- 
stood on the basis of these micro- 
scopical changes. There is a great 
roughening of the lining, which is 
thrown up into irregular folds and 
nodular swellings, some translu- 
cent and pearly, others yellowish 
and opaque where there is fat ac- 
cumulation. But nowhere is there 
any formation of calcified plates 
nor any ulceration. Beginning 
usually at the aortic orifice, and 
generally involving the aortic 
valves, this change is most commonly found in the arch and extending 
downward into the descending aorta, where it usually stops abruptly at 
a point somewhere above the orifices of the abdominal vessels. Rather 
rarely it extends below these, and the rest of the vessel is smooth and 
elastic, or there is a sharply outlined patch in only one part of the 
vessel. The aortic valves are thickened and shortened, so that they 
become insufficient, and the aortic ring is widened, intensifying the in- 
competence of the valves. A further characteristic of the appearance of the 
Fig. 180.-Syphilitic aortitis, showing a 
peculiar irregular scarring of the wall of the 
aorta with sharp demarcation. 351 
OBLITERATIVE ENDARTERITIS THROMBOANGEITIS OBLITERANS 
intima is its peculiar wrinkling. It is thrown into longitudinal rugae, 
quite unlike anything seen in arteriosclerosis (Fig. 180). Thinned out and 
scarred areas are frequently seen in the walls, and dilatations of all sorts, 
from small saccules to aneurysms of the hugest size, may accompany the 
later stages of the disease. The orifices of the intercostal vessels may be 
partly occluded, and even the carotids may be narrowed at their mouths. 
This encroachment on the lumen of the branches of the aorta is most 
important in the case of the coronary vessels, which may be constricted 
at their origin to a very small calibre, since it seems probable that it is 
in some cases responsible for the symptoms of angina pectoris. 
In the smaller arteries and veins, such as those of the meninges, syphilis 
causes changes which are much like those produced by tuberculosis, in that 
minute gummata are formed in the walls, growing in the adventitia and 
intima, and destroying the intervening media in such a way as to produce 
an excentrically placed nodule, which greatly narrows the lumen and ap- 
pears as a little pearly lump in the course of the vessel (Heubner, Nonne, 
Verse, Goldsborough). Such lesions of the meningeal vessels are usually 
accompanied by a definite cellular meningitis, similar to that caused by 
tuberculosis, and in which the wandering cells are predominantly of the 
mononuclear types. The most varied clinical symptoms result, as one 
may read in the monograph of Nonne. 
LITERATURE 
Benda: Handb. d. Geschlechtskrankh., 1913, iii. 
Chiari, Benda: Verh. Dtsch. path. Gesellsch., 1904, vi, 137, 164. 
Dohle: Dtsch. Arch. f. klin. Med., 1895, Iv, 190. 
Goldsborough: Johns Hopkins Hosp. Bull., 1902, xiii, 105. 
Gruber: Doehle-Heller'sche Aortitis, Jena, 1914. 
Longcope: Arch. Int. Med., 1913, xi, 14. 
Nonne: Syphilis und Nervensystem, 1902; second edition, translated by Ball, 1913 
Verse: Ziegler's Beitrage, 1913, Ivi, 580. 
Wright and Richardson: Publ. Massachusetts Gen. Hosp., 1909, ii, 395. 
It has been pointed out that typical arteriosclerotic thickening of the intima 
may narrow or almost obliterate small arteries in some cases, and that 
calcification of the media, often associated with such internal changes, may 
also do this. There are still other physiological and pathological methods 
of occlusion which are especially important in the small vessels when the 
mechanics of the circulation or the protection of the body requires their 
obliteration. In the embryo one channel survives in a plexus of vessels' 
because the others are closed by the mere adhesion of their walls when blood 
is no longer forced through. When the course of the circulation changes, as 
it does after birth with the enlargement of the pulmonary stream-bed, the 
old channel through the ductus arteriosus is gradually closed by a growth 
of the intimal tissue which narrows the lumen. This method is probably 
the one used in the slow obliteration of the blood-vessels in the atrophy of 
OBLITERATIVE ENDARTERITIS-THROMBOANGEITIS OBLITERANS 352 
TEXT-BOOK OF PATHOLOGY 
such organs as the breast, uterus, and ovaries in which, after sexual activity 
is over, the blood supply is diminished. Nevertheless in these vessels calci- 
fication of the media is frequently seen (Fig. 181). In other situations 
chronic inflammatory processes throughout the tissue are accompanied by 
a gradual occlusion of the small blood-vessels by a slow thickening of their 
intima by the new formation of connective-tissue cells beneath the endo- 
thelium. It is difficult to draw a sharp line between the narrowing of 
vessels because of the lack of an adequate blood-stream, and this effect of 
Fig. 181.-Wall of senile uterus: obliterative endarteritis with calcification. 
surrounding injury and inflammation. Such "obliterating endarteritis" 
is common in the shrunken kidney of chronic nephritis, in indurative affec- 
tions of the lungs and other organs caused by tuberculosis and syphilis, 
in some tumors, and in a host of other sites of protracted injury and irrita- 
tion. Sometimes, as in the advance of a tuberculous cavity or in the wall 
of a gastric ulcer, the closure of an artery which is being encroached upon 
may be a life-saving event. It is only when the excavation proceeds too 
rapidly and surprises the vessel that great haemorrhages occur in chronic 
phthisis. OBLITERATIVE ENDARTERITIS-THROMBOANGEITIS OBLITERANS 
353 
The plugging of a vessel by a clot or thrombus often has a protective significance in 
that it abruptly obstructs the flow of blood. It is the natural method of stanching 
haemorrhage, and although it may be ineffectual when a large vessel is cut, it successfully 
closes the torn ends of the small ones. When a vessel is ligated, a clot forms at the point 
of the ligation and extends to the next branch, where the blood-stream is still active. 
If the wall of the vessel is injured, the stream may continue until the lumen is filled by 
the clot which forms on the walls. Since this is formed in the moving blood it will have 
the character of a thrombus. When a vessel is obstructed at a point by a thrombus so 
that the lumen is open on each side, efforts are made to reestablish the circulation. The 
thrombus is " organized " by the springing up of capillaries and connective tissue from the 
vessel-wall which replace it with a vascular granulation tissue. Crevices in its substance 
are lined with endothelium and constitute new blood spaces. The dilatation and 
anastomosis of these new vessels and blood spaces may produce new channels which will 
again carry blood through the obstructed area. They are in time supplied with muscular 
and elastic coats like those of any other vessel (Fig. 182). A vessel thus reinstated seems 
like an elastic cord, but from its cut end many fine streams of blood spurt. 
Fig. 182.-Vein with old thrombotic occlusion recanalized by new blood-channels, 
Thrombotic occlusion with organization appears to play a prominent part 
in another form of obliterating endarteritis which occurs in the arteries of 
the extremities. Von Winiwarter described the obliteration as due to pro- 
liferation of soft tissue from the intimal coat, while Zoege von Manteuffel 
and Weiss thought it essentially the result of thrombosis with organization. 
Apparently both processes can occur, and in the end-result it is difficult 
to determine exactly how the obliteration occurred, although it is easy to 
distinguish these obliterated vessels from those which have been obstructed 
by arteriosclerotic thickenings of their walls. This can be made clear by 
describing the process as it affects the peripheral arteries. 
In some cases in relatively young people, and principally in Russian 
Hebrews, serious symptoms arise without any warning, beginning with 
coldness and pallor of the extremities, pain and peculiar tickling or burning 
sensations, inability to walk more than a short way without rest, and 354 
TEXT-BOOK OF PATHOLOGY 
finally gangrene of the toes or of the whole foot or leg. The inability 
to walk, which is called intermittent claudication, is explained by the fact 
that the arteries of the extremities are practically pulseless, and converted 
into a firm cord, so that not enough blood reaches the muscles to allow 
them to contract properly. 
In these cases x-ray pictures show no shadow of the vessels whatever, 
and, indeed, they are usually found not to be calcified. On section, too 
Fig. 183.-Obliterating endarteritis (thrombo-arteritis obliterans) with shrinkage of the 
walls and partial recanalization. 
(Fig. 183), they present an extraordinary contrast to those found in senile 
and diabetic gangrene, inasmuch as there is little or no change in the media, 
although it and the adventitia and surrounding tissue may be infiltrated 
with wandering cells and indurated by the new-growth of fibrous tissue. 
Nor is the internal elastic lamella stretched, distorted, and frayed out, as in 
that more truly arteriosclerotic process. Instead, it maintains its normal ANEURYSMS 
355 
wavy contour around the lumen of the vessel. But the lumen is filled with 
vascular granulation tissue, sometimes with endothelium-lined spaces, 
through which a little blood may flow. 
In this case, too, there is a question as to whether the obliteration is due 
to a growth of tissue from the intima or to the organization of a thrombus, 
but thrombi are so generally present in all stages that Burger concludes 
definitely that it must be named thromboangeitis obliterans. The ob- 
struction is generally accompanied by the formation of adhesions between 
the vessel and the surrounding tissue, and although no definite ideas as 
to its causation are to be found in the literature, it seems probable that 
it is of infectious or toxic nature. 
Burger: Amer. Jour. Med. Sci., 1908, cxxxvi, 567. 
Von Winiwarter: Arch. f. klin. Chir., 1878, xxiii, 202. 
Weiss: Dtsch. Zeitschr. f. Chir., 1894, xl, 1. 
Zoege von Manteuffel: Arch. f. klin. Chir., 1898, xlvii, 461. 
LITERATURE 
A difficulty has always existed in deciding exactly wThat constitutes an 
aneurysm, since there are so many different forms of enlargement of the 
artery and cavities in connection with arteries which might fall under this 
name. There has long been a distinction between true aneurysms, in 
which the cavity was supposed to be formed by the stretching of the wall 
of the artery itself, and spurious aneurysms, in which rupture of the artery 
wall opened its lumen into a blood-filled cavity formed in the tissue outside. 
But since it has been shown that in all cases the wall of the sac is formed 
of tissue of a character very different from that of the normal arterial wall, 
this distinction is anatomically no longer so valid, although naturally the 
conditions set up in these ways are in principle very different. Benda has 
tried to cut this knot by saying that an aneurysm is any pathological 
widening of the arterial lumen caused by change in its walls, which for a 
time, at least, stands in open communication with its blood-stream. 
The most common aneurysms are saccular widenings of the artery, 
opening out from its regular channel by a wide or narrow orifice, but the 
opening may be so wide, and the distension so shallow, that the saccular 
form is lost, and if, as sometimes happens, the widening occupies the whole 
circumference of the artery, we have a fusiform aneurysm or aneurysmal 
dilatation. Aneurysms of these types occur in diseased arteries in many 
situations. They are most common in the aorta, especially in the region 
of the arch, but may arise in any part of its course or in any of the smaller 
arteries-even in those which lie embedded in the substance of an organ. 
Generally classed with aneurysms are certain peculiar widenings and 
enlargements of the blood-vessels, which also increase their length so that 
in a given area a whole mass of wide, tortuous, and tangled, pulsating 
ANEURYSMS 356 
TEXT-BOOK OF PATHOLOGY 
vessels is found {cirsoid or racemose aneurysm). One is inclined to suspect 
that this rare form may be of a 
nature more allied to that of angi- 
omatous tumors, and distinct from 
ordinary aneurysms. 
Dissecting aneurysms are produced 
by the rupture or tearing of the inner 
coats of the artery-usually the in- 
tima and half of the media, and the 
extravasation of the blood into a 
cavity which it makes for itself by 
burrowing into the wall of the 
artery. In sclerotic arteries it is 
easy to split the wall in this way, 
and the blood may work its way 
down the whole length of the aorta 
and along many branches, convert- 
ing each partly or completely into 
two tubes, one within the other, 
and separated by the extravasated 
blood (Fig. 184). After this the 
blood may break through the outer 
tube and accumulate somewhere in 
the tissues, or again through the 
inner tube, thus reentering the 
regular circulation. Except in the 
last case the whole process is really 
merely the formation of a haemor- 
rhage or haematoma in the artery 
wall, but it sometimes happens- 
and I have seen one case*-that 
when the rupture back into the 
lumen of the vessel takes place, the 
extravasated blood actually circu- 
lates, and the space in the wall be- 
comes lined by endothelium, so that 
something like a double aorta is 
produced (Fig. 185). 
Arteriovenous Aneurysm.-Occa- 
sionally when a stab wound or the 
wound produced in venesection 
opens an artery and a vein side by 
Fig. 184.-Dissecting aneurysm of 
aorta splitting the arterial wall far into 
the branches. A haematoma near the bi- 
furcation of the aorta. 
* MacCallum: Johns Hopkins Hosp. 
Bull., 1909, xx, 9. ANEURYSMS 
357 
side, a hsematoma or massive extravasation of blood into the tissue appears, 
and later retains its communication with both vessels, so that the blood 
Fig. 185.-Old dissecting aneurysm which has ruptured again into the aorta and 
established a double aortic channel. 358 
TEXT-BOOK OF PATHOLOGY 
circulates through it from the artery into the vein. Such a cavity forms a 
dense, fibrous wall for itself, and the communication is permanent. In a 
Fig. 186.-Arteriovenous aneurysm caused by a stab wound of the femoral artery 
and vein. 
case seen in Baltimore the femoral artery and vein communicated in this 
way through a great sac. There was a loud, humming murmur, and a ANEURYSMS 
359 
thrill over this sac, and the pressure of the arterial blood into the vein 
prevented the return of the venous blood from the leg. On the shin of that 
leg there were great varicose veins, and a persistent varicose ulcer, quite 
like those seen in old people, although the other leg of this boy was per- 
fectly normal. 
In other cases, the so-called false aneurysms, the artery alone is ruptured, 
and the haematoma becoming encapsulated, remains in open communica- 
tion with the blood-stream, being constantly washed out by an eddy of 
blood. 
Of all these, it is evident that the most important and interesting form 
is that which develops through disease of the arterial wall by a gradual 
bulging out of some portion into a sac, or widening of other form. As to 
the aetiology, we are even yet insufficiently informed, although the work of 
Doehle, Heller, Benda, Chiari, and others on syphilitic aortitis has thrown 
much light on it. There is great diversity of opinion as to the part played 
by syphilis, for although Heller found 85 per cent, of aneurysms to be due 
to syphilis, Braun, in a very large collection, found only 17 per cent. 
Marchand, too, finds the percentage of proved syphilis rather low. Never- 
theless, the character of the syphilitic disease of the arterial wall, which is 
so preeminently calculated to weaken it in the presence of a strong blood- 
pressure, makes it seem probable that more accurate methods of investiga- 
tion will show the participation of that disease in a very large proportion of 
the cases, if not in all, and our experience, which includes the study of 
an especially large number of aneurysms, tends to impress us with the con- 
viction that all are due to syphilis. Since the recognition of syphilitic 
aortitis every case has been readily shown to depend upon this affection. 
Of course, it must be remembered, however, that encroachment of destructive 
tuberculous processes may weaken the outer wall of an artery and allow the production 
of a small aneurysm, just as the advance of a gastric ulcer toward such an artery as the 
splenic may allow it to bulge and finally rupture in the base of the ulcer. So, too, 
emboli of bacteria may weaken the arterial walls, and multiple "mycotic" aneurysms 
appear, while certain parasitic nematodes living inside the arteries in the same way pro- 
duce aneurysmal dilatations (strongyle infection in the horse). 
The general character of an aneurysm may be made clear by the de- 
scription of one of the commoner forms-the saccular aneurysm of the 
aorta. In such a case (Fig. 187) it is found that the sac most commonly 
springs from the convexity of the arch, and that intense arteriosclerotic 
alterations of the aorta surround its mouth. The orifice is round or 
irregular in outline, and the edge is rolled over into it somewhat, so as to 
almost overhang its cavity. The cavity itself may reach a very great size, 
the sac thus formed pushing aside the surrounding organs or embedding 
itself in them in the most remarkable way (Fig. 188). Mechanical effects 
produced in this way are of great variety, depending largely upon the point 
of origin and size of the sac. Pressure on the recurrent laryngeal nerve pro- 
duces an alteration of the voice from spasm or paralysis of the vocal cord, 360 
TEXT-BOOK OF PATHOLOGY 
coughing, dyspnoea, etc. Pressure on the trachea flattens it and causes 
dyspnoea-later, the aneurysm may rupture into it, after eroding its wall. 
The lungs yield and collapse before the aneurysm. Pressure on a bronchus 
narrows it, and behind the obstruction bronchiectasis arises. When the 
sac reaches the bony structures of the thorax, which do not yield, it ham- 
mers its way through them, appearing under the skin through a hole in 
Fig. 187.-Aneurysm of aortic arch. Aortic valvular insufficiency, probably syphilitic. 
A second aneurysm in the dorsal aortic wall. 
the ribs or sternum. If it extends backward to the spine, it destroys the 
centra of the vertebrae even down to the spinal canal (c/. Fig. 29), leaving the 
yielding intervertebral discs standing almost unaltered-in the same way it 
may break through the ribs in the back and appear under the skin there. 
Then it is not long before the skin becomes thinned out and bluish, and ANEURYSMS 
361 
finally the sac ruptures, so that death follows at once. Often it ruptures 
long before reaching the skin-into the pleura or pericardium, trachea, or 
oesophagus, or even into the superior or inferior vena cava. 
The character of such a sac which can produce a huge and destructive 
tumor, which destroys itself as soon as it completes its advance, must be 
interesting. It is not really composed of the stretched-out walls of the 
vessel, for microscopic examination with suitable stains shows that prac- 
Fig. 188.-Saccular aneurysm projecting between the aorta and the heart. Its orifice 
shows in the aorta. 
tically all those elements stop sharply at the edge of the orifice (Fig. 189). 
The elastic tissue and the muscle are suddenly interrupted. Endothelium 
may persist and attempt to line the sac, but it is evident that it soon fails 
in this and is lost. Indeed, nothing but connective tissue, and that essen- 
tially new formed, goes to make up the sac. It grows largely by new 
breaks in the wall which seem to be made good by further formation of 
fibrous tissue. The current of blood eddies about in the cavity, and its 362 
TEXT-BOOK OF PATHOLOGY 
pulsation gives the sac its power of breaking down the resistance of the 
tissues. But the endothelial lining is imperfect, and thrombosis occurs, and 
if time be allowed, as it so often is, layer after layer of compact thrombus 
material may be hammered down on the wall of the sac until it is in large 
part filled up (Fig. 190). Occasionally the aneurysm may be completely 
obliterated in this way. The character of the fibrous wall is such that little 
Fig. 189.-Edge of a small aneurysm, showing the abrupt cessation of the elastic 
tissue at the margin of the sac. One wall of an adjacent vein is seen at the bottom of 
the drawing. 
upgrowth of organizing granulation tissue into the thrombus appears, 
and the lower layers become even more compact, until, on a smoothly cut 
section, they look like onyx. The wall itself becomes hyaline, and it is 
often impossible to say, in a microscopic section, where the wall ends and 
the thrombus begins. In the smaller and fresher aneurysmal sacs the 
wall, wrinkled and irregular, is generally shining, thick, and rather trans- ANEURYSMS 
363 
lucent, and quite uncovered with thrombi or covered with only the merest 
film. 
Quite the same characters are found in aneurysms in the abdominal aorta 
or its branches, in the arteries of the extremity or the head. Sometimes 
several small ones occur side by side, even in the aorta; sometimes when 
one in a peripheral artery has been cured by operation, a new one will 
appear in another vessel. There was a syphilitic negro cook on a steam- 
boat who returned to the hospital three times, each time with a new aneu- 
rysm. But usually one is enough if it affects the aorta, and all the vaunted 
Fig. 190.-Aneurysm of the abdominal aorta, with laminated clot almost completely 
filling it. 
methods of cure are rather unsatisfactory, except in rare cases. In the 
small arteries of the brain Charcot has described miliary aneurysmal sacs 
which are said to be the points at which haemorrhage occurs in apoplexy. 
Benda: Ergebn. d. allg. Path., 1902-1904, viii, 196. 
Marchand: Verb. Dtsch. path. Ges., 1904, vi, 197. 
Osler: Practice of Medicine, 1905, sixth edition. 
Osler and MacCallum: Johns Hopkins Hosp. Bull., 1905, xvi, 119. 
LITERATURE 364 
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CEREBRAL APOPLEXY 
Haemorrhage into the substance of the brain is one of the most direct conse- 
quences of arteriosclerotic changes in the arteries, and may be briefly 
discussed here. While haemorrhages may, of course, occur in the meninges, 
and even in the brain, as a result of injury and in connection with infectious 
processes, the most characteristic and common forms are those which arise 
spontaneously or in the course of some violent exertion, from rupture of 
one of the arteries which penetrate into the brain substance. Many 
branches are liable to such rupture, but in fact it most frequently occurs in 
Fig. 191.-Apoplexy, both fresh and healed. The large, fresh haemorrhage has burst 
into the ventricle. The old one is represented by a cavity with pigmented walls in the 
substance of the opposite hemisphere. There is a small clot in the ventricle of that side. 
an artery which turns off at right angles from the middle cerebral artery to 
pass to the lenticular nucleus and internal capsule (Fig. 191 A). This is the 
so-called lenticulostriate artery, named by Charcot, on account of its fre- 
quent involvement in apoplexy, the artery of cerebral haemorrhage. It is 
not usual for haemorrhage to occur from diffusely sclerotic arteries: rather 
it arises from definite local alterations which are described as miliary aneu- 
rysms. These are minute globular enlargements of the artery, two or three 
millimetres in diameter, which are not very conspicuous, but which may be 
found by carefully washing away the brain substance with a stream of 
water. Even the ruptured one may be demonstrated in this way. CEREBRAL APOPLEXY 
365 
The haemorrhage mpy occur in the cortex, in the basal ganglia involving 
the central portion of the brain, in the crura or pons, or even in the medulla 
or spinal cord. In these latter cases other causes are usually at work. 
Haemorrhage into the cerebellum is not very uncommon. In by far the 
greater number of cases the haemorrhage is found to involve the corpus 
striatum and the internal capsule; sometimes, as shown in the drawing 
(Fig. 191), bursting into the cerebral ventricles. Such extravasation tears 
through the soft tissue, interrupting nerve-fibers and destroying nerve- 
Fig. 191A.-Diagram showing the branches of the middle cerebral arteries which 
supply the basal ganglia. The innermost are the lenticulo-optic, the outer two on 
each side the lenticulo-striate arteries. The outermost of these which pierces the in- 
ternal capsule to end in the caudate nucleus is known as the " artery of cerebral 
haemorrhage." Modified from Charcot-Duret. 
cells. It is irregular in extent and in outline, and at the margins there are 
always little extensions into the adjacent tissue, where one usually finds 
the lymphatic sheath of each vessel distended with blood. The mere 
appearance of such a quantity of blood inside the rigid cranial enclosure 
is enough to raise the pressure there, and by compressing the brain generally, 
to cause unconsciousness and a general flaccid paralysis, and it is in this 
condition that the victim falls in the street. Later, when some of the blood 
has been absorbed and the pressure lowered, the direct effect of the tearing 366 
TEXT-BOOK OF PATHOLOGY 
of the nerve-tracts becomes evident, and a clear-cut hemiplegia or one- 
sided paralysis stands out instead. 
If the haemorrhage is not confined to the brain tissue, but bursts through 
into the ventricles, much freer bleeding can occur, and the blood filling both 
ventricles and running down through the aqueduct of Sylvius intensifies the 
effects of increased general pressure. 
The distribution of the paralysis depends, of course, on the situation 
of the destruction of the brain substance. The hemiplegia is complete 
when face, arm, and leg on one side are paralyzed, and this arises when the 
haemorrhage involves the internal capsule and the beginnings of the pyr- 
amidal tract high enough to include the origin of the facial nerves. If, 
however, it is in the lower part of the pons, the nuclei of the cranial nerves 
may be injured, and then the facial paralysis will be on the side opposite 
that of the arm and leg. {Cf. Osler's Medicine, 1905, fourth edition, 
972, Fig. 9.) 
Healing of the area of haemorrhage takes place by the disintegration of 
the blood and its gradual removal by phagocytes. Sometimes a cavity is 
left, lined by granulation tissue, which is deeply pigmented and contains 
a clear yellow fluid (Fig. 191). The neuroglia may play a large part in 
forming the wall of this cavity. 
Monakow: "Gehirnpathologie," Nothnagel's spec. Path. u. Ther., 1897, ix, pt. 1. 
Ellis: Publications, Jefferson Medical College, Phila., 1915, v, 1. 
Duret: Arch. de. Physiol, norm. et. pathol., 1874, 2me, Ser. 1. 
LITERATURE CHAPTER XVIII 
TYPES OF INJURY: PHYSICAL AND MECHANICAL INJURIES 
Mechanical injuries: Pressure, direct violence affecting bones, central nervous system, etc. 
Gunshot and other wounds. Secondary effects: Complication with injection. Shock. 
Experimental study and various theories. Effects of heat: Burns, heat-stroke, insolation. 
Effects of cold: Freezing. Effects of light-rays and radiant energy on skin, blood-forming 
organs, etc. Electricity: Effects of strong currents. 
MECHANICAL INJURIES 
The variety of mechanical injuries is almost infinite, and is constantly 
increasing and changing with the invention of new machinery. The old 
swashing blow with the broadsword has given place to the penetrating 
wound of the high-speed bullet; wounds of encounter with wild beasts are 
rarer now than those from the fall of an aeroplane. But the principles 
concerned are relatively few, and with a knowledge of the complexities of 
organ structure and function the effect of any type of injury can be pretty 
readily constructed. 
In general, mechanical force may be applied to the body in the form either 
of pressure or of stretching, and according to the shape or character of the 
instrument, and the rate and violence with which it is applied, different 
results follow. Thus gradual exposure to a high air- or water-pressure 
will produce one sort of effect, while a sudden blow with a blunt weapon or 
crushing between two flat surfaces will have quite a different outcome. 
If the instrument be sharp or impinge upon the body with great velocity, 
it cuts or penetrates, separating tissues which might be only bruised or dis- 
located by a blunter or more slowly moving object. 
Distension by gases or fluids, stretching and tearing of extremities 
caught in machinery, and the dismemberment of the body by the force of 
an explosion are examples of the application of a stretching force which 
often involves the exertion of pressure also on some other part of the tissue. 
The effects of such violence are not only upon the tissues directly attacked, 
but since the whole structure of the body is in a state of elastic tension, the 
severing or destruction of any tissue allows those remaining to gape apart. 
Especially is this true of the elastic blood-vessels, in which the blood is 
under high presssure. Any break in the wall of one of these vessels opens 
more widely and allows the escape of blood. Nor is the effect of any such 
mechanical injury necessarily limited to its direct result. Here, as else- 
where, it is usually one link in a chain of events which in the end leads to 
quite unexpected terminations. Thus a man whose back is broken will 
die from the formation of abscesses in his kidneys, but there is a long series 
367 TEXT-BOOK OF PATHOLOGY 
368 
of causes and effects which finally bring this about. It is an example of the 
far-reaching effects of injuries to the nervous system. 
A brief account of some of the common types of mechanical injury will 
suffice to direct the reader to the literature of the subject. 
Pressure.-A diver seen deep in clear water through a glass-bottomed boat 
becomes perfectly white from the compression of the blood-vessels of the skin. 
Doubtless this may have some influence upon the general blood-pressure, but 
when air is supplied through a helmet, no great discomfort is felt if the changes 
of pressure are gradual enough. The same anaemia, lasting for a long time, 
if locally produced by the weight of the body on the bed, or by a tight 
bandage, may be more complete in the area affected, and if the circulation 
is sluggish, and especially if the nerve supply is interrupted, death of the 
anaemic areas will follow (decubitus, bed-sores). Thus a person paralyzed 
by an injury to the spinal cord will quickly develop deep ulcers over the 
sacrum, heels, etc., if left lying in one position, and the same is true of 
those bedridden by some disease or infection which greatly lowers their 
vitality. Violent mechanical pressure on the trunk, as in cases of people 
buried under an avalanche of coal or grain, or caught under an elevator, 
may cause death by actual crushing, but short of this it produces an ex- 
treme obstruction of the circulation by preventing the movement of the 
venous blood toward the heart. The head and neck become blue black, 
and haemorrhages occur from the burst vessels. Slighter pressure applied 
continuously to any tissue over a long time interferes with the complete- 
ness of its blood supply, and prevents or stunts its growth. Well-known 
examples are found in the distorted feet of Chinese women, the flattened 
heads of certain Indians, etc. Tumors, pressing in their growth against 
other tissues, cause the cessation of growth and gradual absorption. This 
is true everywhere, but becomes especially striking in the case of the rigid 
bone, which can be hollowed out by an advancing tumor growth. Prac- 
tically the same thing is seen in the liver as the result of constriction by 
tight clothing, but also in the form of deep grooves over the upper surface, 
which correspond with rigid, contracted bands of the diaphragm. Aneu- 
rysms which push aside yielding tissues and destroy in their advance bone 
and anything else which is resistant, afford another example in which the 
effect of pressure is probably aided by the actual beating of the pulsating 
sac against the bone, for such eroded bones show not only wasting or 
atrophy of the tissue, but fragmentation of the bony lamellae. 
On the other hand, intermittent pressure which allows the resumption of 
the circulation and of the proper metabolism of the cells in the intervals 
often causes an excessive growth of tissue, as one sees in the case of corns 
and other callosities, and probably also in the ingrowing toe-nail. 
Heightened air-pressure, to which workers in caissons and submarine 
engineering operations are subjected, is injurious chiefly through sudden 
changes in the degree of pressure. The sudden application of a high pres- 
sure may cause haemorrhages in the ears. Sudden decompression produces MECHANICAL INJURIES 
369 
a whole series of phenomena, chiefly dependent upon the expansion of gases 
which cannot readily escape; the air in the middle ear and the gases 
in the intestine produce discomfort or injury by being suddenly released 
from pressure. Most important, however, is the appearance, in the form 
of bubbles, of the gases which under higher pressure were dissolved in the 
blood. These are chiefly nitrogen and carbon dioxide, and if a workman 
is too quickly "decompressed," that is, if he remains too short a time in the 
air-locks in which the air is at an intermediate pressure, these bubbles 
appear in the blood-stream and act as emboli, plugging the arterioles and 
obstructing the blood supply until they can be redissolved. In this way 
the sensitive tissue of the brain and cord undergoes anaemic necrosis in 
focal areas, and if death does not follow, extensive paralysis and other 
nervous disturbances appear (the so-called "bends" of caisson workers) 
Tearing of the tissues by such bubbles seems less important. Exposure 
to low atmospheric pressure, as in balloon ascensions, mountain climbing, 
etc., brings with it symptoms that are milder because the change of pres- 
sure must be more gradual. Rapid respiration, rapid pulse, and an in- 
crease in the number of red corpuscles of the blood are evidences of adapta- 
tion to the lowered oxygen tension of the atmosphere. Weariness, nausea, 
drowsiness, fainting, etc., make up the condition known as mountain- 
sickness. 
Trauma.-Violence in the form of blows may, of course, have many 
different results. The commonest is perhaps the bruising of tissues, with 
the stretching and tearing of many minute blood-vessels, from which blood 
escapes and filters into the crevices round about. If the tissue is soft and 
loose, as it is below the eye, a blow may cause a very extensive infiltration 
of blood, while in a denser place a much harder knock will leave no such 
great black-and-blue spot. At first it is red or purplish red, but with the 
stagnation of the escaped blood a venous color supervenes which, in the 
course of the next days, gives place to a series of changing colors as the 
haemoglobin of the laked blood passes through the stages of the formation 
of haemosiderin and its gradual removal. Hues of green and brown and 
yellow finally fade away completely after all the pigmentary remains of the 
escaped blood have been carried away. 
A stronger blow or a twist may dislocate a joint; that is, separate the two 
articular surfaces by stretching the articular ligaments or by forcing one 
bone through them. Haemorrhage occurs, as a rule, and unless the bone is 
replaced properly, new tissue may be formed in such a way as to render the 
abnormal position permanent. Such a blow may, even though it does not 
break the skin, cause the rupture of internal organs or the fracture of a 
bone. In the first case, if the organ is a solid one, rich in blood-vessels, 
like the kidney or liver or spleen, a great or even fatal haemorrhage may 
occur. This does not necessarily follow, however, for occasionally there 
are found evidences of recovery from rupture of the liver in the presence of 
masses of liver tissue surrounded by, and healed into the omentum. 370 
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Fracture of bones can occur in a thousand ways known to every one. 
It may be only partial, leaving the rest of the bone bent (greenstick frac- 
ture), or it may be complete, so that the fragments override and are held 
in the false position by the muscles. When the bone is shattered into 
many fragments (comminuted fracture), the dislocation may be even 
greater. Occasionally one fragment is driven into the substance of the 
other, so that it remains embedded there (impacted fracture). When the 
skin is broken and the fractured bone exposed to contamination from the 
outside (compound fracture), infection is very likely to occur. Fractures 
of the skull the bones of which are so intimately associated with infected 
cavities are also exposed to this danger which, in preantiseptic times, made 
a compound fracture almost inevitably fatal. Healing occurs by the forma- 
tion of an abundant new tissue (callus) about and between the ends of the 
bone. Excessive at first, and composed of vascular fibrous tissue, carti- 
lage, and spongy bone, it later becomes compact, diminished in amount, 
and consolidated into dense bone, which is gradually modified and adapted 
to give the greatest strength to the welded point of fracture (Fig. 192). 
Blows on the head, besides causing fracture of the bones of the skull, 
which may be driven into the brain, are capable of injuring the brain either 
by concussion or by producing a haemorrhage from either or both sides of 
the dura, or from the pial vessels before or after their entrance into the 
brain. A blow on the skull frequently produces its greatest injury at a 
point opposite that upon which it impinges (contrecoup). 
The mechanism of contrecoup has been variously explained in a vague way as the 
effect of driving the soft brain substance against the unyielding opposite side of the skull, 
the concentration of forces passing round the arc, etc., but to me it seems more plausible 
to assume that the skull, like a hoop struck sharply at one point, takes an elliptical form, 
so that the side opposite the blow actually approaches that which is struck. At any 
rate it is common to find laceration of the brain and meninges with haemorrhage, at a 
situation most distant from the blow. 
Concussion is recognized as the effect of a shock to the brain substance, 
which, although it produces no obvious gross lesion of any sort, does cause 
unconsciousness of brief or longer duration and many temporary disturb- 
ances of the intellect, sensory, or even motor sphere. It is thought to be 
due to dissociation or disarrangement of the cells, possibly with tearing of 
many dendrites, axones, and association-fibers. 
Meningeal haemorrhage is important above other haemorrhages, not only 
because it may tear into and destroy the soft brain substance, but because 
it can, even when it is outside the dura, occupy so great a space within the 
rigid cranial cavity as to compress the brain, and especially to prevent the 
access of blood (Fig. 194). A gradually deepening loss of consciousness 
with flaccid paralysis of the whole body may lead to death-the blood- 
pressure rises very high, while the pulse sinks. Operative removal of the 
clot may allow all the functions to return to normal almost instantly. 
Much greater violence is necessary to wound the spinal cord, but crushing 371 
MECHANICAL INJURIES 
Fig. 192.-Healed fracture of middle of femur, shown also in 
section. 
Fig. 193.-Well- 
healed fracture 
showing remaining 
overstrengthening 
of the shaft. 372 
TEXT-BOOK OF PATHOLOGY 
and twisting force may fracture the vertebrae or dislocate them so as to 
sever or compress the cord. Extravasation of blood in the substance of the 
cord (hcematomyelid) extends up and down in the gray matter, destroy- 
ing much of the tissue as it burrows, but, as a rule, not entering the 
white matter. The so-called compression myelitis, produced by crushing, 
occupies part or all of the diameter of the cord, and interrupts the course 
of the fibres. In such an area, debris of cells and fibres remains, together 
with quantities of phagocytic wandering cells loaded with globules of 
lipoid material from the disintegrating myeline sheaths. 
The effects vary with the extent, and especially with the position, of the 
injury. Low down in the spinal cord the lower motor neurons are es- 
Fig. 194.-Subperiosteal and subdural haemorrhage in new-born child with compression 
of the brain. 
pecially affected, and paralysis is flaccid, leading to atrophy of muscles 
and reaction of degeneration. Higher up a lesion gives rise to a mixture 
of upper and lower neuron types, while still higher the effect is to produce 
paralysis predominantly of the type following destruction of the upper 
motor neuron, such as comes from a lesion of the brain: the muscles retain 
their tone, do not atrophy, and stimulation of the nerves shows no change 
of electrical reaction. The paralyzed area may be entirely anaesthetic, or 
with a zone of hypersesthesia at the upper limit. Other disturbances of 
sensation also occur. Reflexes are variable, and after a time may be 
exaggerated, especially with high lesions. The sphincter of the bladder is 
not paralyzed, although other muscles controlling urination are, so that the 
bladder becomes greatly distended. MECHANICAL INJURIES 
373 
Wounds made with a cutting instrument sever tissues and allow them to 
gape apart, or in the case of stab wounds, penetrate various organs. They 
are especially important in that blood-vessels are laid open, nerves cut, 
and hollow organs punctured, so that their infected contents are allowed 
to escape. Aside from the direct destruction of the tissues traversed, 
such wounds are also dangerous because dirt and bacteria are carried in to 
the tissue. In all these respects they are similar to gunshot wounds, which 
have, however, a special character, depending on the type of missile and 
the force and velocity with which it passes through the tissues. 
Gunshot Wounds.-A hard bullet of very high velocity passes cleanly 
through the body. A soft bullet spreads and tears the tissue, inflicting 
much greater damage: either will shatter bones in its course. A bullet 
almost spent or of low velocity may be deflected by a bone and pursue a 
most devious course, so that its track is difficult to follow, even at autopsy. 
The path of a bullet widens as it proceeds, especially in the case of the soft 
ones, so that the wound of exit is larger than that of entrance. Ordinarily 
such a bullet brings practically no infection to the tissues unless it carries 
in with it bits of clothing. It was for this reason that the Japanese in 
recent actions bathed and put on sterilized clothes. 
Immediate Effects.-In all cutting and penetrating wounds the most 
important immediate effect, unless the brain or spinal cord is injured, is 
likely to consist in the laying open of blood-vessels. A wound of the heart 
is fatal not especially because the heart is injured, but because blood escapes 
into the pericardium (haemopericardium), and by occupying the limited 
space, prevents the entrance of the venous blood into the heart and stops 
the circulation. In the case of the aorta or other large vessel, death results 
rather from direct escape of blood into the pleura or pericardium or to the 
outside. A vessel, in virtue of its elasticity and muscular contractility, 
gapes open and allows a maximum escape of blood if it is only partly 
cut through, while if completely cut across, an artery of moderate size 
may retract among the muscles, and partly by their compressing effect, 
partly by its own contraction, the flow of blood may be stopped before a 
fatal loss has been suffered. 
Peripheral nerves may be cut through, or crushed and later surrounded 
by dense scar tissue formed during the healing process, and in either case 
the injury may be sufficient to prevent the transmission of impulses. 
Degeneration of the peripheral portion of the nerve quickly follows, and 
in a few days lipoid globules are found in place of the myeline sheaths, 
the axis-cylinders are disintegrated, and electrical stimuli produce no 
effect (Fig. 31). There may be recovery of the power to transmit im- 
pulses if the injury is not too severe, and in the meanwhile the muscle 
loses its power to contract to galvanic stimuli, but soon recovers it and 
becomes more excitable than normal. During this period of high excitabil- 
ity, which later passes away, the contraction is, however, not instan- 
taneous, but slow and lazy, and almost without effect (reaction of de- 374 
TEXT-BOOK OF PATHOLOGY 
generation of Erb). There are many variations in these relations, depending 
upon the extent of injury of the nerve and the degree to which the muscle 
suffers, which must be read of elsewhere. Trophic disturbances, thought 
by many to be due to the destruction of special trophic nerves, consist in 
the gradual wasting of the muscle. It is shown that constant fine stimuli 
are being sent to muscles in health maintaining their tone, and that when 
the nerve is cut and the muscle becomes flaccid, its metabolic gaseous ex- 
change is far less than that of the properly innervated muscle, even when 
completely at rest. It seems possible that this might be the basis upon 
which atrophy after section of the nerve could be most readily explained. 
Secondary Effects.-Many secondary results follow such injuries as 
have been mentioned, some of which can be avoided by proper surgical 
care. Haemorrhage, as already stated, may cost the person's life through 
sheer loss of blood or through the compression of the brain or the heart; 
the perforation of an aneurysm into the trachea may fill the lungs and 
practically drown the individual. But in another way, especially in the 
brain and spinal cord, the burrowing of blood in the soft tissues is most 
destructive. In the walls of the aorta, particularly when the seat of 
arteriosclerotic changes, a blow or strain may break the inner layers, 
usually the intima and half of the media, and allow blood to escape into 
a space which it tears open in the middle of the media, the so-called 
dissecting aneurysm. In one case of this kind the formation of a huge 
haematoma about the roots of the splanchnic nerves was apparently the 
cause of paralysis of the intestine, with such extreme distension as to 
tear the muscular coat in many places. 
The occurrence of bacterial infection in wounds adds, of course, greatly 
to their seriousness, and many mere pin-pricks terminate fatally because 
bacteria have been introduced. This is common in the case of strepto- 
coccus and tetanus infections, but it is equally true of syphilis, glan- 
ders, anthrax, and a host of other infections. Indeed, it is the very 
insignificance of the wound, leading to its being neglected, which affords 
opportunity to the bacteria to gain a foothold. The presence of any 
foreign body in conjunction with the bacteria helps them greatly in gaining 
this foothold, and it has been shown repeatedly, in the case of experi- 
mental infection, that bacteria which fail to grow when inoculated into an 
animal alone, will often do so if implanted together with some inert foreign 
material. Sometimes this acts by merely protecting the bacteria, but at 
other times it forms a medium upon which they can grow and multiply. 
This is true of extravasation of urine when the bladder is ruptured, or of 
accumulations of tissue fluid in the cavity of a wound. Most important 
in this respect, however, is the presence of dead tissue in a wound exposed 
to infection. This has been mentioned before, but from a surgical point 
of view cannot be mentioned too often. No matter how rigid the aseptic 
technique, the leaving behind in the wound of any considerable quantity 
of tissue constricted so as to be incapable of surviving, is almost sure to be MECHANICAL INJURIES 
375 
followed by infection. In other cases the foreign body itself may be 
irritating and destructive of tissue, so as to furnish a place in which bacteria 
can thrive. Considerations of this sort became extremely important dur- 
ing the war, when surgeons were confronted with wounds which involved 
not only mangling of the tissues and extensive soiling but also on account 
of delay in transportation, actual infection of the injured structures. 
Whenever possible it became the practice to perform a so-called "debride- 
ment," which means the wide excision of everything about the wound 
until healthy, uninfected tissue was reached, after which the whole wound 
might be closed, and primary healing attained. Of course, it was in the 
estimation of the extent of the infection and the general state of resistance 
of the patient that the judgment of the surgeon became of especial impor- 
tance. 
With regard to the bacteria concerned, and especially the anaerobic 
forms, consult Bulloch and McIntosh, Med. Research Committee, Special 
Report, Series No. 12, 1917. 
Perforation of the stomach or duodenum, which are in themselves 
nearly sterile, nevertheless sets up peritoneal infection because of the 
escape of food and of the irritating digestive juices. Perforations of lower 
portions of the intestine are even more quickly productive of infection 
because of the colossal numbers of bacteria which pour out with the in- 
testinal contents into the peritoneum. This is one of the chief sources of 
danger in gunshot wounds of the abdomen, in which several loops of intes- 
tine may be pierced. 
The crushing or shattering of tissues, involving rupture of blood-vessels, 
often allows the entrance of groups of cells or single cells of various organs 
into the blood-stream in such a way that they are swept along and lodge 
as emboli in the lungs or elsewhere. This is most commonly true of the 
bone-marrow, where, instead of cells, droplets of fat may enter the blood- 
current. Practically every fracture of a bone and even severe blows upon 
bones may produce such fat embolism of the lungs. Usually it does no 
harm, and even at autopsy can be discerned only by the aid of the micro- 
scope, but occasionally the amount of oil is so great as to cause death by 
obstructing too many of the capillaries of the lungs. 
Traumatism is, of course, a more serious matter for persons already 
weakened by disease than for those in full health, and it may be the occa- 
sion for the flaring up of an infection hitherto latent. On the other hand, 
the injury of tissues may produce a point of lessened resistance, where a 
subsequent infection can be established in a way scarcely possible in an 
uninjured person. This is doubtless the explanation of the common history 
of a fall or blow which antedated, by some time, the appearance of a focus 
of tuberculous infection in a bone or joint. This, too, is doubtless the 
immediate predisposing cause of the so-called contusion pneumonia of 
Litten, which follows crushing blows on the chest. 
It must be remembered that certain persons suffer directly from slight in- 376 
TEXT-BOOK OF PATHOLOGY 
juries far more than others, for example, a scratch which would scarcely be 
noticed by a normal individual may allow a fatal haemorrhage in a member 
of a haemophilic or bleeder family, while a blow which at most might cause 
a bruise in one of us, will break the femur of one afflicted with osteopsathy- 
rosis or fragilitas ossium. And in the same way the sequelae of injury, 
such as wound infections, resisted easily by a normal person, will bring 
about the death of one whose resistance is low, with fulminant symptoms 
of general septicaemia. This was exemplified recently in the case of a 
man, apparently in good health, who had his tonsils removed preparatory 
to a vacation-a streptococcus infection ensued, of which he died in two 
days, with evidences of acute endocarditis and multiple embolism. 
LITERATURE 
Bailey: Diseases of the Nervous System from Accident and Injury, New York, 1909. 
Henke: Krehl and Marchand, Handb. d. allg. Pathologic, 1908, i, 21. 
Hill, L.: "Influence of Atmospheric Pressure," Lancet, 1905; ii, 1865, Proc. Roy. Soc., 
1905-6, Ixxvii, 442. 
Lagarde: Gunshot Wounds, New York, 1914. 
Mobius: Diagnostik der Nervenkrankheiten, Leipzig, 1894. 
Stimson: Fractures, Phila., 1912. 
SHOCK 
This is a peculiar disturbance of almost all the functions of the body, 
especially characterized by apathy or torpor, dulling of sensibility, failure 
of the circulation with great lowering of the blood-pressure, irregular gasp- 
ing respirations, which may be the first thing to fail completely, and sub- 
normal temperature. Fischer's description of such a case may be quoted 
from Dr. Meltzer's paper: 
"A strong and perfectly healthy young man was struck in the abdomen 
by the pole of a carriage drawn by runaway horses. No recognizable injury 
was done to any of the internal organs. Nevertheless, grave symptoms 
made their appearance immediately after the accident. The injured man 
was lying perfectly quiet, and paid no attention to anything going on 
around him. His face was drawn and peculiarly elongated, the forehead 
wrinkled, and the nostrils dilated. His weary, lustreless eyes were deeply 
sunken in their sockets, half covered by the drooping eyelids and surrounded 
by broad rings. The eyes had a glassy and vacant expression. The skin 
and the visible mucous membranes had a marble-like pallor. Large drops 
of sweat hung on forehead and eyebrows. The rectal temperature was 
subnormal. The sensibility of the entire body was greatly reduced; the 
patient reacted slightly, and only to very painful impressions. No spon- 
taneous movements of any sort were made by the patient. On repeated 
and urgent requests he showed that he could execute limited, brief move- 
ments with his extremities. When the limbs were lifted passively and 
then let go, they fell down like lead. The sphincters were intact. The 
urine obtained by catheter was scanty and concentrated, but otherwise 
normal. The almost imperceptible pulse was rapid, irregular, and un- 
equal. The arteries were narrow and of very low tension. The patient 
answered slowly, reluctantly, and only after repeated urgent questioning. SHOCK 
377 
His voice was hoarse and weak, but well articulated. On being repeatedly 
questioned, the patient complained of cold, faintness, and deadness of all 
parts of the body. When he shut his eyes he felt nauseated and dizzy. 
The respirations appeared irregular; long, abnormally deep, sighing in- 
spirations interchanged with rapid and superficial ones, which were scarcely 
visible or audible." 
This is a typical example of shock following traumatism, a condition well 
known to surgeons to come on immediately or a short time after some 
extremely painful injury, such as the crushing of a testicle or mangling or 
laceration of the body in machinery. It is especially common in injuries 
which involve the exposure and mishandling of the abdominal organs, but 
practically the same complex appears after extensive burns, and in the case 
of intense peritoneal and other infections and some intoxications. Possibly 
the infections and intoxications may be distinct in their mode of action, 
but in the present confusion of our knowledge the results seem to be prac- 
tically identical. 
An immense amount of experimental study has as yet failed to explain 
this phenomenon, or even to determine exactly what happens. Keen, 
Mitchell, and Morehouse, and later Crile, thought the fall in blood-pressure 
to be the essential feature, and this they explained as due to exhaustion of 
the vasomotor centre, which allowed relaxation of the peripheral arterioles 
and the accumulation of the blood in the large splanchnic veins. Crile 
advised massage or compression to drive the blood again to the heart. 
He observed, however, that death in most cases resulted from stoppage of 
respiration while the heart continued to beat. 
Porter, Seely, Mann, and others have shown, however, that the vaso- 
motor centre is by no means exhausted, but still active, and that the 
peripheral vessels are distinctly contracted and quite susceptible to 
vasoconstrictor impulses, which can be elicited by sensory stimulation. 
Nor is it a fact, as Boise claimed, that the heart is exhausted, for 
if blood be supplied to it and pressure maintained, it works perfectly 
well. The nervous control of the heart is intact; so, too, the nervous 
mechanism which controls respiration is able to respond to various 
stimuli, although (Mann) it is probably the most easily injured and most 
seriously damaged of the medullary centres. Henderson ascribes the 
whole phenomenon to an affection of the respiratory centre following the 
violent forced respiration which is set up by painful traumatism. This, 
he states, sets free so much carbon dioxide from the tissues that the 
condition of "acapnia" arises, namely, a poverty of the carbon dioxide 
which is necessary for the stimulation of the respiratory centre. Mere 
lack of oxygen, he says, has no influence in stimulating respiration, and 
in the absence of carbon dioxide the centre remains inactive, so that in this 
period of apnoea the individual dies from lack of oxygen. It seems hard 
to believe that the excessive respiration, which is often so slight, could 
produce so extreme a change, or that the carbon dioxide produced while 378 
TEXT-BOOK OF PATHOLOGY 
the animal was dying for lack of oxygen should not be able to stimulate 
the respiratory centre, since throughout this time the heart continues to 
beat. Meltzer regards the whole process as the expression of a preponder- 
ance of inhibitory action of the nervous system, which after such ex- 
treme stimulation affects even the organs of fundamental importance, 
the regulation of which is usually so well protected. 
Mann emphasizes the predominant part which injuries to the peritoneal 
contents play in the production of shock, and, finding great increase in the 
specific gravity of the splanchnic blood and changes in the relation of the 
blood-cells, thinks the symptoms due to the great loss of cells and fluid 
from the blood of the splanchnic vessels-a sort of acute inflammatory 
exudate. The production of shock in cases where such things are easily 
excluded seems to militate against this idea. Haemorrhage does aid in the 
production of shock, and the effects of very severe haemorrhage are hardly 
to be distinguished from it. So, too, the effects of such infections and in- 
toxications as are found in general streptococcal peritonitis or in fatal 
diphtherial intoxication are, as has been pointed out by Passler and Rom- 
berg, in every respect similar. They lay stress on the vascular relaxation 
and stagnation of blood in the great veins which involves decreased flow in 
the coronary arteries and cardiac failure, and I could confirm this by show- 
ing that if the blood-pressure be maintained by a mechanical device, and 
the blood driven, regardless of the vasomotors, through the arteries and 
veins into the heart, the imminent collapse is warded off. Much has been 
written by Crile and his assistants about disintegrative changes in the 
ganglion-cells of the brain in shock, but it seems that these may be rather 
the effect than the cause. 
H. H. Janeway and E. M. Ewing conclude, from their experiments, that 
acapnia is not important in producing shock, but that artificial respira- 
tion can do so, when forcible enough, by preventing the flow of blood from 
the veins into the heart. Shock may be produced while the carbon dioxide 
content of the blood is high. Further, although the early stages of shock 
produced by the handling of the intestine are due to inhibitory efferent 
impulses, the nerve centres are not exhausted, but there is a complete local 
peripheral splanchnic paralysis, so that blood accumulates there, producing 
in the end a fatal fall in blood-pressure. This permanent loss of vasomotor 
control is the all-important factor in the development of shock. 
These older ideas, while leaving no clear impression of the nature of 
shock, are not inconsistent with those which have resulted from the very 
extensive studies made during the war. Various suggestions, such as those 
which ascribed shock to pulmonary and cerebral fat embolism or to acid- 
osis, have been proposed, only to be abandoned. It has been observed 
that in most intances several causes have been combined; cold, haemor- 
rhage, crushing and laceration of tissues, and anaesthesia stand out most 
prominently, and it is found that in many instances the addition of one 
or more of these factors is decisive in precipitating shock. Ether anaesthesia SHOCK 
379 
is far more harmful in this respect than that with nitrous oxide and oxygen. 
Rich has shown that while extirpation of the adrenals gradually leads to 
a lowering of blood-pressure, and shock is produced by manipulation of 
the intestines more rapidly in these animals than in controls, this is not 
true of the pinching of the intestines, follows immediately upon the de- 
struction of the adrenals before hypotension sets in. Then they pass 
into shock exactly as do the normal controls. He also finds that cardiac 
failure is not a factor in the production of shock, and that even during 
deep shock the vasomotor and cardio-inhibitory centres continue to func- 
tion; further, curiously enough, ether anesthesia for an hour before the 
trauma renders the animals very resistant to shock, although this pro- 
tection disappears if the animal is allowed to recover from the anaesthesia 
before the trauma is begun. 
Distinction is made between primary shock, which appears to be the 
immediate reflex effect of a sudden injury due to the inhibition of the 
heart through the vagus and dilatation of the arteries in the splanchnic 
area (Goltz's experiment), and secondary shock, which is more gradually 
produced and depends upon other causes. 
In secondary shock the blood-pressure drops sharply, then with a tem- 
porary constriction of the arterioles rises almost to the original level, 
after which it gradually sinks to a very low one. When it reaches this 
level the heart still beats well, but there is very little blood in the arteries 
or veins and the pulse is not to be felt. By the vital red stain method it 
has been shown that there is a great diminution in the blood volume (Keith), 
and it is clear that the arteries and veins are collapsed; the heart appears 
to be propelling only a very small amount of blood. The explanation of- 
fered is that the enormous capillary stream bed, which under normal con- 
ditions is only partly used, is now widely opened to the blood by the paral- 
ysis of the capillary walls. It is recognized that the endothelial walls of the 
capillaries have a certain contractility of their own and that they are capa- 
cious enough when this tone is lost to receive almost the whole volume of 
the blood, which thus occupies largely capillaries which are ordinarily 
collapsed and not traversed by blood. With this comes an increased 
permeability of their walls so that fluid passes out into the tissues and the 
blood becomes concentrated. Of course, there is not enough fluid available 
to give any appearance of oedema. Respiration may cease and the patient 
die with all his nerve centres and his heart inactive from lack of nutrition. 
It has been found that the introduction of large quantities of blood or of 
a 6 per cent, solution of gum acacia with salt often relieves the situation 
by furnishing fluid enough to allow the heart to work and to maintain its 
own nutrition and that of the nervous system. 
Crushing of tissues seems especially likely to be followed by severe shock, 
and so too does the re-establishment of the circulation through tissues 
which have long been cut off from their blood-supply; something forms in 
crushed muscles or in injured tissues which is later distributed by the cir- 
culating blood and acts as a poison. Dale recognized this, and stated that 380 
TEXT-BOOK OF PATHOLOGY 
from its effects it must be a body resembling the histamine or beta-imido- 
azolylethylamine which he had extracted from ergot. Dr. Abel finds that he 
can extract histamine itself from practically every tissue and thinks that it 
may well be the substance actually concerned. The effects of injection of 
histamine are exactly those of shock. It causes a sinking of blood-pressure 
through paralysis of the walls of the capillaries which widen and receive 
most of the blood and become more permeable so that much of its fluid is 
lost into the tissues. Rich has shown this directly by the injection of 
histamine into the peritoneum with study of the changes in the calibre of 
mesenteric and omental vessels. Dale does not claim that this is the 
only factor in the production of shock, but Cannon, Bayliss, McNee, and 
others bring great support to the idea from their observations of the 
effect of experimentally crushing muscle and other tissues. They speak, 
therefore, of traumatic toxaemia as the important underlying condition in 
shock. 
(Dale, Wallace, Bayliss, Cannon, McNee, Keith, and others, Report of 
the Special Investigation Committee on Surgical Shock and Allied Con- 
ditions, National Health Insurance, Special Report Series Nos. 25, 26, 27, 
London, 1919.) 
All of these studies are very recent, but seem to offer a very plausible 
explanation for at least some cases of shock. 
LITERATURE 
Abel and Kubota: Jour. Phar. and Exp. Therap., 1919, xiii, 243. 
Crile: Exp. Inquiry into Surgical Shock, Philadelphia, 1899. 
Janeway, H. H., and Ewing, E. M.: Annals of Surgery, 1914, lix, 158. 
Keen, Mitchell, and Morehouse: Circular No. 6, Surgeon General's Office, 1864. 
Malcolm: Lancet, 1905, ii, 573; Med. Chir. Trans., 1907, xc, 563; Clin. Jour., 1909, 
xxxiv, 328. 
Mann: Johns Hopkins Hosp. Bull., 1914, xxv, 205. 
Meltzer: Archives Internal Med., July, 1908, i, 571. 
Rich, A. R.: Johns Hopkins Hosp. Bull., 1922, xxxiii, 79. 
Seelig and Lyon: Jour. Amer. Med. Assoc., 1909, lii, p. 45; Surg., Gyn., and Obst., 
1910, xi, 146. 
Yandell Henderson: Amer. Jour. Physiol., 1908-1910, xxi-xxvi; Johns Hopkins Hosp. 
Bull., 1910, xxi, 235. 
INJURIES FROM HEAT 
Animals can live cnly within certain temperature limits, which are different 
for different forms. Lambert has shown, by culture of tissue in vitro, that 
there is a definite temperature at which cells grow, while growth decreases 
toward certain extremes at which it ceases. Nevertheless, these extremes 
may be passed without the actual death of the cell. Marchand and others 
have found that a temperature of 50° to 51° C. (about 122° F.) is sufficient 
to cause heat coagulation of leucocytes. So, too, distortion and fragmenta- 
tion of red corpuscles occur at that temperature, and even the necrosis of 
epidermis and deeper layers of the skin. Actual haemolysis is produced by 381 
INJURIES FROM HEAT 
a higher temperature-59° to 60° C.-or by longer exposure at the lower 
point. 
Burns.-Actual burning or scalding through exposure to much higher 
temperatures causes various degrees of alteration in the skin, according to 
the intensity and duration of the action of the heat; the skin may be 
reddened, or blistered, or finally it may be actually roasted or charred. 
Burning of extensive skin surfaces usually causes death within twenty-four 
hours, but more limited burns and those of slighter intensity may be sur- 
vived for a longer time or even permanently. The patient suffers the most 
excruciating pain, becomes delirious or stuporous, but extremely restless, 
and finally passes into coma which ends in death. The pulse is small, 
respiration rapid and shallow, and the blood-pressure sinks, producing the 
whole symptom-complex of shock, such as follows great trauma. 
At autopsy nothing is found except congestion of the brain and meninges, 
and occasional small haemorrhages in the mucosa of the digestive tract. 
The duodenal ulcers so often mentioned are really rare. Bardeen empha- 
sized swelling and focal necroses in the lymphoid structures, but these seem 
to be not especially characteristic. There is a good deal of fragmentation 
of the red corpuscles and some laking of the blood. Haemoglobin is ex- 
creted through the glomeruli and precipitated in irregular, globular masses 
in the tubules of the kidney; but although the haemoglobinuria is marked, 
it does not indicate blood destruction enough to account for death. The 
blood is concentrated by the loss of plasma, evidently through great evapor- 
ation from the skin. Thrombosis of the minuter vessels has been described 
by several, but others have failed to demonstrate any such occlusion, and 
it can hardly play an important part. The suggestion has been made 
very frequently that some toxic material may be absorbed from the burnt 
skin which could account for the collapse and death, but there is no direct 
evidence of this. It seems possible that since the symptoms resemble so 
closely those of traumatic shock, the same poisons, histamine or related 
substances, may be concerned. Extracts of such burnt skin have had little 
or no poisonous effect. In this uncertain state of knowledge it is generally 
believed that death is actually due to shock produced by the extreme insult 
to the nervous system. 
Injurious Effects of High Temperatures.-The temperature of the so- 
called cold-blooded animals varies, as does that of any other object, with 
the temperature of the surrounding air, but in man and warm-blooded 
animals in general, the heat-regulating mechanism is effective to maintain 
the body-temperature at a fairly constant level. Clothes and other 
artificial protections are important in aiding this in the case of man, but 
even without them the mechanism will suffice for brief periods of exposure 
to extremes of heat and cold. There are numerous experiments (Blagden 
and others) to show that a man may remain for many minutes without 
any serious discomfort in a room the air of which is heated to many degrees 
above the boiling-point of water (120° C. or 248° F.). Saturation of the air 
with moisture, so that the cooling evaporation from the skin cannot take TEXT-BOOK OF PATHOLOGY 
382 
place, or a longer stay will finally break clown this protection, with serious 
or fatal results. 
Heat-stroke; Heat Prostration.-In very hot weather, especially in 
places where the air is heavily saturated with moisture, it is not uncommon 
for persons here and there, to fall unconscious in convulsions, and sometimes 
to die, as a direct effect of overheating. These are usually debilitated 
people, or those who make great muscular exertion in clothing which pre- 
vents the rapid evaporation of moisture from the skin surface. Occasion- 
ally in periods of extreme heat and humidity great numbers of people may 
be prostrated, as though the affection were epidemic (Alex. Lambert). 
The mildest effect (heat prostration) consists in headache, moderate rise 
in temperature, pains in back and limbs, and extreme exhaustion. More 
severe is the asphyctic form, in which great dyspnoea and cyanosis, with 
delirium or unconsciousness, are added to these symptoms. Still more 
severe, and very frequently fatal, is the hyperpyretic type, in which un- 
consciousness and collapse come on suddenly, or after several days of vague 
premonitory symptoms. There are convulsions, delirium, or profound 
coma, with shallow and gasping or very deep respiration, and finally failure 
and stoppage of the heart. The skin, at first covered with sweat, becomes 
hot and dry, and the temperature rises to phenomenal levels. Lambert 
describes one case in which the rectal temperature reached 117.6° F. 
Another which we observed reached 108° F. before death, but after death 
continued to rise to nearly 120° F. In that case the most advanced putre- 
faction with great distension of the body appeared within twenty-four hours 
after death, and this is a phenomenon regularly observed and worthy of 
study. 
Nothing definite is found at autopsy to explain such a death. There is 
intense rigor mortis, which sets in at once; the blood is fluid, but thick and 
dark from the asphyctic phenomena of the last hours. No infection nor 
intoxication has been demonstrated. It is thought that the centres of the 
medulla are directly impaired, and that the extreme hyperpyrexia which 
follows the disordering of the regulating mechanism, as well as the dis- 
turbances of respiration and circulation, are of central origin. McKenzie 
and LeCount found oedema of the brain and meninges in such cases; there 
was swelling of the brain with flattening of the convolutions, and upon 
extraction a high percentage of fluid. The lungs were cedematous, there 
was cloudy swelling of the liver, kidneys, and myocardium, with petechial 
haemorrhages. These features together with the acute splenic tumor 
suggest the type of changes usually found in an acute infection. 
Sunstroke or insolation must be distinguished from this, since it is the 
effect of exposure, especially of the head and neck, to the direct rays of 
the sun. Violent headache, with excitement reaching to maniacal out- 
bursts, convulsions, and loss of consciousness characterize the attack, and 
if it does not end fatally in this acute stage or some days later, there may 
remain permanent mental and nervous disturbances. 
Nothing is found at autopsy except congestion and swelling of the face INJURIES PRODUCED BY COLD 
383 
and scalp, and a similar hyperaemia and oedema of the brain and meninges. 
It is thought (Schmidt) that it is rather the bright rays of the sun than 
the ultraviolet rays which penetrate the skull and cause these injuries to 
the brain-an opinion which seems open to question. 
LITERATURE 
Bardeen: Jour. Exp. Med., 1897, ii, 501; Johns Hopkins Hosp. Rep., 1898, vii, 135. 
Lambert, Alex.: Medical News, 1897, Ixxi, 97. 
Marchand: Handb. d. allg. Path., 1908, i, 49. 
McCrae, J.: Trans. Assoc. Amer. Phys., 1901, xvi, 153. 
McKenzie, P., and LeCount: Jour. Amer. Med. Assoc., 1918, Ixxi, 260. 
Schmidt, P.: Arch. f. Hygiene, 1903, xlvii, 292. 
INJURIES PRODUCED BY COLD 
The heat-regulating mechanism in the case of man is rather less effective 
in exposure to cold than to high temperatures, and since it works only- 
through retention of the body-heat, it fails when lowering of the oxidative 
processes reduces the production of heat. Our artificial means of protec- 
tion have become absolutely necessary to us, since we are not hardened to 
the exposure of the whole body to cold, and are no longer thickly covered 
with hair. 
With prolonged exposure to extreme cold there are at first excitement 
and unrest, but later the skin becomes livid or pale, blood is driven back into 
the interior of the body, the temperature sinks, metabolism is slowed in all 
the organs, and their activity consequently reduced, the limbs become stiff 
and weak, the person is overcome by an irresistible desire to sleep, the 
respiration grows shallow, and the pulse small and weak-the temperature 
still sinks, and when it reaches 20° to 18° C. the heart stops beating and 
death follows. Nothing distinctive is found at autopsy, and it seems prob- 
able that death is due to just these changes which have been mentioned, 
just as a perfused heart, beating well upon Ringer's fluid at body-tempera- 
ture, slows down and stops if the fluid is cooled to 18° C. As to the possi- 
bility of recovery, it is easy enough to start the perfused heart beating 
again by warming the fluid, but the resuscitation of a person is a different 
matter. 
There has been much discussion and experiment as to the resuscitation 
of lower animals which have been frozen, and the most divergent results 
have been obtained. It seems pretty clear, from many apparently trust- 
worthy reports, that all sorts of animals and plants may be exposed to 
extremely low temperatures for a limited time, and then resume their vital 
activities when they are warmed again. But it is generally objected that 
they are not actually frozen-that is, their fluids do not actually crystallize, 
for when this occurs, the injury is too great to allow of recovery. Even 
when freezing does not take place, prolonged exposure to great cold kills. 
Lambert has shown this accurately with tissue grown in vitro; whereas by 
placing it in relatively concentrated plasma or salt solution it may be kept 
alive and ready to grow at - 4° to - 6° C. for five days, it is quickly killed in 384 
TEXT-BOOK OF PATHOLOGY 
a less concentrated plasma, in which it actually freezes at this temperature. 
Even if it does not freeze, it is killed by ten days' exposure and by lower 
temperatures in a far shorter time, so that it cannot survive exposure to 
- 20° C. for twenty minutes. 
The noxious effect of the freezing is explained either as due to mechani- 
cal tearing of the cell as the ice crystals are formed, or to the concentration 
of salt around the crystals, or to the withdrawal of water from the cell to 
form the ice. It appears that the injury to the cell is the direct effect of 
the cold, and independent of the rate at which the tissue is thawed out. 
Rischpler describes in detail the anatomical changes, which consist in 
vacuole formation in the protoplasm and disintegration of the nucleus, 
and finally of the whole cell-body. It is easy to see that this must be fol- 
lowed by serious inflammatory reaction or by gangrene. This is indeed 
the case, but it must be stated at once that the gangrene of extremities 
which follows such chilling is by no means always directly due to the cold. 
On the contrary, it is the result of protracted ischaemia from extreme con- 
traction of the blood-vessels or their obstruction by thrombi. Frozen feet 
or toes become livid or cyanotic, somewhat swollen, and pulseless, and turn 
purple and finally greenish black. The process is quite like the gangrene 
described in other connections, and the necrotic areas become sharply 
demarcated and dry up, or disintegrate or putrefy if they are not removed 
by the surgeon. Repeated freezing for very short periods at intervals 
is not so harmful as such long-continued freezing. Instead of necrosis, it 
tends to produce a remarkable hyperplasia of the tissue, with giant-cell 
formation in the epidermis. 
Exposure to less extreme cold with moisture produces, especially in cer- 
tain susceptible persons, slighter injuries, evidently largely dependent on 
the contraction of the vessels and the resulting anaemia. The fingers or 
toes are livid or cyanotic, and when brought back into the warmth, remain 
purplish, but swell and become painful and disabled (chilblains). After 
some days the epidermis may peel off in patches, while the normal color 
comes back gradually. Another exposure to cold will bring on another 
attack. 
It is a matter of common experience with many people that if they sit 
in a draft or get wet and are chilled they "catch cold." This means that 
an infection of the respiratory tract occurs by bacteria which are present 
there during perfect health, but which gain a foothold and multiply be- 
cause of favorable conditions produced by the chilling of the skin. Exactly 
what those conditions are is not clear, although it is generally vaguely 
stated that chilling of the skin causes congestion of the internal organs. 
This seems an inexact explanation, since congestion is usually rather inimi- 
cal, than otherwise, to bacterial invasion (Bier). The investigations of 
Mudd and Grant have shown, however, that if, when the skin is experimen- 
tally chilled, a thermopyle is applied to the mucosa of the nasopharnyx it 
shows a corresponding fall in temperature, indicating that the chilling of 
the skin causes a reflex vasoconstriction in the mucosae. This anaemic LIGHT AND OTHER RADIANT ENERGY: ELECTRICITY 
385 
condition is much more compatible with the invasion of bacteria than the 
congestion which we formerly assumed to occur. That some definite 
change is brought about is plain, however, from the fact that the same sort 
of exposure will cause painful stiffness in the muscles of the neck or back, 
which must be of inflammatory character (muscular rheumatism), while 
in other persons it brings on an attack of diarrhoea. Probably in all 
instances the chilling acts as a predisposing factor, favoring the invasion 
of 'bacteria, but it must be remembered that, although it is common in 
pneumonia, coryza, etc., it is by no means an indispensable factor, and 
every one realizes that it is perfectly possible to catch a cold from some 
one who is already suffering,without having been chilled. 
Lambert: Jour. Exp. Med., 1913, xviii, 406. 
Marchand: "Die Kalte als Krankheitsursache," Krehl and Marchand, Handb. d. allg. 
Path., 1908, i, 541. 
Mudd, S., and Grant, S. B.: Jour. Med. Research, 1919, xl, 53. 
Rischpler: Ziegler's Beitriige, 1900, xxviii, 541. 
LITERATURE 
LIGHT AND OTHER RADIANT ENERGY: ELECTRICITY 
No attempt can be made here to discuss in detail this subject, which be- 
comes daily more complex with the astounding discoveries in the realm 
of physics. References to recent works which present the subject from its 
physical aspect are given, so that the student may consult the literature. 
Nature of Different Rays.-Radiant energy takes the form of rays moving with the 
same velocity, but with different wave lengths, according to which its peculiar character 
varies. Analyzed into a complete spectrum, it appears that the rays of greatest wave 
length are electric; then follow thermic, optically visible, and finally chemically active, 
rays, which have the minimal wave length. The atoms of each substance contain 
electrons which are positively and negatively charged. The vibrations of these electrons 
communicate electromagnetic vibrations to the ether. These waves, impinging upon 
other bodies, are absorbed by their electrons, which vibrate at the same rate, and since 
the electromagnetic vibrations of the negative electrons have the wave length of the 
ultraviolet rays, the latter are readily absorbed. 
Some substances have the power, when thus influenced by certain radiations, of giving 
forth light-rays of another quality. This so-called fluorescence is of great biological 
significance. 
Other forms of radiant energy, different from the electromagnetic transverse vibrations 
of the ether, are the so-called corpuscular rays, which consist in an actual bombardment 
of negative electrons at a velocity somewhat less than that of light. Where they impinge 
upon metals, they produce the Rontgen-rays. The positively charged electrons pass in 
the other direction, and correspond to the a-rays of radium. The shower of negative 
electrons, the kathode rays, correspond with the /3-rays of radium. Where kathode 
rays strike upon metal or glass, there are produced the y-rays, which are emanated from 
radium and are related to the Rontgen-rays. Like the electromagnetic rays, these 
corpuscular rays may produce electric, thermic, optic, and chemical changes (Aschoff). 
Effect of Light Upon the Tissues.-General.-Ordinarily we meet with 
conditions in which the tissues are acted upon by a whole series of different 386 
TEXT-BOOK OF PATHOLOGY 
forms of radiant energy at once, and until recently no attempt has been 
made to analyze accurately these effects, and to experiment with them by 
separating the waves of different length and allowing them to act alone. 
Of the visible or optically active rays, it has been said that those toward 
the red end have the longer waves and are associated with effects of heat- 
beyond the red rays are invisible rays with long waves, which are merely 
heat-waves. On the other hand, toward the blue-violet end the waves are 
shorter, and their photochemical action is intense; far beyond the violet 
are invisible rays spread out in the spectrum which have the greatest power 
of influencing chemical action. These very short-waved rays correspond 
most closely with the vibration of the negative electrons of the tissues, and 
are quickly absorbed by the most superficial layers, especially when they 
are colored by pigment deposits. I he red and infra-red rays penetrate 
much deeper. 
Little effect is produced by the red rays as compared with the violet 
and ultraviolet. They are capable of producing an influence upon cells 
only in the presence of oxygen. The ultraviolet rays have a really intense 
effect on the tissues, in which they seem to act as catalytic agents. It is 
not quite clear how they produce their peculiar influence, but it is appar- 
ently through inducing intense chemical decomposition and oxidation. 
Their relation to the lipoid substances is peculiar in that the rays sensi- 
tize them and prepare them for oxidation or fermentative decomposition. 
An intracellular oxidation is brought about without the advent of extra 
oxygen, through the facilitation of decomposition of the lipoid substances 
by the action of the light. For this the red-yellow rays require an actual 
excess of oxygen. Ferments are affected also, but perhaps only secondarily, 
by way of the altered lipoids, which themselves, under the influence of light, 
acquire a photoactivity. 
Such effects may appear in extraordinarily contrasting forms, according 
to their intensity, so that at times a new impulse to growth is conferred, 
at other times the tissues are disintegrated and destroyed. A peculiar 
influence is exerted by fluorescent bodies, which may depend upon the new 
rays set free by them when exposed to light or to their acting in some way 
as sensitizers. In the dark their presence has no significance, but if bac- 
teria in a fluid containing eosin are exposed to sunlight, they are killed very 
rapidly. Enzymes, haemolytic substances, venoms and toxins, etc., are 
weakened or destroyed in the same way. The tissues of higher animals 
seem to be exposed to a new intensity of action of light-rays if they are 
impregnated with eosin or some similar fluorescent material (cf. Flexner, 
Noguchi). 
Sittenfield found, as Tappeiner and others had already observed, that 
animals injected with minute quantities of haematoporphyrin remained 
normal when kept in the dark, but died quickly when exposed to sunlight 
or to the rays of an arc lamp. In the kidneys and other organs of these 
animals there were to be found distinct lesions in which fragmentation of 
nuclei and disintegration of cells were conspicuous. The part played by LIGHT AND OTHER RADIANT ENERGY: ELECTRICITY 
387 
the fluorescence is, however, still uncertain, for some of the most highly 
fluorescent substances are but slightly toxic under exposure to light. Mrs. 
Clark, after studying the effect of such substance as eosin on rennin, inclines 
to the idea that the inhibition of the action of the rennin is due to the de- 
composition of the eosin with the liberation of its halogen constituents, but 
v. Tappeiner showed that paramoecia were killed and disintegrated in an 
illuminated solution of eosin even when it was neutralized, but maintained 
their form for hours in a solution in which free acid had killed them. It is 
evident, as Seilards says, that the subject is as yet comparatively unde- 
veloped. 
Effects of Ultraviolet Rays.-The sun's light contains the ultraviolet 
rays, together with all the others, but they are produced much more abun- 
dantly by the electric arc and other artificial light. We may consider their 
pathological effects and their therapeutic use in pathological conditions. 
Exposure to the sun or its reflected rays (from the surface of water or 
snow) produces the familiar sunburn. This is far more intense upon the 
tops of high mountains than at the sea-level, where the ultraviolet rays are 
to a great extent absorbed by the thick layer of the atmosphere. 
The effect is not noticed at once, but after some hours there comes 
on an intense inflammatory reaction which is painful and often accompanied 
by blisters. The conjunctivae also become inflamed. Evidently there is 
definite injury to the skin, for layers of it peel off after the inflammation 
has subsided. The blisters may leave white, scarred patches with pig- 
mented border. Pigment is increased in the skin, and is recognized as 
distinctively protective in its function. Every one is familiar with the 
people who burn, others who acquire freckles, and still others who tan 
gradually to a dark brown without much suffering. The dark pigmenta- 
tion of southern races and of negroes is evidently a protective adaptation 
for those living in hot countries. 
Histologically, the epidermis in the sunburned place is found loosened 
and vacuolated, exudate permeates the corium, blood-vessels are widened, 
and in every respect the inflammatory reaction is like that produced by 
some mild chemical irritant. Occasionally the repetition of such sunburn 
in certain persons produces a chronic condition of pigmentation and ex- 
cessive keratinization which may lead to cancer formation (the so-called 
xeroderma pigmentosum). In other persons the subject of certain diseases, 
such as smallpox, pellagra, etc., the sensitiveness to the effects of light is 
much intensified, and the example of buckwheat rash in cattle seems to 
make it probable that this susceptibility is due to the existence of a sensi- 
tizing or fluorescent substance in the tissues in those diseases. 
Therapeutic use of ultraviolet and other rays is made in virtue of their 
more or less specific destructive influence upon pathological tissue elements. 
The epithelioid cells of cutaneous tuberculosis (lupus vulgaris) are especially 
susceptible to this effect. Certain rays of short wave length are capable 
of causing an increase in the number of lymphocytes, and this may be an 
explanation of their beneficial effect, especially upon tuberculosis of bone. 388 
TEXT-BOOK OF PATHOLOGY 
On the other hand, smallpox patients are kept in rooms from which the 
ultraviolet rays are excluded by red glass in order to protect their sensitized 
skin. Most interesting is the recently demonstrated power of the ultra- 
violet rays to cure rickets. In this respect they seem to exert as sure and 
as specific an influence as cod-liver oil, and further, it appears that the 
tetany which so often accompanies rickets can also be cured by exposure 
to these rays. 
LITERATURE 
Bering: Lubarsch u. Ostertag Ergebn., 1914, xvii, 790. 
Clark: Amer. Jour. Physiol., 1918, xlvii, 251. Physiological Reviews, 1922, ii, 277. 
Seilards: Jour. Med. Research, 1918, xxxiii, 293. 
v. Tappeiner and Jodlbauer: Wirkung fluoreszierender Stoffe, Leipzig, 1907. 
The Effects of x-rays and Radium on the Tissues.-In an x-ray tube the rays which 
start from the kathode and play on the anode (kathode rays) are really streams of nega- 
tive electrons which impinge upon the metallic anode, and there cause the production of 
electromagnetic vibrations of the ether which are very short, very irregular, and dis- 
continuous. These are the Rbntgen-rays. There is a stream of positively charged 
electrons passing in the opposite direction, which, if the kathode is perforated, pass 
through the holes and are, therefore, called channel rays. From radium there are given 
off analogous rays, the a-rays, which, like the channel rays, are really a corpuscular 
stream of positively charged electrons swung off from the decomposing atom, while the 
similarly discharged stream of negatively charged electrons constitutes the /S-rays, 
which correspond with the kathode rays. These, through striking on metal or glass, 
produce -y-rays, in just the same way as the kathode rays produce the Rbntgen-rays. 
They are like the Rbntgen-rays, but have a much greater power of penetration. 
By the use of adequate filters the effect of the different rays can be analyzed. 
Rbntgen-rays have little injurious effect upon bacteria, but the a- and 
/3-rays from radium kill them directly, although they do not render the 
medium in which they grow poisonous to them, as light-rays do. Toxins 
are variously affected, but the toxalbumins, such as snake venoms, are 
weakened by radium-rays. 
In the case of animals and man, the action of Rbntgen-rays and radium- 
rays is very similar, the /3-rays behaving like the kathode rays. Their 
effects have been studied especially in certain susceptible persons, in whom 
the so-called x-ray burns have appeared after a relatively short exposure 
for diagnostic, or therapeutic purposes, and also in radiologists who have 
been careless in exposing their hands in operating the apparatus. Now that 
protection is afforded the radiologist by leaden screens, and the patient 
screened by a thick aluminum plate, the corpuscular rays which seem 
responsible for the injurious effects are eliminated, and burns are becoming 
a matter of history. 
The Skin.-Although in some cases a reddening of the skin appears at 
once, this is usually due to heat, and the real effects of the burn become 
evident only after a long latent period of about two weeks. Then the skin 
becomes swollen and reddened, the hairs fall out, and a pigmentation ap- 
pears. Blisters and excoriations with fibrinous exudate may persist for a 
time, or the skin becomes a necrotic slough over the affected area. Such 
ulcers as result from the discharge of this dead tissue show only slow at- LIGHT AND OTHER RADIANT ENERGY: ELECTRICITY 
389 
tempts at healing, and repair is never complete, as is pointed out by Wol- 
bach in some of his cases examined many years after the last exposure. 
The hands of radiologists show best the chronic effects of long-repeated 
brief exposure, the lesions dating usually from the early days of radiology, 
when they neglected or were ignorant of screens. Really dreadful distor- 
tion and disfigurement have resulted in many of these men. The skin is 
dry, reddened, and scaly, with painful fissures and cracks here and there 
which refuse to heal, or after healing give place to others. The hairs are 
lost, and with the later atrophy of the skin sweat-glands also disappear. 
More extensive ulcerations, which are likewise very persistent, occur. 
The nails are thin and brittle, and are usually badly split and broken. 
Wolbach has described the histological changes in many cases, and finds 
that the epidermis in places produces excessive dense keratinized layers; 
in other places the cells maintain their plump, deeply staining nucleus, 
and show no tendency to keratinization. At times vacuolated and evi- 
dently in process of downfall, the epidermal cells are often found in active 
mitosis growing downward into the corium. The corium is indurated in 
its depths, rarefied in the more superficial layers, where it becomes poor in 
cells and blood-vessels, and may show areas of necrosis. The capillaries 
which are there often become greatly distended, and are even so much 
widened as to give the appearance of telangiectases, through the skin. 
Such wide capillaries often become thrombosed, and Wolbach describes 
the invasion of these by the growing epithelial cells. Obliteration of ar- 
teries and veins and of capillaries in these layers of the skin by changes in 
the endothelium and by thrombosis and later organization, seems to him 
responsible for much of the necrosis in the corium and the inability to heal. 
With the destruction of the corium in foci, the epidermis is stimulated to 
grow down, invading unusual positions. It is not surprising, therefore, to 
find that this brings about actual epithelial tumor growth. There are 
many cases in which a proliferation of the epithelium, at first indefinite, 
later becomes recognizable as an actively growing skin cancer, which de- 
stroys the tissues in its line of progress and metastasizes into other organs. 
More will be said of this later, as it offers a point at which the study of 
cancer development seems promising. 
The Blood-forming Organs.-Prolonged exposure to x-rays quickly di- 
minishes the number of lymphocytes in circulation; the other leucocytes 
are affected slightly, but the red corpuscles seem, if anything, to increase 
in number. Brief exposure, on the contrary, causes an increase in the 
lymphocytes. Cases of leukaemia treated with x-rays sometimes show an 
extraordinary reduction of the white cells in the blood, while the red cor- 
puscles are unaffected. Doubtless the influence is upon the blood-forming 
organs, which are especially sensitive to these rays. The spleen is quickly 
reduced in size and becomes much pigmented. In the thymus the 
lymphocytes disappear rapidly, and even the framework of epithelial cells 
is injured. Lymph-glands lose their lymphocytes and become mere 
skeleton frameworks. In the bone-marrow the red corpuscles do not 
suffer, but the lymphocytes and myelocytes are destroyed. 390 
TEXT-BOOK OF PATHOLOGY 
An animal thus deprived of its lymphocytes has been shown by Murphy 
to be far more than normally susceptible to tumor implantations and also 
to tuberculosis. On the other hand, Sittenfield and Kessel have thought 
they observed a retardation of the invasion of tubercle bacilli after exposure 
to x-rays. 
Genital Glands.-Testes and ovaries are also highly susceptible to the 
injurious influence of the radiation, the cells of the testicular tubules which 
produce the spermatozoa being especially affected there, while interstitial 
cells of Leydig and Sertoli cells are apparently resistant. After sufficiently 
long exposure the spermatic fluid is found to be devoid of spermatozoa. 
In the same way the Graafian follicles in the ovary suffer, although it is 
less easy to determine whether complete sterility is produced in that way. 
Other Organs.-In all the other organs similar, if less definite, changes are 
produced, destructive when the exposure is intense enough, but rather 
stimulating to proliferation and cell division when less intense. Experi- 
mental radiation of developing eggs and embryos usually produces either 
death or the development of malformations of all sorts. 
Pathological tissues seem to be especially susceptible to destruction by 
these rays, whether derived from radium or the x-ray tube, and a great 
deal of work has been done upon their application in the case of cancers 
and other tumors, as well as in the treatment of various skin diseases and 
in leukaemia, Hodgkin's disease, and other affections of the blood-forming 
apparatus. This is not the place to discuss the results, but it may be said 
that while the effects are only palliative in advanced tumors and those in 
which metastases have already formed, there are some tumors, especially 
those of sarcomatous or lymphosarcomatous nature, such as occur commonly 
in the nasopharynx, which melt away as though by magic under their in- 
fluence. Janeway comments on this and also refers to good results in cu- 
taneous epitheliomas. In leukaemia a temporary improvement may be 
produced, but I saw one case recently in which the irradiation of a mediasti- 
nal lymphosarcoma coincided with the appearance of leukaemic changes 
in the blood, soon followed by death. The destructive changes in the cells 
of tumors exposed to these rays have been studied by Alter. 
LITERATURE 
Janeway, H. H.: Surg., Gyn., and Obst., 1918, xxvi, 233. 
Boggs, R. H.: Amer. Jour. Med. Sei., 1918, clvi, 690. 
Alter, N.: Jour. Med. Research, 1919, xl, 241. 
EFFECTS OF ELECTRICITY 
Electric waves, such as the Hertzian waves, are not known to have any 
effect upon living beings. Most important are the effects of the passage, 
through the body, of powerful currents of electricity from artificial sources 
or from lightning. 
Judicial electrocution or the accidental contact of the body with the 
conductors of some light or power current furnishes examples of the former. EFFECTS OF ELECTRICITY 
391 
In electrocution the contact is carefully arranged, so that the current will 
pass through the nervous system. In accidents it usually happens that 
the person touches an overhanging conductor and allows the escape of the 
current through his body to the ground, or forms with his body a short 
circuit between two conductors. In the case of lightning he becomes in 
the same way a conductor through which the discharge from the cloud 
passes to the earth. 
Except for the so-called lightning figures, which Jellinek ascribes to 
paralysis of blood-vessels, and which are branching red lines radiating over 
the skin, the effects of lightning and the passage of the electric current are 
the same. 
Fatal shocks may be produced by a direct current with electromotive 
force of 500 volts. With alternating currents the effect depends partly 
upon the rapidity of alternation, and when this is extremely rapid, as in 
the Tesla currents, its passage may become quite harmless. The effect of 
such electric shocks depends largely upon the resistance of the skin and of 
the whole body, and differs in different animals. Horses whose resistance 
to conduction is very slight are especially sensitive. 
The pathological effects are most evident in the skin and underlying 
tissues, where at the point of contact deep burns are produced, often de- 
stroying the tissue down to the bone. At the point where the current 
leaves the body a similar charred wound may be found, with an appearance 
almost like that of a gunshot wound, a resemblance which is often inten- 
sified by the singeing of the neighboring skin and by the radiating tears 
in the tissue. These wounds in non-fatal cases are, like x-ray burns, extra- 
ordinarily persistent and hard to heal. Riehl distinguishes four degrees of 
severity in the injuries produced by strong electric currents, and states 
that they are by no means to be confused with the effects of burns. The 
exact cause of death is not clear, since little is to be observed in the internal 
organs aside from small hsemorrhages and the curious, irregular streaks of 
contraction and hyaline change in the muscles described by Schmidt. 
There are great changes in blood-pressure and evidences of shock, but 
whether these are due to changes in the medulla oblongata or to direct 
action upon the heart it is impossible to say. 
Aschoff: Krchl and Marchand, Handb. d. allg. Path., 1908, i, 144. 
Councilman and Magrath: "Xeroderma pigmentosum," Jour. Med. Research, 1909, 
xxi, 331. Rich, Johns Hopkins Hosp. Bull., 1924. 
Flexner and Noguchi; Noguchi: Jour. Exp. Med., 1906, viii, 1, 252, 268; 1907, ix, 281, 
291; 1908, x, 30. 
Heineke: Mitth. a. d. Grenz, d. Med. u. Chir., 1905, xiv, 21. 
Jellinek: Elektropathologie, Stuttgart, 1903. 
Murphy: Jour. Exp. Med., 1914, xx, 397, and Riehl, G.: Munch, med. Woch., 1923, 1119. 
Porter: Jour. Med. Research, 1909, xxi, 357. 
v. Schlapfer: Pfliiger's Arch., 1905, cviii, 537; 1906, cxiv, 301. 
Schmidt: Verh. d. Deutsch, path. Gesellsch., 1910, xiv, 218. 
Wolbach: Jour. Med. Research, 1909, xxi, 415. 
LITERATURE CHAPTER XIX 
TYPES OF INJURY (Continued).-CHEMICAL INJURIES 
Nature of poisons: their varying effects. Reaction of organism; elimination, detoxica- 
tion, resistance. Auto-intoxication. Poisoning by illuminating gas, corrosive substances, 
cyanides. Chloroform, alcohol, metallic poisons, etc. 
CHEMICAL INJURIES 
Nature of Poisons.-Injurious chemical substances or poisons are those 
which enter into chemical reaction with the tissues in such a way as to 
injure them. All the activities of the body are based on chemical reac- 
tions, and many substances which we regard as foods are necessary and 
helpful to these chemical processes. Others which prevent them or actually 
destroy the structure of the cells are poisons. 
Many of the substances which derange the activities of the cells do so 
only temporarily, and are changed into some harmless form or excreted 
completely before long. It is difficult to say, therefore, in many cases, 
whether or not we should call them poisons, but in some instances the repe- 
tition, through years, of the slight effects of single doses leaves the organs 
much altered, and we realize, in recognizing this chronic poisoning, that 
each dose had its own injurious effect. 
It is essential to the complete understanding of the action of a poison 
that we should know its chemical composition, and that of the protoplasm 
with which it comes into relation, as well as the nature of the interaction. 
Perhaps even more important is a knowledge of the chemical process 
through which the cell carries on its function, and in which the poison inter- 
feres at some point, but at present it is only in the rarest instances that we 
possess all this information in accurate detail. 
The study of all types of poisons is the province of toxicology, but it is 
equally interesting to the student of pathology for whom the structural 
changes and alterations of function form the subject of investigation. 
These are so manifold that no attempt can be made to describe them here, 
and we must be content with an outline of the principles involved. 
Varying Effects of Poisons.-Without knowing why, we realize that the 
effects of many poisons vary greatly with their quantity and concentra- 
tion, so that while small doses stimulate the tissues to intensified biological 
activity, larger or more concentrated doses have the opposite effect, prob- 
ably because they render impossible some part of this activity. Often 
this is effected through making the tissue at first more sensitive, and then 
less sensitive, to the normal stimuli. 
When a poison produces definite structural changes in the cells, its 
392 CHEMICAL INJURIES 
393 
effect, so far as those cells are concerned, is permanent, although the 
animal may recover in virtue of the great reserve power of every organ, 
which can, with the remnant of its tissue, carry on the whole function 
long enough to tide over the crisis and allow new cells to form and repair 
the loss. But if, as is so common, the poisoning is repeated frequently, 
the efforts at compensation and repair finally become inadequate, and the 
man with advanced chronic nephritis dies from the effects of renal in- 
sufficiency. 
The extraordinary resources in the face of such attacks, and the long life 
that may be dragged out with such injured organs, are very striking, in 
contrast with the sudden violent symptoms and death which follow a 
rapid and extensive destruction of their tissues. Of course, in the latter 
case the margin of safety is overstepped, and there is not enough tissue 
left alive to carry on the organ's function, but in the former, where the 
destruction is gradual, there is a chance for accommodation to the reduced 
efficiency of the organ. 
Unlike these poisons, there are others whose action is a temporary or 
invisible one; the functions of the tissue elements are disturbed only while 
the poison is dissolved in their fluids, and quickly return to the normal 
when it is washed away. A familiar example is found in the awakening 
from narcosis, during which the ether or chloroform is thought to be dis- 
solved in the lipoids of the brain-cells. 
The body has numerous fairly effective methods of removing poisonous 
substances, or even of protecting itself against their action. Irritating 
corrosive substances are vomited from the stomach, which throws out a 
thick, tough layer of tenacious mucus to protect its mucosa against what 
remains. Elimination of poisons is hurried by the development of 
diarrhoea, but also occurs, in the case of volatile substances, through the 
breath, and in the case of many others through the kidneys or the in- 
testinal mucosa. 
In the case of some poisons, such as arsenic, opium, cocaine, alcohol, 
etc., it is a matter of common knowledge that habitues become able to 
take far larger doses than other people without any poisonous effect. The 
explanations attempted for this are very unsatisfactory, especially, perhaps, 
with regard to the hunger for morphine and alcohol which these people 
develop when the drugs are denied them, and which often produces such 
stormy symptoms. No such theory as Ehrlich has devised for the immu- 
nity or resistance which comes after poisoning with bacterial or animal 
poisons will apply here, for the mechanism seems to be quite different and 
is still to be discovered. In the case of arsenic it is said that the larger and 
larger doses of the drug fail to poison because the intestinal mucosa acquires 
the power of refusing to absorb it, so that even in a person able to swallow 
an enormous dose without any ill effects the subcutaneous injection of the 
same material is just as poisonous in small doses as it would be to the most 
unaccustomed person. 394 
TEXT-BOOK OF PATHOLOGY 
The mechanism of resistance to bacterial toxins, snake venoms, and 
some related plant poisons, such as ricin and abrin, has been detailed else- 
where. (Cf. Zinsser.) Its far-reaching importance cannot be over- 
estimated, but even this mechanism may be turned to unfortunate use at 
times, as it seems to be in producing the anaphylactic poisoning and injury 
to the tissues (Longcope, Jobling). 
On the other hand, there are some poisons, such as strychnine and digi- 
talis, which have a so-called cumulative effect, in that successive doses 
seem to build up their effect upon those which have gone before, and act 
with increasing intensity. 
While rapid elimination and variously acquired resistance thus work 
toward the warding-off of the effects of many poisons, there are many 
which are neutralized in other ways by losing their chemical characters 
under the influence of the body. Inorganic poisons, when they are simple 
combinations in the form of a salt, are dissociated as electrolytes in the 
body fluids, and the action is an action of separate ions. Arsenic, mer- 
cury, and lead act in this way, as kations, in virtue of their metallic pecu- 
liarities, while the anion in sodium bromide or fluoride or iodide is the one 
which appears as a poison. When the combination is very stable and com- 
plex, these metals may be introduced in forms in which they are not 
easily dissociated, and then fail to unfold their characteristic poison- 
ous effects. It is further true that combinations of atoms, in themselves 
innocuous, may acquire, in virtue of their peculiar arrangement, toxic 
characters of the greatest intensity. Therefore it is not surprising that 
mere processes of oxidation may sometimes be capable of disarranging 
this fatal combination and rendering the poison inert. Similarly, syn- 
thetic combinations may occur with the same result-carbolic acid, in 
itself a violent poison, becomes harmless in the form of a double ethereal 
sulphate, while other substances are decomposed, sometimes to render 
them innocent, at other times only to liberate a more poisonous combi- 
nation. 
Interesting and complex antagonisms between various inorganic sub- 
stances occur in their action upon cells, and in so far as they are not mere 
precipitations of the poison, are very hard to explain. Meltzer has shown 
that the injection of a calcium salt will awake instantly, from the deepest 
coma, a rabbit poisoned with magnesium, and the papers of J. Loeb throw 
much light upon similar antagonistic action between calcium and sodium 
or potassium salts, and many others, as tested on developing eggs, muscular 
activity, etc. He at least proves that it is not merely the neutralization 
of differently charged ions. 
No effort shall be made here to give a classification of poisons; the stu- 
dent is referred to text-books on toxicology and pharmacology. In general 
poisons are derived from inorganic or mineral sources, from plants, 
including bacteria and fungi, and from animals. Of the inorganic sub- 
stances, the most familiar poisons are the salts of heavy metals, such as ABSORPTION AND GENERAL EFFECTS OF POISONS 
395 
lead, arsenic, antimony, mercury, chromium, manganese, etc., and the 
halogen group, fluorine, bromine, iodine. /From plants come great num- 
bers of highly poisonous alkaloids and glucosides, oils, terpenes, alco- 
hols, and coal-tar products, as well as all the enormously complex toxins 
produced by bacteria and moulds, which have the special peculiarity of 
stirring up resistance and immunity in the poisoned animals. Quite 
similar in this respect are those other plant poisons of which ricin and abrin 
have already been mentioned. From animals there originate many vehe- 
ment poisons, of which those specially secreted in glands for offensive pur- 
poses (snake venoms, etc.) are the most interesting. Other animal products, 
especially the partly digested or disintegrated proteins, such as albumoses, 
seem to be poisonous when introduced subcutaneously or intravenously; 
although they, like snake venoms, are innocuous if swallowed. These 
protein materials, including the venoms, also have the power of inciting a 
reaction of immunity, and, indeed, one can, by injecting frequently the 
proteins or the cells of one animal into another of a different species, pro- 
duce in the blood of that second animal a substance which would be dis- 
tinctly poisonous if now injected into the body of the first. Such cyto- 
toxins, which include haemolytic sera, have already been referred to. 
Different in principle is the development of poisonous substances in 
putrefying fish or flesh. Although part of these familiar sudden and vio- 
lent poisonings, which may end fatally in whole groups of people who have 
partaken of stale shellfish, fish, meats, or milk products, have long been 
ascribed to ptomaine-poisoning, it is possible that in most cases such epi- 
demics are really due to infection with certain bacteria (B. botulinus of 
Van Ermengen, B. enteritidis of Gartner, and allied forms). 
Much is written of autointoxication, or the absorption of poison from 
some place where it is formed in the body itself. In so far as the proper 
evacuation of the excreta is interfered with by obstruction or disease of 
the excretory organs, this is easily comprehended. Obstruction of the in- 
testine may be rapidly fatal, and so, too, may such disease of the kidneys, 
or obstruction to the outflow from ureters and bladder as can stop or 
greatly decrease the excretion of urine. Ursemic poisoning falls into this 
latter class. The absorption of bacterial poisoning from the unobstructed 
and otherwise not diseased intestine has long been widely accepted, but 
must be taken with caution, while it seems more confusing than helpful to 
class the alterations of metabolism which follow disease of the organs of 
internal secretion as autointoxication. Most of these are in reality the 
effect of the lack of some secretion proper to the injured gland, although, 
of course, in the imperfect metabolism, toxic substances may arise, as in 
the case of ^-oxybutyric acid in diabetes (q. v.). 
Most poisons are taken into the digestive tract, although volatile or gaseous 
poisons may be absorbed in the lungs, and other substances, such as mer- 
ABSORPTION AND GENERAL EFFECTS OF POISONS 396 
TEXT-BOOK OF PATHOLOGY 
cury, may penetrate the skin, or, as in the case of snake-venoms or the 
drugs administered in a hypodermic syringe, be introduced directly into 
the tissue or the blood-stream. 
They act locally, as when strong acids or alkalies or caustic metallic 
salts corrode and kill the tissues, or else they are absorbed into the blood 
and then exercise a more general effect. When poisons are introduced 
into the streaming blood, they disappear very rapidly and are not to be 
quantitatively recovered from the blood, nor equally from all organs, but 
often concentrate themselves in certain tissues with a markedly selective 
action. Under such circumstances the poison often reaches the nervous 
system or other vital organs in greater concentration than after the slower 
absorption from the alimentary tract. Naturally, in the case of bacterial 
toxins and the less defined products of protozoan and other animal para- 
sites, the distribution of the parasites determines to a great degree the 
spread of the poison, although there are, at least, two bacterial infections 
(diphtheria and tetanus) in which the bacteria grow locally on a mucous 
surface or in a wound, and diffuse their poison throughout the body. 
It has been said that most poisons seem to show a certain selective 
action in the way they affect especially one organ or another. It would be 
better to say that those organs exhibit a special affinity for certain poisons, 
but it is usual to classify poisons as cardiac poisons, renal poisons, blood- 
poisons, etc. Since there is little in common among the members of 
such groups, the classification seems hardly rational, and we must be- 
lieve that the organ absorbs them and is affected by them for different 
reasons. For example, of the poisons which affect the central nervous 
system, narcotics, strychnine, and magnesium salts must behave very 
differently. 
Here, if anywhere, it should be easy to carry out the general aim of this 
book and set in order the pathological results on the basis of aetiology, but 
the number of poisons is so limitless, and their effects are so variegated, that 
any classification, to be at all accurate, must include an immense number 
of headings. For this space at least is lacking, and once more the student 
must be referred to works on toxicology and pharmacology. It is desir- 
able, however, to discuss briefly the very common forms of poisoning which 
are found at autopsy, and which occur nowadays usually in cases of suicide 
or in persons who have worked with poisonous materials in one of the dan- 
gerous industries. Doubtless in the old days, when poisoning was a fine 
art, the subject was vastly more interesting. 
Persons committing suicide by poison are generally ignorant of the pain- 
ful effects of the poison which they choose to take, but are impelled, by the 
lurid descriptions in the newspapers, to swallow what some other suicide 
is said to have taken. Hence whole epidemics of poisoning with bichloride 
of mercury have occurred recently. Many other substances are used 
because they can be obtained easily, and this is true of carbolic acid and 
cyanide of potassium, and of the ever-accessible illuminating gas. ABSORPTION AND GENERAL EFFECTS OF POISONS 
397 
Illuminating-gas Poisoning.-The essential factor in this is the carbon 
monoxide, which is present in greater concefitration in the so-called water- 
gas than in the other types of illuminating gas. Breathed into the lungs, 
it quickly replaces oxygen in the red corpuscles, by virtue of its very much 
greater affinity for haemoglobin and the tenacity with which it holds to this 
combination. It can be gradually washed away by prolonged breathing 
of pure air or oxygen, so that carbon monoxide haemoglobin is not a perma- 
nent and stable combination. The blood, and consequently all the organs, 
assume a bright, cherry-red color, which is little affected by the condition 
of asphyxia of the tissues, for it is as difficult for carbon dioxide to dislodge 
Fig. 195.-Carbon monoxide poisoning; symmetrical necroses in lenticular nuclei. 
the carbon monoxide as it is for the oxygen. There are usually fever and 
leucocytosis, but no direct injury to the lungs, nor, as a rule, pneumonia. 
It is common to find at autopsy symmetrical areas of softening with minute 
hsemorrhages in the corpora striata and lenticular nuclei of the brain 
(Fig. 195). 
Corrosive Poisons.-Strong acids and alkalies and some metallic salts, 
swallowed usually with suicidal intent, produce deep lesions in the stomach 
wall, which, while very characteristic when fresh, are more difficult to 
recognize as the typical effect of a particular poison when the persons sur- 
vive long enough to allow the digestive action of the gastric juice to reduce 
them all to a similar appearance. TEXT-BOOK OF PATHOLOGY 
398 
Nitric acid produces deep necroses in the stomach-wall which are dis- 
colored and mottled with white and black debris, but characteristically 
colored in places, at least, by the bright orange yellow of the xantho- 
proteic reaction. Hydrochloric acid fails to produce this color, while strong 
sulphuric acid chars the mucosa into a crumbly black mass. 
In all these cases the immediate effect is to make the stomach contract sharply, so 
that the crests of the folds of mucosa are pressed together and form a smooth surface, 
while the depths between are protected and secrete much thick mucus for their further 
protection. Distension of the stomach tends 
to make the effect more diffuse, but food, when 
present, aids in the protection of the mucosa. 
Carbolic acid is much favored by 
suicides, and is usually swallowed in 
concentrated form. White eschars 
about the mouth and in the oesophagus 
prepare one for the appearance of the 
stomach, in which again the crests of 
the folds suffer most intensely (Fig. 
196). They are covered with a white, 
opaque layer of necrotic tissue. Car- 
bolic acid is an excellent fixing fluid, 
and in microscopical preparation these 
areas of the mucosa seem perfectly 
normal. The fixation or coagulation 
may extend through the wall of the 
stomach and involve adjacent organs, 
which look as though they had been 
cooked. Lysol poisoning produces a 
peculiar effect in the stomach, and 
here, as in the case of carbolic acid, the 
deeper cells of the mucosa, killed but 
not fixed by the poison, are digested by 
the ferments of the stomach (Fig. 197). 
Uyeno has described extensive changes 
in the kidney from long-continued car- 
bolic-acid poisoning. These are hardly 
• to be found in the acutely fatal cases. 
Caustic alkalies are generally swallowed by mistake, and this accident is 
especially common among children in the south, where concentrated 
lye is sometimes used for household purposes. If they die, the gastric 
mucosa is found greatly swollen and haemorrhagic, and often rather gelatin- 
ous, from the direct effect of the alkali. If they survive, the destructive 
changes which are commonly produced in the wall of the oesophagus lead 
to narrowing of its lumen by scar tissue. Such strictures must be dilated 
to prevent starvation. 
Fig. 196.-Carbolic-acid poisoning. 
Coagulation of crests of the folds of 
mucosa in the stomach. 399 
ABSORPTION AND GENERAL EFFECTS OF POISONS 
Prussic acid and cyanides have no corrosive effect in the stomach, but 
the mucosa assumes a bright, chestnut-brown color which is characteristic. 
Here, as in carbolic-acid poisoning, the odor of the stomach-contents and 
tissue is a very great help in recognizing the nature of the poison. The 
cyanides cause death by their action on the nervous sytem and heart, and 
by their wide-spread interference with oxidation and ferment processes 
throughout the body. 
Fumes from nitric acid, which, according to Wood, are essentially nitro- 
gen tetroxide, although mixed with other oxides, may be inhaled in acci- 
Fig. 197.-Lysol poisoning. Superficial necrosis and partial digestion of the gastric 
mucosa. 
dents, explosions, etc., and may cause death, as in one case which we 
studied, with extensive desquamation of the lining epithelium of the 
lungs, with lobular pneumonia and oedema of the lungs. Strong ammo- 
nia and chlorine vapors have a somewhat similar corrosive effect, asso- 
ciated with other more general evidences of intoxication. 
It is impossible to discuss here all the manifold effects of the poison- 
ous gases used in the war, and the student must be referred to the 
special literature upon the subject. The most important gases used were 
mustard gas, the phosgene, chlorpicrine, chlorine group, and the arsine 
compounds. In brief, the lesions produced are summarized by Pappen- 400 
TEXT-BOOK OF PATHOLOGY 
heimer as follows: No data are available on the lesions in human beings 
from the arsine compounds. Mustard gas (dichlorethylsulphide) produces 
blisters on the skin after a long latent period. Its inhalation causes 
necrosis of the respiratory mucosa with formation of a diphtheritic mem- 
brane extending deep into the bronchi, and followed by purulent bron- 
chitis with regeneration of the epithelium, usually with squamous meta- 
plasia. All types of lobular, haemorrhagic, and interstitial pneumonia 
follow, sometimes resulting in gangrene, extensive organization, or 
bronchiectasis. Intestinal and cerebral haemorrhages have been found, 
and there is aplasia of the bone-marrow resulting in leucopenia. The 
changes caused by phosgene, chlorine, etc., consist essentially of extreme 
oedema of the lungs, coming on after a latent period with areas of 
atelectasis and emphysema. When recovery is not immediate, various 
types of pneumonia follow. No other visceral changes are observed. 
Other volatile substances can be absorbed through the enormous capil- 
lary surface exposed in the lungs, and take effect with a rapidity almost 
as great as though they had been injected into the veins. Among these 
chloroform, ether, and the other narcotics are most prominent. 
Chloroform has a distinctly poisonous effect, as is shown by the necrosis 
and fat accumulation which it produces in the liver. Its more rapidly fatal 
effects seem to be due to the paralysis of the heart which it brings about 
when administered in too great concentration. Evarts Graham states 
that the poisonous effect of chloroform is due to its decomposition within 
the cell with liberation of free hydrochloric acid. 
Alcohol is, of course, the commonest of poisons that affect huma^ 
beings. Methyl-alcohol in relatively small doses produces coma and death, 
or recovery with blindness. Its action is in part due to the fact that it is 
changed to formic acid in the tissues. Ethyl-alcohol has the well-known 
effect of producing drunkenness, and after protracted habitual use seems to 
give rise to many anatomical changes in the organs. The proof of this 
connection is not so clear as it should be, and is questioned by many, 
especially since such changes cannot be produced experimentally -with any 
degree of constancy. This is true of cirrhosis of the liver, which can be 
caused by so many other kinds of injury and which is absent in such a large 
percentage of those who have abused alcohol to the last degree for many 
years. Nevertheless, it is unreasonable to deny its part in this process, 
since it undoubtedly has poisonous qualities and seems capable of such a 
banal effect. Probably it acts in this respect in combination with some 
other poisons as shown in the recent work of Lamson, who finds that 
carbon tetrachloride is allowed to exercise its poisonous action, especially 
when alcohol is taken at the same time. The destructive effects upon 
the brain are more evident in the functional disturbances which are clearly 
traceable (delirium tremens; alcoholic insanity, etc.). With regard to 
the relation of alcohol to chronic nephritis, arteriosclerosis, etc., the same 
may be said as for cirrhosis of the liver. ABSORPTION AND GENERAL EFFECTS OF POISONS 
401 
Mention may be made of a few poisons absorbed by workers in various 
dangerous industries. This subject is so broad that the reader is referred 
to the special literature upon occupational diseases. 
Lead.-Chronic lead poisoning (saturnism) among painters occurs in 
pottery workers, white-lead workers, and many others who constantly deal 
with dusty operations with lead in various combinations, and is so common, 
as to assume great importance among industrial poisonings. Acute lead- 
poisoning is rare. 
Anaemia, intestinal colic, a bluish line along the gums of those who neg- 
lect the cleanliness of their teeth, paresis of the extensor muscles, resulting 
in the so-called wrist-drop and toe-drop, and occasionally outspoken mental 
disturbances are characteristic of this affection. Lead may be found in 
the brain, bones, kidneys, and liver in proportion varying according to differ- 
ent investigators. It is excreted in urine, faeces, saliva, bile, etc. 
In the blood there is decrease of red corpuscles, which show a baso- 
philic granulation, and there may be jaundice (icterus saturninus). The 
colic, which is very painful, is thought by Kobert to be due to an irritation 
of the motor nerve elements of the intestinal muscles and blood-vessels. 
A form of gout associated with chronic saturnism may be partly due to de- 
posits of a lead combination with uric acid. Local anaesthesia and blind- 
ness occur. Cerebral disease, the so-called "lead encephalopathy," with 
depression, delirium, convulsions, and even general paralysis, is found to 
be due to chronic degenerative changes in the cortical cells, vascular 
changes, scarring, and meningeal thickening, together with pigmentation 
and small haemorrhages. The condition resembles in some respects that 
found in dementia paralytica. 
The motor paralysis affects some cranial nerves, but more especially 
the spinal motor nerves, musculo-spiral, peroneal, etc. It is a peripheral 
neuritis, not primarily an affection of the anterior horn cells, and the 
muscles show a secondary degeneration, although retaining for a time their 
excitability. Chronic diffuse nephritis of the arteriosclerotic type, with 
extensive scarring, obliteration of blood-vessels and glomeruli, is char- 
acteristic of lead poisoning, and evidently depends largely upon the effect 
of the poison upon the smaller blood-vessels. 
Arsenic.-Once most extensively used for purposes of murderous poison- 
ing and for suicide, arsenic poisoning is now accidental or connected with 
its absorption from adulterated foods or from various paints, and dyes used 
in coloring wall-papers, cloths, etc. There may be expected, therefore, 
acute and slow chronic poisoning. Acute Form.-When taken into the 
stomach in poisonous doses, the effect may be rapid death from direct 
influence upon the brain and heart, but more often the symptoms are 
referable to the digestive tract, where the lesions are accentuated by the 
reexcretion of absorbed arsenic through the mucosa. Swelling, haemor- 
rhage, diphtheritic inflammation with ulceration, are characteristic, and 
in the mucosa of the stomach crystals or particles of the swallowed arsenic 402 
TEXT-BOOK OF PATHOLOGY 
persist. When Paris green or some other brightly colored combination is 
swallowed, this is a conspicuous feature. Fat accumulation in liver, kid- 
neys, and other intestinal organs is common. Chronic Poisoning-In 
the chronic forms which may appear late, after even one severe poisoning, 
the nervous system suffers especially, but conspicuous changes are found in 
the skin. The cutaneous lesions are manifold, the most extreme being 
forms of excessive keratinization and deep pigmentation. The nervous 
changes have the character of a neuritis, with paralyses, followed by mus- 
cular atrophy and contractures. There may be also cerebral disturbances 
of varying degree. Most important is the danger of blindness from 
arsenical destruction of the optic nerves, after the careless use of salvarsan 
and others of the newer synthetic arsenical remedies. Arsenic is finally 
lodged in the bones, and may long be recognized there. 
Phosphorus.-As an industrial poisoning in those who work in match 
factories, and as a poison accessible to all for suicidal purposes in the heads 
of old-fashioned matches, phosphorus is more important in Europe than 
in this country. Acute poisoning, with vomiting, depression, jaundice, 
haemorrhages, swelling of the liver, etc., may lead to death. Aside from 
the haemorrhages, which may be widely scattered, one finds intense icterus 
and great enlargement of the liver, with wide-spread necrosis and autolytic 
disintegration of the cells. Whatever cells are left are distended with fat 
and lipoid globules. With recovery, the liver decreases in size and may 
become greatly scarred. Kidneys, heart muscle, and even skeletal muscles 
are loaded with fat. Chronic poisoning occurs especially in those exposed 
to vapors of phosphorus, and is particularly characterized by producing 
necrosis of the jaws. This begins with suppuration at the root of a tooth, 
which sets free a quantity of pus, when it finally loosens and drops out. 
The destruction with suppuration does not cease there, but progresses, 
to destroy the whole jaw or even to extend into the neck. Evidently 
the aid of bacterial infection is necessary to the process. 
Mercury.-Suicidal poisoning with mercuric bichloride is at present in 
favor, since the public imagination is stirred by the detailed reports of 
several cases. A few years ago there were cases of the same sort of poison- 
ing due to the inordinate irrigation of wounds with this substance, which 
was used as an antiseptic. The poisoning from careless use of mercurial 
drugs or from the inunction of syphilitics with mercurial ointments is 
usually milder and more chronic in its course, and since it shows itself in 
salivation, the loosening of teeth, and foetor from the mouth, is likely to be 
checked before producing a fatal result. Industrial poisoning with mer- 
cury is not uncommon in such trades as mirror making, gilding, ther- 
mometer making, etc. 
The acute poisoning provokes intense gastro-intestinal symptoms, with 
pain, metallic taste, vomiting, diarrhoea, etc. The stomach shows various 
lesions, according to the nature of the poison and the dose. A large 
quantity of a solution of mercuric bichloride may fix the mucosa so that ABSORPTION AND GENERAL EFFECTS OF POISONS 
403 
it appears normal microscopically, although white and opaque to the 
naked eye. A solid tablet may it seems act intensely on one spot and cause 
the death of the tissue, with subsequent ulceration. If this be survived, 
the symptoms may practically disappear, but later others ensue-anuria 
and evidences of inflammation in the colon. Death follows days or even 
weeks later from renal insufficiency. Since mercury once absorbed is 
reexcreted through the mucosa of the intestine, it is surprising to find at 
autopsy the most intense diphtheritic and hsemorrhagic enteritis (Fig. 198). 
Mercury can be recognized by appropriate tests in the necrotic mass lying 
Fig. 198.-Mercuric chloride poisoning Diphtheritic and haemorrhagic colitis 
upon the mucosa, and in the mucosa itself. The kidneys present most 
extensive necrosis of the epithelium of the tubules, with deposition of cal- 
cium in and about the dead cells. Later, with the liquefaction of these 
cells or their disintegration by phagocytes, the calcium becomes coalescent 404 
TEXT-BOOK OF PATHOLOGY 
in irregular masses within the tubules (Fig. 127). The remaining epithelial 
cells proliferate rapidly, to replace those which were lost, and often be- 
come large protoplasmic masses with many nuclei, which act as phagocytes 
and engulf those which are in process of disintegration (Fig. 128). (Cf. 
Heineke.) 
It does not fall within the scope of this book to treat of the multi- 
farious effects of poisons of plant and animal origin. They might be 
classified according to their point of action, as in other text-books of pathol- 
ogy, and mentioned by name, but except for their discussion in other con- 
nections, it seems better to refer the student to works on toxicology where 
they are satisfactorily treated. 
Boehm: Krehl and Marchand, Handb. d. allg. Path., 1908, i, 198. 
Ford: "Plant Poisons and Antibodies," Centralbl. f. Bakt. u. Paras., 1913, Iviii, 129. 
Heineke: "Sublimate Poisoning," Ziegler's Beitrage, 1909, xlv, 197. 
Jobling: Jour. Exp. Med., 1914, xx, 37. 
Kobert: Lehrb. der Intoxikationen, 1902-1906, Stuttgart. 
Lamson and others: Jour. Pharmacology and Exp. Therap. 
Loeb: "Antagonistic Salt Action," Biochem. Zeitschr., 1911, xxxvi, 275. Jour. Biol. 
Chern., 1914, xix, 431. 
Longcope: Jour. Exp. Med., 1913, xviii, 678. 
Meyer and Gottlieb: Lehrb. d. exp. Pharmakologie, Berlin, 1914. 
Schall: "Aetzgifte," Ziegler's Beitrage, 1908, xliv, 458. 
Thompson: "Illuminating Gas Poisoning," Med. Record, 1904, Ixvi, 41; Occupation 
Diseases, New York, 1914. 
Uyeno: "Exp. Carbolic Acid Poisoning," Ziegler's Beitrage, 1910, xlvii, 126. 
Wood: Trans. Assoc. Amer. Phys., 1912, xxvii, 407. 
Peterson and Haines: Text-book Legal Medicine, Philadelphia, 1903. 
Welch: Pathological Effects of Alcohol, Boston, 1903. 
War Gases: 
Marshall, Lynch, and Smith: Jour. Pharm. and Exp. Therap., 1918, xii, 265. 
Mackenzie: U. S. Naval Med. Bull., 1918, xii, 173. 
Winternitz: Mil. Surgeon, 1919, xliv, 476. 
Warthin and Weller: Jour. Lab. and Clin. Med., 1918, iii; 1919, iv. 
Pappenheimer and Vance: Proc. Soc. Exp. Biol, and Med., 1919, xvi, 92. 
LITERATURE CHAPTER XX 
TYPES OF INJURY (Continued).-EFFECTS OF OBSTRUCTION 
OF THE FLOW OF CONTENTS OF HOLLOW ORGANS. OB- 
STRUCTION IN THE ALIMENTARY TRACT 
Salivary ducts: bile-ducts (gall-stones, cholecystitis, jaundice). Pancreatic ducts (pan- 
creatic cirrhosis, acute pancreatitis). Obstruction of digestive tract. (Esophagus, stomach 
(gastric ulcer). Intestine; varying mechanism of obstruction (hernias, intussusception, 
volvulus, compression or kinking by adhesions, paralysis, stenosis). 
The possession of a duct or canal for the discharge of secretions, or for the 
reception and transmission of fluid, gaseous, or even solid materials, is 
an arrangement common to a great many organs. Wherever this plan is 
made use of, there may arise obstruction of the canal, and the effects which 
follow are so much alike that it seems desirable to consider them together, 
and to regard this as one of the types of injury which underlie pathological 
processes. The mechanical principles are very nearly the same in. all, 
although it may at first glance seem absurd to bring together in any way 
such processes as bronchiectasis and hydronephrosis. As a rule, an 
accumulation of material occurs on one side of the obstruction, which causes 
the gradual widening of that part of the canal, while the part on the other 
side remains normal or even shrinks together. This and the general 
behavior of the organ depend, however, very largely upon whether the 
obstruction is complete or only partial. Some organs can go on secreting 
for a while, attempting to force their secretion into the duct against a com- 
plete obstruction, but in many cases they quickly stop all activity under 
those conditions and the duct never becomes distended. On the con- 
trary, when the obstruction is only partial or intermittent, secretion or 
the entrance of material into the canal goes on until it becomes greatly 
dilated. Examples from various parts of the body will make these princi- 
ples clear, and show further many modifying influences. These conditions, 
varying as they do, afford a large proportion of the operable disturbances 
which may be treated by the surgeon. 
RESULTS OF OBSTRUCTION IN THE ALIMENTARY TRACT 
Naturally, since the glands of the stomach and intestine open by indi- 
vidual canals, it is rare to find any obvious effect of their obstruction, 
although it is quite true that in some old inflammatory changes in the 
mucosa they may be constricted at their orifice or obliterated by healing 
processes so that their continued secretion distends them into tiny cysts. 
This is more frequent in the colon than elsewhere. But the accessory 
405 TEXT-BOOK OF PATHOLOGY 
406 
glands, which empty into the alimentary tract, are often victims of some 
form of occlusion of their ducts. 
In the salivary glands this is not especially common, but there do occur 
calculous concretions in the salivary ducts which partly or completely oc- 
clude them and cause inflammation and dilatation of the duct, with gradual 
atrophy of the gland. Such calculi are rough and irregular and white, and 
are composed chiefly of calcium phosphate and carbonate. 
Bile-ducts.-In the case of the liver, the canal giving exit to the biliary 
secretion is somewhat complicated by the presence of a reservoir, the gall- 
bladder, joined on laterally. Obstruction of the canal may, therefore, take 
place at such a point as to affect the whole system, only the lateral reservoir, 
or only the liver or portions of the liver. The obstruction may be caused 
by compression of these ducts from the outside at any point; by changes in 
their own walls, which, becoming thickened, encroach upon the lumen, 
or by some solid plug which may lodge at any point in their lumen. Not 
uncommonly these factors are found combined, as when there arises about 
an obstructing gall-stone an inflammatory thickening of the wall of the 
duct or even a tumor. 
Much has been said in discussing the rather broader topic, jaundice, 
about the important part played by various forms of obstruction in its 
development, and this need not be repeated. The principles underlying 
such obstruction are, however, well exemplified in the variegated phenomena 
which are associated with the formation of gall-stones (cholelithiasis). 
Gall-stones.-In the first place, it is becoming clearer in later years that the primary 
formation of gall-stones is itself largely dependent upon stagnation of bile, such as may 
arise in the gall-bladder if an intermittent or incomplete closure of the cystic duct be 
brought about by such things as tight lacing, pregnancy, or even the unequal sagging of 
the abdominal viscera. Then, although some bile moves in and out of the gall-bladder, 
there is stagnation, and even in the clear, uninfected fluid, cholesterine crystals may sepa- 
rate out and cluster about a central point until there is formed a solitary round or oval, 
slightly roughened, stone-like mass, which usually Res loose in the neck of the gall- 
bladder.* This is the first type named by Aschoff and Bacmeister, the radiate choles- 
terine stone (Fig. 199), because it is found on cross-section to be composed of coarse, 
radiately arranged crystals of nearly pure cholesterine, which project to produce the 
roughened surface of the stone. There is so little admixture of other materials that such 
calculi are quite clear or only pale yellow. Pure crystalline masses of this sort are not 
very common, for usually they become covered with yellow, brown, or greenish material 
by a secondary deposit. This happens when, after the stone has lain in the gall-bladder 
for some time, infection with bacteria arises around it and causes inflammation of the 
gall-bladder wall (cholecystitis). With the appearance of the inflammatory exudate, 
which is rich in calcium, there are deposited on the surface layer after layer of a com- 
bination of calcium and bilirubin. It may be emphasized that, whereas the cholesterine 
is a constituent of the bile and crystallizes out from it calcium appears in appreciable 
quantities only in the course of inflammation. Such a mixed stone with a nucleus 
* Recent investigations of Stewart, Hermann and Neumann, and others show that, 
during pregnancy, the blood and bile are rich in cholesterine. Doubtless this is important 
in the production of gall-stones, which are so common in women who have borne several 
children. Rothschild and Wilensky support this in their studies of the cholesterin con- 
tent of the blood in this and other conditions, but there are others who deny the relation. RESULTS OF OBSTRUCTION IN THE ALIMENTARY TRACT 
407 
Fig. 199.-Two large radiate cholesterine gall-stones, one of which is broken, together 
with several small, mixed pigment and cholesterine stones with outer covering of cho- 
lesterine. 
Fig. 200.-Subacute and chronic cholecystitis with gall-stones. There is one rounded 
stone of pure cholesterine, together with nine faceted mixed pigment calculi. The 
small irregular mass was found in the duct. 408 
TEXT-BOOK OF PATHOLOGY 
formed of cholesterine and a mantle of calcium bilirubin may be regarded as the second 
type. The mode of its formation by apposition is shown in sections by the fact that 
each projecting crystal of the cholesterine nucleus is separately covered by a layer or 
two of the brown mantle before the depressions are sufficiently filled up to allow the 
next layer to be laid on smoothly. 
There are other types, such as the laminated calcium cholesterine stones, and the soft, 
blackish green, calcium bilirubin concretions, which are usually formed in the hepatic 
ducts, and more rarely get into the gall-bladder; but all these are rarer and of less 
importance than the last form, which is the common ifiixed calcium bilirubin-cholesterine 
stone (Fig. 200). These form the great majority of all gall-stones, and occur sometimes 
in hundreds or thousands in a single case, although there may be only two or three large 
ones filling up the gall-bladder. These large ones are rounded or barrel-shaped and 
faceted where they abut on one another. The smaller ones vary in color from pure, 
silky white through yellow, brown, and green to black. They may be so small as to be 
almost like sand, or a centimetre or two in diameter. Often a great number of stones 
of almost exactly the same size may be found together. Usually they are faceted against 
one another, and fit together by their polished surfaces like dice. Sometimes, indeed, 
they seem to show the effects of rubbing, for several laminae may be exposed. On cut- 
ting through and polishing one of these there is found to be a soft, greenish-brown or 
yellow central mass which is composed of conglomerate crystals with much organic 
material and pigment, and then, surrounding this, there are laminae, often alternating 
in color, of a much denser consistence, and composed, as stated above, of a mixture of 
cholesterine with calcium bilirubin (Fig. 201). 
Ribbert's interesting study of these stones gives many details of their structure, 
showing that the central portion contracts upon drying in such a way that sharp clefts 
extend radially as far as the laminated outer part. He devised a new way of studying 
them in section, and finds that the part played by the calcium is perhaps less than gen- 
erally supposed. 
All the types of gall-stones described contain a great deal of organic material derived 
from desquamated epithelial cells and coagulated albuminous matter, as well as pigment. 
Many of them contain bacteria, and are formed in infected bile and within a gall-bladder 
which is inflamed, because in this vicious circle the presence of the stone aids in giving a 
foothold to bacteria, while they in turn, through the inflammation they set up, aid in 
the growth of the stone. 
The bacteria are of many sorts, but the typhoid and colon bacilli are common invaders, 
and doubtless the pyogenic cocci are important in causing the acuter forms of inflamma- 
tion. How they enter has been much discussed. Probably the typhoid bacilli, since 
they are distributed everywhere by the blood-stream, might reach the gall-bladder in 
that way, but they may also be excreted from the liver in the bile, and may be found 
there for months after convalescence from typhoid fever. There is some evidence that 
they may, by being agglutinated in clumps, produce nuclei upon which gall-stones may 
form, but this evidence is not conclusive, since it has been shown that bacteria may 
quickly wander into such stones. The lower end of the common duct is always infected, 
so that, especially when calculi lodge in the duct and obstruct the stream, bacteria may 
wander up in that way. The occurrence of cholecystitis following appendicitis seems to 
suggest the possibility that bacteria may be carried from the appendix by way of the 
portal vein, and back into those branches which drain the gall-bladder. 
Cholecystitis.-There is nothing peculiar about the inflammatory process 
in cholecystitis. The beginnings are seldom seen, but apparently infection 
takes place in the so-called Luschka's crypts, or under gall-stones which 
press on the wall. It commonly produces diffuse, abscess-like infiltration 
of the wall {acute phlegmonous cholecystitis), often with extensive ulceration 
of the mucosa. Gall-stones may come to lie in these deep ulcers, or even Fig. 201.-Gallstones of various types cut and polished. 4, 7, 13, 14 and 17 show 
primary gallstones at first composed of almost pure cholesterine, later covered with 
pigment. 3, 5, 6 and 11 are facetted secondary stones. 9 and 19 show well the thin 
laminae found under the facetted surfaces. RESULTS OF OBSTRUCTION IN THE ALIMENTARY TRACT 
409 
to pass through perforations in the wall if the ulcer goes deep enough, 
sometimes into a neighboring hollow organ, like the colon, if there have 
been adhesions, at other times into the open peritoneum. I have seen 
one case in which recovery took place after such a discharge of stones, 
and long afterward they were found hanging in fibrous capsules from the 
omentum like so many cherries. 
Occasionally the acute forms of cholecystitis heal completely, but usually 
there are many recurrences, especially when stones persist and bile is stag- 
nant, and the ulcerated mucosa, as well as the whole thickness of the wall, 
becomes much occupied by scar tissue {chronic recurring cholecystitis) 
(Figs. 202, 203, 204). The remnants of mucosa are thrown up into relief, 
and attempts at repair on the part of the epithelium result in the formation 
of distorted, gland-like structures, or even complicated, adenoma-like 
masses. Enormous thickening with rigidity of the connective-tissue walls 
may take place, and in these walls accumulations of wandering cells 
loaded with lipoid substances and bile-pigments give the whole a dull, 
ochre-yellow color. 
The mechanical effects of the gall-stones are manifold, for by no means 
all of them are passed down through the cystic duct to escape into the 
intestine. Some do make this descent, causing great pain, and may lodge 
at various points. Occluding the cystic duct completely, they prevent 
ingress and egress of bile. That which remains in the gall-bladder is soon 
absorbed, but the sac does not collapse, for it is full of a clear, glairy mucoid 
secretion from its own walls. When there are other stones in the gall- 
bladder, it often happens that its thickened wall shrinks down about 
them until there is no lumen left, and the whole gall-bladder is reduced to 
a mass of stones tightly bound in a fibrous covering. 
When the calculus passes into the common duct, jaundice results-a 
jaundice which may be lasting until the gall-stone is removed by opera- 
tion, or by its escape into the intestine, or until the death of the patient. 
In those cases where the stone is not large enough to occlude the duct 
completely, the jaundice may vary in intensity, but usually the accom- 
panying inflammation is enough to complete the obstruction. 
When the ampulla of Vater is large and receives both bile-duct and pan- 
creatic duct, and opens by a narrow orifice, the occlusion of this orifice 
by a small stone may cause the retroj ection of bile into the pancreatic 
duct, an occurrence which is followed by acute haemorrhagic necrosis of 
the pancreas, with all its sequelae. Large gall-stones which escape into 
the intestine may become impacted, and even be sufficient to cause an 
obstruction of the intestine. Other mechanical effects may be produced 
by these large stones if they remain in an adherent gall-bladder through 
the pressure which they exert upon the adjacent organs; and there 
are a number of cases reported in which great dilatation of the stomach 
has followed the partial obstruction of the pylorus produced in this 
way. 410 
TEXT-BOOK OF PATHOLOGY 
Fig. 202.-Acute and chronic cholecystitis with many faceted gall-stones. 
Fig. 203.-Large gall-stone impacted in neck of gall-bladder. Subacute and chronic 
cholecystitis. RESULTS OF OBSTRUCTION IN THE ALIMENTARY TRACT 
411 
Finally, the persistent presence of the gall-stones in one position in the 
gall-bladder may stir up a change in the character of the mucosa, so that 
a cancerous growth appears there and tightly clasps the gall-stone. In 
one case I saw a round, radiate cholesterine stone held as in a cup in the 
fundus of the gall-bladder by the thickened cancerous wall, which passed 
over abruptly into the thin, unaffected wall of the rest of the sac. One 
could hardly escape the impression that the presence of the gall-stone 
Fig. 204.-Chronic cholecystitis with scarring and diverticula. 
had produced this change in the mucosa, although this idea is by no means 
accepted by every one. 
In the liver itself obstruction to the escape of bile soon causes rupture 
of the walls of the bile-capillaries by destroying the liver-cells which form 
those walls. This is probably not merely a mechanical effect, but due to 
the poisonous action of the bile, as well as to the enforced inactivity of the 
cells. Indeed, Steinhaus, Beloussow, and others have described rather 
extensive necroses in the liver following in the wake of obstructive jaundice, 
and think that they may underlie the scarring seen in the so-called biliary 412 
TEXT-BOOK OF PATHOLOGY 
cirrhosis. It is precisely in the liver, however, that obstruction of the 
ducts may be survived by the organ for a long time in spite of the most 
intense jaundice. Is it possible that this is because the cells are so actively 
engaged in carrying on functions which have nothing to do with bile 
production, so that, even when that is stopped, they are not entirely 
inactive? At any rate, the effect of obstruction is far less obvious than in 
Fig. 205.-Margin of cholangitic abscess of liver, showing compression of liver-cells 
and layer of fat-laden phagocytes. There were multiple bile-stained abscesses resulting 
from obstruction by gall-stones and infection. 
the case of other glands. In those cases in which obstruction of the bile- 
ducts is accompanied by infection of their stagnating contents it is common 
to find numerous abscesses (Fig. 205) scattered through the liver and evi- 
dently formed about the bacteria which have penetrated into the smallest 
ducts. These cholangitic abscesses may become quite large and contain pus 
which is deeply bile stained. RESULTS OF OBSTRUCTION IN THE ALIMENTARY TRACT 
413 
LITERATURE 
Aschoff and Bacmeister: Die Cholelithiasis, Jena, 1909. 
Bacmeister: "Aufbau und Entstehung d. Gallensteine, " Ziegler's Beitrage, 1908, xliv, 
528. 
Naunyn: Klinik d. Cholelithiasis, Leipzig, 1892. 
Riedel: Pathogenese, etc., d. Gallensteinleidens, Jena, 1903. 
Ogata: Ziegler's Beitrage, 1913, Iv, 236. 
Ribbert: Virchow's Archiv, 1915, ccxx, 20. 
Rothschild and Wilensky: Amer. Jour. Med. Sci., 1918, clvi, 239, 404. 
Obstruction of the Pancreatic Ducts.-Usually there are two ducts 
opening separately, and sometimes hardly anastomosing in the substance 
of the pancreas. One of these, the duct of Wirsung, which usually opens 
with the ductus communis choledochus, is much more exposed to influ- 
ences which might block it than the other, the duct of Santorini, which 
opens separately. Tumors, especially adenocarcinomata of the head of 
the pancreas, gall-stones in the common bile-duct, aneurysms in neighbor- 
ing vessels, and pancreatic calculi in the duct itself are the commonest 
causes of its occlusion, and exert their effect upon that part of the gland 
which it drains. The rest, which is drained by the duct of Santorini, 
may remain quite normal. Of all these causes, probably the tumor growths 
most commonly produce the completer forms of occlusion, while with the 
passage of gall-stones temporary and incomplete obstruction may arise. 
Occasionally, whether from infection of the duct or other causes, the 
mucosa lining the smaller ducts may proliferate into such voluminous folds 
as to plug the duct and set up the most intense changes in its drainage area 
(Winternitz). Pancreatic calculi are like irregular, rough bits of marble, 
and are, as their appearance suggests, composed chiefly of calcium carbon- 
ate. Their impaction in the duct may again give a foothold for bacteria, 
and when they are surrounded by an abscess-like area of inflammation, the 
obstruction is usually complete. When some pancreatic juice can escape, 
the duct is apt to become greatly dilated, and even when none can pass, 
one usually finds that the duct is widened behind the obstruction, perhaps 
from an earlier stage in which it was incomplete. 
When the duct has been stopped up for a long time its drainage terri- 
tory is usually found extremely shrunken, hard, and leathery, in sharp con- 
trast to the well-preserved, lobulated part, which is still free to discharge 
its pancreatic juice by way of the other duct. Microscopically, one finds 
that the lobules have lost most of their acini and are hardly to be outlined. 
The remaining acini show a dilatation of their lumen and a thinning or flat- 
tening of the epithelial cells, and the whole of this persisting pancreatic 
tissue is embedded in abundant scar tissue, which has grown to replace 
those acini which are lost. It is evident that the damming-up of secretion 
under some tension and the enforced inactivity have led to the gradual 
disappearance of the secreting cells and their replacement by scar tissue 414 
text-book OF PATHOLOGY 
(Fig. 206). Here and in many other instances it will be observed that there 
is no evidence that the scar tissue is the cause of the destruction of the 
pancreatic cells. On the contrary, there is every reason to regard its 
presence as an attempt to heal the gap left by the loss of those cells, be- 
cause the islands of Langerhans, which occur in most of the lobules, and 
which are not connected with the pancreatic ducts, remain uninjured, and 
finally stand out conspicuously as about the only intact tissue left. Ex- 
Fig. 206.-Chronic pancreatitis following obstruction of the ducts. Fat and fibrous 
tissue have replaced many lobules of the gland. 
perimentally, we have ligated the duct of a large part of the pancreas in 
a dog, and found, after a year, that this portion was reduced to a thin 
film-a mere opalescence in the transparent mesentery in which pan- 
creatic acini had disappeared and only islands of Langerhans were left.* 
* MacCallum: Johns Hopkins Hosp. Bull., 1909, xx, 265. 
Kirkbride: Jour. Exp. Med., 1912, xv, p. 101. RESULTS OF OBSTRUCTION IN THE ALIMENTARY TRACT 
415 
Acute Pancreatitis.-There are several forms of acute destructive changes in the 
pancreas in which obstruction in some sense plays a part, if only by allowing the intro- 
duction of the injurious agent into the gland. These are acute haemorrhagic pancreatitis, 
with its less common sequel, gangrenous pancreatitis, and the more localized suppurative 
pancreatitis. 
Fitz, in 1889, made clear the existence of these three affections, and described many 
cases. Since that time much anatomical and experimental work has shed light on their 
nature, but even yet there are many obscurities. 
Fig. 207.-Acute haemorrhagic necrosis of pancreas: cholelithiasis and impaction of 
a small gall-stone in the common duct and in the ampulla of Vater. Abundant fat 
necrosis. 
Acute Hemorrhagic Pancreatitis.-This condition arises suddenly with violent symp- 
toms of pain, collapse, cyanosis, and vomiting. In these respects it resembles rather 
closely obstruction of the intestines at a high level. Death follows quickly with general 
intoxication in most cases. If the abdomen is opened, there is a blood-stained fluid in 
the peritoneum, and in the fat of the omentum and mesentery there are found opaque 
white patches of pasty consistence. These are areas of necrosis in the fat, and are indica- 416 
TEXT-BOOK OF PATHOLOGY 
tive of pancreatic disease. The pancreas is swollen and deep red or purplish-black in 
patches (Figs. 207, 208). On section, the brown or black patches are found to be rather 
dry and dull looking, and extend widely through the substance of the gland surrounded 
by hsemorrhage In places they may be softened. Opaque, white, necrotic patches 
are found in the fat in the interstices of the pancreas. Microscopically, the dark areas 
are found to be patches of necrotic pancreas, infiltrated with changed blood, and showing 
about the margins, at least, an intense acute inflammatory reaction. Sometimes nearly 
the whole pancreas may have undergone this coagulative necrosis with hsemorrhage 
Fig. 208.-Pancreatic fat necrosis in the omentum. 
and inflammation. Occasionally the process is so fresh that there is but little inflam- 
mation, and Chiari suggests the name "acute hemorrhagic necrosis" of the pancreas. 
The cause of this was quite obscure, until Opie discovered a case in which a small 
gall-stone had become impacted in the orifice of the ampulla of Vater in such a way that 
neither bile nor pancreatic juice could escape, although bile could run back from the 
common bile-duct into the pancreatic duct. Naturally, if the ducts had opened side by 
side instead of into a common ampulla, or if the stone had been too large to obstruct the 
orifice of the ampulla only, no such access of bile to the pancreatic duct would have been 
possible. Opie readily showed that injection of bile into the pancreatic duct would pro- 
duce acute haemorrhagic pancreatitis in animals, and Flexner showed that gastric juice 
and many other irritating substances would do so too. He found that fresh bile was. 417 
most effective, that much mucus rendered its action far milder and produced rather 
chronic effects. Several other cases have been found in which exactly the same un- 
fortunate combination of circumstances has led to the results found by Opie, but there 
are many cases in which no such good explanation is to be found. 
Any injury to the pancreas which causes the death of cells and allows the escape of 
pancreatic juice into the tissues seems to be capable of causing a little of such haemor- 
rhagic necrosis, and it is probable that this is at the root of the formation of those 
areas of gangrene which are sometimes found in its substance. Doubtless if the person 
could live after an extensive haemorrhagic necrosis, infection would follow by way of the 
ducts, and a putrefactive liquefaction of the dead tissue might occur. Whether such 
necrosis and self-digestion form the basis upon which localized infection and abscess 
formation occur in the gland is not so clear. The fact remains, however, that abscesses 
of considerable size are occasionally discovered there in cases in which intense symptoms 
point to their existence. 
The fat necroses (Fig. 208) are due to the dissemination of the ferments of the pan- 
creas, which are able, by the lipolytic action, to decompose the fat in the fat-cells which 
they have rendered necrotic. The neutral fats break up into free fatty acids and glycerin, 
and usually bunches of needle-shaped crystals of fatty acids are visible in these areas. 
Combinations with calcium salts often produce, in those situations, the insoluble white 
calcium soaps which add to the whiteness and opacity of the foci. Any injury to the 
pancreas which tears its tissue allows the dissemination of the ferments. In one case 
in which a small incision was made into a pancreas by accident in the course of an opera- 
tion there appeared a crop of fat necroses in the neighborhood. Ligation of the duct 
usually produces them. In the cases of acute haemorrhagic pancreatitis they are very 
wide-spread, and in animals in which this condition is produced experimentally they are 
found in the subcutaneous abdominal fat, and even in that of the pericardium and 
pleura. Lipases have been demonstrated in these areas, and also in the urine in such 
cases. 
Of course, there is nothing in common between these forms of haemorrhagic pan- 
creatitis and the so-called pancreatic apoplexy, which is a rapidly fatal haemorrhage into 
and about the pancreas from a large diseased artery. In one case at autopsy I found a 
retropancreatic haemorrhage of almost two liters which came from the rupture of the 
sclerotic pancreatico-duodenal artery as it passed through the head of the pancreas. 
OBSTRUCTION OF THE LUMEN OF THE INTESTINAL TRACT 
LITERATURE 
Balch and Smith: Boston Med. and Surg. Jour., 1910, clxiii, 384. 
Fitz: "Acute Pancreatitis," Boston Med. and Surg. Jour., 1889, cxxi, 607. 
Opie: Johns Hopkins Hosp. Bull., 1901, xii, 182. 
Watts: Southern Med. Jour., 1913, vi, 174. 
OBSTRUCTION OF THE LUMEN OF THE INTESTINAL TRACT 
The most extraordinary variety of phenomena, based on slight modifica- 
tions of a few underlying principles, occur here, and one might foretell 
easily enough the effect of obstruction at any given point. The same 
general types of occluding agent appear, but there are some modifications, 
owing to the strong muscular character of the wall of the canal. Foreign 
bodies in the lumen, tumors in the walls sometimes encircling the canal, 
constricting scars resulting from healing ulcers, twists and kinks and com- 
pression from outside by tumors or by constricting bands, the escape of a 
loop of intestine through a narrow hole in the abdominal wall, or the 
telescoping of a part of the intestine into itself-all these things and manv 418 
TEXT-BOOK OF PATHOLOGY 
others may impede the flow of the intestinal contents in the normal direc- 
tion. Even the mere lack of propulsive muscular contractions over a 
length of intestine may be enough to allow the contents to stagnate and 
give the symptoms of obstruction (paralytic ileus). 
(Esophagus.-Two common causes of oesophageal obstruction exist, 
namely, the narrowing of the lumen by the shrinkage of scar tissue formed 
in the healing of an ulcer caused by the swallowing of some corrosive poison, 
such as concentrated lye, and, secondly, the encroachment of a cancerous 
tumor growing from the mucosa. Other things, such as the pressure of a 
tumor or an aneurysm from the outside, may have a similar effect, and 
make it difficult or impossible for food to pass into the stomach. Extreme 
narrowing, usually at the cardiac end of the oesophagus, may be produced, 
in the stricture following ulceration, but since the food is easily regurgitated, 
there is usually no great dilatation of the canal above the closure, nor any 
very marked hypertrophy of its muscular walls. 
On the contrary, in some rare cases, of which we have recently seen one, 
without any apparent obstruction the oesophagus may be found enormously 
lengthened and widened, so that it sags and kinks, and food is regurgitated 
unchanged without ever entering the stomach. There seems to be no 
explanation except that this may be a congenital anomaly. More local- 
ized dilatations are the traction and pulsion diverticula. The traction di- 
verticula are common, and usually small and funnel shaped; they arise 
from the persistence of connections between the oesophagus and trachea, 
or from the adhesion and contraction of adjacent inflamed lymph-glands. 
The pulsion diverticula are the outcome of local weakening of the wall and 
the forcing out of a hernia-like sac. These may become quite large, and 
are annoying in that they receive the food until they are full, and may, 
by their bulk, offer obstruction to the main channel. 
Obstruction in the Stomach.-The same types of obstruction are met 
with in the stomach, and the occlusion may be at the cardiac orifice or at 
the pylorus. In the first instance, in which the growth of a cancerous tumor 
is the common cause, the individual tends to starve, because food does 
not easily reach the stomach. In the second case, in which the cause 
is a cancerous growth or the contracting scar of a round ulcer at the 
pylorus, the orifice of the pylorus may be reduced to a very narrow channel 
(Fig. 209). Stagnation and accumulation of the stomach-contents follow, 
with great changes in the gastric juice, which often loses its antiseptic 
acidity. Putrefaction of all this material produces poisonous substances, 
which are absorbed, to the great detriment of the patient. Besides, the 
frequent vomiting causes the loss of much water and the normal con- 
stituents of the gastric juice, and one might surmise that this, as well as 
the absorption of poison, could give rise to the symptoms which sometimes 
follow. Not uncommon among these symptoms is the development of 
tetany, with greatly heightened nerve excitability and violent convulsions. 
The stomach may become hugely dilated, so as to be capable of holding OBSTRUCTION OF THE LUMEN OF THE INTESTINAL TRACT 
419 
four or five litres, and the most incredible mass of material, dating from 
meals long past, may accumulate there. The wall becomes thick, the 
muscular coat hypertrophic, in the attempt to drive the contents through 
Fig. 209.-Scarred ulcer of the pylorus, dilatation and hypertrophy of the stomach. 
Fig. 210.-Gastric ulcer (round or peptic ulcer). 
the pylorus, and the mucosa seems to hypertrophy by the production of new 
glands to comply with the necessity for covering all that increased space. 
There are other ways in which such gastrectasis can be set up, as by the 420 
TEXT-BOOK OF PATHOLOGY 
pressure of outside tumors or by the sagging of the stomach and the kink- 
ing of the pylorus, but the two causes mentioned are by far the more 
common. The symptoms are not acute in these cases, nor do they quickly 
end fatally, because vomiting is capable of relieving them to some extent. 
Gastric Ulcer.-There are several types of ulceration of the gastric wall produced in 
as many ways, and distinguished by nothing specially characteristic. For while the 
intact living mucosa resists perfectly the digestive action of the gastric juice, anything 
like a strong corrosive poison which can kill the tissue, or even anything like a haemor- 
rhage, which may interrupt the circulation of a patch of mucosa for a time, exposes that 
area to the liquefying power of the juice, and in an incredibly short time there is 
produced an ulcer which extends to the depth reached by the anaemia or coagulation 
of the tissue. Even the little ecchymotic haemorrhages which appear after violent 
vomiting present themselves very shortly as pits of pinhead size in the mucosa. Emboli 
in the larger vessels have no such consequences, since the intercommunication of the 
arteries is so extremely rich. If we try experimentally to produce an area of anaemia 
in the wall of the stomach of an animal, we fail, even though we tie several large vessels. 
Their current is instantly supplied backward, if necessary, from other arteries. It is 
only by injecting a suspension of coarse particles which plug all the small vessels, or by 
causing a spasmodic contraction of the muscular wall, which clamps down the col- 
lateral arteries, that we can produce an anaemia of the mucosa serious enough to allow 
the gastric juice to attack and digest it, and thus form an ulcer. But although many 
things will produce an ulcer, the mucosa is surprisingly capable of healing it over. I 
have removed large squares of the mucosa of the dog's stomach, only to find, a short 
time later, such complete healing that it was impossible to say where the ulcer had been. 
It is perhaps a peculiarity, therefore, of the so-called peptic or round ulcers of the 
stomach that they persist as such. Most of them do heal, and we find only the scar, but 
others, although they are the seat of energetic efforts at healing, not only persist, but 
progress, boring deeper and deeper into the thickening stomach-wall. Very similar 
ulcers are found in the duodenum, where they follow a course much like that of the 
gastric ones. All the theories as to their origin seem inadequate, from that of Virchow, 
who thought them to be due to the embolic occlusion of the artery supplying that area, 
to the more recent ones, which attempt to incriminate bacteria and other parasites, or, 
as in the case of van Yzeren and Palma, ascribe them to changes in the innervation of 
the stomach, which maintains part of its wall in a bloodless state through cramp of the 
muscle.* 
They occur in relatively young persons, usually in association with hyperacidity of 
the gastric juice, and cause a peculiar pain. There may be only one or several. Many 
of them are irregular in outline, and there are small ulcers, as well as wide-spread erosions, 
but the name arises from the fact that many of them are quite round and smooth (Fig. 
210). Such ulcers look as though they had been cut out with a gunwad cutter, except 
that their base is terraced and funnel shaped, and may run slantingly into the stomach- 
wall, or else their edges are undermined. All around such an ulcer the wall becomes very 
thick and hard, so as to be easily recognized from the outside when the stomach is 
exposed. Often there are adhesions formed over it, so that in case the ulcer extends quite 
through the wall, it is likely to encounter first the adhesions and then the adherent organ. 
Since they often perforate the posterior and inner curvature of the stomach, the pan- 
creas is likely to be the bulwark and to be rapidly excavated, until, sometimes, the splenic 
artery is cut into. The liver may sometimes form this buffer, but it is not very uncom- 
mon to have the gastric contents emptied through the perforated ulcer directly into the 
peritoneum. Microscopically, the edge of such an ulcer shows an abrupt cessation 
*Stromeyer: Ziegler's Beitrage, 1912, liv, 1. OBSTRUCTION OF THE LUMEN OF THE INTESTINAL TRACT 
421 
of the mucosa. The precipitous walls are lined with a thin layer of formless, hyaline 
material, and pass through the greatly thickened submucosa, the musculature, and even 
the thickened subserous tissue. There is often not much infiltration with wandering 
leucocytes to indicate any active inflammatory process. On the contrary, the ulcer 
may look as if bored through a dense, hard, fibrous tissue. In the floor of the depression 
one may sometimes see an artery laid bare, or even find its exposed wall so thinned 
that the blood-pressure has been sufficient to bulge it out into an aneurysmal sac. It is 
obvious, though, that one would be more likely, under such circumstances, to find the 
little sac burst into shreds after an alarming or fatal haemorrhage had called attention to 
the ulcer. 
Aside from these two dangers, the most serious effect of the ulcer may arise in the 
course of its healing, if it happens to encircle the pylorus. It is then that the contrac- 
tion of the scar may produce the most extreme narrowing of that orifice, and a conse- 
quent enormous dilatation of the stomach. 
Duodenal ulcers are similar in their course and even in their general effects, for they 
may perforate into the peritoneum or into blood-vessels or adjacent organs. They some- 
times appear when gastro-enterostomy has been performed at the point where gastric 
juice pours into the intestine, and I have recently seen a case in which five ulcers bur- 
rowing and connected in the most tortuous way were formed in this manner. 
Intestinal Obstruction.--Although there are many different ways in 
which the lumen of the intestine may be closed so that nothing can pass, 
the result is in one sense the same in all. Still, the effects of such obstruc- 
tion vary according to the point in the intestinal tract at which it occurs, 
its completeness, and the condition of the intestinal wall. 
In general, when the occlusion is produced by a foreign body which acts 
as a plug, the symptoms are rather less violent than when the canal is 
closed from outside, as it might be with a ligature. More important in 
this respect, however, is the fact that obstructions high up in the small 
intestine are usually accompanied by far more violent symptoms than those 
in the rectum or sigmoid flexure. Perhaps the fact that impaction of 
faeces in the rectum, with no discharge for days or even weeks, may cause 
nothing more serious than headache, will illustrate this, for sudden closure 
of the small intestine is very quickly followed by vomiting, pain, abdom- 
inal distension, and evidences of shock, with death in a few days if not 
relieved. These symptoms (grouped under the term ileus) are often es- 
pecially fulminant, when something occurs to cut off the blood supply 
from the wall of the obstructed intestinal loop. 
The actual cause of these extraordinarily intense symptoms has been 
searched for experimentally, and by other means, for years, but even yet 
it is far from being clearly understood. The intestine above the point 
of closure becomes distended with gas and a very foul-smelling fluid which 
swarms with bacteria. Even when there is no outward obstruction to the 
circulation, its wall is soon so stretched as to interrupt the free flow of 
blood in the capillaries, and necrosis and ulceration of the mucosa appear, 
often with actual tears in the muscular wall and serous covering of the gut. 
Kocher has called these ulcers distension ulcers. It is evident that poison- 
ous materials are absorbed from this sac-like loop of intestine, which is 
practically like one huge bouillon culture of bacteria, and in many cases 422 
TEXT-BOOK OF PATHOLOGY 
it is clear enough that the bacteria themselves have passed into and through 
the intestinal walls, and have caused not only an acute peritonitis, but a 
generalized infection. 
In other cases, though, with just as intense symptoms, there may be no 
definite peritonitis nor general infection, and these make it necessary to 
find some other explanation. Whipple finds that, from the contents of the 
obstructed intestine, he can extract a material which, on being injected 
into veins of other animals, produces all the symptoms which follow acute 
intestinal obstruction. This substance is derived from the mucosa of the 
obstructed intestine, its production being stimulated by the bacteria present 
in such numbers, and is purified by being precipitated with alcohol and 
washed. Davis and Stone found that the duodenal secretion from which the 
pancreatic juice was excluded is not toxic so long as it is kept from bacterial 
decomposition. Dragstedt and his co-workers agree with this, and emphasize 
the importance of the presence of bacteria, which decompose proteins, and 
of the injured state of the mucosa. Whatever is absorbed leads to no 
production of antibodies and is, therefore, probably not a protein. The 
symptoms produced in intestinal obstruction are so like those of shock 
that it is difficult to escape the temptation of assuming that the poisonous 
material is the decomposition product of proteins which Dr. Abel recognizes 
as histamine. Dale refers shock and the related phenomena to histamine- 
like bodies derived from the disintegration of injured tissues, and the con- 
ditions presented in an obstructed loop of intestine seem ideal for the 
formation of a quantity of this material. Possibly the origin of histamine 
from the protein contents of the intestine may explain its greater abundance 
in the upper intestine, for there is relatively little protein left to decompose 
in the contents of the colon. Should this explanation prove true it would 
also account for the paralysis of the smooth muscle of the wall of the com- 
pletely obstructed loop after sufficient time has elapsed. 
Mechanism of Intestinal Obstruction.-Ordinarily the contents of the 
small intestine are quite fluid, and the musculature of the colon, aided by 
that of the abdominal wall, is strong enough to expel the more solid con- 
tents of that part of the intestine. Still it occasionally happens that a 
foreign body which was swallowed and has passed through the stomach 
sticks somewhere in the intestine. This is true, too, of the so-called en- 
teroliths, which may be very large, and partly composed of hair and of 
large gall-stones, as well as of the indurated masses of faeces which some- 
times become impacted in the colon and obstruct it. 
Tumors or aneurysms outside the intestine rarely compress it enough in 
the yielding abdominal cavity to produce obstruction, unless the tumors 
have surrounded it and involved it in their growth. After abdominal 
operation, however, in which the intestines have been roughly handled and 
displaced, and especially when there exists a focus of infection and inflam- 
mation of long standing, such as an abscess around the appendix, or a gen- OBSTRUCTION OF THE LUMEN OF THE INTESTINAL TRACT 
423 
eral infection of the peritoneum, adhesions are apt to bind the intestinal 
coils together. Then the symptoms of obstruction commonly appear, and 
the surgeon must separate and loosen and straighten out such loops. Usu- 
ally in such a case the occlusion is produced by the angular kinking of the 
gut, but sometimes the most extraordinary long bands of fibrous tissue are 
found stretching from one point to another, entangling, as in a ligature, 
a loop of intestine. Doubtless this latter condition is brought about by 
the peristaltic and passive movements of the intestine, which entangle 
it in the adhesions. 
Hernias.-Quite analogous to this method of obstruction is that found 
in the various sorts of hernias, where again the movements of the intestines 
(this time chiefly the passive movements, caused by the press of the abdom- 
inal muscles) forcibly intrude them into compromising situations. The 
omentum, and in some forms of hernias, even other abdominal organs, may 
be forced to accompany the intestinal loops. These structures pass through 
a weak point in the abdominal wall, pushing ahead of them a sac composed 
of the peritoneum, usually with accompanying layers of the tissues which 
lie outside it in that area. When the violent muscular effort is over and 
the heightened intra-abdominal pressure is relaxed, the intestine may 
slip back or be pushed back by the surgeon. But the sac remains, and the 
intestine is easily forced into it again-the more so as with each time it 
grows larger and receives more and larger loops of the gut, which may 
remain there without causing any trouble. Such a sac often contains serous 
fluid, and is subject to inflammations, just as is the peritoneum in general. 
Inguinal hernias are those in which the sac is pushed through the abdominal wall just 
above Poupart's ligament. Those which pass through the internal abdominal ring, 
that is, outside the deep epigastric artery, pass along the track of the inguinal canal or 
through the unobliterated inguinal canal, when that has remained open, into the scrotum. 
They are the oblique inguinal hernias. Those which push through to the inner side of 
the epigastric artery and likewise project through the external abdominal ring into the 
scrotum are the direct inguinal hernias. 
Femoral hernias are such as arise from the propulsion of a peritoneal sac through the 
space between the femoral vein and Gimbernat's ligament, beneath Poupart's ligament, 
to project through the saphenous opening. 
Umbilical hernias are often of great extent when congenital, and may contain most 
of the abdominal viscera. They are acquired in later life through the protrusion of a sac 
through the weakened scar tissue about the navel, and are common in women who have 
borne many children. Hernias through the abdominal wall may occur anywhere where 
a large operation wound has resulted in delayed healing, and the scar has remained as 
a weak place. 
Other hernias which are less conspicuous and far less common occur, and some of 
these are the so-called internal hernias. Thus the left side of the diaphragm may be 
thinned and stretched into a sac, and in a case which we recently observed nearly the 
whole of the stomach, the spleen, and the splenic flexure of the colon lay in this sac far 
up in the thoracic cavity. The most unexpected places may be pitched upon by the 
intestinal loops for invasion, and extraordinary results follow. For example, the fossae 
about the junction of the duodenum and jejunum, which are ordinarily quite small 
recesses, may become distended into great sacs in which numerous loops of intestine 424 
TEXT-BOOK OF PATHOLOGY 
are found ensconsed. The same is true of the fossae about the caecum and at the root of 
the sigmoid, and I have recently reported a case in which a notoriously weak place in 
the root of the mesentery of the jejunum was attacked, and just as a flock of sheep in a 
street, left for a moment to themselves, will hurry into any open door, the whole of the 
small intestine had become inclosed in a sac which hung to the right of the midline. 
All this seems to have little to do with intestinal obstruction, but it is 
precisely in these hernias that a common form of obstruction takes place. 
For although ordinarily the neck of the sac is wide and the intestinal con- 
tents circulate through the loop in the sac without hindrance, more intes- 
tine than usual may sometimes be forced into the sac. All these hernias 
tend to grow in this way, and it may even happen that the abdomen is so 
emptied of its contents and contracted and the sac so large that it is 
impossible to reduce the hernia, that is, to replace its contents in the 
abdominal cavity. The formation of adhesions between the intestine and 
the wall of the sac may also make the hernia irreducible. Such a condition 
may exist for a long time. 
If, through a sudden violent exertion, a loop of intestine be forced through 
a very narrow orifice, or if an excessive amount of intestine or too much of 
the intestinal contents be forced into the sac, the afferent and efferent por- 
tions as they pass through the neck of the sac become compressed. Then 
not only is it impossible to reduce the hernia, but the intestine is obstructed 
and all the symptoms of an acute ileus, distension of the loops above the 
constriction, faecal vomiting, etc., make their appearance (incarcerated 
hernia). This is not all, however, for the compression of the veins of the 
mesentery of the incarcerated loops soon causes oedema of those loops, and 
increases still further the bulk of the contents of the sac until the flow of the 
circulation is quite stopped, and the whole included loop becomes the seat 
of a haemorrhagic infarction (strangulated hernia). The wall becomes 
greatly thickened and infiltrated with blood, and dies, after which the 
bacteria in the lumen pervade the dead tissue and set up an inflammation 
in the sac. If some time elapses before the sac is cut open by the surgeon, 
the intestine is found to be purple or greenish black, but if relief is rapid, 
circulation may be reestablished and the loop saved alive. 
Somewhat similar in principle to this process is the prolapse of the rec- 
tum, in which the relaxation of the tissue in and about the rectal wall 
allows its mucous surface to be everted through the anus until a consider- 
able length has been turned outside and protruded. 
Intussusception.-Higher up in the intestine one portion of the wall 
may be telescoped into the next section below. This invagination or intus- 
susception is frequently found to take place in the irregular peristalsis which 
arises just after death, perhaps more often in children than in adults. 
But it does occur also during life, and quickly leads to complete obstruc- 
tion of the intestine and all the acute symptoms of ileus. For, as will be 
seen in the drawing (Fig. 16, p. 38), the portion which is invaginated drags 
with it its mesentery, while the portion which receives it is stretched until OBSTRUCTION OF THE LUMEN OF THE INTESTINAL TRACT 
425 
it constricts its contents closely. Especially at its beginning or upper end, 
where the mesenteric mass at least is most bulky, it forms a tight ring con- 
stricting the mesenteric veins. The result, as in the strangulated hernia, 
is the production of a haemorrhagic infarction in the two internal folds, which 
thereby become even more swollen. It is said to have happened that the 
normal entering intestine, by healing to the upper end of the outer or receiv- 
ing intestine, allowed the whole of the invaginated portion to be sloughed 
off and discharged per rectum, but this must be a rare occurrence. In the 
early stages, before circulation has been interrupted too long, the sur- 
geon may pull out the intussuscepted part and relieve the whole condi- 
tion. But after the infarction of the invaginated part is complete, a 
more radical operation is necessary. Irregular peristalsis is held responsi- 
ble for this process, but sometimes there is a stalked polypoid tumor hang- 
ing from the mucosa which is forced along the intestinal canal and drags 
the wall with it. Once started, the invagination tends to increase rapidly. 
Volvulus.-Volvulus is another type of constriction from without which 
depends upon the twisting of a loop of intestine through more than 180 
degrees, so that the two ends of the loop compress each other as in a knot. 
For this there must be a long loose mesentery, and the condition is most 
common in the sigmoid flexure. Complete obstruction occurs, with the 
isolation of a loop. When the twist is tight enough to embarrass the cir- 
culation, the condition comes to resemble closely that in the strangulated 
hernia. 
Instances of post-operative obstruction due to adhesions which compress 
or kink the intestine, or among which the intestine can entangle and 
strangle itself, are not very uncommon, but almost as common are those 
cases in which evidences of obstruction arise very soon after the operation, 
when there has been no time for dense adhesions to form, and in which, 
at a second exploration, the intestine is found bent on itself at a sharp angle 
above which it is greatly distended. These are rather hard to explain, 
but they seem to be due to a combination of a paralysis of the intestinal 
wall with any slight mechanical displacement, which, after the first hand- 
ling of the intestines, is maintained even by weak fibrinous adhesions. The 
capability of mere paralysis of peristalsis in a length of the intestine to 
produce the symptoms of obstruction is well known (paralytic ileus), and 
the inert segment which does not help in the propulsion of the intestinal 
contents will, if it is long enough, prove to be as effective a barrier as a 
ligature. It is not always easy to explain how the paralysis is produced. 
Sometimes, as in a phlegmonous inflammation of the intestinal wall, when 
the infiltrated wall becomes rigid, the cause is clear, and so, too, are those 
in which thrombosis or embolism of the mesenteric vessels causes the 
death of a whole length of the intestine, with haemorrhagic infarction, but 
at other times we are reduced to the idea that the nervous controlling 
mechanism is disturbed. I have already mentioned one instance in which 
a dissecting aneurysm had ruptured into the tissues about the aorta, so 426 
TEXT-BOOK OF PATHOLOGY 
that there was a great clot of blood stretching from the upper thoracic 
to the lumbar region. The most striking symptoms were those of in- 
testinal obstruction, for the relief of which an operation was per- 
formed. The man died, and at the autopsy the intestines were dis- 
tended with fluid and gas to a colossal size, so that from the stretching 
the muscular wall showed numerous tears, but there was no obstruction 
except from the paralysis of the intes- 
tines. 
It seems possible that in many cases 
this may be the effect of some toxic 
agent acting directly upon the smooth 
muscle of the intestinal wall, and as in 
the case of mechanical obstructions 
the poison which suggests itself is that 
derived from the bacterial decompo- 
sition of proteins or from the injured 
tissues themselves. 
Stenosis and Stricture.-Finally, 
obstruction may be gradually produced 
by the development of a tumor encir- 
cling the lumen of the intestine, or by 
the contraction of a scar produced in 
the healing of a girdle ulcer. Cancer- 
ous tumors of this sort are most com- 
mon in the large intestine, and they 
may produce obstruction by their in- 
creasing bulk or by the scar tissue 
formed after their partial degenera- 
tion. In the small intestine annular 
lymphosarcomata, and more rarely 
carcinomata, may cause the same 
thing. Ulcers of tuberculous origin 
rarely heal far enough to cause strict- 
ure, but syphilitic ulcers, especially in 
the rectum, frequently do so. All these things produce a gradual narrow- 
ing with slowly advancing incomplete obstruction, so that the symptoms 
are not the acute and violent symptoms of ileus. Instead, the intestine 
above the stenosis becomes greatly distended and also greatly thickened 
through the hypertrophy of the muscular wall, which attempts constantly 
to drive materials through the narrow opening (Fig. 211). Below the 
stricture the intestine is collapsed and thin walled. An almost continu- 
ous stream of fluid intestinal contents is driven through the stricture, and 
may cause the so-called paradoxical diarrhoea. Above the stricture the 
mucosa of the distended intestine often presents extensive ulcerations, 
which are thought to be due partly to its disturbed nutrition, partly to 
Fig. 211.-Carcinoma of the rectum 
encircling the gut and producing a 
stricture. OBSTRUCTION OF THE LUMEN OF THE INTESTINAL TRACT 
427 
the stagnation of masses of infected faecal material in contact with it 
(stercoraceous ulceration). Sometimes an acute diphtheritic inflammation 
of the mucosa of this area is produced in the same way. 
Thus if we look back over this review of intestinal obstructions, we find 
that no matter what the mechanism by which occlusion of the intestine 
is produced, the effect is fairly constant, and varies only with the com- 
pleteness and situation of the obstruction. It differs from the effects 
of the occlusion of the duct of a gland on account of the immediate vital 
importance of the intestine, its circulatory relations, and its abundant 
content of bacteria. 
LITERATURE 
Lichtwitz: Ergeb. d. innere Medizin u. Kinderh., 1914, xiii, 1. 
Opie: Diseases of the Pancreas, Philadelphia, 1903. 
Wilms: "Ileus," Handb. d. prakt. Chir. (Bruns, Garre, Kuttner), 1913, iii, 336. 
Graser: "Hernias, etc.," ibid., 421. 
Whipple, Stone, and Bernheim: Jour. Exp. Med., 1913, xvii, 286, 307. 
Brooks, Schumacher, and Wattenberg: Ann. Surg., 1918, Ixvii, 210. 
Davis and Stone: Jour. Exp. Med., 1917, xxvi, 687. 
Dragstedt, Moorhead and Burcky, and others: Ibid., 1917, xxv, 421; 1919, xxx, 109. 
Dragstedt and Chase: Amer. Jour. Physiol., 1918, xlvi, 365. 
Smith and Hardt: Arch. Int. Med., 1918, xxi, 307. CHAPTER XXI 
TYPES OF INJURY-OBSTRUCTION (Continued).-OBSTRUCTION 
OF RESPIRATORY TRACT 
Nose (coryza, adenoids, etc.). Larynx (oedema, diphtheria, foreign bodies, compression, 
stenosis'); bronchi (foreign bodies, stenosis). Atelectasis: its causes. Mechanism of bron- 
chial dilatation. Bronchiectasis. Emphysema. 
NASAL OBSTRUCTION 
In the upper air-passages, especially in the nose, there are several common 
forms of occlusion which impede respiration, with peculiar results. Swell- 
ing of the Schneiderian membrane in ordinary coryza may make it impos- 
sible to breathe through the nose, so that the throat becomes dried from the 
prolonged breathing through the mouth. More serious, because more 
prolonged, is the blocking of the nares by certain polypoid oedematous fibro- 
mata, which hang down from the septum, or by the growths of adenoid 
tissue which project from the roof of the pharynx. In young persons the 
latter, at least, give rise to great deformity of the face, with flattening of 
the features, which, since the mouth is constantly open, gives the person 
a most vacant expression. 
The difficulty in breathing through the nose, with the consequent violent 
inspiratory efforts, brings about curious deformities of the chest. A 
lateral caving in of the soft ribs leaves the sternum prominent (pigeon- 
breast), while the tension of the diaphragm at its insertion may cause a 
furrow-like retraction of the ribs along that line (Harrison's groove). 
OBSTRUCTION OF THE LARYNX 
Spastic closure of the glottis in children, especially in such conditions as 
tetany, causes a peculiar difficulty in inspiration, with stridor (laryngismus 
stridulus), while paralysis of the vocal cords may produce a similar obstruc- 
tion in another way. Actual asphyxia may occur. Asphyxia is much more 
commonly the result of oedema about the larynx or of other types of inflam- 
matory exudate there. 
(Edema of the Larynx.-This is, in many instances, only a part of a wide-spread oedema 
of the tissues such as is seen in cases of cardiac failure or renal disease, or due to some 
local disturbance of the circulation, which may be caused by posture, but at other times 
it is the effect of an inflammation in or about the larynx (Fig. 212). Masser and others 
have pointed out the existence of an erysipelas-like infection of the larynx and pharynx 
in the course of which extreme oedema may arise. So, too, abscesses in the neighbor- 
hood of the tonsils, and more especially the phlegmonous inflammations starting about 
the submaxillary glands (Ludwig's angina) or from the mucosa, or even the skin, may 
produce the most intense infiltration of the tissues of the neck, with inflammatory oedema 
of the especially loose structures of the larynx. The epiglottis swells into a balloon- 
like mass, and each aryepiglottic fold assumes huge dimensions, so that the opening of 
the larynx may easily be closed and suffocation ensue. 
428 429 
OBSTRUCTION OF THE LARYNX 
Diphtheria, by blocking the larynx and trachea with a tough, inflam- 
matory pseudomembrane may also asphyxiate a child, and it is to obviate 
this that tracheotomy is sometimes necessary. Exactly the same soft of 
asphyxia arises when a foreign body, such as a piece of meat, is drawn into 
the opening of the larynx (Fig. 213). Incredible as it may appear, it is not 
uncommon to find, in the autopsy upon drunken persons who have died 
Fig. 212.-(Edema of the glottis 
Fig. 213.-Meat impacted in 
the glottis. Sudden death from 
asphyxia. 
with symptoms of choking, such masses so firmly wedged into the glottis 
as to be removed with difficulty. 
From without, the trachea may be compressed by the growth of goitres, 
aneurysms, and tumors of the neck. In the case of goitres, it is not unusual 
to find the lumen of the tube flattened into a slit from the pressure exerted 
on each side. Dyspnoea increases in intensity with the narrowing of the 430 
TEXT-BOOK OF PATHOLOGY 
passage. Syphilitic ulceration of the tracheal wall, with scarring, is no 
uncommon cause of stricture. The narrowing is generally ring-shaped, 
and may occur just above the bifurcation, or sometimes even in one of the 
main bronchi. 
It will be seen that, while some of these conditions can last only a short 
time, others are of long standing and are gradually produced. The latter 
can in time produce anatomical changes in the lung which are perhaps 
less striking, though analogous with those produced by similar narrowing 
of the bronchi. 
OBSTRUCTION OF THE BRONCHI 
The bronchi, like the trachea, may be completely or only partly occluded 
in any part of their course by foreign bodies of all sorts accidentally drawn 
into the larynx. Seeds, fruit-stones, teeth, pieces of bone, nails, buttons, 
pieces of tracheotomy tubes, etc., are the common objects found there. 
In the case illustrated in Fig. 214 a fragment of bone, together with a 
tangle of string, partially occluded the large bronchus, supplying air to the 
middle and lower lobes, leaving the bronchus to the upper lobe quite open. 
Tumors, caseous lymph-nodes, and aneurysms may also gradually close 
the bronchus by pressure, or by actually growing into the lumen of the 
tube. 
The result, when the occlusion is complete, is the collapse of the cor- 
responding part of the lung (atelectasis), because the air which remains in 
the alveoli when the closure is completed is soon absorbed by the circulating 
blood. 
Atelectasis.-The foetal state of the lungs is comparable to the condition 
of collapse seen in later life, except in that, until the first breath is taken, 
the alveoli have never been expanded. Since, in the adult, the thorax 
has grown to a size greater than could be filled by the collapsed lungs, 
there is even in the position of forced expiration a disproportion which 
keeps the lungs partly distended with air. In the infant, for a time, 
so nearly does the lung tissue fill the thorax, that the air which is found in 
the lung is quite proportional to the respiratory movements. Atelectasis 
is, therefore, more easily produced or maintained in the infant than in the 
adult. Indeed, areas of lung tissue often remain undistended with air, 
and if the condition persists, become obliterated and reduced to scar 
tissue. In the adult, when the lung has been expanded, the condition of 
collapse may be produced by: (1) Complete occlusion of the bronchi, or 
(2) by pressure from without. Only exceptionally is collapse produced in 
another way, as in those cases in which, while the bronchus is widely open 
to the trachea, it communicates also through a hole in the lung with the 
pleural cavity. When air can thus enter the pleura without the necessity 
of expanding the lung, that tissue gradually collapses. This requires some 
time, so that if, instead, a hole is made in the chest-wall, complete collapse 
of the lung does not occur at once. 
The first mode of production of atelectasis by complete occlusion of a OBSTRUCTION OF THE BRONCHI 
431 
bronchus depends upon the fact that the air in the corresponding alveoli 
after the obstruction is complete, is soon dissolved in the circulating blood, 
so that the alveolar walls fall together. The area appears sunken and of a 
translucent, bluish-purple color. On section it is pasty and often congested, 
the congestion being due to the kinking of the veins, which prevents the 
blood from escaping. Such airless patches are found about the regions of 
consolidation in lobular pneumonia, where they represent the parts of the 
lung supplied with air by branches of bronchi which, at a higher point, are 
obstructed by the inflammatory exudate. Precisely the same result is 
found if a foreign body completely closes the bronchus. 
Pressure from without, the second cause referred to, is most effective 
when applied gradually and slowly, for the most forcible attempt to press 
air out of the lungs rapidly, fails unless the alveoli are ruptured, because the 
smaller bronchioles bend sharply on themselves and prevent the escape of 
the air. The growth of a tumor, however, or the gradual accumulation of 
fluid in the pleural cavity, may render airless the part of the lung pressed 
upon (cf. Fig. 92). A whole lobe or part of it, usually the lower and pos- 
terior part, may thus collapse into a soft, pasty, bluish, airless tissue, which 
sinks in water and gives no crepitation between the fingers. When cut 
into, it may be dry and inelastic, thus differing from an oedematous lung 
in which the air has been replaced by fluid. By stretching a little of the 
tissue, first in one direction and then in another, the movements of the 
alveolar walls, can be seen so plainly that the condition of collapse is easily 
distinguished from that of inflammatory consolidation. Adhesions be- 
tween the alveolar walls and the growth of fibrous tissue through them 
sometimes indurate and solidify the lung permanently, so that it cannot 
expand again. 
Bronchiectasis.-When the obstruction is incomplete, the bronchi distal 
to it become dilated (Fig. 214). This is because both inspiration and expira- 
tion become difficult in that portion of the lung on account of the partial 
blocking of the bronchus, although they go on easily enough in the rest 
of the lung. Quiet expiration is a more or less passive process, due to the 
elastic recoil of the distended lung, the sinking of the ribs from their 
actively elevated position, and the relaxation of the diaphragm and of the 
distended abdomen, although, of course, violent muscular contraction of 
the chest is available in forced expiration. 
Thus the force available to carry air into the lung when the chest is 
expanded is the whole atmospheric pressure, part of which is used in 
stretching the elastic lung.* The force which drives the air out in quiet 
respiration is only the elastic contraction of the lung, aided by gravity 
and a relatively slight muscular action. 
Consequently, if there arises a partial obstruction of a bronchus, offering 
* Just what pressure relations will exist on each side of a complete obstruction of the 
main bronchus within the chest in inspiration will depend upon the amount of air already 
in the lung. 432 
TEXT-BOOK OF PATHOLOGY 
a constant resistance to the passage of air, inspiration will fairly readily 
overcome the resistance, drawing air into the distal part, while expiration 
will prove too feeble to drive it out. Air in such a case accumulates behind 
the obstruction until it is under a pressure equal to that which overcame 
Fig. 214.-Partial obstruction of a bronchus by foreign bodies. Bronchiectasis involving 
the corresponding branches. 
the resistance of the obstruction, and at this pressure it will remain as long 
as breathing continues, while other air passes in and out, just as tide-water 
passes in and out over a dyke, leaving a great depth imprisoned behind, up 
to the level of the top. It is this continuous distension of the obstructed OBSTRUCTION OF THE BRONCHI 
433 
bronchus which finally widens it and is a prominent cause of the condition 
known as bronchiectasis, although Dr. Crowe tells me that in dogs in which 
he has produced stricture of a bronchus, easily seen through the broncho- 
scope as an extreme narrowing of the lumen, there is no dilatation of the 
distal part as long as the bronchus remains uninfected. 
There are several different types of dilatation of the bronchi, which are 
best separated from one another according to their causes, rather than 
their anatomical form, although we are not well informed as to those 
causes. 
Quite distinct is the group described by H. Meyer, Grawitz, Stoerk, and 
others as occurring in infants, and sometimes found persisting in adults. 
In this form the lung, or part of it, is found to be converted into a mass of 
cysts lined with high epithelium and full of fluid. Since they are generally 
not connected with bronchi, it seems hardly proper to speak of them as 
bronchiectasis. They represent rather a congenital malformation of the 
lung. Atelectatic bronchiectasis is that widening of the bronchi described 
by Heller, Buchmann, and others as occurring in portions of the lung which 
have become permanently collapsed in early life. Such a lobe or lobule 
of the lung remains unpigmented, and consists of a sponge of wide bronchi 
embedded in a firm tissue in which alveoli can no longer be easily dis- 
tinguished. Such widening may well be the result of the tendency of 
a portion of the lung which is not taking its normal part in filling the 
thorax, to dilate during inspiration. 
Other forms of bronchiectasis are acquired in later life, and are in all 
cases associated with infection and inflammation of the bronchi. This in 
itself is not sufficient cause for the widening of the bronchi until there is 
added to it a mechanical distension. By bronchiectasis is meant the forma- 
tion of abnormally wide channels in the lung from the dilatation of bronchi. 
Since these cavities are surrounded by the stretched bronchial wall, the 
term does not include caverns excavated in the substance of the lung itself, 
although these may secondarily be formed in connection with true bron- 
chiectasis by gangrene or tuberculosis. The bronchi may be widened dur- 
ing an acute inflammatory disease, but the larger dilatations are produced 
more slowly by chronic processes, and are often accompanied by the most 
profound changes in the surrounding lung tissue. When such cavities are 
formed, they may be recognized by auscultation and by the sudden dis- 
charge of great quantities of characteristic sputum, which have collected 
in them during the night when the patient does not cough. 
Anatomically, they vary greatly in appearance. In those acutely pro- 
duced, the bronchi are deeply congested, thin walled, and soft, and filled 
with a purulent secretion. They are usually associated with lobular 
pneumonic patches of consolidation. In the more chronic cases the same 
cylindrical dilatation may appear, but it is perhaps more common to find 
the widening excessive at the ends of the bronchi, so that they become club- 
shaped. Occasionally they are beaded with separate dilatations, or they 434 
TEXT-BOOK OF PATHOLOGY 
may be blown out into wide sacs which can rupture into one another or 
into the pleura. In all these cases the bronchial wall is intensely inflamed 
and thickened by the accumulation of inflammatory exudate in its sub- 
stance. The mucosa is thick and ragged, the musculature and elastic tissue 
spread apart, torn, and weakened, and the connective tissue as well, infil- 
trated with fluid and wandering cells. The cartilaginous plates tend to 
disappear, and a newly formed connective tissue occupies the bulk of the 
wall. All this tends to diminish greatly the strength and elasticity of the 
wall. 
The lung tissue in these protracted cases is sometimes very emphysema- 
tous, but in others it is converted into a dense fibroid substance partly by 
the organization of inflammatory exudate within the alveoli, partly by the 
growth of fibrous scar tissue in the walls of the alveoli and the other tissues 
of the lung. 
It is not well known what changes occur in the channels of communica- 
tion between these widened bronchi and their alveolar tissue, but it is 
probable that, according as there is narrowing or complete obstruction of 
the tiny bronchioles at their entrance into the dilated bronchus, there will 
be emphysema or atelectasis in the corresponding alveoli. 
Many theories have been formulated to explain the distension of the 
bronchi, but in these all are agreed upon one point only, that the infection 
and inflammation which weakens the bronchial wall and destroys its 
elasticity is a necessary factor. Not all cases of bronchitis are followed by 
bronchiectasis, and it may be that special bacteria, such as the influenza 
bacillus, which has often been found in bronchiectasis, are particularly able 
to cause the weakening of the wall. In the course of the recent epidemic, 
in which the bacillus of Pfeiffer was frequently found, bronchiectatic dila- 
tation was described by many writers. 
Pleural adhesions generally accompany chronic bronchiectasis, and 
Corrigan and Biermer express the idea that in indurated and adherent 
lungs the contraction of the scar tissue between the bronchi pulls upon 
them from all sides and thus dilates them. Possibly this is true in some 
cases, but it cannot be a general explanation. 
Others declare that the accumulation of secretion in the bronchi is suffi- 
cient to distend them to the degree found, but it seems that this can at 
best be only an accessory influence, because by itself the secretion can 
never exert any great pressure. Most writers, too, lay stress upon the 
effects of the violent expiratory effort with closure of the glottis in coughing, 
as capable of distending the bronchi. Reflection will show, however, that 
although under those circumstances the trachea might be distended, the 
pressure on the walls of the bronchi within the chest is from outside, so 
that it cannot distend them, as a rubber and glass model of the respiratory 
organs will demonstrate to perfection. Indeed, bronchiectasis may be 
experimentally produced in animals in the complete absence of cough. 
On the other hand, the violent inspiratory distension of the lung preparatory OBSTRUCTION OF THE BRONCHI 
435 
to coughing may be able to widen the bronchi if they are weak and it is 
constantly repeated. 
This leaves the idea of the inspiratory dilatation, whether exerted directly 
or through the imprisonment of inspired air behind some obstruction, as 
the most plausible explanation. It was, indeed, the explanation given by 
Laennec in his first work on bronchiectasis in 1819, and it has been recalled 
by Aron, and by Thornton and Pratt in their experimental work. When we 
attempt to apply this explanation to the cases of bronchiectasis as they 
occur, we find that it is completely satisfactory in those in which there is 
an obvious partial obstruction. But there are many others where obstruc- 
tion is not so obvious, and these offer difficulties. It is true that we may 
say that thick, sticky, mucoid secretion may exert a valvular action in 
the bronchi, preventing the easy exit of air; or we may assume, with Hoff- 
mann, that the weakened bronchus may kink during expiration like an 
old rubber tube, while stretching open on inspiration, in this way fulfill- 
ing the theoretical conditions. 
But these things are hardly definitely demonstrated as yet, and the 
question needs further study. 
(Edema of Larynx: Peltesohn: Berl. klin. Woch., 1889, xxvi, 931. 
Congenital and Atelectatic Bronchiectasis: Grawitz: Virchow's Archiv, 1880, Ixxxii, 
217. 
Stoerk: Wien. klin. Woch., 1897, x, 25. 
Edens: Dent. Arch. f. klin. Med., 1904, Ixxxi, 334. 
Buchmann: Frankf. Ztsch. f. Path., 1911, viii, 263. 
Bronchiectasis: v. Criegem: Akute Bronchiektasie, Leipzig, 1903. 
Posselt: Med. Klinik, 1909, vi, 1845. 
Thornton and Pratt: Johns Hopkins Hosp. Bull., 1908, xix, 230. 
Open Pneumothorax: Graham and Bell: Amer. Jour. Med. Sci., 1918, clvi, 839. 
LITERATURE 
The effect of partial or intermittent obstruction of the air-passages upon 
the alveolar structure of the lungs may next be examined. It has been 
said that complete obstruction of a bronchus quickly results in atelectasis 
or collapse of the corresponding part of the lung, but it is also true that 
partial or intermittent obstruction causes an overdistension of the alveoli 
with air. There are many other • causes assigned for the overdistension, 
but the importance of this one will become evident in studying the type 
condition, emphysema. 
Emphysema.-Excessive distension of the alveoli may be produced 
rapidly in the lung, when the tissue of the alveolar walls is quite nor- 
mal, so that if the air be allowed to escape, the alveoli at once return 
to their normal size, and their stretched walls to their normal thick- 
ness. If this overdistension be maintained at not too great a degree, the 
capillaries are, as Tendeloo has shown, widened so that nutrition of the 
alveolar wall may be well kept up. A still greater distension narrows and 436 
TEXT-BOOK OF PATHOLOGY 
compresses the capillaries, so that the blood passes with difficulty or not at 
all. Nutritive changes possibly dependent on this great stretching and 
the impaired blood supply weaken the elastic alveolar wall after a time, 
so that it may remain permanently stretched, or, after the breaking of its 
elastic fibres, give way at one or more points. Then the margins about the 
hole retract, and two alveoli are thrown into one.* At times great sacs 
are formed on the surface and along the edges of the lung by this process, 
while the remainder of the organ is softened and assumes a very coarse 
texture, from the wide-spread loss of alveolar walls. Such a lung is very 
voluminous, but feels peculiarly soft and non-resilient. The characteristic 
crepitation or crackling felt on pinching the lung tissue is altered, and one 
has the sensation of bursting large bubbles under the finger instead of the 
fine crackling produced in the normal tissue. There is also a peculiar pallor, 
which is due to the obliteration of so much of the capillary bed and to the 
absence of coal-pigment. 
Microscopically, the most striking feature is the large size of the alveolar 
spaces and the extreme thinness of the alveolar walls. With suitable 
stains one may observe the fracture of the strands of elastic tissue and the 
formation of holes in the walls, as well as the narrowing, obliteration, and 
rupture of the capillaries. 
This is the chronic substantive emphysema in which one may some- 
times discern evidences of attempts at repair in the new formation of elastic 
tissue and the growth of new blood-vessels and connective tissue. Atrophy 
of the lung tissue is perhaps the most characteristic feature of a subtype, 
the so-called senile emphysema. In old people the lungs are sometimes 
found to collapse into a very small bulk on opening the chest. They may 
contain much coal-pigment, but the tissue is extremely soft and wide 
meshed. In such cases it is customary to ascribe much of the thinning 
out and disappearance of the alveolar walls to senile atrophy, but it may be 
questioned whether it is not sometimes the end result of a very protracted 
process of the kind described above. 
The causes of emphysema are somewhat different in the various forms, 
although only a few principles can be concerned. When, through lobar 
pneumonia, tuberculosis, tumor formation, etc., a large portion of the lung 
is rendered solid, so that it cannot expand with the enlargement of the 
thorax, the whole inspiratory effort is expended upon the remaining open 
lung tissue, which thus becomes overdistended (vicarious emphysema). 
So, too, in drowning, water is drawn in to fill part of the lung, while further 
violent inspiratory efforts above water overdilate the rest of the alveoli 
with air. 
* The alveolar walls contain a rich network of capillaries, abundant elastic tissue, 
and some wavy fibrils of connective tissue, and are covered on each side by the respira- 
tory epithelium. The elastic tissue stretches across in coarse bands, frayed out here and 
there into fibres which join again in other directions to form new bands. Another set 
of fine fibrils arises from the elastica of the vessels and accompanies the capillaries 
(Orsos). Pores in the alveolar walls (pores of Kohn) are frequently seen, but there is 
much evidence that they are present only in diseased lungs. OBSTRUCTION OF THE BRONCHI 
437 
In many conditions in which the trachea or bronchi are partly obstructed, 
continued distension of the alveoli occurs by the imprisonment of air 
introduced in inspiration over the obstacle in the way described in connec- 
tion with the formation of bronchiectasis. This is especially clear in the 
case of valvular obstructions which allow inspiration only, as in the case 
of a stalked polyp in one of these air-passages, or a flapping film of diph- 
therial false membrane. It is true also of the thick, sticky, mucous exudate 
which may collect in the inflamed bronchioles in chronic bronchitis, and is 
particularly shown in the areas of emphysema which occur side by side 
with areas of atelectasis in the neighborhood of patches of broncho- 
pneumonic consolidation. Asthma, in which the bronchioles are narrowed 
partly by muscular contraction, partly by swelling of their mucosa and 
by exudate, presents the conditions mentioned. Inspiration is violent, 
and expiration prolonged and labored, and emphysema is the regular 
accompaniment. In all these cases it seems to be the inspiratory effort 
which is active in dilating the alveoli. Generally this is effective in pro- 
ducing a permanent anatomical change only when aided by a partial 
obstruction, and when kept up through a long time. Whether it itself 
can thus produce the nutritive disturbances which lead to rupture of the 
alveolar wall is not perfectly certain. Doubtless other injurious agencies 
may also play a part, because it is known that the lungs of certain people 
exposed to mechanical conditions of this sort develop emphysema, while 
others do not. 
Nearly every writer on the subject ascribes the widening of the alveoli 
to the increased intrathoracic pressure produced by cough, which is a 
forced expiration during closure of the glottis, suddenly relieved by its 
opening. It must, however, be clear that, as in the case of bronchiectasis, 
the increased intra-alveolar pressure is produced only by their compression, 
with decrease in their size. Only in such an unprotected place as the 
suprathoracic apex of the lung could one imagine this pressure capable of 
blowing out the alveoli. In the sternal margins it is still more doubtful. 
But cough is preceded each time by an extreme inspiratory distension of 
the lung, which, incessantly repeated, might lead to changes in the size of 
the alveoli. Tendeloo presents some interesting arguments with regard 
to the predominantly marginal and apical distribution of emphysema, 
based on his ideas as to the unequal expansion of the alveoli in different 
parts of the thorax. His laws seem, however, to depend upon doubtful 
evidence, and must be read in the original. When there are no adhesions 
in the pleural cavity, nor consolidated areas in the lung, the expansion of 
all alveoli would appear to us to be uniform. 
In wide-spread emphysema of long standing, such as often accompanies 
chronic bronchitis or asthma, the capillary bed in the lungs is so much 
narrowed by the obliteration of many channels that the blood passes with 
difficulty, and hypertrophy of the right side of the heart is a consequence. 
Such persons usually present a peculiar thoracic deformity-the chest is 438 
TEXT-BOOK OF PATHOLOGY 
enlarged, with the ribs constantly in the position of inspiration, so that 
further respiratory movements are shallow. The costal cartilages often 
become calcified and rigid, and Freund has suggested that this condition 
may be primary and constitute the real cause of the emphysematous 
enlargement of the lungs. The evidence is not clear, however, in favor of 
this idea. 
LITERATURE 
Eppinger: Ergeb. d. allg. Path., 1904, viii, 267. 
Tendeloo: Ursachen d. Lungenkrankheiten, 1902. Ergebn. d. inn. Med., 1910, vi, 1. 
Freund: Lungenkrankheiten u. Rippenknorpel-Anomalien, Erlangen, 1859. 
Marchand: Asthma, Ziegler's Beitrage, 1915, Ixi, 251. 
Orth: Berl. klin. Woch., 1905, xlii, 1. 
Ors6s: Ziegler's Beitrage, 1907, xli, 95. CHAPTER XXII 
TYPES OF INJURY-OBSTRUCTION (Continued).-OBSTRUC- 
TION OF THE URINARY TRACT 
Urethral stricture; prostatic obstruction. Hypertrophy of prostate. Cystitis. Urinary 
calculi. Hydronephrosis. Renal calculi. Ascending renal infection; pyelonephritis. 
The course of the urinary tract in the male is beset with so many more 
difficulties in the form of narrow places than in the female that the greater 
proportion of obstructions may naturally be expected in that sex. 
URETHRAL STRICTURE 
In the female the bladder opens by a canal so short and wide that obstruc- 
tion to the flow of urine is seldom observed below the ureters. In the male 
it may occur at the prepuce, at the meatus, in the urethra, and especially 
in its prostatic portion, and at the vesical orifice. Phimosis, which is a 
congenital or acquired narrowing of the prepuce, may sometimes be suffi- 
cient to offer a considerable obstacle, and even give rise to fatal complica- 
tions. A similar effect is produced by those constrictions of the meatus 
by scar tissue which occasionally follow the healing of an ulcer of the glans 
or a syphilitic chancre. It is, however, much more common to find the 
narrowing of the urethral canal higher up, and there it is due sometimes to 
mechanical trauma, but far more often to gonorrhoea. When the urethra is 
torn across, as in those cases in which a man falls from a height astride a 
beam, it is difficult for the surgeon to secure such perfect healing that 
there is not some narrowing at the place. Nevertheless, such cases are 
very amenable to treatment. Far different are those in which, in the course 
of a protracted gonorrhoeal infection, the wall of the urethra becomes ulcer- 
ated and infiltrated with inflammatory exudate. This usually produces its 
most profound effects in the bulbous portion, although other places may be 
involved instead. The organisms penetrate deep into the mucosa, and 
lodge in the lacunae and crypts, where they keep up the injury in the most 
persistent way. Healing with scarring of the ulcerated tissue results in the 
narrowing of the canal, and such strictures (Fig. 215) frequently make it 
impossible for the bladder to empty itself. To this are often added the 
injuries caused by forcible attempts to pass catheters which, in inexper- 
ienced hands, pierce the urethral wall and wound the surrounding tissue. 
The healing of these false passages, added to the mass of scar tissue around 
the urethra which constricts and deforms it, is the cause of ever-impending 
occlusion. 
439 440 
TEXT-BOOK OF PATHOLOGY 
PROSTATIC OBSTRUCTION 
Complex conditions exist about the region of the prostate, so that a variety 
of alterations take part in producing obstructions there. Among these 
abscess of the prostate and cancerous tumors springing from the gland 
are important, but by far the most common is the so-called hypertrophy of 
Fig. 215.-Gonorrhoeal stricture of the urethra. At A the urethral canal is surrounded 
by scar tissue and greatly narrowed. There is hypertrophy of the bladder. 
the prostate of old men. The obstruction caused by an abscess is transient, 
and depends upon the bulging of the prostate until the urethra is pressed 
flat, while that caused by the cancer is quite irregular, because the tumor 
may encroach on the urethra in any way. But the hypertrophy of the PROSTATIC OBSTRUCTION 
441 
prostate follows roughly certain general rules, and the type of obstruction 
is for that reason fairly constant. 
Hypertrophy of the Prostate.-Despite the most lengthy discussions, our ideas are 
still quite hazy as to the reasons for the enlargement of the prostate which is so frequent 
in men over sixty years of age, and even as to its anatomical characters the most diverse 
statements are made. It is evidently desirable that more accurate observations in this 
regard should be made and analyzed. 
The prostate is a sexual gland derived from the Wolffian body, just as are the seminal 
vesicles, and its function is not to control the flow of urine, but to furnish its secretion 
in jets at the moment of ejaculation, in such a way as to mix it with the sperm in the 
urethra. In accord with this requirement we find that its abundant smooth muscle 
is arranged around the glands, so that it can suddenly exert pressure upon them. The 
internal sphincter of the bladder controls the discharge of urine, and is practically inde- 
pendent of the musculature of the prostate. So, too, the external sphincter of Henle, 
which consists largely of voluntary muscle, is independent, although its fibres extend 
in some cases into the prostate. 
The bulk of the gland tissue in the prostate is collected in the lateral lobes, where it 
forms pyramidal radiating masses opening through 40 or 50 ducts into the urethra. The 
glands are acinar, lined with cubical or cylindrical epithelium, and often contain yellow, 
hom-like, concentrically laminated concretions (corpora amylacea). The posterior 
commissure is chiefly muscular, and contains few glands. There are a few, however, 
which extend upward toward the bladder inside the sphincter. There are also urethral 
glands there, such as are to be found throughout the course of the urethra. The anterior 
commissure is tightly connected with the symphysis pubis. 
Enlargement of the prostate is due, in the great majority of cases, to the develop- 
ment of more or less distinct nodules of a granular, opaque, and rather spongy appear- 
ance, embedded in the substance of the original gland, which itself may be much 
compressed by their presence. They are surrounded by the dense stroma with some 
muscle, but, on the whole, the muscle seems to be rather atrophied than increased. 
Taken together, these nodules may often be shelled out in one large, irregular mass, 
leaving the remnants of the old prostate tissue. 
Microscopically, they are composed of newly formed glands, which ramify abundantly 
and are fined with cylindrical epithelium. Often these are partly filled with papillary 
growths of epithelium. At other times they are more nearly tubular than acinar in 
form. From the cylindrical form of the epithelium and the extraordinary ramification 
and papillary ingrowth, it seems clear that these are newly formed glands, and that 
there is an enormous multiplication of these elements. 
Without such hyperplasia of the glands the increase of the stroma and of the smooth 
muscle may sometimes cause enlargement of the prostate, but such cases are not com- 
mon, and those in which there is a distinct myoma or muscular tumor growth are rare. 
In the glandular nodules one occasionally finds cystic dilatations which may contain 
epithelial debris and sometimes concretions, although the latter are not so frequent as 
in the original glands. 
Inflammatory infiltrations of wandering cells are common, especially about the ducts. 
The enlargement may affect one or both of the lateral lobes, and is sometimes rather 
diffuse, sometimes irregular, inasmuch as it is produced by only a few nodules. In these 
cases the prostatic urethra, being fixed to the symphysis pubis, is stretched backward 
so as to assume the form of a narrow slit, which is bowed backward and may even be 
enlarged instead of being constricted (Fig. 218). This need not produce any obstruc- 
tion, and urination is often normal. But such increase in the bulk of the lateral lobes 
tends to displace the posterior half of the ring of the sphincter upward, so as to form 
a transverse muscular fold (Mercier's barrier) behind the vesical orifice of the urethra, 442 
TEXT-BOOK OF PATHOLOGY 
which may act as a valve. In another set of cases there appears, often in association 
with hypertrophy of the lateral lobes, a pear-shaped mass of glandular tissue which springs 
up inside the sphincter and lifts up the floor of the trigonum, projecting upward into 
Fig. 216.-Hypertrophy of lateral lobes of prostate. Cross-section showing lateral 
compression of urethra. Prostatic concretions. 
Fig. 217.-Hypertrophy of lateral and middle lobes of prostate. Great hypertrophy 
of the bladder. PROSTATIC OBSTRUCTION 
443 
the bladder. This is the hypertrophied midlobe, which seems to arise from hyperplasia 
of that insignificant group of glands which lies in the midline and extends in front of the 
posterior half of the sphincter.* It may attain a great size, and in one of our specimens 
must weight at least 50 grams. Obstruction to the outflow of urine is almost sure to 
result, because with the contraction of the bladder the midlobe, extending as it does 
through the sphincter, acts as a conical plug to close the urethral orifice. Besides, the 
stretching of the sphincter from its presence is often sufficient to produce incontinence 
of urine. 
As to the nature and cause of this enlargement of the prostate, numerous ideas have 
been expressed, most lasting among which are- (1) that of Ciechanowski and many 
others that it is the result of a chronic inflammation, due probably to gonococcal infec- 
tion of long standing, with the formation of scar tissue about the ducts, constricting them 
and producing dilatation of the glands, and (2) that maintained by Chiari and others, 
Fig. 218.-Hypertrophy of lateral and midlobes of prostate, showing anteroposterior 
widening of the urethra. 
that it is a definite new-growth of adenomatous or tumor-like character, the direct cause 
of which is unknown. Chiari distinguishes the nodules as papillary intracanalicular 
adenomata, fibro-adenomata, and tubular adenomata. 
With regard to these theories, it may be said that it seems impossible to explain the 
enormous solid growths, as Ciechanowski does, on the basis of mere obstruction of the 
ducts, especially in the case of the midlobe, which must arise from such a rudimentary 
group of glands. At any rate, many authors fail to find inflammatory processes in all 
cases, and regard them, when found, as secondary infections. Still we are familiar with 
* It must be said here that Marion and Lendorf have recently declared that the 
enlarged midlobe, and, indeed, most, if not all, of the enlargements of the prostate, 
develop inside the sphincter from the urethral glands and not from the prostate at all. 
They support this view by the statement that the prostate is seen compressed and flat- 
tened outside of the stretched layer of muscle which represents the sphincter. 444 
TEXT-BOOK OF PATHOLOGY 
certain infections, such as the coccidiosis of the rabbit's liver, which produces colossal 
overgrowths of epithelium, so that it is not inconceivable that infection might be at the 
origin of the process, although not in so mechanical a way. The condition arises most 
commonly, if not exclusively, in married men, and has been ascribed to sexual excesses. 
It begins usually long years after gonococcal infection has subsided, even if it ever were 
present, and the nodules tend to recur when removed. Thus it is that some authors 
unhesitatingly refer them to the effects of inflammation, while others just as firmly rele- 
gate them to the category of tumors. Ribbert feels no doubt as to their tumor nature, 
and shows that as adenomatous nodules they are derived from a group of glands on each 
side of the urethra near the colliculus and belonging to the great lateral lobe, which he 
calls the lower urethral prostatic glands. The growth of such nodules is accompanied by 
some enlargement of the adjacent gland tissue. The adenomata of the sphincter region 
below the urethra (midlobe) usually develop only in association with those of the 
urethral prostatic glands. 
Ciechanowski: Mitth. a. d. Grenzg. d. Med. u. Chir., 1900, vii, 183. 
v. Frisch: Nothnagel, Spez. Path. u. Therap., 1899, xix. 
Wichmann: Virchow's Archiv, 1904, clxxviii, 279. 
Chiari: Strassb. med. Zeitung, 1912, ix, 1. 
Ribbert: Ziegler's Beitrage, 1915, Ixi, 149. 
LITERATURE 
OTHER FORMS OF OBSTRUCTION 
It is not only in the urethra that obstructions to the emptying of the 
bladder appear, for plugs may be formed in the bladder itself. These are 
often loose in the cavity of the bladder, in the form of urinary stones or 
foreign bodies, which have been pushed into the bladder through the ure- 
thra. Then there are the stalked, papillary, tassel-like tumors, which very 
commonly reveal themselves later as carcinomata, and which can drift 
into the urethral orifice and cause a temporary obstruction. Tumors invad- 
ing from the uterus or rectum through the bladder-wall may block the 
urethra, just as the tumors of the bladder-wall itself, but their usual fate is 
to break down into a canal into the rectum or vagina, which allows the 
escape of urine but renders infection of the bladder inevitable. 
Very important in connection with the mechanical obstruction of the 
flow of urine is the presence of solid calculi composed of materials derived 
from the urine. These are found not only in the bladder, but in the pelvis 
of the kidney, and, indeed, it seems that the renal pelvis is the seat of orig- 
inal formation of many of them. It is not clear that obstruction has any- 
thing to do with their primary formation, although the growth of some of 
them at least seems to be greatly favored by such changes in the urine as 
follow obstruction. But they themselves are effective, just as in the case 
of gall-stones, in acting as plugs which retard the flow of urine either inter- 
mittently or continuously. 
Urinary Calculi.-Concretions of crystalline material, mixed usually with some 
organic substance, and found at any point from the renal papillae and renal pelvis to 
the urethra, constitute the group of urinary calculi. According to their position, they 
have the opportunity to assume one form or other, and an irregular mass from the pelvis OTHER FORMS OF OBSTRUCTION 
445 
of the kidney, if it be swept into the bladder, is likely to become round by the con- 
tinuous application of new layers of crystals. These calculi vary in their chemical com- 
position, and accordingly in their appearance, depending partly upon the position in 
which they are formed, but chiefly and almost entirely upon the chemical character of 
the urine in which they form. Since the urine may frequently change its character 
during the months or years which go by in the growth of the stone, the end result is 
apt to be made up of layers or laminae of quite different color, consistence, and chem- 
ical composition (Fig. 219). 
Ebstein thought that the organic or albuminous supporting framework which one 
can find in every calculus was the necessary skeleton upon which the deposit of crystals 
took place, and that without such a nucleus of organic material no crystallization in 
this form would occur. Aschoff, Moritz, Kleinschmidt, and others dispute this, and 
think this organic meshwork which is present in crystals, even when they are made to 
form in urine in vitro, is an accidental accompaniment of the crystals, probably formed 
through their own power of absorption. Still, they admit that it is of some help in hold- 
Fig. 219.-Laminated vesical calculus. Central 
mass of uric acid with peripheral zones of carbon- 
ates and phosphates. 
Fig. 220.-Urinary calcu- 
lus of uric acid in laminae 
about a central quartz pebble. 
ing the forming stone together. The application of new layers of crystals to a concre- 
tion already formed is thought to occur, just as rock candy crystallizes on the string. 
But it involves the idea of an oversaturation of the urine with crystallizable substances, 
or else such changes in the urine that it becomes less able to hold those substances in 
solution. Thus if the urine is acid, uric acid may crystallize out, while if it is alkaline, 
phosphates, ammonio-magnesium phosphates, and ammonium urates may appear. 
Or something may cause the precipitation of those colloid materials in the urine which 
tend to hold the uric acid in solution, after which it quickly appears in crystalline form. 
Bacterial infection, especially when it produces ammoniacal decomposition of the urine, 
is favorable to the formation of phosphatic concretions. 
Thus there is no insurmountable difficulty in explaining the growth of such stones 
once started, but it is more difficult to explain their origin. Of course, some are formed 
around foreign bodies-hair-pins, pieces of catheters, etc., which have been introduced 
into the bladder, but these incrustations are relatively rare (Fig. 220). Ebstein and 
others, including Kleinschmidt, are reduced to the explanation that most calculi, whether 446 
TEXT-BOOK OF PATHOLOGY 
found in the renal pelvis or in the bladder, are formed originally in the tubules of the 
kidney. This idea has been elaborated especially for the uric-acid stones, because they 
are the commonest and because the conditions found in the so-called uric-acid infarcts 
of the kidney do explain their origin fairly well. These are frequent, especially in the 
kidneys of children and infants, and produce a curious yellow streaking of the papilla 
of the pyramid, sometimes with actual stony concretions embedded in ragged cavities 
near its tip. Microscopically, it is found that this is due to the abundant excretion of 
uric acid by the cells of the tubules. Sometimes (Aschoff) these are uninjured and 
secrete the uric acid in minute crystals on their surface. Other cells may be destroyed 
in the process. The uric acid appears in minute, round "sphseroliths," which become 
massed together with an albuminous material, secondarily gluing them together. This 
forms the primary concretion, which may 
pass quite out through the urethra, or may 
form the nucleus for a urinary calculus. 
Calculi may form in normal non-albu- 
minous urine, and may grow to a consid- 
erable size without causing any symptoms 
-usually from their angular form they 
Fig. 221.-Uric-acid calculi with fine lamination. 
wound the wall of the renal pelvis or of the bladder, and then cause bleeding and in- 
flammation, which in turn are likely to change the reaction of the urine and initiate 
the deposition of layers of material of a different character from that which composed 
the stone. When the stone causes obstruction and bacteria are introduced, this change 
in reaction and the deposit of phosphates are inevitable. 
Kleinschmidt classifies all these calculi as non-inflammatory and inflammatory, in 
each of which groups there are primary and secondary formations which represent stages 
in the history of the stone, just as do successive strata in a geological formation. Several 
of the crystalline substances in the urine may form concretions without any appreciable 
admixture of other things, so that in these calculi the chemical composition is the same 
from the centre to the surface. Such practically pure concretions are those composed 
of uric acid, calcium oxalate, xanthin, cystin, or calcium phosphate. Some of them OTHER FORMS OF OBSTRUCTION 
447 
grow in the same way as mixed stones to a large size. In other cases they form the nu- 
cleus upon which, with a change in the character of the urine, layer after layer of other 
substances are deposited. When there is no inflammatory process, such secondary 
stones may be formed upon a uric-acid concretion as nucleus with layers of uric acid and 
urates, or layers of oxalates and calcium phosphate. So, too, a calcium oxalate nucleus 
may be turned into a secondary calculus by being enveloped in layers of uric acid or cal- 
cium phosphate. 
When bacterial infection and an inflammatory process supervene, phosphates, 
especially the ammonio-magnesium phosphate, sometimes with calcium carbonate, etc., 
make their appearance as strata of white, rather crumbly crystals, on the surface of one 
of these nuclei, just as they form an incrustation over any foreign body in the bladder. 
Indeed, they may form the whole calculus by themselves, without any obvious non- 
inflammatory stone or foreign body as a nucleus. 
Uric-acid calculi (Fig. 221) are hard, smooth, oval or rounded stones when formed 
in the bladder, or moulded to the cavity when in the renal 
pelvis. There is often a central granule of ammonium 
urate about which fine, delicate yellow or yellow-brown 
laminae of very compact appearance and great regularity 
are laid down. In other cases the consistence is more 
like that of pumice-stone, especially when there is much 
admixture of urates and the lamination is correspondingly 
indistinct. 
Fig. 222.-Vesical calculi formed of calcium oxalate. One in section shows laminae of 
phosphates and carbonates. 
Pure calcium oxalate stones are rare, but mixed stones in which it forms a consider- 
able part, are common. They are often formed about a nucleus of uric acid or urates, 
and the oxalate covers this in layers of varying thickness, distinguished by their dark- 
brown color and by the extremely rough, jagged external surface which they present 
(Fig. 222). The irritation caused by this usually leads to the deposition of carbonates 
and phosphates, which fill up the depressions and smooth off the surface (Fig. 223). 
Urates may also alternate with layers of oxalates. Such stones are extremely hard, 
usually fairly round, and occur especially in the bladder. 
Phosphatic Calculi.-In other cases, especially when the bladder is inflamed, ammo- 
nio-magnesium phosphate and calcium phosphates and carbonate predominate, usually 
on a nucleus of uric acid. These stones may or may not be laminated (Fig. 224). They 
are nearly pure white, with occasional yellow or brownish layers, and the surface is rough. 
Rarely, instead of being chalk-like, these phosphate stones are radially crystalline. The 
non-laminated type are usually round and rough, loosely built, pumice-like concretions 
of a yellowish-white color, but material of this sort is often deposited irregularly on 448 
TEXT-BOOK OF PATHOLOGY 
Fig. 223.-Mixed oxalate and urate calculus coated with phosphates. 
Fig. 224.-Phosphate calculus with a layer of oxalates. CYSTITIS 
449 
other stones, especially when they are cracked or irregular and lodged in a bladder where 
there is ammoniacal decomposition of the urine. 
The obstruction produced by calculi is dependent, as long as they are loose in the 
bladder, upon the posture of the patient and upon the size and shape of the stone, so 
that unless it is impacted in the urethra, the obstruction is intermittent. 
D. Kleinschmidt: Die Hamsteine, Berlin, 1911. 
W. Ebstein: Natur u. Behandlung der Harnsteine, Wiesbaden, 1884. 
H. A. Fowler: Johns Hopkins Hosp. Reports, 1908, xiii, 507. 
LITERATURE 
Paralytic Dilatation of the Bladder.-Normally, when the bladder is filled 
to a certain degree it tends to contract and empty itself, the act of micturi- 
tion being under the voluntary control of a sphincter, and being in itself 
the effect of nervous reflexes by way of nerves which run to and from the 
lumbar and sacral cord. When injury of the spinal cord results in complete 
paralysis of the lower extremities and of the lower part of the body, as is 
so frequently the case in fractures of the spine, etc., neither afferent nor 
efferent impulses are effective. There is no sense of overfilling of the 
bladder, no desire to micturate, and often no power, even by the aid of 
the abdominal muscles, to empty the bladder. Hence it gradually becomes 
distended to an enormous size, and must be emptied by the introduction of 
a catheter. 
These various conditions offer a more or less insuperable obstacle to the 
discharge of urine from the bladder, and the immediate result is its incom- 
plete instead of complete evacuation. Ordinarily the residual urine does 
no harm, except in that it occupies space in the bladder which thereupon 
fills more quickly, so that micturition becomes abnormally frequent. That 
is true so long as the urine remains sterile, but with increased difficulty in 
urination it may become necessary to pass a catheter into the bladder, and 
sometimes this operation falls to the hands of the patient himself. Natu- 
rally, in such conditions it is not long before bacteria are carried into the 
residual urine and find there an excellent culture-medium. As soon as 
this happens, the urine, which may have been clear before, becomes turbid 
and alkaline, full of bacteria, desquamated epithelial cells, and leucocytes, 
showing that the response to infection in the form of an acute cystitis has 
appeared. 
Naturally, a great variety of bacteria may be concerned in this process, 
and in such cases there is commonly a mixture of several forms, sometimes 
even with yeasts and fungi in addition. The inflammation (cystitis) which 
they set up will vary in its intensity according to the type of infection, but 
more especially according to the degree of obstruction and the resistance 
of the individual. 
CYSTITIS 
Forms of Cystitis.-We may distinguish catarrhal, purulent, and diphtheritic forms, 
and there are others that almost merit the name gangrenous. 450 
TEXT-BOOK OF PATHOLOGY 
In the mildest infections the bladder-wall becomes swollen and reddened, and a few 
leucocytes pass through. The urine is acid when Bacillus coli is the infecting agent, 
but otherwise it is often alkaline, with a small amount of ammonia and a sediment of 
phosphates, desquamated cells, and mucus. The purulent form follows upon more 
intense infections, and is characterized by haemorrhages in the mucosa and pus-contain- 
ing urine. These haemorrhages may be mere petechiae. 
In the diphtheritic form much more extensive haemorrhages appear, surrounding the 
patches of most intense inflammation. In these areas the bacteria are found to have 
caused a superficial necrosis, with the coagulation of a layer of yellowish or greenish 
fibrin upon the surface and into the depth of the necrotic mucosa. The loosening of 
such a false membrane leaves an ulcer with haemorrhagic base, and surrounded by a deep- 
red halo. Such ulcers are usually found at first upon the more prominent parts of the 
wall, where the muscular trabeculae project, and upon the smoother trigonum. In 
advanced, long-standing cases, though, the ulcers become deeper and may cover much 
of the bladder-wall, some of them are scarred, while others are newly formed; discolora- 
tion occurs; there arises much blackish-green staining, probably largely from sulphides, 
which blacken the haemosiderin formed in the haemorrhagic areas, and the bladder-wall 
presents an extremely foul, ragged, and deeply stained surface. In a bladder of this 
type the urine contains all the materials which could be shed from such a wall. 
Usually a great dilatation of the bladder follows upon such long-continued 
obstruction to the outflow of urine. Its walls become stretched, and 
particularly those portions which lie between the main muscular trabeculae 
may be bulged out into diverticula. At the same time there is a distinct 
hypertrophy of the muscle bundles-a work hypertrophy which arises in 
the oft-repeated attempt of the bladder to discharge its contents (Figs. 215 
217). Whether the dilatation or the hypertrophy will predominate de- 
pends upon the age and general condition of the patient. There are old 
men without much obstruction in whom atrophy of the muscle of the 
bladder allows it to become distended and to retain residual urine. 
The entrance of the ureters into the bladder is oblique, through the 
muscular wall, so that the more tensely the bladder is distended, the 
greater is the pressure tending to flatten and close the end of the ureter 
as it slants through the bladder-wall. In addition to this the actual ori- 
fice is guarded internally by valve-like folds of mucosa which readily allow 
the urine to pass downward only. Therefore the entrance of fluid from the 
bladder into the ureter is normally excluded, and it is impossible, even with 
great force, to inject colored fluids into the ureter by distending the bladder 
with them. It requires some destructive change in the intravesical part 
of the ureter to make this influx possible-either the erosion of all these 
guarding tissues or something which will render the ureter so rigid that it 
will not collapse when the bladder is distended. Nevertheless, it is evi- 
dent that if it becomes difficult for the urine to escape from the bladder, 
it becomes equally difficult for it to leave the ureter and enter the bladder, 
so that an obstruction which ends in distension of the bladder is equally 
an obstruction to the escape of urine from the kidneys and ureters. 451 
EFFECTS OF OBSTRUCTION ON THE KIDNEYS 
EFFECTS OF OBSTRUCTION ON THE KIDNEYS 
We have now to consider the effects upon the kidney with its pelvis and 
ureter of-(a) Obstruction without infection; (6) obstruction with infection; 
and (c) the rare infection by way of the urinary tract without obstruction. 
Hydronephrosis, by which is meant a dilatation of the pelvis of the kid- 
ney, often accompanied by hydro-ureter and practically invariably by a 
Fig. 225.-Hydronephrosis resulting from stricture at the uretero-pelvic junction, 
Extreme dilatation of the calyces. 
distension and thinning of the renal substance itself through the accumula- 
tion of fluid in that cavity, may result from various causes. All those types 
of obstruction which lead to distension of the bladder may be accompanied 
by hydro-ureter and by hydronephrosis, but, in addition, there are those in 
which the ureters are blocked in some way. Therefore in the latter group 
the hydronephrosis may be unilateral. The pressure of tumors from the 
outside, such as those which arise from the uterus and ovaries, even if 452 
TEXT-BOOK OF PATHOLOGY 
they do not invade the substance of the ureters, often sets up such a block- 
ing of their lumen. The same effect may be produced by an inflammatory 
process in the ureteral wall which leads to stricture formation, and Samp- 
son has diagrammatically figured the effect in this direction of those opera- 
tions for the removal of pelvic tumors in which the blood supply of a por- 
tion of the ureter has been disturbed. Necrosis with scarring, and even 
rupture of the ureteral wall after the distension has begun, may follow. 
Renal calculi formed in the pelvis of the kidney, when small enough, 
pass through the ureter, causing intense pain, but, as is well known, there 
are normally several constrictions in the course of this tube, and the 
calculus may stick at one of these so as to cause complete or partial plugging. 
Fig. 226.-Renal calculus in pelvis forming a complete mould of all the calyces, and ex- 
tending into the ureter. 
Higher in the neck of the ureter or in the pelvis itself the same thing may 
happen. 
Renal calculi, formed as has been described above, present themselves in various forms 
and sizes, the larger ones being moulded into the calyces and about the papillae so as to 
present a complete cast of the pelvis of the kidney, branching into each recess and ex- 
tending in a pointed, curved projection down into the ureter (Fig. 226). Sometimes 
they are in several pieces, and the fragments may be fitted to one another as though 
articulated. At the other extreme we find small, loose, irregular calculi, sometimes no 
more bulky than coarse sand. It seems that unless they become impacted in the meter 
these calculi cause no great distension of the pelvis. In children the common uric- 
acid infarcts already mentioned are often associated with concretions which may 
be partly embedded in the renal substance itself. 
Finally there are some deformities of the pelvis, especially with relation 
to the insertion of the ureter, which can give rise to hydronephrosis, and 453 
EFFECTS OF OBSTRUCTION ON THE KIDNEYS 
which in turn are emphasized by it. These are especially the instances in 
which the ureter springs from a point high up in the pelvis and leaves it at 
an acute angle. There is then a valve-like arrangement, which is brought 
into play by any disarrangement of the kidney and completed by the dis- 
tension of the pelvis. Sometimes the ureter divides before it reaches the 
hilum of the kidney, so that the pelvis is in several compartments with 
their corresponding calyces and papillae. Then it is possible to have a 
partial hydronephrosis if only one of these branches is obstructed. 
Geraghty and Frontz mention also a form of hydronephrosis which de- 
pends on the constriction of the ureter by an inflammatory process with 
scarring, which is likely to occur near the transition of the pelvis into the 
ureter. Hunner has also made a careful study of the various types of ureter- 
itis with stricture and hydronephrosis, and finds them far commoner than 
was formerly suspected. We have recently met with such a case at autopsy 
which is illustrated in Fig. 225. 
The fluid which accumulates is generally clear, and contains urea and 
other urinary constituents, although in unusual proportions. It has 
generally been looked upon as urine, but except perhaps in those cases in 
which the obstruction is intermittent, it will be seen, from the mode of 
development, that it must differ a good deal from normal urine. It often 
contains casts of the renal tubules and desquamated epithelium. 
Cohnheim made the statement that only partial or intermittent obstruc- 
tion is followed by great distension of the pelvis, while complete obstruc- 
tion results in cessation of the flow of urine and atrophy of the kidney. 
In human beings this has the appearance of being true, for in cases 
of complete obstruction of the ureter one finds the kidney reduced to an 
insignificant, flattened, fibrous mass, in which hardly any well-ordered 
renal substance can be found (c/. Fig. 70). On the other hand, an inter- 
mittent or partial obstruction can cause the distension of the ureter and 
pelvis until a sac is formed which may occupy a great portion of the 
abdominal cavity. It has been shown recently by Ponfick and others 
that the absolute closure of the ureter is followed by such distention of 
the pelvis and the kidney as to reduce the kidney to a thin layer of firm 
fibroid tissue, although many recent investigators combat this idea vigor- 
ously. In the earlier stages the bulk and weight of the kidney substance, 
exclusive of the accumulated fluid, actually increase up to about thirty- 
six days after the ureteral ligation, after which they decrease steadily. 
In view of this we may easily conclude that the atrophic remnants which 
we find in human beings after the ureter has been plugged by a stone are 
the final results of a much longer period of obstruction than even the seven 
months through which Ponfick watched his experiments. 
With the distension of the pelvis the calyces become widened and the 
papillae flattened until in time they come to form only circular portions of 
the wall of the hemispherical calyces, the orifice being located only as a 
slight central elevation with radiating blood-vessels and tubular markings. 
Even more complete distortion occurs, and hardly any trace of the papilla 454 
TEXT-BOOK OF PATHOLOGY 
is left-the whole kidney is reduced to a multilocular sac in which 
the partitions, as Ponfick points out, are held in place by the blood- 
vessels, whose course they indicate. The section shows that the pyra- 
mids lose their radiate appearance because the tubules come to lie parallel 
with the surface of the kidney (Fig. 227). The cortex becomes very thin, 
and loses its striations, which are obscured in the gray, scar-like tissue 
which takes their place. It is strange that sometimes this effect is very 
irregular, so that one finds patches of relatively thick renal cortex scattered 
in the otherwise thin wall of the sac. Possibly this is due to the unequal 
diminution in the blood supply of various areas of the cortex, which comes 
through vessels which run in the partitions of the sac and may be exposed 
to different degrees of pressure. 
Most observers agree that the secretory process ceases at a point before 
the fluid attains a pressure higher than that of blood. Ponfick describes 
the appearance of hyaline casts, of leucocytes, and especially of red blood- 
Fig. 227.-Hydronephrosis. Section shows the thinning and flattening of cortex 
and pyramid, with great distension of the pelvis and calyces. The flattened papilla 
is at a; the margins of the calyx, at b, b. 
corpuscles, together with a coagulable fluid in the tubules and glomerular 
capsules. The epithelial cells, at first swollen, later become flattened, and 
even the glomerular tufts may disappear, leaving spaces that look like 
tubules. There is apparently the formation of an actual exudate of inflam- 
matory character in response to the destructive effect upon the cells. 
Associated with it comes a diffuse formation of abundant new connective 
tissue everywhere - between the tubules and about the glomeruli. The 
end-result is that we have in an advanced case an extraordinary thinning 
out of the renal substance, which assumes a gray, uniform, translucent ap- 
pearance, and an almost leathery consistence. In this the tubules are found 
lined by a uniform, flattened epithelium, and often interrupted by the col- 
lapse of their walls, so that spindle-shaped or even rounded portions remain, 
filled with hyaline casts. The glomeruli are obliterated and converted 
into fibrous nodules, or else surrounded by a thickened fibrous capsule, and 
everywhere the interstitial connective tissue is prominent not only through 
its actual increase, but because of the disappearance of many tubules. It EFFECTS OF OBSTRUCTION ON THE KIDNEYS 
455 
will be seen that this process is, in nearly every respect, analogous to that 
which follows the ligation of the duct of such a gland as the pancreas. 
Ascending Renal Infection.-In all forms of obstruction to the outflow 
of a secretion we have traced the liability of the tissues to infection, and the 
kidney is no exception to this rule. With the advent of virulent bacteria 
in an already formed hydronephrotic sac there arises an inflammation 
which is of a far more intense character than any which may have been 
associated with the mere mechanical obstruction, and when the sac is filled 
with a purulent fluid, we speak of the condition as pyonephrosis. A 
similar condition, naturally with somewhat different course and clinical 
symptoms, may arise when the distending fluid is from the first infected 
and the inflammatory process is intense throughout. Thus, when there 
appears an infection about impacted renal calculi which may not in them- 
selves have caused an effective obstruction, or when an obstruction lower in 
the ureter or in the bladder or urethra causes the damming-up of urine which 
quickly becomes infected, we have a distension which is by no means so 
great, but in which the pelvic walls are injured by the bacteria and 
present a haemorrhagic, ulcerated, and purulent surface. 
It is hard to draw a line between the cases in which the distension is pre- 
dominant and those in which the inflammatory processes are more impos- 
ing. These latter, which are known under the name pyelitis, or more 
usually pyelonephritis, constitute a form of ascending suppurative nephritis 
which is most commonly associated with obstruction and stagnation of 
urine. But it must be borne in mind that, with very slight differences, an 
inflammatory process in the kidney with suppuration and secondary inflam- 
mation of the pelvis may be caused by bacteria brought to the kidney 
through the blood-stream when there is no disease of the lower urinary 
tract at all. This can often be easily distinguished, and we shall speak 
of it elsewhere. 
In all these cases in which infection of the kidney is associated with 
obstruction and infection of the urinary passages, there appear abscesses 
in the substance of the kidney itself, in addition to the acute, oftentimes 
very intense, inflammation of the mucosa of the pelvis. These are usually 
situated chiefly in the cortex, and are sometimes very small, but generally 
conglomerated, so that they reach the size of a pea and bulge on the surface. 
If one tears off the capsule of the kidney, many of them are broken open and 
exude a greenish-yellow pus. On section, the tissue around them is gray- 
ish red and swollen, and has lost the distinctness of its markings. Often, 
but not always, there are grayish-yellow, opaque streaks running down 
through the pyramid toward the papilla, which are produced by extensions 
of the abscesses along the conducting tubules (Figs. 228, 229, 230). 
Active discussion has raged for a long time as to the paths followed by 
bacteria, which, from an infected bladder, arrive at the production of more 
or less isolated abscesses in the cortex of the kidney, and many views have 
been proposed. It has been stated that the organisms get into the blood- 
stream from the bladder, and lodge finally in the kidney, which is rendered 456 
TEXT-BOOK OF PATHOLOGY 
Fig. 228. 
Fig. 229. 
Figs. 228 and 229.-Pyelonephritis-case of prostatic obstruction with cystitis. EFFECTS OF OBSTRUCTION ON THE KIDNEYS 
457 
susceptible by the obstruction. Others think they pass along the lymph- 
atics of the ureter or by the venous anastomoses between the vessels of the 
pelvic organs, ureter, and kidney. Neither of these last views seems to 
me based on probability, because they involve retrograde embolism, which 
is not to be lightly called to our aid. 
The more common view is that the bacteria pass up the lumen of the 
ureter to the pelvis, and thence into the kidney. They cannot easily ascend 
Fig. 230.-Pyelonephritis. There are beginning abscesses in the cortex, shown as 
areas of necrotic tubules with purulent exudate about them. Many of the tubules con- 
tained bacteria. 
the ureter when it is open and flushed by the normal stream of urine, but 
if it is obstructed and occupied by a nearly stagnant column of urine, it is 
easy to believe that bacteria may spread to the kidney. This is especially 
true if any inflammation of the ureteral wall in its intravesical part has 
rendered it rigid, and thus rendered useless the guard at the ureteral opening. 
Having attained the pelvis and produced a pyelitis, it remains to explain TEXT-BOOK OF PATHOLOGY 
458 
their entrance into the kidney. Orth looks askance at the glibly expressed 
belief that they wander up the tubules, but Schmidt and Aschoff have found 
bacteria in the tubules in animals in which they have experimentally 
obstructed and infected the ureters, and adopt this idea. Without it we 
must have recourse to the blood-vessels, of which, of course, only the ar- 
teries are available, or to the lymphatics. Muller thinks he can prove the 
lymphatic transmission by finding the tubules attacked and perforated on 
one side by exudate, which also fills the lymphatics. It is difficult, how- 
ever, when the inflammation has proceeded to such a degree, to say which 
way it is working, and the findings of Schmidt and Aschoff, which show that 
the bacteria can enter the tubules, seem, after all, most convincing. 
Ponfick: Ziegler's Beitrage, 1910, xlix, 127; 1911,1, 1. 
Orth: Lehrb. d. spez. Path., 1893, ii, 59. 
Schmidt and Aschoff: Pyelonephritis, Jena, 1893. 
Jores: Ergeb d allg. Path., 1907, xi2, 146. 
Geraghty and Frontz: Jour. Urology, 1918, ii, 161. 
Vernon David: Surg., Gyn., and Obst., 1918, xxvi, 159 
Hunner: Johns Hopkins Hosp. Bull., 1918, xxix, 1. 
Sampson: Ibid., 1903, xiv, 334. 
LITERATURE CHAPTER XXIII 
TYPES OF INJURY-OBSTRUCTION (Continued).-GENERAL 
DISTURBANCES OF CIRCULATION 
Mechanism of circulatory organs. Pericardial and pleural effusions. Emphysema. 
Chemical influences. Effects of arterial and myocardial disease. Myocarditis. Valvular 
disease. General mechanism of the obstruction thus produced. Various valvular lesions 
and their special effects. Cardiac hypertrophy and dilatation. Decompensation; chronic 
passive congestion. Disturbances of conduction system in heart. 
Mechanism of Circulatory Organs.-Reflection upon the general mechan- 
ism of the circulation of the blood will give one an idea of the extraor- 
dinary number of things that can fail in playing their proper part and 
upset the smooth working of the whole. Incidentally, it gives, too, a sense 
of wonder that a machine of such marvelous complexity should work at 
all, and not be constantly interrupted or overtaxed by the variable tasks 
laid upon it and the difficulties thrown in its way. It is found, however, 
that not only does it keep up a definite standard output of work day and 
night, but it will do this in spite of the most unreasonable obstacles. 
The Heart.-The heart, as a bulbous muscular pump, must keep the blood 
moving in two circles, one through the lungs, the other through the rest 
of the body, for which reason it is in two halves; and it must do this 
promptly, having a new supply of blood ready when it has discharged 
one, wherefore it has its auricles. There are wonderfully perfect valves 
to maintain the direction, and the left side of the heart is more powerful 
than the right, because it drives the blood into a larger field and against 
greater resistance. Still, with these unequal tasks, which may vary 
between two beats, one side of the heart may not eject more or less blood 
than the other. If the right ventricle throws out so much as one drop more 
than the left in each beat, the lungs would be overdistended and burst 
within a few minutes. This perfect coordination between the two sides 
is even more remarkable when we think that the ventricles are formed 
essentially from two coils of one long muscle band, the tendinous ends of 
which are attached to the valves as the chordse tendinese, and that the 
tasks of the two sides are not only different, but vary differently. To be 
effective, the auricle must empty itself into the ventricle at the precise 
moment required, and the ventricle must be ready for its new load; to 
expel the blood with adequate force, the walls of these chambers must con- 
tract not only rhythmically, but uniformly, and to insure this rhythmic 
and perfect contraction there arc special telegraphic connections with 
central stations at at least two places, from which controlling impulses are 
sent out-one sets the pace, the other relays the message. 
The Blood-vessels.-The heart is aided in its work by the arteries, and 
459 460 
TEXT-BOOK OF PATHOLOGY 
to a less extent by the veins. They are not merely elastic tubes, in places, 
in the veins at least, furnished with valves, but active contractile organs, 
which not only drive on the blood by a sort of peristaltic contraction, but 
control the head of pressure with which the heart works, by narrowing or 
widening their own calibre. Were it not for this healthy opposition to the 
push of the heart, there would arise one of the vicious circles that may 
prove disastrous to the whole circulation; not only would the arterial 
blood escape into the distensible veins through the capillaries, but the 
back pressure into the coronaries, upon which the nutrition of the heart 
depends, being gone, the heart would fail at once. The fact that this con- 
trolling contraction and relaxation of the arterioles occurs locally in differ- 
ent regions of very different extent explains the possibility of rapid varia- 
tions in pressure, which must be compensated either by extra effort of the 
heart or by other changes in calibre in the vessels. 
Control of Blood-vessels.-The heart and blood-vessels then, work in 
cooperation almost as intimate as that of the two sides of the heart. This 
must be managed by the nervous system. There are nerves important in 
this respect, the accelerator and augmentor nerves, which form part 
of the sympathetic system, and to which the inhibitory vagus nerves act 
antagonistically. The blood-vessels are made to contract by vasocon- 
strictor fibres, which, starting from the ganglion-cells of a centre in the floor 
of the fourth ventricle, reach the blood-vessel walls by relays of cells 
through the sympathetic ganglia. They are made to dilate by inhibitory 
vasodilator fibres, which seem to have no definite centre in the brain and 
do not act rhythmically, like the vasoconstrictors, which maintain a tone 
in the vessels. These mechanisms which govern the vessels may be set 
in action reflexly by impulses conducted along sensory nerves, but prob- 
ably by special fibres, some of which act to stimulate the release of vaso- 
constrictor impulses (pressor fibres), while others set in action vasodilator 
impulses (depressor fibres). From the aorta and heart there even runs a 
nerve whose sole function is of an afferent depressor character. Psychical 
stimuli, as well as those from various organs, may affect the vascular con- 
trol, and in a reflex way cause the blanching or flushing of different parts 
of the body. Indeed, violent painful stimuli may produce sometimes 
such extreme relaxation of the vessels that the blood-pressure falls to a 
degree which proves fatal (shock). Certain chemical stimuli, such as 
extracts of the adrenal and pituitary glands, are known to have a powerful 
influence upon blood-pressure through causing changes in the calibre of the 
blood-vessels, and it is often suggested, though not quite proved, that the 
control of the balance is largely dependent on the activities of these organs 
of internal secretion. 
Other Influences.-There are other factors of a more mechanical nature 
which have a very great influence upon the circulation, namely, respiration, 
the condition of the abdominal contents, posture and muscular activity, 
and many others. Respiration aids the flow of venous blood to the heart 
by producing a partial vacuum in the thorax during inspiration, and at the 
same moment increasing the intra-abdominal pressure. Most of this is PATHOLOGICAL OBSTRUCTIONS 
461 
done by the diaphragm, which both sucks and presses the blood out of the 
abdominal veins. Enteroptosis or sagging of the abdominal viscera, which 
pulls down the diaphragm and diminishes its excursion, annuls to a great 
extent this beneficial action. Great accumulations of fluid or large tumors 
in the abdomen bring about the same result in a different way, by pressing 
the diaphragm up and immobilizing it. The circulation is made easier 
by the recumbent posture-more difficult by the erect, but, of course, this 
is not felt much by the normal heart. Violent muscular exercise elicits 
greater activity of the heart, both to aerate the blood more rapidly and to 
bring it in increased quantity to the active muscles. The heart may be 
overtaxed by too great and prolonged effort, so that it dilates and the man 
falls in a faint or dies. This is really an example of the response of the 
heart to demands which arise from an enormously accelerated metabolism. 
From all this it is seen that in the circle through which the blood is 
forced the conditions in each part are influenced by those in the preceding 
and succeeding parts. Each portion of the circle is governed by regulating 
mechanisms, and instantly adapts itself to new conditions, whether these 
are produced by changes within the stream-bed or by influences from out- 
side, and this very adaptation, like the original change, is felt not only 
just in front of or just behind that point, but all around the circle. All 
these regulatory mechanisms act together to maintain the arterial blood- 
pressure at a fairly definite standard, which reaches 110 to 150 mm. of 
mercury during systole in the larger arteries, falling with each pulsation to 
60 to 80 mm. in diastole. As the blood advances into the arterioles and 
capillaries, the pressure sinks and the differences between systolic and 
diastolic pressure disappear, so that in the veins the stream is constant, 
and at a pressure which still decreases toward the heart. In the pulmonary 
circulation its pressure is very much lower and the pulsatory variations 
less, but it passes with greater velocity through those capillaries than 
through the capillaries of the systemic organs. The importance of the 
maintenance of this pressure and the corresponding rapid exchange of 
blood are most evident in the coronary circulation of the heart and in the 
brain. The nice balance of this mechanism is maintained with great 
tenacity, and the effects of disturbing influences may often be found not in 
changes in the blood-flow itself, but only in the differences in the machine 
developed to compensate for the interference. 
PATHOLOGICAL OBSTRUCTIONS 
Pericardial Effusion.-Mechanical influences quite outside the circulation 
itself can have such effects. The accumulation of fluid in the pericardial 
cavity may go on gradually until the sac is enormously distended, but if it 
comes suddenly, as in the case of a haemorrhage from the heart, or when one 
injects it experimentally in an animal, the pericardium has no time to 
stretch. Then the heart is greatly embarrassed because it cannot expand 
to allow the entrance of blood from the veins. Great distention of the 
veins occurs, with heightening of the blood-pressure there, while the amount 
of blood thrown into the aorta becomes so small that even the action of the 462 
TEXT-BOOK OF PATHOLOGY 
vasoconstrictors fails to keep up the blood-pressure, little blood goes into 
the coronary arteries and the heart gives up its beating. Quick removal of 
the fluid from the pericardium may restore the normal conditions in time 
to start the heart once more. Moderate collections of fluid (hydroperi- 
cardium or pericarditis) may cause only a tolerable overfilling of the veins 
and decrease in the arterial blood-flow. 
Intrapleural and Pulmonary Obstruction.-Effusions of fluid into the 
pleura compressing the lung (c/. Fig. 92), tumors in the pleura, narrowing 
and distortion of the thorax by deformities, such as curvature of the spine 
(skoliosis, kyphosis, etc.), and destructive changes in the lungs themselves 
have a similar effect in obstructing the circulation, but act at a different 
point. Now the difficulty which still affects the whole blood-stream lies 
in forcing the blood through the compressed or reduced pulmonary stream- 
bed, and the burden is put upon the right ventricle. It rises at once to its 
increased task, and may be able to perform it by drawing on its reserve 
power. Often it can go on like this, forcing the obstacle and maintaining 
the normal circulation, in time growing in thickness and strength of wall 
through the increased exercise. But if it fails only partially, the blood 
accumulates in the veins and in the auricle, and reaches the aorta in 
diminished amount. 
Emphysema.-One of the common obstructions acting at this point is 
emphysema of the lungs (see p. 435), in which the rarefaction of the lung 
tissue obliterates much of the stream-bed in the lung. Other changes, 
which, by cramping the thoracic organs or obstructing the pulmonary 
blood-flow, produce the same effect, will be referred to later and easily 
understood. This is the narrow pass for the whole circulation. After- 
ward in the systemic circle nothing can so readily obstruct the whole blood- 
flow, since there are always roundabout ways, and the closure even of large 
arterial trunks has practically no effect upon the blood-pressure. Even 
the whole aorta below the renal arteries may be ligated, with only a trifling 
rise in blood-pressure. Ligation of the renal arteries adds little to this; 
that of the splanchnic arteries has much more effect, but even this (Long- 
cope and McClintock) is a matter of only a few millimetres of mercury. 
Such extreme obstructions are, of course, rare and of little importance, as 
far as the circulatory apparatus goes; their importance relates rather to the 
nutrition of the tissues which those vessels should supply. 
Toxic Influences.-Chemical influences have great importance also, in 
so far as they affect the nervous control of the heart or arteries (atropine, 
adrenaline, etc.), or the muscular walls of these structures (barium, ergot, 
etc.), but their effects are transient and need not be considered further here. 
The poisons at work in many infections act upon the heart to injure its 
muscle and weaken its power, or, as in the case of diphtheria, affect also 
the vasomotors, paralyzing their control over the vessels and thus allowing 
a fall in blood-pressure which may be fatal in withdrawing blood from 
the coronary circulation. This constitutes the underlying principle of 
the shock in which patients die in such intoxications. THE EFFECT OF MYOCARDIAL DISEASE 
463 
Anatomical Changes in the Blood-vascular Apparatus.-Changes in the 
circulatory apparatus itself are productive of great changes in the blood- 
flow, nearly always in the sense of an obstruction, or diminution in .the 
efficiency of its propulsive power. These commonly affect the elasticity 
and contractility of the arterial walls, the muscular power of the heart- 
walls, the efficiency of the valves, and the mechanism which maintains the 
rhythm of the heart, and may be considered in this order. 
THE EFFECT OF ARTERIAL DISEASE 
Disease of the arterial walls (c/. p. 333) results commonly in their partial 
rigidity. At least the elastic tissue which gives them their resiliency is 
broken and degenerated and greatly decreased in amount. What remains 
is rendered useless by the formation of stiff fibrous tissue, or even calcified 
patches which will not stretch. In the same way the smooth muscle, so 
important in changing the calibre of the vessel, and in propelling the blood 
by its contractions, is partly destroyed, partly splinted by the new tissue, 
which thickens the once delicate inner layer of the vessel, and thus 
changes it to a rigid tube, perfectly incapable of aiding the heart. Beside 
this, the lumen of these tubes is often narrowed by this process, and some- 
times to an extreme degree. 
The general effect is to withdraw from the heart whatever aid the vessels 
previously afforded in the propulsion of the blood. While this is important, 
it is not so great that an extreme burden is put upon the heart by its loss. 
Nor, except in the case of the splanchnic vessels, is the narrowing of the 
channels likely to cause a noteworthy rise in blood-pressure. Extra work 
is, of course, put upon the heart by both these factors, and the wall of the 
left ventricle thickens and becomes stronger in response to it, but there is 
still uncertainty as to the degree to which the arterial changes alone are 
responsible for this; probably their effect has been frequently overestimated 
in cases in which several factors are available in explaining high blood- 
pressure and the enlargement of the heart. The opinion has been expressed 
by many (Hasenfeld, Longcope) that rigidity and narrowing of the splanch- 
nic vessels are by far the most important in this respect. An analysis of 
the autopsy records in a large number of cases of long-standing arterial 
hypertension shows that while this runs parallel with chronic nephritis 
there is practically no definite relation between its occurrence and that of 
arteriosclerosis. 
Of special interest are the changes in the coronary arteries of the heart, 
for any interference with the abundant blood supply necessary to that 
muscle must bring with it injuries of the heart-wall, to the detriment 
of the general circulation. 
THE EFFECT OF MYOCARDIAL DISEASE 
The arrangement of the musculature of the heart-walls (J. B. MacCallum, 
Mall) is such as to control with the greatest completeness the propulsion of 464 
TEXT-BOOK OF PATHOLOGY 
the blood-not only does it obliterate the cavity of the ventricles, but by 
the contraction of the papillary muscles it insures the proper tension 
and perfect closure of the auriculoventricular valves. Further, special sub- 
divisions of the muscle support the semilunar valves, and maintain 
their closure in such a way that even with slight imperfections of 
the valves leakage is much diminished by this muscular action. The 
heart muscle has always been regarded as a network of cells attached 
to one another along transverse cement lines, but in recent years 
there has been a tendency to look upon it as a sort of syncytium with- 
out cellular limits, the cement lines being thought to be the product of 
physical influences which act more intensely with the advance of age 
(Cohn, Aschoff, and Tawara). The muscle fibrils, with their sarcoplasmic 
discs, are arranged in each fibre around a central space, in which lies 
the nucleus surrounded by undifferentiated protoplasm. It is in this 
space at the poles of the nucleus that a yellowish pigment begins to accumu- 
late in early years of life, and increases with the advance of age. With 
great wasting of the heart muscle this pigment may become so abundant 
as to give a chestnut-brown color to the whole heart (brown atrophy). 
As indicated elsewhere, it is one of the lipochrome pigments and takes a 
reddish stain with Sudan. The specific stimulus-conducting system of 
fibres will be described later. 
Myocardial Injuries.-Myocarditis.-Degenerative and destructive 
changes occur in the heart muscle in the course of various infections, in- 
toxications, and nutritive disturbances, but are not specially characteristic 
of any. Fat accumulates in the form of fine droplets arranged in the sarco- 
plasmic discs, and therefore often in longitudinal lines. This fat is, as a 
rule, not uniformly distributed, but is very abundant in certain little 
groups of fibres, while almost absent in the neighboring ones. On the 
whole, it is far more abundant in the inner layers of the heart-wall than the 
outer. This results in the peculiar mottling with minute, opaque, yellow 
patches, most commonly seen in the wall of the right ventricle below the 
orifice of the pulmonary artery, and in the papillary muscles of the left 
ventricle, although it may be spread all over the interior and deep in the 
substance of both ventricles. This is the so-called tigering or faded-leaf 
appearance (cf. Figs. 32 and 33). Hibbert thinks that this peculiar dis- 
tribution is due to unequal nutrition in the regions of different minute 
branches of the coronary arteries. It is found most often in extreme and 
long-standing anaemias, protracted febrile states, and in chronic diseases, 
such as nephritis, associated with anaemia. The presence of the fat seems 
to have very little detrimental effect upon the function of the heart, or per- 
haps it should be said that the diseased condition of the muscle which leads 
to the retention of the fat does not greatly impair its activity. Dr. Welch, 
in studying animals kept for a long time at a fever heat, found abundant 
deposition of fat in their hearts, but no special functional alteration. In 
the same way we find a certain cloudiness of the heart muscle in such infec- THE EFFECT OF MYOCARDIAL DISEASE 
465 
tions as typhoid, but although we may name this parenchymatous degenera- 
tion, we cannot find that it indicates much harm to the heart. 
On the other hand, in a few very acute and intense infections or toxic 
processes, such as diphtheria and scarlet fever, there may be actual necrosis 
or hyaline degeneration of fibres here and there, much like that seen in the 
rectus abdominis in typhoid fever, and these or even slighter lesions, not 
easily seen as changes in the muscle, may in these diseases give rise to a 
wide-spread acute inflammatory reaction with focal accumulations of leuco- 
cytes, oedema, and fibrinous coagula. It is impossible that these things, 
involving as they do the loss of many of the muscle-fibres, should not 
weaken the heart. Such is its reserve power, however, that it generally 
continues to beat well enough in spite of them. They have been regarded 
by many authors (Stejskal and others) as the cause of the sudden collapse 
and death at the height of diphtheria (and also in peritonitis and other 
septic infections), but Passler and Romberg, MacCallum, and others 
have shown that deaths of this sort are due rather to failure of the vaso- 
motor control of the arteries (or possibly to the effect of Dale's capillary 
poisons), which allows the blood-pressure to fall and the whole heart to 
suffer acutely from lack of nutrition. Abscesses in the myocardium in 
the course of general septic infections or resulting from embolism of the 
coronary branches by infected fragments of endocardial vegetations (septic 
infarcts), and extensions into the myocardium from endocardial vegetations, 
produce similar effects, but they will be considered elsewhere. 
Calcified foci are sometimes found which may be the outcome of the 
healing of such necroses. So, too, it must be admitted that scar tissue of 
no specific character may remain as the result of their healing, and that, 
therefore, these lesions may give one explanation of the origin of the so- 
called fibrous myocarditis. That there are other changes potent in bring- 
ing about this scarring of the heart muscle we shall see. 
Tubercles and syphilitic gummata are rare in the heart, but after acute 
articular rheumatism, the aetiology of which is still uncertain, there appear, 
as Aschoff, Bracht and Wachter, and many more have shown, minute 
elongated nodules of peculiar structure, scattered especially in the poste- 
rior wall of the left ventricle near its base, and much more rarely situated 
elsewhere. These are often periarterial, and are composed of large pale 
epithelioid cells with large vesicular nuclei (Fig. 231). Some of the cells 
become very conspicuous from the size of their nucleus, and others stand 
out as actual giant-cells. Eosinophiles and polynuclears accompany them 
sparsely. Aschoff is probably correct in contending that these cells are 
derived from mononuclear wandering cells, and not from the muscle or 
connective tissue. There is no definite evidence of their influencing the 
muscular activity to a recognizable degree. 
Affections of the coronary arteries are particularly important in pro- 
ducing changes in the heart muscle. In some cases fragments of the 
thrombotic vegetations upon the heart valves may be thrown as emboli 466 
TEXT-BOOK OF PATHOLOGY 
into these vessels, suddenly obstructing a branch or the whole artery. 
In others arteriosclerotic thickening of the vessel-walls gradually leads 
to narrowing of the lumen, which may be extreme, or which may be 
quickly completed by the formation of a thrombus upon the degenerated 
plaque, obstructing the flow of blood altogether. Any of these modes of 
obstruction is effective in shutting off the blood supply from a certain 
part of the heart-wall because, although Spalteholz has shown clearly 
by injections that there are rather numerous anastomoses between the 
coronary arteries, these are insufficient to maintain the enormous supply 
of rapidly moving blood which the heart muscle needs. A less active 
organ might find it sufficient, but in the case of the heart-wall a part rather 
Fig. 231.-Aschoff body in the heart in acute rheumatism, showing the rather charac- 
teristic relation to the blood-vessel. 
less in extent than the region supplied by the obstructed artery dies. The 
dead area promptly assumes the character of an anaemic infarction, and 
may at times occupy large parts of the walls of both ventricles, together 
with part of the interventricular septum. Experimental occlusion of 
various branches of the coronary arteries shows a variable result; often 
the heart stops beating at once, especially in the case of the anterior 
descending branch of the left artery, but in other cases, or in an animal of 
another kind, it may not. That human beings can often withstand 
extensive occlusion of the coronary arteries is familiar to every one from 
autopsy experience, for it is not uncommon to find large infarctions, re- 467 
THE EFFECT OF MYOCARDIAL DISEASE 
vealed only by death from their rupture or from some other cause. Indeed, 
many of these heal completely into a rather thin fibrous scar, which re- 
places the heart-wall, becomes bulged out into an aneurysmal sac, and 
lined with thrombi (Fig. 232). Pericardial adhesions are generally found 
on their surface. 
The effect of such obstructions when they concern the smaller branches 
is to produce little infarcts, which can be seen and felt upon the surface or 
in the interior of the heart as inelastic, hard, yellow, opaque masses with 
Fig. 232.-Hypertrophied heart with apical myocardial scar, aneurysmal dilatation, 
and laminated thrombus formation. 
a halo of deep red. More common still is the discovery of various stages 
in the healing and scarring of such infarcts. But from finding scars in the 
heart-wall one cannot be sure that infarcts preexisted-indeed, many of 
these scars seem to have been gradually formed by the wasting away of 
undernourished heart-muscle fibres and their replacement by fibrous tissue, 
especially in cases where no obvious obstruction or extreme narrowing of 
the vessels can be found. And, after all, in that stage one cannot feel sure 468 
TEXT-BOOK OF PATHOLOGY 
that they have not arisen through the healing of focal areas of toxic or 
infectious injury, which, after passing through a stage of inflammatory 
reaction, have ended in scars. Indeed, it has been suggested by R. Keith 
that the extensive scars and aneurysmal dilatations of the ventricular walls 
are the end-results of a tertiary syphilitic process with gumma formation, 
and he was able to collect a very complete series of hearts showing the most 
gradual transitions from fresh gummata through all stages of healing to 
Fig. 233.-Vascular soft scar in the heart-wall. This is an early stage in the replace- 
ment of dead heart muscle by scar tissue. 
the well-developed aneurysmal sac. While this is not proof, the lack of 
marked sclerotic changes in the coronaries in some of these cases and the 
frequency of syphilitic lesions in other parts of the circulatory apparatus 
make the idea seem very plausible. 
Thus, although from the presence of fresher stages in the form of infarcts 
it is sometimes possible to feel certain that the scars are due to embolic or 
arteriosclerotic and thrombotic occlusion of the coronary vessels, it is by THE EFFECT OF MYOCARDIAL DISEASE 
469 
no means always so. The fresher of these scars can often be felt on the 
surface of the heart as soft, depressed areas, which on section look gel- 
atinous or spongy, and are grayish red and semi-translucent (Fig. 233). 
They are composed of a loose, soft granulation tissue, very rich in small 
blood-vessels, which have doubtless grown in from neighboring vascular 
areas. The older ones are dense, shining, tendon-like, pearly-white 
patches, sometimes very small and finely distributed, sometimes so large 
Fig. 234.-Old scars in the heart-wall (chronic fibrous myocarditis) 
as to occupy much of the thickness of the wall (Fig. 234). They are often 
indefinite in outline, and radiate into the neighboring tissue (Fig. 235). 
Under the microscope they are formed of compact fibrous tissue poor in 
blood-vessels, but sometimes pigmented. Around their margins the muscle- 
fibres are frayed out, often reduced to pigmented strands (J. B. Mac- 
Callum), or swollen, with very much enlarged and deeply staining nuclei. 
Whenever any of these scars reaches the endocardial lining of the heart, 
it is covered by thrombi which doubtless began to be formed in earlier 470 
TEXT-BOOK OF PATHOLOGY 
stages, when injured heart tissue was exposed to the passing blood. One 
may not say that all thrombi formed on the lining of the heart overlie such 
definite areas of destruction of the heart-wall, but nearly always, on cut- 
ting through the base of a globular intertrabecular thrombus, there is 
found a superficial scar. As mentioned above, it is at the apex of the heart 
that the conversion of the whole wall into scar tissue, thickly lined with 
thrombus material, is most common. 
There is much dispute as to the effect of these scars, or rather of the 
injuries which give them origin, upon the muscular power of the heart. 
Unquestionably the destruction of heart muscle and its replacement by 
rigid scar tissue must deprive the heart of some of its strength, but such 
is the phenomenal reserve power of this organ 
that a great deal may be destroyed before the 
circulation is impaired. In a dog one may inject 
strong alcohol with a hypodermic syringe into 
the muscle of the heart-wall, so as to coagulate 
instantly a patch of the muscle; the slight fall 
of pressure is almost instantly made up, and this 
may be repeated a dozen times, until almost all 
the wall of the ventricle is turned into a hard, 
dead white mass before the circulation finally 
begins to fail. Aschoff and Tawara lay little 
stress on such scarring of the heart as a cause of 
the final breakdown of the circulation, and most 
clinical writers also agree that even extreme de- 
grees of fibrous alteration may exist for a long 
time without giving rise to any symptoms. Ir- 
regular, feeble, slow pulse and dyspnoea are gen- 
erally given as the symptoms, but these are not 
particularly distinctive. Whether the conversion 
of a part of the heart muscle into scar tissue is 
followed by hypertrophy of the rest of the mus- 
cle, so as to enlarge the whole heart, is a question 
difficult to answer, because the condition seldom 
occurs without other changes within or outside of the heart, which could 
also be concerned in causing cardiac hypertrophy. Exact experimental 
study seems not to have been carried out with reference to this point, 
except that Stewart has found that when myocarditis is producedby injec- 
tions of adrenaline, the scarred hearts are distinctly hypertrophied and weigh 
more than the normal in proportion to the body weight. He thinks the 
action of the adrenaline, which causes the formation of scar tissue and en- 
largement of the muscle-fibres, results in an enlarged organ whose func- 
tional capacity is below normal. Naturally, although the scars probably 
occupy less space than the muscle which they replace, the increase of the 
Fig. 235.-Tangential 
section of heart-wall show- 
ing old scars. THE EFFECT OF MYOCARDIAL DISEASE 
471 
remaining muscle, in its attempt to carry on the work of the heart, might 
more than compensate for this, and result in an enlargement of the whole 
heart. 
Fragmentation of the Heart Muscle.-In many hearts, especially those of old people, 
and perhaps also those of persons who have long suffered from chronic infections or from 
advanced circulatory decompensation, there is found wide-spread disintegration of the 
heart muscle, nearly every fibre being fractured transversely once or twice. These 
Fig. 236.-Fragmentation of the myocardium, showing simple transverse fractures. 
uneven or step-like breaks seem to cross the muscle-fibre at any point, and are not essen- 
tially separations of the fibres at the so-called cement line. J. B. MacCallum dis- 
tinguished simple fragmentation (Fig. 236) from a degenerative form (Fig. 237), in which 
the fibre breaks across a place where it was evidently in extreme extension, and where 
the fibrils break at different levels, so as to produce an area made up of many short 
lengths of individual fibrils. It seems possible to recognize the existence of this con- 
dition in many cases from the softness and flabbiness of the heart. There has been much 
dispute as to its significance, and since it seems incompatible with the continued activity 
of the heart, and yet is surrounded by no evidence of any reaction on the part of the 472 
TEXT-BOOK OF PATHOLOGY 
tissues, it is generally thought to occur during the death agony, and to be produced by 
the final irregular contractions. Such evidence is not conclusive, however, and we must 
await further information. 
Fig. 237.-Fragmentation of the myocardium with disintegration of the fibrils (degenera- 
tive fragmentation). 
LITERATURE 
Hasenfeld: Dtsch. Arch. f. klin. Med., 1897, lix, 193. 
Longcope and McClintock: Johns Hopkins Hosp. Bull., 1910, xxi, 270. 
J. B. MacCallum: Johns Hopkins Hosp. Rep., 1900, ix, 307. Jour. Exp. Med., 1899, iv, 
409. 
F. P. Mall: Amer. Jour. Anat., 1911, xi, 211. 
A. Cohn: Verh. Dtsch. path. Gesellsch., 1909, xiii, 182. 
Aschoff and Tawara: Path. Anat., Grundlagen der Herzschwache, Jena, 1906. 
Passler and Romberg: Dtsch. Arch. f. klin. Med., 1899, Ixiv. 
Stejskal: Ztschr. f. klin. Med., 1902, xliv, 367. 
MacCallum: Amer. Jour. Med. Sci., 1914, cxlvii, 37. 
Aschoff: Verh. Dtsch. Path. Gesellsch., 1904, viii, 46. 
Geipel: Miinch. med. Woch., 1907, liv, 1057, and 1909, lvi2, 2469. 
Bracht and Wachter: Dtsch. Arch. f. klin. Med., 1907, xcvi, 493. 
H. A. Stewart: Jour. Exp. Med., 1911, xiii, 187; Jour. Path, and Bact., 1912, xvii, 64. 
Fleischer and Loeb: Arch. Inter. Med., 1909, iii, 78; 1910, vi, 427. CARDIAC VALVULAR DISEASE AND ITS CONSEQUENCES 
473 
CARDIAC VALVULAR DISEASE AND ITS CONSEQUENCES 
Mechanism of the Obstruction.-In another place (page 245) the nature 
of infectious endocarditis was discussed, and it was found that thrombotic 
vegetations on the valves might impair the accuracy of their closure; 
further, that the erosion and destruction of the valves would produce ex- 
treme incompetency to close the orifice. On the other hand, even if heal- 
ing ensued, the valves became so stiff, distorted, and contracted by the for- 
mation of the scar tissue that they no longer reached one another, or met 
so imperfectly that leaks occurred. In some cases they fused into a rigid 
ring that greatly narrowed the orifice. This may result not only from 
bacterial infection, but from traumatism, arteriosclerotic changes, and as 
congenital malformations. Since the circulation depends so largely upon 
the perfect action of the valvular mechanism, it is important to study, in 
cases where it is defective, the changes in the rate and volume of the moving 
blood and the consequent changes in blood-pressure. In a mechanical 
model, such as that of v. Basch, these relations are complicated, but they 
become much more so in the living circulatory apparatus, where many 
compensatory mechanisms are at work. Every valvular lesion produces 
an obstruction to the circulation, either by opposing a barrier to the flow or 
by failing to maintain the advance effected by the contraction of the 
heart. Accumulation of blood, therefore, occurs behind each diseased 
valve, and unless exceptional compensation is available, the amount of 
blood actually propelled into the circulation beyond it, is reduced by the 
amount of that accumulation. It is not meant that any particular cor- 
puscles or cubic centimetres of the blood remain stagnant behind the 
injured valve, but that, while there may be constant mixing in this region, 
it is as though a stream ran in and out of a lake. The vessels in that 
area are overfilled and distended, and the exchange of blood is slow-not 
like the torrent which normally sweeps the stream-bed clean at each beat. 
When an obstruction or regurgitation occurs at any valve, say the aortic, 
the amount of blood thrown into the aorta must be constantly less than 
normal as long as the cavity of the ventricle retains its normal dimensions, 
and the wall its normal force of contraction. This may be modified by the 
power which the ventricle possesses of dilating to receive more blood, and 
expelling it with greater force, but in order to throw the normal quantity 
of blood into the arteries the left ventricle must receive that amount plus 
the amount regurgitated. This is possible only if there is an actual addi- 
tion to the amount of the blood, although constriction of the arterioles 
may keep up the normal blood-pressure. If for a time a diminished 
amount, less than the normal by the quantity held back or regurgitated, 
circulates in narrowed vessels, there would be a rapid addition of fluid from 
the tissues and water taken into the stomach until the circulating amount 
was again normal. Indeed, one receives the impression from observing 
the amount of blood in the vessels at autopsy in cases of long-standing TEXT-BOOK OF PATHOLOGY 
474 
chronic passive congestion from cardiac lesions, that there is a great in- 
crease in its quantity. 
The changes in the distribution of the blood may be thought of perhaps in terms of 
numbers, quite arbitrarily selected, to represent the amounts of blood concerned. This 
is, of course, entirely schematic, but it serves as a concise way of describing the probable 
changes. 
Thus if the amount handled by any one part of the heart in one systole, say the right 
ventricle, be represented by 10, the left auricle will receive 10 and the left ventricle also 
10. If, now, insufficiency of the mitral valve arises, a portion, say 4, is driven back from 
the left ventricle into the left auricle, and 6 goes on into the aorta. With the same 
systole 10 again reaches the left auricle and meets the 4 regurgitated from the ventricle, 
so that the left auricle now contains 14. That which follows will depend upon the 
activity of the left ventricle. If it will not receive more than the usual 10, 4 remains 
stagnant in the auricle, 6 is thrown into the aorta, and 4 more regurgitates. By this 
time 6 is thrown into the auricle from the right ventricle instead of 10, and meets with 
8 of regurgitated blood, making up 14, of which 10 goes again into the ventricle. Thus 
the circulating blood amounts to 6, while the stagnant blood in the pulmonary circula- 
tion amounts to 4. The right ventricle forces 6 into the pulmonary circulation, already 
containing 4, and into which the left ventricle simultaneously forces 4. 
It is usual, however, for the left ventricle under such circumstances to dilate and to 
exert greater force in the expulsion of the greater amount of blood received. This may 
be represented as follows: 
When the left ventricle has thrown 6 into the aorta and there is 14 in the left auricle, 
the ventricle dilates at the next diastole-perhaps not enough to receive the whole 14, 
but enough to receive 12. Of this, it expels 8 into the aorta, while 4 is again regurgi- 
tated. The regurgitated 4 meets now with 6 driven in by the right ventricle, and 2 left 
behind from the 14, making in all 12. With the next diastole the ventricle receives the 
whole 12, regurgitates 4, and throws 8 into the aorta. By this time the amount 8 
thrown out by the ventricle into the aorta reaches the auricle and meets the 4 regurgi- 
tated. The whole 12 passes into the ventricle, and thus a circulation is established in 
which 8 circulates while 4 is regurgitated with each systole. 
These examples assume the ability of the ventricle to empty itself completely, but if, 
finally, it does not, a new set of conditions arises in which the ventricle itself forms part 
of the reservoir for stagnant blood. Many other conditions which commonly occur may 
be represented and discussed in this numerical way. 
What has been said shows clearly enough that an increased strain is put 
upon the chamber of the heart behind the defect, because it is made to 
handle an increased amount of blood, and often, though not always, to 
propel it against an increased resistance. 
As explained, the heart is particularly remarkable in being able to rise 
instantly to the emergency if an excess of work is suddenly demanded of it, 
and this adaptation takes place so smoothly that not a single beat is lost 
or disturbed. This is an evidence of its great reserve power, which is 
ordinarily not drawn upon, but which permits it to perform greatly in- 
creased work for a limited time, as one sees in the case of any violent mus- 
cular exertion during which the heart pumps with increased force and 
rapidity. But if the excessive work must be kept up for a long time, 
the heart-wall thickens like the muscle of a blacksmith's arm, to enable 
it the more easily to bear its burden. Such hypertrophied hearts and CARDIAC VALVULAR DISEASE AND ITS CONSEQUENCES 
475 
even normal hearts, when the muscle is injured or badly nourished or 
finally exposed to entirely excessive strain, may give way and dilate to 
a degree which makes their proper pumping impossible. 
While these are, in outline, some of the principles concerned in the 
effects of valvular lesions, they come into play differently with lesions of 
different valves. 
Aortic Insufficiency.-Regurgitation through the aortic valves may 
follow destruction of the valves by fresh or repeated bacterial infection, 
Fig. 238.-Aortic insufficiency. There is great thickening with shortening of the 
aortic valves, which are thereby rendered incompetent. Hypertrophy of left ventricle. 
Endocardial thickening beneath aortic valve. Network of soft white bands extending 
from the septum to the papillary muscle. 
but it is most commonly the result of syphilitic infection which produces 
a specific type of arteriosclerosis of the aorta, and analogous scarring and 
retraction of the aortic valves (Fig. 238). Very often they are fused 
together at their base, or in other cases merely thickened into a cord-like 
roll at the edge, so that they are shortened, and the filmy edge which 
normally completes their closure is lost. At times the diseased valves 
rupture or tear, the fragments flapping in the stream. Experimentally 
one may imitate this disease by cutting through a valve with a hook, which 
can be pushed down the carotid artery, after which the effects are quite 476 
TEXT-BOOK OF PATHOLOGY 
like those observed clinically. There need be no great disturbance of the 
circulation nor of the blood-pressure. The pulse is changed to a bounding, 
collapsing type, with a dicrotic wave low on the descending limb. This 
character is due to the lowering of the diastolic pressure after each beat 
by the rapid regurgitation of the blood, so that the aortic wall is not kept 
at its usual high tension. The pulse pressure is high, because the systolic 
pressure remains nearly normal, while the diastolic pressure cannot be kept 
up. With such a condition the pulse is felt in the most distal vessels like 
a water-hammer, and can be seen as alternate flushing and paling in the 
capillaries of the fingers and toes. 
During diastole the regurgitant blood returns to the ventricle, making 
a loud diastolic murmur, and the ventricle dilates to receive it as well as 
the auricular blood. So perfect is the left ventricle in its power of response 
to the increased demand that ordinarily it succeeds in ejecting an amount 
into the aorta sufficient to allow of regurgitation and still maintain the 
normal filling of the vessels. This requires the ability to dilate and to 
handle the excess of blood, and generally the left ventricle is found enlarged 
and its wall thickened, but without necessarily producing any change in the 
pulmonary circulation or the right heart. Extreme defects of the valves, 
especially when the ring of muscle in the conus arteriosus which supports 
them fails, may be followed by failure on the part of the left ventricle to 
carry on the great excess of work without leaving a great deal of residual 
blood in its cavity. Then it becomes difficult for the auricle to empty 
itself, the pulmonary vessels remain partly filled, and the right ventricle 
hypertrophies in the attempt to drive its blood through them. Compensa- 
tion is, however, maintained in aortic insufficiency much better than in 
other lesions, and death often comes unexpectedly from a final sudden 
failure. 
Stewart has claimed that the collapsing character of the pulse is due to the rapid 
escape of blood, not by regurgitation, but through widened peripheral capillaries, and 
that in view of the very slight regurgitation the hypertrophy of the left ventricle is due 
to its exposure to the diastolic pressure of the aorta. These results I have not been 
able to accept, although the last statement implies a regurgitation during diastole. 
Aortic Stenosis.-Aortic stenosis (Fig. 239), produced by thickening and 
fusion of the aortic valves, narrows the aortic orifice so as to offer a mechan- 
ical obstruction to the expulsion of blood; usually since the valves are 
incapable of closing accurately there is some regurgitation too. The blood 
is forced out slowly with a rasping systolic murmur, producing a pulse 
which, in contrast to that of aortic regurgitation, is small and rather slow. 
Again, the increase in effort is felt and assumed by the left ventricle, which 
hypertrophies in response, but for a long time does not dilate. It is not until 
it finally fails to accomplish its momentary task of expelling the blood that 
residual blood plus that from the auricle overdistends it, and it becomes 
difficult for the auricle to empty itself. In both aortic insufficiency and CARDIAC VALVULAR DISEASE AND ITS CONSEQUENCES 
477 
stenosis it seems inevitable that the coronary circulation should be im- 
paired in the extreme degrees of the disease, thereby weakening the heart 
itself. 
Mitral insufficiency (Fig. 240) gives rise to rather complicated and 
extensive disturbances of the circulation, because the ventricles, the effec- 
tive compensating mechanisms, are put at a disadvantage. Part of the 
blood received by the left ventricle rushes back into the auricle during 
systole, producing, as usual, an audible murmur. This diminishes the 
amount available for the aorta and distends the auricle and pulmonary 
veins. The right ventricle drives its blood into this partly filled pul- 
Fig. 239.-Aortic stenosis with hypertrophy of the left ventricle. 
monary circulation with increased effort, and in time hypertrophies. The 
pulmonary circulation remains overdistended, and the left auricle, laboring 
with blood under higher pressure and in increased amount, dilates and 
hypertrophies. 
The left ventricle, too, takes part in the compensatory process, and 
dilates to receive an excess of blood until it can, in addition to the regurgi- 
tant amount, throw out a nearly normal quantity into the aorta. Conse- 
quently the left ventricle dilates and hypertrophies. The pulsation pro- 
duced by the systolic regurgitation is felt through the pulmonary circuit, 
and the wave impinges upon the wall of the right ventricle before its valves 478 
TEXT-BOOK OF PATHOLOGY 
are closed. In a sense the right ventricle is working against the left, 
which doubtless contributes to the need for hypertrophy. Compensa- 
tion begins to fail through the final inability of the left ventricle to expel 
all the blood brought to it, and the emptying of the left auricle and the 
pulmonary veins is embarrassed. The same obstruction is felt by the 
right side of the heart, and with the dilatation of the right ventricle which 
may follow, a relative insufficiency of the tricuspid valves can arise-that 
is, the tricuspid ring becomes so wide that the normal valves are too small 
to close it. Doubtless, however, here, as in the case of the mitral valve, 
the failure of the usual muscular support of the valves which helps to close 
the orifice contributes largely to the insufficiency. Such relative insuffi- 
Fig. 240.-Mitral insufficiency. The valves are thickened and shortened, and the 
chordae tendineae are heavier than normal, but there was no actual stenosis. 
ciency or even the difficulty which the right ventricle finds in expelling all 
its contents into the overdistended pulmonary circulation will impede the 
outflow of the systemic venous blood, and a general chronic passive con- 
gestion ensues. The patient becomes cyanotic and very short of breath, 
with a cough which expels sputum tinged brown by the presence of pig- 
mented cells. (Edema of the extremities and the body and effusion into 
the serous sacs follow. The end is usually brought about by continued 
dilatation of the heart and final failure, although temporary recovery with 
partial disappearance of the symptoms may take place over and over. 
Such decompensation or break in compensation is also a feature of other 
forms of valvular disease. CARDIAC VALVULAR DISEASE AND ITS CONSEQUENCES 
479 
Mitral Stenosis.-The narrowing and rigidity of the mitral valves 
(Fig. 241) present an obstacle to the outflow of blood from the auricle 
into the left ventricle. Usually the change in the valves is such that the 
orifice is bounded by thick, precipitous edges, which may fit together fairly 
well if they can move into approximation-otherwise if they are rigidly 
held apart there is necessarily mitral insufficiency combined with the 
stenosis. This is the usual condition, and is really avoided only in those 
rare cases in which a delicate film persists past the line of rigidity and calci- 
fication, capable of completing the closure. The narrowing of the actual 
Fig. 241.-Mitral stenosis with great hypertrophy of the left auricle, which has been cut 
across. Stenosis of the tricuspid. 
orifice through which all the blood must pass may be extreme, so that a 
mere crescentic slit is left with rigid margins only a few millimetres apart, 
and it is wonderful that life can be maintained until this is developed. 
Globular thrombi formed in the auricle may sometimes add to the obstruc- 
tion, or even suddenly complete it by plugging the mitral orifice. 
With such difficulty in expelling its blood the left auricle dilates and 
becomes hypertrophied. The blood is driven through the narrow hole and 
produces a thrill and a simultaneous presystolic rough murmur. But 
much of it fails to get through and accumulates in the pulmonary vessels, 480 
TEXT-BOOK OF PATHOLOGY 
where the circulation is accordingly very slow and under a high pressure 
because of the compensatory activity of the right ventricle. 
The effects of this upon the lung are described below, but the right 
ventricle must obviously hypertrophy. If it does so adequately, it may 
prevent the appearance of any symptoms except those from the lung if the 
stenosis is not extreme, and enough blood may be forced through to allow 
the left ventricle to propel a satisfactory quantity into the aorta. If the 
orifice is so narrowed that the left ventricle receives much less than it 
should handle, its wall atrophies and it shrinks to a relatively small size 
as compared with the enlarged and thickened left auricle and right ventricle 
in the same case. As in mitral insufficiency, a final break in compensation 
produces cyanosis, serous effusions, cough, dyspnoea, and often the cough- 
ing-up of blood from the lungs (haemoptysis). 
Pulmonary stenosis is nearly always a congenital anomaly, and is one 
of the commonest and most important of those found in the heart. It 
is generally associated with other imperfections, such as an open foramen 
in the septum ventriculorum. Pulmonary insufficiency is rare and some- 
times due to malignant endocarditis. 
Tricuspid regurgitation, generally due to a relative insufficiency (though 
sometimes caused by endocarditis), is often secondary to lesions on the 
left side or to obstruction in the pulmonary circulation-it causes a mur- 
mur and pulsation as well as great distension of the systemic veins. 
Tricuspid stenosis also occurs, and is accompanied by symptoms generally 
resembling those of mitral stenosis, i. e., presystolic murmur, cyanosis, 
etc., but this is less significant, as it is usually associated with valvular 
lesions on the left side. 
Indeed, valvular lesions affecting several valves at once, either to pro- 
duce insufficiency or stenosis or both, are the rule rather than the exception, 
and hence in the calculation of the effects, complexities arise. It is possible 
that one lesion may partly compensate for another, although such com- 
pensation is seldom an unmixed good. Mitral stenosis may diminish 
the regurgitation if added to mitral insufficiency. In all cases the outcome 
depends largely upon the extent of the defect, and persons with definite 
valvular lesions go on leading an active life for years without any symp- 
toms because the strength of the compensating ventricles is not too greatly 
overtaxed. 
Compensation, Cardiac Hypertrophy, Dilatation, Decompensation.-It is 
clear, from the description of all these valvular lesions, that in each case 
extra work is demanded of the heart, and that while this task is some- 
times assumed by the chamber directly behind the obstruction, the burden 
is in the end usually felt by the whole heart. When blood regurgitates into 
a chamber so that it must dilate to accept more than its usual quantity, 
it does so, and emptying itself with the next systole, it rises to the emergency 
by the use of its reserve power. When the systolic discharge is opposed 
by a stenosis, the chamber again uses its reserve power to drive out the CARDIAC VALVULAR DISEASE AND ITS CONSEQUENCES 
481 
blood, but does not necessarily dilate. Such work at high tension is possible 
for a time for the normal heart, as we see every day in people who make 
violent muscular efforts. When they are again at rest the heart subsides 
to its normal work and is itself unchanged. In its growth it probably 
merely maintains its proportion to the body musculature. 
It is different with such an effort as is required of the heart by a valvular 
defect, because that is a constant, never-lifting burden which weighs on the 
ventricle wall with every beat night and day. After a time the heart- 
wall thickens and strengthens itself, probably chiefly by an enlargement 
of the muscle-fibres rather than an increase in their numbers. Its reserve 
force increases in proportion, and now what was an extreme effort near to 
the maximum limit, for the normal heart is a moderate achievement for 
the hypertrophied one, to which still greater putting forth of strength is 
possible through its newly advanced reserve power. 
This has not been agreed upon by all writers. Martius stated that while the abso- 
lute power of the hypertrophied heart was greater than that of the normal, neverthe- 
less, in carrying on the increased work, it was nearer to its limit of endurance than the 
normal heart was with the lesser burden-in other words, its reserve power made up a 
relatively small part of the new strength. But Romberg and Hasenfeld think that the 
hypertrophied heart is just as alert and capable as the normal in response to increased 
demands, although it must be remembered that the hypertrophied heart is commonly 
working at an increasing disadvantage. 
Hypertrophy is usually thought of as the response to increased work, and 
it is often called a work hypertrophy. Although this does not explain it, 
unless perhaps we think that excessive work demands an increase in the 
metabolism of the cell and thus promotes growth, it is no better explained 
by Horvath's idea that growth depends on stretching, or by E. Albrecht's, 
that it is a sort of inflammatory process, or even by Loeb's theory of the 
imbibition of water with subsequent addition of new material. Stewart 
thought it due to injury of the heart muscle, followed by enlargement and 
scarring, in the hypertrophy produced by adrenaline injections. 
The attempts at explanation of cardiac hypertrophy on other grounds 
than the response to increased work have been made chiefly because of the 
cases of so-called idiopathic hypertrophy, in which enormous enlargement 
of the heart appears without any valvular lesions or other evident obstruc- 
tion to its work. Difficult as it is to explain these cases, the suggestion that 
they are of toxic or inflammatory origin seems quite unsatisfactory unless 
abundant scars are found in the heart muscle. Then, perhaps, the hyper- 
trophy of the remaining muscle might effect a compensation for that which 
was lost. But still, and even in this case, the only acceptable explanation 
seems to be the increased demand upon the muscle. 
Stewart has pointed out that even in experimental aortic insufficiency, where the left 
ventricle encompasses its new task without any increase in pressure in the auricles, the 
walls of the auricles hypertrophy. Whether this co-hypertrophy is quite independent 482 
TEXT-BOOK OF PATHOLOGY 
of obstruction of the flow of blood or not in this particular case, the usual cause of the 
hypertrophy seems to be the extension of the influence of the obstruction from one cham- 
ber to another. It may be possible for the ventricle, in the case of aortic insufficiency of 
moderate degree, to assume all the new work, quickly expanding in each diastole to re- 
ceive the original normal amount of blood from the auricle, as well as the amount 
regurgitated, and expelling it into the aorta, but even here, with an increase in the extent 
of the insufficiency of the valve, as well as the hypertrophy and power of dilatation, 
there might occur a disparity during which the auricle would have to make an effort, 
perhaps partly unsuccessful, to force all its blood into the ventricle. Then arises the 
need for auricular hypertrophy. But aortic insufficiency is well known to be the best 
compensated of valvular lesions. In mitral insufficiency the auricle must hyper- 
trophy, the right ventricle must hypertrophy, and as soon as it fails, in the way just 
described, the right auricle feels the strain. Combined insufficiencies of the valves are 
even more certainly followed by a distribution of the excess of work all through the 
heart. 
Thus no compensation restores the circulation to its original condition. 
In every case some part of the heart is working at a disadvantage, either 
against abnormal resistance or with an excessive proportion of the blood. 
Slowing of the pulse-rate may sometimes aid in compensating the first of 
these, while an addition to the amount of the blood in circulation may 
make up for the blood which [lingers in the heart or in the pulmonary 
vessels, so that the aorta is once more normally filled. But such defects 
as mitral insufficiency or stenosis can hardly be completely compensated, 
for in all cases there remains the overfilling of the vessels of the lungs. 
At best all these compensations are subject to the probable increase in 
the severity of the valvular lesion itself, and to the fact that their defi- 
ciencies, such as the constant congestion of the lungs in mitral disease, 
may be aggravated to an intolerable degree by muscular effort or psychic 
disturbance which would be scarcely felt by a normal person. 
Failure of compensation is, then, an impending danger in all these cases, 
and while, as we have seen, the hypertrophied heart is stronger both in its 
ordinary and its reserve power than the normal, there are many ways in 
which it can be overtaxed. Besides muscular exertion and psychic excita- 
tion, which have been mentioned and which in general the patient with a 
cardiac defect must sedulously avoid, there must be mentioned all the 
diseased conditions of the heart muscle which have been described above, 
and which are particularly common in hypertrophied hearts. Those 
which are acutely produced in such hearts must weaken the walls through 
destruction of muscle-fibres. Scars and old remains of such injuries in- 
dicate rather that that danger has been survived, and probably that part 
of the hypertrophy has arisen to make up for the fibres whose loss they 
signalize. Nevertheless, such a scarred heart is weakened and subject 
especially to the influences which conduce to failure. Sclerosis of the 
coronary arteries is particularly important in restricting the nutrition of 
the heart-wall, and sudden complete failure of its activity may follow occlu- 
sion of these vessels by thrombi. Surprising degrees of sclerosis are sur- 
vived, however, and even extensive infarctions of the wall. CARDIAC VALVULAR DISEASE AND ITS CONSEQUENCES 
483 
Perhaps more important still in disturbing compensation in such a hyper- 
trophied heart with valvular defects is the functional disturbance of the 
coronary circulation, either when, with extreme destruction of the aortic 
valves, the entrance of blood into the coronary arteries is deficient, or when 
great accumulation of blood under high pressure in the right heart and 
systemic veins impedes the return of the coronary blood into the right 
auricle. The wall of the heart suffers then a chronic passive congestion 
which involves malnutrition, and it fails through the action of this vicious 
circle. 
Extraneous influences, such as chronic nephritis, extreme arteriosclerosis, 
pericardial effusions and adhesions, advancing pulmonary disease with 
obliteration of vessels, pleural adhesions, etc., may gradually heap more 
work on the heart until, in spite of its hypertrophy, it is unable to keep up 
its activity. Whether it can stop from sheer weariness and exhaustion 
one can hardly say, but it seems probable. 
The first effect of failure of the heart-wall to meet the demand is the 
accumulation of blood in its cavities and its passive dilatation. Unlike the 
competent ventricle which expands and sucks in an excess of blood which it 
readily expels, the wall is overstretched and incapable of closing completely 
on the blood in its cavity. For some time it may continue to drive out 
part, dilating again to receive more, so that thus a feeble circulation is 
maintained. Sometimes, especially with the administration of drugs, it 
may recover and return to its former competency, but often it only grows 
weaker and finally stops beating, hugely distended with the accumulated 
blood. It is in the course of such dilatation that the muscle of the auricu- 
loventricular orifices fails to support the valves by narrowing those orifices, 
and relative insufficiencies with regurgitation occur. Extreme distension 
of the veins results, with cyanosis and often with dropsy. Profound dysp- 
noea attends the same condition in the lungs, and the patient lies helpless 
and gasping, propped up in bed until death or one of the temporary re- 
coveries relieves him. Lewis and his colleagues have recently suggested 
that such dyspnoea is identical with renal dyspnoea, and due to the produc- 
tion of acids other than carbonic acid. Peabody, however, in his important 
discussion of cardiac dyspnoea, to which the reader is referred, states that 
acidosis plays no part in the dyspnoea of pure cardiac disease except in 
the extreme stages of decompensation, while in cases in which the cardiac 
disability is complicated by renal disease acidosis becomes more significant 
in that it renders the patients unusually susceptible to the production of 
dyspnoea by exertion. In general, the tendency to dyspnoea depends upon 
a diminution of the patient's pulmonary reserve, that is, a decrease in the 
maximum volume of air which he is capable of breathing in its relation to 
the volume of air which he breathes while at rest. The vital capacity or 
volume of air which can be expired after the greatest possible inspiration 
may be decreased during cardiac decompensation by many factors which 
limit the expansion of the lungs so that the margin of safety is narrowed. 484 
TEXT-BOOK OF PATHOLOGY 
The question of dyspnoea in heart disease is shown to be much more compli- 
cated than we suspected, and our knowledge is still incomplete. 
Chronic Passive Congestion.-From what has been said regarding the 
overdistension of the pulmonary and systemic veins and the consequent 
slowing of the circulation of at least part of that blood, one might expect 
to find changes in the tissues so supplied. With increasing failure of com- 
pensation the veins become more and more dilated by the increasing pres- 
sure of the blood, and less arterial blood is driven through the tissues into 
them. The capillaries are widened and pulsation passes into them-the 
tissues assume a deep bluish color and the veins stand out tensely. In 
places, as in the subcutaneous tissues of the legs, they are irregularly dilated 
and tortuous. Everywhere there is malnutrition of the tissues, accom- 
panied by certain pressure effects from the widening of the veins and 
capillaries. Neither nutritive nor gaseous exchange is carried on as it 
t ig. 242.-Chronic passive congestion of the lung with induration and muscular hyper- 
trophy. Some alveoli contain the pigmented "heart failure cells." 
should be, and doubtless excretory products accumulate there. An almost 
universal result associated with the injurious effects upon the more sensi- 
tive tissues is the new formation of connective tissue in the congested and 
cyanotic organs. 
The Lungs.-The lungs are most readily affected in mitral insufficiency 
and stenosis when compensation fails, and in myocardial disease, but local 
congestion may appear with the same results in collapsed areas of a lung 
on account of the kinking of the venules and obstruction of the return flow 
of blood. The capillaries in the alveolar walls become greatly dilated and 
tortuous, so that they project in loops into the alveolar cavities. Gross- 
man and von Basch speak of a sort of rigidity of the lung produced by this 
overfilling. The alveolar epithelium is ill nourished, and very many of the CARDIAC VALVULAR DISEASE AND ITS CONSEQUENCES 
485 
cells are desquamated into the air-cell; fluid exudes from the tense capil- 
laries, often with red blood-corpuscles. These quickly disintegrate, and 
hsemosiderin is formed from their haemoglobin and taken up by the phago- 
cytic epithelial cells. Such cells, when desquamated, are large and round, 
and often fairly loaded with this brown pigment in clumps and granules. 
They are coughed up in the sputum, and give a clinical indication of the 
existence of disease of the heart with pulmonary congestion, for which 
reason they are called heart-failure cells. In the lungs they are generally 
sufficiently numerous to give a distinct rusty color to the cut surface 
(c/. Fig. 13). 
As to the origin of these cells, there is room for discussion because it is not perfectly 
clear that they are epithelial cells which have become phagocytic. Although this is the 
generally accepted idea, one finds in many cases that the cells which can be recognized 
with certainty as epithelial from their position in a layer on the alveolar wall, are not at 
all pigmented, although the alveolus is full of the phagocytic cells. Further, the fact 
that the pigmented cells are found wandering in the perivascular tissues of the lung 
suggests their closer relation to the large wandering mononuclear cells which are the 
usual phagocytes in other tissues. 
The smooth muscle in the septa that form the vestibules in each lobule 
is greatly increased in bulk, and the alveolar walls in extreme cases become 
thickened and indurated by the appearance of new connective tissue (brown 
induration of the lung-Fig. 242). 
The sluggishness of the circulation which causes such general malnutri- 
tion makes it impossible for one arterial branch to supply, as in the normal, 
nutrition for the territory of another which may be plugged by an embolus. 
Hence it is that haemorrhagic infarctions are found in these congested 
lungs and practically only there. 
Great dyspnoea usually accompanies such chronic passive congestion, 
and the explanation is not difficult in view of the inadequate aeration 
which the blood receives when it requires so long to send all of it through 
the lungs. 
Such lungs at autopsy quickly lose any bluish color they may have 
had; instead, they are usually rather pale, sometimes dry, sometimes 
oedematous, and of a distinct rusty brown color, which, on the applica- 
tion of ferrocyanide of potassium and hydrochloric acid after fixation, 
turns to an intense Prussian blue (Perl's reaction for an iron-containing 
pigment). The consistence is altered, too, and the lung feels dense and 
elastic. In cases of long-standing congestion, especially in mitral stenosis, 
where the pressure in the pulmonary vessels has been high, arterio- 
sclerotic patches in the pulmonary artery and its branches are common. 
The Liver- When the systemic veins are overdistended for a long time, 
the liver is among the first organs to exhibit the effects. It is enlarged so 
that it may be felt extending below the costal margin, and often it pul- 
sates. At autopsy it projects as a tense bluish mass in which the impress 486 
TEXT-BOOK OF PATHOLOGY 
of a finger remains for a little and is slowly filled up. On cutting the 
great veins the liver often visibly collapses and loses its uniform dark 
color, assuming a lobular mottling. On section this is extremely bright 
and distinct, the alternation of deep red and yellow or gray markings 
giving rise to the name "nutmeg liver" (Fig. 243). 
Close examination of the cut surface with a lens, if necessary, or of a 
thick frozen section without staining, shows that the ordinary lobular 
Fig. 243.-Chronic passive congestion of the liver (nutmeg liver) 
markings are much modified by the conversion of so much of the tissue 
into the deep red zones. Indeed, in places, quite extensive patches may be 
homogeneously red, spongy, and ooze blood. The grayish yellow islands 
are found to surround in every case the minute twigs of the portal vein 
and hepatic artery, a gray zone lying directly against the vein, and then a 
bright yellow zone which passes sharply into the crimson. Scattered in 
the anastomosing, irregular crimson bands there are often sharply outlined, 
opaque, orange-yellow flecks. Microscopical study explains all this CARDIAC VALVULAR DISEASE AND ITS CONSEQUENCES 
487 
promptly. (See Fig. 145.) It is the lobule of Sabourin which is outlined 
and preserved in part as the pale islands-that is, for a certain distance 
around the afferent portal vein and hepatic artery the liver-cells are pre- 
served. Those nearest are well preserved and show gray; further out they 
are injured and loaded with refractive yellow fat-globules. Still further 
they are dead, and in so far as patches of dead cells sometimes remain, 
appear as opaque, orange-colored flecks (colored somewhat by blood-pig- 
Fig. 244.-Chronic passive congestion of the liver. Necrosis of the cells about the 
efferent vein. 
ment). But in this region the overwhelming distension of the capillaries 
with venous blood and the escape of that blood into the intercapillary 
spaces formerly occupied by the liver-cells converts the whole tissue into 
a blood-filled sponge in which only the framework and capillary walls 
remain, with some debris of cells. 488 
TEXT-BOOK OF PATHOLOGY 
Referred to the old idea of the lobule, we must say that the blood-filled portion lies 
about the central or efferent vein, but that, owing to the course of the capillaries (c/. 
p. 295), it maintains a distribution equidistant from the portal vein, and hence extends 
from lobule to lobule. 
Ordinarily all this is thought to be caused by the increased pressure of 
the venous blood in the capillaries, which is said to be felt with especial 
force in the liver because it is near the heart, but I think that these dying 
Fig. 244A.-Chronic passive congestion of liver with dilatation of capillaries. Atrophy 
of liver cells without necrosis. (Lambert and Allison.) 
cells (Fig. 244) in no way resemble compressed cells, such as one sees 
about a tumor in the liver, nor does this seem a plausible explanation from 
a mechanical point of view, since if the pressure in the efferent vein were 
higher than that in the portal vein and hepatic artery, the blood must run 
the other way. Further, one may find well-nourished liver cells in contact 
with the walls of larger hepatic veins which seems inconsistent with their 
being injured by pressure. On the contrary, it is easier to believe that the 
sensitive liver cells are badly nourished by the sluggish venous stream, and 
that oxygenation is especially interfered with, so that those which receive 489 
CARDIAC VALVULAR DISEASE AND ITS CONSEQUENCES 
the blood-stream last suffer most severely and in time disappear, leaving a 
space which is then filled up with blood. On this ground the gradual 
transition from practically normal cells near the source of nutritive supply 
through fatty to necrotic cells may be explained. 
Fig. 244B.-Chronic passive congestion of the liver, Type 4. Necrosis and 
haemorrhage about the efferent vein, with a narrow zone of fatty cells surrounding each 
necrotic area. (Lambert and Allison.) 
Mallory regards the necrosis of the cells as due to toxic influences usually of infectious 
origin and minimizes the effect of changes in blood-pressure. Lambert and Allison, 
who have gone over the literature and have studied 112 cases in which chronic passive 
congestion of the liver was well marked, divide the cases into five groups in which the 
lesions are as follows: (1) capillary dilatation with atrophy of the cells toward the centre 
of the lobule, (2) central degeneration with or without capillary dilatation, (3) marked 
fat accumulation in the cells about the hepatic veins, with midzonal hypersemia, 
(4) central necrosis with haemorrhage, and (5) collapse fibrosis. The more extreme the 
stasis, the more certain is the central necrosis and haemorrhage, while the collapse 490 
TEXT-BOOK OF PATHOLOGY 
fibrosis depends naturally upon a protracted course. They too think the necrosis to 
depend upon stasis alone which causes asphyxia in the most distal cells. Infection plays 
a minor part if any. 
The Spleen.-The most striking features of the change in the spleen 
wrought by chronic passive congestion are its deep purple color and its 
extreme hardness (cyanotic induration). Enlargement is usually moder- 
ate, and the great increase in the size of the spleen in connection with 
Fig. 245.-Chronic passive congestion of the spleen. Induration of the tissues between- 
the venules renders them conspicuous. 
cirrhosis of the liver is probably due to other causes than the mere con- 
gestion. The capsule is tense and smooth, and the cut surface stands 
firmly at right angles to it, neither bulging nor sinking into a concavity, 
as in so many enlargements from other causes. Malpighian bodies, 
trabeculae, and vessels stand out sharply in the background of the smooth, 
deep purple, splenic pulp. Microscopically (Fig. 245) one is impressed 
by the great clearness with which the splenic venules or sinuses are out- 
lined. Their walls are thickened so as to present themselves as very defi- CARDIAC VALVULAR DISEASE AND ITS CONSEQUENCES 
491 
nite membranes lined with endothelium, and every one is distended with 
blood. In the interstices there is a moderate increase in the connective- 
tissue framework, but no great accumulation of the cells of the pulp. 
The kidney in such chronic congestion is sometimes little altered, since, 
as has been said, the effect of circulatory obstruction is often very unequally 
distributed. But the characteristic change is a notable swelling, with 
extreme rubbery hardness, such that the kidney tissue will snap away 
Fig. 246.-Haemorrhoids. Vertical section showing distended vein near anus, partly 
occluded by a thrombus. 
from between the fingers and almost rebound if dropped. The whole 
organ is deep purplish gray in color, the surface smooth, the capsule not 
adherent, and on section, in the thick, grayish-purple cortex, one sees the 
striations with startling distinctness, the blood-vessels and glomeruli 
standing forth prominently in deep red, while the tubular portions are 
opaque and gray. The pyramids are also deeply reddened. 
Microscopically little more is to be seen-the capillaries, especially of the TEXT-BOOK OF PATHOLOGY 
492 
glomeruli, are distended with blood, and there may be some coagulated 
fluid in Bowman's capsules or hyaline casts in the tubules. The tubular 
epithelium shows perhaps a moderate degree of cloudy swelling, but even 
this need not be marked. Interstitial connective-tissue increase may 
occur in extreme cases, but it is scarcely evident, as a rule, and it seems that 
the hardness is chiefly due to the distension with blood. 
In contrast to this indefinite microscopical picture the functional changes 
are very marked. By itself chronic passive congestion can lead to the 
excretion of albumin and casts of various sorts in the urine, and also to dis- 
tinct disturbances in the function of the kidney with regard to the excre- 
tion of water, salt, and other substances, for which, as is well known, the 
kidney has specific powers of secretion. 
It is particularly important to estimate the part played by such con- 
gestion in producing the derangements found in cases of chronic nephritis 
complicated by heart disease, for they can particularly aggravate the 
deficiencies of an already disabled renal function. If, then, there is hope 
of relieving the factor of chronic passive congestion, the outlook for the 
patient is greatly improved. 
Similar conditions of malnutrition with overdistension of the vessels 
are found in all other organs. In the stomach and intestine they lead to 
moderate digestive disturbances, often with excessive secretion of mucus 
and with desquamation of many epithelial cells. In the rectum the 
enlargement of the veins produces the painful haemorrhoids, which often 
bleed and in time cause an extreme anaemia (Fig. 246). They are, however, 
perhaps more often due to local conditions and especially to obstinate con- 
stipation. In the limbs we find the varicose veins mentioned above, often 
associated with such derangements of the nutrition of the tissues that great 
ulcerations that refuse to heal appear over the shins. 
LITERATURE 
v. Basch: Allg. Phys. u. Path, des Kreislaufes, Wien, 1892. 
MacCallum: Johns Hopkins Hosp. Bull., 1906, xvii, 251. 
MacCallum and McClure: Ibid., 260 (mitral insufficiency). 
Martius: Erg. d. allg. Path., 1895, i2, 38. 
Krehl: Pathologische Physiologic, 1912, Nothnagel's Spec. Path. u. Therap., xv, Th. 1, 
Ab th. 5. 
Hasenfeld and Romberg: Arch. f. exp. Path., 1897, xxxix, 333. 
Moritz and Tabora: Krehl and Marchand: Handb. d. allg. Path., 1913, ii. 
Thorel: Ergeb. d. allg. Path., 1903, ixb 559; 1907, xi2, 694; 1911, xiv2, 133; 1915, xvii2, 90. 
MacCallum: Johns Hopkins Hosp. Bull., 1911, xxii, 197 (aortic insufficiency). 
Stewart: Arch. Int. Med., 1908, i, 102 (aortic insufficiency). 
Stewart: Jour. Exp. Med., 1911, xiii, 187; Jour. Path, and Bact., 1912, xvii, 64 (hyper- 
trophy). 
E. Albrecht: Die Herzmuskel, Berlin, 1903. 
Aschoff and Tawara: Grundlagen der Herzschwache, Jena, 1906. 
Lewis and others: Heart, 1913, v, 45; 1914, v, 367. 
Peabody: Amer. Jour. Med. Sci., 1918, civ, 100. 
Lambert and Allison: Johns Hopkins Hosp. Bull., 1916, xxvii, 350. PATHOLOGY OF THE CONDITION BUNDLES OF THE HEART 
493 
Until quite recently the study of the diseases of the heart concerned 
chiefly the mechanical results of distortion of the valves, of weakening of 
the muscle, etc., but the extraordinary discovery of His, Keith and Flack, 
Tawara, and others of an unsuspected connecting system of specialized 
strands of muscle stretching from one part of the heart to another has 
opened a new field for this study. It quickly became apparent that these 
strands, like the electric signals in an engine-room, or like nerves, con- 
trolled from a central station the activities of other parts of the heart, and 
at once there was hope of clearing up the obscure chapter of the disturb- 
ance of its rate and rhythm. This hope has not been disappointed, and 
with the aid of several new technical methods it has become possible to 
study with extreme accuracy all these disturbances and to explain them 
clearly. Most of these results have been worked out experimentally in 
animals, after which cases have been found in human beings which cor- 
respond so exactly to the experimental results as to make diagnosis easy 
and certain. 
The conduction system (Fig. 247) consists of: (1) An elongated node 
(the sino-auricular node of Keith and Flack), which lies in the angle 
between the superior vena cava and the right auricle, extending downward 
for a distance of one to two centimetres along the sulcus terminalis; (2) a 
second node or mass of tissue lying at the posterior and lower part of the 
right auricle, just in front of the coronary sinus. This gives rise to the 
main stem of the conduction bundle which extends along the interauricular 
septum forward and to the left until it reaches the septum membranaceum 
behind the tricuspid valve. There it follows the lower part of this septum, 
thus lying at the upper margin of the muscular portion of the interventric- 
ular septum, and runs forward to divide into two main branches, one of 
which continues under the endocardium of the right ventricle toward its 
apex. The other branch pierces its way into a similar situation in the left 
ventricle. The node, in which Aschoff has recently distinguished two parts, 
is the auriculo ventricular node of Tawara, while the continuation across 
the septum membranaceum into the two branches is the bundle of His. 
These branches subdivide to distribute themselves throughout the muscle 
of the ventricles, especially stout branches passing to the papillary muscles. 
In spite of patient search no definite specialized connections have been 
found in the auricular walls between the sino-anricular and the auriculo- 
ventricular nodes. 
These nodes and bundles are composed of muscle-fibers of a peculiar 
kind, very narrow, striated, with numerous nuclei and rich in glycogen. 
In the nodes they are matted together, but in the fasciculi they lie parallel. 
They form no direct connection with the musculature of the heart, but 
unite with the Purkinje fibres, which are large, pale, faintly striated fibres 
lying just under the endocardium, and which in turn unite with the ordinary 
muscle-fibres. Numerous nerve-fibres are interwoven with the muscle- 
PATHOLOGY OF THE CONDUCTION BUNDLES OF THE HEART 494 
TEXT-BOOK OF PATHOLOGY 
fibres of the bundle of His and of the nodes, so that it is impossible to exclude 
the participation of the nervous system in their activities. All these 
Fig. 247.-Diagrammatic representation of the conduction system: 1, Sino-auricular 
node; 2, atrioventricular node; 3, bundle of His. 
structures are enclosed in connective tissue and fat and are supplied by 
special arteries. PATHOLOGY OF THE CONDUCTION BUNDLES OF THE HEART 
495 
In the embryo, when the heart has the form of a curved tube, and before 
the ingrowth of any nerves has occurred, a sort of peristaltic contraction 
wave takes place. Although the ingrowth of the epicardium to form the 
central lamina of the auriculoventricular valves interrupts in mammals 
most of the connection between auricular and ventricular muscle, a por- 
tion of the continuous musculature remains and becomes specialized as the 
specific conduction bundle. The function of this system has been clearly 
shown by numerous experiments to lie in the initiation and propagation 
of the normal impulses which set in motion, in an orderly way, the muscu- 
lature of the heart. The impulse begins normally, as shown by the experi- 
ments of Lewis and others, in the sinu-auricular node of Keith, and spreads 
thence to the auriculoventricular node, whence it is transmitted to the 
ventricle by the bundle of His. The heart muscle itself is excitable and 
capable of conducting the impulse; its excitability is such that, however 
Fig. 248.-Simultaneous tracings of the jugular pulse, the carotid pulse, and the apex- 
beat (Bachmann, from Howell). 
great or slight the impulse which is capable of causing a contraction, that 
contraction is a maximal one. On the other hand, having once con- 
tracted, the muscle enters on a refractory phase, during which no stimulus 
will provoke a contraction. These peculiarities account for some of the 
phenomena of disturbance in rhythm to be described. 
The movements of the heart normally follow one another in an orderly 
succession, and at a regular rate which can be accurately studied in various 
ways. In addition to the auscultation of the heart and the palpation of 
the pulse, which give only rough information, tracings are made by means 
of the sphygmograph or polygraph to show simultaneously the pulsations 
of the radial or of the apex of the heart, and of the jugular vein. Such TEXT-BOOK OF PATHOLOGY 
496 
tracings are supplemented by electrocardiographic tracings, which give 
a clear idea of the movements of the heart. When we compare the trac- 
ings from the jugular with those from the carotid (Fig. 248), it is found pos- 
sible to recognize in the jugular tracings a wave (a) which is due to a contrac- 
tion of the auricle, a second or c wave (s), caused in part by changes in 
pressure in the auricle at the closure and lifting up of the tricuspid valves, 
and in man also by the transmitted carotid pulse, and a third (v) which 
Fig. 249.*-Electrocardiogram from a normal person showing the orderly sequence of 
waves which have been distinguished arbitrarily by letters P, R, T, etc. In the second 
curve, which is spread over a greater space by the rapid movement of the paper, there 
is also a microphonographic record of the heart-sounds. 
represents the filling of the auricle and veins during the latter part of sys- 
tole, with elevation of the base of the heart, after which the sudden drop 
is due to the opening of the tricuspid valves. 
The electrocardiogram is a curve made by photographing, on a moving 
film, the shadow of a fine thread of silvered quartz stretched between the 
* These and the following curves were kindly given me .by Dr. Horatio Williams. PATHOLOGY OF THE CONDUCTION BUNDLES OF THE HEART 
497 
poles of a magnet, and connected by its ends with wires leading to electrodes 
attached to the two arms or one arm and a leg of the patient. The part 
of the heart muscle which is contracting at a given instant becomes electro- 
negative to the rest, and the slight electrical current thus produced, passing 
through the silvered thread, causes it to be deflected toward one pole or 
other of the magnet. In the tracing there is recorded, in order, the 
deflection produced as the wave of excitation, i. e., electronegativity, 
passes through the heart. The result, as shown in Fig. 249, gives an 
elevation (P) representing the spread of the excitation wave throughout 
the auricular musculature, followed immediately by auricular contraction; 
a high-pointed elevation (P), the descending limb of which goes below the 
line (8), and later another rounded elevation (T). The latter three result 
from the spread of the excitation wave throughout the ventricles. This 
is the normal curve, and any abnormality in the rhythm is at once visible 
in the curve taken from the irregularly beating heart. 
Irregularities in the rate and rhythm of the heart-beat may arise either 
(1) through changes in the rate of the impulses originating in the sino- 
auricular node, and normally transmitted through the rest of the system 
(homogenetic impulses); (2) through changes in the conducting power of the 
bundle of His or other part of the system, or (3) through the occurrence of 
abnormal impulses starting elsewhere in the system than in the sino- 
auricular node, or even in the musculature of the heart, quite outside the 
conducting system (heterogenetic impulses). 
1. Changes in Rate of Homogenetic Impulses.-Tachycardia, in which 
the cycle of the heart-beat is normal, but in which the beats follow one 
another more rapidly than normal, arises in the sino-auricular node after 
an effort, or an emotion, or in the course of fevers, tuberculosis, etc., as 
well as under the influence of such poisons as atropine. Probably in most 
cases this is due to the diminution of the activity of the vagus nerve, but 
in some it may be a direct action on the node. Bradycardia, in which the 
pulse is slowed to 45 to 50 beats per minute, generally transient, occurs in 
ursemia, icterus, mitral disease, convalescence from acute infections, etc., 
and is probably due to excitation of the pneumogastric, since it can be 
made to disappear by the administration of atropine, which paralyzes 
that nerve: jugular tracings and electrocardiograms present normal cycles, 
although widely separated. There are also sinus arrhythmias, which show 
normal electrocardiographic complexes irregularly spaced. They usually 
disappear on exertion. 
2. Disturbances Due to Partial or Complete Interruption of Conduction, 
-(a) An interruption between the sino-auricular node and the rest of the 
system, which would correspond to the first ligature of Stannius, has given 
different results in the hands of different experimenters. The heart may 
stop entirely or assume a different rhythm, in which impulses arise else- 
where. If the interruption is incomplete, some of the impulses may pass 
through so that whole cardiac cycles are missed, while others occur. 498 
TEXT-BOOK OF PATHOLOGY 
(6) Interruption of conduction in the bundle of His may occur in various 
degrees of completeness. When it is confined to a slight retardation of 
conduction, there are no symptoms, but the jugular tracings show a length- 
ening of the interval, etc. Corresponding with this, the electrocardiogram 
presents an elongation of the space between P and R. When the inter- 
ruption is more intense, some of the impulses from the sino-auricular 
node fail to reach the ventricles, so that while in the jugular tracings the 
elevations a a, which represent the auricular contractions, are equidistant 
from one another, some are not accompanied by the elevations c, v, that 
is, they are not followed by ventricular contractions. Thus a 3 :2 rhythm 
or a 2:1 rhythm may be established. Complete interruption of the 
conduction allows the auricles to proceed in their regular contraction, 
while no impulses reach the ventricles from the sino-auricular node. Then 
the ventricles beat about 30 times per minute, but with a rhythm quite 
independent of that of the auricles (idioventricular rhythm), so that 
in the tracings one can determine no relation between them. Under such 
circumstances the elevations produced by auricular and ventricular con- 
tractions are sometimes superposed, sometimes separate, or if their rates 
happen to be multiples they may give the impression of an incomplete 
dissociation. Such dissociation is commonly spoken of as heart-block 
(Fig. 250). 
The severer grades of disturbed auriculoventricular conduction (Stokes- 
Adams disease) are often accompanied by crises or paroxysms of syncope 
or by epileptiform convulsions, due to the insufficient flooding of the brain 
with blood. These may pass off as the heart-rate improves, but occasion- 
ally end in death, when the slowing of the ventricular rhythm is extreme. 
Strangely enough such crises are rather less common in the cases of com- 
plete heart-block than in those in which dissociation is only partial. 
All these conditions can be produced experimentally by gradually con- 
stricting the bundle of His, and in human beings there is generally found 
at autopsy some destructive lesion in the bundle. This may be a gumma 
or a gummatous infiltration surrounding the tract, or a scar or atheromatous 
calcified mass may extend from the neighboring valves so as to interrupt 
it. Cases have been described, however, in which absolutely no lesion 
of the bundle could be found despite the existence of heart-block. In 
such cases it seems possible that excitation of the pneumogastric may be 
responsible, for it has been shown that such excitation can greatly aggravate 
the effects of a slight lesion of the bundle, and also that excessive doses of 
digitalis can thereby produce heart-block without any injury of the bundle. 
3. Arrhythmias Due to Heterogenetic Impulses.-Arrhythmias or dis- 
turbances of rhythm arising from the origination of impulses elsewhere than 
in the sino-auricular node may assume several types. They depend on the 
fact that, although the normal source of impulses is as described, the node of 
Keith, nevertheless the node of Tawara, or the bundle of His, or any part of 
the wall of the heart itself, may give rise to such impulses, which spread then PATHOLOGY OF THE CONDUCTION BUNDLES OF THE HEART 
499 
either in a normal or quite abnormal direction. It seems scarcely possible 
to say whether these impulses arise in the ordinary heart muscle itself or 
in the terminal ramifications of the conducting bundle, but at least the 
character of the electrocardiogram is sufficient to show that they do not 
originate in the main trunk of the bundle of His. 
When such an impulse leads to a contraction interpolated in the ordinary 
rhythm, it is denominated an extra-systole (Fig. 251). The simultaneous 
sputtering of such impulses from many points in the heart's wall causes 
a disorganized, uncoordinated, waving contraction (fibrillation) which 
Fig. 250.-Electrocardiogram in heart-block. The auricular beats are not regularly 
followed by ventricular systoles, and apparently have no influence upon them. 
Fig. 251.-Pulsus bigeminus in which premature beats arise in the auricles. 
produces no impulsion of the blood. Such a condition may exist in the 
auricles, but quickly leads to death if it occurs in the ventricles. 
(a) Fibrillation in the auricular wall leads to complete arrhythmia, or 
the pulsus irregularis perpetuus. Such is the tremulous quivering of the 
wall of the auricle that no contraction of the auricles is registered in the jug- 
ular curve, though minute oscillations occur in the electrocardiogram, and 
at occasional and irregular intervals impulses pass through to the ventricles, 
so that their contractions are in complete disorder and show no constant 
rhythm. Such arrhythmia is commonest in connection with disease of the 500 
TEXT-BOOK OF PATHOLOGY 
mitral valve, when the auricle is distended and its wall scarred in places. 
Usually, but not always, it is permanent. The cause of the auricular 
fibrillation is not certain, but is apparently due to degenerative changes 
in the myocardium. 
(b) In other cases, again often in connection with mitral disease, extra- 
systoles starting in various points in the auricle are transmitted to the 
ventricles, and give rise to attacks of tachycardia of auricular origin. The 
cycles are complete, but follow one another so rapidly that in the tracings 
the elevations a and v may overlap, and in the electrocardiograms P and 
T, in which case the deflection will be the algebraic sum of the two. 
(c) As in the auricles, impulses may arise in any part of the ventricles 
and give rise to effective extra-systoles which are, however, independent 
of the normal impulse. These may, when the heart-rate is slow, be simply 
interpolated between the normal heart-beats, but usually, owring to the 
Fig. 252.-Pulsus bigeminus with premature beats or extra-systoles arising in the 
ventricles. 
refractory period which follows a systole, there is a compensatory rest. 
The next impulse from the auricle finding the ventricle in the refractory 
phase produces no response, and the normal cycle is missed. Thus the 
space between the normal cycle preceding and that following the extra- 
systole is that of two normal cycles. Occasionally such extra-systoles may 
follow one another in rapid succession, and even drive back an impulse 
in retrograde direction so as to affect the auricular contractions (ventricular 
tachycardia). Tracings from the jugular, studied together with those from 
the radial during the occurrence of ventricular extra-systoles, show first 
the normal cycle, then the elevation c, followed by the ineffectual eleva- 
tion a, of the auricular contraction, and later the next normal cycle. Occa- 
sionally a and c are superposed and form one high elevation. In the 
electrocardiogram the extra-systole is represented by a diphasic wave the 
point of which is directed up when the impulse comes from the base and PATHOLOGY OF THE CONDUCTION BUNDLES OF THE HEART 
501 
the right ventricle, downward when it arises at the apex or in the left 
ventricle (c/. Fig. 252). Lewis has shown, by the experimental production 
of extra-systoles from different points, that this typical form of the electro- 
cardiogram can be actually used for diagnostic purposes. Nothing is 
known of the aetiology of such ventricular extra-systoles in the human being. 
LITERATURE 
His: Arb. a. d. Med. Klinik, Leipzig, 1, 1893, xciii. 
Tawara: Reizleitungssystem des Saugetierherzens, Jena, 1906. 
Aschoff: Verhandl. Dtsch. Path. Gesellsch., 1910, xiv, 3. 
Hering: Ibid., 36. 
Lewis: Mechanism of Heart Beat, London, 1911. Lectures on the Heart, New York, 
1915, 2d ed., London, 1919. 
Carter: Arch. Int. Med., 1918, xxii, 331. 
Oppenheimer and Rothschild: Jour. Amer. Med. Assoc., 1917, Ixix, 429. 
Keith and Flack: Jour, of Anat, and Physiol., 1907, xli, 172. 
Josue: Localisations cardiaques, XVII Internal. Congress of Medicine, London, 1913, 
iii, pt. 1, 1. (General Pathology.) CHAPTER XXIV 
TYPES OF INJURY (Continued).-OBSTRUCTION OF THE 
CEREBROSPINAL FLUID: HYDROCEPHALUS 
The term hydrocephalus signifies that enlargement of the head which 
arises through the accumulation of large quantities of fluid within the 
cavities of the brain. Its cause has never been properly understood and 
even the anatomical studies of such brains have left much to be desired, 
Left and right foramen of Monro 
Cisterna interpeduncularis7 7/ 
Descending horn of Lateral ventricle // / 
Cisterna pontis' / 
Aqueduct of Sylvius' 
Cisterna chiasmatis 
8-Foramen, 
of Magendie 
Right and left foramen of LuschKa^ 
Cisterna magna 
(cerebello -medullaris) 
Fig. 252A.-Diagram of ventricles of brain and subarachnoid cisternae (Dandy). Dr. 
Dandy has kindly allowed me the use of this illustration from his forthcoming paper. 
since they failed to demonstrate the changes which led to the retention of 
the cerebrospinal fluid, and described only those which followed as second- 
ary effects. Further, they were based on an imperfect or faulty conception 
of the paths of circulation of the fluid in the normal brain. 
Hydrocephalus may be congenital and associated with malformation 
or prenatal inflammation in the brain, it may be the effect of pressure 
502 HYDROCEPHALUS 
503 
caused by tumor or cyst within the skull, or it may arise as the result of 
meningitis. Other causes more rarely give rise to it. 
Advanced stages are easily recognized by the ungainly enlargement of 
the head, which becomes too large and heavy for the child to hold up. In 
the rather rare cases in which the patient survives to middle age, the head 
still rolls about on the shoulders. The skull becomes so thin as to form a 
very slight protection for the brain within; in places the bone is absent 
altogether, although new islands of bone may form in these spaces. The 
fontanelles remain widely open and the whole skull is so large with its over- 
hanging forehead that the face seems to be an insignificant triangular ap- 
pendage beneath. The orbits are 
stretched so that the eyes seem to be 
peering upward from the bottom of 
a space far too large for them. With 
such extreme distention the child, 
even if it survives for some time, usu- 
ally becomes imbecile, but there are 
records of persons who retained an 
acute intelligence in spite of most ad- 
vanced changes of this sort. Slight 
degrees of hydrocephalus are not so 
easily recognized except by Dandy's 
newly devised method of filling the 
ventricles with air, after which their 
dilatation is easily seen in a radiogram. 
At autopsy the convolutions of 
the cerebrum are found flattened and 
smoothed out, the ventricles are di- 
lated and filled with fluid, sometimes 
to so enormous a degree that the 
substance of the brain is reduced to a 
thin film of tissue which collapses like 
a wet cloth when the fluid is allowed 
to escape. This is true not only of 
the cerebral hemisphere but also of 
the tissues which form the walls of the third and fourth ventricles. The 
corpus callosum, the septum lucidum, the commissures, and the fornix be- 
come extraordinarily attenuated, and even the corpora striata and optic 
thalami become flattened, although they resist the pressure longer than 
the rest. In some of the cases the spinal cord is also affected, the central 
canal being dilated (hydromyelia). Atrophy of the ganglion cells of the 
cortex and of other parts of the brain and disappearance of the axones 
which belong to these cells is an inevitable consequence of this stretching 
of the tissue, and degenerations of the tracts in the cord result, although 
to an extent less than might be expected. 
Fig. 252B.-Hydrocephalus in a child 
following cerebrospinal meningitis. 504 
TEXT-BOOK OF PATHOLOGY 
The mechanism of this retention of fluid has been clearly explained in 
the papers of Dandy and Blackfan, and more especially in Dandy's reports 
of his operative and experimental studies. The cerebrospinal fluid is 
secreted by the choroid plexuses in the cerebral, third, and fourth ventri- 
cles. This is proven by the fact that if the foramen of Monroe on one 
side be plugged, that ventricle becomes greatly dilated with fluid, but if 
afterward the choroid plexus be removed from that side, the ventricle 
collapses and no more fluid appears there, so that it soon becomes obliter- 
ated. In the normal brain the cerebrospinal fluid passes downward into 
the fourth ventricle from which it escapes into the meshes of the sub- 
arachnoid space through the foramina of Majendie and Luschka. 
Reaching the cisterna magna and the other spaces on the under surface of 
the brain it spreads upward and forward over the cerebellum and over the 
Fig. 252C.-Hydrocephalus following cerebrospinal meningitis with old adhesions 
about the base of the brain. Transverse section looking forward, showing great dila- 
tation of lateral and fourth ventricles, and of the aqueduct of Sylvius. 
midbrain as it passes through the tentorium to the surface of the cerebral 
hemispheres, flowing always in the meshes of the subarachnoid space 
until it finally reaches the vertex and bathes the whole surface of the 
brain. Similarly, it flows downward into the spinal meningeal spaces. 
Absorption into the circulating blood seems to take place throughout this 
wide-spread area, although it is most active over the cerebral hemispheres, 
probably because of the greater extent of the absorbing surface. There 
are, however, other ideas as to the mechanism of absorption which assume 
the presence of specialized arachnoidal villi in close relation with the 
venous sinuses of the dura mater. 
Dandy and Blackfan showed that cases of hydrocephalus fell into two 
groups according to their behavior when phenolsulphonephthalein was 
injected into the cerebral ventricle. In one group little or none of this HYDROCEPHALUS 
505 
colored material appeared in the spinal fluid, while in the other it appeared 
there at once. They designated these groups obstructive and communicat- 
ing hydrocephalus respectively, and found it possible to explain them on 
anatomical grounds from what was discovered at autopsy. In the obstruc- 
tive group the fluid cannot escape from the ventricles because there is an 
obstruction somewhere in its usual path. This may be in one or both for- 
amina of Monroe, or in the aqueduct of Sylvius, or there may be an occlu- 
sion of the foramina of Majendie and Luschka. Naturally, if the obstruc- 
tion is in the foramen of Monroe on one side, the dilatation will be limited 
to that ventricle. An obstruction in the aqueduct of Sylvius will cause 
Fig. 252D.-Hydrocephalus following obstruction of the aqueduct of Sylvius, showing 
dilatation of the lateral ventricles and of the foramina of Monroe. The basal ganglia 
are less affected and become prominent. 
the distention of both cerebral and third ventricles. In the fourth ventricle 
the foramen of Majendie and both of the foramina of Luschka must be 
obstructed, else the obstructive type of hydrocephalus is incomplete. In all 
these cases the fluid is retained within the cavities of the brain, and never 
reaches the subarachnoid spaces at all. It is very different with the second 
group, the so-called communicating forms. In these, which are commonly 
the late results of meningitis with adhesions obliterating the meshes of 
the arachnoid and the cisternee, the obstruction lies in these adhesions 
which also bind the arachnoid to the dura about the midbrain where it is 
closely surrounded by the tentorium and prevents the passage of the fluid 506 
TEXT-BOOK OF PATHOLOGY 
into the subarachnoid spaces over the convexity of the cerebrum. Probably 
even more important is the obliteration by adhesions of the cisternae from 
which this distribution normally occurs. Colored fluid injected into the 
ventricles can pass out through the foramina in the roof of the fourth ven- 
tricle and down into the spinal meninges, but cannot reach the cerebral 
subarachnoid spaces from which nearly all the absorption takes place. 
Therefore the ventricles become dilated, and in some cases there is also a 
distention of the spinal meninges (meningocele). This is the type seen in 
meningococcus and tuberculous meningitis, but it must be remembered 
that in the presence of an inflammatory process there is another reason for 
the disproportion between the amount of fluid secreted and that absorbed. 
Dandy and Blackfan: Amer. Jour. Dis. Child., 1914, vii, 406; 1917, xiv, 424. 
Dandy: Johns Hopkins Hosp. Bull., 1919, xxx, 29. Annals of Surg., Dec., 1918; Aug., 
1919. 
LITERATURE CHAPTER XXV 
TYPES OF INJURY (Continued).-BACTERIAL DISEASE 
General character of bacterial infection: Nature of bacterial action. Pyogenic micrococci. 
Streptococcus infections-of the throat, the middle ear, the digestive tract. Wound infection: 
Erysipelas, pneumonia, endocarditis. General septiccemia; acute splenic tumor. 
GENERAL CHARACTER OF BACTERIAL INFECTIONS 
As a type of injury, the harmful effects of bacteria play an exceedingly great 
part in the causation of disease, and must generally be reckoned with at 
some stage or other, even when they are not the primary cause of the ail- 
ment. 
Of course, only a small number of the existing bacteria are harmful to 
man, and it seems that we must believe that these have gradually acquired, 
through long adaptation, their ability to thrive in contact with the living 
tissue. The rest live outside the body under all sorts of conditions, requir- 
ing in their struggle for existence heat, moisture, and nutriment. The 
latter they get partly from animal or vegetable matter, in which they 
hasten the process of decay, which depends largely upon their ferment 
activities. Such saprophytes may occasionally acquire the faculty of 
parasitic existence, and point the way followed by those which we now 
think of as obligate parasites. 
Many of the disease-producing organisms scattered ordinarily in small 
numbers in the outside world may gain entrance into the body in over- 
whelmingly effective numbers, merely because they have had an oppor- 
tunity to multiply in some culture-medium. A few typhoid bacilli which 
might readily be overcome in the intestine of any healthy man can, as in a 
recent case, cause a fatal epidemic if they are introduced into warm food 
and left to multiply until it is time for the crowd to partake of refresh- 
ments. 
Bacteria live in great numbers on the body surface; they are taken 
into the digestive tract in great quantities in the food, and penetrate 
readily into all the external orifices of the body. At each point there is a 
mechanical or chemical guard of a sort, but nevertheless there is constantly 
an army of them besieging each portal. The impermeability of the horny 
layer of the skin, the constant irrigation of the conjunctival sac, the cilia 
of the respiratory tract, the acid gastric juice, the irrigation of the urinary 
tract, the acid vaginal secretion-all act as outpost guards. Nevertheless, 
in each of these positions it is known that bacteria are not entirely des- 
troyed and that there is a characteristic flora, including pathogenic forms, 
waiting, as it were, to break through the second line of guards. The 
507 508 
TEXT-BOOK OF PATHOLOGY 
whole upper respiratory tract is smeared with bacteria; the mouth is a per- 
fect incubator of dozens of forms, and while the stomach and duodenum 
are relatively free, the lower intestine, and especially the colon, contains 
myriads. 
Doubtless a few bacteria brought thus into the most intimate relations 
with the body surfaces pass into the real interior, that is, into the tissues 
themselves in healthy persons, but there is strong evidence to show they are 
rapidly overcome and destroyed by phagocytic cells and by the destructive 
action of the blood and tissue fluids. Were it not for these defences every 
one would quickly die from infection. Since infection does occur with 
fatal results, it is obvious that there must be failure of the defence or else 
the introduction of such overwhelming numbers of bacteria that defence 
is unsuccessful. 
The chief portals of entry are, of course, the various mucosae of the body, 
which are really as much exposed to bacteria as the outside skin, and the 
skin itself, which, through abrasions or wounds, can allow their entrance. 
Having penetrated into direct relation with the tissues, most bacteria 
fail to multiply, but those which are adapted to such surroundings may do 
so, although constantly hampered by the antagonistic action of the body 
defences, especially such as are presented by the reaction of inflammation. 
Virulent bacteria in a person whose resistance is low may, however, grow 
rapidly and be quickly transported to other parts of the body by the 
lymphatic channels, or even in some cases by the blood-stream. If an 
intestinal loop is ruptured, pouring great quantities of infected material into 
the peritoneum, the bacteria are taken into the lymphatics of the dia- 
phragm, and hence through the mediastinal lymph-channels to the retro- 
sternal lymph-glands with the greatest celerity, and after a very few 
minutes may be found in the circulating blood. 
Bacteria alone introduced into the tissues or body cavities are relatively 
easily killed. If, however, foreign bodies or dead tissue are present there, 
to afford a shelter against the disinfecting action of the tissue juices until 
multiplication to great numbers has occurred, the bacteria can more readily 
gain a dominating position. Bacteria in the uterine cavity in the puerperal 
state might be practically harmless were it not for the protected culture- 
medium offered by remains of detached and dead placenta, in which they 
reinforce themselves by growth until they can victoriously invade the 
uterine wall. 
Changes in the virulence of bacteria, easily produced experimentally by 
repeated passage through the animal body, appear in the most striking 
fashion in the course of many epidemics, and the fading out of the epidemic 
seems to be due usually to the lack of any further susceptible material 
rather than to any decline in the virulence of the organism. In the recent 
epidemics of streptococcus pneumonia this intensification of the activity 
of the streptococcus seems to have been exemplified. 
It is not always easy to explain the very obvious changes in the power GENERAL CHARACTER OF BACTERIAL INFECTIONS 
509 
of resistance shown to bacteria. Many external conditions, such as chilling 
or starvation, may aid in this, but previous disease seems even more 
potent in this way. Almost every one harbors pathogenic bacteria in his 
throat, but it requires a sudden chilling or exposure or injury to favor their 
invasion into the lungs and the production of pneumonia. Similarly, one 
sees in the lungs of a man long known to have suffered from tuberculosis, 
old scarred lesions at the apex, clearly stoutly resisted in their time, and 
fresh extensive and rapid destruction of the lower lobes, caused by the same 
bacteria which have seized upon a period of lowered resistance to push their 
advantage. 
This is doubtless the explanation of the so-called secondary infections, 
which are so common and which underlie the statement that a "man seldom 
dies of the disease with which he sickens." He really dies of the secondary 
infection, which thrives in the body weakened by the original disease. 
One might say that the fatal outcome in cancerous disease is usually not 
from the effects of the cancer, but from the bacteria that invade the 
emaciated subject. And so with destructive chronic tuberculosis of the 
lungs, in which the hectic symptoms seem to be due rather to the strepto- 
cocci and staphylococci and other bacteria which secondarily infect the 
cavities in those organs. 
Persons who die after long illness with such affections as chronic nephritis, 
cardiac disease, or cirrhosis of the liver may show no special symptoms of 
infection other than a sudden fever at the end, but in their tissues at autopsy 
one finds, as pointed out by Flexner, streptococci or other bacteria which 
have finally invaded the failing tissue and have added the intolerable last 
straw. Such terminal infections are extremely frequent, and although they 
may not produce any gross lesions in the organs, they are very often repre- 
sented by a terminal bronchopneumonia or diphtheritic enteritis. 
Nature of Bacterial Action.-We are by no means clearly informed as 
to how bacteria produce their injurious effects. It is easy to say that 
they do so by elaborating poisons, but in reality, except in the case of a 
few, such as diphtheria and tetanus bacilli, which produce soluble toxins 
of great intensity, it is extremely difficult to demonstrate any poisons in 
the cultures of bacteria, even though they are known to be exceedingly 
virulent. It was thought that poison might be retained within their 
bodies (endotoxins), and liberated only upon their death and disintegration, 
so that the destructive effects would depend upon their death. It is true 
that when these bacteria are pulverized and extracted, poisonous substances 
are obtained with which the symptoms of the disease may be produced, 
but they scarcely compare in virulence with those formed by the diphtheria 
and tetanus bacilli; and it seems that perhaps the whole explanation is 
not yet before us. It is quite conceivable, however, that bacteria in the 
body may produce a more active poison than when grown in artificial 
culture-media. 
The effects upon the tissues differ widely with the different bacteria, but 510 
TEXT-BOOK OF PATHOLOGY 
in general they produce the death or profound injury of the adjacent cells, 
and quickly call forth an inflammatory reaction. A few, such as the 
typhoid bacillus, although causing necrosis of the neighboring cells, do 
not elicit the ordinary response of the neutrophile leucocytes, but rather 
produce a curious reaction, in which mononuclear phagocytic cells pre- 
dominate. Others, such as the tubercle bacillus, may live a long time 
among cells which are not only alive, but actively multiplying, only to 
cause in time their complete destruction. The effect seems to vary, then, 
with the chemical nature of the substances produced in the body of the 
bacteria, and these various reactions must be considered later in some detail. 
According to the character of the bacteria, their number, their concentra- 
tion, and the resistance of the individual, infection may assume various 
forms. Some organisms, notably those which produce soluble toxins 
(diphtheria and tetanus), appear to grow only at the point of inoculation 
or first infection, although they distribute themselves in small numbers in 
the blood-stream and tissues. From this local growth they diffuse their 
poisons. Others, having gained a foothold, tend to spread diffusely through 
the tissues, causing havoc wherever they go. Such are the streptococci, 
while the staphylococci are accustomed to concentrate themselves at 
various points in the tissues, and stir up an intense concentric inflam- 
matory reaction around themselves {abscess formation). Either of these 
forms and many others may, however, in one way or another invade the 
blood-vessels and pour themselves into the flowing blood. When bacteria 
can be recognized in the circulating blood, we call the process septiccemia, 
and this term is being found to apply properly to more and more infectious 
diseases as careful blood cultures are made (pneumonia, typhoid fever, endo- 
carditis, etc.). By pycemia we mean that condition associated with septi- 
caemia or bacteriaemia in which suppurative foci are formed here and there. 
The student should read in this connection the interesting works of Metch- 
nikoff, Welch, and others upon these general topics of infection and immu- 
nity which can merely be outlined here. The remarkable progress in 
knowledge of this region of medicine in recent years has made the gen- 
eral and special consideration of infection and resistance the subject not 
only of many text-books, but of a literature so extensive as to be almost 
beyond the compass of one man's reading. 
Metchnikoff: Immunite dans les maladie infectieuses, Paris, 1901. 
Welch: "Surgical Bacteriology," Dennis' System of Surgery, Philadelphia, 1895. 
Simon: Infection and Immunity, Philadelphia, 1912. 
Zinsser: Infection and Resistance, New York, 1922. 
LITERATURE 
The Pyogenic Micrococci.-While the bacteria belonging to this group 
unquestionably cause different diseases according to the special peculiarities 
of each, there is still a striking resemblance in their mode of action, and 
there are many things, such as endocarditis, lobular pneumonia, and men- STREPTOCOCCUS INFECTIONS 
511 
ingitis, which may be caused by each of them in nearly the same fashion. 
We may, therefore, consider together in this chapter the effects produced 
by the Staphylococcus pyogenes aureus, the Staphylococcus albus, the 
Streptococcus longus or haemolyticus, Streptococcus mitis or viridans, 
the pneumococcus or Micrococcus lanceolatus in its various types, the 
gonococcus, the meningococcus or Micrococcus intracellularis meningi- 
tidis, together with other forms and varieties. No attempt will be made 
to describe the organisms, nor to discuss their systematic relations, which 
are subjects for books on bacteriology. Together with these affections 
there may be discussed acute rheumatic fever, the cause of which is un- 
known, but which resembles them in many respects. 
STREPTOCOCCUS INFECTIONS 
Since the time of Schottmiiller, who first made use of the haemolytic 
power of some streptococci for purposes of classification, many authors 
have been engaged in the attempt to put this upon a satisfactory basis, but 
even yet without any very enduring result. The names of Gordon, Andrews 
and Horder, Holman, Smith and Brown, Blake, Smillie, Swift, and Kinsella 
are especially connected with this work, and certain things stand out 
clearly which were obscure before. It is agreed that the possession or lack 
of the power of haemolysis is of fundamental importance, so that strep- 
tococci are divided primarily into haemolytic and non-haemolytic forms. 
Attempts have been made by Holman to divide these groups further by 
studying the reactions of all the strains with various sugars, and while 
this gives reliable results, it is found that most of the subgroups are repre- 
sented by rare examples because they are not the forms commonly con- 
cerned in the production of human disease, and we still find authors writing 
simply of haemolytic or non-haemolytic strains. Kinsella and Swift showed 
by the method of complement fixation that all the haemolytic strains are 
alike, while the non-haemolytic group is quite heterogeneous. Dochez has 
found, however, by testing the protection conferred by specific antisera 
that the haemolytic streptococci fall into four distinct groups which are 
not as yet to be distinguished in any other way. Brown states that strepto- 
cocci of human and bovine origin can be differentiated best by quantita- 
tive estimation of their haemolytic power, while Avery and Cullen make 
this distinction on the basis of the maximum acidity produced in the cul- 
ture-medium, which is greater for the bovine type. Smith and Brown, and 
later Brown in his monograph on the use of the blood-agar plate in the 
study of streptococci, describe as the a type of haemolysis the methaemo- 
globin formation and slight laking found round the colonies of the non- 
haemolytic form, S. viridans, while their /? type of haemolysis is the 
complete ring of laking found about those of the haemolytic form, S. 
haemolyticus. The r type is a non-haemolytic form which produces no 
methaemoglobin. 
It must be evident from this that great difficulty is encountered in 512 
TEXT-BOOK OF PATHOLOGY 
making any finer distinctions among these extremely common and wide- 
spread organisms. None of the old lines of classification based on the length 
of the chains, etc., are used any more, and Streptococcus mucosus, which 
formerly occupied a place here, is now recognized as Pneumococcus Type 
III. 
It seems that we can separate rather sharply the pathological changes 
caused by the two main types of streptococcus, although it is possible that 
in some conditions either may be concerned. At least it is true that those 
lesions which are well known to be caused by either one of them are per- 
fectly characteristic, and it is probable that in time all will be found to 
have a specific peculiarity. 
The Streptococcus Haemolyticus.-While this organism is found in water, 
milk, etc., it seems probable that in most cases it is transmitted directly 
from another person to some portal of entry into the body. This is espe- 
cially true in the respiratory infections, less so in the infections of the skin, 
digestive tract, etc. 
Infections of the Respiratory Tract.-Abundant opportunity to observe 
such infections was afforded during the war in the bronchopneumonia 
which followed the epidemics of measles, influenza, and other diseases 
which occurred among the troops, but sporadic cases are not uncommon 
at any time. The invasion seems to take place in the mucosa of the nose, 
pharynx, and larynx, extending quickly to the accessury nasal sinuses, 
and later to the trachea and bronchi. Reddening of the mucosa, with a 
sensation of soreness of the throat, followed by swelling of the tonsils, the 
appearance of patches of whitish, necrotic material on the exposed surfaces, 
fever, and general illness are characteristic and last some days, but usually 
end in recovery. More severe effects of such angina are met with, and may 
be illustrated by the case of one of our colleagues who suffered from repeated 
attacks. In one of these the tonsils became greatly swollen and reddened, 
with thick patches of greenish, necrotic tissue and fibrin, which, on removal, 
left rather deep raw ulcerations. The whole pharynx was intensely in- 
flamed, and firm lumps appeared beneath the angle of the jaw. He was 
profoundly ill, and the surgeons incised the swelling, which proved to be 
due to infection of the adjacent lymph-glands, from which a quantity of 
pus containing streptococci was drained. After that he recovered, but a 
year later the tonsillitis suddenly recurred, the surfaces of the tonsils, as 
well as the whole lining of the pharynx, became intensely inflamed and 
covered with a necrotic false membrane. There were tumefaction and in- 
duration of the glands and high fever. He rapidly became delirious, and 
then comatose. A rash, like that of scarlet fever, appeared over the whole 
body, with pin-point haemorrhages everywhere, and he died within seventy- 
two hours of the onset. 
In other cases arising somewhat differently, from extension of the infec- 
tion from a suppurating salivary gland, from a carious tooth, or from a peri- 
tonsillar abscess (quinsy), there may arise another form of angina, the so- STREPTOCOCCUS INFECTIONS 
513 
called Ludwig's angina, in which all the loose tissues of the neck become 
densely infiltrated with inflammatory exudate in response to the dis- 
semination of streptococci there. One case which we saw recently was 
thought to have started in an infected abrasion of the skin of the neck, but 
most of them arise from extension from the organs about the pharynx. 
The infiltration among the muscles and about the vessels and the pharynx 
is so dense as to be rigid and hard, so that these organs are solidly embedded. 
If death is postponed for a few days, there may be liquefaction of some of 
the necrotic tissue and exudate. 
Important are the numerous cases of streptococcal sore throat which occur 
in great epidemics with high mortality, and are generally traced to some 
dairy in which one or more cows with udders infected with the streptococcus 
give a milk which is thick, yellow, and stringy, and on examination proves 
to be really a mixture of milk and pus, with myriads of streptococci. 
Several epidemics of this kind have been reported recently in this country 
(Pearce, Capps, and others). 
Smith and Brown and, more recently, Brown and Orcutt have studied 
some of these epidemics and have decided that the streptococcus concerned 
is a human parasite infecting the udder of the cow or introduced directly 
into the milk from an infected milker. It is not the bovine form which is 
so commonly present in dairy herds as the cause of the infectious mammitis 
or garget. 
Severe streptococcal infections of the throat are well known to accom- 
pany scarlet fever, smallpox, diphtheria, and some other diseases, and, 
indeed, in the lack of all knowledge of the true cause of scarlet fever, 
there are those who would ascribe it to the streptococcus. 
Measles is another disease which produces a coryza and laryngitis and 
appears to render the tissues very susceptible to the invasion of strepto- 
cocci. We were never able to study the tissues of any case of measles un- 
infected with streptococci, and the nature of the pharyngeal and laryngeal 
changes due to the measles alone is not known. The secondary strepto- 
coccal infection is, however, most destructive. There is rapid loss of voice, 
and at autopsy the whole mucosa of the pharynx, larynx, and trachea is 
found deeply reddened and sprinkled with haemorrhages, or partly covered 
with greenish pseudomembranous exudate; ragged ulcerations of the epi- 
glottis, pyriform sinuses, and especially of the vocal cords and lining mucosa 
of the larynx are common. The tissues of the vocal cords are often so 
deeply eroded that tone production is impossible. With all this the tonsils 
do not seem to be very intensely affected. The streptococci may burrow 
deep into the underlying tissue and produce a phlegmonous infiltration 
which is strewn with enormous numbers of organisms. 
Streptococcal infection of the lungs after measles becomes an extremely 
severe affection and assumes peculiar characters which make it easily 
recognizable. It occurred in extensive epidemics and the mortality was 
high. Later, when measles had become less prevalent, the excessively TEXT-BOOK OF PATHOLOGY 
514 
virulent streptococci continued to produce pneumonia even in those who 
had previously been well. Still later, in the course of the great epidemic 
of influenza, the hemolytic streptococcus once more appeared as a secondary 
invader and caused a rapidly fatal pneumonia. When that epidemic waned 
the streptococcal infections became relatively more numerous and once 
more gave rise to the interstitial type of bronchopneumonia such as we 
observed after measles. 
During and after the epidemic of measles the changes produced by the 
streptococcus in the lungs were about as follows: The organisms evidently 
extended downward into the finer 
bronchioles, giving rise along their 
path in the trachea and larger 
bronchi to an intense inflammatory 
reaction. Arrived at the terminal 
bronchioles they multiplied and de- 
stroyed the epithelium, but were 
rather closely restricted to the 
bronchioles; a few escaped into the 
lymphatics of the bronchial wall 
and of the interlobular septa, and, 
after causing thrombosis of these, 
extended to the network of lym- 
phatics in the pleura. The imme- 
diate effect was the rapid production 
of a pleurisy with an abundant effu- 
sion of brownish turbid fluid loaded 
with streptococci in chains. Only 
much later did this fluid assume a 
purulent character, but the exudate 
on the pleural surface rapidly be- 
came organized into a layer of gran- 
ulation tissue. 
About the infected bronchioles 
there appeared haemorrhage with 
but little emigration of leucocytes; 
later lymphocytes and very dense 
fibrin were added and formed compact plugs in the alveoli. But most 
striking was the infiltration of the alveolar walls themselves with mono- 
nuclear wandering cells and the great thickening of the walls of the bronchi. 
This interstitial infiltration soon accompanied by the formation of new con- 
nective tissue, and even by organization of the exudate within the alveoli 
gave a greatly increased density to the area thus affected. Interlobular 
septa and all other elements of the framework of the lung became much 
thickened and very conspicuous (Figs. 252E, F, and G). 
It is easy to understand that such a process would produce an appearance 
Fig. 252E.-Interstitial bronchopneu- 
monia following measles, and caused by 
the haemolytic streptococcus. 515 
STREPTOCOCCUS INFECTIONS 
Fig. 252F.-Interstitial bronchopneumonia. Later stage; showing extreme infiltration 
and thickening of the bronchial walls. 
Fig. 252G.-Interstitial bronchopneumonia showing clumps of streptococci in the 
bronchus and infiltration of its wall. 
in the fresh lung very different from that seen in the ordinary forms of bron- 
chopneumonia. At autopsy the lungs were often found collapsed by the 516 
TEXT-BOOK OF PATHOLOGY 
great effusion of fluid in the pleura and their tissue was deep blue. Through- 
out there could be felt hard nodules of varying size which on section pro- 
jected as yellowish masses, evidently surrounding bronchioles because 
each showed in its centre the lumen of a bronchus exuding pus. These 
were always broadly surrounded by a zone of haemorrhage. These char- 
acters suggested the name interstitial bronchopneumonia which we have 
used for this type of lesion (Fig. 252E). Haemolytic streptococci were in- 
variably found in predominant numbers and often in pure culture, but 
other organisms, especially the bacillus of Pfeiffer, were sometimes asso- 
ciated, and we have always felt that there might be some question as to the 
part it played, since it is known that a very similar nodular interstitial 
bronchopneumonia may be produced by the Pfeiffer bacillus alone. 
There were other cases in which the haemolytic streptococci grew in ex- 
traordinary numbers through the substance of the lung in large areas. In 
these there was no interstitial infiltration, no nodule formation, and no re- 
striction of the growth and spread of the bacteria. We thought, perhaps 
wrongly, that these must be individuals who were least able to offer any 
resistance to the invasion and destructive activity of the organisms, con- 
trasting in this respect with those in whom the interstitial form of pneu- 
monia appeared. There is the possibility that an anaphylactic sensiti- 
zation may play a part in this as particularly suggested by the observation 
that in some of the cases of interstitial pneumonia there may be patches of 
diffuse consolidation in which the alveoli are filled with an exudate of poly- 
morphonuclear leucocytes with millions of bacteria. This type of acute 
pneumonia is usually patchy and without very definite outlines; the alveolar 
walls are not infiltrated with cells, but there may be extensive hyaline throm- 
bosis of the capillaries. The number of bacteria found among the leucocytes 
of the exudate is far beyond anything I have ever seen in other forms of 
pneumonia. Certain cases show the extreme to which this condition can 
go, in great haemorrhagic patches in which the whole central part of the 
consolidated area is dull and opaque, and on section proves to be necrotic 
and occupied by a perfect feltwork of chains of streptococci. 
Empyema accompanies the diffuse forms of pneumonia as well as the 
others, and often become the most prominent feature of the case if the 
patient survives long enough. Then one may find areas in the lung which 
have become yellow and opaque and completely necrotic, and it is through 
the disintegration of these and their rupture into both bronchus and pleura 
that the pleuropulmonary fistulae arise. 
In most of these cases there was little evidence of the existence of a gen- 
eral septicaemia. There is often a moderate acute splenic tumor, and the 
hyaline degeneration of the rectus abdominis muscles which may also 
accompany pneumococcus and typhoid infections is frequent. The other 
organs showed only slight changes, such as cloudy swelling. 
During the influenza epidemic we saw a few cases of pneumonia caused 
by the same streptococcus, and these were of the maximum intensity, the STREPTOCOCCUS INFECTIONS 
517 
lungs showing patches of diffuse consolidation in which the alveoli were 
filled with fluid, leucocytes, and myriads of streptococci. The oedema and 
the wide-spread necrosis of the lung tissue were most characteristic. The 
intense inflammatory and ulcerative changes in the larynx and pharynx 
and the infection of the nasal sinuses were as striking in these cases as in 
those which followed measles. It is to be emphasized that there is much 
in the anatomical condition which is specific for the ha moly tic strepto- 
coccus so that one may recognize the type of pneumonia caused by this 
organism with a fair degree of certainty. 
Infections of the Middle Ear.-The hamolytic streptococcus is a common 
cause of middle-ear inflammation or otitis media, but is by no means the 
only organism which can do this. Staphylococci and pneumococci may 
be concerned instead and, indeed, the pneumococcus Type III, sometimes 
called Streptococcus mucosus, gives rise to the most severe, treacherous, and 
destructive form. Otitis media seems to be the result of the passage of 
bacteria from the infected and inflamed throat along the Eustachian tube 
to the middle ear. Of course, the opening of the tube is guarded, as Rich 
has shown, by folds of mucosa at its pharyngeal end, and is open only dur- 
ing certain movements of the muscles, especially the tensor palati. But 
when a sneeze is stifled by holding the nose, or when the nose is blown very 
hard, infected material may be driven up the tube. In a case which I 
followed, the attempt to smother a sneeze was followed by a sense of dis- 
comfort in one ear and next day by a sharp pain. The drum of the ear may 
be dulled a day or two later and bulge, or pus may be seen showing through 
it. If it is punctured the infection may clear up if the organism concerned 
is not a very tenacious one, but the outcome is very frequently not so 
happy. Instead the infection extends into the cavities of the mastoid 
process of the temporal bone, which fill with pus. Necrosis of the partitions 
of bone between these cavities takes place and may extend through other 
portions of the temporal bone until it reaches the dura mater with its 
lateral venous sinus. Libman finds that bacteriamia may depend upon 
the thrombosis of the communicating jugular vein, and that it may be 
stopped by ligature below the thrombus. In this country and wherever 
operative interference is reasonably prompt, thrombosis of the lateral 
sinus counts as a late complication, and any further extension through 
the dura to the meninges is rare. But in China and even in Austria and 
Germany the disease is often neglected until the infection has extended to 
produce not only local meningitis or meningeal adhesions, but an abscess 
in the temporal lobe of the brain. I have been especially impressed by 
the frequency of such abscesses in the German autopsy rooms as the cause 
of death, while they form the greatest rarity here. The exudate in the 
mastoid cells is purulent in the streptococcal and staphylococcal infections, 
but in the case of infection with the pneumococcus Type III, it appears as 
a pinkish gelatinous material which fills all the spaces and is loaded with 
the organisms. 518 
TEXT-BOOK OF PATHOLOGY 
Infections of the Digestive Tract.-Vague, and for the greater part un- 
founded, statements were formerly made about the part played by strepto- 
cocci in the causation of dysenteries, but since the recent work of Shiga, 
Flexner, and others, it is clear that those affections are due to a totally differ- 
ent organism. Nevertheless, it still seems probable, although not proven, 
that some at least of the instances of terminal diphtheritic enteritis and 
colitis in persons dying after protracted illnesses may be due to streptococci. 
Definitely of streptococcal origin are the phlegmonous gastritis and 
phlegmonous enteritis, in which the submucosa of the stomach or of the 
duodenum and jejunum is found to be enormously thickened by a tense 
inflammatory exudate loaded with streptococci. Invasion through some 
abrasion or ulceration of the mucosa, sometimes produced by a blow on the 
abdomen, gives origin to this condition. It is interesting from the fact 
that the walls of the digestive tract are rendered rigid and immovable by 
the exudate, and since this tract is unable to propel the intestinal contents, 
obstruction, with its characteristic symptoms, ensues, just as in paralytic 
ileus. 
That the streptococcus may play an important part in appendicitis has 
already been mentioned. 
Wound Infection.-Streptococcal infection through wounds or abrasions 
of the skin are perhaps not so common as those caused by the staphylo- 
coccus, but under certain circumstances, especially familiar to surgeons and 
pathologists, they occur and run a rapid course. A prick with a needle or 
a small unobserved cut during the performance of an autopsy in an infected 
case remains unnoticed for several hours, after which it shows a slight reac- 
tion and becomes painful. Little is to be observed at the point of the inocu- 
lation, but the whole arm aches, red lines, indicating an acute lymphangitis, 
run up the forearm, the epitrochlear and axillary glands swell and become 
very tender. A feeling of extreme illness with fever and perhaps a chill 
ensues. Infiltration of the loose tissues of the arm and axilla may take 
place and require surgical intervention, and although the body resistance 
is likely to overcome the bacteria, death from general septicaemia is not 
rare. 
One instance of this sort in an artist colleague who was making a drawing at an 
autopsy had interesting complications. The swelling and tension in his arm were such 
that extensive incisions were made, in the midst of which the ulnar nerve was injured 
with a clamp. On recovery it was found that half of his hand was paralyzed, and some 
months later a second operation was undertaken to find the point of injury. The nerve 
was found embedded in a dense scar, which was dissected away, after which, doubtless 
through allowing new nerve-fibres to grow down through this obstructed point, mobility 
and sensation gradually but completely returned. 
More extensive wounds with laceration of tissue and soiling are prone 
to develop streptococcus infections. Fracture of the skull extending into 
the accessory nasal cavities may lead to a suppurative meningitis, while 
compound fractures of the other bones formed, in pre-antiseptic days, the STREPTOCOCCUS INFECTIONS 
519 
most feared of traumatic injuries. Of course, since they often developed 
a pysemic condition, it is likely that other organisms, including the staphylo- 
cocci, were frequently concerned, but the diffuse inflammation and septi- 
csemia caused by the streptococcus were not uncommon. Even now, with 
all our vaunted knowledge of bacteriology and antiseptics, the surgeons 
must be careful to treat soiled and lacerated wounds in such a way that 
the circulation is not interfered with by suture or bandages, lest strepto- 
cocci multiply in the hampered tissues and finally invade the whole body. 
The conditions under which soldiers in the trenches in the Great War were 
exposed to lacerating wounds are familiar to every one, and although the 
tetanus bacillus and the gas bacillus added to the dangers, the most fearful 
streptococcus infections were described. 
Erysipelas.-The haemolytic streptococcus responsible for puerperal 
sepsis, etc., is also the cause of the peculiar infection of the skin, which 
starts from some slight wound or abrasion and which has always been 
known as erysipelas. It is commonly seen on the face or head, but it is 
also frequent in other parts of the body. Erdman, who studied 800 cases, 
found that 500 of them were uncomplicated cases of facial erysipelas, while 
far smaller numbers were affections of other parts of the body or migrating 
forms. It is a rapidly spreading inflammation of the skin, which becomes 
reddened and elevated into a dense, advancing, irregular margin, which 
pushes ahead, leaving the previously affected part pale again or somewhat 
pigmented. Where the skin is loose, it becomes oedematous and enormously 
swollen. Where it is stretched or tightly bound to the underlying tissues, 
the spread of the disease is likely to stop, and hence the treatment recom- 
mended by Wdiffer, which consists in stretching the skin with strips of 
adhesive plaster. In the eyelids, scrotum, vulva, etc., the oedema may be 
such that the tense skin becomes necrotic. This is likely to occur, too, 
where erysipelas has started from old leg ulcers, or where it occurs in 
tuberculous or other wasted persons. Great blisters or bullae are formed 
sometimes. The red, elevated, glistening, tense margin shows the char- 
acteristic anatomical lesion, which consists of a profuse infiltration of 
the crevices of the tissue and the lymph-channels with streptococci. None 
seem to be found in the blood-vessels, but their presence in the lymphatic 
canals causes an inflammatory reaction which may be perivascular in its 
distribution. The corium is oedematous, and there are great quantities 
of wandering cells, mostly of a mononuclear character. Occasionally the 
exudate is more nearly purulent, and abundant abscesses, loaded with 
streptococci, may develop in the depths of the corium; but this is a rare 
consequence, and usually the process continues to spread without suppurat- 
ing, by the advance of the streptococci, and fades in the region already 
traversed. It is rather remarkable that in a streptococcal infection, 
which elsewhere is met with an outpouring of neutrophile leucocytes, there 
should be found in the skin chiefly lymphoid or small mononuclear wander- 
ing cells. 520 
TEXT-BOOK OF PATHOLOGY 
The disease affects infants as well as adults, but is less common in older 
children. It is particularly likely to recur, and those persons who are pre- 
disposed may have a great many attacks, which in the end cause a great 
thickening and induration of the skin affected. It is not limited to the 
external skin, but may extend to the mucosae, involving the pharynx, the 
larynx (often with fatal oedema of the glottis), the middle ear, the vagina, 
etc. Death occurs from general septicaemia, pneumonia, etc., but most 
often the cases recover. Erdmann has seen 93 deaths in 800 cases. Were 
it not for the fact that erysipelas commonly appears as a terminal infection 
in persons already weakened by alcohol or disease, the deaths ascribed to 
it might not reach so high a number. In a case which came to autopsy 
recently there was found a wide-spread tuberculosis of the lymph-glands 
and spleen, but during the last two days of life erysipelas had set in and 
spread rapidly over the face and neck, causing such oedema of that side of 
the face that the eye was not only closed, but presented its lids as great 
bulging masses which projected out over the swollen cheek. The Strep- 
tococcus haemolyticus was recovered in the blood. In other fatal cases the 
cloudy swelling of the viscera, the acute splenic tumor, and other char- 
acteristic features of septicaemia were found. In women, attacks of ery- 
sipelas often appear with curious regularity with the periods of menstrua- 
tion. Jordan, Jochmann, Reiche, and others have described cases of ery- 
sipelas caused by the staphylococcus, and Neufeld has found the pneumo- 
coccus responsible, but these are indeed rarely of aetiological importance. 
Chr. Holmes discusses, in an interesting paper, the mystery which has 
long hung about the pathogenesis of erysipelas, and fairly demonstrates 
a plausible explanation of its mode of onset. Formerly a distinction was 
made between spontaneous and wound erysipelas, it being recognized that 
after operation or lacerated wounds an erysipelatous infection was likely 
to start from the edges of the wound. This distinction was given up because 
all erysipelas was later thought to begin in some abrasion, often very in- 
conspicuous in nature. Holmes points out the great frequency of latent 
infection of the nose, nasal sinuses, etc., with streptococci and pneumococci, 
the overwhelming preponderance of facial erysipelas, and among these 
cases the very large proportion starting from the nose. Further, he collects 
many cases in which erysipelas followed operations which lay open infected 
nasal sinuses, infected middle ear and mastoid cells, etc., and quite logically 
draws the conclusion that in all probability facial erysipelas is most com- 
monly the result of the extension of infection from the nasal cavity. He 
further points out the frequency of extension of this inflammation to the 
eyelids, conjunctiva, and the various parts of the eye, where it may pro- 
duce destructive effects. 
Puerperal Endometritis.-The anatomical changes and mode of occur- 
rence of infection of the puerperal uterus have been described in an earlier 
part of this book, and it need only be said here that while the non-haemo- 
lytic forms of the streptococcus may be found in the normal puerperal STREPTOCOCCUS INFECTIONS 
521 
uterus, the presence there of the hsemolytic form is of serious import and 
that the actual cases of puerperal endometritis are usually caused by this 
organism. 
Endocarditis.-With regard to the role of the various forms of strepto- 
coccus in the production of endocarditis, much has already been said 
(Chapter XIV). Since writing that chapter, however, a survey has been 
made of the cases of endocarditis which have come to autopsy in the last 
ten years, with the result that it seems relatively easy to recognize, from 
their gross appearance, the forms of acute endocarditis which are caused 
by the Streptococcus haemolyticus, the Streptococcus viridans, the pneumo- 
coccus, the staphylococcus, and the gonococcus. This statement is per- 
haps exaggerated, since at best only the more typical examples can be 
surely recognized before cultures are made, and even then the forms of 
endocarditis produced by the Streptococcus haemolyticus, Streptococcus 
mucosus, the pneumococcus, and the staphylococcus are so much alike that 
it would be hazardous to venture a guess as to the organism concerned. 
On the other hand, while those organisms form a group, the lesions caused 
by the Streptococcus viridans, by the gonococcus, and by the unknown 
infective agent of rheumatism are so different from them and from one 
another as to be pretty easily recognized. It may be useful to express this 
impression in the form of a table, although the student must realize that 
there are other organisms, such as the Micrococcus zymogenes, influenza 
bacillus, the meningococcus, and many others which can produce endo- 
carditis with lesions which may be peculiar to themselves or only slightly 
different from the ordinary forms. 
Streptococcus H^emo- 
lyticus, Streptococ- 
cus mucosus, Staphy- 
lococcus AUREUS AND 
albus, Pneumococcus 
Streptococcus viridans 
Gonococcus 
Rheumatism 
Large, soft vegeta- 
Firmer yellow or 
Enormous vegeta- 
Small, warty vegeta- 
tions on mitral, 
grayish vegeta- 
tions with extreme 
tions on mitral, aor- 
aortic, and some- 
tions on mitral, 
ulceration, destruc- 
tic, and tricuspid 
times on tricuspid, 
often causing ul- 
ceration. 
extending far on 
auricular wall and 
chordae tendineae. 
Also on aortic 
valves. Little 
ulceration. 
tion of valves. 
valves, with slow 
thickening of valves. 
Sometimes purulent 
Recurrences with 
Vegetations on tri- 
Chronic adhesive peri- 
invasion of myo- 
thickening of the 
cuspid and pul- 
carditis. Peculiar 
cardium. 
valve. General 
septicaemia. 
monary valves,also 
on aortic at times. 
myocarditis. 
General septicaemia 
Infarcts and minute 
General septicaemia, 
Joint inflammation. 
with petechiae, em- 
bacterial emboli in 
peritonitis, joint in- 
Less definite signs of 
bolic lesions, and 
cloudy swelling of 
the viscera. 
kidneys, etc. 
f ections. Gono- 
coccal genital in- 
fection. 
active general sep- 
ticaemia. 
Rapid course. 
Slow course. 
Rapid course. 
Chronic course with 
exacerbations. 522 
TEXT-BOOK OF PATHOLOGY 
The Streptococcus hsemolyticus, whatever its mode of entrance, may 
gain access to the blood-stream and localize itself on the valves. The 
vegetations (Fig. 253) produced there may, of course, be small at first, 
but they tend to grow rapidly into irregular masses which commonly 
extend toward the base of the valve, and in the case of the aortic valves 
often appear on both sides of the cusp; that is, within the sinus of Valsalva, 
as well as on the ventricular surface. In such a case perforation of the 
valve is likely to occur. Two cases have been seen recently in our series 
in which such large holes have been produced as to allow of regurgitation 
through the valve cusps. The bacteria may extend into the musculature 
Fig. 253.-Endocarditis due to the Streptococcus hsemolyticus. Great friable vegetar 
tions on the mitral valves prone to ulceration. 
of the septum or other part of the heart-wall, and produce a deep, abscess- 
like excavation. There was one example in Baltimore in which in this way 
an abscess, formed in the septum in continuity with a large vegetation on 
the aortic valve, projected beneath the pulmonary orifice, and finally 
ruptured there, forming a communication between the two ventricles. 
In another case there were vegetations on the auricular surface of the 
tricuspid valves so large as to make the orifice extremely narrow. They 
bulged up as rough yellow masses into the auricle, and acted as an extreme 
obstruction to the flow of blood. Curiously enough, it sometimes happens 
that such great vegetations exist without marked circulatory disturbances 
or loud murmurs, but this is not always the case. They are associated STREPTOCOCCUS INFECTIONS 
523 
with the most typical evidences of the existence of a generalized strepto- 
coccal septicaemia and often with septic infarction (Fig. 254). 
The N on-haemolytic Streptococci.-We distinguish an organism which is 
indifferent to blood and produces no methaemoglobin, the r type of Brown, 
and the well-known methaemoglobin producing Streptococcus viridans, 
the ct type of Brown. The part played by the / type in the production 
of disease is not quite so definite as that of the Streptococcus viridans. 
Fig. 254.-Margin of septic infarction in the liver. The capillaries in the necrotic region 
are crowded with streptococci. 
They give rise to tonsillitis of a relatively mild form and sometimes to 
an acute or subacute arthritis. 
Endocarditis.-The Streptococcus mitior or viridans of Schottmuller 
produces a type of endocarditis, already mentioned in Chapter XIV, which 
is slower in its progress and subject to remissions or periods of partial heal- 
ing, but which, nevertheless, proceeds relentlessly to the death of the 
patient (Fig. 255). It has been called endocarditis lenta, or subacute 
bacterial endocarditis. The distinct character of this affection was pointed 
out by Schottmuller, Lenhartz, Harbitz, and others, and recently Libman, 524 
TEXT-BOOK OF PATHOLOGY 
in several papers, has added to the clearness of its outline. The disease 
begins insidiously with pains, fever, evidences of involvement of the heart 
valves, and progresses through several months or a year to death from 
cardiac decompensation, cerebral embolism, nephritis, or an intercurrent 
infection such as pneumonia. There may be tonsillitis, mild joint pains, 
and enlargement of the spleen. There is a progressive anaemia with leucocy- 
tosis, a brownish pigmentation of the face in some cases, petechial haemor- 
rhages, and tender, erythematous nodules in the skin, sometimes with 
purpuric patches. Bacteria are found circulating in the blood, although 
Fig. 255.-Endocarditis due to the Streptococcus viridans. Vegetations on auricle wall, 
mitral valve, and chordae tendineae. 
in the later stages they may be absent for a time, and such stages Libman 
considers to be characteristic and evidence of partial or temporary healing. 
The symptoms are continued, however, through such bacteria-free stages 
possibly by the casting off of small emboli. Renal changes are almost con- 
stant, and while in the kidneys examined during the early stages they are 
recognizable as hyaline occlusions of the capillaries of the glomeruli, they 
may bring with them later much more extensive destruction of renal tissue 
as the result of glomerular obliteration. These lesions were discovered 
by Lbhlein, and later described again by Baehr. STREPTOCOCCUS INFECTIONS 
525 
At autopsy it is found that there are old, scar-like thickenings of the 
affected heart valves and chordae tendineae, so that Libman assumes that 
the Streptococcus viridans produces its infective lesions on the basis cf old 
alterations which may have been rheumatic in character. It is also con- 
ceivable that it itself might have produced the healed lesions, so that 
the fresher vegetations are merely a new crop in the old site. These vege- 
tations are found especially on the mitral valve, extending down on the 
chordae tendineae and covering them, coating over the broken ends of those 
which are ulcerated and eaten through, as so often happens. They extend, 
too, far up on the wall of the left auricle, where they form a thick, rough 
mat. This distribution is so characteristic, especially taken together with 
the coarse, rough character of the vegetations, that the gross appearance 
alone is almost enough to give the diagnosis. There is usually no peri- 
carditis and no characteristic myocardial change. 
Infarcts are to be found, of course, in the swollen spleen or in the kid- 
neys, and sometimes in the brain, but the typical picture of the acute septic 
changes in all the organs is not so striking as in the endocarditis produced 
by the Streptococcus haemolyticus and other more virulent organisms. 
General Streptococcus Septicaemia.-Although the clinical and anatom- 
ical features of a general septicaemia or invasion of the streaming blood by 
bacteria have many special characters, depending on the type of organism, 
there is a great deal in common among them, and at autopsy one frequently 
recognizes the existence of a general septicaemia from the condition of the 
organs without being able to say whether it is due to a streptococcus, 
pneumococcus, staphylococcus, or some other organism. Of course, a 
staphylococcus septicaemia is likely to be marked by the presence of numer- 
ous abscesses, typhoid septicaemia by lesions peculiar to it; septicaemia due 
to Friedlander's bacillus by peculiarities of the exudate, and so on, but 
there are still features common to septicaemia in general. 
While at times it is possible to find streptococci or other organisms cir- 
culating in the blood, this seldom continues for any great length of time 
unless there is a constant source of supply, such as a large vegetation loaded 
with growing bacteria, hanging upon a valve of the heart, and shedding the 
bacteria continuously into the blood-stream. For this reason we have be- 
come skeptical of the existence of a septicaemia as such, and think of the 
presence of bacteria in the circulating blood as the temporary result of 
their discharge from a focus of infection which is in close or direct communi- 
cation with the blood-stream. That the bacteria grow and multiply in 
the blood, so as to constitute a true bacteriaemia, seems in most instances 
extremely unlikely, and occurs, if at all, shortly before death in the fatal 
cases in which we may suppose the antibacterial powers of the blood at a 
low ebb. After death the blood becomes filled with them, so that cultures 
from the heart's blood at autopsy, unless immediately after death, are of 
very little interest. These statements seem to be supported by the experi- 526 
TEXT-BOOK OF PATHOLOGY 
merits of Hopkins and Parker who observed the fate of streptococci in- 
jected into the blood-stream in cats which are insusceptible and rabbits 
which are susceptible to infection. In both, the bacteria disappeared from 
the blood very quickly, but in the rabbits, after foci of infection were estab- 
lished in the tissues, the organisms were once more shed into the blood. 
Nevertheless the instances in which there are foci of infection quite ade- 
quate to allow a more or less continuous escape of bacteria into the blood 
are so numerous that we are justified in describing the symptoms and ana- 
tomical effects of a general septicaemia. 
The symptoms begin with a chill and high fever, which continues in 
various forms, sometimes continuously high, but more often with remissions 
and daily exacerbations with chills. The blood is quickly and profoundly 
altered. There is a great increase in the number of leucocytes, although 
in the severe cases, in which resistance fails, the lack of any increase 
or an absolute decrease in their numbers may be an index of an unfavorable 
outlook for the patient. The destruction of blood-corpuscles proceeds 
rapidly, and extreme pallor may quickly ensue. In the skin and in the 
retinae the clinician is made aware of the presence of bacteria by the appear- 
ance of minute points of yellow opacity, surrounded by little flecks of haemor- 
rhage. These are due to the plugging of tiny blood-vessels with emboli 
of bacteria, or, when there is endocarditis, with fragments of the vegeta- 
tions loaded with bacteria. In the skin the thickness of the tissues makes 
them appear as homogeneous petechial haemorrhages, but in the con- 
junctiva or retina, or in the serous surfaces at autopsy, it is usually possible 
to distinguish a central necrotic fleck. In the skin such emboli may pro- 
duce no haemorrhage, but instead tender, nodular swellings, which on section 
reveal a focus of inflammatory infiltration around the obstructed vessel. 
Extensive purpuric haemorrhages may spread throughout the skin, some- 
times becoming confluent over considerable areas. In other cases ery- 
thematous rashes appear, resembling those of scarlatina or of measles. 
In the case of streptococcus septicaemia there are found relatively few 
focal internal lesions produced by the lodgment of the bacteria. The most 
common are those in the lungs, which may take the form of broncho- 
pneumonic patches or abscess-like infiltrations, and those in the joints, 
where at times there is found an intense inflammatory reaction with a 
purulent exudate in the synovial cavity. 
In many cases these focal affections are absent. Endocarditis is, of 
course, focal in this regard, and, as stated, the dislodgment of fragments 
of the vegetations mechanically produces lesions elsewhere. But the more 
direct effects of the diffusion of bacteria in the blood are seen in the cloudy 
swelling of the liver and kidney, and such other organs as are composed 
of tissue capable of showing a cloudiness from changes in the water or 
granule contents of the cells. The nature of this is discussed elsewhere 
(Chapter VII). The heart muscle partakes of this dull, opaque appear- 
ance, which is intensified there, as in the liver and kidney, by the appear- STREPTOCOCCUS INFECTIONS 
527 
ance m the cells of many minute globules of fat. The acute and subacute 
nephritis which has been described elsewhere requires time to develop, 
and is rather an accompaniment of those streptococcal infections which 
have already lasted for some time. The bone-marrow, actively exercised 
in the production of leucocytes, is often found to have assumed the opaque 
cellular appearance which is also found in anaemias, where active regen- 
eration of the blood is required. In septicaemia death may occur before 
this stage of activity is reached, but if 
the patient survives long enough, ex- 
amination of the marrow will reveal a 
great increase in the number of myelo- 
cytes which form the polymorphonu- 
clear leucocytes, and also of those cells 
which go to form red corpuscles. 
The spleen is enlarged and soft, with 
peculiar alterations of its substance 
which are discussed under the non- 
committal phrase acute splenic tumor. 
Acute Splenic Tumor.-In practically all 
acute infectious diseases, but especially in 
such intense forms as the septicaemias under 
discussion, the spleen becomes tumefied, so 
that it is readily palpable beneath the margin 
of the ribs. Its size varies greatly, but its 
weight may reach 600 to 700 grams or more. 
The capsule is tense, but the organ is soft, so 
that when it is cut through the cut surface 
swells forward, everting the edges of the cap- 
sule (Fig. 256). One may scrape oft with the 
knife or even with the finger a quantity of 
smeary, paint-like pulp. Indeed, the spleen 
is so soft sometimes that it spreads out on the 
pan or even flows as a semifluid material. 
The trabeculae are sunken below the swollen 
surface, or else, if the cut surface has been 
scraped, they alone may be left as shaggy 
threads after the pulp has been wiped away to a considerable depth. In such extreme 
examples of softness it is difficult even to see the Malpighian bodies. In other cases 
they are much enlarged and conspicuous, sometimes with an opaque, yellowish, central 
fleck in each. Ordinarily the splenic pulp in such swollen spleens has a velvety or pasty 
appearance, and is very opaque and of a dull, pinkish-gray color. In these latter par- 
ticulars the acute splenic tumor of septic conditions is very different from that of typhoid 
fever, which is deep red in color, and almost jelly-like in consistence, owing to the great 
quantities of red corpuscles held in its pulp. In order to give any idea of the nature of 
the change in the spleen it is necessary, first, to refer briefly to the main points in its 
structure, as worked out by Weidenreich, Mollier, and others. The Malpighian bodies, 
rather sharply marked out from the actual splenic pulp, are collections of lymphoid 
cells in a reticulum formed from the adventitia of the arterioles, so that they are peri- 
arterial lymphoid nodules. After leaving the Malpighian body the branches of the 
Fig. 256.-Acute splenic tumor from a 
case of endocarditis. 528 
TEXT-BOOK OF PATHOLOGY 
arteriole empty each into one of the peculiar wide venules, which, entangled together, 
make up the bulk of the splenic pulp. These venules have walls which are formed of 
peculiar, elongated endothelial cells, whose central nucleus is relatively large, causing 
a bulging at the middle point of the long tapered cell, which projects somewhat into the 
lumen. Cross-sections of the venules sometimes pass through many of the nuclei; 
sometimes, on the contrary, they show chiefly sections of the protoplasm of the cell. 
Outside these each venule is surrounded by a basketwork of elastic reticulum fibrils, 
which are connected with the general reticulum of the pulp. Whether there is also an 
Fig. 257.-Acute splenic tumor: septicaemia associated with acute endocarditis and 
acute diffuse nephritis. 
intervening structureless membrane, upon which the endothelial cell lies, is not per- 
fectly clear. Weidenreich states that there is such a membrane perforated here and 
there. In the spaces between these venules there lie the cells of the splenic pulp, 
which are of various sorts, and it is in connection with them that our information seems 
least precise. Many red corpuscles are normally found there, and many mononuclear 
cells of various forms. Polymorphonuclear leucocytes occur, but are less abundant. 
It is difficult to say whether any of these mononuclear cells are peculiar to the spleen, 
or whether they contribute largely, or at all, to the circulating blood. Morris found 
them swept out in numbers in the blood of the splenic vein, while others have found STREPTOCOCCUS INFECTIONS 
529 
the reverse, i. e., the mononuclear cells which entered the spleen with the arterial blood 
retained there, while polymorphonuclear leucocytes pass through. There seems no 
doubt that when the conditions demand it myelocytes can be formed in the splenic 
pulp, giving it some of the characteristics of the bone-marrow. Further, it is clear that 
the cells of the pulp are active as phagocytes, and are often found laden with pigment. 
This is true of the endothelial cells of the venules, just as it is of Kupffer's cells of the 
hepatic capillaries. As in the lymph-glands, it appears that there are large, pale 
reticulum cells in the splenic pulp which can act as phagocytes. 
In acute splenic tumor in infectious diseases it seems that there may be a variety of 
changes. In some infections the Malpighian bodies seem little changed, and in the fresh 
spleen sink into insignificance, in contrast with the great swelling of the splenic pulp, 
which, on the cut surface, bulges or flows over them, so as almost to hide them from view. 
In other cases the prominent alteration is in these bodies. 
In the acute splenic tumor accompanying streptococcus and staphylococcus septi- 
caemia, pneumonia, etc., there is little blood in the spaces between the venules in the 
splenic pulp (Fig. 257). Indeed, the venules themselves seem compressed and partly 
emptied by the enormous increase in the number of nucleated cells between them, and 
it is this great accumulation of loose cells which gives the pastiness and grayish opacity 
to such spleens. In our ignorance of the exact nature of the process one gains the 
impression that this great hyperplasia is analogous to that seen under similar conditions 
in the bone-marrow, where hyperplasia of cells is associated in our minds with the furnish- 
ing of necessary elements to the blood. Jawein, however, regarded the swelling of the 
spleen as a process associated with the destruction of red corpuscles, and found that it 
occurred only in those intoxications and infections in which there was much blood 
destruction. The advent of so many cells would, for him, represent a phagocytic 
function. 
While in the typhoid spleen this phagocytosis of red cells and other debris is a very 
obvious feature, and most extensively carried on, it is by no means conspicuous in the 
spleens of septic infections, and, indeed, one sees relatively little phagocytosis at all in 
this pulp. Bernhardt, who studied especially the spleens of cases of scarlet fever and 
typhoid fever, draws this same contrast in another connection. He finds that in scarlet 
fever huge numbers of blood-platelets accumulate and are engulfed by phagocytic cells. 
Probably this occurs also in other infections, but in order to prove that these platelets 
are not merely the debris of red corpuscles, he shows that in typhoid fever, where there 
is such active phagocytosis of red corpuscles, platelets are relatively few in number in the 
spleen. This is another theory of phagocytosis to explain the swelling of the spleen, 
but hardly more completely satisfactory than that of Jawein. Occasionally one sees 
great numbers of polymorphonuclear leucocytes in the meshes of the splenic pulp, but 
this is not constant. 
In diphtheria Washkewitz points out that the especial enlargement of the Mal- 
pighian bodies is due to the appearance of a central mass of large, pale phagocytic cells, 
which she thinks are probably derived from the lymphoid cells and not from the retic- 
ulum, as Ziegler had thought. These conspicuous pale central masses of large cells in 
the Malpighian bodies are by no means confined to diphtheria, but occur in many 
types of infections, especially in children and young people. We have reviewed the last 
500 autopsies in this regard, and have found many cases in which they occur. They are 
all in cases of infection of one sort or another, with bronchopneumonia, tuberculosis, 
diphtheria, peritonitis, and many toxic processes, among which skin burns are notable. 
But they are not particularly a feature of the acute splenic tumor, in which the splenic 
pulp is especially swollen. The large cells have pale, vesicular nuclei, abundant pale- 
staining protoplasm, and are frequently loaded with fragments of other cells which they 
have engulfed. They themselves often show degenerative changes; their nuclei become 
fragmented, and in time the mass may come to look like a focal necrosis with clumps of 
broken nuclei. TEXT-BOOK OF PATHOLOGY 
530 
It must be said that further work is required to make clear the complex nature of 
acute splenic tumor, which in some cases seems to be a response to the presence of the 
debris of red corpuscles or other cells, in others to the diffusion of a toxin or bacteria. 
The part of the spleen in reconstructing the blood seems to be little understood in spite 
of numerous studies which have been made recently, but more will be said on this point 
in connection with the diseases of the blood. 
F. A. Evans has carried out in our laboratory since this was written a study of the 
forms of acute splenic tumor in human beings and those produced experimentally in 
animals, employing vital stains and the oxydase reaction in the attempt to distinguish 
the various cells found there. He confirms the sharp distinction made between the 
red type found in typhoid fever and the gray one in the infections with all the pyogenic 
bacteria. The red type is distinguished by hyperplasia and phagocytic activity of the 
reticulo-endothelial macrophages and decrease in the number of the other cells of the 
pulp. The gray type, on the contrary, shows a great increase in the pulp cells, es- 
pecially the oxydase-containing myeloid elements, with no change in the reticular and 
endothelial cells. These changes result largely from a functional demand for leucocytes. 
LITERATURE 
Capps and Davis: Trans. Assoc. Amer. Phys., 1914, xxix, 279. 
Smith and Brown: Jour. Med. Research, 1915, xxxi, 455. 
Holman: Ibid., 1916, xxxiv, 377. 
Kinsella, Kinsella and Swift: Jour. Exper. Med., 1918, xxviii, 169, 181. Arch. Int. 
Med., 1917, xix, 367. 
Smillie: Jour. Infectious Dis., 1917, xx, 45. 
Gay: Jour. Laboratory and Clin. Med., 1918, iii, No. 12. (Extremely good review of 
recent literature.) 
Avery and Cullen: Jour. Exp. Med., 1919, xxix, 215. 
Hopkins and Parker: Ibid., 1918, xxvii, 1. 
Brown: Monograph Rockefeller Institute, No. 9, 1919. Jour. Exp. Med., 1920, xxxi, 
35, 49. 
Dochez, Avery, Lancefield: Jour. Exp. Med., 1919, xxx, 179. 
Evans: Johns Hopkins Hosp. Bull., 1916, xxvii, 356. 
Gay and Rhodis: Erysipelas, Jour. Infec. Dis., 1922, xxxi, No. 2. 
MacCallum: Monograph, Rockefeller Institute, No. 10, 1919. 
Libman: "Otitis," Amer. Jour. Med. Sci., 1909, cxxxviii, 409. 
MacCallum: "Phlegmonous Enteritis," Johns Hopkins Hosp. Bull., 1906, xvii, 252. 
Erdmann: Jour. Amer. Med. Assoc., 1913, Ixi, 2048. 
Jochmann: Mohr u. Staehelin, Handb. d. inneren Medizin, Berlin, 1911, i, 578, 717. 
Joseph Koch: Ergeb. d. allg. Path., 1909, xiiii, 135. 
Fehleisen: Aetiologie des Erysipels, Berlin, 1883. 
Lenhartz: "Septische Infektionen," Nothnagel, Spec. Path. u. Therap., 1899. 
Holmes: Annals of Otology, Rhinology, and Laryngology, xvi, 457, 1907. 
Libman: Trans. Assoc. Amer. Phys., 1912, xxvii, 157; 1913, xxviii, 309. 
Schottmuller: Miinch. med. Woch., 1903, 1, 849. 
Lohlein: Med. Klinik, 1910, vi, 375. 
Baer: Jour. Exp. Med., 1912, xv, 330. 
Jawein: Virch. Arch., 1900, clxi, 461. 
Washkewitz: Virch. Arch., 1900, clix, 137. 
Bernhardt: Ziegler's Beitrage, 1913, Iv, 35. 
Weidenreich: Arch. f. mikr. Anat., 1901, Iviii, 247. 
Mollier: Arch. f. mikr. Anat., 1911, Ixxvi, 608. CHAPTER XXVI 
TYPES OF INJURY.-BACTERIAL DISEASE (Continued).-STAPHY- 
LOCOCCUS INFECTIONS 
General character. Furunculosis. Paronychia, impetigo, etc. General septicaemia, 
pyaemia, suppurative nephritis, endocarditis, lobular pneumonia, osteomyelitis. 
The Staphylococcus pyogenes aureus, Staphylococcus albus, and other 
less important forms, including the Staphylococcus citreus, are concerned 
in these infections. Much of their peculiar effect is dependent upon their 
tendency to grow in clumps and to cling together, rather than to spread 
diffusely. Hence in the tissues there is a focal character in the lesions 
they produce, in contrast with the more spreading lesions of the strepto- 
coccus. For the same reason the entrance of the staphylococcus into the 
circulating blood results in its deposition at numerous points, where it 
grows into compact colonies which produce focal lesions. Unlike the 
streptococcus, which grows most commonly on mucous membranes, such 
as that of the pharynx, and enters the body thence, the staphylococci are 
dwellers on the skin, and infection is usually from abrasions or cracks in the 
skin, although, as shall be stated, infection from the genito-urinary tract 
is not uncommon. 
Owing to the attributes just mentioned the formation of abscesses is the 
usual effect of the invasion of this organism, a process already described 
in Chapter XIV. No matter how extensive the lesions, they have the 
same general character of concentration which makes possible the lique- 
faction of the tissue and exudate. 
Furunculosis.-Cultures from the skin of healthy persons show (J. 
Koch) a great number of staphylococci, partly saprophytic, partly truly 
pathogenic. The haemolytic power of these cocci seems to be almost a 
measure of their pathogenic character. Even in the depths of the skin, 
probably in the sebaceous glands and the clefts about the roots of the 
hairs, there are constantly present staphylococci which grow white on 
culture-media (Staphylococcus epidermidis albus, Welch), and it is thought 
that these are responsible for stitch abscesses when sutures are made 
through the skin. To avoid them, subcutaneous sutures have been 
employed by surgeons with great success. With such a flora present, it is 
very easy to understand that abrasions, or even a constant rubbing which 
does not erode the skin, as in the case of a collar or cuff, might give an 
opportunity for the beginning of furunculosis which is so familiar. It 
depends evidently upon a predisposing lowering of resistance, which, 
according to Wright, may be recognized in the decreased activity of 
531 532 
TEXT-BOOK OF PATHOLOGY 
phagocytic leucocytes (lowered opsonic power of the plasma). At any rate, 
once begun, furuncles or boils are likely to continue to appear, sometimes 
in hundreds. Athletes in training, who are roughly rubbed down, are a 
prey to them, and, on the other hand, persons long ill with such wasting 
diseases as typhoid fever, are likely to have a crop of boils. The active 
immunization by the injection of repeated doses of killed cocci usually has 
an extraordinary effect in raising the resistance and completely stopping 
their appearance. They begin usually about a hair, and the abscess 
develops until the hair can be seen standing up in the middle of a small, 
opaque yellow fleck. From that the infection burrows deeper and spreads 
laterally a little under the corium, which in the thicker parts of the skin 
prevents for some time the complete evacuation of the pus to the outside. 
In time, however, through the bursting of the central necrotic cap of skin, 
it escapes and the hole thus left heals up by the formation of granulation 
tissue. The surgeon can hasten this process by stretching or bursting 
open the hole with as little injury as possible to the adjacent tissue. If he 
squeezes or cuts that adjacent tissue so as to impair its blood supply, 
extension of the infection is almost inevitable. 
When the resistance is very low, the cocci may quickly extend to form 
a whole group of connected abscesses, with several projecting necrotic 
points side by side in the skin. The whole swollen mass is honeycombed 
with channels full of pus in the necrotic tissue, and the further expansion 
proceeds rapidly. Such a threatening affection is known as a carbuncle, 
and requires prompt surgical intervention. They occur anywhere, but 
most commonly on the back of the neck or on the lip or buttocks. Those 
on the upper lip are particularly to be feared, since extension along the 
lymphatics or thrombophlebitis extending upward through the nose to the 
cavernous sinus may lead to meningitis. 
Infection of the finger extending about the nail (paronychia, panaritium) 
or of the palmar surface are guided in their extension by the fasciae of the 
finger and hand. Involvement of the tendon-sheaths is a particularly 
destructive complication. 
Impetigo contagiosa, a skin disease of children, appears to be caused by 
the staphylococcus, although, as shown recently by Burky and Smith, 
many cases give cultures of a streptococcus. It produces pustules about 
the face, especially around the nose and mouth, which burst and dry up 
into a honey-yellow crust without much surrounding reaction. It may 
spread over the entire body, especially where the child can scratch the 
skin, and is contagious for other children, although not all are susceptible. 
General Septicaemia.-While the Staphylococcus aureus is perhaps the 
most common cause of the forms of furunculosis just described, the 
Staphylococcus albus takes part, and in infections which become general, 
it, too, is quite often found. General distribution of staphylococci through 
the blood-stream occurs readily, even from small infected scratches or cuts, 
or from some other local infection, all of which may heal up and disappear 
before the general infection is well under way. The wide-spread character STAPHYLOCOCCUS INFECTIONS 
533 
of such general infections may be most clearly brought out by describing 
cases which have recently come to my attention at autopsy. 
A man fell in a Pullman car against some projection which caused an 
abrasion between his shoulders; death occurred two weeks later, and at 
the autopsy, although the abrasions were partly healed, huge abscesses 
were found among the muscles of the back; the right knee was distended 
with a purulent fluid, and an abscess, filled with thick greenish pus, bur- 
rowed among the muscles of the thigh. 
Fig. 258.-Multiple abscesses in the heart- 
wall from a case of general staphylococcus 
septicaemia. 
Fig. 259.-Staphylococcus septicae- 
mia. Minute abscesses in the pericar- 
dium surrounded by haemorrhagic 
flecks. 
A plumber, who had cut his finger with a piece of tin some weeks before 
his death, making a trifling wound which had healed completely, was 
brought to the hospital in a condition of delirium without definite localizing 
symptoms. At the autopsy there was found a general infection with the 
Staphylococcus aureus, which was cultivated from the blood. There were 
small abscesses in nearly all the organs, everywhere presenting themselves 
as opaque yellowish spots surrounded by a zone of haemorrhage. The 
heart muscle was studded everywhere with them (Fig. 258), while upon TEXT-BOOK OF PATHOLOGY 
534 
the aortic valves there were soft vegetations. The pericardium showed 
numerous haemorrhagic flecks (Fig. 259), with central opacities, as did the 
pleural and peritoneal surfaces. Throughout the intestinal mucosa there 
were haemorrhagic nodules, and similar foci appeared in the kidneys and 
liver. In the lungs the abscesses were larger, with central softening, and a 
zone of haemorrhagic pneumonic consolidation about each. 
Sometimes it is difficult to determine upon the portal of entry of the cocci, 
as in the case of a sailor brought off a ship to the hospital. He, too, was 
in a state of coma, extremely anaemic, with signs of patchy bronchopneu- 
monic consolidation, and with abundant staphylococci in a culture from 
the circulating blood. At autopsy practically the same wide-spread focal 
lesions were found as described in the preceding case, the heart muscle 
Fig. 260.-Staphylococcus septicaemia. Multiple abscesses oi the kidney, 
and kidneys being especially thickly set with small abscesses (Fig. 260). 
No source of infection could be found after the most minute search, until 
a decayed canine tooth was pulled from the upper jaw, when a gush of pus 
came from the antrum, which evidently represented the portal of entry. 
It should be noted that in such infections, especially when they are not 
quite so severe and rapidly fatal, localization of the bacteria in the joints 
with the production of a purulent synovitis is not uncommon. 
Suppurative Nephritis.-Aside from their appearance as part of a general 
pyaemia, staphylococcus infections of the cortex and medulla of the kidney, 
transported there by the blood-stream, come to the attention of the surgeon 
more commonly than is generally thought. Jordan, Brewer, and others 
have described them as multiple foci, involving necrosis of the renal tissue 
in the cortex, and extending into the pyramids. They are probably formed STAPHYLOCOCCUS INFECTIONS 
535 
in the effort of the kidney to exciete the staphylococcus brought by the 
blood-stream, and may develop about the bacteria, which accumulate with 
casts in the tubules (staphylococci are known to be abundantly excreted in 
the urine in general infection). Brewer looks upon them as rather of 
embolic origin, and therefore starting from the neighborhood of the plugged 
arteriole or glomerulus. They may produce multiple extensive haemor- 
rhagic patches of necrosis in the substance of the kidney (Fig. 261). Simi- 
larly, as the only internal lesion produced by transportation of cocci from 
Fig. 261.-Haemorrhagic septic infarctions of the kidney produced by the Staphylo- 
coccus aureus (Brewer). 
some cutaneous infection, there may be formed a perirenal abscess which 
can later encroach upon the kidney. 
There is always the question as to whether such haematogenous infec- 
tions of the kidney are to be regarded as the basis for the forms of sup- 
purative pyelonephritis associated with infections of the urinary bladder. 
As in the case of tuberculosis of these organs, there are those who regard 
the process as the result of ascending infection from the bladder, while 
others assume it to be haematogenous or indirect. It seems that both 536 
TEXT-BOOK OF PATHOLOGY 
types may occur, although when abscesses appear in the kidneys as the di- 
rect continuation of an illness which begins with obstruction to the out- 
flow of urine from the bladder, infection by catheterization, cystitis, and 
ureteritis, it is almost impossible to resign oneself to the idea that in those 
cases the bacteria enter the kidney by the blood-stream. All this can be 
more appropriately discussed in another place, since the staphylococcus 
Fig. 262.-Abscesses in the lung. These abscesses were close set, and caused relatively 
little reaction. Usually they are isolated, haemorrhagic, and much larger. 
is not often primarily concerned in such cases. On the other hand, the 
chills which follow catheterization are really in most cases the expression 
of a general staphylococcus septicaemia of mild character initiated by the 
trauma in the operation. 
Endocarditis is a very common accompaniment of staphylococcus infec- 
tion, the mitral and aortic valves being especially affected, while the vege- 
tations are occasionally found upon the tricuspid or upon the walls of the STAPHYLOCOCCUS INFECTIONS 
537 
heart. They are usually rather large, soft thrombus masses, which readily 
crumble and give rise to emboli. 
Lobular Pneumonia.-As in the case of streptococcal infections of the 
lung, there is nothing especially characteristic about many of the cases in 
which the staphylococcus forms the infectious cause of bronchopneumonia, 
except in those instances in which the concentration is such as to produce 
definite abscesses (Fig. 262). The mode of entrance into the lung tissue is 
probably in part responsible for this. Chickering and Park describe an 
epidemic of pneumonia following influenza in the course of the great 
epidemic, caused by the Staphylococcus aureus, and characterized by 
the presence of many minute abscesses throughout the lungs. 
LITERATURE 
Chickering and Park: Jour. Amer. Med. Assoc., 1919, Ixxii, 617. 
Osteomyelitis.-It is in producing a destructive lesion in the bones, 
involving periosteum, cortex, marrow, and even extending to the cartilages, 
that the staphylococcus plays one of its most characteristic roles, although 
here, too, other organisms, such as the pneumococcus, the typhoid bacillus, 
and others may take its place and cause similar lesions. In the great 
majority of the cases, however, the staphylococcus is found. Here it 
shows particularly well its tendency to localize itself and grow in a place 
already injured mechanically. If several ribs or other bones are fractured 
in a rabbit, it is said that a subsequent injection of a culture of the Staphy- 
lococcus aureus will produce an abscess at the site of each fracture. These 
may be considered as points of lowered resistance, or perhaps the inter- 
ruption of blood-vessels allows the bacteria to be caught there instead of 
being swept on by the blood-stream. In the same way in human beings 
a blow upon a bone appears to predispose it to the settling there of bac- 
teria. 
The organisms reach the bone either from a recognized focus of infection, 
or from some small infected abrasion or wound which heals and is for- 
gotten before the disease of the bone is evident. It is the latter case which 
has given rise, no doubt, to the idea that there may be a primary osteomye- 
litis, a situation which is realized in cases of infected compound fractures. 
The long bones are affected far more often than the others; nevertheless 
osteomyelitis involving the tarsal aiid carpal bones, the vertebrae, the 
clavicles, and the bones of the pelvis is not rare. The disease occurs most 
frequently in children and young persons, the cases being most numerous 
in those between the ages of thirteen and seventeen, after which they fall 
off rapidly. 
The cocci usually lodge in the shaft of one of the long bones in such a position as the 
upper third of the tibia or the lower third of the femur, and there produce an abscess in 
the cancellous substance of the bone which involves the cortex and the periosteum, 
lifting up the latter from the surface of the bone. As in other abscesses, the presence of 538 
TEXT-BOOK OF PATHOLOGY 
the bacteria leads to necrosis of the tissue round about, and from the fact that this 
necrosis extends far wide of the clump of cocci, it may be agreed that they produce a 
Fig. 263.-Large 
necrotic fragment of 
bone or sequestrum 
from the tibia in 
osteomyelitis. 
Fig. 264.-Osteomyelitis show- 
ing the sequestrum, the involucrum 
with orifices which represent the 
sinuses, and periosteal osteophytes. 
Fig. 265.-Chronic perios- 
titis with osteophytes. 
toxic substance. (This, in fact, is well proved for the staphylococci.) The leucocytes 
which accumulate liquefy the necrotic tissue and attack the bony lamellae, which they STAPHYLOCOCCUS INFECTIONS 
539 
reduce to fragments. Frequently large portions of the cortex thus become necrotic 
and rarefied, and finally isolated from the still living bone as a sequestrum (Fig. 263) 
which practically floats in a pus-filled cavity. Generally it is not so completely loosened 
for some time, but in its extent it may amount to nearly the whole shaft of the bone. 
I recall vividly one such case from my assistant time in the surgical wards, upon which 
I was allowed to operate. It was a boy of about twelve, whose left leg, as he was 
brought into the hospital, was greatly swollen below the knee, tense, and oedematous. 
He was suffering a great deal of pain and had a high temperature, but there was found 
no obvious point of infection elsewhere, from which the disease of his leg might have 
started. A long incision was made, and quantities of rather gritty brown pus flowed out. 
The periosteum had been lifted up from nearly the whole length of the tibia, and evi- 
dently had been torn to let the pus escape into the intermuscular tissues. The bone 
itself was already rough, and some portions of it were easily pulled away. These were 
ragged, as if worm-eaten. Much of the rest was chiseled or gouged away, leaving, as 
I remember it, the posterior half of the bone exposed in the wound which remained open. 
Healing occurred in a remarkable fashion by the growth of the most luxuriant granula- 
tion tissue, from the crevices in which tiny fragments of bony lamellse were discharged 
for some time. Even when the skin covered most of the granulating surface, a fistula 
extending to the bone at one point remained for a time and discharged bony granules, 
but this in time healed up. This boy remained well, but it is frequently the case that 
before one focus is completely cleaned out and healed, another appears in some far-dis- 
tant bone. Occasionally they follow one another in rapid succession, destroying or 
mutilating one bone after another, and ending often in the development of a general 
septicaemia with hundreds of small abscesses in the internal organs. 
When not treated by radical surgery, the most remarkable results may ensue, especi- 
ally when the infective agent is not so virulent as to lead rapidly to very extensive 
destruction or to general septicaemia. While in the acute forms the necrotic bone is 
rapidly rarefied and partly disintegrated, it may happen that in the more slowly pro- 
gressing forms there is time for prolonged activity on the part of the osteoblasts which 
cover the bony lamellae in the neighborhood of the focus of infection, before that sur- 
rounding bone tissue is involved in the necrosis. Then each lamella becomes greatly 
thickened, and the bone becomes compact as ivory (ebumation or sclerosis). It is for 
this reason that the necrotic sequestrum is sometimes found to be extremely dense and 
hard. In such subacute cases, which are more localized, the extension of the infection 
and inflammatory exudate to the periosteum lifts up and ruptures only a small part of 
it. The pus then burrows in a channel among the muscles to the skin, where it causes 
a bluish-red bulging, which finally ruptures like an abscess. In this way a sinus is 
formed through which a probe can be passed down until it scrapes upon the rough dead 
bone. Through this sinus fragments of bone may be discharged with the pus for a 
long time. If any considerable mass of the cortex has been thus converted into a loose 
sequestrum, extensive healing processes go on about it, even though it maintains a con- 
stant source of infection. It is true that the bacteria may die out, but even then the 
mass of dead bone acts as a foreign body of which the tissues cannot get rid. Instead, 
abundant new bone with much granulation tissue is formed about it, usually still per- 
forated by the sinus or sinuses which extend to the skin. In time there may be pro- 
duced in this way (Fig. 264) a sheath of new bone which practically represents the old 
shaft (the involucrum) inside which the sequestrum persists. A great part of this is 
formed by the periosteum, but those portions of the shaft which remain alive produce 
much new tissue by the aid of their endosteal cells. It is easy to understand that if that 
portion of the cortex of the shaft which is destined to become necrotic and sequestrated 
can, in the mean while, undergo sclerosis or ebumation by the new formation of layers 
of bone in all its Haversian systems and on the surfaces of all its lamellse, the rest of the 
bone will do the same. It is for this reason that whatever remains of such a shaft is 
found to be heavy and dense. Indeed, if the infectious process proceeds very slowly 540 
TEXT-BOOK OF PATHOLOGY 
and without gross destruction of the cortex, the whole bone may preserve its form, but 
become almost solid and very dense and heavy. Quite aside from the actual area of 
necrosis or in its absence, the inflammation which involves the periosteum results 
in its producing a great deal of new bone superficially applied to the shaft, so that the 
surface of a bone in old osteomyelitis is usually greatly roughened by such osteophytes 
(Fig. 265). As we shall see, a quite similar process of periosteal bone formation is fre- 
quent in other slowly progressing inflammatory affections, and is especially striking in 
syphilis. 
When osteomyelitis caused by the staphylococcus involves the bones 
of the skull, or in the cases in which otitis media is due to its agency (it is 
very frequently active here, and the cause of nearly all the chronic forms), 
when metastatic abscesses occur in the brain, or when extension of the 
infection takes place from furunculosis of the nose or lip, acute meningitis 
may arise, involving the coverings of the brain and extending to the 
pia-arachnoid of the spinal cord. Its nature is similar to that caused by 
the streptococcus, pneumococcus, and other organisms, and it will more 
conveniently be described elsewhere. One form of meningitis is of inter- 
est, however, in this connection, namely, the purulent pachymeningitis 
or inflammation of the dura. That this should occur with osteomyelitis 
of the bones of the skull is self-evident, but one occasionally sees cases of 
another type in which, from an abscess in the perirectal tissue, extension 
of the infection occurs along the nerves, to enter the sacral foramina or 
even the lumbar foramina to the space outside the dura and within the 
spinal canal. The outer surface of the dura then becomes bathed in pus. 
Neisser and Lipstein: Handb. v. Kolle u. Wassermann, 1903, iii, 105. 
Jos. Koch: Ergebn. d. allg. Path., 1909, xiii, 205. 
Lenhartz: Nothnagel's Handb. d. spez. Path. u. Therap., 1903, iii, Teil 2, 329. 
Lexer: "Osteomyelitis," Volkmann's klin. Vortrage, 173. 
LITERATURE CHAPTER XXVII 
TYPES OF INJURY. BACTERIAL DISEASE (Continued).-PNEU- 
MOCOCCUS INFECTION 
Character of organisms. Lobar pneumonia: consolidation, resolution, organization, etc. 
Septicaemia. Endocarditis. 
Character of Organisms.-The pneumococcus or Micrococcus lanceolatus 
is best known on account of its preeminent relation to the clear-cut disease, 
lobar pneumonia. It is true that it is concerned in many other infectious 
processes, including otitis media, meningitis, various inflammations of the 
nasal sinuses, pleurisy, pericarditis, general peritonitis, and even general 
septicaemia, as well as the more indefinite forms of lobular or patchy pneu- 
monia. On the other hand, a few other organisms, such as Friedlander's 
capsulated bacillus, have been detected at times as the cause of unmistak- 
able acute lobar pneumonia. 
The pneumococcus is very widely distributed, and occurs in the mouths and upper 
respiratory tracts of most normal persons. It varies greatly in virulence, as has been 
shown by animal inoculations, and those cultivated from pneumonic lungs are not neces- 
sarily more virulent than those from the mouths of healthy persons. It produces a 
toxic substance which is feebly hsemolytic, but which must be extracted from the dis- 
solved bodies of the organism. It has the power of converting haemoglobin into met- 
haemoglobin, and can be neutralized by cholesterine. Studies of Neufeld, and especially 
of Cole and his assistants, have revealed the fact that there are several kinds of pneu- 
mococci which can be distinguished sharply from one another by their biological charac- 
ters, although morphologically and culturally they are alike. By the aid of sera pro- 
duced by inoculating living pneumococci of different strains into large animals Cole, 
Dochez, and Gillespie have been able to distinguish sharply at least four types, which 
have been found to occur in 150 cases of pneumonia in the following proportions: 
Type 1 57 
Type II 44 
Type III (Pneumococcus mucosus) 17 
Type IV (heterogeneous) 32 
A potent serum was obtained for Type I, a less satisfactory one for Type II. Attempts 
to produce a protective serum against Type III failed completely, but this organism, 
which is the Streptococcus mucosus of Schottmiiller, is readily distinguished by its very 
large capsule, its stringy growth in culture, and by the glutinous exudate in the lungs in 
pneumonia caused by it. It produces the severest infections. Type IV is made up of 
a great many different strains, none of which ordinarily produces a very severe pneu- 
monia. They are the forms found in the mouths of healthy persons; they are overgrown 
by Types I, II, or III in pneumonias caused by those types, but reappear in the mouth 
on convalescence after the infecting type has disappeared. Protective sera can be pro- 
duced for each member of Type IV, but they are quite specific, and powerless against any 
541 542 
TEXT-BOOK OF PATHOLOGY 
other member of the group. So, too, the sera for Types I and II have no protective effect 
against Types III or IV, nor against one another, but are quite specific for the homologous 
organisms. Although infections produced by Type III are so far insusceptible of treat- 
ment by any serum, the serum for Type I is used in large doses, with excellent effect. 
Infections with Type IV are so mild as scarcely to require serum treatment. With the 
aid of these specific sera the organism in any case of pneumonia can be referred to its 
type either by inoculating mice and ascertaining which protective serum causes them 
to survive, or by testing the agglutination of the organisms with each serum. It is 
impossible to discuss here the rather indefinite toxins which have been extracted from 
various types of pneumococcus. The student is referred to the papers of Cole. Some 
promising results have been obtained by Cole, Cecil, and Austin in protecting large 
bodies of troops from pneumonia by the use of a prophylactic vaccine. 
Pneumonia is an acute infectious disease which begins suddenly, usually 
with a sharp pain in the chest and with a chill and high fever. It proceeds 
with extensive consolidation of the lung, evidences of intoxication, and 
various metabolic disturbances, to the death of the patient or to sudden 
disappearance of the symptoms and rapid passing away of the consolida- 
tion (crisis), or to a slower and more gradual defervescence and relief from 
the symptoms of the disease (recovery by lysis). Occasionally, while the 
symptoms of the acute illness disappear completely and convalescence 
seems complete, a form of consolidation of the lung persists and is found to 
be due to a replacement of the exudate by fibrous tissue. Other com- 
plications which delay recovery or lead to death will be discussed later. 
Since most persons harbor pneumococci in their mouths, and since pneu- 
monia seems not to be a particularly contagious disease, although rarely 
occurring in small epidemics, the question arises as to the mode of entry 
of the organisms into the lungs and the conditions under which they pro- 
duce pneumonia. It is shown that many persons who do not contract 
diphtheria are carriers of virulent diphtheria bacilli, and the same is true, 
in a modified way, of other organisms. Therefore unless it should prove 
that those who develop pneumonia do so always from the invasion of a 
pneumococcus of a type different from that which they have harbored in 
their mouths, we must search for some predisposing cause for their invasion. 
It has long been known (Litten) that crushing or contusion of the thorax 
is frequently followed by pneumonia, and there is also the general impression 
that alcoholism predisposes to it, and that some sudden exposure to cold 
is likely to precipitate invasion of the infection. Blake and Cecil have 
shown in an important series of experiments that a sufficiently virulent 
pneumococcus will produce lobar pneumonia in susceptible animals when 
a very small number of organisms are allowed to trickle down into the 
trachea and bronchi. They find that the pneumonia begins near the 
hilum of the lung and spreads peripherally, and think that the organisms 
invade primarily the lymphatics and interstitial tissues through the 
walls of the bronchi and bronchioles and are thus quickly spread. They 
LOBAR PNEUMONIA LOBAR PNEUMONIA 
543 
base this on the fact that they find a striking interstitial inflammation in 
the beginning which is later masked by the exudate in the alveoli. Un- 
fortunately they studied the very early stages in only one or two monkeys, 
leaving the rest to develop the later and more complex conditions. Permar 
has repeated this work in rabbits, studying especially the conditions found 
from one-half hour to four hours after inoculation. He concludes that 
pneumonia arises as an acute inflammatory reaction of trachea, bronchi, 
alveolar ducts, atria, and alveoli, the severity of the reaction being greatest 
in the terminal bronchioles and alveoli, but that acute interstitial pneu- 
monia does develop early in the course of this as an acute lymphangitis, 
arising in the peripheral lymphatics and extending to the subpleural net- 
work and to the hilum. This augments the primary bronchogenic inflam- 
matory process and tends to hasten the complete involvement of the 
affected lobe. 
Ether Pneumonia.-Pneumonia which occurs after a surgical operation 
with general anaesthesia is not infrequent, and presents some problems 
of interest. It was thought to be lobular in character, and due to the aspi- 
ration of various bacteria with saliva, etc., during the anaesthesia, owing to 
the abolition of the normal reflexes which would prevent the access of such 
materials to the lungs. A. O. Whipple has shown, however, in an interesting 
study of many cases of this kind that some of these consolidations are 
lobar in type and that they are usually caused by infection with pneumo- 
cocci of Group IV, which are known to be common in the throats of per- 
sons who are not ill. 
LITERATURE 
Armstrong and Gaskell: Jour. Path, and Bact., 1921, xxiv, 369. 
Blake and Cecil: Jour. Exp. Med., 1920, xxxi, 403-708. 
Permar: Jour. Med. Research, 1923, xliv, 1. 
Whipple, A. O.: Surg., Gyn., and Obst., 1918, xxvi, 29. 
Anatomical Changes.-The inflammatory reaction is commonly divided 
into several stages. Of these, the first, the so-called stage of engorgement, 
is rarely seen at autopsy, except perhaps at the edges of an advancing 
consolidation, and it must be conceded that its characters are to some 
extent constructed from the known course of inflammation elsewhere. 
The capillaries of the alveolar walls are dilated with blood, and there 
exudes into the air-cells fluid from the blood, together with leucocytes 
and red corpuscles. The second stage, which is the earliest one com- 
monly seen, is called the stage of red hepatization (because the lung is 
red and solid, like the liver). At this stage an abundant inflammatory 
exudate is found to have filled the alveoli and to have clotted. As 
in the case of a perfectly fresh clot of blood in a glass dish, which is 
so firm and dry that the dish can be inverted without spilling it, these 
clots in the air-cells are firm and dry. In sections they are seen to 
fill the air-cell (Fig. 266) and to be composed of a coarse-meshed net- 544 
TEXT-BOOK OF PATHOLOGY 
work of fibrin in which are entangled numerous pneumococci, many red 
corpuscles, many polymorphonuclear leucocytes, and some desquamated 
epithelial cells. Furthermore, at this stage, and even in the earlier stage 
there are seen quite numerous mononuclear wandering cells or lympho- 
cytes. This feature has been pointed out by Pratt, and is far less char- 
acteristic of later stages. Perhaps the most distinctive thing about 
the exudate from the microscopical point of view is its freshness and 
good state of preservation. The red cells are intact, and stand out clearly 
with their normal haemoglobin content; in other words, they show as yet 
no sign of laking or haemolysis. The leucocytes are clearly outlined 
Fig. 266.-Lobar pneumonia; red hepatization. A single alveolus showing fresh exu- 
date with well-preserved cells. A megalocaryocyte in one of the capillaries. 
and turgid. All these cells can be seen clearly because they are rela- 
tively few in numbers and stand out distinctly in the fibrin network. 
Many of the leucocytes show active phagocytosis and contain several 
pneumococci. LOBAR PNEUMONIA 
545 
In its gross appearance at this stage such a lung is very characteristic. 
The consolidation may involve one or more lobes, which are dense and 
hard and heavy. Their pleural surface has lost its normal gloss and is 
seen to be covered, over the consolidated area, with a delicate, scarcely 
perceptible layer of yellowish fibrin. On section the bronchi are reddened 
and may be plugged in their smaller branches with moulds of fibrin. The 
cut surface of the lung is usually dry, rough, and of a deep red color. 
The roughness is due to the slight projection from each alveolus of its plug 
of coagulated exudate. In sharp contrast with this flat plateau of con- 
Fig. 267.-Lobar pneumonia; gray hepatization, showing retraction and consolidation 
of fibrin and partial disintegration of leucocytes. 
solidated lung, the remainder collapses and allows the escape of some 
of its content of air. It still crackles and crepitates under the finger, while, 
of course, the consolidated lobe is firm and airless. In spite of what was 
said about the stage of engorgement, it is rather rare to find anything but 
an abrupt transition from the consolidated to the unaffected lung substance. 546 
TEXT-BOOK OF PATHOLOGY 
The third stage is the stage of gray hepatization, although it is usual- 
indeed, almost the rule-to find the consolidated lung in an intermediate 
condition, and of a color half-way between red and gray. The nature of 
that intermediate stage will be readily understood from a description of the 
gray hepatization. 
In section the alveoli are found to be densely packed with a cellular exu- 
date (Fig. 267). By this time, although the bacteria have increased in 
number and the alveoli are crowded tightly with many more polynuclear 
leucocytes, which frequently contain the cocci, the fibrin is not observed 
Fig. 268.-Lobar pneumonia; red hepatization, showing megalocaryocytes in the capil- 
laries. 
to have increased specially in quantity. Instead, it is packed together, 
often in pretty compact masses, and scarcely shows any longer the graceful 
network which was to be seen in the earlier stages. Red corpuscles are 
hardly to be found in the advanced stage of gray hepatization, except that 
with careful scrutiny the shadowy outlines of those which have lost their 
haemoglobin may be made out here and there among the closely crowded 
leucocytes. The capillaries of the alveolar wall are quite patent, as can 
be shown easily by injection, but they seem compressed by the mass of LOBAR PUNEMONIA 
547 
exudate and no longer look distended with blood. In this stage and in the 
stage of red hapatization one may often find capillaries obstructed by a 
huge cellular mass which proves to be a megalocaryocyte from the bone- 
marrow, swept into the lung in the general rush of leucocytes from the 
marrow (Fig. 268.). In both stages, too, one may make out the fact that 
the fibrin threads in any one air-cell often seem to twist themselves into a 
thin cord, and pass directly through the alveolar wall, to spread out again 
into the network of the next air-cell. This is because of the presence of 
the so-called "pores of Cohn," which may be normal apertures in the wall, 
although it has been contended by many that they occur only in lungs 
somewhat altered by emphysema. 
The most distinctive feature of the stage of gray hepatization from the 
microscopical point of view is the degenerated condition of the cells of the 
exudate. Not only have the red cells undergone laking and disintegra- 
tion, but the leucocytes have lost their clear outline, if not their whole 
protoplasm, and have become granular, ragged, partly disintegrated cells, 
which, however, still show evidences of their phagocytic activity. Most 
of them contain fine droplets of fat, and some contain yellow pigment, evi- 
dently produced at the expense of the haemoglobin of the broken red cor- 
puscles. Desquamated epithelial cells are rather more abundant, and they 
too contain fat-droplets and pigment-granules. 
It is especially important to observe also that the pneumococci degener- 
ate, disintegrate, and lose their power to stain brilliantly as they did in 
the stage of red hepatization. Indeed, they have also largely lost their 
power to infect, and a rabbit will survive when inoculated with a mass of 
exudate from an area of gray hepatization, but succumb to the same dose 
for an area of red hepatization. Armstrong and Gaskell suggest that the 
completion of this destruction may be the occasion for the crisis in pneu- 
monia. 
In the gross appearance (Fig. 269) the lung at this stage is still more 
enlarged, dense, and heavy. Its surface is covered with a much thicker 
layer of fibrin, which can be peeled off, leaving a dull pleural membrane. 
Not only does this cover the consolidated lobe, but it often extends over the 
whole lung and the parietal pleura. Frequently there is a considerable accu- 
mulation of turbid fluid in the pleural cavity, separating the surfaces, which 
elsewhere may be found glued together by the exudate. On section the cut 
surface of the consolidated lung is found to be gray, yellowish gray, grayish 
white, or yellowish white, although, as mentioned, the cases in which some 
redness persists at death are much more common. The surface is not dry 
nor so rough as before, but gives the impression that the alveoli are filled 
with coarse plugs of softer, almost unctuous material, a condition which is 
doubtless due to the retraction of the fibrin setting free serum in each 
alveolus, and to the much greater number of leucocytes, together with the 
accumulation of fat-droplets in their substance. The color is easily ex- 
plained by the laking of the red corpuscles, the yellowish tint being con- 
tributed, no doubt, by the hsemosiderin which is produced from their TEXT-BOOK OF PATHOLOGY 
548 
haemoglobin, and by the fat-content of the leucocytes, aided by the gen 
erally anaemic state of the lung. 
Fig. 269.-Lobar pneumonia: gross appearance of the lung in early gray hepatization 
with involvement of both lobes. 
A later stage, that of resolution, is seldom seen at autopsy, but it can 
occasionally be studied when the person dies from some other cause, as, LOBAR PNEUMONIA 
549 
for example, the development of pneumonia in the other lung, meningitis, 
or pericarditis. In two cases which I have seen in this stage the change in 
the lung was quite wonderful. The enormously enlarged organ was in 
each instance very soft and friable, and had assumed a very distinct trans- 
lucence, so that one could discern blood-vessels in the depths of the tissue. 
The alveolar contents had lost to a great extent their appearance of being 
in the form of plugs, and the whole lung appeared gray and jelly-like. 
In section the change was not so obvious, since it apparently consisted 
only in a more advanced disintegration of the leucocytes and fibrin. It is 
well known, however, that, through the agency of the proteolytic ferments 
of the leucocytes themselves, the whole mass of exudate is liquefied in a few 
days, and while some of it is expectorated, the greater quantity is absorbed 
by the lymphatics and carried away. 
The stage of healing is even more rarely recognized. It must consist in 
the relining of the alveoli with alveolar epithelium after the complete 
removal of the exudate. It is to be noted that throughout this intense 
inflammatory affection of the lung there is very little infiltration of the 
lung tissue itself with the exudate. The alveolar walls, bronchial walls, 
and perivascular tissues remain throughout almost free from bacteria and 
exudate. It is rather as though the whole process were taking place 
upon a mucous membrane without any invasion into the depths, and it 
results that after the exudate is removed there is no damage to repair 
other than the loss of the epithelial cells, which are quickly made good by 
those which remain, so that it would be impossible to say two weeks later 
that that lung had been the seat of a pneumonia. 
In sharp contrast to this are the effects of the streptococcus and influenza 
bacillus, described elsewhere. 
Lobar pneumonia caused by the Pneumococcus mucosus differs from that 
produced by the members of the other types in the viscidity of the exudate 
and in the severity of the disease, and the same may be said of the rarer 
cases, in which the capsulated bacillus of Friedlander is the cause. In one 
case of this kind which we saw, the exudate was so glutinous that it could 
be lifted up from the cut surface in long strings which hung from the 
knife. 
Complications of pneumonia, which are perhaps commoner in the case 
of various types of lobular pneumonia, are abscess formation, organization 
of the exudate, and gangrene. 
Abscess Formation.-In the late stage of a severe pneumonia the con- 
solidated tissue appears to succumb sometimes, to an especially intense 
injury on the part of the bacteria, so that the alveolar walls give way 
throughout a limited area, and the lung substance breaks down into a 
purulent fluid. Such an abscess-like focus may extend into the pleural 
cavity, producing a purulent pleurisy or empyema. One is inclined to sus- 
pect in such cases the presence of a mixed infection with streptococci or 
staphylococci. 550 
TEXT-BOOK OF PATHOLOGY 
Organization or Cornification.-Ordinarily, when a fibrinous exudate is 
thrown out on any such surface as that of the pericardium or the pleura, 
healing leads to its replacement by granulation tissue, which in those situ- 
ations is likely to end in the formation of fibrous adhesions between the 
opposed surfaces. It is, therefore, rather remarkable that in pneumonia 
the exudate, which is apparently quite the same in character, should be 
completely removed without the least attempt at such replacement or 
organization. Possibly the rapidity with which the whole reaction pro- 
ceeds is accountable for this, or there may be some other explanation. 
Fig. 270.-Organization following pneumonia. Strands of connective tissue extend 
through several alveoli and are in part covered with epithelium. 
Occasionally, however, the exudate fails to be removed promptly, whether 
because the bacteria persist or the mechanism of autolysis fails, and blood- 
vessels and fibroblasts do spring up and invade the fibrinous plugs in the 
alveoli, finally replacing them with vascularized tissue. The origin of this 
vascularized tissue is interesting, since it seems not to arise from every point 
of the alveollar wall. This is partly because the exudate retracts and LOBAR PNEUMONIA 
551 
remains in contact with the walls at certain points only, but even so, it 
seems that the new blood-vessels fail to spring up from all these points. 
Instead, it may be found by reconstruction that the connective tissue 
which replaces the exudate in any given lobule of the lung often springs 
essentially from the wall of the terminal bronchiole, or from one of those 
angles of the alveoli where an arteriole is surrounded by more tissue than 
goes to make up the alveolar wall. Then it follows the exudate, extending 
into each alvfeolus, and keeping clear of the walls (Fig. 270). Where the 
fibrin extends through one of the pores of Cohn the connective tissue follows, 
thickening itself into a stout cord and stretching the pore. Having pene- 
trated into an alveolus belonging to another bronchiole, it extends to replace 
the exudate in that system. Consequently in the end it seems that a con- 
Fig. 271.-Organizing pneumonia; cut surface of lung as seen with a lens, showing 
scar tissue extending through the lung, and points of yellow opacity produced by fatty 
cells. 
tinuous network of strands of fibrous tissue stretches about in the alveoli, 
connected only here and there with their walls, so that if the lung substance 
could be dissolved away, the new connective tissue might remain as a 
sponge-like mould of its cavities. When the new connective tissue has 
replaced the exudate, or even when it has succeeded, as it often does, in 
forming a sort of mantle about the exudate, epithelial cells creep up from 
the alveolar walls and cover it. This whole process gives a dense elastic 
consistence to the lung, and obviously impedes greatly its expansion. 
Later, however, with shrinkage of the fibrous tissue, there is left much 
more air-space in the cavity of each alveolus, although even then the 
function of the lung must be greatly impaired (Fig. 271). TEXT-BOOK OF PATHOLOGY 
552 
Gangrene.-Retarded recovery in some cases of pneumonia is accom- 
panied by an exceedingly foul odor from the breath and sputum, which is 
a recognized indication of the existence of a gangrenous process in the lung. 
This is a commoner complication of lobular pneumonia, and is the result of 
a secondary infection with organisms of a different type. It has already 
been described in Chapter XIV. 
Pneumococcus Septiccemia.-In the course of pneumonia the pneu- 
mococcus may gain access to the general blood-stream, and be recogniz- 
able in cultures from the blood. Jochmann leans to the view that this is 
a very frequent occurrence, since by using large quantities of blood in 
culture he has succeeded in discovering the organism in a large percentage 
of his cases. Cole, on the other hand, recognizing that occasional cocci 
may enter the blood-stream, has found that any considerable or even 
recognizable bacteriaemia occurs only in the most severe cases, and near 
the fatal termination of the disease. 
The accompaniments of such bacteriaemia are endocarditis, meningitis, 
and acute arthritis, although other rarer localizations are also recognized. 
Endocarditis caused by the pneumococcus resembles closely that pro- 
duced by the Streptococcus haemolyticus, or that of the staphylococcus 
infections. Large gray or greenish-gray soft vegetations are formed on the 
aortic or mitral or sometimes the tricuspid valves, and are of such friable 
consistence as to be a source of emboli. 
Meningitis is a fairly common accompaniment of such endocarditis and 
of pneumococcus bacteriaemia in general. The distribution of the exudate 
is usually very general, involving the spinal cord, and extending into the 
ventricles. 
Arthritis may take the form of a serous exudate in the joint cavity in 
which the pneumococcus is found, or in other cases there is found a purulent 
exudate with intense swelling and inflammation of the synovial membranes, 
erosion of the cartilages, etc. 
The pneumonia itself is by no means necessarily confined to one lobe, or 
even to one lung. The whole of one lung may be involved, together with 
the development of patchy or lobular areas of pneumonia in the other. 
Or there may be lobar involvement of both lungs. Occasionally the spread 
or extension of the consolidation may be observed clinically, and in a recent 
summary of the cases at the Presbyterian Hospital it was noticed that 
before and during the extension of an area of consolidation the temperature 
and leucocytosis frequently sank to low levels, indicating perhaps a lower- 
ing of the powers of resistance which allowed the infection to spread. 
Pleurisy has been mentioned, and it may be said further that following 
pneumonia, or in some cases without pneumonia, the pneumococcus gaining 
entrance into the pleura may cause a suppurative pleurisy or empyema in 
which great quantities of purulent fluid accumulate, compressing the lung 
and ultimately requiring surgical intervention. 
Pericarditis of serofibrinous or fibropurulent character may be due to LOBAR PNEUMONIA 
553 
extension through the pleuropericardial membranes, and is a serious and 
often fatal complication. 
Similarly, apparently by extension of the infection through the dia- 
phragm, a generalized peritonitis may be set up. Such pneumococcal peri- 
tonitis is described in children and occurs sometimes in women. Its portal 
of entry is not always clear, since no lesions of the abdominal organs are 
found, and it may sometimes occur without pneumonia. The exudate is 
greenish and soft and rich in fibrin, which is loosely attached to the serous 
surfaces. 
Portals of entry for the pneumococcus other than the lungs should be 
mentioned. The nasal sinuses frequently become infected from the nose, 
giving rise to a painful and persistent inflammation. Extension of the 
infection from the nares and pharynx through the Eustachian tube is the 
cause of those cases of otitis media which are due to the pneumococcus. 
From the frontal or ethmoid sinuses, as well as from the middle ear, exten- 
sion may occur to the cranial cavity, with the production of meningitis. 
LITERATURE 
Cole and others: Jour. Exp. Med., 1912, xvi, 644-718; 1914, xx, 346, 363. Archives of 
Int. Med., 1914, xiv, 56. Jour. Amer. Med. Assoc., 1918, Ixxi, 635. 
Wadsworth: Jour. Exp. Med., 1912, xvi, 54. 
Lamar and Meltzer: Jour. Exp. Med., 1912, xv, 133. 
Wollstein and Meltzer: Loc. dt., 1913, xviii, 548. 
MacCallum: Ziegler's Beitrage, 1902, xxxi, 440. (Organizing pneumonia.) 
Avery, Chickering, Cole, and Dochez: Monograph, Rockefeller Institute, No. 7, 1917. 
Kline: Jour. Exp. Med., 1917, xxvi, 239. 
Cecil and Austin: Jour. Exp. Med., 1918, xxviii, 19. CHAPTER XXVHI 
TYPES OF INJURY.-BACTERIAL DISEASE (Continued) 
Meningococcus infections: Epidemic cerebrospinal meningitis. Endocarditis. 
Gonococcus infections: Urethritis and sequelae. Salpingitis and sequelae. Arthritis, 
ophthalmia, dermatitis, endocarditis, vulvovaginitis in children. 
Acute rheumatism: Tonsillitis, arthritis, endocarditis, pericarditis, myocarditis. 
MENINGOCOCCUS INFECTIONS 
Infection with the meningococcus or Diplococcus intracellularis menin- 
gitidis of Weichselbaum occurs sporadically or in epidemics, and usually 
gives rise to a febrile disease in which the symptoms are due to the predom- 
inant affection of the meninges. In England it is called cerebrospinal 
fever. This disease has been known for a long time and there has always 
been great interest in its occurrence in epidemics mysteriously arising in 
widely separated places. Much might be written of the history of its va- 
rious appearances, of the terror which it has always inspired, and of the 
prolonged efforts to gain some insight into the mode of transmission and 
the life history of the organism which causes it. So much has been accom- 
plished in recent years, especially through studies made upon the great 
numbers of cases which occurred among the troops during the war, that 
our ideas are now much clearer than before, although many obscurities 
remain. 
The meningococcus itself has been studied by new methods, and especially 
through the work of Gordon, Hine, Flack, Dopter, and Flexner it has been 
learned that, as in the case of the pneumococcus, by the application of ag- 
glutination tests and especially by the absorption of agglutinins, it is pos- 
sible to divide the strains mto several types. Dopter in 1911 distinguished 
as parameningococcus one strain, which now becomes one of the types. In 
brief, Gordon's Type I stands at one end of a series. His Type IV, which 
corresponds with Dopter's parameningococcus, at the other end. Types 
II and III occupy places between in the series, but there are many other 
strains which are intermediate. Indeed, more than fifty different subtypes 
have been distinguished approaching more or less closely in their agglu- 
tinative characters one or other of these main types. It is stated in this 
form because there is, even with this most accurate method of recognizing 
a specific organism, a certain amount of cross agglutination, so that it is 
only an organism which gives the maximum reaction with a serum produced 
by the arbitrary original Type I and the minimum reaction with the serum 
of Type IV that is classed with Type I. Doubtless with further study 
554 MENINGOCOCCUS INFECTIONS 
555 
other differences may be found, as in the case of the Pfeiffer bacillus, which 
will make this differentiation more stable. 
No very sharp distinction can be made between these types as far as 
concerns their virulence and ability to produce disease. It is true, however, 
that there is a great difference in the susceptibility of individuals, since 
many become the healthy carriers of one or other type, probably through 
mere contact with infected persons. Others after surviving the disease 
remain as carriers of the organisms which are lodged in the nasopharynx. 
It was the problem of the recognition and disposition of such carriers 
which at first occupied so much attention in the various armies. As to 
the mode of infection, there is little doubt that transmission is by way of 
organisms which pass from the nasopharyngeal secretion of infected per- 
sons or carriers to the nasopharynx of others. The fact that persons known 
to carry these organisms in the nasopharynx may later develop meningitis, 
and the further fact that persons exposed to contact with these carriers 
become similar carriers or quickly develop the disease, support this. 
From the nasopharynx invasion may be conceived of as occurring directly 
through the ethmoid plate, through the sphenoid or ethmoid sinuses, or 
through the middle ear. Although Andre has shown that prolongation of 
the subarachnoid spaces extend along the olfactory filaments into the nasal 
fossae, apparently offering an easy path, no one has actually demonstrated 
organisms on their way through. On the other hand, there have been 
many cases in which an invasion of the blood-stream with the production 
of septicaemia has preceded the appearance of any organisms in the clear 
cerebrospinal fluid, but has been followed later by meningitis. This has 
been especially emphasized by Dopter, many English writers, Worster- 
Drought, Kennedy, and others, and in this country by Herrick. Indeed, 
Weed and his collaborators, in studying the infection of the cerebrospinal 
fluid in general, have shown that after the experimental production of sep- 
ticsemia the cerebrospinal fluid becomes infected easily when pressure is 
reduced there, but only rarely if the pressure is normal or heightened. They 
even suggest that the removal of fluid by lumbar puncture during septi- 
csemia may give opportunity for the development of meningeal infection. 
On the whole, therefore, in spite of authoritative voices to the contrary, I 
think the evidence is in favor of the infection of the meninges by the blood- 
stream, especially since the meningitis has nothing of the local character 
often seen when infection is obviously by direct extension from a neighbor- 
ing abscess. From this it appears that we may regard the disease as one 
in which, while various localizations of the organisms may occur as in 
heart valves, joints, etc., the usual local manifestation is in an inflamma- 
tion cf the meninges. 
The symptoms most characteristic of this affection are the sudden onset, 
vith chills, headache, and vomiting, with rigidity of the neck, inability to 
extend the leg while the hip is flexed (Kernig's sign), petechial and pur- 
puric rash, herpes, and slow pulse with high fever. It may run a 556 
TEXT-BOOK OF PATHOLOGY 
rapidly fatal course, or be more subacute in its development, or finally be- 
come a chronic affection, in which case various complications arise. Diag- 
nosis is made most certainly by the aspiration of the cerebrospinal fluid by 
lumbar puncture, with the recognition of the meningococcus by cultural and 
morphological characters, and the treatment by injection of correspond- 
ing amounts of the antimeningococcal serum, which has been developed by 
Flexner and others, is going far to reduce the mortality due to this disease. 
The pathological alterations in the central nervous system vary in their 
character according to the acuteness of the process. In the acute forms 
and sometimes even in the hyperacute or fulminant cases there is an ac- 
cumulation of purulent exudate in the meshes of the pia-arachnoid extend- 
Fig. 272.-Cerebrospinal meningitis 
ing widely over the base of the brain and over the convexity of the cere- 
brum and down over the spinal cord, where it tends to occupy the meninges 
of the posterior aspect. The dura is smooth, although sometimes hyper- 
aemic, and the surface of the arachnoid, while it may have lost its gloss, is 
not covered by any noticeable layer of pus. The exudate is collected, 
especially in the sulci and in those regions where the arachnoid is less 
closely connected with the pia. The ventricles contain no great excess of 
fluid, but this fluid is turbid or purulent, and there is swelling of the choroid 
plexuses, sometimes with minute hemorrhages. In the less acute forms the 
exudate is often much more abundant, forming a thick, greenish-yellow 
layer, and then fluid accumulates in greater quantity in the ventricles 
(Fig. 272). Occasionally distinct foci of necrosis are found in the brain MENINGOCOCCUS INFECTIONS 
557 
substance bounding the ventricles or beneath the pia, and the blood-vessels 
entering the brain are surrounded by exudate. 
Histologically, there are found degenerative changes in the epithelium of 
the choroid plexus, in the more superficial cell layers of the cortex, and even 
in the nerve roots. The inflammatory exudate (Fig. 273) is composed chiefly 
of polymorphonuclear leucocytes, although a few lymphocytes and red cor- 
puscles are to be found. Councilman and his fellow-workers have called 
Fig. 273.-Cerebrospinal meningitis showing the limitation of the exudate and the varied 
character of its cells. 
attention to other much larger cells which are present in considerable num- 
bers and which are probably to be regarded as large mononuclear wander- 
ing cells. These have an abundant cytoplasm and are actively phago- 
cytic, containing often the fragments or whole bodies of several smaller 
cells. Meningococci are numerous, and in spite of the name, intraceUularis, 
are often free. Fibrin forms a delicate network throughout the exudate. 
The walls of the vessels are markedly affected, being infiltrated with leu- 
cocytes which accumulate especially beneath the endothelium. After TEXT-BOOK OF PATHOLOGY 
558 
their entry into the brain their perivascular lymph sheaths are often found 
filled with leucocytes. 
In those cases in which the infection goes on to a chronic course the 
cerebrospinal fluid may become almost clear, and there arises a chronic 
progressive hydrocephalus which produces a train of symptoms and me- 
chanical effects resembling those seen in other forms of hydrocephalus. 
This is due to the fact that organization of the exudate gives rise to ad- 
hesions between the surface of the brain and the dura, but more particularly 
to such as cover the foramina of Magendie and Luschka, or obstruct the 
communication of the cerebrospinal space about the cerebellum and me- 
dulla with that over the cerebral hemispheres. Drainage from the ven- 
tricles is interfered with and they become distended with fluid. Retraction 
of the neck persists with the various pareses which may be found in the 
acuter stages. Great emaciation, persistent vomiting, a stuporous mental 
state, with irritability, blindness, and deafness, contractures, and bed- 
sores end finally in death. 
Lesions are produced in other organs either by direct extension of the 
infection or as the result of septicaemia. The infections of the eye may be 
thought of as the result of the wandering of the bacteria along the lachrymal 
duct to the conjunctiva, or along the optic nerve with its accessory tissues. 
These have not been actually demonstrated, and Worster-Drought and 
Kennedy think infection by way of the blood-stream most probable. Con- 
junctivitis, keratitis, iridochoroiditis, and even panophthalmitis are ob- 
served. The latter processes, through organization of the purulent 
exudate which accumulates in the chambers of the eye, lead to various 
forms of distortion of the eye, with blindness. Blindness may also 
follow hydrocephalus or destructive lesions in the occipital cerebral 
cortex. 
While otitis media is uncommon, permanent deafness results in many 
cases of meningitis from direct involvement of the eighth nerve by exten- 
sion of the infection and exudate from the meninges. Its atrophy leads 
to absolute deafness, which is usually bilateral, and in young children is 
followed by mutism. 
Various more or less transitory paralyses may occur. Hemiplegia, pos- 
sibly from a destructive lesion in the internal capsule, and monoplegias, 
more distinctly due to injuries in the lower motor segment involving nerve 
roots or even the spinal cord, have been observed. 
Arthritis affecting any joint, but most commonly the knee- or shoulder- 
joint, is another complication, or may occur in the course of a meningococcal 
septicaemia without any meningitis. The same may be said of endocarditis. 
We observed one case (Cecil and Soper) in which the meningococcus was 
present in the crumbling vegetations on the heart valves, and Fairley and 
Steward, Worster-Drought, and Kennedy report others. The other organs 
show, as a rule, only such changes as are common to many acute infectious 
processes. MENINGOCOCCUS INFECTIONS 
559 
Worster-Drought and Kennedy: Cerebrospinal Fever, London, 1919. 
Gordon, Hine, Flack: Medical Research Committee Report on Cerebrospinal Fever, 
1916-17, London. 
Flexner: Mode of Infection, etc., of Epidemic Meningitis, Rockefeller Institute, New 
York, 1917. 
Flexner with Jobling and Amoss: Jour. Exp. Med., 1907, ix, 105, 142, 168; 1908, x, 141, 
690; 1913, xvii, 553; 1916, xxiii, 683. Jour. Amer. Med. Assoc., 1906, xlvii, 560; 
1913, lx, 1937. 
Councilman, Mallory and Wright: Report of State Board of Health of Massachusetts, 
Boston, 1898. 
Weed, Wegefarth, Ayer, and Felton: Monograph No. 12 of Rockefeller Institute, 1920. 
Herrick: Arch. Int. Med., 1918, xxi, 541. 
LITERATURE 
GONOCOCCUS INFECTION 
The realization of the extent to which gonococci may infect the body is a 
matter of very recent years. The portal of entry is, in the majority of cases, 
the mucosa of the genito-urinary tract, since the infection is commonly 
transmitted by coitus. But it may occasionally be transferred by infected 
clothing, towels, etc., in spite of the ease with which the organism is de- 
stroyed by drying and exposure. Especially in infants and children is 
this possible, and in orphan asylums and hospitals epidemics of gonorrhoeal 
vulvovaginitis are of extremely common occurrence. In direct or indirect 
ways the infection can also be introduced into the mucosa of the mouth, 
nose, rectum, conjunctiva, and especially in the eye may produce serious 
results. 
Gonococcal Urethritis and its Sequels in the Male.-There is, after 
exposure to infection through coitus, during which the organisms reach the 
orifice of the urethra, a short period of incubation, averaging two to eight 
days. Then there begins a thin, mucopurulent exudate from the urethra, 
which in a short time becomes definitely purulent. The orifice, with its 
tumefied edges, oozes thick, greenish pus, which besides desquamated epi- 
thelial cells, contains abundant leucocytes, both neutrophile and eosino- 
phile. Gonococci are found in great numbers, many of them, if not the 
majority, contained in the bodies of the leucocytes, where they seem to 
suffer no harm. Ordinarily this inflammatory process may affect only 
the anterior portion of the urethra, where it passes through a florid stage, 
with profuse exudate, gradually to recede after several weeks. In this 
latter stage, which may end in healing and the disappearance of the cocci, 
the exudate becomes less abundant and mucoid, gluing together the edges 
of the meatus. But in many cases there is an extension to the posterior 
urethra, where healing is more difficult, and from which the important 
complications in other organs arise. 
There are, in the course of the urethra, many accessory structures, some, such as the 
paraurethral channels, partaking of the character of malformations, while others, the 
lacunae or glands of Littre and the glands of Cowper and various folds of mucosa, are 560 
TEXT-BOOK OF PATHOLOGY 
normally present. Directly communicating with the urethra there are, of course, the 
more developed accessory structures-the prostate and seminal vesicles. All of these 
are commonly involved in the more chronic or persistent gonorrhoeal infections, and 
serve to maintain the infection in spite of thorough disinfection of the urethra itself. 
In connection with the anterior urethra 
the follicles or glands of Littre may 
become converted into hard, inflamed 
nodules. 
The mucosa in the acute in- 
flammation is swollen, with des- 
quamation of many epithelial 
cells. The gonococci penetrate 
among those which remain, and 
extend even into the subepithelial 
tissues. Where there are patches 
of stratified epithelium, such as 
often occur normally, the cocci 
obtain an especially good foothold 
and resist disinfection. When the 
process has become more chronic, 
especially in the posterior ure- 
thra, there appear ulcerations, 
with scarring and polypoid ex- 
crescences. The scarring results 
in strictures or stenoses (see Fig. 
215) of the urethra, which cause 
obstruction to the outflow of 
urine and render catheterization 
necessary. Not only is cystitis a 
common result of this, but in 
attempts to pass instruments 
through the stricture, wounds of 
the adjacent tissue are produced, 
which may become the origin of 
intense infections. These may 
assume a phlegmonous character, 
or there may develop an abscess 
in the perineal region. The ex- 
travasation of urine into such 
wounded areas favors the devel- 
opment of the infection (Fig. 275). 
Chronic gonococcal urethritis is commonly recognized by the presence 
of shreds of filaments of mucus with leucocytes and epithelial cells in the 
urine. These may contain gonococci, but often the organisms are rare 
and difficult to demonstrate. 
Fig. 275.-Gonorrhoeal stricture after 
forcing of false passage. Extensive de- 
struction and inflammation. Hypertrophy 
of the bladder; diphtheritic cystitis. GONOCOCCUS INFECTION 
561 
Cystitis, while it can be produced by the gonococcus alone, is rarely 
due to that organism, but usually to secondary invaders. Ureteritis and 
pyelonephritis are reported as due to ascending infection with the gono- 
coccus, but are rare. 
Prostatitis and Vesiculitis.-Various types of infection of the prostate 
by the gonococcus are described arising in connection with posterior ure- 
thritis. These differ greatly in intensity, for while there may be a sort of 
catarrhal inflammation of the ducts and acini of the gland, there may, in 
other cases, be far more intense and destructive changes involving abscess 
formation. A chronic persistent inflammation with a secretion containing 
cocci, and leading to the enlargement, or in other cases to scarring and 
atrophy of the gland, is most frequent. The seminal vesicles may in the 
same way present acute inflammatory changes or more chronic altera- 
tions, including scarring and obliteration of their lumina. 
Epididymitis.-A common sequel of urethritis is produced by the 
wandering of the gonococci along the vas deferens to the epididymis, 
where an intense inflammation involving the neighboring tunica vaginalis, 
in many cases leads to great swelling and induration. The gonococci can 
be found in the exudate, even though in some cases they cannot be recog- 
nized in the vas deferens and have produced no lesions there. Scarring 
and stricture or obliteration of the canal of the epididymis and of the vas 
deferens may lead to complete azoospermia if the epididymis had been 
affected on both sides. 
Gonococcal Infection in the Female.-In the female the urethra, the 
vagina, Bartholin's glands, and the cervix become infected and react in the 
same way as does the mucosa of the male genito-urinary tract. The ure- 
thra, being shorter and without complicated accessory structures, the in- 
flammation does not lead to such serious results. A swelling of the mucosa, 
with the exudation of the characteristic pus, occurs. Bartholin's glands 
become greatly swollen and indurated, and from them there can be ex- 
pressed a similar purulent exudate. These things may occur without 
the extension of the infection into the internal genitalia, and, indeed, in 
the vulvovaginitis of children, this more external type of inflammation, 
with reddening and swelling of the nymphse, is relatively common. In the 
child the vagina is more intensely involved than in the adult, where its 
epithelium is rtfuch more resistant. Indeed, in the adult, gonorrhoeal 
vaginitis occurs practically only as an acute process, and is then relatively 
unimportant. A chronic gonococcal vaginitis is uncommon. On the other 
hand, the cocci readily pass into the cervical canal, and establish them- 
selves in the mucosa with its glands, extending also to those of the fundus. 
Slight erosions, a tumefaction of the mucosa, and the secretion of a purulent 
exudate mark their presence there. More important is the effect of their 
further wandering into the Fallopian tubes. 
Gonococcal Salpingitis.-In the acute stage the tubes become swollen, 
hyperaemic, and oedematous, the change being especially striking in the 562 
TEXT-BOOK OF PATHOLOGY 
fimbriated extremity. In the mucosa alterations due to the presence of 
the organisms among the epithelial cells of the complex folds are in general 
similar to those in the urethra. Later chronic alterations appear, de- 
pendent upon the deeper invasion of the cocci into the tissues. Adhesions 
Fig. 276.-Subacute gonorrhceal salpingitis with great thickening of the folds of mucosa 
by the cellular infiltration. 
are formed about the tube, and through the organization of exudate there 
is occlusion of its lumen at both ends and the accumulation of a quantity 
of pus in its cavity. Kinking of the tube may be partly responsible for 
these occlusions. The progress of the infection leads to great changes in 
the mucosa, which in operative cases are usually seen in their subacute GONOCOCCUS INFECTION 
563 
stages. The folds of the mucosa, ordinarily so delicate and complicated, 
become distended into thick lamellse (Fig. 276), which often adhere to one 
another and grow together so that they cover over the intervening spaces, 
which then, in cross-section, look like epithelium-lined channels in the tube- 
wall (Fig. 277). Microscopically, these thick folds are found to be 
Fig. 277.-Pseudofollicular salpingitis. The appearance of closed cavities is produced 
by fusion of the folds of the mucosa. 
stretched by great numbers of wandering cells, among which lymphocytes 
and plasma cells are very numerous and conspicuous. Eosinophile cells are 
often very abundant. Schridde and Amsbacher claim that the finding of 
such an infiltration of lymphocytes and plasma cells is sufficient proof of 
the gonococcal nature of the infection, but this is, probably rightly, con- 
tradicted by Muller and Menge, who state that other organisms, such as 564 
TEXT-BOOK OF PATHOLOGY 
the streptococcus, may produce the same lesions if time is allowed for 
the development of a subacute or chronic salpingitis. The distension of 
the obstructed tube with pus (pyosalpinx) may greatly separate and flatten 
the folds of the mucosa, and the tube itself assumes then a variety of forms, 
Fig. 278.-Chronic gonococcal salpingitis or pyosalpinx. 
Fig. 279.-Hydrosalpinx. 
according to the arrangement of the adhesions which may attach it to the 
uterus, to the ovary, to the rectum, or the pelvic wall (Fig. 278). Most 
often it is roughly retort shaped. Rupture of such a sac may occur through 
violence with discharge of the pus into the peritoneum. Ordinarily, there GONOCOCCUS INFECTION 
565 
is not produced any very severe peritonitis, and this is explained by the 
fact that cultures from the pus are usually sterile. In other cases the exu- 
date may lose its purulent character after the occlusion of the ends of the 
tube has occurred and become more serous. Such a tube may develop into 
a large, thin-walled sac full of clear fluid (hydrosalpinx) (Fig. 279). Natu- 
rally, either of these results ends in the complete loss of function of the tube, 
and if both tubes are affected, sterility follows. 
Gonococcal infections of the ovary occur in the form of abscesses or false 
abscesses, caused by the invasion of the cocci into freshly ruptured follicles 
or corpora lutea. 
Gonococcal peritonitis is an outcome of the acute stage of infection of the 
uterus and Fallopian tubes, the cocci entering through the fimbriated 
extremities. It may also be produced by transfer of the organism by the 
blood-stream. The exudate is fibrinous or serofibrinous, and is likely to 
lead to extensive adhesions among the loops of intestine. This condition 
is not of common occurrence, except in the more localized form of pelvic 
peritonitis, which is extremely common in association with salpingitis, and 
in its late stages is found to have bound the pelvic organs together by 
firm or lax adhesions. 
Gonococcal Arthritis.-Somewhat late in the course of an acute urethritis, 
that is, after the inflammation has reached the posterior urethra and has 
lasted several weeks, there often arises a painful involvement of a joint, 
which is due to the transportation of the gonococci by the blood-stream to 
the synovial membrane. This appears to be commoner in men than in 
women, and usually only one joint is involved, although others may be 
affected in succession later. The joint most commonly infected is the 
knee, and the inflammation may take several forms. The mildest is that 
in which there is a mere accumulation of fluid without pain or marked 
impairment of function. More frequently there is formed a serofibrinous 
or even purulent exudate, with infiltration of the surrounding tissues and 
extreme pain, so that the joint is held flexed. Erosions of the cartilage 
and rarefaction of the cancellous bone may occur, and fixation of the joint 
with ankylosis of the bones sometimes follows. Gonococcal infection of 
the bones themselves is reported, but is rare. 
Gonococcal Ophthalmia.-Infection of the eye with this organism is 
extremely serious, and often leads, even under the most careful treatment, 
to destruction of the eye. It occurs in infants from infection during birth 
from the inflamed genitalia of the mother, and this so-called ophthalmia 
neonatorum, although relatively easy to guard against or cut short by 
instillation of nitrate of silver into the infant's eyes, is nevertheless the cause 
of an enormous number of cases of blindness among children everywhere 
in the world. In older children-and this probably includes the cases of 
'Tate birth infections," which develop after five days postpartum-gono- 
coccal conjunctivitis is a fairly common accompaniment of the epidemic 
gonococcal vulvovaginitis. 566 
TEXT-BOOK OF PATHOLOGY 
In adults such conjunctivitis is caused by the introduction of the organ- 
ism into the eye with the soiled fingers, towels, etc., or, especially in phy- 
sicians, by the spurting of gonorrhoeal pus into the eye. It is said that there 
may also arise an infection of the deeper parts of the eye through trans- 
mission of the organism by the blood-stream, and in this case there are no 
cocci in the conjunctival sac. 
The conjunctivitis begins with the injection of the blood-vessels, swell- 
ing of the lids, and the pouring-out of a thick, purulent exudate, which 
tends to glue the eyelids together. The conjunctiva over the bulb swells, 
so that the cornea is sunken beneath it. The slightest touch upon the 
cornea is sufficient to start an erosion there, which progresses to ulcera- 
tion and often to infection of the anterior chamber, which fills up with a 
purulent exudate. Healing of these ulcerations is likely to cause such scars 
or opacities in the cornea that the eye becomes useless. But there also 
may be produced extensive infiltration of the iris and neighboring tissues, 
resulting in distorting adhesions. Indeed, the whole eye may be invaded 
and extensively injured by the infection. 
It is conceivable that infection of the nasal sinuses or even meningitis 
might arise from such a process, but although de Jong and others have 
described cases of gonococcal meningitis, the proof of the identity of the 
organism which is so similar to the meningococcus is not satisfactory enough 
to allow these cases to be generally accepted. 
Gonococcal Dermatitis.-Lesions of the skin said to be caused by the 
gonococcus assume many forms, among which are erythematous rashes, 
urticaria, erythema nodosum, haemorrhagic and bullous exanthemata, 
and hyperkeratoses. Of these, perhaps the latter are most character- 
istic. 
Gonococcal Endocarditis.-It is evidence of the transportation of the 
cocci by the streaming blood, and therefore of the existence of a general 
gonococcal septicaemia, that endocarditis may owe its origin to this organ- 
ism. Gonococcal septicaemia is particularly characterized by the occur- 
rence of the arthritis already mentioned, and of the endocarditis, and is 
not an absolutely fatal occurrence. Cases have been reported as recover- 
ing even after the valvular lesions were very evident, and the cocci re- 
peatedly demonstrated in the blood. 
The alterations of the heart-valves are rather characteristic, in that the 
vegetations are frequently extremely large and friable. They seem to 
effect the destruction of the valves with great rapidity, for in three cases 
which I have seen the valves were reduced to ragged strands, which flapped 
in the stream, bearing on their ends large crumbling remnants of the vegeta- 
tions. Apparently the aortic and the mitral valves are most often affected, 
but we were impressed with the occurrence of these vegetations in our own 
cases on the tricuspid and pulmonary valves. Pericarditis and myo- 
carditis of focal or diffuse character often accompany the endocarditis. 
The organisms are found in abundance in the vegetations. GONOCOCCUS INFECTION 
567 
Vulvovaginitis in Children.-With regard to the infection itself, there 
are some interesting features. It has been pointed out that epidemic 
vulvovaginitis in little children is a very common thing, and that in some 
orphan asylums it is never absent, but is known to produce so little real 
harm that it is somewhat ignored. Dr. Northrup tells me that in contrast 
to this familiar mild infection, the incomparably more serious effects of 
infection from the gonococcus from urethritis in the adult impressed him 
strongly in two cases. These were in two young girls, who were infected 
in some way from their mother, who had been infected from the acute 
urethritis of the father. They became profoundly ill, with circulatory 
collapse and symptoms that were thought to indicate appendicitis. One 
was operated upon and the appendix removed. Although it was normal, 
the whole peritoneum was intensely reddened, and there was a slight serous 
exudate. There were no other complications and they recovered. Re- 
cently, apparently with this idea in mind, Dr. Pearce has investigated the 
organisms concerned in an epidemic in a children's asylum, and has found 
that they do differ biologically from those isolated from urethritis in the 
adult. Her conclusions are in part as follows: 
Two principal types of gonococci may be recognized by the methods of 
agglutination and complement fixation, and correspond to the adult and 
infant types of infection seen clinically. The gonococci isolated from cases 
of ophthalmia belong to the adult type. It appears that there may be 
many more varieties, and that these two types are not sharply marked out, 
but are connected by intervening forms. 
Jadassohn: 
Ehrmann: 
Scholtz: 
Grosz: 
Elschnig: 
Schlagenhauf er: 
Buschke: 
Menge: 
LITERATURE 
Handbuch der Geschlechtskrankheiten, 1910, i; 1912, ii, pp. 1-612. 
(These papers are excellent but very prolix.) 
L. Pearce: Jour. Exp. Med., 1915, xxi, 289. 
C. Bruck: Ergeb. d. allg. Path., 1912, xvii, 134 (literature). 
Harris, Dabney, and Johnston: "Endocarditis," Johns Hopkins Hosp. Bull., 1901, xii, 
68; 1902, xiii, 236. 
Thayer and Blumer: Ibid., 1896, vii, 57; Jour. Exp. Med., 1899, iv, 81. 
Thayer: Amer. Jour. Med. Sci., 1905, Ixxx, 751. 
Amersbach: Ziegler's Beitrage, 1909, xlv, 341. 
Watjen: Ibid., 1914, lix, 418. 
ACUTE RHEUMATISM 
The disease affects young people especially, causing repeated attacks of 
painful swelling of the joints, with fever, but usually without leaving any 568 
TEXT-BOOK OF PATHOLOGY 
permanent disability of the joints. It is usually preceded by tonsillitis, 
and often followed by chorea, a spasmodic nervous affection which may 
last a long time. Nearly always there are serious changes in the heart, 
involving the valves, the heart muscle, and the pericardium. The cause is 
unknown in spite of the most careful studies, although numerous writers 
have described bacteria for which they claim an setiological role. Of these, 
the majority are micrococci in pairs or in chains. Those described by 
Singer and by Poynton and Paine are perhaps most discussed, but it is by 
no means proved that they are the real cause of the disease. In our cases 
cultures from the blood and joint fluids, as well as smears and cultures from 
Fig. 280.-Rheumatic endocarditis; verrucose vegetations on mitral valve. Aschoff 
bodies in myocardium of left ventricle and subacute pericarditis. 
the vegetations on the heart valves, have usually shown no bacteria unless 
some terminal affection, such as pneumonia, brought bacteria to com- 
plicate the situation. Protracted studies by Swift have failed to reveal 
any organisms which might be the cause of the disease. 
From the frequency of tonsillitis in the early stages it seems that the 
tonsils form the portal of entry for the organisms. Occasionally there is 
laryngitis, rhinitis, or otitis media. With the swelling of the joints there ACUTE RHEUMATISM 
569 
are high fever and profuse sweating. When the fever is extremely high, 
death is likely to ensue. 
The joints most often affected are the knee, shoulder, and ankle, although 
finger-joints may be involved in those who work especially with their 
fingers. The swelling is very largely periarticular, and the excruciating 
pain is chiefly in the attachment of tendons. The joint fluid is usually 
Fig. 281.-Small homogeneous hyaline vegetation, without evident bacteria, upon the 
mitral valve. Rheumatic endocarditis. 
clear, or contains a few leucocytes, although there is sometimes a purulent 
exudate. Purpuric or haemorrhagic patches often appear in the skin, and 
seem to be due to changes in the walls of the blood-vessels, thought by some 
to be caused by embolic inflammatory processes. These have the char- 
acter of erythema nodosum. There are also nodes in the skin and in the 
periosteum which are of inflammatory character. These are really sub- 
cutaneous nodules most common about the knees and elbows, although 570 
TEXT-BOOK OF PATHOLOGY 
found also elsewhere. They vary in size from that of a small shot to that 
of an olive, or are even larger, and are found usually after the acute joint 
symptoms have disappeared. 
The most important lesions are undoubtedly those in the heart, and the 
surprising constancy of their form and the ease with which they can be dis- 
tinguished from the other infectious diseases of the heart make it seem more 
likely that they are caused by some peculiar infectious agent. 
There is nearly always pericarditis, with a sticky exudate of fibrinous 
character, which soon brings about the firm adhesion between the two 
layers of the pericardium (Fig. 280). Since death generally occurs some 
time after repeated attacks, the pericardium is usually found densely 
adherent to the heart. Vegetations appear on the valves along the line 
of closure, and nearly always in the form of small, warty, tough nodules, 
which run like a string of beads around the whole valvular orifice. They 
are found especially on the mitral, but also on the tricuspid and aortic 
valves, but seldom extend on the heart-wall or on the chordae tendinese. 
Healing of such lesions leads to the thickening and scarring of the valves, 
and often to extreme narrowing or stenosis of the orifices. Doubtless 
renewed attacks would add a new beaded string of vegetations to such 
scarred valves, and so might the advent of some other infection. While it 
seems probable that rheumatism may well be the original cause of mitral, 
Fig. 282.-Aschoff body in the heart. 
tricuspid, and aortic stenosis and insufficiencies, it is usually difficult to 
prove this, especially if some other infection has supervened and produced 
fresh vegetations quite different in character from those of rheumatism. 
Thus it is common to find the characteristic distribution of fresh vegetations ACUTE RHEUMATISM 
571 
caused by the Streptococcus mitior or viridans on old scarred valves, which 
may well have been distorted by rheumatic infection of years before. Most 
interesting are the myocardial changes, now that their peculiarities have 
been pointed out by Aschoff, Horder, Bracht and Wachter, Rothschild and 
Thalhimer, and others. Focal collections of peculiar large cells in the 
neighborhood of minute vessels, or entirely surrounding them, seem to be 
the reaction to focal injury to the tissue. These so-called Aschoff bodies 
(Fig. 282) are made up of concentrically arranged wandering cells, most of 
which are conspicuous from their large size and their large nuclei, of which 
they often have several. They are much like the large cells found in 
Hodgkin's disease, although usually not quite so large as those. No bac- 
teria have been demonstrated as constantly present in these foci, but it is 
shown that in healing they leave behind them scars which in the end may 
go far toward producing the condition described as chronic fibrous myo- 
carditis. These myocardial lesions are such constant accompaniments of 
the endocarditis and adhesive pericarditis that some have spoken of the 
rheumatic lesions of the heart as rheumatic carditis. 
In a series of cases of rheumatism which we have studied recently we 
have found the Aschoff bodies regularly in the myocardium, especially 
at the base of the left ventricle, where they are sometimes large enough 
to be visible to the naked eye. There was in nearly all of these cases 
a great infiltration of the wall of the left auricle with many eosinophile 
and non-granular, mononuclear, wandering cells with the formation of 
much new tissue, so that there was a great patch of rough thickening of 
the auricle wall such as might remain from the healing of the vegetations 
which occur in this position in the endocarditis produced by the Strepto- 
coccus viridans. But the rheumatic character of the lesion seems estab- 
lished by the presence of very numerous Aschoff bodies in this new tissue 
just beneath the endocardium. 
The subcutaneous nodules bear a considerable resemblance micro- 
scopically to the Aschoff bodies of the heart. They are really irregularly 
outlined masses of compact tissue made up of very large cells with large 
vesicular nucleus and irregular cell body. Much hyaline degeneration 
occurs among these cells. Blood-vessels are numerous, often with greatly 
thickened walls and there is an abundant infiltration of wandering cells 
which are chiefly eosinophile. 
When the eetiological factor is discovered and established, it should be 
easy to determine its precise relation to these lesions, as well as to the ac- 
companying purpura, iritis, chorea, tonsillitis, arthritis, etc. 
Aschoff: Verh. d. Deut. Path. Gesellsch., 1904, viii, 46. 
Bracht and Wachter: Deut. Arch. f. klin. Med., 1909, xcvi, 493. 
Futcher: Johns Hopkins Hosp. Bull., 1895, vi, 133. 
Jacki: Frankf. Ztschr. f. Path., 1919, xxii, 82. 
LITERATURE 572 
TEXT-BOOK OF PATHOLOGY 
Poynton and Paine: Rheumatism, London, 1914. 
Singer: Deut. med. Woch., 1914, xl, 788. 
Swift and Kinsella: Arch. Int. Med., 1917, xix, 381. 
Thalhimer and Rothschild: Jour. Exp. Med., 1914, xix, 417. 
Watjen: Verh. Dtsch. Path. Gesellsch., 1921, xviii, 223. 
Wiesel: Wien. med. Woch., 1914, Ixiv, 661, 746. CHAPTER XXIX 
TYPES OF INJURY.-BACTERIAL DISEASE (Continued) 
Diphtherial infection: Diphtheria of respiratory tract. General effects upon the heart, kid- 
neys, etc. Paralysis. 
Tetanus infection: Mode of occurrence and mechanism of distribution of the toxin. 
The diphtheria bacillus is, as is well known, an organism which produces 
its wide-spread disturbances in the body by the agency of a soluble poison. 
In this respect it is paralleled by the tetanus bacillus, but by few, if any, 
other organisms. It can, however, in growing at the point from which it 
diffuses its toxin, produce a considerable local lesion, a power which is less 
striking in the case of the tetanus bacillus. 
Diphtheria is commonly a disease of children and young people, and from 
the readiness with which the bacteria are transferred, is likely to occur in 
epidemic form. Many healthy persons have been found to harbor the 
bacilli in their mouths and throats, and are thus a menace to others. 
The organisms may become localized in the throat, producing character- 
istic lesions on the mucosa of the fauces, the uvula, the tonsils, the pharynx 
or larynx, often extending into the trachea and even deep into the smaller 
bronchi. Similar lesions occur in the nose, rarely in the ear, more often 
in the vulva and vagina, and sometimes in the skin, especially in connec- 
tion with maceration of the epidermis or skin lesions, which prepare the 
way, or with ulcers and wounds. Since the character of the local lesion is 
essentially the same everywhere, a description of the more common form 
in the throat will suffice. 
A few days after the bacteria lodge in the mucosa, that is, after the lapse 
of enough time to allow them to grow and gather their forces, redness of 
the whole lining of the throat appears, with soreness, difficulty in swallow- 
ing, and evidences of an acute illness-fever, leucocytosis, etc. White or 
yellowish-white flakes appear on the reddened surface at one point or other, 
and spread. It is seen that the confluent patches thus form a slightly 
elevated, dull, opaque, membrane-like layer, which is pretty tenaciously 
adherent to the underlying tissue. This can be peeled off, but leaves a raw 
surface which oozes blood, and upon 'which a new false membrane quickly 
forms. In other places the pseudomembrane may be less adherent, 
and this is likely to be the case within the larynx and trachea, where it 
sometimes forms a complete lining, stretching for a long way (Fig. 283). 
Evidence of this looser connection is seen in the frequency with which 
DIPHTHERIAL INFECTION 
573 574 
TEXT-BOOK OF PATHOLOGY 
children cough up the whole lining, or at least large areas of it. The 
reasons for the closer adherence of the false membrane to the mucosa 
of the pharynx and mouth than to that of the larynx and trachea must 
be discussed later. 
While this is the ordinary type of local lesion, the diphtheria bacilli 
may produce much milder inflammation 
of a more catarrhal character, or, on the 
other hand, especially when there is a 
mixed infection and virulent streptococci 
add their effects, there may be the most 
destructive affection of tonsils, fauces, 
and larynx, with deep necrosis and 
sloughing of the tissues, together with 
the most violent inflammatory reaction, 
and with great oedema of the surround- 
ing parts. 
Occlusion of the respiratory tract, 
either by the great swelling produced as 
just described, or more commonly by the 
accumulation and folding together of 
the false membranes, can cause death by 
asphyxia. Indeed, in spite of trache- 
otomy, deaths from this cause were fre- 
quent. O'Dwyer's method of intubation 
went far to save children from this evil, 
and the timely administration of anti- 
toxin has practically cleared away the 
danger. 
Pathological Anatomy of the Lesion.- 
The diphtheria bacillus is one of the many 
agencies which can produce a diphther- 
itic inflammation. It has been remarked 
that it may also produce milder forms, 
but even alone it is able to produce this 
most severe form. 
It may be repeated, however, that many 
strong alkalies or acids or salts of heavy metals, 
such as mercury, can produce typical diphther- 
itic forms of inflammation, just as many bacteria 
can. In other words, the term diphtheritic is 
used in a purely anatomical sense, to describe the nature of the lesion and not its 
aetiology. 
The lesion consists in an effective destruction of some of the superficial 
cells of the mucosa, which, under the influence of these bacilli, undergo 
necrosis and coagulation. The destruction of the overlying cells starts 
Fig. 283.-Diphtheritic mem- 
brane extending far down into the 
trachea. The tonsils are slightly 
swollen. DIPTHERIAL INFECTION 
575 
and favors the pouring-out of a coagulable fluid, which permeates them 
and spreads on the surface. The formation of fibrin through the 
coagulation of this fluid not only upon the surface, but everywhere in 
and among the dead cells, establishes the false membrane. Leucocytes 
appear in great numbers and there is some haemorrhage. Thus the first 
false membrane to appear is composed of the vaguely outlined coagulated 
bodies of the dead cells, buried in a feltwork of fibrin, together with many 
Fig. 284.-Diphtheritic membrane in a bronchus. Acute laryngeal and bronchial diph- 
theria. The exudate has the arrangement in arcades. 
leucocytes. If this is torn off, the next membrane which forms to replace 
it will consist chiefly of fibrin and leucocytes, unless the growth of bac- 
teria at the base of this fresh ulcer causes more necrotic tissue to become 
incorporated into the new membrane. Where the necrosis is wide-spread, 
the false membrane will be found firmly attached by a broad base. In 
the trachea (Fig. 284) and bronchi the membrane is found to be attached 
only at the points where the epithelial cells are necrotic and the base- 576 
TEXT-BOOK OF PATHOLOGY 
ment membrane is destroyed. Through such places it exudes on the sur- 
face, becoming confluent over the intervening intact epithelium in a series 
of arcades. Beneath these arcades much of the epithelium may remain in- 
tact and serve to regenerate cells to repair the gaps after the disease is over. 
The old discussion as to whether a diphtheritic membrane was to be regarded as 
formed by a fibrinoid degeneration of the superficial cells of the tissue, and not by fibrin 
from the blood, raged violently for a long time among such men as Orth and Marchand, 
on one side, and Neumann and his supporters, on the other. A historical review is given by 
Gaylord (Jour. Exp. Med., 1898, iii, 1). Even yet there are echoes of this in the acri- 
monious paper of Dietrich in criticism of Sudsuki (Ziegler's Beitrage, 1901, xxix, 562; 
xxx, 414). It seems clear enough that most of the fibrin must come from exuded plasma, 
but that necrotic cells embedded in it may become indistinguishable and add to the bulk 
of the mass. Fibrin formed through and through their dead bodies would still give its 
characteristic staining reaction. 
Sequelae.-While the mechanical effects of such a membrane are often 
serious, the more remote sequels of the infection are even more important. 
Bronchopneumonia is a common one, and is probably due in most cases 
to accompanying streptococci which pass into the bronchi. 
The other things result from the diffusion of the strong toxin from the 
place where the bacilli are growing into the circulating blood. 
Death may take place in the height of the intoxication, evidently from 
its direct action upon the heart and circulatory system. In the heart 
itself in such cases no gross changes are to be seen, and, indeed, the micro- 
scopical changes, cloudy swelling, fat infiltration, and fragmentation of 
the heart muscle do not offer convincing evidence of the cause of death. 
As has been mentioned elsewhere, Bassler and Romberg held the opinion 
that the effect of the poison was chiefly upon the vasomotor control of the 
blood-vessels, allowing them to relax so that circulation failed. I was 
able to confirm this by artificially maintaining the blood-pressure in the 
brain and coronary arteries, upon which life was greatly prolonged. But 
it seemed clear that the heart itself was also injured, since it would not 
beat quite so long as a normal heart. It is even more difficult to explain 
the gradual or sudden weakening of the action of the heart, with increased 
pulse-rate and altered rhythm, which may occur after or during con- 
valescence. It is generally ascribed to myocardial degeneration, some- 
times to derangement of the nerves which control the heart. Low des- 
cribes slight alterations of the conducting bundle of His in such cases, 
but is unwilling to claim this as the cause of the heart failure. 
Albuminuria is common in diphtheria, and the kidneys show acute and 
subacute changes in most fatal cases. These rarely have the character of 
a glomerulonephritis, but are more commonly instances of acute inter- 
stitial nephritis. 
The lesions in other organs are essentially those of any acute infection, 
except that the changes in the adrenals are likely to be more intense, 
resulting in haemorrhages and cellular degenerations. TETANUS INFECTION 
577 
Paralysis of motor and to a less extent of sensory nerves is dependent 
upon degenerative and destructive changes in the nerves themselves, as 
well as in the nerve-cells. The axones disintegrate, and the myeline 
sheaths lose their homogeneous character, fatty globules which stain with 
osmic acid appearing in their place. The nerves which supply the palate 
and larynx, those of the extrinsic muscles of the eye and of the muscles 
of accommodation, suffer especially. Paresis or definite or temporary 
paralysis of the muscles of the extremities occur, but are less common. 
Guillain and Laroche find that the toxin is fixed in the gray matter 
of the central nervous system apparently in combination with the phos- 
phorized lipoids of the brain, and Walshe, in a review of the localization of 
the poison, brings evidence to show that while paresis of the muscles of 
accommodation and generalized peripheral neuritis are probably due to a 
hsemotogenous intoxication of the nervous system, there are distinct local 
paralyses corresponding with the site of the diphtheritic infection and 
apparently resulting from the transportation of the toxin along the 
lymphatic channels in the nerves to their centers in the spinal cord or 
medulla. Hence the paralysis is of central origin, but naturally distributed 
according to the source of the toxin 
Skin lesions in the height of the infection are usually in the form of an 
erythematous rash, but petechiae and extensive purpuric haemorrhages 
sometimes appear in the severest cases. 
LITERATURE 
Oertel: Pathogenese der epidemischen Diphtherie, Leipzig, 1887. Deut. Arch. f. klin. 
Med., 1887-8, xlii, 511. 
Nuttal and Graham Smith: Bacteriology of Diphtheria, Cambridge, 1908. 
Behring: Zeit. f. Hygiene u. Infektionskr., 1892, xii, 1-58. 
Welch: Johns Hopkins Hosp. Bull., 1892, iii, 17; 1895, vi, 97. Amer. Jour. Med. Sci., 
1894, n. s., cviii, 437. 
Low: Ziegler's Beitrage, 1910, xlix, 1. 
Walshe, F. M. R.: Medical Science, 1924, ix, 267. 
TETANUS INFECTION 
This, like diphtheria, is essentially an intoxication, since the bacteria 
grow only at the site of inoculation, usually in a wound into which dirt 
has been forced, and there produce a soluble toxin, which is diffused 
throughout the body. A certain latent period elapses after the infection 
before the symptoms appear, and the longer this lasts, the less serious 
are the effects. Those cases in which the incubation period is only four 
days are almost sure to end fatally. The effect of the poison is to produce 
extension and extreme rigidity of the extremities, often preceded by clench- 
ing of the jaw (hence lockjaw) and stiffness of the neck, and followed by 
violent contractions of the muscles of the back, such as to throw the body 
into a rigid backward curve (opisthotonos). When the muscles of respira- 
tion are involved, death ensues, or it may result from exhaustion. Reflex 578 
TEXT-BOOK OF PATHOLOGY 
or spontaneous convulsions of great violence may occur. At autopsy no 
lesions are found which are characteristic of the disease. It is true that 
Goldscheider and Flatau, Nissl, and others, have found swelling and frag- 
mentation of the tigroid bodies of the motor ganglion-cells and shrinkage 
with deep staining of the nuclei, but this condition is found under many 
other circumstances and is by no means specific. Tetanus must then be 
regarded as a functional disturbance produced by the toxin. Exactly the 
same phenomena can be produced in animals by the injection of the bac- 
teria-free toxin, which is an extremely virulent poison. 
In the pathogenesis of tetanus the greatest interest lies in the point of 
action of the poison and its mode of distribution. It is observed that 
there may be a local rigidity of the muscles in the neighborhood of the 
point of infection (local tetanus), but that while this may sometimes be the 
only symptom, it usually leads to a similar rigidity of the opposite extrem- 
ity, and finally to an involvement of the whole body (ascending tetanus). 
Another form, beginning with clenching of the jaw and stiffness of the 
neck, quickly spreads to all the extremities (universal or descending 
tetanus), while a third form is that in which convulsions form a striking 
feature. 
It was shown by Meyer and Ransom that the toxin travels from the 
point of inoculation up the nerves to the central nervous system, although 
it is also diffused to some extent by the blood and lymphatics. In the case 
of the local tetanus, which is less striking in man than in experimental 
animals, there arose some question as to the possibility of its being due to 
a direct effect of the toxin upon the muscles, but the experiments of Permin 
show clearly that if the nerve be cut shortly after the injection of the toxin, 
no such local rigidity appears. But the rigidity persists if the section of 
the nerve be performed after it is well established, probably owing to second- 
ary changes of unknown character in the muscles themselves. Similarly, 
Meyer and Ransom showed that the injection of antitoxin into the nerve 
above the point of inoculation would block and neutralize the toxin. Further, 
since it might be supposed that diffusion by the blood-stream could bring 
the poison to the ganglion-cells of the cord, Permin has shown by experi- 
ment that if antitoxin be injected first, so as to neutralize the poison carried 
by the blood, a distinct local tetanus can be produced by a small dose of 
toxin injected into the muscles. The poison passes along the nerves 
rapidly, probably in the axis-cylinders, since destruction of the peri- 
neurium does not halt it, and reaches the corresponding ganglion-cells 
of the anterior horn. If it is limited in quantity so as to affect only this 
group, a local tetanus will appear. Otherwise it can spread to affect the 
whole spinal cord and brain, and rigidity of the muscles over the whole 
body follows. 
In other cases in which the toxin gains more ready entrance to the blood- 
stream, or in which it is injected into the vein in an animal, the uni- 
versal or descending type appears. BOTULISM 
579 
The question as to the type of nerve which conducts the poison seems not 
yet settled,* nor whether the anterior horn cells become spontaneously 
active in sending impulses to the muscles, or only excessively irritable and 
responsive to sensory impulses, to which they act as in reflexes. Permin 
showed that, by cutting all the posterior roots on one side and injecting 
toxin into both legs, one produces local tetanus only on the intact side, 
while the leg, from which no sensory impulses reach the cord, remains 
relaxed. 
In the case of the convulsive attacks it seems that the impulses come from 
the brain itself, which in those cases has been affected by the poison. 
They can be prevented by the removal of the motor cortex in animals, 
and can be produced in their most extreme form in other animals by inject- 
ing the toxin into the brain or into the eye, whence it quickly passes into 
the brain. Tetanus is thus ordinarily the effect of the toxin upon the 
spinal cord, the convulsive features being due to its spread into the brain. 
The enormous importance of this disease, especially in the late war, 
where wounds were contaminated with the highly manured soil, in which 
the bacilli were abundant, has led to great efforts to counteract the poison. 
Antitoxin, so useful in guarding against the poison, and so active in neu- 
tralizing it in the blood, cannot follow it from the circulation into the 
nervous system. Therefore, unless it be injected into the nervous tissue, 
it is relatively valueless. As stated, it will block the passage of toxin 
along the nerve if injected into the substance of the nerve, but it must 
remain difficult to diffuse it into the substance of the cord and brain in 
more advanced cases. The mortality remains high, although certain 
narcotics are useful in stopping the flow of impulses from the ganglion- 
cells. 
LITERATURE 
Flatau: Flatau, Jacobsohn, and Minor, Path. Anat, des Nervensystems, Berlin, 1904,. 
i, 1290. 
Meyer and Ransom: Arch. f. exp. Pathol., 1903, xlix, 369. 
Moschowitz, A.: Annals of Surgery, 1900, xxxii, 416. 
Permin: Mitth. a. d. Grenzgeb. d. Med. u. Chir., 1913-14, xxvii, 1. 
BOTULISM 
For a long time it has been known that the eating of spoiled sausages, 
preserved meat, etc., might produce a fatal illness. This was especially 
common in Wurttemberg in the last century, but is now recognized every- 
where, and spoiled canned fruits and vegetables have also proven to be 
the cause. Van Ermengem cultivated a large Gram-positive anaerobic 
spore-bearing and gas-producing bacillus from spoiled ham in one such 
group poisoning, and this has proven since to be concerned in the later 
* Nevertheless, Meyer and Ransom produced only pain and greatly increased reflex 
excitability to pain by injecting the toxin into the spinal cord or posterior roots (tetanus 
dolorosus), while injection into peripheral sensory nerves was without result. They 
therefore think the motor nerves the paths of conduction of the poison. 580 
TEXT-BOOK OF PATHOLOGY 
outbreaks. It was called Bacillus botulinus, or Clostridium botulinum, 
and is evidently capable of producing a powerful toxin for which an anti- 
toxin can be made. As shown by Dickson, who has devoted himself to the 
study of this affection, the imperfect methods of home canning often allow 
this organism to develop in such things as canned beans, asparagus, fruits, 
etc., and these, if not boiled again before eating, convey the disease even 
when partaken of in minimal amounts. Chickens and other animals are 
also susceptible. The illness is essentially an affection of the nervous 
system with ophthalmoplegias, difficulties of deglutition and speech, and 
respiratory failure, and fatal results are very common. 
The studies of the pathogenesis of the disease are, however, entirely 
unsatisfactory. Ophuls and Dickson report multiple small thrombi in 
the vessels of the brain, but give no information about the presence of the 
bacilli or their localization. It seems to be assumed that the disease is 
caused by the toxin. It is evident that further studies of the exact 
relationship of the bacilli to the lesions must be made, and at present 
it seems hardly justified to regard this as a condition precisely analogous 
with diphtheria and tetanus, in which a local development of organisms 
allows a wide transfer of toxin to the nervous system. 
LITERATURE 
Dickson: Monograph of Rockefeller Institute, 1918, No. 8. 
Geiger, Dickson, Meyer: Public Health Bulletin, No. 127, 1922 (Epidemiology). 
Van Ermengem: Z. f. Hyg. u. Infektionsk., 1897, xxvi, 1. 
Warthin: Transactions Assoc. Amer. Phys., 1922. CHAPTER XXX 
TYPES OF INJURY.-BACTERIAL DISEASE (Continued) 
Asiatic cholera: Intestinal lesions. General intoxication. 
Bubonic plague: Transmission. Bubonic type. Pneumonic type. 
Glanders: Acute and chronic forms. 
Anthrax: Infection through skin, digestive tract, lungs. 
Influenzal infection. Relation to epidemic influenza; pneumonia, meningitis. 
Several other types of bacterial infection must be considered here, some 
of them infections of enormous importance at certain times, when they rage 
as epidemics, or in tropical countries, where they exist constantly as en- 
demic plagues, but described here only in outline. 
ASIATIC CHOLERA 
An epidemic disease spreading with the course of human travel, and occur- 
ring either in groups of cases or suddenly affecting a whole community. 
It is largely dependent upon infection of water supply or of food, and hence 
the rapidity of its spread in cities where the drinking-water comes from an 
infected source, as was the case in the Hamburg epidemic. It is endemic 
in India, and is the cause of hundreds of thousands of deaths every year 
in that country. 
Taken into the stomach and intestines, the spirillum of Koch requires 
forty-eight hours or more to develop to a sufficient extent to cause the symp- 
toms. Then the disease proceeds with extreme violence. There are sev- 
eral forms, in the mildest of which there is intense diarrhoea, which may 
pass off in a few days. In the so-called cholerine, there are diarrhoea, vom- 
iting, and extreme prostration. These conditions may pass into the more 
severe form, in which, with great desiccation of the tissues, there are pain- 
ful muscular cramps, cold sweats, stagnation of the cutaneous circulation, 
delirium, and collapse. In others the patient passes into coma and dies. 
Anuria, which may persist until death, is in many cases a most prominent 
feature, and is accompanied by acidosis. This is largely due to the extreme 
dehydration of all the tissues which leaves no water for excretion by the 
kidneys, and a very rational treatment which is in general use consists 
in the continuous infusion of salt solution in a slow stream into a vein. 
The following impressions of the pathological anatomy are copied from 
notes made in Manila at a time when I had an opportunity to perform a 
large number of autopsies in cases of cholera during an epidemic of con- 
siderable severity. When the body is brought warm to autopsy, rigor 
mortis appears during the autopsy and often draws the arms and legs into 
581 582 
TEXT-BOOK OF PATHOLOGY 
a cramped position. In cases which have lain several hours there is usually 
the most extreme rigidity. The face is not distorted, but the eyelids are 
drawn up so as to expose the uprolled eyes. The arms and legs are like 
iron and it requires one's full strength to break down such rigor. The 
pectoral muscles are hard and offer a wooden resistance to the knife. The 
hands and feet are blue and shrivelled and shrunken in the most curious 
manner. The skin over the balls of the fingers is wrinkled and in some 
cases almost hornlike and transparent. The same change is visible over 
the palms of the hands and soles of the feet. Elsewhere the skin is very 
inelastic and pasty, and when pinched up takes a long time to smooth down. 
The blood which oozes from the heart and blood-vessels is viscid and very 
deep red, almost black. In this state of extreme concentration it seems 
to coagulate less firmly than normal. 
The organs in general seem almost normal, and it is as though one were 
performing a series of autopsies on the normal victims of some railway 
disaster. The peritoneum contains no free fluid; even in the recesses and 
fossae there is usually not a drop. The peritoneal surfaces are dull and dry 
and are no longer slippery; when quickly pulled apart they sometimes ad- 
here a little and draw out minute threads of viscid fluid. The small in- 
testines are usually distended with fluid and gas, and are of a dull grayish 
rose color, showing injected blood-vessels. They are relaxed and tend to 
lie flat. The colon and parietal peritoneum contrast rather sharply with 
this on account of their relatively normal pearly white color. 
The pleural cavities, like the peritoneum, are dry, but the pericardium 
contains a little fluid. The thymus is enlarged in nearly every case. In 
children it is especially bulky, reaching 10 to 12 grams, and extending down- 
ward as a thick mass. Even in adults the organ lies over half the pericar- 
dium and may measure 10 cm. in length. This persistence of the thymus 
is especially striking and probably accords with the lymphoid swelling in 
the intestine. The heart shows no changes in anything except the pres- 
ence of many ecchymoses in the epicardium and in the endocardium, 
especially in the papillary muscles and trabeculae of the left ven- 
tricle. In marked contrast with the extreme rigidity of the body 
muscles the myocardium is rather soft, opaque, and grayish brown, 
and in its inner layers more yellowish. In the lungs there was in 
two or three cases a patchy lobular pneumonia, and in as many 
more distinct oedema. But in most instances there was no character- 
istic alteration. The spleen is not enlarged or, indeed, changed in any 
particular from normal. In no case was there found anything which 
could be described as an acute splenic tumor. The liver too is practically 
normal; the lobules are distinct and easily outlined and are not dull or 
cloudy looking. There were several cases, however, in which the liver seemed 
drier than normal and was very dark grayish red. The bile ducts seem 
normal and the gall-bladder is full of green bile which usually contains the 
cholera spirilla. It is said to show a definite cholecystitis at times, with ASIATIC CHOLERA 
583 
turbid fluid and reddened mucosa, but I saw no such cases. The pancreas 
shows no gross abnormality. The stomach is usually empty and its mucosa 
pale. The duodenum begins at once to show the characteristic lesions of 
cholera and these continue throughout the small and large intestine. 
The contents of the small intestine vary greatly; they are, as a rule, fluid, 
but not quite watery, for there is a viscidity due partly to the admixture 
of mucus. The fluid is like thin barley soup, gray and turbid. When the 
intestine is opened the fluid pours out with radiating shreds of gray mucus 
which are readily washed off the mucosa. Toward the lower ileum it often 
becomes tinged rose color, but this is by no means always so, and it may 
continue like thin gruel through the whole colon. "Rice water" must be 
a poor descriptive phrase, for the stools seem more viscid, turbid, and mucoid 
than that could be. Microscopically the contents of the upper ileum shows 
myriads of bacteria and thick masses of desquamated epithelium with few 
or no leucocytes. The bacteria are of many kinds, large stout bacilli, 
long rods both coarse and thin, minute thin bacilli, but rather few spirilla. 
They can be found after rather long search, but, of course, grow out abun- 
dantly on selective media. The epithelial cells seem to be partly digested 
and few of them will take a nuclear stain. They are often to be found in 
sheets. 
The mucosa is lax, smooth and slippery, and spreads out easily as though 
half decomposed. It is not swollen as in oedema, but seems to be easily 
permeated by the fluid, and not to hold it back. When washed it shows 
the individual villi as tiny opaque grayish-white threads. The mucosa has 
a certain opacity, about as intense as that of wet white tissue paper. It 
allows the red of the injected submucosa to show through as a rose color 
veiled by the gauzy wet mucosa. Lower in the intestine there may be many 
minute haemorrhages so fine as to give a pale red color to the mucosa in 
the neighborhood of the Peyer's patches and solitary nodules. In the lower 
ileum these lymphoid structures become swollen and prominent, not to 
the degree seen in typhoid fever or marked status lymphaticus, but still 
enough to make them quite conspicuous. There is no ulceration, although 
there may be haemorrhages of small extent. A frequent phenomenon is the 
appearance of a grayish-green opaque spot in the centre of each solitary 
nodule and each unit of the agminated patch. In a few cases the haemor- 
rhage is more intense, and in one case the whole mucosa was deep blood red 
with only a few patches of normal color. Occasionally there are, in pro- 
tracted cases, patches of diphtheritic exudate. 
The mucosa of the colon is almost exactly like that of the small intestine. 
It is pale, lax, moist, and rather white and opaque. In some cases there are 
many sharply outlined haemorrhages. The mucosa of the appendix is sim- 
ilarly altered, although to a slighter degree. The contents of the colon are 
like those of the ileum in most cases, but it must be remembered that there 
are some in which death occurs before diarrhoea appears, and in these cases 
of cholera sicca the colon contains formed faeces. TEXT-BOOK OF PATHOLOGY 
584 
The adrenals show nothing abnormal. The kidneys when not modified 
by old changes are practically normal in their general appearance. The 
capsule strips off smoothly, leaving a pale yellowish-gray and rose-colored 
surface. The size and consistence are normal. On section the striations 
of the cortex and glomeruli are normal in arrangement and the only abnor- 
mality consists in a slight opacity and yellow hue in the labyrinthine por- 
tions. Even in cases in which there was anuria for days before death I 
was able to see little more than this blotchy yellow opacity in the bands 
which contain the convoluted tubules. In other cases the kidney was found 
dry and dull looking, dark grayish-red, pasty, and inelastic. 
The urinary bladder is always empty or, at most, contains a few drops of 
thick, viscid, turbid yellow urine. The bone-marrow is soft, fatty, and 
often shows patches of dark red. The brain and cord show no obvious 
changes. 
Microscopically examined, the wall of the intestine shows an almost 
complete loss of the epithelium from the mucosa. Only in the depths of 
the crypts is any left, and the villi project quite uncovered. Their limit- 
ing membrane is still continuous, but the cells which fill them at their tops 
are all necrotic. The lymphoid nodules are swollen and show many frag- 
mented cells in their central portions, but there is no ulceration. The 
mesenteric lymph-nodes nearly always present wide areas of necrosis 
which occupy the position of the sinuses. The kidneys, in accordance with 
their naked-eye appearance, are undisturbed in their anatomical arrange- 
ment, and there is no inflammatory reaction, but in the severer cases there 
are profound destructive changes in the epithelial cells of the convoluted 
tubules. Even in the less advanced, certain tubules are partly lined by 
cells which are swollen and contain large hyaline droplets, but in those 
which have passed through several days of anuria the convoluted tubules 
are choked throughout their whole course with masses of necrotic cells. 
No constant changes can be made out in the spleen and liver in this series 
of cases, although, as stated, some authors have observed, apparently in 
cases which survive for some time, an acute cholecystitis and even an ex- 
tensive cholangitis. 
Great differences of opinion prevail as to the exact nature of the infection 
in cholera, especially with regard to the distribution of the organisms in 
the body. I found difficulty in distinguishing the spirilla in the mass of 
miscellaneous bacteria in the intestinal contents, while Schobl and others 
speak of that fluid as a pure culture of cholera vibrios. Most authors state 
that the specific organisms are confined to the intestinal tract, and that 
the violent symptoms are due to the absorption of toxic materials, but Col- 
onel Greig has found patches of bronchopneumonia loaded with the spirilla 
and has cultivated them also from the spleen. He therefore naturally 
regards the cholecystitis and cholangitis, and even the mere infection of 
the bile of the gall-bladder, as due to circulation of the bacteria in the 
blood, rather than to wandering from the intestine by way of the gall-duct. BUBONIC PLAGUE 
585 
The necrosis of the mesenteric glands which occurred so often in our series 
would suggest an escape of the organisms by way of the lymphatics. The 
necrosis of the renal epithelium has the appearance of a toxic process, es- 
pecially since the cholera vibrios have been so rarely found in the urine, 
although so carefully searched for. But so far cultures from the circulat- 
ing blood have been negative. 
The great frequency of infection of the bile is of much importance, since 
it is the basis of the persistence of the organisms in the excreta of convales- 
cents, just as in typhoid fever, although probably these persons do not 
remain infected for nearly so long a time. The stools have been found to 
contain the spirilla for forty to ninety days after recovery, but Kulescha 
had one case in whose bile-ducts they were found ten months after the 
onset of the disease. 
LITERATURE 
Krause and Rumpf: Handb. d. Tropenkrankheiten, Mense, 1914, iii, 242. 
Koch, R.: Arb. a. d. Kais. Gesundheitsamte, 1887, iii. 
Crowell: Philippine Jour. Science, 1914, ix, 361. 
Th. Fahr: Ergebn. d. allg. Path., 1909, xiiib 1. 
Schobl: Philippine Jour. Science, 1915, x, 11. 
Heiser and Ernst: Wood's Ref. Handb. Med. Sci., New York, 1917, viii, 552. 
Greig: Indian Jour. Med. Research, 1914, i, 67. 
Goodpasture: Philippine Journal of Science, 1923, xxii, 413. 
BUBONIC PLAGUE 
The plague is another affection endemic in certain countries, where it is 
essentially a disease of rats and other rodents, but spreading with the trans- 
portation of infected materials or rats to other countries. It has occurred 
with the same virulence in winter weather in Manchuria as in the heat of 
India or Africa. 
Plague is caused by the Bacillus pestis, discovered by Yersin and 
Kitasato, an organism of extraordinary virulence, capable of causing infec- 
tion from the slightest inoculation, and producing a highly mortal disease, 
in which it becomes distributed in enormous quantities through the 
body. Infection can occur through the skin, through the respiratory tract, 
and, possibly, though this is unimportant, through the digestive tract. 
By far the most common are infections through the skin, either through 
wounds (Diirck describes infection from a rat-bite) or through the bites of 
infected fleas. The rather rare cases of primary plague pneumonia are often 
caused by the inhalation of bacilli carried in fine droplets of sputum ex- 
haled by another person with plague pneumonia. In the great Manchurian 
epidemic of 1910-11 Strong tells me the cases were nearly a1! of the pneu- 
monic type and were uniformly fatal. He and his assistant escaped infec- 
tion by wearing thick masks of cotton. 
By far the greater number of the cases in ordinary plague are not of the 
pneumonic type, but are characterized by buboes or suppurations of the 
inguinal, axillary, and other lymph-glands. In these the infection is prob- 586 
TEXT-BOOK OF PATHOLOGY 
ably caused by the bites of fleas which have infected themselves from plague- 
stricken rats. C. J. Martin has shown me the plugs of plague bacilli which 
form in the proventriculus of the flea, preventing the access of any blood 
to its stomach. Such a flea, constantly hungry, will bite again and 
again, each time transferring plague bacilli to its victims. 
Fig. 285.-Pneumonic plague. The exudate and congestion are such as are described 
for the stage of engorgement in ordinary pneumonia. Great quantities of bacteria in 
the tissues, especially in the lymphatics of the bronchial walls. 
Bubonic Type -After a short incubation period, painful swellings appear 
in the groin. In the early stage these glands are swollen and sprinkled with 
haemorrhages. The lymph sinuses are packed with phagocytic cells which 
contain the bacilli in numbers. Necrosis follows quickly and becomes 
extensive, and is associated with much haemorrhage and outpouring of 
leucocytes. Diirck thinks it largely due to circulatory obstruction. The 
whole centre of the gland breaks down into an abscess cavity and may be BUBONIC PLAGUE 
587 
discharged. Metastases of the bacilli occur to the next glands, and 
shortly to the lungs and other organs. In the lungs foci of necrosis of the 
tissue with suppuration are produced by this embolism, and the same is 
true for the liver. There is a great swelling and softening of the spleen 
with grayish opacity, caused by the new formation of cells, which Diirck 
thinks are endothelial cells from the sinuses. Abscesses occur there also. 
In the kidneys there may be definite focal necroses, abscess like in 
appearance, with many bacilli, or more commonly an acute haemorrhagic 
nephritis with necrosis and desquamation of the epithelial cells, both in 
the glomerular capsules and tubules. 
On the whole, the appearance is that of a fulminant general septicaemia, 
with the lodgment of enormous numbers of bacilli in any or all of the organs, 
and their transportation in quantities in the lymph and circulating blood. 
Pneumonic Form.-In the bubonic form there may be found, in some 
cases, lobular consolidation of the lung, sometimes discrete, more often 
confluent. This is, in fact, the commoner type of pneumonia found in 
such epidemics as that of Manchuria, but Strong emphasizes the fact that 
the somewhat hypothetical stage of engorgement, always described for the 
pneumococcus pneumonia, is really the commonest phenomenon in these 
cases, since the affected persons die before actual hepatization can be pro- 
duced (Fig. 285). He describes lobar consolidation also, in which, how- 
ever, only a small part of the lung was ever found in the 'stage of gray 
hepatization, another part in that of red hepatization, while the greater 
part was in the stage of engorgement. Even in the gray stage there is 
little fibrin, while in the more usual stage of engorgement there are hardly 
any leucocytes, although the alveoli are filled with bacteria and fluid and 
desquamated epithelium, and the capillaries are greatly distended. 
In the other organs there were found evidences of an intense general 
septicaemia, with cloudy swelling and haemorrhages, but usually no such 
embolic lesions as described for the more slowly advancing bubonic form. 
LITERATURE 
Diirck: Ziegler's Beitrage, 1904, Suppl. vi. 
Albrecht and Ghon: Beulenpest im Bombay, Wien, 1898-1900. 
Strong and Teague: Philippine Journal of Science, 1912, vii, 129, 137. 
GLANDERS 
Primarily a disease of horses, mules, etc., infection with the Bacillus mallei 
may occur in those who handle horses or who are exposed in some way to 
contagion from them. In a few cases fatal infections have occurred in 
persons working in laboratories with cultures of the organism. 
In horses the disease is largely an affection of the nasal and respiratory 
tracts, and frequently assumes a chronic course. Nodules appear in the 
nasal mucosa, especially upon the septum, which are quite firm at first, 
but later present a necrotic centre and develop into ulcers, which heal with 588 
TEXT-BOOK OF PATHOLOGY 
extensive scar formation, recognizable by its curious stellate arrangement. 
Affections of the trachea and lungs, of the intestines, lymph-glands, spleen, 
etc., are also found in these animals (Kitt). 
In man the formation of necrotizing or pustular eruptions in the nose has 
been described, and in such cases the destructive action of the bacilli leads 
before long to the ulceration and perforation of the septum of the nose, 
partial destruction of the turbinate bones, or even of the palate. More 
Fig. 286.-Glanders. Focus of lobular pneumonia with abscess-like destruction of 
tissue and organization of adjacent exudate. 
common are infections through the skin, which give rise to deep indurated 
swellings which persist until incised, or until they burst spontaneously, 
setting free a thick, stringy pus. Such abscesses heal very slowly, and 
usually a sinus persists for a long time. In other cases serpiginous ulcers 
are formed in the skin which extend in one or other direction, leaving 
behind a partly healed or scarred area. Most of the cases have presented 
deep muscular abscesses which evacuate the same thick pus and are slow to ANTHRAX 
589 
heal. At times the bone is attacked, and in many instances there have been 
necrosis and final perforation of the bones of the skull. Multiple embolic 
lesions in which necrotic or caseous material is formed and surrounded by a 
dense granulation tissue are found in various situations in the body. Pul- 
monary lesions are especially frequent, and assume various forms. In one 
case which I studied in Professor Marchand's laboratory the man had been 
accidentally infected by thrusting the needle of a syringe full of a culture of 
Bacillus mallei into his thumb. Two months later he died with what 
appeared to be a diffuse tuberculous pneumonia. In these lesions, however, 
there were found the bacilli in pure culture, and microscopically the changes 
were quite unlike those of tuberculosis. Instead (Fig. 286), there were 
foci of necrosis with debris of cells and tissue closely coagulated together, 
but without nuclear stain, surrounded by a zone of fragmented nuclei, 
and this in turn by a thick infiltration of leucocytes. The adjacent lung 
tissue was the seat of an organizing pneumonia, and there was extensive 
filling of alveoli with large mononuclear cells, as in caseous pneumonia. 
In this case there was nothing of the formation of nodules with giant-cells 
which has been so generally described in the lesions of glanders. Especially 
in the foci in the nasal mucosa, but also in glanders lesions elsewhere, there 
is said to be an extensive new formation of epithelioid cells and even of 
giant-cells which gives the lesions something of the character of a tubercle. 
As Duval points out, this occurs only with bacilli of relatively low virulence 
and in the more chronic cases. Otherwise the necrosis of the tissue is 
quickly produced and the surrounding granulation tissue is less characteristic. 
LITERATURE 
G. D. Robins: Studies from the Royal Victoria Hosp., Montreal, 1906, ii, No. 1. 
J. H. Wright: Jour. Exp. Med., 1896, i, 577. 
Th. Kitt: Path. Anat. d. Hausthiere, 1901, ii, 138, etc. 
MacCallum: Ziegler's Beitrage, 1902, xxxi, 440. 
ANTHRAX 
A disease which affects cows, sheep, and other herbivorous animals is caused 
by infection with the well-known Bacillus anthracis, and is transmitted to 
man through contact with the sick animals, or through handling their 
infected hides. In certain industries which have to do with hides (tanning, 
etc.) or with hair or wool in the making of mattresses, paper, etc., infection 
may occur, sometimes almost in epidemic form (wool-sorter's disease, 
Hadernkrankheit). 
Cattle are infected especially in pastures which are subject to inundation, 
but a field once infected may remain so for a long time, and the infection be 
added to by the excretions of the cattle themselves, or by the soiling of the 
ground with the remains of cattle which have died or been slaughtered 
and buried there. Naturally, chances for infection occur in the stalls 
where such cattle are kept. TEXT-BOOK OF PATHOLOGY 
590 
In these animals the disease may be very acute, killing within a few hours, 
or there may develop definite carbuncles or more diffuse oedema in the skin 
or in the intestinal tract. At autopsy there is found a general septi- 
caemia-the blood-vessels are full of the bacilli, and the internal lesions in 
general are ecchymoses, acute splenic tumor, cloudy swelling of liver and 
kidneys, etc., such as might be found in other acute infections. 
In man the portal of entry may be through the skin, the digestive tract, 
or the lungs. In the case of the skin some slight abrasion is usually the 
point of entrance, although it has been shown experimentally that anthrax 
bacilli rubbed on the intact skin can pass through the hair-follicles. During 
the war there were several cases in which the infection was traced tc the 
use of shaving brushes made of hair from infected animals. A small pain- 
ful red nodule appears, resembling a flea-bite, and rapidly enlarges 
and shows a greenish, necrotic centre, induration and reddening of the 
surrounding tissue, with blisters filled with yellowish or bluish fluid. 
This phlegmonous infiltration of the skin and subcutaneous tissue spreads 
quickly, and the central part dries up into a leather-like crust under which 
the tissue is necrotic and loaded with anthrax bacilli. Such a carbuncle 
is at least evidence of a certain resistance, although from it the bacilli 
may spread in quantities into the blood. There is another type in 
which, instead of a localized carbuncle, a wide-spread oedema of the skin 
and underlying tissue appears, with myriads of bacilli. This indicates a 
poorer ability to resist, and passes on to a more surely fatal outcome. In 
the more resistant cases the leucocytosis is high and phagocytosis is active, 
but in some the bacilli surround themselves with thick capsules, and are 
then not readily taken up by the leucocytes. It is thought that the forma- 
tion of such capsules is an indication that the bacilli are gaining the upper 
hand in the struggle, and the prognosis is correspondingly bad. The 
neighboring lymph-glands become swollen and haemorrhagic, and thence 
the infection becomes generalized. 
In the persons who work with hair, hides, and wool, inhalation of the 
dust which bears the anthrax spores produces a singularly fatal form of the 
disease, which is primarily a lobular or lobar pneumonia, distinguishable only 
by the recognition of the bacilli from other types of pneumonia. Eppinger 
has described many cases in which he found lesions chiefly in the thoracic 
viscera; the pleural and pericardial surfaces were covered with a fibrino- 
purulent or haemorrhagic exudate, and the lungs were partly consolidated. 
A lobular or confluent hepatization of the lungs with exudate of a soft or 
haemorrhagic character was found, and microscopically the alveoli, as well 
as the lymphatics and tissue crevices, were loaded with bacilli. Neighbor- 
ing lymph-glands were greatly enlarged and haemorrhagic, and elsewhere 
there were the changes of a general septicaemia. Rise! described in this 
connection great haemorrhagic infiltration of the mediastinal tissues, as well 
as of the bronchial lymph-glands. In persons who have swallowed infected 
meat or milk there arise intestinal carbuncles, just as in cattle. These are 
usually single, but may be multiple, and occur most commonly in the ANTHRAX 
591 
jejunum. The lesion seems to begin in the depths of the mucosa, or in the 
submucosa, and appears as a red, pea-sized to plum-sized swelling, which is 
made up of cedematous tissue loaded with bacilli and leucocytes. The 
whole adjacent mucosa and submucosa become infiltrated, and the car- 
buncle itself ulcerates deeply. The mesenteric glands swell and are 
haemorrhagic. 
In all these cases there are evidences of the most intense acute general 
infection. Probably in no other disease do such quantities of bacteria 
appear in the circulating blood. So extensively do they fill the capillaries 
Fig. 286A.-Anthrax meningitis. 
that it has even been suggested that in this disease the symptoms may be 
due to that obstruction. The bacilli can be recognized by staining a single 
drop of the circulating blood. The spleen becomes greatly swollen and 
soft and turgid with dark blood. Indeed, it is from this dark color and 
incoagulability of the blood, which give the spleen such a peculiar appear- 
ance, that the disease derives its various names (Milzbrand, charbon, an- 
thrax). Cloudy swelling of the liver and kidneys is constant, but there 
may also be necrosis and disintegration of the cells in these organs. 
Haemorrhagic meningitis appears to be not uncommon, and in one of 
Risei's cases it formed the most striking feature. There were in the 
nasal mucosa ulcerated nodules extending into the submucosa, and from 
these a haemorrhagic cellular exudate rich in bacilli could be traced along 
the lymphatic sheaths of the olfactory nerves to the brain. 592 
TEXT-BOOK OF PATHOLOGY 
Figure 286A illustrates the meningeal lesions from a recent case which 
we studied. 
LITERATURE 
Risel: Zeit. f. Hygiene, 1903, xlii, 381. 
Eppinger: Die Hadernkrankheit, Jena, 1894. 
Koranyi: Nothnagel's Handb., 1897, Bd. v, Th. v, Abt. i. 
Salmon and Smith: United States Department of Agriculture, Bureau Animal Im 
dustry, Circular 71, 1904. 
W. Koch: Deutsche Chirurgie, 1881, Lief 9. 
Herzog: Ziegler's Beitrage, 1915, lx, 513. 
INFLUENZA 
From remote antiquity the disease which is now called influenza or la 
grippe has been known on account of its extraordinary power of spreading 
with great rapidity over whole countries, or even over the whole world. 
The history of the disease, which may be read in Hirsch's Geographical 
and Historical Pathology, or in the monographs of Ripperger and of 
Leichtenstem, is truly remarkable, since the records of the epidemics go 
back to the tenth century and show that in some way not yet understood 
the peoples of all countries have been visited periodically. There is no 
definite regularity about the appearance of the great epidemics, although 
it. has been thought that they come about every thirty years. Then the 
disease sweeps round the whole world, progressing westward in a general 
way, although this too is questioned. The last pandemic outbreak was 
in 1889, after which vague local epidemics occurred without attracting 
special attention until 1918, when the more familiar recent world visita- 
tion occurred. 
The name influenza, which merely means "influence" in Italian, is de- 
rived from the mistake of someone, who, in attempting to read an Italian 
treatise, thought it the name proposed for the disease. It has long been 
recognized as a specific infectious disease, and from the general uniformity 
of the symptoms when occurring in epidemic distribution it has been easy 
to identify it in each new outbreak. Isolated cases at other times are, 
however, not so certainly diagnosed. 
This affection is described at this point not because there is anything 
to show that it is a bacterial disease, but because there is no sufficient 
proof that it should be classed otherwise. It has, however, the general 
characters of the exanthematic diseases, such as measles and scarlet 
fever, which we do not think of as caused by bacteria. Indeed, Bloom- 
field and Harrop have described a rash and an eruption in the mouth as 
quite characteristic. 
The symptoms are much like those of a cold, with fever, catarrhal in- 
flammation of the mucosae of the nose and throat, general aching and pros- 
tration. There is no leucocytosis, but a marked decrease in the number of 
leucocytes (leucopenia), and in association with this the resistance to INFLUENZA 
593 
bacterial invasion is greatly lowered-more, indeed, than in any other 
disease. No one as far as we know has died of influenza, and we are 
practically entirely uninformed as to the nature of any changes in the 
internal organs which may result from it. It passes off after a few days 
and apparently confers an immunity, although it is difficult to make this 
statement with any assurance. It seemed nevertheless that those who 
had lived through the epidemic of 1889-91 were seldom affected in the 
recent epidemic, while young, strong persons were attacked. In remote 
islands of the Pacific and elsewhere this did not come out clearly, and it 
seemed to be the old and weak who suffered. Experiments conducted 
by Prof. M. J. Rosenau for the purpose of inoculating volunteer non- 
immunes failed completely. Every conceivable mode of transmitting the 
disease from patients in every stage of the illness was tried, but in no way 
could he provoke the appearance of influenza in his volunteers. Similar 
experiments were carried out in California with young volunteers who had 
never been exposed to the disease, and these also gave negative results. 
Sputum, blood, and other fluids were inoculated, without the slightest 
effect. Nevertheless the disease spreads with the most astounding 
rapidity, and appears, as it seems, explosively in all quarters of a city or 
of a country at once. It seems incredible that anything but human 
intercourse could be responsible, but all sorts of other explanations have 
been proposed without much solid foundation. Much has been made .of 
the fact that in several instances epidemics of influenza have appeared 
on ships while coasting along the shore of a country where the disease 
raged, although the ship never touched land. 
Although no one has died of influenza directly, the predisposition of 
those affected to secondary infection with all sorts of bacteria is such 
that hundreds of thousands and even millions of persons have died in 
the course of the present epidemic (for a recrudescence seems to be in prog- 
ress) from the pneumonia produced by the secondary invaders. Almost 
all the bacteriologists and pathologists in the world have seized the op- 
portunity to investigate the disease, and the results up to the present have 
been most confusing. After the last pandemic appearance of the influenza 
R. Pfeiffer studied the bacteria in the bronchial secretion of sporadic 
cases of bronchitis and pneumonia, and discovered a minute bacillus 
which was Gram negative and required haemoglobin for its growth. Al- 
though the epidemic had been over for two years, he announced without 
any proof whatever that this bacillus was the cause of influenza, and it 
took the name Bacillus influenzae. Nothing could have been the source 
of more confusion, for this organism or one of its varieties is extremely 
widely distributed and common at all times and can be found in the 
throats of many healthy people, as well as in the bronchi of those with 
tuberculous and other pulmonary diseases. Rivers has found that 
there are pathogenic and non-pathogenic forms readily separable by cul- 
tural and agglutination characters. The pathogenic group is a serious TEXT-BOOK OF PATHOLOGY 
594 
cause of disease and is prominent among the secondary bacterial invaders 
in producing pneumonia after influenza. 
There are still some investigators who think this bacillus of Pfeiffer 
is the cause of the epidemic disease influenza, and Blake and Cecil think 
they have reproduced the epidemic disease in monkeys by intratracheal 
inoculations of the bacillus of Pfeiffer. I myself do not think the epidemic 
disease influenza is caused by this bacillus, because the forms of pneu- 
monia which follow influenza 
are not all alike, and there is 
one perfectly characteristic 
group which is caused by the 
Pfeiffer bacillus in pure cul- 
ture. Further, there are many 
cases in which I have been 
unable to find the bacillus at 
all, although other organisms, 
such as the pneumococcus or 
streptococcus, were present 
and produced pneumonia. It 
is, of course, possible that 
some bacterium might cause 
the epidemic disease and then 
be overgrown and obliterated 
by another, which produces 
the secondary pneumonia. 
But it is especially because of 
the phenomenal rapidity of the 
spread of the infection, which 
is so unlike that of any bacte- 
rial disease, that it seems im- 
probable that it should be due 
to the bacillus mentioned. In 
Camp Meade, where the ad- 
vent of the epidemic was 
awaited, since it had pro- 
gressed from the north to New 
Jersey, 3 cases appeared in one 
day and 3000 next day. 
Sequelae of Influenza.-In many cases pneumonia follows quickly 
upon influenza and is accompanied if untreated, by an intense inflammation 
of the larynx and trachea. The pneumonia is caused by pneumococci of 
all types-by a haemolytic streptococcus, by the Staphylococcus aureus, 
Friedlander's bacillus, the bacillus of Pfeiffer, or by a mixture of two or 
more of these and various other organisms. The anatomical character 
of the pneumonia varies with the resistance offered, as in the case of the 
Fig. 286B.-Pneumonia caused by the pneu- 
mococcus during the epidemic of influenza in a 
person still suffering from that disease. INFLUENZA 
595 
post-measles pneumonias described under the heading Streptococcal In- 
fections, but for some of the organisms there are more or less typical 
forms, since in all the patients the resistance is greatly lowered. 
The pneumococci produce a confluent lobular consolidation (Fig. 
286B) which begins in very sharply outlined blocks of elastic oedemat- 
ous haemorrhagic tissue in which the ductuli alveolares are lined with a 
hyaline membrane and are filled with fluid, while the alveoli contain a 
Fig. 286C.-Pneumococcal pneumonia in influenza. The ductuli alveolares are dis- 
tended with fluid and lined with a peculiar hyaline material. The alveoli contain an ex- 
tremely fresh exudate. 
fresh red clot of exudate made up of a loose fibrinous exudate with well- 
preserved red corpuscles and leucocytes and myriads of organisms (Fig. 
286C). This hyaline lining membrane runs from the bronchioles down 
into the alveoli, but keeps the form of a thin layer. It does not give the 
reactions for fibrin. It is a substance which we have not seen in other 
cases of pneumonia than those following influenza, although it is said to 
appear in the lungs of those who have been killed by war gases. Good- 596 
TEXT-BOOK OF PATHOLOGY 
pasture has published a paper stating that this membrane is one at least 
of the specific lesions due to the influenza itself. Staphylococci may be 
associated with a similar consolidation, but tend to produce discrete ab- 
scesses. Friedlander's bacillus causes an analogous consolidation, but 
with a viscid glutinous exudate. The haemolytic streptococci bring 
about a wide-spread and extreme oedema with extensive confluent consoli- 
dation. The tissue is loaded with organisms, and necrotic where they 
are most abundant. We found no cases in which the patient's tissues 
were resistant enough to produce 
the interstitial form seen after 
measles. 
The influenza bacillus of Pfeiffer 
when present in pure culture causes 
in those persons who appear to be 
least resistant an intensely haemor- 
rhagic consolidation in which the 
lobular areas run together. The 
leucocytic exudate is not very con- 
spicuous, but is especially dense 
about the bronchioles. In other 
cases which appear to be more re- 
sistant the Pfeiffer bacillus alone 
produces numbers of yellowish- 
white, firm, nodular areas of con- 
solidation about terminal bron- 
chioles (Fig. 286D). These project 
from the cut surface almost like 
tubercles, but are found on micro- 
scopical examination to be due to 
the great thickening of the wall of 
the bronchiole and of the walls of 
the neighboring alveoli, partly by a 
new growth of connective tissue and 
partly by infiltration with wander- 
ing cells. The alveoli and the 
bronchiole are filled with leucocytes. 
This is a form of interstitial bron- 
chopneumonia somewhat different from that caused by the hjemolytic 
streptococcus. The bacilli are not strictly limited to the bronchiole, the 
exudate is composed of polynuclear leucocytes with little or no haemor- 
rhage, the lymphatics of the interlobular spaces and vessel walls are not 
specially involved, and there is no great pleural effusion. Usually these 
lungs are dry and pale and adherent to the parietal pleura. This sort of 
nodular interstitial bronchopneumonia caused by Pfeiffer's bacillus is 
quite common in children as a sequel of whooping-cough, measles, etc., 
Fig. 286D.-Interstitial bronchopneu- 
monia caused by the bacillus of Pfeiffer 
in a person who began with influenza. INFLUENZA 
597 
and is sometimes almost indistinguishable from tuberculosis when viewed 
only with the naked eye. 
Healing processes end in extensive organization of exudate, bronchiec- 
tasis, and a most remarkable hyperplasia of epithelium in the alveoli 
which produces epithelial masses which sometimes look like giant cells, 
sometimes like an invading tumor. 
The anatomical picture in each type of Pfeiffer bacillus pneumonia, 
fresh and late, is so frequently repeated that it seems to be characteristic 
enough to afford a very good indication of the bacterium concerned. 
The bacillus of Pfeiffer has been found several times as the cause of 
acute endocarditis. It is also found not infrequently and especially in 
children as the cause of acute fibrinopurulent meningitis in the exudate 
Fig. 286E.-Interstitial bronchopneumonia caused by the bacillus of Pfeiffer. 
of which it is abundant. Dr. Howland has had 21 cases of this affection 
and they appear to be wholly independent of any epidemic. In one of 
these cases I found at autopsy not only the acute meningitis, but an acute 
peritonitis in which the same organism was present alone in the exudate. 
It is probably in the upper air passages that it is most frequently to 598 
TEXT-BOOK OF PATHOLOGY 
be found. Crowe and Neville found it often infecting the antrum of 
the upper maxilla. In the lung it appears to accentuate the develop- 
ment of tuberculosis, and in the cavities and in bronchiectatic spaces it 
persists for a very long time. 
LITERATURE 
Hirsch: Handbook of Geographical and Historical Pathology, New Sydenham Society, 
1883, vol. i, 7. 
Leichtenstern: Influenza, Wien, 1912, A. Holder. 
Ripperger: Influenza, Munchen, 1892, Munch. Med. Woch., 1893, xl, 775. 
Davis, D. J.: Jour. Infect. Dis., 1912, x, 259. Amer. Jour. Dis. Child., 1911, i, 249. 
Chickering and Park: Jour. Amer. Med. Assoc., 1919, Ixxii, 617. 
Opie and others: Ibid., p. 556 
Goodpasture: Ibid., p. 724. U. S. Naval Med. Bulletin, 1919, xiii, No. 2; Amer. Jour. 
Med. Sci., 1919, clviii, 863. 
MacCallum: Jour. Amer. Med. Assoc., 1919, Ixxii, 720. Medical Record, May 10, 1919. 
Bloomfield and Harrop: Johns Hopkins Hosp. Bulletin, 1919, xxx, 1. 
Nolf, Spehl, Colard et Firket: Archives Med. Beiges, 1919, Ixxii, 1. CHAPTER XXXI 
TYPES OF INJURY.-BACTERIAL DISEASE (Continued) 
Typhoid infection: General relations. Intestinal, lymphatic, splenic, and other lesions. 
Necroses in various organs. Affections of circulatory, respiratory, and nervous system. 
Paratyphoid infection: Relation to typhoid and enteritis infection. Acute gastro-enteritis, 
accessory lesions. 
Dysentery: Various organisms concerned. Intestinal lesions. 
TYPHOID INFECTIONS 
Infection with the Bacillus typhosus ordinarily produces characteristic 
lesions only in man, although Greenbaum has succeeded experimentally 
in setting up similar effects in the organs of chimpanzees by inoculation. 
In the smaller laboratory animals a general septicaemia may follow infec- 
tion, but there are none of the destructive anatomical changes observed 
in man. 
In man, although attention has long been concentrated upon the more 
local manifestations, there occurs a general septicsemia in which the bacilli 
are readily demonstrated in the blood in the earlier days of the disease, less 
readily or not at all in the later stages. While in most cases the local altera- 
tions of the intestines are most striking, they may be completely absent, 
so that it seems that the less conspicuous changes due to the general dis- 
tribution of the bacilli are more constant and characteristic features. 
The bacilli gain entrance by way of the digestive tract, being introduced 
with drinking-water, vegetables grown on infected ground or watered with 
infected water, and infected milk and other food into which the bacilli 
may have been introduced in the process of preparation. Even ice and 
oysters seem to have been the source of infection in epidemics. Flies 
may carry the bacilli from exposed faeces, etc., to food. Since persons 
who have recovered from typhoid fever may harbor the bacteria in bile, 
urine, and faeces for many years, they become a menace to others, and 
especially when they act as cooks the danger of their transferring the bacilli 
to food is very great. Thus a recent epidemic in the Sloan Hospital was 
traced to a cook who was a typhoid-bacillus carrier. Another, reported 
in the Journal of the American Medical Association in 1915, was traced in 
the same way to the cook who prepared a large panful of spaghetti, even 
though it was cooked in another place and not again touched by her. It 
was shown that in the spaghetti, which had stood overnight, there had been 
a great growth of the bacilli, which in the cooking were scarcely warmed in 
the centre of the mass. 
Typhoid fever is essentially a disease of unsanitary conditions of life, 
599 600 
TEXT-BOOK OF PATHOLOGY 
and disappears in proportion as the food and water supplies are kept 
clean. But the introduction and perfection of the method of vaccination 
against typhoid infection by Wright and Russell has gone far toward ob- 
literating the disease altogether. When the troops were called together 
in the camps during the war, some such plague of typhoid fever as occurred 
at the time of the Spanish War might have been expected. But vac- 
cination of every recruit was compulsory, 
and there was no typhoid. It is one of 
the few great triumphs of preventive 
medicine, but it is not all powerful, for 
overwhelming doses of bacilli will still 
produce the disease. Although the wards 
of the hospital used to be filled with these 
cases, they are rare now, and the only 
autopsy we have seen in the last year was 
in the case of a cleaner in a laboratory 
who must have swallowed a culture. 
Infection with the Bacillus typhosus 
produces in man a protracted febrile dis- 
ease, which begins usually one or two 
weeks after infection and lasts for five or 
six weeks or more. There are localized 
changes in the intestines, especially in the 
lymphoid structures, in the abdominal 
lymph-glands, the spleen, and bone-mar- 
row. There is a general cloudy swelling 
of the organs, with wide-spread focal ne- 
croses, and other less constant lesions. 
Intestinal Lesions.--In the first week 
of the disease the lymphoid nodules of 
the intestines, including, of course, the 
Peyer patches, become swollen and stand 
up above the surrounding mucosa (Fig. 
287). This may be caused partly by hy- 
peraemia, but is chiefly due to an increase 
in the numbers of lymphoid and other 
cells. The change is most evident in those 
Peyer's patches and solitary nodules in 
the lower part of the ileum, becoming less marked, and finally fading away 
toward the upper part of the intestine. In the colon the degree of swelling 
varies greatly-sometimes it is imperceptible; in other cases it is extreme 
and overshadows the slighter changes in the ileum. On gross inspection 
it appears that this swelling is sharply limited to the lymphoid structure, 
which thus become very conspicuous and prominent, but it may be con- 
cluded, both from the microscopical examination in this stage and from 
Fig. 287.-Typhoid fever with 
swelling and beginning ulceration 
of Peyer's patches. TYPHOID INFECTIONS 
601 
the later ulceration, that the alteration in the tissue extends beyond 
their limits. There is a catarrhal inflammation of the rest of the mucosa, 
which may be evident as a moderate hyperaemia, but is often incon- 
spicuous. 
Later, in the second week in most cases, the superficial parts of the swollen 
Peyer's patches and nodules lose their reddish-gray color and the velvety 
smoothness of their surface, and in smaller or larger areas become opaque 
and dry looking, and in these areas become stained a brownish-green from 
the intestinal contents. This is the formation of the slough, which is an 
expression of the partial necrosis of the swollen patch. Sometimes the 
change progresses rapidly and goes 
deep, involving all but the margin 
of the patch. In the nodules the 
necrotic slough appears as a little, 
rough, greenish plug embedded in 
the top, and surrounded by the hy- 
persemic margin. From the outside 
the Peyer's patches can be recog- 
nized, as a rule, by their darker 
color and by the injection of the 
subserous blood-vessels, but, as a 
rule, the solitary nodules scarcely 
show through at this stage. 
Not all the swollen Peyer's 
patches or solitary nodules advance 
to this stage. Indeed, in every case 
at autopsy it is usual to find some, 
perhaps even the majority, which 
have proceeded no further than the 
swelling, as far as the unaided eye 
can see. It is quite common to find 
the advanced change only in those 
situated rather low in the intestine, 
near the ileocsecal valve, although 
it is quite true that there are other 
cases in which all the lymphoid areas throughout the greater part of the 
ileum have run the whole gamut of changes. In persons who recover 
and in whom these swollen lymphoid structures which have not pro- 
gressed to necrosis return to normal, there must be a process of resolu- 
tion somewhat analogous to that in pneumonia. Still later other 
changes occur in those Peyer's patches which present necrotic areas. 
The greenish mass retracts a little from the edge and loosens all 
around its margin. The crevice goes deeper toward the middle (Fig. 
288), and soon the whole slough is dislodged and falls into the lumen 
of the intestines, leaving an excavation or ulcer of corresponding depth 
Fig. 288.-Typhoid fever. Swollen 
Peyer's patches with beginning separa- 
tion of the slough. 602 
TEXT-BOOK OF PATHOLOGY 
(Fig. 289). If the slough is completely removed, it leaves a clean ulcer, 
the bottom of which is usually formed by the muscular layers of the 
wall, which show plainly the parallel arrangement of their fibers. Some- 
times the ulcer is more shallow, and then its floor is part of the infiltrated 
submucosa-at other times it is deeper and may even extend quite through 
Fig. 289.-Typhoid ulcers after the discharge of most of the necrotic tissue. 
to the subserous tissue, in which case complete perforation is likely to 
occur. One may find such ulcers on the point of perforation with only a 
thin, easily torn film of the necrotic wall remaining. From the outside this 
appears as an opaque, greenish-gray patch surrounded by a dark haemor- 
rhagic zone. 
It has already been said that the ulcer need not excavate the whole of TYPHOID INFECTIONS 
603 
the swollen patch. One frequently finds several small and rather deep 
ulcers in one Peyer's patch, separated from one another by partitions of 
still living tissue. On the other hand, the ulceration may extend quite 
beyond the margin of the lymphoid tissue, so as to correspond no longer 
with the original form, and in the neighborhood of the ileocsecal valve 
it is common to find neighboring ulcers confluent to such a degree that 
only small islands of mucosa are left. Higher up it is usual to find the 
ulcers more limited to the outlines of the Peyer's patches and solitary nod- 
ules. Quite similar processes take place in the colon and in the vermiform 
appendix, and it is not uncommon to have a perforation in the base of an 
ulcer in the latter situation. Since these perforations occur rapidly with- 
out time for any adhesions to form between the intestinal loop and other 
tissues, a general peritonitis is the common result. Naturally, in this 
respect perforations in the free moving ileum are more serious and likely 
to be fatal than those in the appendix, where localizing agencies are more 
available. 
In many cases there is bleeding from the ulcerated intestinal wall, the 
blood escaping with the stools sometimes in such quantities that the 
patient dies from its loss. It is rare that one can find any vessel which can 
be shown to have been the source of the haemorrhage. 
After the ulcer is cleaned of its slough, healing begins by the formation 
of a layer of granulation tissue in the base, soon followed by the growth 
of a single smooth layer of epithelium across its surface. The depression 
into which this epithelium must grow is before long made up to its original 
level by the new formation of lymphoid tissue, and it becomes impossible 
to tell where the ulcer had been. No great scar formation occurs, and 
there seems never to be a stricture of the intestine due to the healing of a 
typhoid ulcer. 
The nature of these lesions is rather different from any of the effects of 
bacterial invasion met with so far, and is to be understood only in the light 
of the general effect of the typhoid bacillus upon the body. The bacteria 
hitherto studied have been found to produce a reaction on the part of the 
bone-marrow, which liberates into the circulating blood great numbers of 
polymorphonuclear leucocytes. Such a leucocytosis fitted well with the 
mechanism of ordinary inflammation, and even though we recognized the 
presence of many mononuclear wandering cells in all stages, and especially 
in the more chronic forms of inflammation, the polynuclear neutrophiles 
dominated the scene in fresh inflammations. In typhoid fever there 
is no such leucocytosis-the total number of leucocytes per cubic milli- 
metre is rather decreased, and the lymphocytes become relatively numer- 
ous. Even in the presence of secondary infections, which in normal 
persons produce a leucocytosis, the bone-marrow seems incapable of 
responding actively, and there is only a halting leucocytosis. 
In the typhoid lesions the bacilli are found-indeed, they are carried 
everywhere in the circulating blood, but their presence rather repels the 604 
TEXT-BOOK OF PATHOLOGY 
polymorphonuclears. Nor is it possible, as in the case of the staphylo- 
coccus, to demonstrate the bacilli as the central point about which the 
lesion is concentrated. Instead, one finds clumps of bacilli in the tissues 
without any striking reaction about them, and elsewhere foci of coagula- 
tive necrosis, with few or no bacilli. 
In the earliest stages of medullary swelling (Fig. 290) the Peyer's patches 
and solitary nodules show an increase of the lymphoid cells, which become 
scattered into the adjacent mucosa and into the submucosa underneath. 
But the lymphocytes, many of which seem to have emigrated from the 
blood-vessels, are soon rendered less conspicuous, and separated by the 
appearance of great numbers of large pale cells with rather pale vesicular 
nuclei. It is about these cells, which occur in all typhoid lesions, that 
violent discussion has raged, especially with regard to their origin. They 
are most actively phagocytic, and engulf the injured lymphocytes until 
soon the latter are found only in groups, while the large cells, each of which 
may contain two or three bodies of lymphocytes, occupy most of the field. 
Fig. 290.-Typhoid fever. Beginning swelling of a lymph-nodule in small intestine. 
Hoffmann and Billroth described these cells and noted their phagocytic capacity. 
Mallory decides that, since they behave like endothelial cells, they are endothelial cells, 
and without further ado calls them endothelial cells throughout. Marchand, more 
cautious, thinks that they may be partly derived from the reticulum cells, partly from 
the endothelium of the lymphatics. Saltykow thinks that he can trace them from the 
endothelial cells of the lymph sinuses, but finds them mixed in the sinuses with lymphoid 
cells of various types. It is a matter most difficult to decide by the fallible methods 
of tracing transitions, and especially difficult in this case, since it is so rare a piece of 
fortune to be able to study the typhoid lesions in their earliest stages. 
The cells seem to be mobile not only because they are phagocytic, but because they 
are found in abundance far in the tissue of the submucosa, away from the reticulum 
of the lymphoid tissue and from the lymphatic channels. They are not peculiar to 
typhoid fever, but occur in identical form in tuberculosis and other affections. 
It seems, indeed, that they are indistinguishable from other large mononuclear wander- 
ing cells, and that the conception of the lesions in typhoid fever becomes far simpler 
if we look upon them as a form of reaction in which the wandering cells which come 
into the neighborhood of the bacilli are the various types of wandering mononuclear 
cells instead of polynuclear leucocytes. That some endothelial cells can act as phagocytes 
is unquestionable, but that the whole reaction to the presence of the typhoid bacilli should TYPHOID INFECTIONS 
605 
be ascribed to endothelial cells makes typhoid fever a disease without an analogue. 
While it is perfectly clear that in the spleen the endothelial cells of the venous sinuses 
are in typhoid fever, as in other conditions, actively engaged in phagocytosis, it is not 
Fig. 291.-Edge of swollen patch in early stage of typhoid fever. The large phago- 
cytic cells are accumulated in the submucosa, and there are two lymphatic channels dis- 
tended with them. In the detail some of these phagocytes are shown with their content 
of injured lymphocytes. 606 
TEXT-BOOK OF PATHOLOGY 
so clear in other situations, such as the substance of the lymphoid tissue or the submucosa 
of the intestine, that the phagocytic cells are derived from the endothelium. Confusion 
arises perhaps from the persistence of the idea that all crevices in the tissues are lined, 
if only incompletely, with endothelial cells. It is my belief, on the contrary, that endo- 
thelial cells are not thus scattered everywhere, but that they form the specialized 
lining of closed blood-channels and lymphatic channels. The lymph-sinuses of the 
lymph-gland in connection with the lymphatic trunk are lined with continuous endo- 
Fig. 291A.-Typhoid fever. Margin of swollen and slightly ulcerated Peyer's patch. 
thelium, but these cells are not found everywhere among the elements of the lym- 
phoid tissue. This specific position, as the lining tissue of channels, is even more clearly 
seen in such tissue as the submucosa, where it is not confused by the great mass of 
lymphoid cells. How such lining cells could disperse themselves in such quantities and 
wander everywhere through the tissue without completely disorganizing the blood- and 
lymph-channels is not clear. This is, after all, the same question which confronts us TYPHOID INFECTIONS 
607 
every where as to the origin of the mononuclear phagocytic wandering cells, and it 
now seems clear from the work of Dr. Sabin that in the embryo they arise from the 
vascular endothelium at least in part and later wander in the tissues. Whether this origin 
is everywhere possible in adult life remains a problem. Instead, therefore, of calling 
them endothelial cells, I prefer to speak of the large, phagocytic cells briefly as macro- 
phages, and to regard them as members of the familiar, if much misunderstood, group 
of mononuclear wandering cells which are present in some stage of their development 
and wandering career everywhere through the tissues, and are especially ready to 
swallow up injured cells and fragments of cellular debris. 
The accumulation of the wandering cells, and especially of the pale 
macrophages, goes far to obliterate the architecture of the Peyer's patch 
and convert it into a continuous mass of cells. On the surface various bac- 
teria are found. Some of these may invade the interior, but this is es- 
Fig. 292.-Typhoid fever. Later stage, with superficial slough and beginning ulceration. 
pecially true of the typhoid bacilli, which are found in clumps in the tissue. 
Foci of coagulative necrosis appear irregularly, and not in any especial 
relation with the bacilli, and becoming confluent, form the slough (Fig. 
292). There is no leucocytic reaction to the presence of these patches of 
dead tissue-a zone of fragmented nuclei may mark them out. Some 
authors have thought them due to the diffusion of a poison produced by the 
bacilli; others ascribe them to anaemia produced (Orth) by compression 
of the blood-vessels or (Mallory) by thrombosis of the small arterioles and 
venules. Mallory describes many such thrombosed vessels, the thrombus 
being caused sometimes by the clumping of injured endothelial cells within 
the vessel, at other times by the lifting-up of the lining endothelium by 
cells and fibrin accumulated beneath it. 
At this stage, when the necrosis becomes confluent, nearly all the cells 
of the compact mass, even at a distance from the necrosis, show signs of 
degeneration and disintegration. Doubtless many macrophages burdened 
with lymphocytes and other materials fall into fragments, which are 
swallowed in their turn by other phagocytic cells. 
The lymphatic channels are often packed with cells, which they trans- 
port to the sinuses of the nearest lymph-gland. The stroma of the neigh- 608 
TEXT-BOOK OF PATHOLOGY 
boring mucosa presents changes almost exactly like those in the lymphoid 
nodules and in the submucosa, through the muscle, and in the subserous 
tissue one finds the fixed tissue elements spread apart by the abundant 
wandering cells. 
Lymphatic Glands.-The mesenteric lymph-glands become greatly 
swollen, soft, and often haemorrhagic. The retroperitoneal glands take 
some slight part in this, but the glands most affected are those which 
Fig. 293.-Mesenteric lymph-node in typhoid fever. The sinuses are filled with large 
mononuclear cells, among which are necrotic clumps. 
drain the most involved part of the intestine (Fig. 293). Bacilli are scat- 
tered in their sinuses and tissues. The lymph-cords show exactly the 
same changes as are seen in the Peyer's patches. The sinuses are enor- 
mously widened and packed with cells, which are mostly macrophages, 
although there are many lymphocytes. Probably most of these cells are 
swept into this situation from the intestinal lesions, but some may appear 
in the gland itself. Necroses quite like those described are found begin- 
ning in the mass of cells which fills the sinus, and extending thence to TYPHOID INFECTIONS 
609 
the lymph-cords. Sometimes nearly the .whole gland becomes necrotic. 
From the glands great quantities of the large cells and others can be swept 
on into the thoracic duct, and thus into the subclavian vein. In one in- 
stance (Verh. Dtsch. Path. Gesellsch., 1903, ix) I found them transported 
in this way in such quantities as to plug many branches of the pulmonary 
artery. 
The Spleen.-The acute splenic tumor, which is very constant in typhoid 
fever, differs from that found in other infections in the extreme abundance 
Fig. 294.-Acute splenic tumor in typhoid fever. The splenic pulp shows great accumu- 
lations of blood with phagocytic cells containing red corpuscles. 
of red corpuscles, both loose in the splenic pulp and engulfed in numbers 
by large phagocytic cells (Fig. 294). The presence of these "red-corpuscle- 
carrying cells" is, of course, the result of the profuse scattering of red cor- 
puscles out of the venules into the pulp. Many of them are clearly the 
endothelial cells of the splenic venules. Others correspond to the macro- 
phages seen elsewhere. There are relatively few nucleated cells in such a 
pulp, and if the haemoglobin is washed out by fixation of the piece of spleen 
in alcohol, the tissue looks rarefied under the microscope. Necroses occur 
in the splenic pulp, exactly as they do in the lymph-glands and Peyer's 610 
TEXT-BOOK OF PATHOLOGY 
patches. The result of these changes is the great enlargement of the 
spleen, which sometimes weighs 900 grams. The organ becomes extremely 
soft, and may rupture during life, with alarming or fatal haemorrhage. At 
autopsy it is usually like a semifluid mass of deep-red color, and on section 
the relatively unchanged Malpighian bodies are scarcely to be seen through 
the overflowing splenic pulp. In other cases the splenic pulp may con- 
tain many more macrophages than are shown in the drawing. 
Blood and Bone-marrow.-The blood contains bacilli through most of 
the course of the disease. The leucocytes are low, with usually a relative 
increase of the mononuclear cells. Platelets are decreased in number. 
In the course of the disease, especially in its later stages, there may arise a 
severe anaemia. The bone-marrow responds to the infection by the pro- 
duction of abundant lymphoid cells and others resembling plasma cells, but 
the formation of granulated myelocytes, the forerunners of the neutro- 
phile leucocytes, appears to be in abeyance. Everywhere through the 
marrow there are found the macrophages, which show here, as in the 
Peyer's patches, a great avidity for the injured bodies of other cells. 
Necroses occur, just as they do in the spleen and the lymphoid apparatus 
(Longcope). 
Liver and Gall-bladder.-The liver is always swollen, and on section 
appears dull, opaque, and inelastic. It forms a typical example of cloudy 
swelling, and microscopically the cells present the changes characteristic 
of that condition. Occasionally in the fresh-cut surface, or through the 
capsule, one can see minute, opaque, yellowish spots, which sometimes 
reach a diameter of 1 to 2 mm. These are focal necroses, which are con- 
stantly present in the liver in this disease, although they are usually so 
small as to be scarcely made out with certainty with the naked eye. Mal- 
lory describes two types-one produced in the lymphoid tissue, which 
occurs in the so-called portal spaces, and which shows changes identical 
with those in the Peyer's patches; the other occurring anywhere within the 
lobule, and involving the destruction of a group of liver-cells. The first 
type must be uncommon or very inconspicuous. The second is the type 
found in every typhoid liver. The foci consist of compact masses of dis- 
torted and fragmented cells, bound together with fibrin, and pretty sharply 
marked out from the surrounding tissue. Mallory regards these foci as 
anaemic areas caused by the plugging of the capillaries of the liver by macro- 
phages which have been swept in with the portal blood. These large cells, 
lodging in the capillaries, soon become surrounded by thrombi, which 
continue the occlusion. Frankel and others have thought the necroses due 
rather to the direct action of the toxin upon the liver-cells, with secondary 
invasion of wandering cells. 
It has always been difficult to believe that the occlusion of the capillaries, 
even if it occur on all sides of such a minute mass of tissue, should cause the 
death of the liver-cells in these tiny areas, since they might receive enough 
nutrition from the adjacent capillaries. In a series of dogs we have injected TYPHOID INFECTIONS 
611 
corn-starch in suspension so as to plug a great many capillaries, but with- 
out producing necroses, except perhaps in one case, where the capillaries 
became distended into great spaces filled with the granules and the liver- 
cells were compressed and displaced. Even then it was scarcely possible 
to demonstrate actual necrosis of the cells. 
Something analogous to this seems to occur in the typhoid liver, in which, 
in the necrotic and coagulated patches, one does not find many actual 
necrotic liver-cells. We 
have had an opportunity 
to study the beginning 
of the lesions in the liver 
of a man who had been 
ill only a few days, and 
in whom the autopsy was 
performed one hour after 
death, and it becomes 
perfectly clear that these 
foci are not primarily 
areas of necrosis of the 
liver-cells at all, but ac- 
cumulations of the large 
mononuclear cells swept 
in by the portal stream, 
which distend the capil- 
laries to a huge size and 
push aside the liver-cells 
(Fig. 295). Even in the 
middle of such a mass, 
that is, between two such 
distended capillaries, the 
liver-cells are found to be 
alive. It is possible that 
they may be so included 
as to be involved in the necrosis, but most of them are pushed aside, and 
the necrosis, when it appears, is essentially the degeneration and disinte- 
gration of a mass of macrophages which has packed itself into the widened 
capillaries at a point in the liver tissue from which the liver-cells have 
been for the most part dislodged, and has there become matted together 
by fibrin. When the areas become larger by the constant accumulation 
of the cells floating in the blood, it is no longer possible to determine how 
they were formed, but from the early stages one many convince oneself 
that the coagulative necrosis is primarily an affair of the wandering cells, 
and that the liver-cells are only accidentally involved in the mass. 
Rarely large necroses or abscess-like foci occur in the liver. 
The gall-bladder may become infected with the bacilli, probably by way 
of the bile-ducts, either from the intestines or from the liver, although it is 
Fig. 295.-Typhoid fever. Beginning focal necrosis 
in liver; accumulation of wandering cells with little 
evident injury of liver-cells. 612 
TEXT-BOOK OF PATHOLOGY 
perfectly possible that they might arrive there by the blood-stream. They 
may cause no trouble, but may remain and multiply there for many years. 
Such persons are among the typhoid carriers mentioned above. Occa- 
sionally there are attacks of pain in the region of the gall-bladder during 
the fever, but more frequent are the cases of acute or chronic cholecystitis 
occurring some time after recovery. In Hunner's case, eighteen years had 
elapsed since the attack of typhoid fever. The exudate is sometimes puru- 
lent, but more commonly mucoid, and is usually associated with gall-stones. 
Fig. 296.-Typhoid fever. Larger focus in liver in which the area is occupied by pha- 
gocytic cells, the liver-cells having been displaced or destroyed. 
Cushing was able to cultivate the Bacillus typhosus from the centres of the 
gall-stones, as well as from the bile, and thought that agglutinated bacilli 
might constitute the nucleus upon which gall-stones could form. The 
evidence in this question has been discussed elsewhere (Chapter XX). 
Kidneys and Bladder.-The kidneys show a cloudy swelling of the cor- 
tex comparable to that of the liver. (Edema with great pallor is some- 
times observed. Actual acute nephritis with exudative changes is, in my 
experience, rare. The bacilli pass through the kidney evidently through TYPHOID INFECTIONS 
613 
lesions of some sort, and appear in the urine. Although the bladder and 
ureters are not commonly affected, catarrhal or diphtheritic cystitis may 
occur. The urine continues to show the presence of bacilli for a long time 
in some cases. 
Respiratory Organs.-Lobar and lobular pneumonia may accompany 
typhoid fever, the former rarely, the latter as a common terminal affection. 
Lobar pneumonia caused by the Bacillus typhosus is of a peculiarly haemor- 
rhagic character. Usually the pneumococcus is the causative agent when 
this complication occurs, and there may be a combined septicaemia with 
both organisms (Robinson). In the bronchopneumonia the typhoid 
bacillus may cause the lesions, and appear in the sputum, but probably 
in most cases other organisms are concerned. 
In the pharynx and larynx there is sometimes an extensive diphtheritic 
and haemorrhagic inflammation in a late stage of the disease. 
Circulatory Apparatus.-The heart muscle is soft and flabby and opaque, 
and may contain a little fat. Endocarditis is uncommon, but has been 
described, the vegetations containing the bacilli. There are instances in 
which the peripheral arteries, especially the arteries of the brain, have been 
occluded by thrombi. In other cases thrombosis of brachial or femoral 
arteries has led to gangrene. Thayer has examined the arteries in many 
cases after typhoid fever, and finds, in rather a high percentage, evidences 
of beginning arteriosclerosis. This is, however, not peculiar to this infec- 
tion. 
Thrombosis of the veins is far more common than that of the arteries. 
It occurs usually in the left femoral and saphenous veins, and causes the 
extremely painful swelling of the leg which has long been known as "milk- 
leg," or phlegmasia alba dolens. With the organization of the clot and 
its recanalization, together with the development of collateral channels, 
the oedema disappears and the leg can again be used. Other veins may 
also be affected. 
Muscles.-A wide-spread hyaline degeneration of the substance of the 
muscle-fibres, first described by Zenker, is often found, especially in the 
abdominal muscles and in the muscles of the thigh. (See Fig. 39.) The 
muscle-fibres lose their striations, and are divided into irregular, formless 
clumps within the sarcolemma. Rupture of such injured muscles gives 
rise to gross haemorrhages, and if one observes a great haemorrhage within 
the sheath of the rectus abdominis, suspicion is at once directed to a 
typhoid infection, although the condition is not peculiar to typhoid. 
Bones and Joints.-After convalescence, or even many years later, there 
sometimes arise painful, abscess-like swellings over the ribs or the tibiae, 
or, indeed, over any bone. Incision allows the escape of a thick, stringy, 
purulent fluid, and it is found that an abscess cavity extends down through 
the periosteum or into the bone. The periosteum is greatly thickened 
and uplifted from the bone, and there may be necrosis and sequestration 
of part of the bone. Mixed infections occur, but the typhoid bacillus is 
found and may cause these changes alone. Such infections are very per- 614 
TEXT-BOOK OF PATHOLOGY 
sistent, and unless thoroughly cleaned out, fail to heal. Typhoid arthritis 
occurs, but is very rare. 
Skin.--Prominent among the changes in the skin is the roseola or typhoid 
rash. Slightly raised, flat, rose-colored spots appear early in the disease, 
and are an evidence of the diffuse septicaemic character of the disease. 
The bacilli have been cultivated from these rose spots, and Frankel, in 
sections, found branched colonies of the bacilli in what he thought were 
the lymph-vessels of the papillae. Purpuric spots, diffuse erythema, etc., 
may also occur. Furunculosis, so common in the later stages, is due to a 
secondary staphylococcus infection. 
Nervous System.-The disease has its name from the stuporous con- 
ditions produced by the infection. Nevertheless, actual cerebral changes, 
recognizable anatomically, are rare. I have described one case of purulent 
leptomeningitis due to the Bacillus typhosus alone, and Cole has collected 
many others from the literature. The exudate resembles that in the epi- 
demic cerebrospinal form, but is richer still in macrophages which contain 
the debris of cells. Here it seemed especially clear that these large cells 
are to be regarded as part of the army of mononuclear wandering phago- 
cytes. Local and multiple neuritis occurs, but is not serious, and quickly 
disappears in convalescence. 
Genital Organs.-Typhoid bacilli have been cultivated from the uterus 
in cases in which typhoid fever occurred during pregnancy. Lesions of the 
placenta of haemorrhagic type give one explanation for the transmission of 
the bacilli to the foetus, but it seems that this may occur without obvious 
placental changes. Lynch shows that the effect is a foetal septicaemia, and 
that the child dies in utero or soon after birth. Mastitis is a rare sequel 
of typhoid fever. McCrae has recorded three cases. 
In rare cases orchitis follows convalescence and may lead to indurative 
atrophy or abscess formation. 
Parotitis.-Owing to the prolonged illness and the stuporous condition, 
the mouths of these patients become foul unless continually cleansed. Paro- 
titis may arise by extension of infection along the duct, or by lodgment of 
bacilli carried there by the blood. Suppuration may destroy much of the 
gland and extend into the adjacent tissue or into the neck. In these cases 
there is commonly a mixed infection. 
LITERATURE 
General.-Osler: Principles and Practice of Medicine, New York, Sixth Edition, 1905. 
"Studies in Typhoid Fever," Johns Hopkins Hosp. Reports, 1895, v; 
1902, x. 
Curschmann: Nothnagel, Spec. Path. u. Ther., 1902, Bd. iii, Th. 1. 
Hoffmann: Veranderungen der Organe beim abdominal Typhus, Leipzig, 
1869. 
Brouardel and Thoinot: La Fievre Typhoide, Paris, 1905. 
Mallory: Jour. Exp. Med., 1898, iii, 611. 
Posselt: Ergebn. d. allg. Path., 1912, xvib 184. 
Gay: Typhoid Fever, New York, 1918. PARATYPHOID INFECTIONS 
615 
Typhoid Septicaemia.-Rudiger: Trans. Chicago Path. Society, 1903, v, 187. 
Cole: Johns Hopkins Hosp. Bull., 1901, xii, 203. 
Lartigau: New York Med. Jour., 1900, Ixxi, 944. 
Roseola.-E. Frankel: Zeit. f. Hygiene, 1900, xxxiv, 482. 
Typhoid Cholecystitis.-Cushing: Johns Hopkins Hosp. Bull., 1898, ix, 91, 257n 
Hunner: Ibid., 1899, x, 163. 
Placental Transmission.-Lynch: Johns Hopkins Hosp. Reports, x, 283. 
Typhoid Meningitis.-Cole and MacCallum: Johns Hopkins Hosp. Reports, 1904, xii, 
411. 
Bone Lesions.-Parsons: Johns Hopkins Hosp. Reports, 1895, v, 417. 
Miscellaneous.-McCrae: Ibid., 1902, xiii, 20. 
A. L. Mason: Boston Med. and Surg. Jour., 1897, cxxxvi, 449, 468. 
Longcope: Centralbl. f. Bakt. u. Paras., Abt. i, 1905, xxxvii, Ref. 23. 
Robinson: Bull. Ayer Clinical Labt., 1906, iii, 96. 
Vaccination.-Russell: Mil. Surgeon, 1909, xxiv, 479. 
PARATYPHOID INFECTIONS 
In discussing the effects of poisons upon the tissues reference was made to 
the outbreaks of severe gastro-intestinal disturbances produced by the 
eating of infected or partly decomposed meat, and it was then shown that 
such epidemics of what seems to be a form of poisoning are really commonly 
due to infection with some member of that group of bacilli, of which the 
Bacillus enteritidis of Gartner is the type. These are somewhat allied to 
the Bacillus typhosus, and it has been more recently recognized that there 
are at least two types of bacilli which are not only members of this family, 
but produce at times a disease practically indistinguishable from a mild 
attack of typhoid fever. These are the paratyphoid bacilli A and B, of 
which A is an acid producer, B an alkali producer. Of these, the latter 
occurs far more frequently and is so like the Bacillus enteritidis of Gartner 
as to be most easily distinguished by the agglutination reactions. They 
were first described in America by Gwyn. 
The infection occurs by the gastro-intestinal tract, probably from eating 
from an animal infected before slaughtering, meat which, upon standing, 
has become far richer in bacilli. Two chief types of infection occur- 
the acute gastro-enteritis and the typhoid form. The acute gastro- 
enteritis represents at least a part of the cases of cholera nostras, and is dis- 
tinguishable from true cholera by bacteriological study only, although, 
of course, the attendant circumstances may make the diagnosis easy. 
There is intense diarrhoea with desiccation of all the tissues and collapse, 
sometimes leading to death. At autopsy no changes are found except 
some general swelling and reddening of the gastro-intestinal mucosa. 
The second type, probably long mistaken for typhoid fever, is, in fact, 
almost precisely like that disease in its clinical symptoms, details such as 
the roseola, laryngitis, etc., being exactly repeated. There are also quite 
similar complications, such as paratyphoid meningitis, cholecystitis, cystitis, 
pyelitis, etc. Few cases have been studied at autopsy, and these are re- 
viewed by Burckhardt. In a large proportion of them there were found 616 
TEXT-BOOK OF PATHOLOGY 
swelling in the lymphoid structures of the intestines, and ulceration resem- 
bling, even in histological detail, the lesions of typhoid fever. Others showed 
no affection of the intestine whatever (Longcope). In the cases with ulcer- 
ation there was swelling of the mesenteric glands, whose sinuses were filled 
with phagocytic cells and presented necroses here and there. The spleen 
showed'no characteristic alterations, but necroses (so-called lymphomata) 
were found in the liver. From these cases the Bacillus paratyphosus 
B was isolated in pure culture from the organs, the bile, and the circulating 
blood, and recognized by its cultural characteristics and by its agglutina- 
tion properties. Two cases studied at autopsy in which there was infec- 
tion with paratyphoid A showed in one case ulcers in the intestine, in the 
other case none. 
In most cases the course is mild and brief, but the complications, espe- 
cially cystitis and pyelonephritis or pyelitis, may persist a very long time, 
with constant discharge of the bacilli, which are far more destructive in 
those situations than the typhoid bacillus. 
It is evident that much more light will be shed on these infections shortly, 
and already the literature concerning them is abundant, if somewhat unsat- 
isfactory. 
J. L. Burckhardt: CentralbL f. allg. Path., 1912, xxiii, 49. 
Johnston, Hewlett, Longcope: Amer. Jour. Med. Sci., 1902, cxxiv, 187. 
Gwyn: Johns Hopkins Hosp. Bull., 1898, ix, 54. 
Pratt: Boston Med. and Surg. Jour., 1903, cxlviii, 137. 
Schottmuller: Mohr and Staehelin, 1911, i, 519. Zeitschr. f. Hygiene, 1901, xxxvi, 368. 
The literature since 1916 is voluminous, but adds little exact information. 
Huebschmann: Ziegler's Beitr., 1913, Ivi, 514. 
Saltykow: Virch. Arch., 1913, ccxi, 467. 
Loele: Ergebn. Allg. Path., 1915, xviii, i. 546. 
Rathery: Les fievres paratyphoides B, Paris, 1916. 
Vincent and Muratet: Typhoid and Paratyphoid Fever, London, 1917. 
Dawson: Proc. Roy. Soc. Med., 1915, ix. Quart. Jour. Med., 1915-16, ix, 98. 
Mallie: Infection paratyphique, Paris, 1916. 
Sacquepee, Burnet, and Weissembach: Reunion med. de la 4me Armee, 1915. 
LITERATURE 
DYSENTERY INFECTIONS 
The bacilli responsible for the causation of the endemic and epidemic dys- 
entery which prevails so widely in the tropics and in occasional epidemics 
in temperate zones were recognized by the aid of the agglutination reaction 
with the patient's serum. Four types, differing in this agglutination and 
in certain biological characters, are recognized, and known as the Shiga, 
Flexner, Y type of His and Russel, and the type of Strong. Of these, the 
Shiga type seems to be most widely disseminated, and produces a distinct 
toxin. The Flexner type has only a very slight power of toxin production. 
Epidemics arise in the rainy season, especially where there are sudden 
variations of temperature, and in the hot seasons in more temperate zones. 
The bacilli are disseminated by people who have partially or completely DYSENTERY INFECTIONS 
617 
recovered from a previous attack, but still carry and discharge the organ- 
ism. They are distributed in drinking-water, in food, by direct and indi- 
rect contact, by flies, dust, etc. The unsanitary mode of life in many parts 
of the tropics and in many cities favors their rapid spread. 
The disease is chiefly an infection of the colon, although the lower part 
of the ileum may also be involved. It begins with hypersemia of the mucosa 
and the secretion of abundant slimy, clear, mucoid fluid, which is later 
Fig. 297.-Dysentery. Diphtheritic and haemorrhagic inflammation of the intestine 
involving the crests of the folds of the mucosa. The pseudomembrane is still adherent, 
and there is extensive haemorrhage beneath it. 
streaked with blood. The swollen mucosa shows points and streaks of 
haemorrhage, and soon there appear chaff-like, opaque flecks on the crests 
of the folds (Fig. 297). Even at this stage, when these flecks indicate 
the death of the surface of the mucosa, resolution or healing may take 
place, but usually the diphtheritic character of the lesion becomes more 
evident and progresses to ulceration. The more prominent parts of all 
the folds become covered with a thick, dull layer of exudate, which con- 618 
TEXT-BOOK OF PATHOLOGY 
stitutes a false membrane and is continuous with the densely coagulated 
dead layer of mucosa (Fig. 298). All around, haemorrhage and an intense 
inflammatory reaction with oedema appear. With the sloughing off of this 
layer irregular ulcers are left. These vary in size and depth, and while 
sometimes quite large sheets 
of dead and coagulated mucosa 
and exudate escape with the 
stools, at other times the ulcers 
are more localized, but pene- 
trate deeper into the submu- 
cosa, the musculature, or even 
the subserous tissues (Fig. 299). 
Perforations occur, but are rare. 
The presence of this process ex- 
cites the most violent diarrhoea, 
with tenesmus and the passage 
of liquid, mucoid, and blood- 
tinged stools. So constant is 
the passage of fluid stools, and 
so violent the continual strain- 
ing, that the patient becomes 
exhausted. Vomiting may be- 
gin; the skin is covered with 
sweat; the voice hoarse and eyes 
sunken, and the whole condi- 
tion cholera like. Such patients 
may die in collapse. If the at- 
tack is not fatal, there may 
be relapses from time to time, 
lasting over a long period, and 
finally the disease settles into 
a milder chronic process. The 
ulcers heal by the formation of 
granulation tissue, over which 
a smooth layer of epithelium 
grows without the new forma- 
tion of glands. Much scar tis- 
sue develops in the gut wall in 
the base of such ulcers, and 
contracts so as to constrict or 
kink the intestine. Very nar- 
row strictures may be formed 
thus. The ulcers are irregular in extent and outline, and are often con- 
fluent, leaving islands of mucosa which stand out above the new epithe- 
lium as pedunculated polypoid masses. In one case which I saw there 
were long bridges of mucosa which had been undermined and which, in 
Fig. 298.-Acute diphtheritic and haemor- 
rhagic dysentery. Colon of a child, showing 
abundant pseudomembrane on the crests of the 
folds of the mucosa. 619 
DYSENTERY INFECTIONS 
some places, having broken away at one end, hung in the intestine like 
long pendulous polypi. 
Even in the acute disease the other organs are not much changed; there 
is no septicaemia, and therefore there are no cutaneous changes. There is 
no acute splenic tumor and no pronounced cloudy swelling of the viscera. 
The bacilli are found in the swollen mesenteric glands and also in the 
Fig. 299.-Dysentery in a child. Extensive ulceration of the colon, which involved 
also the ileum to a less extent. 
spleen and liver, but not elsewhere. Painful joint changes are not uncom- 
mon, consisting in effusions into the joints, especially those of the foot, 
knee, and hip. When the pain and swelling subside in one joint, another 
may become affected, and with each there is a rise in temperature. They 
recover their normal condition without any inflammatory residue. Tran- 
sient paralyses, which sometimes involve muscular atrophy, also occur. 620 
TEXT-BOOK OF PATHOLOGY 
In children in summer epidemics it has been shown by Basset and Duval, 
Knox and Wollstein, that the Shiga bacillus is the causative agent of the 
dysentery, which is practically identical with that of adults, and in which 
the mortality is high. It has long been known that in asylums and prisons 
outbreaks of dysentery were due to some such infection, doubtless in- 
troduced, as we now appreciate, by a bacillus carrier. Kruse spoke of 
this as pseudodysentery, which was unfortunate, since it has been shown 
that these cases were due to the Shiga bacillus (Vedder and Duval). 
As stated, the blood of dysentery patients acquires, after eight to ten 
days, the power of agglutinating bacilli of the same type. But the serum 
of those infected with the Shiga type agglutinates only the Shiga bacillus 
except in very concentrated form, while the serum of those suffering from 
infection with the Flexner type will agglutinate both in considerable dilu- 
tion. The Shiga bacillus produces a strong toxine which has long been 
known to cause in rabbits not only a severe intestinal lesion with haem- 
orrhages but also paralysis. This is well described and illustrated by 
Doerr in his monograph on the toxine. Clinicians have recognized the oc- 
currence of postdysenteric paralyses in human beings, and have ascribed 
them to some form of neuritis, but Dopter has shown that in rabbits 
at least the paralyses are due to definite lesions in the gray matter of the 
central nervous system. Olitzky and Kligler have recently restudied the 
toxine, and have found that there may be distinguished an exotoxin which 
is heat labile, and which attacks the nervous tissues, and an endotoxin 
which is more stable and which is responsible for the intestinal lesions. 
Antitoxins can be produced for each of these, and are specific. 
LITERATURE 
Shiga: Centralbl. f. Bakt. u. Paras., 1898, Abt. 1, xxiii, 599. Ibid., 1898, xxiv, 817. 
Osler and McCrae, Modern Medicine, 1913, i, 766. 
Flexner: Univ, of Penn. Med. Bull., 1901, xiv, 190. Trans. Cong. Amer. Phys, and 
Surg., 1900, v, 61. Studies of Diarrhoeal Diseases of Infancy, New York, 1904. 
Duval and Bassett: American Medicine, 1902, iv, 417. 
Whitmore: Philippine Jour, of Science, 1911, vi. 215. 
Vedder and Duval: Jour. Exp. Med., 1901-05, vi, 181. 
Kruse: Deut. med. Woch., 1900, xxvi, 637. 
Lentz: Kolle and Wassermann, 1909, 2 Ergnzbd., 391. 
Ruge, Mense: Hand. d. Tropenkrankheiten, 1914, iii, 158. 
Kossel, Singer: Munch, med. Woch., 1915, Ixiii, 85, 183. 
Doerr: Das Dysenterietoxin, Jena, 1907. 
Olitsky and Kligler: Jour. Exp. Med., 1920, xxxi, 19. CHAPTER XXXII 
TYPES OF INJURY.-BACTERIAL DISEASE (Continued) 
Leprosy: Nodular and anoesthetic forms. The bacillus and transmission. Lesions of the 
internal organs. Affections of nerves and their sequeloe. 
Actinomycosis: General character of the disease and organism. Related organisms. Mode 
of infection. The destructive lesions. 
LEPROSY 
Known in detail in ancient times as a contagious disease of destructive 
character and quite incurable, leprosy has spread over practically all the 
countries of the world, and lepers are now, as in the time of Moses, objects 
of horror and aversion. 
The disease is the result of infection with the Bacillus leprae, discovered 
by Hansen in 1874, and is a slowly developing affection, of extreme chron- 
icity, in which nearly all the tissues become invaded by the bacilli. It 
occurs in at least two main forms, although there are many combinations 
and modifications of these types. One is the tubercular or nodular leprosy, 
in which the skin, especially in the exposed parts, is lifted up over firm 
nodules, which in time break through and ulcerate. The other is the so- 
called anaesthetic leprosy, in which, without much change in the skin, dis- 
ease of the nerves leads to a loss of sensation, which is followed by trophic 
changes in the extremities and by mutilations from unnoticed injuries. 
The lepers live for a long time and become fearfully deformed, dying 
finally from the disease itself, or from some intercurrent affection. 
Since writing this chapter the first time I have had the opportunity of 
visiting many leper colonies in the South Sea Islands, the East Indies, the 
West Indies, and in South America, and have had occasion to perform 
some autopsies in advanced cases. The affection is far more prevalent 
than we are accustomed to think it, and on account of its disabling char- 
acter and the isolation it enforces is one of the most tragic of all diseases. 
The mode of transmission is not really known, although various state- 
ments are made with an air of authority. Mere contact with those suf- 
fering from the disease is probably sufficient if prolonged enough because 
so many bacilli are discharged from the nose and from open ulcerations, 
but we must hasten to add that the Catholic Sisters and others who spend 
their lives in nursing and caring for these patients, are practically never 
infected. No doubt they are well aware of the risk and are very careful, 
but they do not avoid contact with the sick. There is no good evidence 
that leprosy is inherited, even when both parents are lepers, and there 
are many examples of the contrary. But when the children are left to 
621 622 
TEXT-BOOK OF PATHOLOGY 
live with their mothers in the leper colony they frequently develop the 
disease. Of four such children in a colony visited last summer, three 
showed large circinate skin lesions, while the other was clean. Some 
statistics seem to show that transmission is not so frequent between 
husband and wife as might reasonably be expected, and that among rela- 
tives cases are found most often in brothers and sisters. Nevertheless 
it has always been thought that sexual intercourse plays a very great part 
in the spread of the infection. Every sort of biting insect has been in- 
vestigated in the hope that one of them might be found responsible for the 
Fig. 300.-Tubercular or nodular leprosy, showing lesions on face and body. 
carrying of the bacilli, but so far with negative results. It is, of course, 
largely on account of the fact that the incubation period of the disease 
may last over months or years that the difficulty of determining the manner 
of transmission is so great. 
The two forms mentioned above are seldom quite distinct, and it is 
only recently, in Jamaica, that I have seen a considerable number of cases 
of the pure anaesthetic form, with practically no changes in the skin, but 
with mutilation of the hands and feet from which fingers and toes had dis- 
*Photographs in Fig. 300 by the Bureau of Science, Manila, and kindly sent to me 
by Dr. B. C. Crowell. LEPROSY 
623 
appeared so that only stumps were left. The tuberculous form is almost 
always found to show anaesthesias and the nerves are thickened into cords 
Fig. 300A -Tubercular leprosy, showing advanced lesions of face and hands (Kuala 
Lumpur). 
Fig. 300B.-Tubercular leprosy with extreme destructive changes in hands and face 
(Kuala Lumpur). 
and are found at autopsy to be densely embedded in the peculiar tissue 
which is so characteristic of all the lesions. 
It would be difficult to describe all the atypical forms of skin lesion 624 
TEXT-BOOK OF PATHOLOGY 
found in leprosy, and yet the average advanced case presents an almost 
monotonously uniform appearance (Figs. 3C0, 300A, 300B, 300C). The 
disease begins insidiously, sometimes with a febrile illness which passes off, 
to be followed some time later by the appearance of a reddened elevated 
patch somewhere upon the body, or by the partial depigmentation of 
patches of the skin. There is really no basis, however, for the expression 
"white as a leper," for they show no patches or scars which would im- 
press one as white. Leucoderma from other causes is common though, 
and has, no doubt, given rise to this idea. The nodules or elevated patches 
become more numerous and affect especially the face, hands, and feet, 
although they are also frequently enough found on the trunk when 
Fig. 300C.-Anaesthetic leprosy. Mutilation of hands and feet without lesions of face 
(Bali). 
not covered with clothing. The eyebrows and eyelashes fall out, and 
there appears a diffuse thickening of the brows, the upper parts of 
the cheeks, the alse of the nostrils, and the edges of the ears. The lobes 
of the ears are often especially enlarged and are soft so that they swing 
about as the man walks. Later in all these positions the thickening takes 
the form of rough nodules which throw the skin up into great folds and 
eminences. Tumor-like masses form especially on the alse of the nose and 
spread out laterally. The cartilage of the nose often becomes destroyed 
so that the nose is telescoped into itself in such a way that the nostrils 
open forward. By this time the lesions elsewhere are also far advanced 
and usually several fingers have been lost. 
Even early in the disease there are ulcerative changes in the mucosa of LEPROSY 
625 
the nose, and diagnosis often rests upon finding the bacilli in scrapings 
from this ulcerated mucosa. Later many of the nodules in the skin break 
open and fail thereafter to heal for a long time, discharging quantities of 
bacilli with the exudate from the ulcer. The most disfiguring losses of 
substance may occur in this way in the tissues of the face and even in the 
bones underneath, so that sometimes no recognizable face is left. In the 
case of the fingers it is not always the advance of the strictly leprous 
lesions that produces the mutilation, for secondary infections are very 
common. They begin in the form of a panaritium or felon, and in- 
fection extends rapidly along the tendon sheaths so that amputation 
must be performed, if at all, at a point far above that which is obviously 
diseased. 
The conjunctivae and corneae are frequently the seat of leprous lesions 
which spread across and produce opacity, and with healing leave the 
eye quite blind. 
The bacilli, which are acid fast and resemble closely the tubercle bacillus, 
are present in the lesions in enormous numbers. They are in such relation 
to the pathological changes that there can be little doubt that they are the 
actual cause of the disease, although the other postulates for the proof 
of the aetiological relation of an organism to a disease have net been very 
satisfactorily carried out. 
The lesions are all based on the formation of a specific sort of granulation 
tissue which is composed of a loose network of branching connective- 
tissue cells, rich in blood-vessels and especially in wide lymphatics. It is 
infiltrated with mononuclear wandering cells of many forms and sizes, 
all of which appear, however, to belong to one series. Many of these 
attain the size of giant cells and are provided with several nuclei. All 
of the wandering cells are loaded with globules of fat. Such tissue occurs 
in discrete lobules beneath the skin or in the internal organs, which when 
stained with Sudan, appear as solid red masses. Some of the cells become 
so swollen with fat as to lose all recognizable cell structure, and in these 
large fat globules which are sometimes surrounded by several cells there 
is a mass of bluish staining granules which become apparent after the fat 
has been dissolved out. It does not appear that bacilli accumulate in 
such globules. All the cells are thus vacuolated, as seen in preparations 
from which the fat has been dissolved out, and much has been written on 
the foamy cell, characteristic of leprosy. All of these cells are phagocytic, 
and may contain bacilli, but it is chiefly in the swollen endothelial cells 
of the lymphatics and blood-vessels that they are heaped up in red 
staining masses. In other cases we have found the bacilli so numerous 
that almost every wandering cell contained them. Leucocytes play 
very little part in the infiltration, but necrosis of the tissue occurs 
frequently, and in those areas there are many fragmented nuclei and 
some leucocytes. 
In the nodules on the body surface the overlying epithelium is stretched 626 
out in a smooth layer so that the papillae are obliterated (Fig. 301), and 
the tissue beneath is hyaline and almost devoid of nuclei for a short dis- 
tance. After it breaks down the ulcer persists for a long time, but is 
usually filled up at length by a dense scar. The mucosae of the nose and 
nasal sinuses are affected in exactly the same way, and ulcerations on a 
TEXT-BOOK OF PATHOLOGY 
Fig. 301.-Leprosy. The section through a leprous nodule of the skin shows the 
obliteration of papillae and the accumulation of giant-cells, which are loaded with bacilli, 
in the deeper tissues. 
basis of the same sort of tissue are found throughout the pharynx larynx, 
and trachea. Some authors have described leprous lesions of the lungs 
which were hardly distinguishable from tuberculosis, but in the cases 
which I have studied it was really tuberculosis, which seems to be a com- 
mon secondary infection in leprosy. LEPROSY 
627 
Fig. 302.-Leprosy. Focal accumulation of lepra cells in the liver. These cells contain 
many bacilli. 
Fig. 303.-Leprous neuritis with much scar formation about the nerve-bundles. 628 
TEXT-BOOK OF PATHOLOGY 
In the liver and spleen there are scattered everywhere minute foci of 
tissue made up of the same network with vacuolated or fat-holding cells 
as seen elsewhere. These miliary lepromata (Fig. 302) which contain 
bacilli are quite conspicuous in a microscopical section, although they 
cannot be seen with the naked eye. Lesions of the intestines have been 
described, but must be rare. In the lymph-nodes the leprous granula- 
tion tissue is found to occupy the margins of the lymph cords, leaving the 
sinuses fairly free. In the testicle the 
tubules are spread apart by the same 
tissue, loaded with bacilli, and the 
tubules are reduced to hyaline strands. 
In the bones there may exist a kind 
of leprous osteomyelitis, with lesions 
analogous to those of the skin, but 
this is much less important than the 
changes in the bones associated with 
the affection of the nerves and with 
the secondary infections. 
Leprous neuritis or perineuritis is 
one of the most constant features of 
the disease, and the disturbances of 
sensation which result are often the 
first to rouse suspicion of its exist- 
ence. It is by no means limited to 
the anaesthetic form, but is found in 
the tuberculous and mixed forms. The 
nerves of the arm and the more super- 
ficial ones in the leg may be felt through 
the skin as thick stiff cords, which at 
autopsy are found to show the nerve 
bundles spread apart and embedded 
in tissue of the type described above 
(Fig. 303). Bacilli are scattered in 
this tissue, but also make their way 
into the medullary sheaths of the indi- 
vidual fibres. The fibres degenerate 
and sensation is lost long before any 
motor disturbances appear. The lesion 
of the nerve is usually only in patches along the course, but the bacilli may 
be found not only there, but sometimes in the ganglion cells of the root 
ganglia and in the spinal cord and brain. 
Most striking are the atrophies of the bones of the extremities which 
result from this interruption of the nerves which causes the phalanges to 
shrink and the bones to fuse into thin, pointed remnants of bone, attached 
to the metacarpals or metatarsals. These in their turn may atrophy and 
Fig. 304.-Atrophy and distortion 
of the bones of the foot in leprosy 
(Harbitz). ACTINOMYCOSIS 
629 
become disarranged, so that finally the hand or foot, further cramped 
by contractures, assumes the most distorted, claw-like appearance (Fig. 
304). Harbitz, in describing these, has pointed out the fact that this is 
a process of mutilation not necessarily associated with ulceration and in- 
flammation. Indeed, the most disfiguring mutilations arise from the 
insensibility of the hands and feet, which makes it possible for these pa- 
tients to suffer from burns or other injuries without drawing away or 
protecting themselves. Nevertheless, it seems probable, from Harbitz's 
pictures, that most of these deformed extremities are the more direct 
result of loss of nerve impulses. 
Barrera and Chavarria have recently described, either in the course of 
chronic leprosy or in the very beginning of the disease, acute febrile attacks 
accompanied by an exanthem which may take the form of reddish macules 
or of tender spherical or flattened nodules of small size in the depths of 
the skin. Such outbreaks last only a short time, are associated with a 
discharge of bacilli from all excretory channels, .and either result in some 
improvement in the general condition, or, in weakened patients, lead to 
death. The exact significance of such attacks has yet to be made clear. 
LITERATURE 
Sokolowsky: Virch. Arch., 1900, clix, 521. 
Babes: Histologie der Lepra, Berlin, 1898. 
Kedrowski: Arch. f. Derm. u. Syphilis, 1914, cxx, 267. 
Sticker: Handb. d. Tropenkrankheiten, Mense, 1914, iii, 1. 
Uhlenhuth and Westphal: Centralbl. f. Bakt. u. Paras., 1901, xxix, Abt. i, 233. 
Sakurane: Ziegler's Beitrage, 1902, xxxii, 563. 
Harbitz: Archives of Int. Med., 1910, vi, 147. 
Duval: Jour. Infectious Diseases, 1912, xi, 116. 
ACTINOMYCOSIS 
This disease, common in cattle, and recognized as an infectious process by 
Bollinger, was later described by J. Israel for man. The cattle present a 
tumor-like swelling, usually of the jaw, with sinuses and purulent dis- 
charge in which peculiar yellow granules or sulphur grains are found. In 
human beings the affection is quite commonly also a swelling of the j aw, 
but there are several other typical localizations, namely, in the thoracic or- 
gans, in the intestines, or in the skin. Ponfick recognized the identity of 
the disease in man and animals. Examination of the pus or of sections of 
the granulation tissue lining the sinuses shows the causative agent to be a 
branched organism which grows in tangled mycelia. Numerous broken 
portions resembling bacilli or cocci occur. The sulphur grains are knots of 
the mycelium with radially projecting tips, which form a layer covering 
the central tangle. Each of these tips is surrounded by a club-shaped or 
bulbous covering, of homogeneous, refractive material. The micro- 
scopical section through such a granule, therefore, shows a curved or scal- 
loped margin of such clubs, arranged parallel or at least radially. It was 630 
TEXT-BOOK OF PATHOLOGY 
from this arrangement that the name actinomyces or "Strahlenpilz" was 
derived. 
There are many other closely allied organisms, which are commonly spoken of under 
the name streptothrix, and most writers make a point of applying the name actinomyces 
to that organism which produces the disease in man and cattle, saying that the strepto- 
thrices differ from it in not being able to produce the radiate, club-like growths. So 
often has this been repeated that the distinction will doubtless persist for a long time. 
The truth of the matter is, however, very different. Such club-bearing knots of myce- 
lium are not formed by the organisms in culture, but only in the tissues of an animal 
(exceptionally in cultures in serum or animal tissue). So far from their being unable to 
form such clubs, those of the streptothrix group which can infect animals produce the 
most beautiful clubs under the proper conditions. One, commonly known as the 
Streptothrix asteroides, if injected into the peritoneum of a rabbit so that the infection 
meets with more resistance than if injected directly into the blood, will form everywhere 
in the organs graceful, plume-like masses of clubs in every respect similar to those of 
Actinomyces bovis.* Indeed, there is no valid reason for separating these organisms 
into two groups, and since the name streptothrix has long been preempted for an alga, 
it is necessary, according to all rules of nomenclature, to call them all actinomyces, that 
being the first name applied to any of the group. 
It is perfectly true that not all this group have the same pathogenic powers. Some, 
indeed, are entirely saprophytic, while others, such as the Actinomyces asteroides, have 
been found in subacute abscesses in the brain, in generalized peritonitis, etc. 
The Actinomyces bovis, described by Wolff, Israel, Wright, and others, 
is an anaerobic organism, and is recognized as the cause of the disease in 
both cattle and man. It has not been found in the outside world in spite 
of the existence of so many allied forms, and probably lives on the mucosae 
of the mouth and digestive tract. It has always been thought to be intro- 
duced into the tissues by straws or splinters, but it begins to seem more 
probable that it merely takes advantage of the presence of such a foreign 
body to display its pathogenic properties. Details of the morphology of 
these remarkable organisms must be read in the papers cited. 
Having reached the tissue, the presence of the mycelium is quickly re- 
sponded to by necrosis of the cells and by the abundant accumulation of 
leucocytes. The process advances slowly though, and there is a most pro- 
fuse formation of granulation tissue round about such an area after weeks 
or months; while the central part of the lesion is made up of liquid pus 
full of the branching organisms, the outer zones are composed of such 
dense fibrous tissue as to form a tumor-like mass. Lining the cavity is 
still fresher granulation tissue, which is now loaded with large mononuclear 
wandering phagocytic cells, which are themselves so full of fat-granules 
as to give this layer an opaque yellow color. Frequently, lying loose in the 
pus in the centre, there is one of the sulphur grains with its clubs (Fig. 305). 
No giant-cells are found, as a rule, nor any distinctly tubercle-like nodules. 
The mycelium grows and advances into the tissues, destroying and lique- 
* For that matter many bacilli-the diphtheria bacillus, Moller's grass bacillus, and 
others-can do the same thing under favorable circumstances. 631 
ACTINOMYCOSIS 
fying it slowly with the aid of the abundant leucocytic reaction, and is 
attended constantly by the most tremendous formation of encapsulating 
connective tissue. Given such a process, it is not surprising that this 
becomes one of the most destructive of all diseases. The infection bur- 
rows through the tissues for great distances, completely distorting what- 
ever it traverses, and it stops for nothing-bones are penetrated as easily 
as muscles, and from the lung such a mine-like advance may push through 
the pericardium and heart-wall into the interior of the heart. 
Fig. 305.-Actinomycosis. The peculiar lobulated masses of mycelium, edged with 
a row of clubs, are surrounded by leucocytes, outside which is a layer of granulation 
tissue rich in large, fat-laden phagocytic cells. Outside this is dense fibrous tissue. 
More than half of the infections are in connection with the mouth and 
pharynx, and seem to begin in the gums about the teeth, although some- 
times the tongue or cheek is first affected. The abscess-like lesion, with 
its bulwark of connective tissue, usually appears in the parotid or sub- 
maxillary region, extending thence, with destruction of the jaw, into the 632 
TEXT-BOOK OF PATHOLOGY 
neck. Another group begins in the thorax, probably in the bronchi or in 
the substance of the lung, and extends thence, sometimes to appear in 
a sinus or series of sinuses perforating the skin. Naturally, the pleura 
approached by this process becomes enormously thickened. A third site 
of predilection is in the intestines, and especially in the ileocsecal region, 
where a submucous abscess soon forms a mass which progresses with 
Fig. 306.--Actinomycotic abscess in liver. The figure shows the extraordinary scarring 
about the abscesses, which are merely loculi in a dense fibrous mass. 
adhesions to adjacent abdominal organs and to the abdominal wall, often 
forming long, burrowing sinuses between the muscles or reaching bones 
or joints. At times one finds great masses of dense fibrous tissue riddled 
everywhere with cavities full of pus, which represents the ramifying and 
anastomosing suppurating centres. Actinomycosis of the ovary and tubes ACTINOMYCOSIS 
633 
has been observed in many cases. The fourth group of cases, which is 
much smaller, is thought to be due to infection through the skin. Here 
again the deeper tissues, including the fasciae, bones, and joints, may be 
penetrated and destroyed. 
In the course of such a chronic infection metastases into the internal 
organs may occur, and we find abscesses in the spleen or liver (Fig. 306) 
or elsewhere which may become evacuated or may, in their turn, burrow 
and wall themselves off. Usually, however, if the disease has progressed 
to that point, life is cut short by an intercurrent affection ^mvloid is 
often found in the organs at autopsy. 
LITERATURE 
Bostroem: Ziegler's Beit., 1891, ix, 1. 
Ponfick: Die Actinomykose d. Menschen, Berlin, 1882. 
Israel: Virch. Arch., 1879, Ixxiv, 15, 1879, Ixxviii, 421. 
Wright: Jour, of Med. Research, 1905, xiii, 349. 
Shiota: Dtsh. Zeit. f. Chir., 1909, ci, 289. 
Kohler: Frankfurter Zeit. f. Path., 1914, xv, 146. 
Harbitz and Grondahl: Amer. Jour. Med. Sci., September, 1911, cxlii, 386. 
Dresel: Ziegler's Beit., 1915, lx, 185. 
MacCallum: Centralbl. f. Bakt. u. Paras., Abth. i, Orig., 1902, xxxi, 529. 
Abbott and Gildersleeve: Ibid., 547. CHAPTER XXXIII 
TYPES OF INJURY.-BACTERIAL DISEASE (Continued).-TUBER- 
CULOSIS 
Tuberculosis: Aetiology. Distribution and transportation of bacilli. Modes of infection. 
Immunity and hypersensitization. The tubercle, tuberculous granulation tissue, acute 
tuberculous inflammation, distribution of the bacilli in the body. Acute miliary tuberculosis. 
Tuberculosis of respiratory organs, digestive tract, serous surfaces, lymph-glands, genito- 
urinary tract, nervous system, skin, bones, and joints. 
TUBERCULOSIS 
^Etiology.-The disease tuberculosis was known in practically all its 
forms long before its cause was discovered. Since it is of universal dis- 
tribution and causes the death of more persons than any other disease, 
it has always been earnestly studied as far as was possible with the avail- 
able means. Several epochs stand out in this study, although it must be 
confessed that we are still far from a complete understanding of the 
disease, and other epochs are still to come. Laennec knew that pulmonary 
consumption was in some way the same disease as that in which the organs 
were sprinkled with small gray tubercles; Villemin proved it by inoculat- 
ing caseous material into animals and producing tubercles, but it was not 
until 1882 that R. Koch discovered the bacillus. Then, since it was 
shown to be the common cause of all the different manifestations of the 
disease, there should have been no further dispute between the supporters 
of the duality or of the unity of tuberculosis. Nevertheless, this went 
on for years. Koch made the further discovery that a toxic material 
which he called tuberculin could be extracted from the bacilli. For a 
time he maintained that this could be used as a curative or, at least, as a 
protective therapeutic agent and, of course, the whole world was stirred 
by this. But it proved a vain hope, and tuberculin became known only 
as a material which could be used for diagnosis, since it is harmless when 
injected into normal persons, but stirs up a febrile reaction in those already 
infected with tuberculosis. Koch also observed that injection of tuber- 
culin caused a flare up of activity in the tuberculous lesions already 
present, and, what was more important, that injection of live bacilli in 
an animal already tuberculous had something of the same effect. He saw 
that the course of infection by these live bacilli themselves was quite 
different in an animal already tuberculous from what it would be in an 
animal which had never been infected, but he made no further use of 
this observation. 
In 1898 Theobald Smith proved that all tubercle bacilli were not alike 
and that there were easily recognizable differences between the bovine 
634 TUBERCULOSIS 
635 
type obtained from the common tuberculous lesions in cattle and the human 
type. Others later recognized avian, reptilian, and even piscine types, 
which are probably still more remote from the human type. The bovine 
bacillus is shorter and stouter than the human form and grows less easily 
upon artificial media. In acid glycerin bouillon it tends to produce an 
alkaline reaction, while the human type only accentuates the acid reaction. 
But most definite of all is the far greater virulence of the bovine type, since 
it infects rabbits easily, is rather often found producing fatal tuberculosis 
in man, and readily infects cattle. The human type, on the contrary, 
while readily causing tuberculous lesions in guinea-pigs and man, will 
hardly infect rabbits and may be injected with impunity into cattle. 
Indeed, it is used as a harmless organism still possessed of the family 
characteristics to immunize cattle against the bovine form. The tuber- 
culin produced from these two forms is probably identical. There has 
been some question as to whether the human type is not merely an at- 
tenuated bovine type through long passage in human beings, but all ob- 
servations and experiments, such as passage through monkeys, show that 
this is unlikely, and that the types maintain their identity. 
In 1901 Koch went so far in an address in London as to say that there 
was so little in common between the tubercle bacilli of cattle and that of 
man that precautions against infection from milk might safely be omitted. 
The weight of his authority was so great as to insure the acceptance of 
any statement he might make, and for a second time the whole world was 
stirred. But since even then fatal cases of human tuberculosis due to 
the bovine type of bacillus were known, practically all other experienced 
workers, including von Behring and Theobald Smith, immediately at- 
tacked and disproved Koch's assertion, to avert the danger which would 
follow neglect of the measures then in use to prevent the consumption of 
infected milk. 
Distribution and Transportation of Tubercle Bacilli.-Nothing is known 
as to any life or development of the bacilli apart from the animal body, 
so that as sources of infection we must look to infected animals. It is 
true that the tubercle bacilli can remain alive for a long time even when 
dried up in sputum or in dust, and probably even longer when kept moist. 
But exposure to bright sunlight quickly kills them, whether moist or dried, 
so that it seems probable that street dust is of little importance in trans- 
mitting the disease. 
Bacilli in this disease are discharged in quantities from the bodies of 
infected animals because they are abundant in the softened material 
set free from ulcerations in the lungs, intestines, or urinary bladder. 
When there are tuberculous sinuses draining from some internal focus 
the discharges from these canals carry abundant bacilli. But they are 
also set free with milk from cows which have tuberculosis of the udder. 
Therefore, not only milk but butter and even cheese may contain them. 
They are expectorated by consumptives in the sputum, but according to 636 
TEXT-BOOK OF PATHOLOGY 
Fliigge and his students, they are also sent forth suspended in a spray of 
fine droplets with the breath of such a person, especially when he coughs 
or sneezes or talks loudly. 
Since the organism is so tenacious of life and so abundantly evacuated 
from the bodies of those infected, there is small wonder that tuberculosis 
is so wide-spread. It was not, however, until recent years that we had any 
idea of the extraordinary prevalence of this infection, although the extent 
to which actual illness resulted was well enough known. This is primarily 
because in most people the infection is quickly overcome and never pro- 
gresses beyond the formation of a tiny focus of destruction of tissue which 
ends in a scar or in a calcified nodule in a lymph-gland. 
Two methods have been employed, however, to discover how wide-spread 
infection has been: one, the search for the traces of tuberculous lesions in 
all bodies at autopsy, the other, the application of the tuberculin test to 
large numbers of persons in a community. The results are astounding, 
for while they agree almost precisely, they show that the percentage of 
all persons examined and found to show evidence of having been infected 
with the bacilli, increases from about 15 in the first decade, through 
30 to 60 in the second, to 99 in the sixth and seventh. Such are the sta- 
tistics of Nageli, in Zurich, and Burckhardt, in Dresden, from autopsy 
material, while Nothmann, in Dusseldorf, and Hamburger and Monti, in 
Vienna, found by the tuberculin test in children a steady rise from the 
second year to 90 to 100 per cent, in the fourteenth year. These figures 
are from large cities in the central European countries where tuberculosis 
is notoriously common, and are taken from the proletariat of these cities, 
in whom no doubt infection occurs more readily than in the classes which 
live in a more cleanly way. Hillenberg has shown that practically the 
same condition exists in the country in Germany, but still it seems pos- 
sible that in other less densely populated lands where people are not so 
crowded infection may be less inevitable. 
Two things are argued from this: first, that in spite of almost universal 
infection, relatively few develop progressive tuberculosis, and second, 
that those who do develop tuberculosis in later life must in many cases 
have been infected before as children. 
Modes of Infection.-The determination of the mode of entrance of 
the tubercle bacilli into the body is of prime importance and, of course, 
every possibility has been minutely canvassed. It would seem that the 
tubercle bacillus which produces such characteristic lesions should leave 
a plain trace behind it, and usually it does so. Nevertheless there is little 
that is certain in the explanation offered for the commoner forms of in- 
vasion. The rarer forms are clear enough-for example, when in a ritual 
circumcision, a tuberculous individual officiating, applies his mouth to the 
bleeding prepuce of the infant, it is easy to understand the subsequent 
appearance of tuberculous lesions there and in the inguinal glands. 
But infection through the skin or genitalia is relatively unimportant. 
It is true that tubercles may form upon the hands of pathologists, butchers, TUBERCULOSIS 
637 
and others who expose their skin directly to infectious material, but such 
infections are usually self-limited and seldom give rise to pulmonary or 
other wide-spread tuberculosis. 
The great portals of entry are clearly the respiratory and intestinal 
tracts, and a little consideration of the distribution of the bacilli will con- 
vince one that the common sources of infection are to be found in intimate 
contact with consumptives and in the swallowing of infected milk and milk 
products. All sources of bacilli other than the exhalations and sputum 
of consumptives and the milk from tuberculous cows seem remote and 
rarely to be regarded as important. 
Congenital transmission of the infection, it is true, has been prominent 
in the minds of those who are accustomed to see several cases of tuber- 
culosis in a family and who look upon it as an hereditary disease, but there 
is little actual evidence to show that it can occur. Congenital infection 
may conceivably be of two sorts-that in which either the ovum or the 
spermatozoon is infected, or that in which, in a tuberculous mother, tuber- 
culous disease of the placenta forms the path of transmission of the 
bacilli into the body of the fcetus. In the first of these it is possible that 
the bacilli may be merely carried along with the sperm. In animal 
experiments with normal mothers and males with infected seminal ves- 
icles, vasa deferentia, or testicles, there may be produced foetuses in which 
bacilli are found without any evidence of reaction, or offspring with no 
bacilli or ether sign of tuberculosis. Schmorl has found that placental 
tuberculosis is not uncommon, but that its results are of no great practical 
importance in explaining the origin of tuberculosis in later life, since if 
tuberculosis does appear in the suckling it is rapidly fatal. 
Most cases of tuberculous infection are, therefore, to be regarded as 
either due to aspiration or to deglutition of the bacilli. Since the demon- 
stration by Fliigge of the ease with which tubercle bacilli are floated out 
upon the air in a spray of droplets for at least a metre from the face of a 
consumptive, there seems no difficulty in the way of their inhalation. 
The same may be said in the case of infected dust from dried sputum 
stirred up in the house of a consumptive, or in an institution where there 
are many tuberculous inmates, by shuffling feet or by brooms. Kissing 
of children by consumptives and the transfer of moist sputum to the 
mouths of infants who crawl on the floor or sidewalk must also offer chances 
of infection. Having reached the mouth, nose, and pharynx, the great 
question arises as to how they are introduced into the lungs. The finding 
of lesions in the lungs, which appear to be the oldest and best established 
of all the lesions in the body, leads at once to the suggestion that the 
bacilli are directly inhaled or aspirated into the bronchioles, where they 
produce destructive changes, with a later distribution to the lymph- 
glands at the hilum and to other parts of the lung. It would appear that 
the distribution of coal pigment in the lung must offer a model upon which 
we could reconstruct the distribution of the bacilli. This pigment un- 
questionably reaches the most distant parts of the organ, and while part 638 
TEXT-BOOK OF PATHOLOGY 
of it is wafted back by the bronchial epithelium, much of the rest is 
lodged in phagocytic cells as it is carried back in the lymphatics through 
the connective tissue toward the bronchial nodes. It is difficult to help 
believing that it often happens that tubercle bacilli are carried in this way 
directly into the cavities of the lung, ebbing back in the substance of the 
tissue by way of the lymphatics, but lodging in various places and producing 
lesions. Indeed, Heymann and others have settled this question conclu- 
sively by exposing guinea-pigs to inhalation of dust or spray laden with 
tubercle bacilli, after which the animals were killed at short intervals 
and the lungs examined in stained sections. Tubercle bacilli were found 
in the most distant bronchioles and alveoli. This seems a more accurate 
proof than that afforded by the inoculation of portions of such lungs 
into other guinea-pigs, which, however, gave the same results. 
It is clear, however, that there are other possibilities. The study of 
streptococcal infections of the lungs following measles showed me how 
easily bacteria may be transmitted by the peribronchial and perivascular 
lymphatics in any direction, so that pleural infection as well as infection 
of the bronchial nodes is readily produced. Injections of these lymph- 
atics show the extraordinary richness of the networks running in the walls 
of bronchi and vessels and in the interlobular septa, and a preparation 
shown me recently by Winternitz demonstrated particularly their net- 
like arrangement in the trachea with broad anastomoses with those of 
the bronchi. It seems possible, therefore, as a second method of infection 
of the lung that the bacilli might gain entrance into this network any- 
where along the upper part of the respiratory tract and extend, with the 
aid of multiple thrombosis, into the network of the lung. A priori this 
seems less plausible than the first method, but it is thought an important 
factor in pneumonia, and its true significance is yet to be learned. 
The third possibility is that the bacilli absorbed into the lymphatics 
may pass by way of the subclavian vein to the heart, and thus with the 
blood of the pulmonary artery to the lungs. While this is easily con- 
ceivable, it would leave us with the necessity of explaining the strictly 
local beginning of most pulmonary tuberculosis. The rather frequent 
finding of isolated lesions of the bronchial walls affecting especially the 
bronchus which leads to the apex of the lung, would be hard to explain 
upon this theory, and equally hard to understand if we accept the idea of 
a distribution by way of the very capable lymphatic network. 
In connection with all these three possibilities search for lesions in the 
upper respiratory tract indicating the path of the bacilli has, of course, 
been recognized as important. Sinus infections, tuberculous infection of 
carious teeth, tonsillar tuberculosis, tuberculosis of the larynx and of the 
trachea, and perhaps especially the less completely explained secondary 
steps shown in tuberculosis of the cervical lymph-glands-all these have 
been studied, but without demonstrating, as it seems to me, a frequency 
of occurrence quite adequate to explain all the cases of pulmonary tuber- 
culosis. TUBERCULOSIS 
639 
While keeping a perfectly receptive attitude toward the proof for the 
origin of pulmonary tuberculosis through transport of the bacilli to the 
lungs by way of the lymphatics or the blood-vessels, I think we must still 
accept as valid, in most cases, the old explanation of the direct aspiration 
of the bacilli into the bronchioles. 
With regard to the discussion of these possibilities the student should 
read the papers of Opie, Baldwin and Gardner, and of Ghon. 
As far as concerns the other great portal of entry, the alimentary tract, 
there need be little difficulty in accepting the possibility of the safe pas- 
sage through the gastric juice with its disinfecting hydrochloric acid, of 
such resistant and wax-bound organisms as the tubercle bacilli. At 
least it appears that they do reach the intestine in persons with advanced 
pulmonary tuberculosis who must swallow much of their sputum. In 
these cases, however, it may well be that temporary disturbances of gas- 
tric secretion make the passage of the bacilli easy. 
Von Behring points out the fact that in the very young infant the fer- 
ment-secreting glands of the digestive tract are little developed and the 
epithelial lining not yet a serious obstacle to the passage, unchanged, of 
any foreign protein. Antitoxin can be administered effectively by mouth. 
In these infants, therefore, he finds no great obstruction offered to the 
rapid absorption of tubercle bacilli, which leave no trace behind. 
Rossie, Calmette, Ravenel, Orth, and others find a rapid general spread 
of such bacteria throughout the body, lodging in lymphoid tissues every- 
where, and sometimes (Bartel) producing no visible lesions whatever. 
All argue that tubercle bacilli brought into contact with any mucosa are 
readily absorbed without leaving a destructive lesion to mark the place 
of entrance. 
Hence, the uncertainty about the mode of entrance of those bacilli 
which ultimately cause pulmonary phthisis. They may be directly as- 
pirated into the lungs, so that, as Ghon maintains, the primary lesion is 
in the lung. Absorbed through the intestine in infancy, as Ven Behring 
claims, they may give rise years later to pulmonary disease as an autoin- 
fection, much as the tertiary lesions of syphilis appear months or years 
after the primary and secondary stages. Or the pulmonary tuberculosis 
may be caused by a second infection, with organisms from outside the body 
acting upon tissues whose resistance has been changed by the previous 
infection. It is not possible to exclude any of these conceptions, and per- 
haps all are true in their turn. 
They can, however, scarcely be discussed until the fundamentally im- 
portant work of Romer is considered. 
Immunity and Hypersensitization.-Koch, as stated above, had ob- 
served that the progress of tuberculous infection in animals which had 
suffered a previous infection was different from that in fresh uninfected 
animals, but he pursued the subject no further. Romer repeated the 
experiment, being careful to measure the dosage of tubercle bacilli pre- 
cisely, and found that the first infection of a normal animal produces 
tubercles which, if the dose is small and the organism feebly virulent, may 640 
TEXT-BOOK OF PATHOLOGY 
be completely healed, but otherwise may progress so as to produce a wide- 
spread and fatal tuberculosis. 
If now, after the preliminary inoculation has been survived a long time, 
fresh, uninfected guinea-pigs and these tuberculous guinea-pigs be in- 
oculated, side by side, with a constant, small, measured dose of virulent 
bovine tubercle bacilli by injecting the bacilli into the skin itself, it is 
found that the normal guinea-pigs proceed to die with extensive tuberculosis 
of the organs and with a tuberculous ulcer at the point of inoculation, 
while the lesions in the organs of those already tuberculous are not much 
increased, and the point of inoculation, although for a time intensely 
inflamed and necrotic, heals up completely. It is evident that the previous 
infection affords a fairly satisfactory protection against a reinfection, 
provided the dosage in the second inoculation is not too great. Krause, 
in repeating this work, has shown me the contrasting effects at the points 
of inoculation with the virulent bacilli. In the normal animal the reac- 
tion is slow and steadily progressive until an extensive ulcer with tubercles 
is formed and the animal ultimately dies with generalized tuberculosis 
of the internal organs. In the previously infected animal there is a rapid 
appearance of an area of redness and swelling, which fades away com- 
pletely in the course of a day or two. Then a rapidly progressing inflam- 
matory reaction with necrosis and ulceration appears, the tubercle bacilli 
are apparently overwhelmed and killed, and in a few weeks the area heals 
with no further development of tuberculous lesions in the internal organs. 
This rapid inflammatory reaction indicates an anaphylactic condition, 
like the well-known tuberculin reaction. A larger dose of the virulent or- 
ganism might produce so intense a reaction as to kill the animal after an 
acute illness, although in the normal animal it would merely produce a 
more extensive, slowly progressing tuberculosis. This is, then, the char- 
acter of hypersensitization in the immunity produced by a previous infec- 
tion. It is an altered attitude of the body toward the new infection, the 
allergy of Von Pirquet, which brings with it an altered reaction of the 
internal organs to a later dose. This phenomenon has been studied in vari- 
ous internal organs, and although the results are complex and difficult to 
interpret, they appear to be fairly constant. 
Nichols found that normal animals upon subcutaneous injection of 
tubercle bacilli developed numerous tubercles in the lungs, while the 
previously immunized animals, after going through an acute hsemorrhagic, 
inflammatory process, with tubercle formation, survived for a long time 
with encapsulated and fibroid caseous areas in the lungs. Paterson 
found that injection of bacilli into the pleura produced no obvious change 
in normal rabbits, although the bacilli were quickly absorbed and set up 
tubercles in the lungs and other organs. In immunized rabbits, in con- 
trast with this, there was an immediate outpouring of bloody exudate 
which filled the pleura, but healing processes followed, and these animals 
survived the others by a long time. Soper found the same contrast in TUBERCULOSIS 
641 
the liver. Injection of bacilli into the portal vein produces the pro- 
gressive tubercles in normal animals; in the sensitized immune animal 
the tubercles are formed more rapidly, and the lesion is apparently more 
serious, but after two or three weeks it begins to heal and disappear, so 
that these animals long survive the others. 
Besangon and de Serbonnes injected virulent bacilli into the bronchi 
in normal animals and in those previously infected, and found that in the 
fresh animals there arose a caseous pneumonia rich in bacilli, while in those 
which had been previously infected there was first an extraordinary 
dilatation of the capillaries with desquamation of the alveolar epithelium. 
Later, there being a few bacilli there, no caseation occurred, but the lung 
tissue became sclerotic. 
It is rather difficult to interpret this in terms of what occurs in natural 
infections and reinfections. There is, undoubtedly, a distinct immunity 
conferred which, even when the bacteria of the first inoculation are still 
producing lesions in the internal organs, prevents a progressive new in- 
fection in the skin. In this respect it resembles the condition in syphilis 
in which, so long as the spirochaetes are present, reinfection is difficult. 
In most cases the early infection of childhood successfully protects 
against the later infection, but if the first infection is too severe, it leads 
to progressive tuberculosis and death. Similarly, if the second infection 
is too severe, the protection is broken through, with the same result. Can 
we then, on this basis, decide whether the pulmonary phthisis which 
develops in adult life is a late manifestation of the original childhood 
infection, the effect of too large a second infection from outside, which is 
accentuated by the phenomena due to the anaphylactic hypersensitiza- 
tion, or, finally, the result of a second infection modified by the existing 
immunity, but gradually overcoming it? It is difficult to tell, but I, for 
my part, lean to the last possibility. 
More work is required in the exact analysis of the lesions in pulmonary 
tuberculosis and the determination of their relations to these phases of 
infection. It is quite true that throughout the whole course of chronic 
tuberculosis of the lungs there are evidences of great powers of resistance. 
Usually the tracheal and laryngeal mucosa, which are constantly covered 
with tubercle bacilli, show no lesions, although in a normal person such 
exposure would, it seems, surely infect them. 
Should we then attempt to prevent the early infection which is so com- 
mon in childhood and thus sacrifice its protective effect throughout life, 
should we merely try to limit it to a small dose, or should we deliberately 
inoculate the children with non-virulent bacilli? The problem is an open 
one. 
Susceptibility.-Much has been said as to individual predisposition to 
tuberculosis, and there is an impression in the minds of most people that 
even though actual cases of the inheritance of tuberculosis cannot be dis- 
covered, there is inherited a weakened constitution which makes the off- 642 
TEXT-BOOK OF PATHOLOGY 
spring of tuberculous parents especially susceptible to the disease. While 
this idea is rather vague, it can be shown that certain deformities of the 
thorax which lead to narrowing of its upper portion favor the development 
of apical tuberculous disease. Ill development of the circulatory organs 
and of the respiratory musculature may also play a part. Indeed, there is 
a recognizable phthisical habitus which may finally be seen in actual 
consumptives, but whether this is a forerunner of future tuberculosis or 
the effect of its unobserved existence it is difficult to say. 
Practically very important is the predisposition to tuberculous infec- 
tion produced by traumatism, as seen especially in the case of the bones 
and joints, but also in some other situations in the body. This may be 
regarded as due to the establishment of a point of lowered resistance, where 
the bacilli easily gain a foothold. Something similar is doubtless true of 
the predisposing effects of an attack of measles or other infectious disease. 
Indeed, measles is reckoned as a very serious affection, largely on account 
of the frequency with which it is followed by tuberculosis. Pregnancy, 
diabetes mellitus, and other conditions affecting the whole body predis- 
pose in some more general way, and it is known that tuberculosis arising 
in the course of diabetes is usually very intense and rapidly destructive. 
LITERATURE 
Romer and Joseph: Brauer's Beitr. zur Klinik der Tuberkulose, 1910, xvii; 281-427. 
Koch: Mitth. a. d. kais. Gesundheitsamte, 1884, ii, i. Berkl. klin. Woch., 1882, xix, 221. 
Smith, Th.: Jour. Exp. Med., 1898, iii, 451. Jour. Med. Research, 1905, xiii, 253; 
1907, xvi, 435. Trans. Massachusetts Med. Soc., 1907. Harvey Soc., 1906. 
vol Behring: Deutsch. Med. Woch., 1903, xxix, 689. 
BezanQon et Serbonnes: Annales de Medicine, 1914, 149. 
Nichols: Med. News, 1905, Ixxxvii, 638. 
Paterson: Amer. Rev. of Tuberculosis, 1917, i, 353. 
Soper: Ibid., 385. 
Krause: Ibid., 1919, iii, 1; 1920, iv, 558. 
Ghon and Roman: Sitzb. d. k. Akad. d. Wiss. in Wien, Math, naturw. KI., 1913, 
cxxii, 1. 
Orth: Sitzb. d. k. Preuss. Akad. d. Wiss., 1913, iii, 51. 
Trudeau: New York Med. Jour., 1903, Ixxviii, 105. 
Fliigge: XIV Hygien. Kongr., 1907, ii, 42. 
Baldwin: Harvey Lectures, 1914-15, Series X, 154. 
Baldwin and Gardner: Amer. Rev. of Tuberculosis, 1921, v, 429. 
Heymann: Ztschr. f. Hygiene u. Infectionskr., 1908, lx, 490. 
Opie: Amer. Rev. of Tuberculosis, 1922, vi, 525. 
Effects of the Tubercle Bacillus on the Tissues.-The lesions produced 
by the tubercle bacillus are, in their ultimate analysis, essentially like 
those found in any acute and chronic inflammation, but the proliferative 
changes are so marked and come so quickly as to give a quite foreign air 
to them. Then, too, they have in common the peculiarity that wherever 
the bacteria are present in sufficient number with their poisons, the whole 
area dies and becomes coagulated. 
Tubercles.-Most commonly on reaching the tissue the bacilli produce TUBERCULOSIS 
643 
minute, translucent, grayish nodules, which, from being supposed to be 
of about the size of millet-seeds, were called miliary tubercles (Fig. 307). 
We now know, however, that those were really little groups of tubercles, 
and that a single tubercle is a great deal smaller and scarcely visible to 
Fig. 307.-Acute miliary tuberculosis of lung. Small tubercles of almost uniform size 
scattered through the lung. 
the naked eye. The tendency to grouping and coalescence is very strong, 
and such a mass, instead of being round, is really lobulated or mulberry 
shaped. While the tubercles are very fresh and young they remain trans- 
lucent, but very soon they show a spot of yellowish opacity in the centre. 644 
TEXT-BOOK OF PATHOLOGY 
Microscopically, a fresh tubercle is a roughly concentric mass of cells, 
pretty sharply marked off from the surrounding tissue (Fig. 308). These 
cells, clustered around a central area, are sometimes arranged in laminse, 
but are usually attached to one another in less orderly fashion to form 
a pale staining tissue. They have elongated vesicular nuclei, with little 
chromatin and a faintly outlined cell-body, which is irregular in form and 
branches to connect itself with its neighbors. These are the cells com- 
monly known as epithelioid cells, which form the most constant feature 
Fig. 308.-A single tubercle, rather sharply outlined with a giant-cell sending proto- 
plasmic processes among the epithelioid cells. 
of the tubercle. Often, but not always, the central part of the mass is 
occupied by a giant-cell, a large mass of protoplasm containing a great 
number of nuclei which are usually arranged around its periphery or at 
the opposite poles (Figs. 308 and 309). 
This protoplasmic mass also gives off processes which ramify among 
those of the epithelioid cells. In the marginal portion of the tubercle one 
usually finds numbers of mononuclear wandering cells of the lymphoid 645 
TUBERCULOSIS 
type. The whole is supported by a newly formed framework or reticulum, 
which can be demonstrated by digesting away the cells. Usually, too, 
there can be shown to exist a delicate network of fibrin. 
Tubercle bacilli may be found in the body of the giant-cell or lying in 
crevices between the epithelioid cells. But there is absolutely no pro- 
vision for a blood-supply in such nodules, and those capillaries which were 
present at that point before are found to be obliterated, so that if an organ 
Fig. 309.-A single tubercle showing rather irregularly arranged epithelioid cells, 
a large giant-cell, and the peripheral lymphoid cells. The drawing shows also the re- 
ticulum of the tubercle. 
studded with tubercles be injected through the artery with blue gelatin, 
each tubercle will stand out as a white nodule against the blue background. 
This circumstance may aid in bringing about the necrosis of the nodules, 
although they are so small that they might absorb enough nourishment 
from the surrounding fluids. More important is the action of the poison 
produced by the bacilli which first causes degeneration, and finally death 646 
TEXT-BOOK OF PATHOLOGY 
of the cells. The epithelioid cells become distorted, their nuclei elongated 
and twisted, so that they lie radially and for a time take a deep stain (Fig. 
311). Then, beginning sometimes in the giant-cell and involving the whole 
centre of the nodule, there occurs a complete disintegration of the cells, 
which melt together into a formless hyaline mass. 
There has been much dispute over the origin of the cells which consti- 
tute the tubercle. Baumgarten has always maintained that the epi- 
thelioid cells are derived from the fixed tissue, possibly the endothelial 
cells, while certain French authors have regarded them as wandering cells. 
It was shown by Wechsberg and others that the first effect of the lodgment 
of the bacilli is the destruction of a few adjacent cells, responded to by 
an inwandering of polymorphonuclear leucocytes, but that this process is 
Fig. 310 - Conglomerated tubercles composed chiefly of epithelioid cells. 
soon masked by the development of the epithelioid cells. The matter is 
still under discussion, and Wallgren, in his detailed studies of the early 
development of tubercles in the liver, lays stress on the participation of 
lymphoid cells and mononuclear phagocytes, finding that the fibroblasts 
play a secondary and protective role. He recognizes an occasional pro- 
liferation of the endothelium of the capillaries. Similarly, v. Fieandt, in 647 
TUBERCULOSIS 
studying meningeal and cerebral tubercles, finds a primary invasion of 
leucocytes and later a secondary invasion when they are attracted by the 
dead tissue. The part played by the large mononuclear wandering cells is 
specially important, the plasma and lymphoid cells occupying a second 
place. It is much later-one to two weeks after the infection-that 
the fibroblasts proliferate, then forming epithelioid and giant-cells. More 
recently Evans, Bowman, and Winternitz have studied the formation of 
tubercles in the liver, after the injection of the bacilli into the portal vein. 
Fig. 311.-Rather older tubercles with beginning central degeneration and radial ar- 
rangement of the epithelioid cells. 
in animals in which the so-called Kupffer cells of the capillary endothelium 
are stained blue by the administration of a vital stain. They find that the 
part played by the leucocytes is transitory, and that the giant-cells are 
clearly derived from the Kupffer cells, which take up the bacilli, and be- 
come greatly enlarged, the nucleus dividing by mitosis, although the cyto- 
plasm remains unaltered. The epithelioid cells arise also, they think, 
from endothelial cells. Even yet, however, it cannot be regarded as 
entirely settled. The Kupffer cells shown in the drawings in this paper 
are very little like the tubercle giant-cells, and recently Rich and Prommas 648 
TEXT-BOOK OF PATHOLOGY 
have found that while it is true that the Kupffer cells take up the bacilli, 
become multinuclear, and swell greatly; they are killed and disintegrated 
before the final giant-cell appears. The liver cells are not primarily injured 
and the leucocytes play little part. In the fully formed tubercle the charac- 
ter of the mass, as a coherent tissue with the production of a reticulum, 
strongly suggests the participation of fibroblasts. But in other cases the 
tubercle may be a more atypical mass of rounded and evidently inde- 
pendent cells, which are probably wandering cells. 
The formation of the giant-cell has always offered difficulties, and two 
main ideas have been put forward to explain it. The nucleus of the cell 
may divide without the division of the cell body, or the multinucleated 
cell may arise from the fusion of several smaller cells. Mitoses have rarely 
been seen, and an amitotic division of the nucleus has been suggested. 
Coalescence of several cells is thought possible even by those who have 
found mitoses in the Kupffer cells, and was definitely shown to occur in the 
formation of foreign body giant-cells in vitro by Lambert. All are agreed 
that the lymphoid cells are wandering cells which have been attracted to 
the tubercle. 
As has been said, there is a great tendency toward coalescence in these 
Fig. 312.-Large tubercles in the spleen. 
tubercles, and caseation or the production of a cheese-like, necrotic sub- 
stance usually takes place in the whole central part of such a mulberry-like 
mass. It follows that the opaque white material is left, surrounded by a 
scalloped margin composed of the remnants of the outermost tubercles. 
Tumor-like masses of cheesy material as large as a walnut are sometimes 
formed in this way, especially in the spleen or in the brain (solitary tuber- 
cles) (Fig. 312). 
The coagulative necrosis produces at first a fairly firm material, in which 
all cell outlines and nuclear staining are lost. This may be softened later, 
often because of a secondary infection, or in other instances it may be con- 
verted into a mortar-like material or even a stony block by the deposit of TUBERCULOSIS 
649 
calcium salts. Healing may occur in every sort of tubercle-in the large 
caseous ones by inspissation of the necrotic material and the formation of a 
dense surrounding capsule, while the fresh, translucent miliary tubercles at 
times are changed into hyaline fibrous nodules. It is cheering evidence of 
the great powers of resistance possessed by most individuals when it is 
found, as Naegeli and others have shown, that nearly all adults harbor 
somewhere a healed tuberculous lesion. 
LITERATURE 
Baumgarten: Ueber Tuberkel und Tuberkulose, Berlin, 1885. 
Wechsberg: Ziegler's Beitr., 1901, xxix, 203. 
Wallgren: Arb. a. d. path. Inst., Helsingfors, 1911, iii, 139. 
Evans, Bowman, and Winternitz: Jour. Exp. Med., 1914, xix, 283. 
Miller: Jour. Pathology and Bacteriology, 1904, x, 1. 
Tuberculous Granulation Tissue.-Tuberculous lesions are by no means 
exclusively tubercles. There may be formed, especially on a free surface, 
abundant highly vascular 
granulation -tissue, which 
is in most places quite like 
ordinary granulation tis- 
sue, except in that it is 
perhaps more thickly in- 
filtrated with large and 
small mononuclear wan- 
dering cells and contains 
fewer polymorphonuclear 
leucocytes. It is produced 
as a reaction to the pres- 
ence of numerous tubercle 
bacilli, and is especially 
distinguished by its con- 
tent of scattered epithe- 
lioid cells and giant-cells, 
or even well-formed tu- 
bercles (Fig. 313). Further, 
however, it is character- 
ized by its strong tendency 
to undergo, despite its rich 
vascular supply, coagu- 
lative necrosis or casea- 
tion. When, as is so common, it replaces the ulcerated mucosa in lining 
a canal, the caseous material produced by the necrosis of its superficial 
layers is often sufficient to choke the canal. 
The tuberculous granulation tissue may, however, escape this fate in 
Fig. 313.-Tuberculous granulation tissue. 650 
TEXT-BOOK OF PATHOLOGY 
part, in persons whose resistance is high, and then contracts to form a 
dense fibrous layer upon which new granulations form. Sometimes the 
healing is complete and nothing remains but a scar or dense fibrous ad- 
hesions. An example of this is great thickening of the capsule of the liver 
and spleen, regarded by many as the remains of an old tuberculous process. 
The formation of tuberculous granulation tissue is most commonly the 
sequel to an outpouring of inflammatory exudate due to the tubercle bacilli, 
and in this respect it once more resembles closely the analogous tissue 
found after other inflammatory processes. 
Acute Tuberculous Inflammation.-It is quite clear that the tubercle 
bacillus can produce an acute inflammatory reaction which is like that 
produced by other injurious agencies, but peculiar in that mononuclear 
phagocytic cells are the predominant constituent of the exudate, and 
further, in that the presence of the bacilli in large numbers leads to a coagu- 
lative necrosis of both tissue and exudate. All this is most clearly seen in 
the lung when quantities of tubercle bacilli are aspirated into the alveoli 
in a person whose resistance is low. Then there arises a pneumonia with 
the peculiar mononuclear exudate surrounded by a zone of glutinous 
oedema (Fig. 314). The central part of such an area becomes necrotic 
or caseous, while the more peripheral part tends to become organized if 
the person lives long enough. But it is also clearly seen in cases in which 
large numbers of the bacilli gain access to the peritoneum or pleura or 
pericardium, or when they reach the meninges. Indeed, in persons whose 
resistance is not too high, the advent of numerous bacilli may produce 
acute inflammatory lesions in the substance of many organs. Local or 
specific resistance seems to vary greatly in different tissues, for while the 
lymph-nodes and spleen are greatly ravaged, one seldom finds tuberculous 
lesions in thyroid, pancreas, or voluntary muscle. 
It must be kept in mind that except in the experimental inoculation of 
animals, tuberculous lesions are practically always the result of trans- 
portation of the bacilli from some previous focus of infection-that is, we 
are dealing with reinfection. Therefore, except in the case of the elusive 
primary lesion, we may assume that they develop under the influence of 
the allergy described above. The effect of this is, as shown by the experi- 
ments cited, to intensify and accelerate the inflammatory reaction, but 
not to modify it qualitatively except in that through the immunity acquired 
after previous infection there is a tendency to destroy the bacilli. This 
may be successful when the second dose is minimal, but it is unsuccessful 
when there are abundant bacilli spread from the primary lesion. Then, 
exactly as in the experiments of Rossie and Gerlach with inflammation in 
an allergic animal, the lesion is produced with violence and at a rate prob- 
ably greater than might have been observed had it ever been possible to 
study the spleen or lymph-nodes or even the lungs in a previously un- 
infected person when such an overwhelming number of bacilli entered at 
once. TUBERCULOSIS 
651 
The relation between acute tuberculous inflammation and the forma- 
tion of tubercle nodules is still an open question. In many places where 
the tissues appear to the naked eye to be studded with tubercle nodules, 
microscopic examination reveals groups of wandering cells-minute patches 
of pneumonia are very frequently mistaken for tubercles, and the granula- 
tions in the margins and bases of tuberculous ulcers of the intestine turn out 
Fig. 314.-Edge of a fresh area of caseous and gelatinous pneumonia. Note the numer- 
ous large cells in the less affected alveoli. 
on closer examination to be closely packed masses of mononuclear wander- 
ing cells. On the other hand, obvious areas of caseous pneumonia prove 
to be edged with a fringe of tubercles, and so do the granulations in the 
intestinal ulcers, if they have persisted for a longer time. It is perfectly 
clear that fresh tuberculous pneumonia is an acute process, but it is not 
so clear that tubercles are rapidly formed. Indeed, if we follow hour by 
hour the results of injecting tubercle bacilli into the capillaries of the 652 
TEXT-BOOK OF PATHOLOGY 
liver, it is by no means the tubercle which first appears, but rather a 
phagocytic and exudative process which is later enclosed and masked by 
the tubercle. 
The statement will be challenged, but it seems that the formation of 
tubercles is an integral part of the formation of tuberculous granulation 
tissue, and whether one tubercle suffices to encapsulate the infinitesimal 
area of inflammatory reaction to the tubercle bacillus, or a whole fringe of 
epithelioid cells, giant-cells, and fibroblasts constitute the encapsulating 
wall about an area of pneumonia, the principle is the same. The tubercle 
is a defensive reaction on the part of the body quite analogous to the 
granulation tissue which walls off an infarct or encapsulates a foreign 
body. That it in turn breaks down on account of the continued presence 
of the bacilli is natural enough. 
Distribution of Bacilli in the Body.-Having once entered the body, 
the bacilli may be transported by at least four methods-(1) mechanically 
along with air, food, secretions, etc.; (2) by growth through the tissues 
with the production of lesions; (3) by way of the lymphatic channels; 
(4) by way of the blood-stream. 
The first of these is most important in the respiratory organs, where 
bacilli breathed in may lodge in the tissues or be wafted back again by the 
ciliated epithelium. Later, when lesions are established in the lungs, 
bacillus-holding fluid from a diseased area may be poured out into the 
bronchus and aspirated back into another, or it may pass out over the 
laryngeal mucosa. In either case new lesions can be produced in this way. 
So, also, in the digestive tract, the large serous cavities, the urinary organs, 
etc., the organisms are moved about by the contents of these cavities 
under the influence of gravity, secretory streams, and muscular activity. 
In the second case the movement of the bacilli is largely commensurate 
with the formation of lesions, with the gradual involvement of new tissue, 
and the caseation of that previously affected. The third method is often 
dependent upon this, since the lymphatic channels may be invaded by the 
spreading, caseating new tissue, but, quite aside from this, the bacilli may 
be carried into terminal lymphatics and swept along with the stream until 
they lodge somewhere-usually in the next lymph-node. Extension of 
a caseous tuberculous focus so as to erode through the wall of a blood- 
vessel is the usual basis of the fourth mode of transport (Fig. 315). It is 
true that actual tuberculous lesions are sometimes formed inside the 
vessels, but this is rare, while the extension of a caseating process through 
the wall of a vein or artery, so that the bacilli are shed into the passing 
stream, is extremely common. Great numbers of the organisms can in 
this way be suddenly thrown into the circulating blood before the exposed 
caseous material becomes covered with a protecting thrombus. It must be 
remembered that infusion of bacilli-(1) into the systemic veins, brings 
them by way of the right heart to the lungs; (2) into the pulmonary veins, 
distributes them into the whole systemic arterial circulation, while (3) the TUBERCULOSIS 
653 
invasion of an artery causes a distribution only in the field to which it sup- 
plies blood. Less local in its effects is the entrance of bacilli into the 
thoracic duct, for that empties into the subclavian vein, and the result is 
the same as in the case of any systemic vein. The bacilli are very minute, 
however, and in any case they should theoretically be able to pass the 
capillaries and quickly infect any tissue supplied with blood-vessels. 
It happens, however, that these bacilli are quickly caught in such a passage 
through capillaries, so that an organ through which the blood passes acts 
.as a very good sieve. 
Fig. 315.-Caseous tubercle developed in the wall of the pulmonary vein, and separated 
from the blood by a partly organized thrombus. 
In spite of the existence of so many ways by which the bacilli may be 
carried from one part of the body to another, tuberculous infection is gen- 
erally a rather localized process, if we count all cases in which the organism 
gains a foothold in the tissues. This is due to the great power of anni- 
hilating these bacteria possessed by most persons, so that in the end even 
when they have produced distinct lesions they are killed and nothing but 
a scar remains to show where they have been. Still it is clear that when 654 
TEXT-BOOK OF PATHOLOGY 
there is an active focus of disease they get into the blood in small numbers 
and are either killed or produce minute local lesions in other organs. The 
different size and different degree of progression of these tubercles toward 
caseation or healing show that the bacilli have entered the circulation a few 
at a time, sometimes at long intervals. Disturbances of organic function 
can scarcely be expected from such scattered nodules. Other organisms 
behave in the same way, and we are just becoming familiar with the 
effects of occasional intermittent escape of such bacteria as the streptococci 
and staphylococci into the blood-stream. With them we have been more 
accustomed to observe the sudden pouring into the circulation of great 
numbers of cocci, which in the form of an acute septicaemia cause the most 
profound intoxication and set up destructive processes everywhere. This 
happens with the tubercle bacillus also, and not only is the mechanism by 
which it reaches the blood-stream far more distinct than is usual in the case 
of the pyogenic cocci, but practically all the bacilli can be traced by the 
conspicuous nature of the reaction they stir up wherever they lodge. This, 
which is really an acute tuberculous septicaemia, is called, from its ana- 
tomical results, acute miliary tuberculosis. 
Acute Miliary Tuberculosis.-The sudden introduction of thousands of bacilli into 
the circulating blood produces thousands of minute tubercle nodules, all of the same age. 
There is no reason why several such crops should not be produced, and occasionally one 
may distinguish such differences in size and age among the tubercles as to be able to 
conclude that several distinct immigrations of the bacilli have occurred. Usually, 
however, the occurrence of one extensive outbreak is enough to kill the person. 
With sufficient diligence in the use of scissors in following the blood-vessels it is nearly 
always possible to find the hole through which the bacilli were discharged into the 
blood, and Weigert, Sigg, Schmorl, and others have gradually approached 100 per 
cent. The relative number and size of tubercles in the lungs and systemic circula- 
tion may give some clue to aid in this search. It is perhaps most usual to find the 
portal of entry in a branch of the pulmonary vein, but if this fail, the systemic veins 
and the thoracic duct must be surveyed. It is, of course, more likely that those 
veins which run through or near an extensive caseous area should be involved, and 
it proves especially common to find that a caseous lymph-gland attached by adhesions 
to the vein-wall is the source of the material. When the vein is laid open in the 
right place, it is found to be partly obstructed by a granular, cheesy mass, projecting 
into its lumen in such a, way that the soft, bacillus-laden material is washed by the 
passing stream into the general current, or else there is a hole in the wall opening into a 
cavity in an adherent caseous tissue from which bacilli are swept by an eddy of the 
stream out into the vessel. The discharge of bacilli in either case is soon limited by 
the deposit of a protective covering of thrombus material on the exposed surface. 
Of course, it must not be forgotten that, as Benda* and others point out, the dis- 
tributing tuberculous lesion may be formed on the endothelial lining of the vessel (or 
even through the entrance of bacilli into the vasa vasorum), and set free new and 
abundant bacilli only when it has become caseous. This is specially true of the thoracic 
duct, which receives bacilli through its branches and comes in time to be lined with 
caseous, ulcerating areas from which newly grown bacilli are poured off into the blood. 
Rarely one may find tuberculous caseous lesions in the heart discharging bacilli into the 
* Benda: Ergebn. d. allg. Path., 1900, v, 447. Cornet, Nothnagel: Spec. Path. u. 
Therap., 1900, xiv. TUBERCULOSIS 
655 
blood. Intimal tubercles and erosions m the aorta and smaller arteries are uncommon, 
and distribute their bacilli into a limited area only. 
The tubercles which are formed by this wholesale distribution may appear practically 
anywhere. They are sprinkled over the serous surfaces, where they are conspicuous 
and are scattered profusely in such organs as the spleen, liver, and lungs, where they 
are often easier to feel than to see. They are beautifully seen with the ophthalmo- 
scope in the choroid of the living patient. Some tissues, such as those of the pancreas, 
thyroid, muscle, skin, etc., seem very little prone to develop tubercles, but even here 
they are found at times. 
The profound intoxication, like that of typhoid fever, is doubtless due to the sudden 
exposure of so many bacilli through the body, so that they multiply and produce and 
disseminate their poisons. No doubt in advanced phthisis there may be in the lung 
just as many bacilli and even more caseous 
tissue, but there the process is localized and 
the caseous substance is characteristically 
withdrawn from relations with the blood- 
vessels, so that, in a sense, the poison is 
imprisoned. 
The fact that, apart from the acute 
miliary form, tuberculosis is com- 
monly a localized affection, makes it 
possible to refer to the lesions pro- 
duced according to their situation. It 
will be seen, however, that, regard- 
less of the organ involved, the same 
general characters are maintained. 
Tuberculosis of the Upper Respiratory 
Tract.-The mucosa of the nose and phar- 
ynx may become infected by the breathing- 
in of bacilli, but probably more often by 
the direct introduction of the organisms 
from handkerchiefs, etc. Ulcers are formed 
and may extend to the underlying bone and 
to the communicating sinuses. Tubercu- 
lous ulceration of the larynx is common, 
and although thought to be sometimes pri- 
mary, is without doubt most often caused 
by the passage of tuberculous sputum. 
Tubercles are formed just under the epi- 
thelium and become confluent and necrotic. 
Ulceration of the mucosa, which results, affects chiefly the vocal cords, false cords, 
aryepiglottic folds, and epiglottis. The latter is sometimes completely eroded away, so 
that swallowing becomes very difficult. The ulceration of the vocal cords changes the 
voice to a husky, toneless whisper. If it extends so as to denude the cartilages of the 
larynx, they may become necrotic and prone to serious secondary infections. In the 
trachea the infection of the mucosa from the sputum leads to the formation of numerous 
shallow lenticular ulcerations (Fig. 316). 
Fig. 316.-Tuberculous lenticular ulcers 
of the trachea. 
Tuberculosis of the Lungs.-In the lung of the adult the first lesion is 
commonly, though by no means always, in the wall of a bronchus, a cen- 656 
TEXT-BOOK OF PATHOLOGY 
timetre or more below the apex. Why this should be so is not clear, al- 
though many explanations have been offered, based upon supposed differ- 
ences in the blood supply, diminished aeration, immobility, more direct 
access to the bronchus of that part, etc. Freund specially emphasizes the 
immobility, which may be caused by a rigid first rib, and Bacmeister has 
found that if, in rabbits, the apical portion of the chest be held rigidly 
immobile in a wire basket, intravenous inoculation of bacilli produces an 
apical, tuberculous lesion. 
Fig. 317.-Caseous tuberculous bronchitis and peribronchitis. The mucosa on one side 
is still well preserved. 
The apical or subapical lesion was shown by Birch-Hirschfeld to be the 
formation of a tuberculous granulation tissue in the wall of the bronchus. 
This quickly becomes caseous and softened (Fig. 317), and is discharged 
through the bronchus, not, however, before the bacilli have extended their 
growth into the adjacent alveoli, where they form numerous tubercles. 
In such a case a cavity is the central feature in a mass of airless lung sub- TUBERCULOSIS 
657 
stance in which the air-cells are occupied or obliterated by conglomerated 
and partly caseous tubercles, embedded in a radiating fibrous tissue. If 
the development of the focus has been rapid enough, it may be possible 
to see that some of this occlusion of the air-cells has been produced by a 
cellular inflammatory exudate, which becomes caseous and surrounded 
by epithelioid cells, so that it comes to look like caseous conglomerate 
tubercles. 
In many other cases the whole lesion heals and there is found accidentally 
at autopsy an irregular or pyramidal mass of deeply pigmented scar tissue, 
sometimes containing desiccated and encapsulated cheesy nodules, but 
devoid of any resemblance to normal lung tissue. It may be hardened 
by a deposit of lime salts, or still later bone may develop there, with a dis- 
tinct cancellous arrangement and marrow cavities with marrow. Most 
often, however, the patch is contracted and reduced to mere fibrous tissue 
in which no clear evidence of a tuberculous origin can be found. It appears, 
then, as a flat, scale-like scar occupying the surface of the apex of the lung. 
It is somewhat difficult to prove, however, that such subpleural scars are 
really the remains of tuberculous lesions, or, at least, of such lesions as are 
seen in their active form in the subapical tissue. Grober tries to explain 
them, and, indeed, the apical tuberculosis in general, as being due to the 
passage of bacilli from the tonsils by way of the cervical lymph-channels 
to the dome of the pleura, and thence to the apex of the lung, but this 
view has not been generally accepted, and requires confirmation. 
While the establishment of a tuberculous focus with subsequent cavity 
formation near the apex is extremely common, it is not the only way in 
which the disease can begin in the lung. The same process may take place 
in one of the lower lobes, or simultaneously in several places. In the 
opposite lung, by infection from that first involved, hundreds of lesions may 
be simultaneously produced. Or in the entire absence of any primary 
lesion there, miliary tubercles may be showered over both lungs, from a 
focus somewhere else in the body. Especially in children is it common 
to find caseous softening of the bronchial lymph-glands, which, by eroding 
through the bronchial wall, pour bacilli into its lumen and set up at once 
wholesale tuberculous disease of the lung. 
But in spite of these occasional cases, the every-day type of tuberculosis 
of the lungs in adults is that in which there is found a cavity in the upper 
lobe, with all the sequelae which we must now describe. 
Since the cavity is formed by the caseation and hollowing out of the 
bronchial wall and the surrounding tissue, it is always widely open into the 
bronchus (Fig. 318). Secondary connections with other bronchi are formed 
wherever these are cut across as the cavity enlarges, and through all these 
openings the fluid contents pass out into the trachea and are coughed up. 
It is clearly unavoidable that in such violent coughing some of this turbid 
fluid loaded with bacilli should be drawn into other bronchi, and thus into 
parts of the lung not yet diseased. The result is to produce, all through the 658 
TEXT-BOOK OF PATHOLOGY 
lower parts of that organ and in the opposite lung, patches of tuberculous 
bronchopneumonia, exactly as the inhalation of material infected with 
Fig. 318.-Chronic pulmonary tuberculosis with cavity formation and aspiration of 
tubercle bacilli by way of the bronchus, which opens into a cavity. Conglomerate 
patches of caseous pneumonia in lower lobe. Pleurisy with many small tubercles. 
other virulent organisms produces little clusters of solid, airless alveoli 
about the ends of the bronchioles. In the beginning these parts of the lung 659 
TUBERCULOSIS 
may be pale or congested, and rough, dry, grayish-red areas stand out 
a little above the cut surface. At that stage the alveoli are found full of 
fibrinous exudate, with many leucocytes and some red corpuscles. Mono- 
nuclear cells prevail over the polynuclear, and there quickly appear great 
numbers of large pale cells with vesicular nuclei which are generally stated 
to be epithelial cells shed from the alveolar walls, although Orth maintains 
that they are large mononuclear wandering cells. The process is a true 
pneumonia, even though the type of wandering cells is somewhat different 
from that seen with pneumococcus infection. In the neighborhood (see 
Fig. 319.-Large cells found in the alveoli in the neighborhood of areas of caseous pneu- 
monia. They are seen to contain fat-globules. 
Fig. 314) the alveoli are filled with a thick, glutinous fluid, in which float 
many more of the desquamated epithelial cells, which often become 
conspicuously yellow from their content of neutral and anisotropic fat (Fig. 
319). At a slightly later stage nearly the whole consolidated area turns 
white and becomes soft and cheesy, and, although the outlines of the 
alveolar walls, undisturbed in their position, can long be discerned in virtue 
of their highly resistant elastic tissue, every cell dies, loses its nuclear stain- 
ing, and is disintegrated. The bronchial walls become caseous also, and 
among such areas of caseous and gelatinous lobular pneumonia they may be 660 
TEXT-BOOK OF PATHOLOGY 
seen coursing through the tissue as conspicuous tubes with thick, opaque, 
yellowish-white walls (caseous bronchitis) (Fig. 320). 
Occasionally, when very great numbers of tubercle bacilli are introduced 
Fig. 320.-Caseous lobular pneumonia with caseous bronchitis. 
into the bronchioles at one time, a lobar caseous pneumonia follows (Fig. 
321). In such a case a whole lobe or even a whole lung may be uniformly 
consolidated, so that if it were seen in an early stage, it might be confused 
Fig. 321.-Caseous lobar and lobular pneumonia. 
with an ordinary lobar pneumonia. The character of the exudate, with its 
predominant mononuclear cells and the gelatinous, translucent appearance TUBERCULOSIS 
661 
of the adjacent lung tissue, which is not so intensely affected, serve even 
then to distinguish it, and the subsequent caseation en masse makes the 
Fig. 322.-Caseous and gelatinous pneumonia. The consolidation and caseation are 
practically lobar in their distribution. 
differentiation clear (Fig. 322). In a lung studied recently only the tissue 
immediately about the great vessels and bronchi remained alive. Prac- 662 
TEXT-BOOK OF PATHOLOGY 
tically all the rest had assumed the consistence of cream-cheese and was 
perfectly opaque and yellowish white (Fig. 323). Naturally, the softening 
and discharge of such necrotic material will leave huge cavities in the lung, 
and the rapidity with which the organ is destroyed in this way has given 
rise to the name phthisis florida, or galloping consumption. Frankel and 
Troje first clearly described this form of the disease, and drew attention to 
its clinical features, which resemble those of a frank lobar pneumonia until, 
with the protracted course, there appear signs of breaking down of the lung 
and the discharge of a green sputum full of shreds of elastic tissue. 
Even small lobular areas of consolidation become caseous and spill their 
contents, when they have become fluid enough, into the bronchi. This 
liquefaction seems to be partly the work of the enzymes of the surround- 
ing cells, but partly the conse- 
quence of a secondary infec- 
tion-at least there are always 
found numbers of other organ- 
isms in a cavity of any size.* 
Were it to proceed un- 
checked, such destructive tu- 
berculosis would eat away the 
whole lung very shortly, but 
from the beginning there are 
efforts at building up a cellu- 
lar barrier against the exten- 
sion of the caseation, and these 
efforts, pushed to their ut- 
most and lasting over months 
and years, bring about the 
scarring and fibrous indura- 
tion of the lung so character- 
istic of the more chronic sorts 
of phthisis. 
In the pneumonic patches, before the central parts where the bacilli are 
most numerous have become necrotic, a loose wall is formed all around in 
the outskirts of the exudate by its organization. This process, so rare in 
lobar pneumonia, commoner in bronchopneumonia, is practically the rule 
here. New formation of epithelioid cells and of fibroblasts springs up in 
the walls of these alveoli, and shortly a definite tuberculous granulation 
tissue, including abortive and well-formed tubercles, surrounds the rapidly 
caseating area. This wall becomes firmer and more resistant, although 
itself prone to caseation and disintegration, and even in advance of the 
Fig. 323.-Caseous pneumonia (lens enlarge- 
ment). 
* In this connection it should be stated that streptococci, pneumococci, etc., are 
sometimes the chief agents in bringing about the lobular pneumonia which results from 
the aspiration of the contents of a cavern. In such a case both symptoms and anatom- 
ical changes are modified. TUBERCULOSIS 
663 
caseating process it is backed up constantly by new tissue formed in the 
same way outside (Fig. 324). At this stage one could scarcely say whether 
this is a conglomerate tubercle, caseous in its centre, or a pneumonic area, 
caseous but surrounded by a wall of tuberculous tissue. Outside such a 
place, and even at quite a distance, the walls of the air-cells become thick- 
ened and firm. Such indurative pneumonia is most pronounced when the 
Fig. 324.-Caseous and gelatinous pneumonia; beginning encapsulation of the caseous 
areas. 
spread of the tuberculosis has been most successfully combated over a 
long time. 
The appearance of a tuberculous cavity or vomica in the lung might be 
constructed from what has been said. The bronchus may have shallow 
ulcers in its mucous lining, but it is not widened.* It suddenly comes to an 
* There is a common statement that bronchiectasis is most frequent in tuberculosis. 
This is not true of the rapidly advancing forms of phthisis, although it is found in the 
old scarred and indurated lungs, where healing is going on with retraction of the scars. 664 
TEXT-BOOK OF PATHOLOGY 
eroded rough end, where it opens into the cavity. The cavity may reach 
an enormous size, occupying a whole lobe or even nearly the whole lung, 
in which case the organ comes to be a mere sac whose wall is formed by the 
thickened pleura. If this in its turn is perforated, the contents of the cav- 
ity, including air, escape into the pleura unless it has been obliterated by 
adhesions. The cavity usually contains a thick, opaque, greenish-yellow, 
somewhat glutinous fluid, which is full of bacteria, leucocytes, cellular debris, 
fragments of elastic tissue, etc. If it be cleaned out, the wall is still covered 
by an opaque, yellowish-white, caseous necrotic layer, beneath which is a 
tuberculous granulation tissue (see Fig. 318). All bronchi and most of 
the blood-vessels which lay in the area of cavity formation, are inter- 
rupted, but some of the blood-vessels are still found stretching across from 
wall to wall, or standing up as high ridges against one side. If they be cut 
across, many of them prove to be solid cords, but others still have a cen- 
tral lumen, from which one can squeeze a drop of blood. This persistence 
is due to an obliterating endarteritis which thickens the wall, and especially 
the intimal layer, on the approach of the tuberculous inflammation. 
Sometimes loose cords of these vessels hanging in the cavity show that they 
have finally been corroded all the way through, but no haemorrhage has 
occurred. In other cases, when the patient has died from a sudden tre- 
mendous coughing up of blood, the cavity is found full of blood-clot, and 
study of its walls usually shows an artery approached too suddenly to 
allow time for obliteration. Then, as its wall is weakened by the advancing 
caseation, it bulges out into a little sac or aneurysm which bursts with some 
effort of coughing. 
In all such cases the pleura is thickened and covered with a fibrinous 
exudate. Tubercles are to be found in the granulation tissue which lies 
beneath this exudate, and frequently there are quite dense adhesions, 
especially over the region where the cavity approaches the surface. The 
lymph-glands in the lung, and especially those at the hilum, contain 
tubercles or larger caseous areas. All this makes up, as we have said, one 
of the commonest combinations found in the lungs of consumptives at 
autopsy, namely, a cavity at the apex opening widely into the bronchus 
and surrounded by consolidated fibrous lung tissue studded with caseous 
foci, and, below this, numerous patches of pneumonic consolidation, vary- 
ing in age from the freshest to the completely caseous area, walled round 
by organized exudate and tuberculous granulation tissue. 
Aside from the pneumonic patches following bronchial transportation, 
there is a great variety of anatomical lesions in the lung which are due 
to the passage of bacilli along the lymphatics or blood-vessels, or to the 
direct extension of the infection through the lung tissue. In all these 
cases the lesion consists in the formation of tubercles and tuberculous 
granulation tissue, without much outpouring of cellular inflammatory 
exudate. Tubercles produced in the lung by bacilli brought with the 
blood-stream develop in the alveolar wall, but soon project into the 665 
TUBERCULOSIS 
alveolus so as to fill it or become conglomerated with adjacent nodules. 
Sometimes they are so small that their point of origin can be clearly 
determined. Such tubercles may be scattered in any indefinite order 
through the lung. When carried by the lymphatic channels, the bacilli 
produce similar tubercles in strings or clusters along the interlobular 
septa (Fig. 325), in the bronchial walls, or in the walls of the blood-vessels. 
Sometimes this can be plainly seen, but when, in advanced stages, they 
cluster around bronchi and are caseous, it is hard to say whether they 
were not small bronchopneumonic patches. There is one common type 
of tuberculous lesion secondary usually to an apical cavity formation, in 
Fig. 325.-Distribution of tubercle bacilli by lymphatics, with development of tubercles 
in the interlobar septa. 
which large and small firm masses are felt in the otherwise air-containing 
lung (Fig. 326). On section these are found to be quite sharply outlined 
and edged by a border of gray, caseating tubercles. The whole mass, 
measuring sometimes 5 cm. in diameter, is radially arranged, and its inner 
part, back of the progressing margin of fresh tubercles, is a solid, pigmented 
fibrous tissue with still some tubercles and caseous points, but giving 
the impression of having been formed by the healing or obsolescence of 
tuberculous tissue, which is still advancing rapidly at the margin into 
the healthy lung substance. Some such process as this seems to occur 
in many cases about the early apical lesions, and it is a process which is 666 
TEXT-BOOK OF PATHOLOGY 
undoubtedly of great importance in the ordinary spread of any focus of 
the disease in the lung. 
Fig. 326.-Pulmonary phthisis with cavity formation. There are extensive masses 
of pigmented scarred tuberculous tissue the advancing margin of which is made up of 
fresh tubercles. 
The rate of progression, while perhaps about the same in the majority 
of cases, is capable of great variation, so that, on the one hand, we find a TUBERCULOSIS 
667 
man dying a few weeks after the first symptoms appear, on the other, a 
man who has had pulmonary tuberculosis for many years and finally dies 
from something else, revealing extensive scarred and almost healed lesions 
in his lungs. 
This scarring may consist in the permanent encapsulation of each caseous 
area, leaving air-containing and functional lung substance between, but 
Fig. 326A.-Chronic pulmonary phthisis with cavity formation and scattered scarred 
tuberculous areas. 
more often it extends far and wide, and a whole lobe, or even the whole lung, 
bound as it usually is in thick pleural adhesions, is distorted and indurated 
and greatly contracted. On section such a lung reveals cavities at the ends 
of short wide stumps of bronchi, separated by a gray pigmented tissue with 
only islands of recognizable alveoli here and there. Microscopically the 
alveolar walls in these islands are greatly thickened by connective tissue, 
and on account of their rigidity the epithelial cells have become cubical or 668 
TEXT-BOOK OF PATHOLOGY 
even columnar. In other places, and especially near the edges of the lung, 
the alveoli which remain are enormously dilated and thin walled (collateral 
or compensating emphysema). Even quite large cavities may be cleaned 
out and relined by a smooth layer of epithelium, a step toward healing which 
must indicate the most tenacious resistance on the part of the host (Figs. 
326A, 326B, 326C. 
It is important to indicate the functional disturbances produced by the 
Fig. 326B.-Chronic pulmonary phthisis with cavity formation in the upper lobe. 
There are also several cavities in the lower lobe opening widely into a bronchus. 
disease. The formation of even very many minute tubercles in the lungs 
as part of a generalized miliary tuberculosis need not cause any great dis- 
turbance of respiration, but with wide-spread pneumonic consolidation the 
case is different. So, too, with extensive cavity formation and such 
scarring of the lung as has been described there is quite naturally a great 
diminution of the respiratory surface. The bed of the blood-stream through 
the lungs is largely obliterated, and the remaining lung substance is over- 
distended, so that one might expect to find hypertrophy of the right side of TUBERCULOSIS 
669 
the heart caused by the effort to force the blood through. Curiously 
enough, this is seldom the case except in those individuals in whom the 
disease has been held in check for years and the lungs are extensively 
scarred. 
Disturbances of temperature regulation (fever in the afternoon, etc.) 
are common in pulmonary phthisis, but it seems that the most intense 
symptoms of this kind are due to secondary invaders of all sorts (pyogenic 
Fig. 326C.-Chronic pulmonary phthisis with extreme induration and clean cavities 
cocci and bacteria of every other type, yeasts, moulds, and even insect 
larvae), which may get into the cavities and grow there. 
Changes in the general metabolism are of regular occurrence-the con- 
sumptive wastes away and becomes anaemic; the metabolism of fat is dis- 
turbed, so that it accumulates especially in the liver, and there are general, 670 
TEXT-BOOK OF PATHOLOGY 
though somewhat intangible, evidences of poisoning, doubtless from the 
absorption of toxic substances which the bacilli produce. 
Persons with pulmonary phthisis almost invariably infect themselves 
further. The lymph-glands at the hilum of the lung inevitably contain 
tubercles, and other more distant nodes may also be infected. The out- 
pouring of tuberculous sputum very often sets up ulcer formation in the 
trachea and larynx, while, especially in children who do not expectorate 
and in adults who swallow their sputum, the intestines and sometimes even 
Fig. 326D.-Tuberculosis in child's lung. Extensive caseation in the lung substance 
and enormous enlargement of the peribronchial lymph-nodes. 
the stomach develop ulcers. These are the obvious ways for the bacilli 
to spread, but in every such autopsy one finds a few scattered tubercles in 
nearly all the organs, which must indicate the entrance of bacilli into the 
blood-stream. Although it cannot always be traced, the point of en- 
trance is usually quite clear when the invasion is extensive enough to 
produce an unmistakable acute miliary tuberculosis. Localized disease 
in some distant organ, as in a bone or in the kidney or epididymis, may 
be started in this way, and, on the contrary, primary disease of the lymph- 
glands or of a bone may in the end give rise to pulmonary tuberculosis. TUBERCULOSIS 
671 
Tuberculosis in the lungs of children follows a rather difficult course, 
perhaps because their resistance is in most cases not so well established 
as in the case of most adults. It is pointed out by Ghon, Opie, and others 
that a primary lesion in the lung is usually to be found if searched for, but 
that the bronchial lymph-nodes, unlike those of the adult, are almost reg- 
ularly enormously enlarged and caseous (Figs. 326D and 326E). Then 
the lungs become the seat of widely scattered areas of caseous pneu- 
monia which may occur anywhere and are not especially found in the apical 
region. Since this is often associated with similarly extensive lesions in 
spleen and liver, intestines and mediastinal and mesenteric lymph-nodes, 
Fig. 326E.-Tuberculosis in child's lung. Old caseous lesion at the base. Caseation 
of bronchial lymph-node and scattered patches of caseous pneumonia, developed prob- 
ably in this order. 
together with tuberculous meningitis, it is not easy to say with certainty 
how the distribution of bacilli occurred. It seems most probable that most 
of it is by way of the blood-stream, although in the case of the lung alone 
it is tempting to think that a caseous bronchial node has emptied bacilli 
into a bronchus. 
There is great variation according to the resistance of the child. One 
child of three years, studied recently, presented a great cavity surrounded 
by indurated tissue in the upper lobe of one lung, with all the charac- 
teristics of the cavities in the lungs of adults. The bronchial nodes were 
moderately large and caseous, while the lower lobe in that lung was com- 672 
TEXT-BOOK OF PATHOLOGY 
pletely occupied by a caseous pneumonia. The other lung was prac- 
tically unaffected, and the same could be said of spleen, liver, kidneys, etc., 
but the whole mucosa of the lower ileum and colon was worm-eaten with 
tuberculous ulcers. Evidently in this case resistance was high, but a great 
deal of sputum was swallowed. This, however, is a rather unusual form, 
and the common type is that in which the bronchial nodes are large and 
caseous and the lungs are studded with patches of caseous pneumonia. 
LITERATURE 
Birch-Hirschfeld: Deutsch. Arch. f. klin. Med., 1909, Ixiv, 58. 
Durck: Erg. d. allg. Path., 1897, ii, 196; 1901, vi, 84. 
Frankel and Troje: Zeitsch. f. klin. Med., 1894, xxiv, 30. 
Ghon and Pototschnig: Beitrage zur Klinik. d. Tuberkulose, Bd. 40. 
Harbitz: Jour, of Infect. Dis., 1905, ii, 143. 
Ophuls: Trans. Nat. Assoc. Study and Prevention Tuberculosis, 7th Ann. Meeting, 
Amer. Jour. Med. Sci., July, 1900. Trans. Brit. Congr. Tuberc., 1901, iii. 
Opie: Jour. Exp. Med., 1917, xxv, 855; xxvi, 263. Amer. Rev. of Tuberculosis, 1920, 
iv, 629, 641. 
Orth: Nachr. d. k. Gesellsch. f. Wiss., Gottingen, 1901, Heft 2. 
Pertik: Ibid., 1904, viii, 1. 
Ribbert: Deutsch. Med. Woch., 1906, No. 40; 1907, No. 42; 1918, xliv, 144. 
Shennan: Lancet, February 28 and March 7, 1914. 
Tuberculosis of the Digestive Organs.-From what was said above, it 
is evident that while tubercle bacilli may be taken into the digestive tract 
with the food, it is still questionable whether their entrance into the body 
by that path is of great importance in the production of pulmonary and 
general tuberculosis. Isolated primary tuberculosis of the intestine can 
rarely be demonstrated in adults, although commoner in children. Indeed, 
as a consequence of the study of the results of a great many investigators 
Beitzke concludes that in tuberculous children about 25 per cent, of the 
cases show a primary intestinal infection. The result is infection of the 
mesenteric lymph-glands, or even of the ductus thoracicus, or, on the 
other hand, the transportation of the bacilli by the portal blood to the 
liver, where tubercles may be formed. Miliary tuberculosis is apparently 
rarely or never the direct outcome of primary intestinal tuberculosis, but 
if a partial immunity be set up or if the bacteria be relatively non-virulent, 
pulmonary tuberculosis may follow. Thus while it is recognized that 
pulmonary tuberculosis may follow an intestinal absorption or intestinal 
tuberculosis, the readiness with which it is produced by aspiration leaves 
this method of infection in a place of secondary importance, which in adults, 
at least, is probably very slight. 
Tuberculous lesions of the mouth, pharynx, oesophagus, and stomach 
occur, but are quite rare. They arise by direct infection of the mucosa, 
or sometimes, as in the case of the oesophagus, from invasion by caseous 
glands or other tissues from without. In the stomach the lesions are 
miliary and conglomerate tubercles in the mucosa, or ragged and precipitous 
ulcers. TUBERCULOSIS 
673 
The liver regularly presents very minute miliary tubercles when there is 
a general distribution of the bacilli by the blood-stream. In some cases 
these become conglomerate, and even quite large and centrally caseous. 
A type of cirrhosis of the liver results from the presence of these nodules, 
or at least occurs commonly in association with them. The most inter- 
esting form is that in which caseous nodules appear near the bile-ducts, 
and after the discharge of their contents into the ducts become deeply 
bile stained. Tuberculosis of the pancreas is not often observed, and 
usually consists in the presence of miliary tubercles. 
It is in the intestine, however, that the bacilli cause their greatest rav- 
ages, and the lesions there are of interest not only in themselves, but 
because they may lead to other extensions of the disease. Aside from the 
rare instance of isolated primary tuberculosis in adults and those in children, 
in which the bacilli are 
probably swallowed in 
quantities in the milk, the 
intestinal lesions are usu- 
ally caused by the swallow- 
ing of sputum from tuber- 
culous cavities in the lungs. 
The mucus of the sputum 
protects the bacilli in their 
passage through the acid 
gastric juice, so that they 
reach the intestine alive. 
Intestinal Tuberculosis.-The 
lesions in the intestine are pre- 
dominantly ulcerative, and are 
found in their greatest intensity 
in the small intestine above the 
ileocsecal valve. Often enough, 
however, they both extend far up 
in the small intestine, and are 
found in numbers in the colon. They have, therefore, broadly, the same general distri- 
bution as the ulcers in typhoid fever, but they are not nearly so sharply limited to the 
Peyer's patches and solitary nodules. Even though the bacilli may lodge there, they soon 
produce an ulceration which extends wide of those structures and involves indifferently 
the surrounding mucosa. Indeed, the ulcers have a rather strong tendency to encircle 
the whole gut, whence they are often called girdle ulcers. Their beginnings can be seen 
as swollen, conglomerate nodules with central caseation, but the softening and discharge 
of this yellow, opaque central substance into the intestine leaves an ulcer which, when it 
has reached a larger size, is characteristic enough and very unlike the typhoid ulcer in 
its details. The margin is ragged, nodular and irregular, thickened, and undermined 
(Fig. 327). The base is generally covered with yellow necrotic material, but this is 
sometimes cleaned off so as to reveal the tuberculous granulation tissue which really 
lines the ulcer, and which is generally studded with palpable nodules. The submucosa 
or musculature may be exposed, or the ulcer may perforate the whole wall. 
Such ulcers can generally be located from the outside by the congestion of the vessels 
Fig. 327.-Tuberculous ulcer of the ileum. 674 
TEXT-BOOK OF PATHOLOGY 
in that spot, and especially by the crop of minute gray tubercles which spring up m the 
subserous tissue and cluster along the lymphatic channels. Evidently from the mucosa 
the bacilli are carried into these lymph-channels, and the tubercles are actually formed 
inside them in such a way as to block the lumen. It is for that reason that these lymph- 
atics become so conspicuous as they run over the surface of the intestine to the mesentery 
(Fig. 328). Sometimes they are greatly distended with clear fluid, or even with opaque 
white chyle, and are beaded or like a string of sausages, because they are obstructed at 
intervals. In such a case they can often be traced through the mesentery to the lymph- 
gland, into which they empty and which usually shows tuberculous lesions too. 
Microscopically (Fig. 330), the tuberculous granulation tissue is found not only lining 
the base of the ulcer, but formed in the submucosa wide of the actually undermined 
part, and through the crevices 
of the muscle layer even into 
the subserous tissue. It often 
shows patches of caseation 
and abortive tubercles, but the 
tubercles are usually rather 
indefinite in their structure. 
There is one form of intesti- 
nal tuberculosis which is rather 
sharply localized about the 
ileocsecal valve and there pro- 
duces a great mass of hard, 
tuberculous scar tissue, which 
may constrict the intestinal 
lumen until only a large probe 
will pass. In one such case seen 
recently that whole stretch of 
the intestine was removed by 
the surgeon and the young 
man has been quite well ever 
since. More common is the 
localized ulcerative tuberculo- 
sis of the rectum, which, ex- 
tending in the form of a sinus 
to the skin at the anus, gives 
rise to the so-called anal 
fistula. In nearly all these cases the granular lining of the sinus is found to be 
tuberculous. 
It follows, from the anatomical relations, that if tuberculous ulcers extend 
in the intestinal wall so as to present bacillus-holding tissue on the peri- 
toneal surface, or if tuberculous disease of the lungs reaches the pleura, or 
if tuberculous and caseous lymph-glands approach or break into either of 
these cavities or the pericardium, it will not be difficult for the bacilli to 
gain access there and to be spread over an extensive surface by the active 
movements of the contained organs. It is usually in this way that tuber- 
culous pleurisy, pericarditis, and peritonitis arise, although those surfaces 
may, like other tissues, be involved in a general miliary tuberculosis. 
Tuberculous Peritonitis.-The principles followed in the pleura and pericardium are 
so well exemplified by the conditions found in tuberculous peritonitis that a description 
of the latter will suffice. The varied types of tuberculous disease of the peritoneum 
Fig. 328.-The same ulcer of the ileum from the 
outside, showing the chains of tubercles along the 
lymphatic channels. TUBERCULOSIS 
675 
seem to depend upon the number and virulence of the organisms introduced and the 
resistance of the host, for in some cases there is an extensive destruction of tissue, 
while in others there is rather the formation of adhesions and scars which may in time 
lose much of their distinctive tuberculous character. 
The organisms may enter the peritoneum with the blood-stream, as in the produc- 
tion of acute miliary tuberculosis, when they will be deposited in the omentum and sub- 
serous tissues. Or they may be directly poured into the cavity from exposed caseous 
masses, when, for example, a tuberculous focus in a lymph-gland or in the kidney or a 
neighboring bone forms a communication with the peritoneum. Caseous disease of the 
Fig. 329.-Tuberculous erosions of the lower ileum. Both sides of the intestine are 
shown at the same level. 
Fallopian tubes is a prominent source of infection in women, and in some instances a 
generalized peritoneal tuberculosis may arise in the same way from tuberculous ulceration 
of the intestine. The latter, however, more commonly causes rather a localized peritonitis 
with adhesions. The bacilli are distributed by the prevalent streams in the abdominal 
cavity, and reach the vault of the diaphragm and the floor of the pelvis in great numbers. 
Sometimes their effects in the form of tubercles are seen in hernial sacs. In the earliest 
stages minute gray, translucent tubercles may be scattered everywhere over the surface 
of the peritoneum and of the omentum, without disturbing the normal gloss. 
In other cases the tubercles are quickly covered by an exudate of fibrin, sometimes 
nearly dry, sometimes with the effusion of a very great amount of clear or slightly turbid 
fluid, sufficient to float up the intestinal coils and prevent them from being glued together. 
A soft, friable, vascular granulation tissue springs up and replaces the fibrin, so as to 
form organized adhesions in the cases where there is no fluid, and in these adhesions the 676 
TEXT-BOOK OF PATHOLOGY 
tubercles become larger and centrally caseous. The omentum is retracted and folded 
so as to form a solid, prismatic mass, which can readily be felt stretching across the 
abdomen. In its substance tubercles and caseous areas are embedded with the fat lob- 
ules in a tuberculous granulation tissue. With the lapse of time the adhesions become 
Fig. 330.-A tuberculous ulcer of the ileum, with undermined edges. The ulcer 
has penetrated the muscularis, and there are tubercles in the submucosa and in the 
thickened subserous tissue. TUBERCULOSIS 
677 
dense and tough, so as to bind the abdominal contents inextricably together into a 
matted mass (Fig. 330A). Over the liver and spleen, and especially between the liver 
and the diaphragm, quite large caseous areas may form in these adhesions, and even 
the tearing apart of the intestines may open cavities and canals filled with soft caseous 
material. Withal the intestinal mucosa may be quite intact. 
Fig. 330A.-Tuberculous peritonitis. 
In those cases, however, in which the peritoneal infection is due to the exposure of 
caseous tubercles outside intestinal ulcers, the affected areas are usually bound together, 
so that finally perforation of the ulcer produces only localized fecal abscesses in the 
adhesions, or fistulous communications between adjacent coils. Where the resistance 
is high, the intestines may be found matted together by adhesions which are loose 
and fibrous and which show only here and there scattered encapsulated tubercles. 
In other cases large encapsulated and sometimes pedunculated tubercles may occur in 
association with old adhesions, or even without much other change in the peritoneum. 
All these things indicate the possibility of healing, and, indeed, the idea has been widely 
entertained that those thick fibrous plates which are often found partly covering the 
liver and spleen (the so-called iced liver) may perhaps be due to a healed tuberculosis, 
even though they show no distinct anatomical evidences of their origin. In the acute 
forms, where there is much fluid exudate, definite advances toward healing may some- 
times be attained by opening the peritoneum and removing the exudate. This has been 
explained by Wright on the ground that the accumulated fluid has exhausted its bac- 
tericidal power, and that the advent of fresh fluid and cellular exudate brings with it 
new powers of destroying the organisms. 
The distribution of the tubercle bacilli is particularly well followed in the 
study of the lesions of the lymph-nodes, for these organs act as sieves in the 
course of the lymph-channels along which the bacilli are so commonly 
carried. For this reason changes produced and registered in these nodes 
are of assistance as a clue to the portal of entry of the organisms. 678 
TEXT-BOOK OF PATHOLOGY 
Fig. 331.-Scattered tubercles in a lymph-gland. 
Fig. 332.-Packet of caseous cervical lymph-glands. 679 
TUBERCULOSIS 
Tuberculosis of Lymph-glands.-The lesions are quite the same in character as else- 
where. The bacilli lodge in the sinuses of the gland or are carried into the lymph- 
cords, and produce tubercles often with associated tuberculous granulation tissue and 
an inwandering of many large mononuclear phagocytic cells (Fig. 331). The tubercles 
are sometimes discrete and remain so, but more often they become conglomerated and 
suffer extensive caseation, so that almost the whole gland may be reduced to a soft, 
cheesy mass. Healing occurs through hyaline changes and scarring, generally with the 
deposit of calcium in coarse grains, or in such a way as to convert the whole gland 
into something like an irregular pebble tightly bound up in a fibrous capsule. 
All these lesions are most common in the bronchial glands, but are very frequent in 
the mesenteric nodes also, where, especially in children, very great enlargement may 
take place and is sometimes known as tabes mesenterica. 
From tuberculous foci in the tonsils and upper air-passages the cervical chain of 
glands may be infected and caseous. In such a case they become matted together by 
fibrous growth and present a great swelling along the side of the neck (Fig. 332). The 
caseous material may sometimes burrow out to the skin, so that a discharging sinus is 
established. More rarely a similar condition is met with in the axilla or groin, some- 
times as the result of peripheral tuberculous infections. The thoracic duct, receiving 
bacilli from tuberculous abdominal glands, may develop caseating tubercles along its 
lining and thus contribute to the formation of an acute miliary tuberculosis. 
In the spleen there occur miliary and conglomerate tubercles, often 
rather loose and cellular in their structure, and without the coherent 
tissue formation seen elsewhere. In this organ, too, there arise very large 
caseous solitary tubercles with dense fibrous capsule (see Fig. 312). 
Tuberculosis of the Genito-urinary Tract.-The development of the 
tuberculous lesions and their anatomical form, as well as their ultimate 
fate, are quite the same in these organs as elsewhere, but the mode of en- 
trance of the bacilli and their further distribution have long been debatable. 
As has been stated, direct introduction of bacilli by coitus is rarely shown 
to be productive of genital tuberculosis. Infection of the genito-urinary 
tract is practically limited to the deposition there of bacilli brought into 
the blood-stream, but even then there are favorable and unfavorable local- 
izations. In general miliary tuberculosis tubercles can develop nearly 
everywhere. When fewer bacilli are in circulation, however, and the 
development of a tuberculous focus depends in some degree upon favorable 
conditions in an organ, we find that the kidney, the epididymis, and some- 
times the Fallopian tubes are the most susceptible to the infection. It is 
in them that the oldest lesions are found, and it is from these primary foci 
of disease that bacilli spread to infect the rest of the genito-urinary tract. 
Walker and Sawamura find that the initial lesion is practically never in the 
bladder or ureters, in the prostate, seminal vesicles, vasa deferentia, or 
testis, but that all these structures are readily enough infected secondarily, 
when great quantities of bacilli are poured into them from a caseous kid- 
ney or epididymis. So, also, in the female the ovary and uterus are rarely 
affected primarily, while the tissue of the Fallopian tube seems specially 
susceptible and later distributes bacilli in quantity elsewhere. 
With these results in mind there are relatively few difficulties in explain- 
ing the distribution of the disease. With regard to the genital glands in 680 
TEXT-BOOK OF PATHOLOGY 
the male, it is not impossible that tuberculosis of prostate and seminal 
vesicles should arise by infection from the bladder, and that the disease 
should extend along the vas deferens to the epididymis, but the reverse 
direction is more common. More dispute has arisen as to the possibility 
of an ascending tuberculous infection of the kidney from tuberculous dis- 
ease of the bladder, in a way analogous to that admittedly followed in the 
ascending suppurative pyelonephritis following cystitis. A priori this would 
seem the most plausible explanation when one finds, at autopsy, an old 
Fig. 333.-Renal phthisis. The tuberculous process has excavated the calyces of the 
kidney far into the cortex. There is great thickening of the ureter. 
caseous focus in the epididymis, tuberculosis of the prostate and bladder 
and of the ureter, pelvis, and kidney on one or both sides. This is especially 
striking when, as is so frequently the case, the tuberculosis of the kidney 
is limited to the development of small patches of caseous tuberculous 
granulation tissue at the tips of the papillae and along the walls of the 
calyces, without any sign of involvement of the cortex. This, in connec- 
tion with the continuous affection of the ureteral mucosa from the ulcerated 
bladder, makes it hard to resist the idea that the bacilli have been floated 
up from the bladder in the lumen of the ureter. Still the mucosa of the TUBERCULOSIS 
681 
ureter is not, as a rule, continuously tuberculous in these cases, and may 
show little change; on the other hand, when the renal tuberculosis is some- 
what more advanced the whole wall of the ureter is usually thickened 
and rigid, suggesting the involvement of the lymphatics as well, and there 
are many who would explain the advance of the infection from the bladder 
to the kidney by this route. In spite of much investigation of this pos- 
sibility, which has generally led to negative results, it is not finally settled 
and should be studied further. 
Experiments, especially those of Walker, show that while fluids may pass 
out of the bladder into the ureter when, through ulceration, the valve-like 
Fig. 334.-Tuberculosis of epididymis (bilateral). 
ureteral orifice is destroyed, or, when through obstruction, the bladder 
contracts against a quantity of urine which cannot readily escape, deliberate 
infection of the bladder rarely results in the production of an ascending 
infection. Although Walker had a few positive cases, he leans to the view 
that infection is haematogenous and primarily brought by the blood to 
the kidney and only secondarily to the pelvis and ureter. 682 
TEXT-BOOK OF PATHOLOGY 
The conditions found at autopsy leave me still with the belief, how- 
ever, that tuberculosis of the kidney is often an ascending affection, and 
that the conditions of the experiments and the different anatomical 
arrangements of the animals explain the experimental results. 
Tuberculosis of the Kidney.-In generalized miliary tuberculosis minute tubercles 
are found in the cortex of the kidney, beginning, as Benda states, in the glomerular 
capillaries, where masses of bacilli are lodged as emboli. Doubtless they may be 
formed also about the other capillaries, and in their growth and conglomeration they soon 
extend in a direction parallel with that of the conducting tubules, to form gray streaks, 
often with an opaque yellow centre, reaching from the cortex into the pyramid. 
Probably tubercles are also formed by bacilli which lodge in the tubules in the course 
of excretion (Aschoff), and these may take part in the production of the more extensive 
caseous areas which arise in the margin between cortex and pyramid (Israel). Such 
caseous areas grow until they destroy much of the kidney substance and discharge their 
contents into the pelvis. In other cases the caseating area begins in the papillary part 
of the pyramid, usually up in an angle of the calyx, and from there the process of erosion 
extends deeply into the kidney. These are the cases which specially suggest an origin 
from an ascending infection. In any event the late result is the great destruction of 
the kidney substance. What remains of the pelvis is ulcerated; the papillae have dis- 
appeared, and the calyces are represented by irregular cavities lined by caseous granula- 
tion tissue and excavated deep into the kidney (Fig. 333). The organ may be enormously 
enlarged and finally appear as a tabulated, sacculated mass, in the walls of which 
hardly any kidney substance remains. If the capsule is perforated, a perineal tubercu- 
lous infection occurs, and the extension of the caseating process, preceded, as always, 
by the formation of tuberculous granulation tissue, can go on until a fistulous tract is 
opened into the peritoneum or out through the skin. Healing must be very rare, but 
one finds occasionally shrunken kidneys with encapsulated, mortar-like, or stony masses 
of probable tuberculous origin. In persons whose resistance is great the caseation is 
often limited by the enormous production of scar tissue, so that the kidney, while being 
greatly enlarged, contains relatively small pyramidal cavities surrounded by thick walls 
of fibrous tissue. 
It is perhaps unnecessary to describe in any detail the tuberculous 
lesions in the rest of the genito-urinary tract, since in each case they are 
due to the development of tubercles in or under the mucosa, soon be- 
coming associated with abundant granulation tissue which undergoes 
caseation, but causes great thickening of the walls of these organs. 
The ureter becomes a wide but rigid tube, with ragged ulcerated lining, and is easily 
felt through the abdominal wall. In the bladder miliary and conglomerate tubercles 
occur in the mucosa, especially of the trigonum, followed later by shallow, ragged 
ulcerations with nodular base. The seminal vesicles show tubercles in the mucosa, or 
the wall is thickened and the lumen choked with the product of its caseation. Distinct 
tubercles are not usually seen in the prostate, but the gland becomes enlarged and 
riddled with caseous patches. The vasa deferentia are enlarged and filled with caseous 
material, so as to be impervious, and in quite the same way the tuberculous epididymis 
(Fig. 334) forms a great caseous mass which may discharge by fistulse through the skin 
of the scrotum. Invasion into the testicle may take the same form, or there are scattered 
tubercles. 
In the ovary tubercles may be found in preformed cysts or in the tissue itself, the case- 
ation and softening of which produce a cavity. The Fallopian tubes behave much like 
the seminal vesicles-their walls are sometimes thickened and studded with small 683 
TUBERCULOSIS 
tubercles, which, when on the outside, appear really as a form of localized tuberculous 
peritonitis. The tube may later become distended and obstructed with caseous sub- 
stance. In the uterus caseation of the endometrium of the fundus is not very rare. 
LITERATURE 
Benda: Orth's Festschrift, Berlin, 1903, 520. 
Sawamura: Deutsch. Arch. f. Chir., 1910, ciii, 203. 
Walker: Johns Hopkins Hosp. Reports, 1911, xvi, 1. 
Tuberculosis of the Nervous System.-The central nervous system does 
not escape tuberculous infection, which is usually carried to it by the blood- 
stream, although occasionally it may be due to direct extension from a 
caseous focus in neighboring bony structures. In the substance of the 
brain or cord caseating tubercles of every size appear. These may be 
multiple, and are found scattered everywhere as yellow, opaque, caseous 
nodules surrounded by a haemorrhagic zone. It is in the brain that 
there occur sometimes tumor-like caseous masses of great size, which are 
merely enormously overgrown caseous tubercles. These "solitary tuber- 
cles" cause great disturbances both through the destruction of tissue and 
the pressure which they produce. In the spinal cord they are especially 
sure to interrupt important conducting tracts. 
When the bacilli are not thus localized in certain areas in the brain, they 
may be carried into the meninges and there produce miliary tubercles, 
or more commonly a combination of tubercles, with an effusion of cellular 
and fluid exudate which constitutes tuberculous meningitis. This is often 
spoken of as basilar meningitis, since the exudate is likely to be found 
especially over the pons, the floor of the third ventricle, and the optic 
chiasm. Nevertheless, it extends into the fissures over the surface of 
the brain, and on pulling open the Sylvian fissure, one can nearly al- 
ways find tubercles along the blood-vessels with the yellowish exudate 
about them. 
The ependymal lining of the ventricles usually presents similar minute 
tubercles on its surface, and the ventricles are often distended with a turbid 
flaky fluid constituting an inflammatory hydrocephalus. The accumula- 
tion of fluid is increased, however, by the obstruction to its outflow caused 
by the obliteration of the foramina of Majendie and Luschka or of the 
meshes and cisternae of the arachnoid, by the dense exudate. In the 
meninges the tuberculous lesions develop in the walls of the vessels, where 
they may be seen in sections (Fig. 335) as eccentric thickenings affecting 
especially the adventitial coat, but causing also an obliterative growth 
of the intima. The media is generally passively invaded and destroyed 
by the growth of the mass. Such tubercles are usually not sharply de- 
fined, like those miliary tubercles seen in the liver or a lymph-gland, but 
appear as irregular collections of epithelioid cells by no means concentric- 
ally arranged. Ordinarily the person dies before any extensive caseation 684 
TEXT-BOOK OF PATHOLOGY 
occurs, and generally the tubercles are found translucent. They are in 
the most acute cases surrounded on all sides by an exudate which distends 
the meshes of the pia, and even overflows on its surface. This exudate 
is rich in fibrin and full of mononuclear wandering cells, many of which 
are of the lymphoid form, while the large, pale phagocytic forms with 
abundant protoplasm are very numerous and give a special character 
to the exudate. Polymorphonuclear leucocytes are in the minority, 
if they are present at all. 
Fig. 335.-A portion of the meninges from a case of tuberculous meningitis, showing the 
formation of a thick wall of tuberculous tissue in the adventitia of each vessel. 
Tuberculosis of the Ductless Glands.-Among the organs of internal 
secretion the only instance in which we know that tuberculous disease is of 
practical importance is that of the adrenal glands. Miliary and conglomer- 
ate tubercles occur there, but more commonly extensive caseous areas 
develop which can involve the whole gland on both sides and destroy it 
completely. In such cases Addison's disease, of which we shall speak in 
another place, generally follows. 
Tuberculosis of the Skin.-In the skin there are certain definitely tuber- TUBERCULOSIS 
685 
culous conditions, among which lupus vulgaris is the most common, in 
which the bacilli may be found producing tubercles and tuberculous 
granulation tissue. Recently in a case of generalized miliary tuberculosis 
I have seen numerous papules and vesicles scattered all over the body 
and containing tubercle bacilli. There are other lesions of the skin, how- 
Fig. 336.-An old healed tuberculous lesion of the hip which has left the acetabulum 
greatly distorted and with numerous exostoses. 
ever, such as lichen scrophulosorum, which are known as tuberculides, and 
which, though always associated with tuberculosis, have yet been studied 
without avail in the search for bacilli or tuberculous tissue. They have 
been thought to be due to diffused toxins, or even to be the expression 
of an anaphylactic reaction. 686 
TEXT-BOOK OF PATHOLOGY 
Tuberculosis of Bones and Joints.-This subject is so far reaching in 
its details that no attempt can be made here to give more than the barest 
outline. For the rest, surgical works must be consulted. 
The bacilli are brought to the bones and joints by the blood-stream or by 
extension from a neighboring lesion. It is especially in the bones that 
traumatism aids in the development of the infection by forming a point of 
lowered resistance where the bacteria can gain a foothold. Accordingly, it 
is not uncommon to find lesions formed in the bones in the apparent absence 
of tuberculosis elsewhere. 
Tuberculous lesions usually begin, as Guillemain has maintained in 
opposition to Konig, in the bone rather than in the synovial cavities 
of the joints, and it is the cancellous bone which is usually first involved- 
practically never the shafts of long bones. Miliary tubercles may, of 
course, occur, but far more important is the tuberculous osteomyelitis, 
which is not part of a general miliary tuberculosis. This begins in one of 
the short bones, such as a vertebra or tarsal bone, or in the epiphyseal 
ends of the long bones, and is doubtless the result of the lodgment of the 
bacilli in a small vessel. Miliary and conglomerate tubercles with tuber- 
culous granulation tissue form in the cancellous bone, and caseation occurs 
more or less rapidly. Some authors distinguish as "fungous" forms those 
in which the granulation tissue persists a long time without caseation. 
In any case the bone lamellae are destroyed or remain as splinters. Hardly 
any new bone formation occurs around the focus-indeed, it is not un- 
common to find a great rarefaction with replacement of the marrow by fat. 
Such a caseous area often extends in pyramidal or rounded form to the 
joint surface, whereupon the joint becomes infected also; the cartilage 
becomes necrotic, uplifted, and softened. At first, miliary tubercles 
may appear on the synovial membranes, with effusion of fluid. Later the 
joint is lined by a tuberculous granulation tissue, and the condition may 
last for a long time, with persistence of the fluid, induration of the tissues 
around the joint, formation of polypoid clusters of fat tissue and of small 
hyaline bodies, like rice grains, in its cavity. Irregular erosions of the 
surfaces occur, and indeed there follow the most extensive excavations into 
the bone, with collapse and wide destruction of the mechanism of the joint. 
Fistulse are burrowed out through the surrounding muscles and fasciae to 
the skin, through which caseous debris and spicules of bone are discharged. 
Such destructive processes are very common in the hip-joint and especially 
in children. The whole head of the femur may be destroyed and the bone 
dislocated. To relieve the tenderness and pain the leg is drawn up and 
rotated inward, and through disuse it atrophies. When the joint disease 
heals, there remains the condition so often seen in people in the street who 
walk with the affected leg held stiffly bent and with the aid of a crutch. 
Tuberculosis of a vertebra proceeds in practically the same way (Fig. 
337). When caseation has advanced far enough to soften the bone, the 
affected centrum is crushed together by the weight of the body, and an TUBERCULOSIS 
687 
angular deformity of the spine ensues. The burrowing of the material 
produced in this process under the sheath of the psoas muscle, to appear 
below Poupart's ligament, gives rise to the so-called psoas abscess. A 
similar thing can happen in the case of other bones, and we have seen 
recently an extensive burrowing from the region of a tuberculous knee- 
joint. 
Tuberculosis of the bones of the face and of the ribs is generally in 
the beginning a periosteal affection which erodes the bone and produces 
Fig. 337.-Tuberculosis of the vertebrae, with caseation and collapse of the centra 
which cause compression of the spinal cord. 
accumulations of caseous material-the so-called "cold abscess." In the 
fingers there may be central caseation in the diaphysis of the phalanges, 
with secondary new-growth of bone outside. The enlargement of the 
internal cavity and the repetition of the reparatory process result finally 
in a spindle-shaped enlargement of the bony shell (spina ventosa). 
LITERATURE 
Hartel: "Tuberc. Peritonitis," Ergeb. d. Chir., 1913, vi, 370. 
Konig, F.: Tuberculose d. Knochen u. Gelenke, Berlin, 1884. 
Krause, Fedor: "Tuberculosis of Bones," Deut. Chirurgie, 1899, Lief 28a. CHAPTER XXXIV 
TYPES OF INJURY.-INFECTIONS OF UNCERTAIN NATURE 
Typhus: Epidemic distribution. Anatomical lesions. Experimental studies, transmis- 
sion by lice. A bacillus recently discovered. 
Acute poliomyelitis: Infectious nature. The organism. Febrile illness, subsequent paraly- 
sis. Lesions of nervous system. 
TYPHUS INFECTION 
The disease has long been recognized as occurring in great epidemics with 
high mortality. In 1819 and 1846 it raged with especial violence in Eng- 
land and Ireland, although extensive epidemics had been more common in 
Russia and the Balkan countries. It is a disease which associates itself 
with the crowding and unsanitary conditions of war and famine. It was 
common in prisons. We are even now hearing daily of its ravages in the 
Balkan States, where all the favoring conditions exist. 
In spite of the unfortunate choice of name (Typhus exanthematicus), 
it has nothing whatever to do with typhoid fever (typhus abdominalis). 
The distinction between the two diseases was clearly made by W. W. Ger- 
hard in a vivid description which is to be found in the American Journal 
of the Medical Sciences, 1836, after Louis had described the lesions of 
typhoid. 
Typhus is an acute infectious disease marked by high fever, intense illness 
and weakness, an outbreak of a macular or papular eruption which is often 
haemorrhagic, laryngitis, with cough or the more serious symptoms of 
lobular pneumonia. Death occurs with evidence of general intoxication 
and circulatory collapse. 
Lesions.-At autopsy there has been found until recently only the 
general condition found in nearly all acute infectious diseases, namely, 
an acute splenic tumor and some cloudiness of the organs. But many 
investigators have taken advantage of the opportunities for the study 
of the disease which occurred during the war when typhus was so prev- 
alent, and new pathological changes have been found. They are well 
described by Nicol, although neither he nor any of the other students of 
this disease demonstrate any relationship between these lesions and 
any of the aetiological agents which have been described. They consist 
in vascular changes in the brain, affecting especially the minuter vessels 
of the medulla, but also those of other parts of the brain, of the skin, 
and of the heart muscle. The lesion is an arteriolitis and periarteriolitis 
nodosa, with circumscribed proliferation and accumulation of wandering 
cells and leucocytes about the arteriole, but beginning with proliferation 
688 TYPHUS INFECTION 
689 
and necrosis of the endothelium. The illustrations show a perivascular 
infiltration much like that seen in the brain of cases of encephalitis 
lethargica, for which the causative factor is also unknown. It is pointed 
out that the localization of these lesions, which bring with them some ob- 
struction of the small vessels, may well explain those symptoms which 
depend upon disturbances in the function of the important organs which 
are represented in the nuclei in the floor of the fourth ventricle. 
Brill has recognized the existence of a disease in New York which has 
all the characteristics of mild typhus infection, and there is in Mexico 
another affection, called tabardillo, which is quite similar. 
Experimental work in recent years has done a good deal to clear up the 
nature and relation of these infections, although it is by no means finished. 
Nicolle, Goldberger and Anderson, Ricketts, and Wilder have studied 
especially the transmission, using monkeys as test animals. Nicolle and 
his associates found that they could transmit the typhus found in Tunis 
to monkeys by inoculating the blood of patients. Further, that while it 
became evident that infection is not transferred directly, nor through 
bedding, clothes, etc., nor by fleas or bed-bugs, it could be shown that the 
body-louse (Pediculus vestimentorum), becomes infected by biting those 
who have the disease and transmits it in full virulence by biting others. 
Goldberger and Anderson, and Ricketts, were able to confirm this in Mexico 
by allowing such infected lice to bite monkeys or by grinding them and 
injecting a suspension of their bodies subcutaneously. The monkeys de- 
velop a fever and sometimes die, but do not show the roseola which is so 
characteristic of human infection. Nevertheless they become immune and 
after recovery are insusceptible even to injections of blood from a typhus 
patient. All this is also true of Brill's disease, and Goldberger and Ander- 
son think it therefore identical with Mexican and European typhus. They 
found in Mexico that the causative agent is too large to pass through a 
Berkefeld filter, but could not associate it with any particular element of 
the blood. The general impression of typhus fever at this stage was that 
it resembled closely such other diseases as are transmitted by insects and 
would probably turn out to be caused by a parasite of protozoan character. 
Despite many publications during the last three years on the aetiology 
of this disease, it cannot be said that any one of the numerous bacteria, 
protozoa, and spirochaetes appears to have a clear title to that distinction. 
The Weil-Felix agglutination reaction with a form of Bacillus proteus 
has attracted much attention. 
Wolbach, Todd, and Palfrey have made most elaborate studies of 
typhus fever in which they emphasize the aetiological relation of Rickett- 
sia prowazeki to the disease both because uninfected lice fed on such 
patients acquire this infection only, and because the Rickettsia is found in 
the lesions in the patients. The details must be read in their splendid 
monograph. It is only possible to say here that the lesions are vascular 
and perivascular in brain, skin, kidneys, muscles, etc., and that the endo- 690 
TEXT-BOOK OF PATHOLOGY 
thelial cells of the vessels show the parasites especially well and in enormous 
numbers. They were able to confirm the value of the Weil-Felix agglutina- 
tion reaction with a form of Bacillus proteus in most of the cases. 
Strong, Shattuck, Sellard, Zinsser, and Hopkins (Typhus Fever, Serbian 
Epidemic, Harvard Univ. Press, 1920) were not nearly so profoundly 
impressed with the significance of the Rickettsia. There is a wealth of 
detail in both of these monographs which must be read in the original. 
Kuczynski finds that by cultivating the infectious agent with casein it 
proves to be a modification of the Bacillus proteus and once more assumes 
the bacillus form. This is thought to explain the Weil-Felix reaction 
(Med. Klinik., 1922, No. 50). 
Brill, N. E.: Amer. Jour. Med. Sci., 1910, cxxxix, 484; 1911, cxlii, 196. 
Curschmann: Das Fleckfieber, Nothnagel's Spec. Path. u. Ther., 1900, iii, Th. 2. 
Goldberger and Anderson: Hygienic Laboratory Bull., 1912, No. 86. Public Health 
Reports, 1910, xxv, 177; ibid., 1912, xxvii, 71. 
Nicol: Ziegler's Beitr., 1919, Ixv, 120. 
Nicolle, Comte, and Conseil: Comptes Rendus Acad, de Sci., 1909, cxlix, 157, 486. 
Ricketts and Wilder: Jour. Amer. Med. Assoc., 1910, liv, 463. 
Virchow: Virch. Arch., 1849, Bd. ii, 143; iii, 154. 
von Prowazek: Beitr. z. Klin. d. Infektionskr., 1914-16, iv, 5. 
Wolbach, Todd, and Palfrey: Etiology and Pathology of Typhus, Harvard Univ. 
Press, 1922. 
LITERATURE 
ACUTE POLIOMYELITIS (HEINE-MEDIN'S DISEASE; INFANTILE 
PARALYSIS) 
Recent studies have shown that this disease of children, which was 
formerly regarded as a type of paralysis with sudden and unheralded onset, 
is really an acute infectious disease which is transmitted from person to 
person, occurs in epidemics, and can be reproduced by inoculation in 
monkeys (Popper and Landsteiner, Flexner). Indeed, it has been shown 
that the causative agent is small enough to pass through a porcelain filter 
(Flexner, Landsteiner), that it can be grown in pure culture, and that it 
will produce the disease in animals (Flexner, Noguchi). The precise nature 
of the organism and its relations to other living beings are not made 
clear, but while generally invisible it is at least often associated with minute 
coccus-like, globoid bodies, sometimes appearing in chains and causing a 
clouding of the fluid medium. It can be isolated from the infected brain 
and cord and can be shown to be present in the nasal mucosa of inoculated 
monkeys and persons ill of the disease. It seems that all the postulates 
for the proof of the relation of an organism to a disease have been fulfilled 
in this case. Several other investigators have attempted to show that a 
streptococcus is constantly present in these cases and may well be regarded 
as the aetiological factor, but these claims have been satisfactorily refuted 
by Flexner, Amoss, and others. 691 
acute poliomyelitis 
The disease begins, usually in children, with vomiting, fever, leucocytosis, 
and general malaise. Pain in the back, neck, and extremities is nearly 
always present and is sometimes extreme, so that the child winces and cries 
out on being moved. After several days' illness, paralyses suddenly appear 
and extend to involve one or both legs or a leg and arm or even all the ex- 
tremities, together with the trunk muscles. Paralyses of the muscles sup- 
plied by the cranial nerves are not frequent. When the respiratory muscles 
are thus involved, death ensues. 
The paralysis is most commonly of the flaccid type but in some cases it is 
spastic. The mortality is fairly high but many cases recover with perma- 
nent paralysis. Atrophy of the muscles with subsequent contractures 
lead to the most crippling deformities. On the other hand, there are many 
so-called abortive cases in which, after the initial febrile symptoms are 
over, recovery takes place without any paralysis. Survival of the disease 
leaves an immunity, and the serum of such immune individuals has a pro- 
tective effect in animals inoculated with the disease-producing agent. It 
is through the discovery of the existence of such an immunity that one may 
recognize those persons who have passed through an abortive attack. 
Transmission.-Doubtless they, as well as those more seriously affected, 
can act as carriers and transmitters of the disease, and it was partly through 
the recognition of this fact that the chain of events could be made complete 
in the explanation of the epidemic occurrence of this affection. An at- 
tempt was made to show that the transfer of infection was effected by the 
bites of stable flies, but further study has proved that this is not true. 
Flexner has shown that it is difficult to inoculate monkeys successfully, but 
that repeated apparently ineffectual inoculations may finally produce the 
disease. The subdural inoculation of material from the brain or cord of a 
case of poliomyelitis is the most effective means of transmission, but mon- 
keys can also be infected through the nasal mucosa. When the virus is 
injected into the blood, it requires a much longer time to develop. It 
seems, therefore, that the organisms must gain access to the cerebrospinal 
fluid, either by direct transmission from the nasal passages or possibly along 
the lymphatics of the nerve-sheaths. Perhaps the tonsils and digestive 
tract may play some part as portals of entry. 
Lesions.-The chief lesions are found in the central nervous system, 
and commonly the predominant changes are found in the anterior part of 
the spinal cord. There are such variations, however, that Muller has 
proposed a division into cerebral, bulbar and spinal forms. Peabody, 
Draper and Dochez suggest what seems a better division, into affections of 
the upper and of the lower neurone, but this too is open to objections. It 
is useful in separating the spastic cases which are affections of the upper 
motor neurone from those with flaccid paralysis in which the anterior horn 
ganglion-cells are especially attacked. The changes begin, as can be 
studied in experimental animals and in the cases which end fatally in the 
early stages, with hypereemia of the pia and of the blood-vessels which pass 692 
TEXT-BOOK OF PATHOLOGY 
into the cord through the anterior fissure and with the accumulation of 
lymphocytes and polymorphonuclear leucocytes about them (Fig. 338). 
This process quickly extends into the substance of the cord, and not only 
in the gray matter of the anterior horns, as was formerly thought, but 
everywhere, the small arterioles and venules are found surrounded with a 
Fig. 338.-Acute poliomyelitis. Spinal cord, showing a portion of the gray matter 
infiltrated with leucocytes accumulated about the vessels. Ganglion-cells of the anterior 
horn have become indistinct or lost. 
mantle of such cells. Isolated groups of leucocytes are scattered through 
the tissue. Destructive changes become apparent in the ganglion-cells, 
perhaps especially in those of the anterior horn, and they are soon found to 
be in the process of disintegration or shrinkage. There is disintegration and 
fusion of the tigroid bodies and later the nucleus in each cell shrinks and 
becomes deeply stained or fades away and disappears. Direct invasion of 693 
EPIDEMIC ENCEPHALITIS 
phagocytic cells into the bodies of such ganglion-cells is often observed 
and the remains are surrounded by a cluster of them. Many writers try 
to show that the mechanical effect of the inflammation causes the injury 
to the ganglion-cells, but it seems more probable that it is the direct result 
of the presence of the infective agent. 
With recovery, the injured ganglion-cells disappear completely, and after 
the fading of the inflammatory reaction the place is occupied by a dense 
neuroglia scar. Quite analogous lesions are found in the medulla oblongata, 
where the nuclei of cranial nerves become affected, and in the higher parts 
of the brain as well. This is referred to as polioencephalitis (Strumpell). 
In the other organs less characteristic changes are found, but reference 
may be made to minute focal necroses of liver-cells with lymphocyte ac- 
cumulation, and to similar changes in the lymph-glands which have been 
described by Peabody, Draper, and Dochez. In such lymph-glands the 
sinuses are filled with large phagocytic cells, as in typhoid fever. Cloudy 
swelling of liver and kidneys is usual. 
LITERATURE 
Amoss: Jour. Exp. Med., 1917, xxv, 545. 
Bull: Ibid., 557. 
Wickman: Heine-Medinsche Krankheit, Berlin, 1907. Akute Poliomyelitis, Berlin, 
1911. Transl. New York, 1913. 
Harbitz and Scheel: Ak. Poliomyelitis u. verwandte Krankheiten, Christiania, 1907. 
Jour. Amer. Med. Assn., 1907, xlix, 1420; lix, 782. Dtsch. med. Woch., 1907, 
xxiii, 1992. 
I. Strauss: Rep. Collective Investig. Comm. N. Y. Epidemic, 1907. 
Peabody, Draper, and Dochez: Ac. Poliomyelitis, Rockefeller Inst. Monographs, 1912, 
No. 4. 
Flexner, with Lewis, Noguchi, and Amoss: Many papers in Jour. Exp. Med., 1913, 
xviii, 461; 1914, xix, 411; xx, 249; 1915, xxi, 91, etc. Jour. Amer. Med. Assn., 
1913, lx, 362, etc. 
EPIDEMIC ENCEPHALITIS 
During 1917 there was an epidemic in Austria described by Economo as 
a new disease, encephalitis lethargica. This appeared in other European 
countries in 1918 and in America in 1919, and still persists in sporadic 
form. It is an acute and chronic infectious disease with a high mortality 
in the early stages and particularly dreaded because even with recovery 
it leaves such disabling and disfiguring sequelae which may change the 
whole character of the victim. The acute febrile illness is soon accom- 
panied by disturbances of sensation, of reflexes, of motility, and of the 
mental state. There may be somnolence or delirium with insomnia, 
curious rigidities of the muscles and prolongations of their contractions, 
choreiform movements or myoclonic spasms, tremor, neuralgia, paresis 
of the ocular and facial muscles, and, indeed, a great variety of symptoms 
which may simulate all sorts of quite different diseases recognized by the 
neurologist and psychiatrist. Later, the febrile stage being over, the 694 
TEXT-BOOK OF PATHOLOGY 
residual disturbances appear more clearly and are often of the nature of 
pareses or rigidities of muscles. Something closely resembling Parkinson's 
disease or "shaking palsy" may develop rather rapidly and persist. The 
patient acquires a peculiar mask-like face and awkward pose with a rigidity 
and often with a constant movement of the fingers. 
The nature of the infection and its mode of transmission must still be 
regarded as open to question, although many investigators (Loewe and 
Strauss, Levaditi and Harvier, Doern, Flexner, and others) have been able 
to transmit the disease through animals in series by the inoculation of 
material from the central nervous system of persons dead of the disease, 
or sometimes from cerebrospinal fluid, or even saliva. Experiments on 
herpes labialis and corneal herpes show that these conditions are of infec- 
tious nature and that one may inoculate the material from an ordinary 
labial herpes into the cornea of a rabbit and produce herpes there-some- 
times going on to the production of encephalitis with pareses, saliva- 
tion, and death. Material from the brain of a rabbit inoculated from a 
case of epidemic encephalitis will also produce corneal herpes and the 
herpetic and encephalitic viruses in the rabbit cross immunize against 
each other. Some confusion exists from the fact that rabbits have spon- 
taneous encephalitis and this is another example of the unfortunate choice 
of the rabbit as an animal for experiment since it seems to have spon- 
taneously almost every disease that anyone tries to produce. 
With regard to the relation of epidemic encephalitis to poliomyelitis it 
can be said, at least, that the distribution of the lesions and the character 
of the symptoms and residual changes are different, and further, that in at 
least one or two cases, encephalitis has occurred in persons who had 
survived poliomyelitis and were presumably immune. The vagueness of 
our knowledge as to the infective agent makes direct comparison difficult 
as yet, just as it is difficult to decide as to the nature of a peculiar Australian 
disease which has some of the characteristics of both. 
At autopsy, in cases of epidemic encephalitis, the lesions are found 
especially in the gray matter of the optic thalamus, the corpus striatum, 
the substantia nigra, the red nucleus, the hypothalamic region, and in the 
rest of the midbrain and medulla, without much involvement of the 
cerebral cortex, or of the spinal cord. The lesions are very inconspicuous 
to the naked eye, but are sometimes visible in the form of minute hsemor- 
rhages. Microscopically they are found to consist of prominent perivas- 
cular accumulations of mononuclear cells with some haemorrhage and some 
disintegration of the tissue involving nerve cells. But the actual changes 
in the nerve cells and fibres, apart from their displacement by oedema and 
cell infiltration, are really rather inconspicuous as at present described. 
There is nothing to correspond precisely with the destruction of the motor 
cells of the anterior horns of the spinal cord which is so definite in polio- 
myelitis and which leaves such a distinct scar and such permanent paral- 
ysis, and the transience of the pareses seen in encephalitis seems to agree EPIDEMIC ENCEPHALITIS 
695 
with this. Meninges and ependyma seem to be but little affected, although 
some authors mention a congestion of the pia, and there is no striking 
alteration in the character or quantity of cerebrospinal fluid. Cranial 
nerves sometimes show an inflammatory process as described by Burrows. 
Study of the history of epidemic disease appears to show that this is 
really the beginning of a new disease, although there were some previous 
epidemics of small extent which somewhat resembled it. The literature 
so far does not seem to contain any descriptions of the condition of the 
central nervous system at a stage long after recovery from the more acute 
manifestations, and we shall await such studies with interest. 
LITERATURE 
Achard: L'Encephalili lethargique, Paris, 1921. 
Barker: Archives of Neurology and Psychiatry, 1921, vi, 173. 
Flexner: Jour. Amer. Med. Assoc., 1923, Ixxxi, 1688. 
Friedenwald, J.: Archives of Ophthalmology, 1923, lii, 105 (Herpes). 
Hauptli: Dtsch. Ztsch. f. Nervenh., 1921, Ixxi, 1. 
Levaditi and Harvier: Ann. de 1. Inst. Pasteur, 1920, xxxiv, 911. 
Loewe and Strauss: Jour. Infect. Dis., 1920, xxvii, 250. 
Rolleston: Medical Science, 1922-23, vii, 443. 
v. Economo: Wien. Klin. Woch., 1917, xxx, 581. 
Wegeforth and Ayer: Jour. Amer. Med. Assoc., 1919, Ixxiii, 5. CHAPTER XXXV 
TYPES OF INJURY.-SPIROCHAETAL INFECTION 
Syphilis: Etiology and distribution. Course of the disease. Nature of different stages. 
Immunity and transmission. Primary stage, secondary lesions, tertiary stage. Lymph- 
glands, blood, digestive tract, liver, respiratory tract, bones and joints, heart and blood- 
vessels, nervous system. Syphilitic lesions of genital organs. Orchitis. 
SYPHILIS 
^Etiology and Distribution.-Syphilis is an infectious disease caused by in- 
vasion of the Spirochaeta pallida, an organism discovered by Schaudinn 
and Hoffman in 1905. The disease itself had been studied in great detail 
throughout centuries, and numerous other supposed causes had been de- 
scribed, but the discovery of the true aetiological factor has caused a great 
flood of light to be shed upon it during the few years which have followed. 
The infection is not one which remains local-instead, it gives rise in 
each case to a generalized distribution of the organisms with numerous 
local manifestations, often due to concentration of the spirochaetse in those 
places. 
First introduced through an abrasion of the skin or through a mucous 
surface, it produces within a short time a general septicaemia, which in turn 
gives rise to the local lesions, almost countless in their variety. 
The organism is not limited to man as its host, although until the recent 
experimental work, it seems to have been practically so limited. It is now 
known that anthropoid apes, and indeed most of the monkey tribe, even to 
the lower forms, are susceptible, and that with proper precautions rabbits, 
sheep, goats, and other animals may be successfully inoculated. Not in 
all these animals do the lesions present themselves in form and order like 
those found in the human being, but all the postulates necessary to prove 
the relation of the organism to the disease, whether produced experi- 
mentally or not, have been complied with, including the isolation and pure 
culture of the spirochaetse in an artificial medium. 
Ordinarily the disease is transmitted by coitus, but it is also quite fre- 
quently traceable to extragenital infection, as through kissing, the use of 
infected utensils, towels, etc., or through shaving with an infected razor. 
The danger to surgeons and dentists of infecting their fingers through cuts 
or abrasions during an operation upon a syphilitic is considerable. 
Course of the Disease.-Syphilis is usually a very slowly progressing 
disease, and except in the so-called "syphilis maligna," it advances pretty 
regularly through a series of stages first clearly recognized by Ricord. 
Thus, after an incubation period of varying duration (8 to 40 days), there 
696 SYPHILIS 
697 
appears a characteristic local lesion which, when secondarily infected, often 
ulcerates at the point of inoculation. Regional lymph-glands become in- 
fected and swollen. 
After a second incubation period of varying length, often eight to ten 
weeks after the first infection, there appear in the skin and mucous surfaces 
new manifestations caused by a distribution of the Spirochaetae by the blood 
and their multiplication in certain places. These are the lesions of the 
secondary stage, and here the greatest variety of form is shown. Lymph- 
glands in general are enlarged, and some other tissues, such as the iris, 
cerebral vessels, testes, etc., may be involved. The secondary lesions 
usually heal without leaving any great destruction behind them. 
After another period, which may stretch out over very many years during 
which the patient has supposed himself cured, the destructive lesions of the 
tertiary stage appear. These arise in any situation in the internal organs 
or the skin-no tissue seems exempt. Characteristic is the formation of 
tubercle-like nodules, often of large size and firm consistence (gummata), 
becoming caseous internally and ending, after wide destruction of tissue, 
in healing which leaves behind a most extensive scar. Or a less char- 
acteristic, wide-spread, cellular granulation tissue may in the same way lead 
to destruction of the tissue and distortion from scar formation. Warthin 
especially emphasizes this in what he calls the new pathology of syphilis, 
and describes in detail focal accumulations of plasma and lymphoid 
cells about the small vessels and in the interstices of almost all the organs 
in cases of late and often unsuspected or latent syphilis. In many of 
these, especially in the heart, blood-vessels, and central nervous system, 
but also in the pancreas, adrenals, and testes, he has sometimes demon- 
strated the Spirochaetae, while others are recognized as syphilitic by their 
histological identity with those of assured origin. These lesions are so 
much more frequent and therefore of so much greater significance than 
definite gummata that Warthin objects to the usual statement that the 
gumma is the characteristic lesion of tertiary syphilis. In autopsies upon un- 
treated Chinese coolies at the Tan Tock Seng Hospital in Singapore I found 
gummata so regularly and in a form so suitable for the illustration of a 
text-book that I am inclined to the surmise that, were it not for a certain 
inherited immunity in our race and the effects of treatment, the gumma 
would still easily hold its place as the most characteristic feature of ter- 
tiary syphilis. Nevertheless, as the disease exists, Warthin is doubtless 
right in stating that the less conspicuous but wide-spread and destructive 
focal lesions are much more important, since they disable the vital 
organs. 
Following the tertiary stage there may appear still other lesions involving 
especially injury and scarring in the central nervous system (tabes and 
progressive paralysis), which have long been suspected of being syphilitic 
and spoken of as parasyphilitic affections. Recently the Spirochaetae 
have been demonstrated in these tissues (Noguchi) and the matter set 
upon a firm basis. Even successful treatment by specific medication has 698 
TEXT-BOOK OF PATHOLOGY 
been carried out. Such lesions are often said to constitute a quaternary 
stage of the disease. 
Thus, syphilis is seen to be a generalized infection of extraordinary 
chronicity and tenacity in which, at some periods, the whole blood and 
tissues of the host are infected with the spirochsetse, while during years they 
seem to disappear or remain hidden somewhere only to multiply again at 
some point and produce new changes. There is a certain regularity in the 
progression of the different stages, although the length of time required for 
the appearance of each varies extremely. 
It was at one time thought (Ricord) that a person who had once had 
syphilis was quite immune from further infection, and also that while 
materials from the primary lesion or initial sclerosis as well as those from 
secondary lesions were highly infective, the tertiary lesion were non- 
infective. All of this has proven untrue. Finger and Landsteiner showed 
that a gumma contains living Spirochaetae which can produce an initial 
lesion followed by secondary rashes when inoculated, and they and others 
have also shown that while a certain increased resistance may appear after 
the first infection a new inoculation may be successful in any stage of the 
disease (superinfection). There are several instances in which a whole 
series of chancres or primary lesions has appeared as the result of successive 
exposures to infection. 
It must be said, however, at this point, that inoculation of the person's 
own spirochsetse, or of spirochsetse of foreign origin, when it causes new 
lesions to develop in a person already syphilitic, produces not always chancres 
but lesions which belong to the stage of the disease in which he is. Thus 
fresh inoculation of a man harboring tertiary lesions will produce a gum- 
matous or tertiary lesion of the skin and not a chancre, which is a lesion of 
the primary stage. It appears, therefore, that the stages of the disease 
represent different reactions to the same poison and the idea has been sug- 
gested, though perhaps not proven, that the various rashes and other skin 
outbreaks are largely allergic phenomena. 
Congenital Infection.-Syphilis may be transmitted from infected 
parents to their offspring during the course of gestation, so that they are 
born with the disease. This is clearly not a matter of inheritance, but 
strictly an intra-uterine infection. As to the mode of transmission there has 
been much dispute, but it is clear that the infection may come from either 
the father or the mother. It is shown that while the spirochseta does not 
actually invade the sperm cell, as has been surmised, it may nevertheless 
accompany it mixed in the spermatic fluid or the secretions of prostate 
or seminal vesicles. When the mother is definitely syphilitic there is 
little doubt that the transmission occurs through the placenta by passage 
of the spirochsetse into the foetal blood. Sometimes this seems to occur 
only in the late stage, during partial separation of the placenta and direct 
admixture of maternal and foetal blood. Then, there may be an incuba- 
tion period of apparent health after birth before the symptoms develop in SYPHILIS 
699 
the child. But the great problem is whether all infection of the offspring 
is placental or whether infection of the foetus alone can occur from the 
father, excluding any transfer of Spirochaetae from the mother through the 
placenta. This question is particularly suggested by the fact noticed in 
1837 by Colles, that a woman might give birth to a syphilitic child and nurse 
it without ever showing any signs of syphilis herself, although a wet-nurse 
would be at once infected by the child. 
This is the so-called Colles' law, and it seemed to show that the mother 
was immune and that the child bore the whole weight of the infection from 
the father. Recent studies show, however, that the mother, even though 
she presents no lesions, is actually infected with the Spirochaetae and that 
she gives a positive Wassermann reaction. The so-called exceptions to 
Colles' law, in which such a mother is infected with syphilis and shows the 
typical symptoms, must be examples of superinfection, such as we mentioned 
above. More difficult to explain are the cases in which a mother having 
given birth to a syphilitic child by one husband produces healthy children 
by another. 
Prof eta's law, that a healthy child of a syphilitic mother is immune, is 
not true-the child may be healthy, but it is susceptible to infection from 
its mother. 
The weight of evidence seems to be in favor of the idea that if a syphilitic 
child be born of a healthy mother and a syphilitic father it is because the 
healthy mother has been infected by the father probably by way of the 
uterine lining, so that no primary lesion is observed and that, after all, the 
placental mode of transmission may play the important part in the infec- 
tion of the foetus. 
Immunity.-It may be gathered from what has been said that immunity 
in syphilis is by no means so definite as in such diseases as smallpox or 
yellow fever, but that, while there is relative insusceptibility, a new infec- 
tion is possible at any stage. Evidences of the changed reaction of the 
body are made clear in various ways, however, and become useful in making 
a diagnosis. Thus the so-called Wassermann reaction depends upon the 
fact that the complement necessary for the laking of a sample of red cor- 
puscles in a mixture of haemolytic amboceptor and corpuscles, is found to 
have been used up if it is first treated with a mixture of syphilitic serum and 
a lipoid antigen represented by an extract of a known syphilitic organ or 
even an alcoholic extract of a normal heart, whereas when treated with 
normal serum and this antigen, none of the complement is absorbed and 
haemolysis proceeds. 
This method of .deviation of complement is obviously a purely empirical 
discovery, although it seemed at first, when extracts of known syphilitic 
organs were used as the antigen, to be a very purposeful demonstration of a 
specific relation. Its real nature is yet to be determined, but it seems to 
indicate syphilitic infection very accurately. 
Noguchi's method, the luetin reaction, in which an extract of a sterilized 
culture of Spirochaetae is found to produce an inflammatory reaction in the 700 
TEXT-BOOK OF PATHOLOGY 
skin of syphilitics and none in normal persons, seems to depend upon an 
anaphylactic sensitiveness in infected persons. It is positive in tertiary 
and quaternary stages and in latent forms, but seldom so in the primary and 
secondary stages. 
Zinsser and his co-workers have attempted to produce immunity from 
the Spirochaeta in rabbits by various methods. They succeeded in de- 
veloping a moderately strong agglutinating serum and some bactericidal 
effect against culture Spirochaetae, but not against virulent Spirochaetae. 
LITERATURE 
Noguchi: Jour. Exp. Med., 1911, xiv, 557. 
Rietschel: Ergeb. d. inn. Med. u. Kinderheilk., 1913, xii, IGO. 
Matzenauer: Die Vererbung der Syphilis, Wien, 1903. 
Neisser: Beitr. z. Path. u. Ther. d. Syphilis, Berlin, 1911. Also in: Arb. a. d. Kais. 
Gesundheitsamt, 1911, xxxvii. 
Finger: Handbuch d. Geschlechtskrankheiten, 1912, ii, 89G. 
Finger u. Landsteiner: Arch. f. Derm. u. Syph., 1906, Ixxviii, 335; Ixxxi, 147. 
Landsteiner: (Exp. Syphilis) Handb. d. Geschlechtskr., 1912, ii, 873. 
Herxheimer: Ergeb. d. allg. Path., 1907, xi, 1. 
Schaudinn, Hoffman: Arb. a. d. Kais. Gesundheitsamt, 1905, xxii. 
Metschnikoff et Roux: Ann. Inst. Pasteur, 1903, xvii, 809. 
Uhlenhuth u. Mulzer: Arb. a. d. Kais. Gesundheitsamt, 1913, xliv, 307. 
Primary Stage.-The initial lesion or chancre arises, as mentioned above, 
at the point of infection one to four or more weeks after exposure. It is 
nearly always dependent upon an abrasion, although in the case of the 
mucous surfaces it appears that infection can occur directly. The abrasion 
in the skin or mucosa usually heals after a few days without leaving any 
trace, and it is only later that the specific lesion appears in the same 
place. Nevertheless, even though such an area be excised and cauterized 
a few hours after the exposure, it is frequently, if not always, found that 
transportation of the Spirochaetae has already occurred, so that general 
infection later makes itself evident. The delay in the appearance of 
the first sign of the initial lesion is thought to be due to the fact that in 
the process of accommodating themselves to the new host many of the 
spirochaetse are destroyed, so that it requires time for those which sur- 
vive to develop the lesion. This begins sometimes as a tiny vesicle, usually 
as a delicate thickening or induration of the surface tissue, over which, as 
time passes, the epithelium becomes necrotic and converted into a brownish 
crust which comes off, leaving a shallow ulcer. The induration extends 
and becomes a flattened hard mass, easily rendered bloodless by bending or 
by pressure, and easily movable in the surrounding tissue (Figs. 339 and 
340). There is a characteristic, bacon-like translucence about this mass. 
The ulceration may extend and become quite deep, a considerable area may 
be involved, and the chancre may persist for quite a time; but in the end 
it heals up, the induration disappearing, and the ulcer leaving a scar. 
Occasionally, but not often, considerable distortion and loss of tissue 
may be produced. SYPHILIS 
701 
Histologically (Fig. 341), it is found that the induration is produced by 
a great accumulation of cells in the skin and subcutaneous tissue. Ehr- 
mann has shown by injections that great numbers of new blood-vessels are 
formed and that there is stasis in these venules from the pressure of the 
cells, often with haemorrhages and the formation of blood-pigment. The 
accumulated cells are in part polymorphonuclear leucocytes, which are 
Fig. 339.-Primary syphilitic lesion of corona. Early stage (Fordyce*) 
found especially in the base of the ulcer, but predominantly they are mono- 
nuclear cells of the type of lymphocytes, plasma cells, and larger mono- 
nuclears. They are assembled in great numbers about the blood-vessels 
whose internal layer is enormously thickened, and extend from the main 
mass of the induration in the form of thick mantles in and about the ad- 
ventitia of such vessels. Ehrmann described the induration as largely de- 
pendent upon the alterations in the lymphatic channels, which are often 
choked with mononuclear cells or with proliferated masses of their own 
endothelial cells. In our preparations it is difficult to see any such pro- 
* Professor Fordyce has kindly allowed me to use photographs from his clinic for 
Figs. 339, 340, 342, 343, and Dr. Keidel has given the Figs. 344, 345, 350, and others 
from the Department of Syphilis in the Johns Hopkins Hospital. 702 
TEXT-BOOK OF PATHOLOGY 
liferation of the endothelium of lymphatics or blood-vessels, although many 
of them are packed with wandering cells, but there are masses of tissue 
composed of large pale cells of irregular and indefinite outline with large 
vesicular nuclei. These are seen to be proliferated fibroblasts, and they, 
Fig. 340.-Primary syphilitic lesion of prepuce. Later stage, with crust. Secondary 
rash of macular character over body (Fordyce) 
together with the abundant wandering cells, doubtless give the firmness 
and translucence to the tissue. 
Leading away from the chancre are lymph-channels along the course of 
which little nodular accumulations of cells may be found. 
The chancre may develop on the prepuce, in the coronal sulcus, on the 
glans penis or the frenulum, or about the orifice of the urethra, in about this 
order of frequency, or it may appear on the skin of the penis or of the 
scrotum. In the female the labia majora or minora, the orifice of the vagina, 
the clitoris, the vault of the vagina, or the vaginal portion of the cervix are 
the commonest sites. But the lip, tongue, tonsil, or the cheeks, eyelids, 
breast, fingers, etc., may also be infected through the various processes 
of exposure mentioned above. 
A short time after the appearance of the chancre the regional lymph- SYPHILIS 
703 
glands swell and become hard. The inguinal glands are most commonly 
affected, of course. In them the Spirochaetae are found just as they are in 
the chancre. The lymph-sinuses are filled with wandering cells, chiefly of 
the mononuclear type, and later there is a proliferation of the connective- 
Fig. 341.-Edge of chancre, showing ulceration through the epidermis and great ac- 
cumulation of mononuclear cells, especially about the vessels and lymphatics. 
tissue elements. There is little tendency to great swelling or to suppuration 
in such syphilitic buboes in contrast to the condition following infection 
with Ducrey's bacillus (soft chancre or chancroid) and that in gonorrhea. 
Chancres can be experimentally produced in animals by the inoculation 
of spirochsete-containing material, and recently Chesney has found that 704 
TEXT-BOOK OF PATHOLOGY 
Fig. 342.-Chancroid (Fordyce) 
Fig. 343.-Secondary syphilitic lesion of skin. Papular syphilide (Fordyce). SYPHILIS 
705 
when the spirochaetes are smeared on the surface of granulation tissue, 
which has been produced by making an open wound in the skin of a 
rabbit, they develop there and rapidly produce an enormous lesion far 
larger than is commonly seen in human beings. 
Chancroid or Soft Chancre.-This is a type of ulceration of the genitalia trans- 
mitted by coitus or other contact and caused by a small Gram-negative strepto-bacillus 
which was described by Ducrey. The bacillus is easily cultivated and often grows 
in short chains. It is capable of producing a similar ulceration on inoculation in the skin 
of a person already infected or an uninfected one. The ulcer spreads rapidly and has a 
ragged outline with undermined edges (Fig. 342). There is no induration about it, but 
the base is rough and covered with necrotic material and bleeds easily. While the penis 
and labia are most commonly affected, the ulceration may extend to the skin elsewhere. 
Red, tender lines which are palpable run from the ulcers toward the inguinal region and 
are often beaded with little firm nodules. These are the inflamed lymph-channels, and 
the nodules or bubonuli are swollen collections of lymphoid tissue which may become 
abscesses. The inguinal lymph-glands become greatly swollen and tender (buboes'); 
on incision a quantity of purulent material is evacuated and the glands are found to be 
matted together and excavated by the destructive process which extends from one 
gland to another. This lesion, like the ulcers, finally heals, with an extensive scar. 
There are no general symptoms and no lesions in other organs. 
Secondary Stage.-In rare cases, after the healing of the chancre no 
other symptoms appear, and this may be true if vigorous medication be 
instituted in the primary stage. But usually eight or ten weeks after the 
infection, that is, after a second incubation period, the secondary lesions 
of the skin and mucosae make their appearance with fever, loss of appetite, 
muscular pains, etc. No brief description can even outline satisfactorily 
the extraordinary variety of these phenomena. They simulate every kind 
of skin disease and may be mistaken for the rashes of exanthematic dis- 
eases (measles, chickenpox, etc.), as well as those produced by various 
drugs (Figs. 343, 344, 345). They have a tendency to heal up and then 
to recur, but although they may produce the most extensive outbreak all 
over the body, they are seldom destructive and leave little trace of their 
presence. 
The simplest rash is the macular syphilide, which begins on the trunk 
and may quickly appear over the whole body. It is quite like the rash of 
measles in some cases, and histologically presents chiefly a widening of the 
blood-vessels with slight accumulation of cells. Further accumulation of 
leucocytes and oedema is characteristic of the papular syphilide in which the 
eruption is somewhat raised. With the fading of these rashes discoloration 
of the skin may remain for a time. Some often develop superficial crusts 
due to epithelial necrosis and exudation, while others are definitely pustular, 
little abscesses forming in each lesion. Many of these syphilides have a 
tendency to heal in their central part while spreading and producing new 
lesions at the periphery. Ring-formed macular, papular, or pustular erup- 
tions arise in this way. Scaly patches resembling psoriasis appear on the 
palms and soles at a later stage, and still later there may be found the 706 
TEXT-BOOK OF PATHOLOGY 
rounded, terraced, elevated patches with necrotic crusts-the so-called 
rupial eruption, which is more correctly regarded as a tertiary lesion. 
Many other forms and combinations occur, descriptions of which may be 
found in text-books of dermatology. Not infrequent are pigmentary 
changes, in some of which there is a deepening of the color of the skin, 
in others a complete fading away of pigment in certain areas, which leaves 
them white in contrast with the surroundings (leucoderma). Patchy 
falling out of the hair (syphilitic alopecia) is also characteristic of this 
stage of the disease. 
Soreness of the throat, with evident though slight inflammation, is com- 
mon. Most characteristic, however, is the appearance of the so-called 
Fig. 344.-Secondary syphilis: pustular syphilide (Keidel). 
mucous patches in the mouth and throat. These are white areas in the 
mucosa, slightly elevated or superficially ulcerated and infiltrated with 
fluid and cells over which the epithelium is proliferated. They discharge 
the spirochaetse and are a ready source of infection. Similar patches may 
occur in the vagina. 
Besides these lesions of the skin and mucosae in the secondary stage, 
certain others are very prominent. These are the condylomata and moist 
papules, which as inflammatory elevations loaded with Spirochaetae appear 
chiefly about the genitals or on the inner sides of the thighs or anal folds, 
or elsewhere where skin surfaces touch one another, so that sweat or other 
secretions and dirt are retained. They, too, form a common source of in- 
fection. The flat condyloma (to be distinguished from the pointed con-' 707 
SYPHILIS 
dyloma, which is not of syphilitic origin) is a broad, tabulated elevation 
covered with greatly thickened and somewhat macerated epithelium, 
infiltrated with leucocytes. The papillae of the skin are enlarged by the 
widening of the blood-vessels and especially by the great accumulation of 
wandering cells. ■ 
We have recently made an attempt to study the development of the 
secondary skin lesions by excising minute pieces of skin and neighboring 
lymph-nodes from persons showing various forms of the eruption. In 
all the changes consist essentially in perivascular lymphatic accumula- 
Fig. 345.-Secondary syphilis: follicular syphilide (Keidel). 
tions of mononuclear cells with a few neutrophile and eosinophile leuco- 
cytes. The cells are relatively few in the macular forms, but become so 
numerous as to form dense masses in the papillae and deeper layers of the 
corium in the papular forms. In some rather later lesions there were about 
the vessels numerous sharply outlined nodules composed of elongated cells 
and resembling tubercles. These are associated with an infiltration of 
the tissues with mononuclear cells. The adjacent lymph-nodes show a 
characteristic change which consists in the appearance of compact masses of 
large rather pale staining cells in the lymph cords and the presence of 
abundant mononuclear cells in the sinuses. 708 
TEXT-BOOK OF PATHOLOGY 
Doubtless spirochaetes are present in all these lesions, but they are hard 
to demonstrate. 
The Tertiary Stage.-The most characteristic, though not the most 
'common, manifestation of the effects of the Spirochaetae in this stage of the 
disease is the gumma, which received its name from its elastic, rubber-like 
consistency ("Gummigeschwulst"). Most commonly such nodules are 
found embedded in the tissue and surrounded on all sides by radiating 
fibrous tissue, which in itself is not especially peculiar. But the central 
portion is firm, elastic, opaque, and yellowish white, like hard cheese. 
This is the necrotic caseous part, analogous to that found in tubercles, but 
Fig. 346.-Gumma of testicle, showing caseous centre. Atrophy of adjacent tubules. 
different in its elastic, firm consistency and in the slighter tendency to 
liquefy. In it one may sometimes discern faint outlines of pre-existent 
tissue now necrotic. The margin or capsule is often not specially char- 
acteristic (Fig. 346), being made up of a rather dense tissue rich in epi- 
thelioid cells, such as are found in tubercles, and closely infiltrated with SYPHILIS 
709 
mononuclear wandering cells. Giant-cells with multiple nuclei such as 
are found in tubercles occur, but are rarer here. Baumgarten denies 
their existence in gummata, claiming that they are characteristic of 
tubercles, and that if they do occur it is because of a coincident tuberculous 
infection. Such nodules may be of almost any size from minute points 
as small as the smallest tubercle to huge, tumor-like masses easily felt 
through the abdominal walls as they project from the liver, where they 
seem to reach their greatest size. In the miliary gummata there may 
be no caseation or coagulative necrosis and the nodule is seen as a more or 
less concentrically arranged group of epithelioid cells richly mingled with 
mononuclear wandering cells and occasionally with giant-cells. The 
arrangement is usually indefinite and irregular, lacking the sharpness and 
precision of the architecture of the miliary tubercle (Figs. 347-349). 
Spirochaetae have been demonstrated by animal inoculation in larger 
gummata by Finger and Landsteiner, but they are not easily found in sec- 
Fig. 347.-Liver, showing several fresh miliary gummata and small caseous areas 
tions. How, then, is one to tell a gumma from a tubercle when it is found 
at the autopsy? Histologically it seems almost impossible to make an 
absolute differentiation between them. A section through a gumma in 
the lung tissue might have exactly the appearance of one from a large 
caseous encapsulated tubercle. A miliary gumma in the liver might cor- 
respond exactly with some types of tubercles seen there. Demonstra- 
tion of the presence of tubercle bacilli or of spirochsetes would settle the 
matter, but these searches are notoriously uncertain. Better would be 
the inoculation of a guinea-pig with the material. The Wassermann 
reaction might afford decisive evidence. But, as a rule, the gross ap- 
pearance and distribution of the lesions are found to be typical enough in 
each disease to allow one to discriminate-not always from the situation of 
any one lesion, but from its relation to other lesions throughout the body. 710 
TEXT-BOOK OF PATHOLOGY 
Thus gummata are commonly found in the periosteum invading the bone; 
in the skull they are frequently found involving the meninges and extending 
into the substance of the brain. Such a matting together of periosteum, 
skull, meninges, and brain into a solid caseous mass by a tuberculous process 
would be rare. In the brain substance they occur and have a different 
consistence from that of the very similar large solitary tubercles which are 
found there too, but the tubercles would in all probability be associated 
with readily recognizable tuberculosis of the lungs, etc. This is most often 
the really effective aid to diagnosis, for it is not difficult to recognize well- 
Fig. 348.-Beginning miliary gumma of liver. Necrosis of the liver-cells and wandering 
in of mononuclears is followed by the growth of epithelioid cells. 
developed and wide-spread tuberculosis. In the liver small tubercles and 
small gummata are similar-the condition of the other organs will generally 
decide their nature. Large tubercles are rare; large, partly healed gum- 
mata are common. Nevertheless we have recently had a case in which a 
caseous tubercle 7-8 cm. in diameter occurred in the liver. Its abundant 
content of tubercle bacilli and the wide distribution of tuberculous lesions 
elsewhere made the diagnosis pretty clear. In the testicle gummata are 
common, while tuberculous infection practically always begins in the 
epididymis, and only later may extend to involve the testicle. 711 
SYPHILIS 
Gummata have a strong tendency to heal, so that they are commonly 
found as disappearing centres of caseous material in great radiating scars. 
This is far less often true of tubercles. Many other instances might be 
mentioned in which the attendant circumstances give the main clue to the 
diagnosis. The history of the case, the Wassermann reaction, the bacterial 
findings, the distribution of the lesions and their relation to lesions else- 
where, their size, consistence and gross appearance, their tendency to heal 
Fig. 349.-Miliary gummata of the liver with occasional giant-cells. 
or to break down, and least of all their histological structure-these are 
the things upon which the diagnosis of syphilis in the tertiary stage may be 
based. 
Not all tertiary lesions are distinctly gummatous, however, for there 
frequently arises a diffuse infiltration of tissues with wandering cells and a 
proliferation and new formation of connective tissue, which results in the 
formation of a syphilitic granulation tissue analogous to the tuberculous 
granulation tissue which plays so great a part in old tuberculous lesions. 712 
TEXT-BOOK OF PATHOLOGY 
In places this tissue may have a gummatous character and undergo the 
same retrogressive changes (coagulative necrosis) as are seen there, but 
here again the tendency is toward healing, often with much distortion. 
Here, as elsewhere, in syphilitic processes the smaller blood-vessels generally 
show thickening of the intima and changes in the endothelium, which may 
result in their practical obstruction. About these vessels there accumulate 
mononuclear wandering cells in great abundance. 
It will be observed in considering the development of the tertiary syphi- 
litic lesions that they often arise in places where there were secondary 
lesions which had healed, and it has been suggested that they are the effect 
of the further growth of Spirochaetae which had been left behind in the heal- 
ing of the secondary syphilis. The evidence is not entirely convincing in 
regard to this, although there are many well-attested cases in which gum- 
mata appeared on the site of old secondary lesions. It is difficult to say 
whether this holds good for the gummata of internal organs. 
The nature of all these processes may be exemplified in describing their 
occurrence in various organs. 
Lymph-glands.-The regional lymph-glands, as has been said, become 
infected and swell slightly a few days after the appearance of the initial 
chancre. This swelling is never great nor does suppuration take place 
unless there is combined with the syphilitic infection some other, such as 
that characteristic of the soft chancre. Instead, the glands remain small 
and firm and recede after a time to their former size. In the secondary 
stage, that is, at the end of the second incubation period, the lymph-glands 
become enlarged and palpable throughout the whole body. This is so 
characteristic that it becomes a valuable diagnostic aid in this stage of the 
disease. Microscopically in both these stages the change is seen to be 
essentially an increase in the number of lymphocytes, and especially of 
larger mononuclear cells which fill the sinuses and are often phagocytic. 
These large cells are also found with the lymphocytes in the lymph cords 
and are looked upon by most writers as endothelial or reticulum cells. 
Their nature is questionable in this case, as in many others in which they 
appear in the same way. The connective-tissue framework of the glands 
seems to be increased after a time. 
In the tertiary stage a similar enlargement of the glands in certain lo- 
calities may occur, but the most characteristic change is in the develop- 
ment of gummata in their substance. This is not very common and is 
usually found in association with gummatous lesions in the neighboring 
organ. Thus large gummatous masses in the bronchial glands were found 
in a case of syphilitic disease of the lungs, while gummata of the portal and 
retroperitoneal glands accompanied a fresh gummatous cirrhosis of the liver 
with involvement of the vena cava (Johns Hopkins Hosp. Bull., 1903, xiv, 
88). 
The Spirochaetae are found abundantly in the swollen glands accompany- 
ing the primary and secondary stages. SYPHILIS 
713 
Blood changes in syphilis are indefinite and not thoroughly studied; there 
has been much confusion as to the part played in producing them by mer- 
curial treatment, but it seems that the infection by itself can produce a rather 
severe anaemia in the secondary 
stage. This is sometimes spoken 
of as syphilitic chlorosis. A mod- 
erate lymphocytosis is also found. 
Alimentary Tract.-The Mouth. 
-It has already been mentioned 
that primary and secondary lesions 
occur in the mouth, chancres upon 
the tonsils, lips (Fig. 350), and 
tongue being relatively common 
among the forms of extragenital 
infection. Histologically and in 
their gross appearance they resem- 
ble those found elsewhere, and the 
glands which drain these regions 
become enlarged and very hard 
during the existence of the chancre. 
The diagnosis is sometimes diffi- 
cult, especially in the case of the 
chancre of the tonsil, which is often 
anything but characteristic. 
The tertiary lesions are common 
and important. Gummata some- 
times appear on the lips, but more 
often the whole lip becomes indu- 
rated by the formation of a diffuse 
infiltration throughout it of the 
character of the syphilitic granu- 
lation tissue. Ulceration may be 
most extensive, and with scarring 
the mouth is extremely distorted, 
so that, for example, the whole 
upper lip is destroyed, the gap ex- 
tending into the nostrils and ex- 
posing the teeth and gums. With 
healing, the orifice of the mouth 
is drawn into a stiff, triangular 
opening. On the tongue actual 
gumma formation is more common, diffuse infiltration less so. The gum- 
mata, often multiple, arise beneath the surface and extend to the upper 
surface of the tongue, where they break through, forming a deep ulcer with 
steep walls and stiff, translucent base. Healing leaves a distorting scar. 
Fig. 350.-Various examples of chancre of 
the lip (Keidel). 714 
TEXT-BOOK OF PATHOLOGY 
It is important to distinguish such ulcerating gummata from epitheli- 
omata of the tongue and from tuberculous ulcers. The epithelioma starts 
from the surface, usually at the margin, and extends to the floor of the 
mouth, growing more slowly than the gumma. Histologically it is, of 
course, easy to make the distinction. 
The diffuse infiltration of the tongue is more serious, because it causes 
great enlargement and rigidity of the organ, later, in healing, leaving the 
surface deeply fissured but otherwise smooth. This smooth atrophy of the 
villi of the tongue has long been recognized as syphilitic. Particularly 
harmful is the rigidity of the tongue which exposes it, especially where it is 
enlarged, to all kinds of injuries. 
Gummata are rare in the tonsils, but are more common in the hard and 
soft palate. Beginning usually from the nasal side from the periosteum 
the gummatous nodule projects both into the nose and mouth, and, soon 
ulcerating and discharging its contents, it produces great destruction of 
the bones of the nose and an open perforation from the nose into the mouth. 
This allows of a nasal speech (rhinolalia) and also of the passage of food and 
fluids through the nose. It is even worse when the soft palate is in the 
same way partly destroyed, for the necessary opening and closing off of the 
posterior nares is impossible. Gummatous ulcerations of the pharynx 
usually heal with less distortion, but the healing of the lesions of the soft 
palate and fauces is likely to produce a sort of stenosis or great narrowing 
of the buccopharyngeal and nasopharyngeal passages. 
(Esophagus and Stomach.-Primary and secondary lesions of the oesopha- 
gus are practically unknown. Tertiary or gummatous changes have been 
described-gummata arising in the submucosa and rupturing to produce 
ulcers which in healing give rise to stricture of the canal. 
In the stomach there have been found diffuse infiltrative processes in the 
submucosa and mucosa and also gummatous formations which on break- 
ing down produce extensive ulcers, easily enough distinguished from the 
ordinary round ulcer of the stomach. Such lesions may sometimes extend 
into the duodenum. 
Intestine.-Tertiary lesions of the small intestine are usually localized 
in the jejunum, or the upper ileum, where they appear as flat eleva- 
tions of the character of a syphilitic granulation tissue involving submucosa 
and mucosa. Multiple ulcers are found which extend in the form of rings 
round the gut, and which in healing may produce strictures. There is a 
remarkable example of this in the Pathological Museum of Columbia Uni- 
versity; but the condition must be very rare. Indeed, the only syphilitic 
lesions of the intestinal tract which are common are those found in the 
rectum. There, especially about the anus, chancres may appear, and 
secondary lesions in the form of moist papules and flat condylomata are 
extremely common. Various other secondary lesions involving cellular 
infiltration of the mucosa, abscess formation, and even fistula production 
occur at this stage. 715 
SYPHILIS 
But the tertiary lesions arising often very late in the disease, after all 
evidence of the earlier stages of the infection have disappeared, are the 
cause of the most disturb- 
ing changes. Anatomic- 
ally they are analogous 
to those found elsewhere 
and are peculiar only in 
their mechanical effects. 
Gummata appear in the 
submucosa of the rectum 
and are soon exposed to 
the lumen by ulceration, 
and surrounded by abun- 
dant scar tissue. With- 
out actual gumma form- 
ation there may be diffuse 
and wide-spread infiltra- 
tion of the whole wall of 
the gut and especially 
of the submucosa, with 
mononuclear and epithe- 
lioid cells and this infil- 
trated tissue soon breaks 
down into extensive ul- 
cers which partly or 
completely surround the 
lumen. A foul discharge 
accompanies such ulcer- 
ation and the passage of fseces is painful. This is especially so when the 
ulceration becomes very extensive, and when, with secondary infections, 
fistulse are found running into the adjacent tissues or communicating with 
the vagina. Later the dense scar formation about the healing and still 
progressive ulcers constricts the lumen of the gut (Fig. 351). Then, in 
addition to the pain and tenesmus, actual obstruction arises; there is alter- 
nate constipation and diarrhoea and the intestine above the stricture is 
dilated and hypertrophied, and ulcerated from the stagnation of faeces. 
The patient usually dies from some intercurrent infection, for which the 
poisoning caused by this slow intestinal obstruction prepares the way. As 
in other cases of syphilis of long standing, amyloid infiltration of the organs 
is often found. 
The Liver.-Little is known of any secondary syphilitic lesions in the 
liver. The recognized changes are essentially characteristic of the tertiary 
stage and consist in the formation of gummata, often with extensive in- 
flammatory infiltration of the liver substance, and scarring. It is not usual 
to find fresh gummata at autopsy, but in the case illustrated in Figs. 347 
Fig. 351.-Syphilitic stricture of the rectum. 716 
TEXT-BOOK OF PATHOLOGY 
to 349 there were numerous groups of miliary and submiliary gummata 
which, in some places, were beginning to be caseous and in others were sur- 
rounded by scars. The formation of these lesions involves the destruction 
of the liver substance and to a less extent the pushing aside of the tissue. 
They are usually numerous, but sometimes they coalesce into a great 
tumor-like mass (Fig. 352). In one instance which I saw there was a 
great nodular tumor projecting from under the edge of the liver so as to be 
palpated through the abdominal wall. It melted away rapidly under 
energetic antisyphilitic treatment, which, after all, with the history, was 
the chief proof of its gummatous nature. 
Iodides as well as mercury were given in this case, as has been done for many years. 
Jobling and Petersen have recently explained the action of iodides as follows. The soften- 
Fig. 352.-Large gumma of liver. 
ing and removal of caseous necrotic material from a gumma is due to a tryptic ferment. 
The gumma, however, persists and remains firm because it contains large quantities of 
antitryptic substances which are of lipoid nature, being combinations of unsaturated 
fatty acids. Their power of antagonizing the ferment depends upon their unsatura- 
tion, which in turn can, as is well known, be satisfied by iodine, this forming the basis 
of the well-known index used in estimating unsaturated fatty acids. Administration of 
iodine by saturating the antitryptic substances, destroys their power over the tryptic 
ferments, which then dissolve the caseous material. 
Probably the most common condition is that in which numerous distinct 
gummata of the consistence of Swiss cheese are formed throughout the liver, 
and are found as the centres of extensive radiating scars. In one such SYPHILIS 
717 
liver (Fig. 353), in a case which presented evidences of syphilis elsewhere, 
the organ was decreased in size and roughly and very coarsely nodular. 
On cutting through it, it was found to be permeated by a network of coarse 
bands of gray fibrous tissue which separated large masses of relatively 
normal-looking liver tissue, into which, however, finer bands extended. 
At three or four places on the cut surface there were at the nodal points of 
the scars firm, yellowish-white masses of caseous material up to 1 cm. in 
diameter. Further, as it penetrated the diaphragm, the inferior vena cava 
was surrounded by a large gumma originating in the liver and projecting 
through the diaphragm. It involved the wall of the vein and almost 
Fig. 353.--Gummata in the liver with extensive scarring. There is one large gumma in 
the wall of the vena cava, as it passes behind the liver, with thrombosis of the vein. 
occluded its lumen, the closure being completed below by a great thrombus 
which extended down into the renal veins. 
Such are the relatively fresh conditions, but generally only the broad 
scars remain (Fig. 354), and one finds the liver greatly distorted by the re- 
placement of whole areas of liver substance by these scars, which have 
retracted into the organ as though cords had been tightly tied about it, 
cutting deep into its substance. The rest of the liver is normal or, more 
usually, enlarged by a compensatory hypertrophy. Many of the features 
characteristic of cirrhosis of the liver, the regenerative processes, and the 
distortion of the circulation as well as of the liver tissue, may be found in 718 
TEXT-BOOK OF PATHOLOGY 
these cases. Ascites, portal stagnation, splenic enlargement, and jaundice 
may occur, but they vary with the varying mechanical conditions, and the 
presence of large gummata and scars about the portal region and bile-ducts 
naturally plays an important part in this regard. 
Such a deeply lobed, distorted liver (Fig. 355) is almost always the result 
of syphilitic infection. It is not, however, the only effect which can be 
Fig. 354.-Old scar in a syphilitic liver. In the centre is a large vein which has become 
partly recanalized after obliteration. 
produced by that disease, since in other instances one may find a much 
finer scarring, evidently due to a more diffuse affection. 
In the salivary glands, particularly the parotid, and in the pancreas 
gummatous and diffuse syphilitic lesions have been described in a few 
cases. 
Warthin has studied the pancreas in old cases of syphilis, and found that SYPHILIS 
719 
it often shows scarring, and that the scars are frequently the site of 
definite infiltrations of plasma and lymphoid cells, such as he has found 
to be characteristic effects of syphilis in other organs. This chronic 
interstitial pancreatitis, so-called, is often accompanied by diabetes, and, 
indeed, in two cases he found the Spirochaetae in the areas of cellular in- 
filtration. Warthin will not say that diabetes is dependent upon syphilis 
as its common cause; this demonstration is rather part of his general 
thesis that syphilis produces wide-spread injury and cellular infiltration 
of many organs, which is generally overlooked. 
Fig. 355.-Old syphilitic cirrhosis with deep constrictions where there are scars, 
In the kidney gummata are sometimes met with and changes leading to 
diffuse scarring and contraction of the kidneys due to syphilis have been 
said to occur. Probably they depend upon intimal lesions in the renal 
arteries. 
The Respiratory Tract.-Syphilitic lesions are found in the upper air- 
passages, larynx, and trachea, and rather less commonly in the bronchi 
and lungs. 720 
TEXT-BOOK OF PATHOLOGY 
In the nose, chancres are not uncommon, appearing at the orifices of the 
nostrils, or the alae nasi, or even in the interior, on the septum. They are 
caused as a rule by infection from the fingers or from handkerchiefs. 
In the secondary stage the most common manifestation is a syphilitic 
erythema, or reddening, which appears in flecks, sometimes later covered 
by a necrotic layer of epithelium and occasionally giving rise to nosebleed. 
This is the basis of the coryza which is a common accompaniment of this 
stage of the disease. Papules and actual condylomata sometimes arise in 
the nose. Far more important and quite common are the lesions of the 
tertiary stage, which, as elsewhere, are diffuse syphilitic infiltrations or 
gummata. The former may produce thickening of the mucosa over the 
septum or turbinates, generally with ulceration, which may penetrate to 
the cartilage or bone, and, often through 
the aid of secondary infections, leads to 
destructive perichondritis and periostitis. 
Naturally this process involves the risk 
of extension upward to the ethmoid and 
•sphenoid bones, and meningeal infection 
may follow. Sometimes great tumor-like 
masses are formed at the base of the 
septum or elsewhere. Similarly, definite 
gummatous lesions appear in the mucosa 
or in the perichondrium or periosteum of 
the bones which constitute the interior 
of the nose. Extensive deep ulcerations 
follow, and whole bones become necrotic 
sequestra. The septum may be com- 
pletely destroyed, as well as the turbin- 
ates, and large portions of the vomer and 
the nasal bones. The nose is in this way 
hollowed out into a great cavity, the lining 
of which is a scarred and atrophic mucosa. 
The process is accompanied, so long as 
necrotic bone is present, by the most 
nauseating foetor. At times, as has been 
mentioned above, perforation of the hard palate or destruction of the soft 
palate occurs. In the course of healing, the most extensive adhesions and 
strictures of the air-passages develop, so that sometimes the nasal cavity 
may be quite shut off from the pharynx. Great deformities of the face 
result, since, with the collapse of the nasal bones, the nose sinks into the 
opening produced. The mildest form of this is perhaps the saddle-nose so 
often seen in the streets and so common in late cases of congenital syphilis, 
in which the bridge of the nose is sunken and the tip turns upward, expos- 
ing the nostrils in front (Fig. 356). But in countries like Morocco, where 
Fig. 356.-Late congenital syph- 
ilis showing "saddle nose," inter- 
stitial keratitis, and leucoderma. SYPHILIS 
721 
the disease is neglected, one sees the most extreme deformities, produced 
by ulceration through the skin, so that the whole nasal cavity is open 
to the outside and into the mouth, and all semblance of a face has disap- 
peared. 
In the nasopharynx the same series of lesions may appear, and there are 
instances of chancre of the Eustachian tube having been caused by the 
use of an infected Eustachian catheter. 
Larynx.-The lesions of the larynx might be inferred from what has 
been said of the nose. Although secondary changes occur there, the ter- 
tiary phenomena are most important. Gummatous lesions involve the 
arytenoid cartilages and epiglottis most commonly, but may affect any 
other part. The deep precipitous ulcers with abundant yellow secretion 
are capable of destroying the vocal cords and of leading to necrosis of the 
cartilages. They must be distinguished from tuberculous and cancerous 
ulcers in the same places. Healing leads to great deformity and stric- 
ture formation in the larynx, for which tracheotomy is sometimes neces- 
sary. 
We have observed at autopsy one case in which the obstruction of the 
larynx was extreme, the vocal cords being converted into great scarred 
masses which could not be much separated. One effect was the dilatation 
of the trachea and bronchi and an extensive secondary infection of the 
lung with the formation of huge abscesses. 
Trachea, Bronchi, and Lungs.-Tertiary lesions in the trachea and 
bronchi are usually in the form of syphilitic granulation tissue, although 
sometimes definite gummata may arise in the wall or extend from outside. 
The process causes much thickening of the wall with ulceration which 
lays bare and softens or destroys the cartilage rings. 
In such a case the trachea and bronchus may collapse at an angle or be 
compressed. Usually healing takes place with the formation of a scar 
which causes a stenosis of the canal. Almost any part of the trachea may 
be involved, but it seems that the region of the bifurcation is most com- 
monly affected, the stricture narrowing one main bronchus. This was the 
condition found in a case studied in Baltimore, and the effect upon the lung, 
as might have been foretold, was to produce most extensive bronchiectasis. 
The reasons for this are discussed elsewhere. 
The clinical signs in such a case are rather definite, since the harsh stridor 
of the air passing the obstruction, and the prolonged expiratory sound on 
that side, indicate clearly the existence of a stenosis. When the stenosis 
appears in a branch of the main bronchus there are localized changes in 
the breath sounds, and the bronchial dilatation and emphysematous 
alterations in the lung are limited to the area which is supplied with air 
by that bronchus. 
In the lung itself, aside from the congenital changes, the lesions due to 
syphilis are not very clearly nor surely recognized. Gummata of various TEXT-BOOK OF PATHOLOGY 
722 
sizes up to tumor-like masses occur anywhere in the lung. They are 
grayish or reddish-gray nodules, sharply outlined, and radiating fibrous 
strands into the rest of the lung. One occasionally sees these masses, which 
in the absence of obvious tuberculosis and when other signs of syphilis 
exist, it seems proper to diagnose as gummata; but doubtless many of 
those described may have been localized encapsulated tubercles. About 
the large vessels at the hilum of the lung and the large bronchi gummatous 
indurative processes occur, with great thickening of the adventitial walls 
of the vessels and some constriction of the bronchi. Great scars extend 
out into the remainder of the lung and bronchiectasis follows the obstruc- 
tion. This has been called the indurative bronchiectatic type of pulmonary 
syphilis. Whether pneumonic or ulcerative forms of syphilis with cavity 
formation really exist is uncertain. The confusion with tuberculosis, and 
especially the fact that syphilitics are very prone to tuberculosis, makes 
this point difficult to settle (Flockemann: Centrbl. f. allg. Path., 1899, 
x, 469). 
Ehrmann: Handb. d. Geschlechtskr., 1912, ii, 959-1130. Arch. f. Dermatol., 1899, 
xlviii, 256. 
Lang: Pathologic u. Therap. der Syphilis, 2t8 Aufl., Wiesb., 1896. 
Neumann: Nothnagel's spez. Path., 1899, Bd. xxiii. Exhaustive treatment of the whole 
subject of syphilis by Gerber, Pal, Benda, Nobl, Ebstein, Jesionek, Seifert, Hart- 
tung, Braun and others in Handb. d. Geschlechtskr., 1913, iii, 1-951. 
Nonne: Syphilis u. Nervensystem, 1915, 3t8 Aufl., Berlin. 
Adami: N. Y. Med. Jour., 1899, 549. 
Jobling and Petersen: Action of Iodides, Arch. Int. Med., 1915, xv, 286. 
v. Baumgarten: Verh. Deutsch. Path. Gesellsch., 1901, iii. 107 (Histology of gumma, 
with discussion). 
v. Werdt: Frankf. Ztschr. f. Pathol., 1913, xii, 177 (Liver gummata). 
Warthin: Harvey Lecture, 1918, Amer. Jour, of Syphilis, 1918, ii. 
Fordyce: Harvey Lecture, 1914-15, Series X, 221. 
Zinsser, Hopkins, and McBurney: Jour. Exp. Med., 1915, xxi, 576; 1916, xxiii, 323, 
329, 341; 1916, xxiv, 561. 
LITERATURE 
Bones and Joints.-It is said that periosteal inflammation may form a 
part of the secondary stage of syphilis, but there is as yet very little ana- 
tomical evidence with regard to this. Secondary lesions of the joints are 
also mentioned. But the later lesions of both bones and joints are far more 
frequently met with and far more serious. 
Tertiary lesions of the bones seem to affect most commonly the skull, 
the tibia, the fingers, and other bones which are very superficially situated, 
while less is known of those which occur in the more protected bones. 
Possibly this is due to the influence of trauma in determining the site of 
gummatous affections. Part of the anatomical changes due to syphilis 
are distinctly and characteristically gummatous, while there are others 
which are quite like the results of chronic inflammation of the bone produced 
by other causes, except perhaps in their history and in their association SYPHILIS 
723 
with other syphilitic lesions. Probably, however, the study of these 
chronic inflammations for spirochaetse will show more clearly their syphilitic 
character. Although the bone is soon involved, these are at first essen- 
tially affections of the periosteum, which is torn from the bone by an in- 
flammatory infiltration composed chiefly of mononuclear wandering cells. 
With rupture of the periosteum the overlying skin may be broken through, 
after which the place is exposed to further infections. Such an ulceration 
often exposes the underlying bone, parts of which become necrotic and 
separate from the rest as a sequestrum which may be discharged. Syphilitic 
ulcers of this type are long in healing (Fig. 357). By no means all such in- 
flammations end in ulceration; instead, they produce a great new growth of 
spongy bone on the surface of the old cortex, forming in this way a convex 
Fig. 356A.-Tertiary syphilis: ulcerated gumma of leg (Keidel). 
layer which, when the bone is macerated and dried, has something of the 
appearance of rough pumice stone. Sometimes it is much denser and 
may even be very hard and solid (Fig. 357A). Such osteophytes often rise 
in a sort of wall about the area of most intense inflammation where necrosis 
has actually occurred. It is this process which gives origin to many of 
the thickenings with rough, irregular surface which one finds so com- 
monly on the shafts of long bones in any collection, but it must be recog- 
nized that these are not all syphilitic-other non-specific forms of peri- 
ostitis can produce the same thing. In another form the new production 
of bone is more extensive still, and no longer limited to the activity of the 
periosteum; it is laid down in each Haversian system and through the 
cancellous bone in the interior, so that the shaft of the bone becomes dense 724 
TEXT-BOOK OF PATHOLOGY 
and ivory-hke and the whole bone is much heavier than normal. There 
is no special localization for these processes, although it is true that thick- 
enings of the long bones, the clavicles, the sternum, etc., are particularly 
common. 
Somewhat more easily recognized and characteristic of syphilis are the 
gummatous lesions which may arise 
in connection with the periosteum or 
in the interior of the bone. In the 
first case the gummatous tissue ex- 
tends along the blood-vessels into 
the bone, enlarging their canals and 
eroding the bone to a peculiar worm- 
eaten appearance. Sometimes, as 
Fig. 357.-Tertiary syphilis: syphilitic 
ulcers over shins (Keidel). 
Fig. 357A.-Syphilitic periostitis and os- 
teophyte formation. 
in the skull, the periosteum can be torn off, pulling out of their canals a 
lot of these great cellular extensions and leaving a coarsely corroded sur- 
face. Complete destruction of the bone is easily produced by their con- 
fluence, and it is common in these cases to find the skull penetrated by a 
ragged hole filled by the gummatous mass which generally extends to 
involve the dura mater and often enough the underlying brain. But SYPHILIS 
725 
there are many cases in which the dura limits the process and the necrotic 
debris is discharged externally. Osteophytes from the periosteum sur- 
round such an area and make the defect seem deeper. The same gum- 
matous nodes are often found on the shins, extending into the cortex 
and marrow cavity, and often circumscribing and causing the necrosis of 
fragments of the bone. The most extensive destruction may occur in the 
skull (Fig. 358), and especially in old specimens derived from long untreated 
cases, one sees great gaps in the cranium with ragged margin and sur- 
rounded by rough osteophytes. In all these processes the simultaneous 
existence of rarefaction and condensation or sclerosis of the bone is to be 
Fig. 358.-Old syphilitic erosion of the skull. The margins in this case are smoothed off 
by a healing process. 
observed. In this respect the syphilitic changes stand in contrast to the 
tuberculous, where rarefaction of the bone is accompanied by very little 
new formation. 
Gummata formed in the marrow cavity are of sufficiently frequent oc- 
currence, although they were practically overlooked until Chiari demon- 
strated their existence. They are gelatinous patches, often bright yellow 
from their content of fat, which may occur singly or in such numbers and 
continuity as to involve the whole marrow cavity. Generally there is no 
outward evidence of their existence, but the cortex may be attacked and 
eroded and the periosteum outside produce a new layer of bone to corre- 
spond. In this way there may be a spindle-shaped dilatation of the bone; 726 
TEXT-BOOK OF PATHOLOGY 
canals or fistulse are formed through the cortex, and, except for the absence 
of sequestra, the bone comes to look like the end-result of an ordinary 
osteomyelitis. 
Gummatous osteoperiostitis with enlargement and rarefaction and in- 
ternal destruction of the bone in the phalanges, is found in the so-called 
syphilitic dactylitis. The finger swells and sometimes there is fracture of 
the weakened bone or the gummatous material is discharged through a 
fistula. 
These, then, are the usual syphilitic affections of the bone: (a) periosteal 
gumma formation with necrosis of the underlying bone, followed by ulcera- 
tion and exposure through the skin or by extensive osteophyte growth, and 
(b) gummatous osteitis or osteomyelitis with necrosis and erosion of the 
directly affected part and rarefaction or sclerosis of the surrounding bone. 
All these things may make their appearance fairly early in the disease 
or only after long years of apparent health. 
As in the case of the bones, the joints, bursae, and tendon-sheaths often 
reveal a susceptibility to syphilis only after many years of the disease. 
There may be an accumulation of watery exudate only, or the formation 
in the synovial membrane of a syphilitic granulation tissue with ulceration, 
and great proliferation of the adjacent unaffected membrane and synovial 
villi. Probably in many cases the joint affection is secondary to the ap- 
pearance of gummatous infiltration of the epiphysis. 
This lifts up and destroys the cartilage, and healing takes place after 
much loss of time through the obliteration of the cavity by fibrous tissue. 
In the bursae and tendon-sheaths painless swellings due to the appearance 
of a lining of gummatous granulation tissue persist for a long time but 
yield, as do the joint affections, to specific treatment. 
LITERATURE 
Churchman: Am. J. Med. Sc., 1909, cxxxviii, 371. 
Levin: Med. Record, 1908, Ixxiv, 836. 
Schmidt, M. B.: Ergeb. d. allg. Path., 1900-01, vii, 221. 
Harttung: Handb. d. Geschlechtskr., 1912, iii. 
Heart and Blood-vessels.-Syphilis of the blood-vessels has already been 
described (page 350). There it was stated that in the case of such large 
vessels as the aorta, gummatous or diffuse syphilitic infiltration affects the 
adventitia and media, being localized, almost as in the case of the bone, 
along nutrient vessels and that the extreme hyperplastic changes in the 
intima arise in response to the destruction thus produced. In smaller 
vessels, such as those of the meninges, practically the same thing occurs 
except that the gummatous mass, beginning in the adventitia and extending 
through the media to the intima, is relatively very large and produces a 
distinct nodule on the vessel. 
Quite analogous changes occur in the small vessels in the interior of 
organs, although there it is by no means so easy to recognize the stages of SYPHILIS OF THE GENITAL ORGANS 
727 
the process, and the proliferation of the intima and occlusion of the vessel 
is likely to be the most conspicuous thing. 
In the heart, tertiary syphilitic lesions may assume the form of distinct 
gummata or myocardial scars. Doubtless the latter may be due in part 
to narrowing of the coronary vessels by specific changes in their walls, and 
then, of course, they are only an accompaniment of the vascular disease. 
Indeed, it seems that the proof of the direct syphilitic nature of the 
myocardial scars is not easy, but Warthin describes a long series in which 
all transitions from fresh lymphoid and plasma cell infiltrations occur, 
and in which he has demonstrated the spirochsetae in many cases. 
Mention has already been made of the aneurysmal dilatations of the 
apical region of the left ventricle of the heart, which is now fairly clearly 
shown to be of syphilitic origin, all stages being demonstrable between 
the fresh gumma of the septum and wall of the heart and the distended 
scarred sac. 
The gummata may occur anywhere in the muscle, but they have a 
peculiar tendency to appear in and about the conducting bundle of His, 
and especially at the point in the septum behind the tricuspid and below 
the aortic valves, where it is most concentrated. A number of proven 
cases of gumma formation in this situation have been described, with 
studies of the interruption of conduction which they cause. The dis- 
sociation of the rate of beat of the ventricles from that of the auricles 
(Stokes-Adams' disease, or heart block) which results in this way has been 
described elsewhere (p. 498). Syphilitic endocarditis is a vaguely under- 
stood process except in connection with the aortic valves, where, as stated 
(p. 252), the deformities produced are the cause of most of the cases of 
aortic insufficiency. 
LITERATURE 
Chiari: Verh. Deutsch, path. Gesellsch., 1904, vi, 137. 
Benda: Ibid., 164 (Syphilis and blood-vessels). 
Marchand: Ibid., 197 (Discussion). 
Robinson: Bull. Ayer Clin. Lab., 1907, iv, 1 (Gumma of heart). 
Bridgman and Schmeisser: Johns Hopkins Hospital Reports, 1916, xviii, 90. 
SYPHILIS OF THE GENITAL ORGANS 
Of the syphilitic lesions of the male or female genitalia, aside from the 
primary chancres and the condylomatous and other affections of the 
secondary stage which have already been mentioned, the gummatous and 
interstitial changes in the testicle are the most common and important. 
Gummatous and other lesions have been described in the vagina, uterus, 
tubes, and ovaries, and also in the vas deferens, seminal vesicles, etc., but 
these are such rare occurrences and so imperfectly studied that we may 
turn at once to the testicular affections. 
Most characteristic are those in which a definite gumma arises in the 
testis, taking its origin in the interstitial tissue and pushing aside the 728 
TEXT-BOOK OF PATHOLOGY 
testicular tubules. In this respect it differs from the tuberculous process, 
which begins usually in the epididymis, and which, if it does affect the testis, 
does so by causing the formation of tubercles within or in direct relation 
to the tubules. The elastic tissue elements are destroyed thereby, al- 
though in the gummatous orchitis they remain intact. The gumma has 
the characters seen elsewhere and often shows the presence of giant-cells 
in the marginal portions. Such gummata, at first grayish-red on section, 
later become opaque, yellowish, and caseous (Fig. 359). They may extend 
Fig. 359.-Gumma of testicle. The 
firm caseous nodules are surrounded by 
scar tissue. 
Fig. 360.-Syphilitic fibrous orchitis. 
to and through the tunica albuginea and sometimes reach a great size, so 
as to be mistaken for tumors, and excised. With antisyphilitic treatment 
they disappear, leaving an extensive scar. In a specimen before me, while 
the gumma is at the height of its course, the surrounding testicular tissue 
is very oedematous, the tubules being spread wide apart not only by this 
accumulation of fluid, but also by the infiltration of great numbers of 
mononuclear wandering cells. In nearly every tubule there are evidences 
of degeneration and disappearance of the spermatogenic cells, and in most 
there is already great thickening and hyaline degeneration of the connec- SYPHILIS OF THE GENITAL ORGANS 
729 
tive-tissue wall. Undoubtedly these tubules would have lost their func- 
tional activity and merged later into a scar. 
The other form, the so-called orchitis fibrosa (Fig. 360), has long been 
regarded as definitely syphilitic, and clear evidence of syphilis when found at 
autopsy. Except in such stages as described above, in connection with 
active gummata it seems to be known in the form of extensive scars through 
the testicle, which shine on section as pearly white streaks against the dull 
brown of the remaining testicular substance. In these scars are found the 
hyaline, thickened remnants of testicular tubules and some infiltration of 
wandering cells. But, as Chiari, Hansemann, and others pointed out in 
discussing Baumgarten's paper, there is no real proof that all such scars 
are syphilitic. They may, as well, result from the orchitis which follows 
trauma, gonorrhoea, mumps, and many other things. The literature is 
contradictory on the validity of the evidence of the syphilitic nature of 
these scars, but perhaps with the newer surer methods of diagnosis the 
matter will soon be made clear. 
Warthin's recent studies show that in many cases the lesion is to be 
found in the form of loose intertubular scars which show in places accumu- 
lations of plasma cells and lymphocytes, and among these spirochaetes 
are sometimes found. 
LITERATURE 
Baumgarten, Chiari, Orth, Hansemann, and others: Verh. Deutsch, path. Gesellsch., 
1900, iii, 107 (Syphilis of Testicle). CHAPTER XXXVI 
TYPES OF INJURY.-SPIROCHETAL INFECTION (Continued) 
Syphilis: Syphilitic lesions of nervous system. Syphilitic meningitis. Tabes dorsalis. 
General symptoms. Lesions of the nervous system, theories concerning it. Dementia 
paralytica, its relation to tabes; symptoms. Anatomical changes in brain and cord. Con- 
genital syphilis. General relations. Lesions in respiratory organs, liver, pancreas, bones, 
etc. Late forms of congenital syphilis. 
Nervous System.-Syphilitic disease in the nervous system is essentially 
of the tertiary stage, unless we accept the fourth or quaternary stage for 
those so-called parasyphilitic conditions which we now know to be so truly 
syphilitic-dementia paralytica and tabes. From an anatomical point 
of view there are three main types, of which one includes the cases of gum- 
Fig. 361.-Gumma of brain distorting cerebral convolutions and adherent to the 
meninges. 
matous encephalitis or meningo-encephalitis, myelitis, or neuritis; the 
second, the various forms of syphilitic meningitis, and the third the diffuse 
processes described above as quaternary. But between the first two there 
are various gradations, and, further, it is difficult to distinguish sharply 
between them and others which begin in the cranial periosteum and extend 
into the brain. 
The most common are those cases in which a gummatous mass is found 
in the cortex of the brain connected through the pia arachnoid with the 
dura and even penetrating through the skull (Fig. 361). Such a gumma 
may be as large as a filbert, or an irregular conglomeration of caseous masses 
may be much larger. 
A great deal of translucent gray or grayish-red material forms the outer 
730 731 
SYPHILIS OF THE NERVOUS SYSTEM 
portions and radiates into the surrounding tissue, especially along the blood- 
vessels. Parts of it may be reddish-gray, but the central part is usually 
yellow and very opaque and firm. The difficulties in being sure as to 
whether such a lesion is tuberculous or gummatous have been mentioned. 
From the point where the gumma extends to involve the dura, that mem- 
brane may be greatly thickened on all sides by a syphilitic granulation 
tissue, rich in cells and showing in places a tendency to caseation. 
The brain is not merely pushed away-it is invaded and infiltrated in 
this process, and along the vessels there is a great accumulation of mono- 
nuclear wandering cells. It has been thought generally that such a gumma 
Fig. 362.-Part of a gumma of the lenticular nucleus, showing central caseation. 
may not spring from the brain substance itself, but only from the walls of 
the blood-vessels or the meninges. This, however, offers no limitation, and 
one discovers gummata growing deep in the corpus callosum, or in the basal 
ganglia, or the pons. The medulla and substance of the spinal cord may be 
their seat, but it must be said that these deep-seated gummata are less com- 
mon than those which are superficial and connect with the meninges. 
A gumma localized in the lenticular nucleus and appearing as a fairly sharply outlined 
mass to the naked eye affords a good example of the histological characters of these 
lesions. Under the microscope it appears not nearly so sharply outlined nor so uniform 
in its makeup; caseous patches are scattered here and there in a kind of network in a 
diffuse mass of very cellular tissue (Fig. 362). On approaching from the normal brain 
substance the blood-vessels in the outskirts are found surrounded by lymph-spaces which 
are packed with loose cells. Not all of these are plasma cells. Many of them seem much 732 
TEXT-BOOK OF PATHOLOGY 
larger with protoplasm which stains red; many others are lymphocytes. The intima of 
these vessels is often so thickened by new-formed cells as nearly to obstruct the lumen. 
Advancing, one reaches a tissue in which little brain substance is to be recognized; it 
is rich in new capillary blood-vessels and overrun by hordes of mononuclear cells of the 
same varieties of form as are seen in the walls of the blood-vessels. Plasma cells of 
typical form are there; but most of the cells are lymphocytes or else much larger cells, 
with granular or vacuolated cell-body and large vesicular nucleus. In places there is 
a condensation of the ground tissue in which the most prominent cells are like the 
epithelioid cells of the tubercle, with long, pale, vesicular nuclei. Often, among these 
are found beautiful giant-cells with many nuclei. These border on the areas of necrosis, 
and round them the epithelioid cells along the edge of the caseous material have become 
distorted and twisted into a radiate position pointing toward the caseation. 
These caseous areas show throughout the shadowy remains of the continuation of the 
vascular infiltrated tissue which has simply been rendered necrotic. It will be seen 
that in no particular is this process absolutely distinguishable from tuberculosis, but at 
least it is more diffuse and one has less the impression of the formation of firm nodules 
which push aside tissue before they become caseous. This is rather an infiltrating granu- 
lation tissue, parts of which undergo caseation. 
Very small or miliary gummata may be scattered all through the brain. 
Diffuse syphilitic infiltration or granulation tissue formation seems, how- 
ever, to be very rare, although Bechterew described multiple sclerosing 
foci in the spinal cord in one case. 
On the other hand, gummata encroach upon the cranial and spinal nerves 
at their roots, in some cases, and, extending from epi- to endoneurium, in- 
volve the nerve-fibres in their necrosis. Paralysis and degeneration of the 
nerve follow. In the peripheral nerves, gummata occur in the same way. 
One case observed at autopsy in which the nerves of the upper arm were 
matted together in a caseous gumma, with degeneration of the distal por- 
tions, was described by Remsen. 
The meningeal form, which is so apt to extend to involve the brain, affects 
the dura or the pia. Aside from the gumma formation just described the 
dura may present rather diffuse layers of granulation tissue densely in- 
filtrated with lymphocytes and sometimes haemorrhagic. More char- 
acteristic are the affections of the pia and arachnoid, in which one finds 
small gray nodules along the course of the pial blood-vessels (Fig. 363). 
These sometimes have opaque whitish centres and prove to be minute gum- 
mata which begin in the adventitia and quickly invade the media, inciting 
a similar proliferation in the intima, which is often enough to narrow very 
greatly or completely close the lumen. In cross-sections the tiny lumen is 
found at one side, and in the excentric mass the internal lamella, wrinkled 
on the thin side of the vessel wall, is stretched out thin and straight through 
the most affected part. 
Sometimes the lumen is divided into two or more channels and a new 
elastic lamella may form, more closely placed about one or more of these. 
Strassmann has demonstrated the spiroch®t® in these adventitial gummata. 
Outside the vessels the pia is thickened and rendered opaque and yellow- 
ish by a dense infiltration of wandering cells, mostly mononuclear. This 
exudate is generally most abundant over the base of the brain, and espe- LOCOMOTOR ATAXIA, OR TABES DORSALIS 
733 
cially in such regions as that of the optic chiasma. The cranial nerves 
passing through it were, in the case we studied (Goldsborough), roughened 
and swollen from the presence of small gummata which in their caseation 
involved the nerve-fibers. 
Keidel, Moore, and Chesney have studied the occurrence of spirochsetes 
with the cerebrospinal fluid and the cellular and chemical changes of this 
fluid, and find that even without symptoms the invasion of the Spiro- 
chaetae occurs frequently at a relatively early stage in the disease. 
It is manifest that all this must produce the most varied symptoms, 
partly the result of the general meningeal inflammation, partly due to 
direct irritation or paralysis of the affected nerves. Disturbances of the 
functions of the eye muscles, of speech, etc., are especially common. 
Verse found the same process affecting the meningeal veins rather than 
the arteries, and demonstrated the Spirochaetae in great numbers in their 
Fig. 363.-Gumma of pial blood-vessel. Syphilitic meningitis. 
walls and in the adjacent tissue, or even in some cases in thrombi which 
occluded the veins. 
LITERATURE 
Nonne: Syphilis and Nervensystem, 3te Aufl., Berlin, 1915. 
Strassmann: Ziegler's Beitrage, 1910, xlix, 430. 
Verse: Ibid., 1913, Ivi, 580. 
Remsen: Johns Hopkins Hosp. Bull., 1903, xiv, 280. 
LOCOMOTOR ATAXIA, OR TABES DORSALIS 
We may consider this disease here, together with the general paralysis of 
the insane, even though it has not been absolutely proven to be of syphilitic 
origin. Statistical study has given figures which point in an unmistakable 
manner to syphilis as its cause. Erb found syphilis in 89.5 per cent, of 
the cases and others have found a similar percentage. Recently Noguchi 734 
TEXT-BOOK OF PATHOLOGY 
found the Spirochaeta in the cord in one case out of twelve, and it seems only 
a question of further study to prove the constancy of the relationship. 
The disease is in large part an affection of the lower sensory neurons, 
although we shall find that these are unequally altered in different parts, and 
that while many of the phenomena are to be explained as the result of this 
lesion, there are others which are not. 
The clinical aspect of the disease is extremely variegated, though most 
of the symptoms are the result of disturbances of the sensory apparatus, 
partly irritative, partly paralytic. Reflexes and movements depending on 
muscle sense, and, consequently, coordination, are much disturbed. 
Violent stabbing pains in the limbs or elsewhere (lightning pains) occur 
especially at night; sudden attacks of cramp-like pain in some internal 
organ-stomach, larynx, bladder, etc., are known as gastric or laryngeal 
or vesical crises. A period of sexual excitement is followed by impotence. 
The tendon reflexes are abolished; the pupils become inactive and fixed. 
Sensation is dulled or perverted; the patient no longer feels the floor he 
walks on, or feels it like so much wool. He loses his sense of the position 
of his extremities and must watch his feet in order to set them in the right 
place; inattention may result in a fall. The gait becomes peculiar and 
slapping. This ataxia, which has given rise to one of the names, may 
affect any or all of the muscles. 
So-called trophic changes arise in various places. Half of the tongue 
atrophies; an ulcer appears in the foot and proceeds to grow deeper, pain- 
lessly, until it perforates the foot. The bones become fragile and break, 
and fail to heal again. Joints loosen and become disorganized; the car- 
tilage softens and the bone is eroded, or great dislocation may occur. Dis- 
turbed nutrition of the tissues in general seems to arise and the patient dies 
of an intercurrent infection, although seizures, simulating apoplexy and 
epileptiform convulsions, may have been survived. The details of these 
symptoms must be read elsewhere, most clearly perhaps in Marie's 
"Legons sur les maladies de la Moelle." 
Lesions.-At the autopsy the lesions depend upon the stage of the disease. 
If the patient dies at an early period, it may be necessary to search with 
the microscope for any change, but if it has lasted a long time the spinal 
cord with its posterior nerve-roots shows a characteristic appearance. The 
meninges (pia arachnoid) may be thickened and cloudy in part or quite 
normal looking, but the posterior columns are sunken and the dorsal roots 
look gray and smaller than normal. On section, the dorsal columns are gray 
and translucent in contrast to the remaining pinkish, opaque, white matter. 
It is rarely possible to distinguish with the naked eye the exact distribution 
of this gray material in the dorsal columns, but with certain stains the 
microscope shows it well. The grayness and translucence are due to the dis- 
appearance of the lipoid myeline sheaths, as well as the axis-cylinders of the 
nerve-fibres and their replacement by an overgrowth of neuroglia.* If the 
* Observations of which Dr. Tilney has told me seem to show that much of the 
material employed to replace the lost nerve-fibres may be of connective-tissue origin. LOCOMOTOR ATAXIA, OR TABES DORSALIS 
735 
process were fresh enough, the myeline might not have disappeared entirely, 
but its remnants could be made visible as black globules by the use of osmic 
acid, which does not blacken the normal myeline sheath. After a week or 
Fig. 364A.-Tabes dorsalis. Dorsal region of cord. Moderate sclerosis of posterior 
columns (Fordyce). 
Fig 364B.-Tabes dorsalis. Dorsal region of cord with extreme sclerosis of the posterior 
columns (Fordyce). 
two, however, these fat-globules disappear and then the injured area can 
best be made apparent by the Weigert stain, which colors blue-black all 
the normal myeline sheaths and leaves the wasted and scarred area un- TEXT-BOOK OF PATHOLOGY 
736 
stained. It is usually this unstained area which one can demonstrate in 
tabes (Fig. 364). 
It will be recalled that the posterior roots are largely made up of central processes of 
the dorsal root ganglion-cells, which were at one era of development bipolar and still 
are in certain cranial ganglia, but which now have one T-shaped process, one branch of 
the T coming from the periphery, while the other enters the cord. On entering the 
cord in the posterior root the fibres swerve a little to the median side of the end of the 
posterior horn of the gray matter, which does not quite reach the surface. They pass 
through the zone of Lissauer, which is made up of fine fibres which also come in as part 
of the nerve, and turning upward a short way, sweep along with the other fibres into the 
posterior column and into the posterior horn. The fibres entering by the posterior root 
bifurcate, sending a short branch downward, a longer branch upward. Three main 
Fig. 364C.-Tabes dorsalis. Degenerative changes in the posterior nerve-root (Fordyce) 
groups are generally distinguished in the distribution of these upward branches: a short 
group which quickly turns into the gray matter of the posterior horn, a median group 
which runs up in the column of Burdach-sometimes all the way, but often leaving it to 
turn into the gray matter and end about a cell there-and a long group which passes 
into the column of Goll and runs up to 'the nucleus of that column in the medulla or 
even further. It is the column of Goll which brings fibres even from the lower lumbar 
region. 
The fibres of the dorsal root, which enter the gray matter, end in arborizations about 
ganglion-cells of that side, a great many of them constituting the fibre reticulum of the 
column of Clarke; or they pass forward to terminate about a ganglion-cell of the anterior 
horn, or cross by the posterior commissure to end similarly in the gray matter of the 737 
LOCOMOTOR ATAXIA, OR TABES DORSALIS 
opposite side. Each fibre gives off many fine branches or collaterals which terminate in 
quite similar ways about the ganglion-cells of the gray matter, and thus forms abundant 
incidental connections at every stage in its progress upward in the cord, which are 
doubtless of fundamental importance in the establishment of reflex arcs. 
Flechsig, Trepinski, and others have shown that, according to this distribution of the 
fibres, and according to the varying time at which they are matured by receiving their 
medullary sheaths, one may distinguish various subdivisions or tracts in the column of 
Burdach--a posterior, a middle, and an anterior root zone as well as a median zone which 
lies within the column of Goll against the median line. 
In the middle root zone two types of fibres can be distinguished by their different 
time of myelinization, etc. Naturally these fields seen in any cross-section are only the 
expression of the currents of fibres at that particular level and so must change as one 
ascends the cord, except inasmuch as the incoming fibres deport themselves in the same 
way at successive levels. But if a group of fibres entering the cord becomes recognizable 
by any degenerative change it need not be expected that those fibres will occupy the 
same position in the field higher up; on the contrary, they assume a new position or dis- 
appear because they have turned into the gray matter to end. 
Consequently, it could only be through an exact repetition of the same degenerative 
change in each successive root that anything like the same distribution of degenerated 
fibres would be found at different levels, and even then in the higher levels the scarred 
remains of those entering far down and continued upward to that point would be added 
to those newly entering from a higher root. 
The statement is generally made that in tabes dorsalis the beginning 
of the sclerosis or scarring is first seen in the "bandelettes externes," or 
parts of Burdach's column lying against the posterior horn; that the 
middle root zone is early involved and also the zone of Lissauer and the 
column of Goll, but that the anterior or ventral root zone is found in- 
tact until very late in the disease. While this is true, it must be true 
in any given case in different degree in different parts of the cord. The 
complete escape of a whole entering root, or of a series of them, from 
the effects of the disease at a point higher in the cord, allows intact 
fibres to appear in these situations, so that at those levels the areas 
of sclerosis are reduced to the upward prolongations which still con- 
tinue from those below. And it is true that such escape of the roots 
may occur, just as it is true that the lesion need not be symmetrical 
on the two sides. But all this merely emphasizes the fact that the 
degenerative lesion in tabes is not like that produced by the cutting 
of a single dorsal root between its ganglion and the cord. The result of 
that would fade away into the gray matter, except in so far as a few de- 
generated fibres might be recognized continuing up the column of Bur- 
dach or in the column of Goll all the way to the medulla. Instead, in 
tabes there is a nearly constant and nearly symmetrical addition of the re- 
sults of degeneration with the advent of each succeeding dorsal root. And, 
nevertheless, the irregularities show that the process is not to be regarded 
as the complete degeneration of a column or system, but as a succession of 
segmental degenerations accumulating their results in the cord as one passes 
upward. It would be most instructive to have a reconstruction of this 
lesion from an early case of tabes, before the whole posterior tracts had be- 738 
TEXT-BOOK OF PATHOLOGY 
come fused in the sclerotic band, to show the topography of these repeated 
additions of sclerotic tissue in the cord and their relation to the changes in 
the roots. 
It is with regard to the nature of the changes in the roots that the most persistent 
dispute has raged. It is agreed that while the roots are pathologically altered, the 
change in the portion between the dorsal root ganglion and the cord is more extreme than 
that in the peripheral nerves or in the ganglion-cells themselves, and consequently nearer 
to that seen in the cord itself. The following views have been expressed, most of which 
will doubtless disappear in the light of the simple explanation which must finally come 
some day. 
The whole lesion is due to vascular obstruction; it is the effect of injury or destruction 
of peripheral ganglionic elements, which may also be responsible for ascending degenera- 
tions after amputations (Marie); ft is a systemic degeneration of tracts in the cord itself 
Fig. 365.-Charcot joint. Syphilitic arthropathy involving knee, with erosion 
and new formation of a lower articular surface. Extensive destructive changes in sur- 
rounding tissues with fistula;. 
corresponding with their developmental characters (Flechsig, Trepinski); it is the effect 
of destruction of the cells of the spinal root ganglia; it is the effect of meningeal inflam- 
mation about the entering roots which causes their compression and destruction (Na- 
geotte); it is the effect of direct or indirect action of the syphilitic poison on the nerve 
roots, affecting less the ganglia, but producing the degenerative changes described (Red- 
lich, Obersteiner). This is partly based on analogy with similar affections found in 
ergot poisoning and pellagra. 
Of all these, the last seems most likely to prevail, in view of the intimate relation of the 
disease to syphilis and the finding of the Spirochaetae in at least one case in the spinal 
cord. But, as can be seen, the pathogenesis of the disease is far from clear and must be 
much more precisely worked out before we can accept any view as final. 
In the end one finds practically all of the posterior columns in the lumbar 
and dorsal regions reduced to a scar-like mass of neuroglia, the only ex- DEMENTIA PARALYTICA 
739 
ceptions, up to an advanced stage, being the ventral root zone and the 
medial zone. Lissauer's zone, the column of Clarke in the gray matter and 
the column of Goll, with most if not all of the column of Burdach, are thus 
degenerated. In the cervical region the lesion is less extensive and reduces 
itself toward the column of Goll. Since these tracts are so intimately con- 
cerned with muscle sense and with the reflex arcs it is not surprising that 
ataxia, the loss of the sense of position, failure in the discrimination of 
weights, etc., should be prominent features of the disease. 
Tactile sensation, temperature sense, etc., which are so largely concerned 
in the short relayed tracts in the cord and in the other ascending tracts 
not involved in this process, are less affected. The cells of Clarke's column 
connecting with the cerebello-spinal tract must, however, lose some of 
their relations, since the fibres entering with the dorsal roots which arborize 
round them are destroyed. 
It is difficult to explain the various "trophic" disturbances which are 
found in the tissues, such as the bone and joint changes mentioned above 
and the alterations in nails, skin, etc., which are so frequent. It seems quite 
possible, however, with regard to the "Charcot's joints," or tabetic arthro- 
pathy (Fig. 365). that this is directly a syphilitic lesion, as held by Strum- 
pell, Stargardt, and others, rather than a trophic disturbance dependent 
upon the nervous affection. For a discussion of this disease the student is 
referred to the following: 
LITERATURE 
Zoepffel: Berl. klin. Woch., 1911, xlviii, 2032. 
Stargardt: Arch. f. Psychiatrie, 1912, xlix, 936. 
Redlich: Pathol, d. tabischen Hinterstrangserkrankungen, Jena, 1897 
Schseffer, K.: Handb. d. Neurologic, Lewandowski, 1911, vol. ii. 
Marie, P.: Mal. de la Moelle, Paris, 1892. 
Schmaus and Saeki: Ergeb. d. allg. Path., 1900, v, 268; 1904, ix, 217. 
DEMENTIA PARALYTICA (GENERAL PARESIS, PROGRESSIVE PARALYSIS 
OF THE INSANE) 
Another affection long known to be in some way associated with syphilis 
and, like tabes, spoken of as parasyphilitic, is now shown by the aid of the 
Wassermann reaction and by the demonstration of the Spirochaetae in the 
brain to be definitely a syphilitic disease. It has been suggested by Mobius 
and others that this is a disease practically identical with tabes dorsalis 
except in that it is localized in the brain; and it seems that in a sense this 
is true, although the difference in localization makes a great difference in 
the disease as far as the manifestations are concerned; indeed, the lesions 
of the spinal cord in this condition are rather different from those found in 
tabes, and the symptoms resulting from them are also different. 
Clinically, dementia paralytica is a most dramatic illness whose mental 
symptoms vary somewhat with the character of the individual. It is remark- 
able, however, to observe how, under this infection, all minds are planed 740 
TEXT-BOOK OF PATHOLOGY 
down to the same low level. It usually begins insidiously, with drowsi- 
ness, lapses of attention, peculiarities of conduct, and accentuation of pre- 
dominant personal characteristics, and proceeds to graver departures from 
civilized custom which are often shown in their true light in the police 
court. 
Confusion of ideas and failure of memory, together with loss of self- 
restraint, are soon accompanied by delusions of grandeur in which the pa- 
tient becomes most extravagant in his belief in his own powers and pos- 
sessions. 
Even at the beginning of this stage his condition may not have been 
recognized, and he is at the risk of committing mistakes in business or 
otherwise which may cost him dear. 
In later stages memory is lost to an astounding degree; the patient lives 
only in the moment, totally forgetful of what happened an hour ago; writ- 
ing becomes characteristically disturbed and finally impossible; speech is 
slow, blurred, and full of mistakes, the delusions take the place of everything 
else and are occasionally interrupted by violent maniacal outbreaks or by 
apoplectiform or epileptoid convulsions, from which the patient usually 
recovers without any after-effects. With all this, and to the end of life 
in the most miserable bodily and mental disruption, he is in a state of glow- 
ing content. This euphoria, or sense of well-being, is enough to compensate 
for most of the horror of the disease, but in other cases there is deep de- 
pression or complete mental dulling. 
Aside from the mental derangement there are bodily evidences of the ail- 
ment-the pupils are irregular in form or size and usually rigid, as in loco- 
motor ataxia. Paresis of many muscles may appear, and after the disease 
is well advanced contractures in these muscles hold the extremities in a 
helpless rigidity, so that the patient is permanently bedridden. Bed-sores 
of great extent are likely to appear in such cases. Loss of tactile and pain 
sense is common and readily results through inattention, in injuries such as 
burns and lacerations. The so-called trophic disturbances are found here 
as in tabes-perforating ulcers of the foot, great haemorrhages in the outer 
ear following a slight injury, disorganization of the joints, great porosity 
and fragility of the bones, with fractures after trifling blows. Extreme 
emaciation alternates with periods of obesity, but in the end the weight 
usually goes down until, at death, the patient seems almost a skeleton. 
Death occurs after one to three years, though sometimes there are re- 
missions during which mental and bodily health seems pretty good and 
death comes only six or eight years after the onset. It may be the result 
of great emaciation and gradual exhaustion, but most commonly it is 
brought about by an intercurrent infection, especially bronchopneumonia, 
to which these demented people, with their dulled sensation and disturbed 
reflexes, are particularly exposed from the aspiration of saliva or food into 
the bronchi. In any case they are more than usually susceptible to infec- 
tion in their state of disturbed nutrition. 741 
DEMENTIA PARALYTICA 
At autopsy the most striking changes are in the brain and meninges. 
The dura is often lined over one or both halves of the brain with a thick, 
blood-stained layer of new tissue, which it is often possible to separate into 
several sheets, the deeper of which are stained a dull rusty brown by the 
Fig. 366.-Chronic haemorrhagic internal pachymeningitis. 
Fig. 367.-General paresis. Surface cf the brain showing atrophy of the convolutions 
(from Weygandt). 
pigment formed from the extravasated blood (Fig. 366). This haemor- 
rhagic pachymeningitis is not peculiar to general paresis, but is found in 
many other conditions. 
The pia arachnoid is usually opaque and grayish white or very cedematous. 742 
TEXT-BOOK OF PATHOLOGY 
Not infrequently it stretches across quite wide sulci, which are then partly 
filled with fluid, and sometimes the surface of the brain presents a great 
depression full of yellowish fluid, through and over which the arachnoid 
stretches. All these things are the result of the atrophy and shrinkage of 
the cerebral substance, the decrease in the bulk of the convolutions throw- 
ing wide the sulci (Fig. 367). The whole brain is a good deal decreased 
in size-on an average by 150 grams, but the two sides may be asymmetrical. 
The cerebral ventricles are often widened and contain an excess of fluid. 
Their lining is roughened by the appearance of minute gray, sand-like 
nodules which are outgrowths of neuroglia which push the ependyma before 
them. This "ependymitis granularis" also occurs in other conditions. 
Microscopically, alterations are found especially in the more anterior 
portions of the cerebral cortex. The meninges are found to be thickened 
and infiltrated with mononuclear wandering cells, among which plasma 
cells are prominent. They are often intimately adherent to the brain 
substance. The vascular prolongations are accompanied by mantles of 
the same plasma cells and other smaller mononuclears, and even about 
the smallest vessels, which seem dilated and increased in number, the spaces 
are filled with these cells. 
The nerve-cells of the cortex are in all stages of degeneration, shrinkage, 
and disintegration, and great numbers of them have disappeared. Those 
which remain have lost their protoplasmic processes in many cases and 
often their axone fibre. They are also greatly disarranged, so that the 
normal layers and vertical rows are no longer to be made out, but the cells 
lie confused and sparsely scattered in the cortex. Naturally the fibres, 
and especially the tangential association fibres and collaterals, are greatly 
reduced in number. The radial fibres seem more resistant, but even they 
are markedly diminished. In consequence of these losses the cerebral 
convolutions shrink and fall apart. But in the place of the lost cells and 
fibres a great new growth of neuroglia springs up. Abundant neuroglia 
cells, including the so-called spider cells, appear, together with a relatively 
dense network of neuroglia fibres. This is especially concentrated on the 
exposed surface and in those places where the brain substance is invaginated 
by the nutrient vessels. Every vessel is thus surrounded by a network of 
fibres. Sometimes there are even projecting brush-like masses on the outer 
surface, which aid in causing the adhesion of the meninges. The superficial 
layer, normally rather indistinct, here becomes a dense felt-work of neu- 
roglia fibres extending a little way into the cortex and devoid of nerve-cells. 
The Spirochaetae found by Noguchi and Moore in paretic brains were 
scattered in the cerebral substance, not particularly in association with the 
vessels and not in this external neuroglial layer. The cerebrospinal fluid is 
rich in lymphocytes and contains also plasma cells. It is rich in globulins 
and gives the Wassermann reaction in extreme dilution. 
In the remainder of the brain the lesions are very similar, with wide- 
spread loss of nerve-cells and fibres. This is well seen in the basal ganglia, 743 
CONGENITAL SYPHILIS 
the pons and medulla, as well as in the cerebellum, whose peculiar cortical 
cells may be greatly reduced. 
In the spinal cord, tract degenerations are found in limited areas of the 
posterior column, generally together with descending degenerations of the 
pyramidal tracts. Doubtless, while the posterior tract degeneration de- 
pends upon the same setiological factor as the changes in the brain, the 
descending degenerations may be due to lesions in the motor cortex. 
These are the changes in the so-called tabo-paresis, which, as has been said, 
does not correspond precisely with tabes in symptoms or anatomical basis. 
LITERATURE 
Kraepelin: Lehrb. d. Psychiatrie, Leipzig, 1909, General Paresis (Translation Nerv. 
and Mental Dis., Monogr., 1913, series No. 14). 
Alzheimer: Histol. Stud. z. Differential Diag. d. Prog. Paralyse, Habilitationschrift, 
1904. 
Weygandt: Psychiatrie, Munchen, 1902. 
Noguchi and Moore: Jour. Exp. Med., 1913, xvii, 232 
The term congenital syphilis is to be preferred to hereditary syphilis inas- 
much as it appears that the disease is not transmitted as a hereditary char- 
acteristic (dependent upon the chromosomes of the uniting germ cells), 
but rather as an infection transmitted to the foetus in the course of its de- 
velopment, either by spirochaetse which accompany the sperm cell and 
probably infect the mother, or by Spirochaetae from the tissues of the mother, 
herself previously infected. In all these cases, except perhaps in late 
postconceptional syphilis, in which both placenta and child may possibly 
escape, the placenta is the seat of syphilitic alterations which are of rather 
vague character, since actual gummata are only unconvincingly described 
and are at least rare. There are found diffuse infiltrations of the placenta 
with wandering cells, vascular changes both in the placenta and in the 
umbilical cord, distinguished, as elsewhere, by thickening of adventitia 
and intima, and, thirdly, curious modifications of the villi, consisting of 
new formation of loose connective tissue about the central blood-vessels, 
such as to cause a great bulbous swelling of each villus and hence a marked 
enlargement of the placpnta. On this account, a striking disproportion 
between the size of the placenta and that of the child is always suggestive 
of syphilis. 
None of these changes is, however, of absolutely diagnostic importance. 
Evidently the Spirochaetae can enter the foetal blood readily enough from 
such diseased placentae, and finding in the foetal tissues a specially suitable 
medium for growth, proceed to multiply to an extent never approached in 
the tissues of the adult in acquired syphilis. They are to be demonstrated 
in perfectly astounding numbers by the Levaditi method of silver staining 
in most of the tissues of the syphilitic new-born, where they lie scattered 
everywhere among the cells, generally without producing any very evident 
change about them. The lesions which they produce are essentially like 
CONGENITAL SYPHILIS 744 
TEXT-BOOK OF PATHOLOGY 
those of the tertiary stage, although some are evidently of the secondary 
type. Primary lesions do not occur. These tertiary lesions consist most 
commonly of diffuse inflammation, with the formation of a great deal of 
scar-like connective tissue throughout the organ; rarely there are actual 
gummata, and often the effect seems to be shown in the retardation and 
impairment of the normal growth and development of the organ. 
The effects of syphilitic infection in the parents upon the children seem 
to become somewhat weakened with the advance of time and with succes- 
sive pregnancies. The first pregnancies after infection end as a rule in 
early miscarriages; often the foetus is found in an extreme state of macera- 
tion, as though it had been dead a long time. In the later pregnancies the 
child may be born alive with lesions of syphilis, and die soon. Still later 
it may survive and even show no sign of disease at first, but pretty surely 
in childhood or adolescence or even in later life the stigmata or character- 
istic and destructive marks of the disease appear somewhere, either in the 
form of a finished process, or as a progressive disease which may lead to the 
deformity or death of the patient. It is evident that this so-called "syphi- 
lis tardive" forms an interminable subject with quite as many variegated 
possibilities as in the acquired form. 
Indeed, practically all of the effects of acquired syphilis appear in the 
congenital retarded form, even including tabes and general paresis, and 
none of them shall be discussed again here. The following concerns those 
which are peculiar to the congenital form. 
The new-born syphilitic child or dead foetus commonly shows some 
affections of the skin, such as the plantar and palmar pemphigus, in which 
the skin of the palms and soles is lifted up in bullae or blisters filled with 
fluid; another type shows extensive scaling off of the epidermis, sometimes 
over great areas (specific ichthyosis). 
There may be ulcerative lesions over the buttocks and thighs which later 
heal to form inconspicuous scars. Papules and areas of infiltration on the 
lips, especially at the angles of the mouth, burst later and ulcerate, healing 
afterward to form radiating scars-the so-called rhagades. The same thing 
happens in the peri-anal region. 
Coryza or "snuffles" is a practically constant accompaniment and is 
extremely serious to the nursing child, since it cannot breathe through its 
nose while it suckles. On this account it may practically starve to death. 
In still-born infants, or in those which die shortly after birth, the lungs show 
in many cases a peculiar change, generally spoken of loosely as white 
pneumonia or pneumonia alba. There has been much dispute about the 
nature of this, and while some have tried to separate a desquamative from 
an interstitial form, others have found these two processes combined. 
The lungs are enlarged and heavy, the consolidation, usually patchy, 
is smooth, pale, and elastic. Microscopically (Fig. 368), in all the cases I 
have seen, there has been a combination of great thickening of the alveolar 
septa with some desquamation of the epithelium and in places an infiltra- CONGENITAL SYPHILIS 
745 
tion with leucocytes and mononuclear wandering cells. The epithelial 
lining cells are cubical in form from the lack of distension, and while many 
are desquamated into the air-cells, there seems to be no very great multi- 
plication on their part. On the other hand, the connective tissue of the 
lung is enormously increased in bulk about vessels and bronchi and in the 
alveolar walls themselves. These are so thick that the alveoli look like 
Fig. 368.-Congenital syphilis of the lung: pneumonia alba. There is great interstitial 
growth of connective tissue with infiltration of wandering cells and thickening of the 
alveolar epithelium. 
glandular spaces in a solid tissue; the capillaries are wide and seem very 
abundant as they run from side to side of the septa. The connective tissue 
forms a loose network, evidently rather cedematous, in which the connective- 
tissue cells are scattered, sparsely mingled with a good number of mono- 
nuclear wandering cells. In rather rare cases distinct gummata have been 
seen in the lungs. 
In the liver there occurs a variety of lesions. The organ is generally 
enlarged and firm, sometimes it has a normal dark-red appearance on sec- 746 
TEXT-BOOK OF PATHOLOGY 
tion, sometimes it is pale grayish-brown and rather translucent, with 
numerous scattered foci of opaque yellow. Perhaps the commonest 
change is a general retardation of its development, so that at birth it still 
appears as an organ actively engaged in blood formation. Bullard thinks 
of this as a compensatory myeloid activity on account of the general 
fibrosis of the bone-marrow. The capillaries are wide and in places dis- 
tended with groups of blood-cells of all sorts, myelocytes, lymphocytes, 
Fig. 369.-Congenital syphilis of the liver. The liver-cell strands are separated by 
fibrous tissue, and there are accumulations of wandering cells in places. Such foci may 
later become caseous. 
eosinophiles, and particularly nucleated red corpuscles. In other 
places the liver-cell columns are widened into bulbous masses of pro- 
toplasm in which are grouped numerous large nuclei, evidently indi- 
cating a continued new formation of liver-cells. There is nothing clearly 
specific about such an anatomical picture-the same thing may be found in a 
normal foetus of a rather earlier stage of development, but the abundant dis- 
tribution of spirochsetee through the tissue determines its syphilitic nature. 747 
CONGENITAL SYPHILIS 
More distinctive are the cases in which the whole lobular arrangement 
of the liver-cells is rendered indefinite by the diffuse new growth of fibrous 
tissue everywhere through the organ. The liver-cell strands are reduced 
to small distorted bands of protoplasm containing many nuclei, sometimes 
clustered almost as in a giant-cell, and separated everywhere by a loose 
fibrous tissue in which run the isolated capillaries. In the case illustrated 
(Fig. 369) there are numerous foci of necrosis, in which there are crowded 
abundant leucocytes and fragmented nuclei. These evidently form one 
type at least of what are called miliary gummata, although there is nothing 
very specific in their appearance. They, like the rest of the liver, contain 
Fig. 370.-Congenital syphilis. Pancreas of child with excessive interstitial con- 
nective tissue separating acini. The island of Langerhans is still in connection with a 
duct. 
quantities of spirochsetse. Occasionally one finds more definite concen- 
trically arranged miliary gummata, like small tubercles in the liver, and 
these have been well described by Hecker. More rarely there are larger 
caseous gummatous nodules surrounded by scar tissue and ending in a 
lobulated cirrhotic deformity of the liver. 
The pancreas, so rarely involved in acquired syphilis, is commonly 
affected by the congenital form. Again there are rarely gummata of 
definite form, but very commonly diffuse granulation tissue growth and re- 
tardation of development (Fig. 370). One finds the pancreas slightly 
enlarged and gray and firm. On section the acini are spread apart and 
apparently incompletely differentiated, the islands of Langerhans often 
appearing, as in the foetus, in persistent connection with the branches of TEXT-BOOK OF PATHOLOGY 
748 
the pancreatic duct. Focal necrosis of a more or less suggestive gummatous 
character is often found in the interstitial tissue. 
Similarly, congenital syphilitic disease in the kidneys produces rarely 
definite gummata, but often patches of atrophy and destruction of tubules 
and glomeruli with scarring. The same peculiarity is true of the testicle, 
in which the gumma, common in the acquired form, is replaced by atrophy 
or maldevelopment of the tubules, often with interstitial connective-tissue 
formation, which leaves the organ distorted, small, and hard. 
Campos has studied a long series of cases of congenital syphilis in our 
laboratory with regard to the changes in the kidney, and finds regularly 
a retardation in development so that there is still at birth and later a 
neogenic zone at the margin of the cortex. The blood-vessels are almost 
always surrounded by a mantle of cells which prove to be myeloid elements 
so that blood formation is going on here as well as in the liver. 
In the bones the syphilitic osteochondritis first described by Wegner is a 
most definite and characteristic lesion found practically always in the 
syphilitic new-born, although it does not affect equally all the bones, being 
most distinctly developed in the epiphyseal ends of the long bones about 
the knee. The epiphyseal line, which ordinarily 
forms a perfectly even, thin, pearly gray line be- 
tween cartilage and bone, loses this delicate aspect 
and becomes thick, jagged and opaque yellowish- 
white (Fig. 371). Often it has a granular, mortar- 
like appearance and it is seen that it no longer 
marks the line of continuity of the cartilage with 
the bone, but that instead it is really a cleft be- 
tween the two, filled with a fine yellowish gritty 
substance. Sometimes the epiphysis is quite dis- 
located and separated from the bone along this 
line. 
Microscopically (Figs. 372, 373) the reasons for 
this are seen: Along the line of ossification on the 
side of the bone there is developed a layer of 
granulation tissue essentially gummatous in its 
character, and prone to necrosis and disintegra- 
tion; it involves the most recently formed bone, 
and stops the process of bone formation by causing the necrosis of this 
layer, all of which collapses together in a debris of minute bony fragments 
(Fig. 374). Round about, from the periosteum and perichondrium, there are 
reparatory new growths of slight extent, and later, if the child survives, 
all this debris is removed and healing takes place in such a way as to read- 
just lamellated bone to cartilage and allow bone formation to proceed as 
before, although one may imagine that in all such cases a good deal of 
disturbance in the development of the bone must result. Schneider, in a 
very complete study of syphilitic osteochondritis, shows clearly the char- 
Fig. 371.-Syphilitic os- 
teochondritis. The line of 
ossification is irregular and 
is conspicuously opaque. 749 
CONGENITAL SYPHILIS 
acteristic distribution of the spirochsetes which are most abundant in the 
line of ossification and in the periosteum. 
Bullard finds by actual measurement of large numbers of syphilitic in- 
fants and children that growth of the bones in length is distinctly retarded 
as compared with that of normal controls. The blood-forming functions 
of the bone-marrow are almost annihilated by the conversion of the tissue 
into a sort of granulation tissue with few remains of myeloid elements. 
Fig. 372.-Syphilitic osteochondritis, showing slight distortion of the line of ossification. 
There are many other lesions to be found in such newborn syphilitic 
children, but they all proceed on the same principles and these may suffice 
to illustrate. 
Late Forms of Congenital Syphilis.-Very important and difficult to 
comprehend are the syphilitic lesions which appear after the lapse of months 
or years in children born of syphilitic parents, which at birth may not have 
shown any signs of disease. Fig. 373.-Syphilitic osteochondritis. Section showing the changes mentioned, and 
also separation of the epiphysis (a). About the comminuted fragments of calcified 
cartilage and bone is a cellular granulation tissue (c) with extensive necrosis (6) toward 
the line of fracture. 
750 CONGENITAL SYPHILIS 
751 
Fournier, in his book on "La Syphilis Tardive," includes practically 
every ailment that flesh is heir to under this heading, so that at first it 
must seem fanciful; but while one remains skeptical about some of the 
phenomena referred to syphilis, good proof is brought for most of them. 
The scars and deformities or stigmata of syphilis are recognizable, as 
well as the active progressive disease, and often serve to indicate the char- 
Fig. 374.-Syphilitic osteochondritis. Another section from the same case, showing 
extensive efforts at healing, with the formation of new cartilage and cancellous bone 
(d). 
acter of some other more obscure process which is still going on. Various 
deformities due to retardation of development leading even to dwarfism 
are regarded as syphilitic. These as they affect the skull produce irregu- 
larities of form and asymmetries, or a hydrocephalic dilatation which 
might seem due to other possible causes. 
Perfectly distinct, however, are the malformations of the nose, gum- 
matous destruction of the nasal bones producing saddle-nose, while even 
greater deformity is caused by collapse of the cartilaginous part of the 752 
TEXT-BOOK OF PATHOLOGY 
septum, which allows the tip of the nose to telescope into the rest, so that 
there is a fold of skin on each side. 
Various changes in ears and eyes occur with deafness and impairment of 
vision. Of these, the commonest and most easily recognized is the inter- 
stitial keratitis, which gives a steamy opacity to the cornea and which 
may obstruct vision very completely, or finally clear away entirely. 
In the teeth there are many deformities ascribed to syphilis, all rather 
difficult to explain and none surely indicative of syphilis unless it be pos- 
sibly the true Hutchinson's teeth. The change that Hutchinson described, 
affecting most obviously the upper incisors, is such that the teeth are rather 
tapered, usually stand wide apart, and have a single semicircular recess in 
the biting edge (Tig. 374A). 
In the skeleton the lesions of late congenital syphilis are practically 
those of the tertiary stage of the acquired form, including chronic forms of 
periostitis, arthritis, etc. But the atrophy, or rather maldevelopment, of 
bones which produces the extreme delicacy and small size of the skeleton 
in some of these cases is rather different, as is also the extraordinary local 
or partial gigantism, which is of similar origin and follows the great local 
overgrowth of bone. 
Lesions of the nervous system and of the various other organs of the body 
are like those of acquired syphilis, except that they seem to be intensified 
Fig. 374A.-Hutchinson's teeth. 
in these patients, inasmuch as the infection has begun with the beginning 
of their lives and affected their resistance throughout. 
Volk: Placentarsyphilis, Ergcb. d. allg. Path., 1904, viii, 509. 
Schwab: La Syphilis, 1905, Juli. 
Fournier, E.: L'heredosyphilis tardive, Paris, 1907. 
Herxheimer, G.: Ergeb. d. allg. Path., 1908, xii, 499. 
Hecker: Deutsches Arch. f. klin. Med., 1898, Ixi, 1. 
Hochsinger: Studien iiber hered. Syphilis, Leipzig u. Wien, 1898 and 1904. 
Warthin: Amer. Jour. Med. Sci., 1911. 
Campos, E. de Lonza: Johns Hopkins Hospital Bulletin, 1923, xxxiv, 253. 
Schneider, P.: Virchow's Archiv., 1921, ccxxxiv, 378. 
LITERATURE OTHER SPIROCHETAL INFECTIONS 
753 
Space will allow only the briefest mention of certain other diseases known 
or thought to be caused by various spirochsetse, which are of very great 
importance in the tropics, but unfamiliar here. 
Yaws or frambcesia is a disease resembling syphilis in some respects, 
which is caused by the Spirochaeta or Treponema pertenue as shown by 
Castellani. It is not a venereal disease, but is apparently transmitted by 
contact, for the primary lesion may be found in positions which suggest 
this. It is extremely common in the tropics, and most of the children in 
the islands of the Pacific, in the East and West Indies, and elsewhere 
seem to acquire the infection. It is less common in adults. It is thought 
to give rise to primary, secondary, and tertiary lesions, as in the case of 
syphilis, but the primary lesions are not very different from the secondary, 
OTHER SPIROCHETAL INFECTIONS 
Fig. 374B.-Yaws. Secondary erup- 
tion in florid stage (Fiji Islands). 
Fig 374C.-Yaws. Showing exten- 
sive spread of crusted lesions (Tonga 
Islands). 
and the connection of the distorting, destructive processes which are said 
to be tertiary lesions with the others is not entirely convincing, although 
pretty generally accepted. The primary lesion, generally shown as such, 
is usually a vesicle or pustule, developed on the hand or on the hip of a 754 
TEXT-BOOK OF PATHOLOGY 
mother, where the skin came into contact with the infected child she was 
carrying, or on the breast. The secondary lesions appear as a great crop 
of large flattened vesicles, which quickly become changed into honey yel- 
low pustular elevations (Figs. 374B, 374C). These on section show a great 
thickening of the epithelium and a dense infiltration of plasma cells be- 
neath (Fig. 374D). The spirochsetae are most readily found in the early 
stages, before the breaking of the crust allows of secondary infection of the 
pustule. The tertiary lesions are found in the bones and other tissues of 
the extremities or of the face and upper respiratory passages, and there 
they produce the most extensive losses of tissue, with scarring and extra- 
ordinary distortions. The secondary lesions disappear in a magical way 
under salvarsan treatment. 
Fig. 374D.-Yaws. Deeper layers of skin in a secondary lesion showing the great ac- 
cumulation of plasma cells. 
Spirochaetosis Icterohaemorrhagica (Weil's Disease).-This disease, long 
known as Weil's disease, occurs in endemic and sometimes epidemic form 
in Japan, and has recently affected large numbers of soldiers in the trenches OTHER SPIROCHETAL INFECTIONS 
755 
in France, Belgium, and elsewhere in Europe. It is an affection which 
begins suddenly with fever, headache, general aching pains, and nosebleed, 
and is often marked by the vomiting and coughing up of blood, and by the 
passage of blood with the stools. After about five days the fever passes 
off and jaundice appears. After five or six days more the fever reappears 
and lasts for about a week. It has been shown by Inada and his co- 
workers that the cause is a spirochaete which also infects rats, the Spiro- 
chaeta icterohaemorrhagica, and that it is probably transferred through the 
skin of human beings from the infected urine of the rats. This does not 
seem altogether convincing, and it has been suggested that it may possibly 
be transmitted by some biting insect. During the first days of the illness 
it is found in the circulating blood, after the fifteenth day in the urine. 
It seems that a certain amount of immunity is developed and may be pro- 
duced artificially in animals. Relapsing fever and rat-bite fever are other 
diseases of a very similar character, concerning which references are given 
below. 
Yellow fever was, of course, one of the most dreaded plagues of mankind 
a few years ago, but now, since the epoch-making studies of Reed and his 
colleagues, and the very effective application of these principles by General 
Gorgas, it is being rapidly exterminated. It is a very grave, febrile disease 
with vomiting of blood, jaundice, haemorrhages in the skin and elsewhere, 
and extensive necroses in the liver with disturbance of its function. Reed 
showed that it is transmitted by the bite of an infected mosquito, Stego- 
myia fasciata, but only after the lapse of twelve days after the mosquito 
had bitten a person ill of the fever and become infected. Evidently it 
requires twelve days for the development in the body of the mosquito, of 
enough virus to infect a man, or else the virus must go through a twelve- 
day cycle of development in the mosquito. This is a mosquito which is 
very domestic in its habits, living about houses and laying its eggs in 
water found in receptacles there. Since in cities like Guayaquil there is 
no other water-supply than tanks and cisterns about the houses, it is not 
easy to destroy the mosquitos, but otherwise it is only necessary to empty 
out the water from these receptacles once a week to prevent all larvae 
from hatching. Gorgas has shown that it is not necessary to destroy every 
mosquito, but merely to reduce their numbers to a point below that at 
which their presence has a reasonable chance of spreading infection. In 
Guayaquil and in Payta and Piura in northern Peru he has accomplished 
this during the past summer, and apparently ended the infection. No- 
guchi has recently published the results of studies which show that a 
spirochaete, indistinguishable morphologically from the icterohaemorrhag- 
ica, is present in cases of yellow fever, as shown first by the inoculation of 
guinea-pigs, and thinks that this is the cause of yellow fever. Various 
criticisms have, of course, been offered, but it is to be hoped that these 
results will prove correct. He has named the organism Leptospira ic- 
teroides. 756 
TEXT-BOOK OF PATHOLOGY 
LITERATURE 
Yaws: 
Castellani and Chalmers: Manual of Tropical Medicine, London, 1910. 
Seilard, Goodpasture: Philippine Journal of Science, 1923, xxii, 219. 
Spirochoetosis Icterohwmorrhagica: 
Inada, Ido, Hoki, Kaneko, and Ito: Jour. Exp. Med., 1916, xxiii, 377; 1916, xxiv, 471, 
485; 1917, xxvi, 325, 341, 355. 
Nolf and Firket, J.: Archives Med. Beiges, Avril, 1918. 
Stokes and Ryle: Brit. Med. Jour., 1916, ii, 413. 
Garnier and Reilly: Arch, de med. exp. et d'anat. path., 1918, xxviii, 228. 
Martin, C. J.: Jour. Royal Army Med. Corps, 1918, xxx, 102. 
Rat-bite Fever: 
Futaki and others: Jour. Exp. Med., 1916, xxiii, 249; 1917, xxv, 33. 
Kaneko and Okuda: Ibid., 1917, xxvi, 363, 377. 
Blake: Ibid., 1916, xxiii, 39. 
Yellow Fever: 
Reed, Carroll, Lazear, and Agramonte: Amer. Public Health Assoc., 1900, xxviii. Jour. 
Amer. Med. Assoc., Feb. 16, 1901. 
Noguchi: Jour. Exp. Med., 1919, xxix, 547, 563, 585; 1919, xxx, 1, 9, 13, 87, 95, 401; 
1920, xxxi, 135, 159. CHAPTER XXXVII 
TYPES OF INJURY7.-EXANTHEMATIC DISEASES 
Introduction. Measles: Susceptibility, aetiology, course of the disease and pathological 
anatomy. Scarlet fever: Etiology; complicating streptococcus infection, transmission- 
course and pathological anatomy. Scarlatinal nephritis. Smallpox: Relation to vaccinia; 
vaccination; aetiology; symptoms and pathological anatomy. 
EXANTHEMATIC DISEASES 
There follows some description of the more important of a series of dis- 
eases which we recognize as extremely easily communicable and therefore 
undoubtedly due to an infection, but in which, in spite of the most earnest 
efforts, no living organism has been demonstrated with the certainty which 
we demand. It is true that many supposed parasites have been found, as, 
for example, the cytorhyctes in the skin in small-pox, which are looked upon 
with confidence by their discoverers as the specific factors, but their 
descriptions do not carry conviction. It has been well said that if there is 
any doubt about a parasite when you see it, it is usually not a parasite. 
Whatever the nature of these organisms, they must multiply with great 
rapidity and disseminate themselves quickly through the body by way of 
the blood-stream. Indeed, the diseases can probably be transmitted in 
each case by inoculation of blood, as has been shown by Hektoen to be 
true for measles. Doubtless, too, the organisms are very small and per- 
haps, in most cases, capable of going through a porcelain filter. The dis- 
eases have in common the occurrence of an eruption on the skin, or 
exanthem, which no doubt indicates the presence of the organism there, 
but since such eruptions are found in other infectious diseases and even in 
various intoxications it does not really form a good basis for their classifica- 
tion. There are many such diseases, including chicken-pox, rubeola or 
German measles, Duke's fourth disease, erythema infectiosum, etc., but 
the most important are those which follow. Doubtless before long their 
aetiology will be cleared up and we shall be able to form a better idea of the 
way in which the lesions are produced. 
MEASLES 
This is a disease of childhood because susceptibility is practically universal 
and the opportunity for infection so general that few children escape. 
There are few adults to infect, since nearly all have had the disease in child* 
hood. In this is implied the fact that one attack confers immunity. The 
disease may be transferred in utero if the mother is ill with it when the child 
is about to be born. The child of a mother who has never had measles 
757 758 
TEXT-BOOK OF PATHOLOGY 
may contract it almost immediately after birth, while the child of an im- 
mune mother is born with an immunity which lasts one or two months. 
The mother's milk confers no protection. While such a situation prevails 
in most civilized countries, it is well known that in isolated lands, such as 
the South Sea Islands, where the disease was unknown, the advent of the 
infection with early explorers was followed by terrific epidemics which 
killed off many of the natives. 
In the winter of 1917-18 the concentration of troops in training camps 
brought together great numbers of young men who had never had measles, 
and very great epidemics occurred. It was noted that the men fiom rural 
districts of the more sparsely inhabited states of the South were espe- 
cially affected, while those from cities escaped. 
Although under ordinary conditions in which patient's live separately 
in their homes measles is not considered a serious disease, secondary 
infection with a haemolytic streptococcus occurs when many cases are 
housed together and produces a very fatal pneumonia. This can be 
avoided by rigidly isolating those cases which show the streptococcus 
infection, but the history of all great epidemics of measles reveals the prev- 
alence of this type of pneumonia, and I could demonstrate in the ancient 
museum specimens from that which occurred during the Civil War in 1864 
and 1865 not only the character of the pneumonia, but the streptococci 
in chains in the lungs. Secondary infection with the tubercle bacillus or 
the aggravation of tuberculosis already existing has always been empha- 
sized. We saw none of these cases in the camp epidemics, and it has even 
been suggested that the nodular form of bronchopneumonia has been 
mistaken for tuberculosis, but this seems scarcely probable, and the older 
observations may doubtless be accepted. 
Nothing is known of the nature of the causative agent. The experi- 
ments of Hektoen consisted in incubating the blood taken during the erup- 
tive stage in ascitic broth and injecting it into two non-immune persons, 
both of whom developed the disease. Anderson and Goldberger stated 
that they could produce measles in monkeys by inoculation of blood from 
■early stages, that the virus would pass a Berkefeld filter, and that they 
could carry it on from monkey to monkey. Seilards, however, after in- 
oculating eight apparently non-immune volunteers in every way he could 
devise failed to transfer the disease. His paper discusses the whole sub- 
ject. 
Transmission is ordinarily direct from person to person, probably by 
means of the respiratory tract, the infection presumably being carried in 
a spray from the coughing child. 
The period of incubation is eight to nine days; the rash appears after 
about fourteen days. There are thus several days in which prodromal 
symptoms of headache, malaise, and nasal and bronchial catarrh prevail. 
Conjunctivitis, intense coryza with reddening of the pharynx and larynx, 
and, a little later, bronchitis, are characteristic and constant features. MEASLES 
759 
The so-called Koplik's spots in the mouth are minute white flecks sur- 
rounded by bluish and then red zones. They appear early and have a 
diagnostic importance. 
The exanthem or rash appears first on the face and then spreads over 
the rest of the body. It is slightly elevated, grayish-red, and distributed in 
flecks which are sometimes very small but usually conglomerated into larger 
patches which reach 1 cm. in diameter. It is common to observe a cres- 
centic form in these patches. There are fever and leucocytosis and the 
catarrhal symptoms continue. With the lapse of a few days the rash fades 
and there may be desquamation of branny scales. The bronchitis clears 
up also unless there are further complications in the form of lobular pneu- 
monia or other secondary infection. 
Pathological Anatomy.-Sections of the skin which pass through the 
macules show a moderate oedema and hypersemia with some accumulation 
of lymphocytes about the blood-vessels. But there is no necrosis nor in- 
tense inflammatory reaction. The lobular pneumonia which is an ex- 
tremely common complication in the late stage of measles has been described 
in connection with streptococcal infections. It is essentially the result of 
an infection with the haemolytic streptococcus, although other organisms 
were occasionally found associated. It is characterized by its peribronchial 
and interstitial distribution, forming nodules of dense tissue and exudate 
about the terminal bronchioles, with spread of the bacteria by way 
of the lymphatics through the interlobular septa to the pleura. The 
lymphatics are thrombosed and all the skeletal structures of the lung 
become thickened by new formation of tissue. The pleural cavity is 
quickly filled with a thin fluid full of bacteria and organization of the 
exudate on the surface is rapid. While this is the usual condition, there 
are other cases in which low resistance allows the streptococci to produce 
extensive necrosis through the lung with heemorrhage and little response 
of a protective character. 
The other organs, besides the lungs and skin, are not characteristically 
affected in measles. There is usually a moderate acute splenic tumor and 
general enlargement of the lymphoid apparatus. The conjunctivitis, 
rhinitis, etc., are probably caused by the specific agent, but bacteria are 
so regularly associated that the affection is not peculiar. Otitis media is a 
not infrequent sequel. 
von Jurgensen and von Pirquet: Masern, Nothnagel's Handb., Wien, 1911, iv. 
Brucker: Jahrb. f. Kinderheilk., 1902, Ivi, 725. 
Koplik: Archives of Pediatrics, 1896, xiii, 918. 
Hektoen: Jour. Infect. Dis., 1905, ii, 238. 
Goldberger and Anderson: Jour. Amer. Med Assoc., 1911, Ivii, 971. 
Levy and Alexander: Ibid., 1918, Ixx, 1827. 
Seilards: Johns Hopkins Hosp. Bull., 1919, xxx, 257. 
MacCallum: Monograph, Rockefeller Institute, 1919, No. 10. 
LITERATURE 760 
TEXT-BOOK OF PATHOLOGY 
This is generally looked upon as a more serious disease than measles, not 
only in itself but because of the complications which accompany it, and the 
secondary affections which appear after recovery seems well established. 
It is curious, however, that at the present time scarlet fever seems to be 
a very mild affection, although occasional cases assume the maximum 
severity, and this recalls the fact that there have been several periods in 
history during which it prevailed for years as an almost negligible disease, 
each time followed, however, by other periods in which it raged with ex- 
treme violence. Sydenham lived to see such a change. 
^Etiology.-The nature of the infection is still in question. It is true 
that Mallory has described peculiar, rosette-like bodies in the skin, and 
that Gamaleia and others have seen similar things, but these cannot be 
found in skin excised from the living patient, and, on the other hand, 
they can be found in the skin at autopsy in persons who have died of other 
diseases. Their aetiological relation to scarlet fever is at least doubtful. 
Further, it is known that there is always an intense infection of the throat 
with virulent streptococci, and there are those who maintain that scarlet 
fever is nothing more than a streptococcus infection. Recently the work 
of Dick and Dick and of Dochez, Bliss, and others seems to show that this 
is a specific streptococcus always the same in cases of scarlet fever and 
capable of leaving upon recovery a certain degree of immunity. The serum 
of horses actively immunized with this organism, when injected into the 
skin of a person suffering with scarlet fever, causes a disappearance of the 
rash ovei' a large area surrounding the point of injection. Desquamation 
occurs later over the rest of the body, but not over the area thus blanched. 
The production of an infection in animals with rash and desquamation 
has been successfully carried out by Dochez. Krumwiede, Nicoll, and 
Pratt were unable to transmit the disease to monkeys by injection of 
pharyngeal mucus or even by the injection of blood from scarlatina pa- 
tients. On the other hand, scarlatinal infections in surgical incisions, or 
in cuts or scratches received during an autopsy on the body of a person 
dead of scarlet fever, are well known, and the case of Leube, who thus 
infected himself, is famous. 
Course of the Disease.-The disease begins suddenly, after three or 
four days of incubation, with sore throat, fever and swelling of the lymph- 
glands at the angle of the jaw and of the tonsils. With increase in the in- 
tensity of the angina and the appearance of whitish flecks of exudate on 
the red background there comes vomiting. Soon there appears on the face, 
and later over the whole body, the characteristic red rash which is made up 
of flecks much finer than in the case of measles and more closely set; the 
whole face and skin has a flushed red color. In all cases the angina repre- 
sents a streptococcus infection, but there are some which proceed to re- 
covery without much further evidence of bacterial infection, while in other 
cases there are phenomena of the most intense sort which appear to be 
SCARLET FEVER SCARLET FEVER 
761 
largely due to the streptococci. Escherich, therefore, divides the cases 
into toxic and infectious types. In the more severe cases the angina be- 
comes far more intense. The tonsils swell to the point of meeting in the 
mid-line and become partly necrotic. Considerable areas of mucosa of the 
fauces and the walls of the pharynx become covered with a false membrane 
of greenish color, the removal of which reveals deep ulcerations with foul 
base. The scarlatinal angina is thus an extremely destructive process. 
The neighboring lymph-glands in the neck are swollen to a great size and, if 
incised, sometimes exude a greenish pus, sometimes show their central parts 
as firm, necrotic masses which are later discharged. Such scarlatinal 
buboes may occur in this way in the early stages of the disease or appear 
much later after the acute symptoms have passed. 
Pathological Anatomy.-Laryngeal and tracheal inflammation is found 
only in the severest cases and then the occurrence of bronchopneumonia 
is likely. This lobular pneumonia commonly becomes confluent and leads 
to the production of abscesses in the lung. Extension into the pleural 
cavity results in empyema which may readily end fatally. 
In the heart there may be no evident gross lesions even though the child 
die with signs directly indicating its involvement. 
Stegemann shows that even in the early days of the disease there are changes in the 
heart ganglia, including degeneration and necrosis of the nerve-cells and infiltration with 
lymphocytes, and ascribes paralysis of the heart to these lesions. Later, in more pro- 
tracted cases, there is similar infiltration of the heart-muscle and conduction bundle. 
There are no specific changes in the nervous system nor indeed can any 
be recognized in the other organs during the acute stage. It is true that 
necroses have been found in the liver, which is commonly the seat of cloudy 
swelling, and it is thought that these necroses may sometimes lead to a form 
of cirrhosis. The spleen is moderately swollen, markedly so only in cases 
where the streptococcus infection is predominant. There are occasionally 
acute inflammations of the joints, with effusion of sterile fluid into the 
synovial cavities; but these disappear without leaving any disabilities. 
Each has studied the histology of the skin rash and has shown that in 
each fleck there is a focus of acute inflammatory exudation, with outpouring 
of polynuclear leucocytes and red corpuscles into the substance of the skin 
about the blood-vessels. This extends into the epidermis, where there 
may appear small blebs filled with leucocytes. Later there occurs a thick- 
ening and dislocation of the epidermis which forms the well-known chaffy 
scales. A similar influence disturbing the growth of the nails produces a 
transverse groove which, with the passage of time, gradually advances to 
the free edge of the nail. 
There is a definite leucocytosis with a rather high percentage of eosino- 
phile cells. The red corpuscles decrease for a time to about 3,000,000 
per c.mm. Death may occur in the acute stage from general intoxication, 
with cardiac collapse, or from various lesions produced in the respiratory 762 
TEXT-BOOK OF PATHOLOGY 
tract by the streptococcus in association with the main infectious agent, 
or the patient may recover and progress to complete health. Recently 
we have studied a remarkable case in which arms, legs, and face became 
exclusively gangrenous. The child was in the stage of desquamation. 
At autopsy some thrombi were found in the superficial veins, but no clear 
explanation of the process could be gained. This is apparently not an 
unusual occurrence in scarlet fever. 
Nevertheless, in many cases in which the symptoms have passed away 
and recovery is apparently well established, new symptoms appear in about 
the third week. Of these, a fresh swelling of the lymph-glands and signs 
of acute nephritis are the most prominent. These are not due to a second 
complicating disease, as is the case with the tuberculosis which so commonly 
follows measles, but are late manifestations of the scarlatina itself. They 
appear to have about the same relation to the acute phenomena as the 
secondary lesions of syphilis bear to the primary lesions (Escherich), and 
evidently indicate the latent presence of the organism in the body during 
the period of apparent recovery. The enlargement of the lymph-glands 
seems independent of that which occurred in the primary stage and appears 
suddenly with pain. Usually it lasts only a short time and recedes after 
a few days, rarely ending in suppuration. 
The nephritis is more serious. This has already been discussed in the 
chapter on Nephritis, but it may be pointed out again that there appear to 
be two forms-one in which the function of the kidney is not very greatly 
disturbed, except in the more severe cases, and in which the lesion consists 
essentially in the exudation of many wandering cells, chiefly of the character 
of lymphocytes and plasma cells, into the interstices between the tubules. 
This is the so-called acute interstitial nephritis which has been described 
by Councilman and others. The second form is predominantly a glo- 
merulonephritis in which the kidneys are found to be swollen and pale or 
mottled, often with opaque yellowish flecks. On section the glomeruli 
project as grayish translucent dots. There may be ecchymoses in the sub- 
stance of the kidney. Microscopically there are to be found all the 
changes previously described, which lead to obliteration of the glomerulus, 
by haemorrhage into the capsule with organization, proliferation of the 
capsular epithelium, and occlusion of the capillaries of the tuft by thrombi 
or by massed endothelial cells. It is in the scarlatinal forms that the pro- 
duction of crescentic masses of capsular epithelium about the glomerular 
tuft is well seen, although of course this occurs in other types of nephritis. 
Degenerative changes in the tubular epithelium with destruction and des- 
quamation of cells accompany the glomerular changes. Later, with the 
collapse of tubules, much loose connective tissue appears between the ele- 
ments of the cortex, and in time the kidney may be extensively scarred. 
But in many cases complete recovery from all these injuries occurs, and if 
there is opportunity to examine the kidney of such a person much later in 
life, it is probable that only isolated scars may be found as the remains of SMALL-POX 
763 
the early injury. In other words, it is by no means inevitable that the 
occurrence of an acute scarlatinal nephritis should result in the production 
of a progressive chronic diffuse nephritis. The contrary is rather more 
probable. During such an acute and subacute scarlatinal nephritis the 
function of the kidney may be intensely disturbed. The secretion of chlor- 
ides and of water is diminished and there is generalized oedema. There is 
usually marked albuminuria and generally blood is passed in the urine. The 
blood pressure is quickly heightened, and hypertrophy of the heart appears 
rapidly. Ursemic symptoms frequently occur, and may be severe enough 
to cause death. 
Escherich and Schick: Scharlach, Wien, 1912 (Excellent paper with literature). 
Stegemann: Jahrb. f. Kinderheilk., 1914, Ixxx, 491. 
Krumwiede and others: Archives of Int. Med., 1914, xiii, 909. 
Williams, A. W.: Amer. Jour. Obst., 1908, Iviii, 152. 
Rach: Ziegler's Beitr., 1910, xlvii, 455. 
Schridde: Ibid., 1913, Iv, 345. 
Mallory: Jour. Med. Res., 1904, x, 483. 
Field: Jour. Exp. Med., 1905, vii, 343. 
Bliss: Jour. Exp. Med., 1922, xxxvi, 575. 
Stevens and Dochez: Proc. Soc. Exp. Biol, and Med., 1923, xxi, 39. 
Dick and Dick: Jour. Amer. Med. Assoc., 1923, Ixxxi, 1166. 
LITERATURE 
SMALL-POX 
Small-pox is allied to measles and scarlet fever in the sense that it is a 
febrile disease strikingly characterized by the appearance of an exanthem 
or skin eruption. This, however, is scarcely a satisfactory basis for classi- 
fication, and it may well be that when we learn the nature of the setiological 
factors in these diseases their relations will seem less intimate. Chicken- 
pox or varicella is a disease of milder character, but resembles small-pox 
much more closely than do the other exanthemata. A disease of cattle 
closely resembling small-pox, and known as cow-pox, is very rarely seen 
any longer, but is artificially preserved in the form of vaccinia. The re- 
lation of the diseases small-pox and vaccinia is not yet clear, since vaccinia 
inoculated in human beings produces only a local lesion which protects 
against small-pox, while human small-pox inoculated into cattle, rabbits, 
and other animals produces vaccinia and not small-pox. If small-pox be 
inoculated into human beings, as was done at the instance of Lady Mary 
Wortley Montague, before the discovery of vaccinia, a mild and localized 
affection is produced which protects against a severer attack of small-pox, 
but may sometimes be transmitted to other persons as true and severe 
small-pox. 
The disease has occurred in extensive and very fatal epidemics, and when 
introduced into countries where it had not existed before, has in some cases 
exterminated the whole population. Even yet it rages at times with ex- 
treme violence. In 1798 Jenner published his observations on the disease 
of cows (cow-pox) which was often accidentally transmitted to milkmaids 764 
TEXT-BOOK OF PATHOLOGY 
and others and which protected against the rather prevalent small-pox. 
He instituted vaccination, with the life-saving results which are so well 
known to-day. Even yet, however, there are many persons of meagre 
intelligence who oppose the use of vaccination, and on account of their in- 
fluence there are always unvaccinated individuals who are susceptible and 
thus make possible the occurrence of the disease. 
Etiology.-We are not definitely informed as to the cause of small-pox. 
Numerous writers have recognized in the epithelial cells of the pocks 
minute bodies which they have regarded as protozoan parasites. They 
were first seen by Weigert and then described by others. Guarnieri named 
them Cytoryctes variolw, and Councilman and his co-workers have described 
them more fully, having found them in all their cases. Calkins has worked 
out a life-history by comparing the various stages, but tells me that he 
would now modify some of these conclusions. More interesting are the 
observations of Prowazek, Paselieu, and others, who have found in the 
material from small-pox pustules and also in cowpox vaccine myriads of 
extremely minute dancing granules which they regard as the cause of the 
disease. These can also be demonstrated in the epithelial cells in the 
active lesion. We have studied these particles in vaccine and find them 
constantly. Indeed, the infectivity of the material seems to depend upon 
their presence. They are far smaller than the smallest bacterium, occur 
in pairs or short chains or singly, and move slightly. Lambert and Stein- 
hardt, without seeing them, showed that they could be propagated in 
culture with pieces of growing skin and greatly increased in amount as 
shown by inoculation. Noguchi has cultivated the virus in the testicles 
of animals so as to render it bacteria free. Not much more has been done, 
and the problem as to the nature of these particles which Prowazek 
thought related to the Guarnieri bodies is still open. Rivers and Tillett 
have been able to inoculate chicken-pox in cornea, skin, and testicles of 
rabbits and to transmit the disease indefinitely from rabbit to rabbit. 
In all cases of small-pox, except perhaps the very mild or abortive forms, 
there is an accompanying infection with streptococci. It will be remem- 
bered that this associated streptococcus infection is characteristic of scarlet 
fever and of diphtheria also, so that it by no means excludes the idea of 
a separate and specific aetiological factor. Many of the lesions of small-pox, 
especially in the internal organs, are ascribed to the effects of the strepto- 
cocci. 
Symptoms.-The disease begins abruptly with a chill or with headache 
and malaise, and in a short time becomes recognizable by the appearance of 
shotty nodules in the skin which develop rapidly and reach their acme 
about the tenth day (Fig. 375). These at first feel like little firm points, 
but soon become vesicular, and from that quickly assume the yellowish 
opacity which reveals their pustular character. Practically all of them 
show depression or dell, but occasionally this is obliterated, for reasons to 
be discussed. The pocks, or pustules, are usually about 3 mm. in diam- SMALL-POX 
765 
eter, but they may become confluent into irregular patches. They develop 
in no particular relation to hairs or sweat-glands. After the height of their 
growth is reached they do not burst spontaneously, but dry up into crusts 
which adhere for a time and finally fall off. 
Alastrim is a form of small-pox which we studied in a great epidemic 
in Jamaica in the summer of 1920. It differs from the classical small-pox 
only in its mildness and perhaps in its immunological relations, so that 
from the anatomical point of view it seems identical. During that summer 
only about 10 deaths occurred among 3000 cases. The patients, covered 
with a confluent eruption of pocks, 
were profoundly ill for only about one 
or two days at the height of the affec- 
tion, but otherwise the general course 
was as in severe small-pox. 
Pathological Anatomy.-Our study 
of the skin lesions in alastrim showed 
that in the earliest stages the lesion 
consists of an infiltration of mononu- 
clear cells and leucocytes about the 
vessels of the corium. The epithelial 
cells over this become vacuolated and 
separated and a vesicle is formed within 
the layer by the accumulation of fluid 
there-a fluid which is quickly filled 
with leucocytes. There are sometimes 
bridges of epithelium left stretching 
between the roof and the floor of what 
is now a pustule. At first the Mal- 
pighian layer of the epidermis persists 
and it may continue so, but usually 
later the papillae of the corium are laid 
bare in the floor of the pustule, and they and the underlying corium 
become densely infiltrated with leucocytes. 
After the height of the process is over, new epithelium grows from the 
sides over the remaining Malpighian layer which usually forms the bottom 
of the pustule, or over the exposed corium if that layer has been destroyed, 
but also along the under side of the uplifted roof of the pock. Shortly 
it happens that the exudate enclosed now between two layers of epidermis 
of which the upper becomes completely dried up, also dries up and is rubbed 
off as a crust with the adherent upper layer of epithelium. A depression 
is thus left lined with epidermis. If the Malpighian layer has remained 
intact, no deep pitting results, but if the necrosis has extended into the 
corium, the healing of the pock leaves a pit. 
Various modifications in the eruption occur and the disease is roughly 
divided accordingly into mild forms, in which there are hardly any skin 
Fig. 375.-Small-pox. Tenth day of 
eruption (Welch and Schamberg). 766 
TEXT-BOOK OF PATHOLOGY 
lesions or symptoms; abortive forms, in which the lesions of the skin quickly 
recede and disappear; haemorrhagic pustular forms, in which haemorrhage 
occurs in and about the pustules; and purpuric forms, in which more ex- 
Fig. 376.-Small-pox pustule. The pustule is formed in the substance of the epidermis. 
Strands of persistent epithelial cells cross it (Dr. James). 
tensive haemorrhage into the skin forms a feature more conspicuous even 
than the pustules. The last is an extremely severe form in which death 
may occur before the eruption is well developed. 
In the internal organs the changes are partly due to the specific cause of 
the disease, but are partly the effect of the accompanying streptococcus 
infection. 
In the mucosae of the mouth and other body orifices and in that of the 
trachea and digestive tract, there occur specific lesions of the character of 
those in the skin and with the same degeneration and necrosis of the epi- 
thelium, but since there is no protective horny layer to allow of the develop- 
ment of definite pocks, they result in the separation of the epithelial cells, 
the infiltration of the tissue with leucocytes, and the production of 
indefinite small ulcers. 
In the testes and bone-marrow more readily recognizable specific lesions 
occur. In the testes these are found as nodules in the substance, more 
numerous just under the tunica albuginea. They are formed by a focal 
infiltration of wandering cells among the tubules. After a time the tubules 767 
SMALL-POX 
involved become necrotic and invaded by the mononuclear cells. Such 
nodules appear in section as opaque, yellowish spots with a halo of haemor- 
rhage, and heal with the formation of small scars. 
In the bone-marrow very similar lesions are found with central necrosis 
involving the blood-forming cells and marginal infiltration of mononuclear 
elements. The formation of polynuclear leucocytes is seen to be in abey- 
ance in the bone-marrow and many degenerated forms are found. In the 
later stages of the disease the mononuclear types hold a predominant place 
among the emigrating cells on this account. Chiari has described this 
lesion as osteomyelitis variolosa, but it obviously does not resemble other 
forms of osteomyelitis. 
In the liver there is intense cloudy swelling, and focal necroses are oc- 
casionally found. The organ is ordinarily much enlarged. In the kidneys 
there is no characteristic lesion, but degenerative changes appear in the 
epithelium of the tubules and occasionally there is acute glomerulonephritis. 
Interstitial accumulations of mononuclear cells are relatively common. 
Similar non-specific changes may be found in other organs, but it remains 
a question as to whether they are not produced by the streptococci. This 
is true also of the degenerative changes in the heart-muscle, which are like 
those seen in other acute infections, and perhaps also of the swelling of the 
lymph-nodes and spleen. In the lymph-nodes, the changes in the lymph 
sinuses include the appearance of many large phagocytic cells, together 
with abundant smaller mononuclear cells. 
In most cases there is an acute bronchitis and in many there occurs a 
rather severe lobular pneumonia which may be confluent in character. 
This is often the actual cause of death and is probably to be ascribed to the 
bacterial infection. 
Weigert: Anat. Beitr. zur Lehre von den Pocken, Breslau, i, 1874; ii, 1875. 
Councilman and others: Jour. Med. Research, 1904, xi, 1-360, Lit. 
Calkins: Ibid., 136. 
Councilman and Beardsley: Osler and McCrae, Modern Medicine, 1913, i, 783. 
Steinhardt and Lambert: Jour, of Infect. Dis., 1914, xiv, 87. 
Noguchi: Jour. Exp. Med., 1915, xxi, 539. 
Prowazek: Handb. d. Pathogenen Protozoen, 1912, i, 122. 
MacCallum and Moody: Amer. Jour, of Hygiene. 1921, i, 388 (Alastrim). 
Rivers and Tillett: Jour, of Exp. Med., 1923, xxxviii, 673. 
LITERATURE CHAPTER XXXVIII 
TYPES OF INJURY.-DISEASES DUE TO ANIMAL PARASITES 
Introduction. General relation of parasites to host. Table of main zoological divisions. 
Amoebic infections: Types of parasites and life-history; intestinal infection; liver abscesses; 
abscess of lung. Pyorrhoea alveolaris. Malaria: Types and life-history of parasites; 
symptoms and pathological anatomy; Blackwater fever. Trypanosome infections: biology; 
sleeping sickness. 
It has been seen that, through the invasion of the lowliest forms of plant 
life and their adaptation to a parasitic existence in the animal body, many 
diseases arise. This is not less true of members of several of the great 
groups of the animal kingdom which have undergone biological alterations 
in the course of a parasitic mode of existence, involving in many cases 
anatomical changes which separate them from their closest relatives. The 
animals which have thus come to live as parasites belong to the protozoa, 
the worms, and to a less extent to the arthropods. The student must be 
referred for a discussion of their anatomy and their systematic relations 
with one another and with the related free living forms, to works on zoology 
and parasitology, perhaps particularly to the volumes of Brumpt and 
Braun. Only a few types can be mentioned here in their relation to com- 
mon parasitic diseases of man. 
General Relation of Parasite to Host.-Those parasites which live on the 
body surface are more nearly capable of maintaining their existence apart 
from their host than the obligate parasites which spend their lives 
in the interior of the body. The latter may go through their whole 
life-history in the body of one animal, or may pass a stage of it as free living 
creatures in the outer world; but most of them with or without such a 
period of freedom are compelled to pass through an important epoch of 
their development as parasites in a totally different animal. This alterna- 
tion of generations is a most wide-spread phenomenon and leads to great 
complexities in the life-history of such parasites. So difficult to unravel 
are these metamorphoses and changes of host that the whole story of great 
numbers of parasites is still unknown, and that of even the most familiar has 
been revealed only recently. Thus the common tapeworm lives as a ma- 
ture worm in man, while its larval form is found in the ox; the Bothrio- 
cephalus of man passes its larval stage in various fish; the filaria which 
768 GENERAL RELATION OF PARASITE TO HOST 
769 
invades the blood and lymphatics of man is larval in a mosquito, and so on. 
Naturally, in order that the transfer from one animal to the other should be 
made at the proper time, extraordinary adaptations have come about. 
In blood-sucking insects which act as intermediate host, the larvae, or 
spores, as though by an intelligent decision, lodge themselves in the salivary 
glands, and nowhere else in the body, and are consequently inoculated into 
the blood of the next host. The effect of the specific adaptation is further 
seen in the complete dependence of the parasite upon one particular kind 
of intermediate host, as well as its particular kind of main host. Malarial 
organisms sucked into the stomach of a culex mosquito must die there al- 
though they develop in an anopheles, and after they have made the an- 
opheles infective for man they perish if by mistake it bites a cow, and in- 
jects them into the cow's blood. Many nematodes, or round worms, bring 
forth active larvae instead of eggs, and sometimes these are left to fend for 
themselves and attack their new host by their own activities. In this, 
some pursue a most devious course, as when the ankylostoma, necator, and 
strongyloides larvae penetrate into the skin of man and are swept by the 
blood into the lungs and bronchi whence they reach the intestine. Others, 
like ascaris, oxyuris, and trichocephalus, round-worm parasites of the in- 
testines, lead a simpler life, their eggs being transferred with water or 
vegetables to another person's alimentary tract, or more directly to that of 
the patient himself, producing an intense infection. Of their life in these 
hosts, and the duration of their stay, some idea may be derived from the 
examples given. 
Parasites act mechanically in several ways to injure the host. In the case 
of many of the worms which pass their larval stage in man (Taenia echinococ- 
cus, etc.), the great bulk of the cystic larva may occasion mechanical 
injury, especially in the brain, which lies in a confined space. The ordinary 
round worms (ascaris) produce many symptoms by mechanical irritation of 
the intestine and by wandering into such channels as the bile-ducts or the 
Eustachian tube or the appendix, where they cause obstruction. Strongyles, 
and the trematode, schistosomum, which live in the blood-vessels, may 
cause serious obstruction, disturbing the nutrition of the tissues. Toxic 
action is clearly associated with the uncinaria and bothriocephalus which 
produce profound anaemia, and Schaumann and Tallquist have isolated a 
haemolytic substance from the bothriocephalus. In other cases, as with 
malaria, the anaemia is produced in a more mechanical way by the destruc- 
tion of the corpuscles in which the parasites live. The trichocephalus and 
the uncinaria actually suck the blood from the intestinal wall. Inflamma- 
tory reaction following upon tissue destruction is characteristic of infection 
with the trichina, amoebae, and other organisms, and those which lodge in 
the tissues and remain there, commonly set up the new formation of much 
fibrous tissue in their neighborhood. 
The following table will serve to indicate briefly the relations of these 
organisms. TEXT-BOOK OF PATHOLOGY 
770 
PROTOZOA: * 
Sarcodina : 
Rhizopoda: Amoeba, etc. 
Mastigophora : 
Flagellata: 
Trypanosoma (Sleeping sickness). 
Leishmania (Kala azar). 
Giardia (Lamblia) intestinalis. 
Trichomonas, etc. 
Spirochaetae. 
Sporozoa: 
Telosporidia: 
Gregarinida. 
Coccidiidea. 
Haemosporidia (Malarial parasites). 
Neosporidia: 
Myxosporidia (Parasites of fishes). 
Microsporidia. 
Sarcosporidia (Occasional parasites of man). 
Infusoria : 
Ciliata: 
Balantidium, etc. 
WORMS: 
Cestoda (Tapeworms): 
Taenia. 
Bothriocephalus. 
Trematoda (Fluke worms): 
Distoma. 
Opisthorchis. 
Schistosomum, etc. 
Nematoda (Round worms): 
Filaria. 
Trichocephalus. 
Trichinella. 
Ankylostomum (Hook worm). 
Ascaris. 
Oxyuris, etc. 
ARTHROPODS: 
Arachnoidea: 
Acarina: Ixodes (Tick). 
Sarcoptes (Itch mite, etc.). 
Jnsecta: 
Rhyncota: Pediculi (Lice). 
Cimex (Bedbug). 
Diptera: Pulex (Flea). 
Musca (Fly). 
Culex 
Anopheles 
Mosquitos. 
There are known to zoologists great numbers of amoebse, most of 
which are free living; a few are parasitic in various animals, and among 
these are certain forms which infect man. Craig, in his recent paper, 
enumerates all the genera and species and points out that, although forms 
of Vahlkampfia and Trimastigamceba may be of interest as occurring in 
such a way as to be confused with the parasitic forms, it is only in the genera 
Craigia and Entamoeba that true parasites of man are found. Chief in- 
terest is attached to the genus Entamoeba, which, together with about 40 
other species, contains the forms Entamoeba coli and E. histolytica. Briefly, 
it may be said that E. coli is a harmless commensal in the intestine of man. 
It is found in a great proportion of healthy people who have never had 
AMCEBIC INFECTIONS AMOEBIC INFECTIONS 
771 
dysentery, and is distinguished from E. histolytica as follows. It averages 
30 microns in diameter, is grayish and dull-looking, without clearly defined 
ectoplasm, and possesses a large nucleus. Its movements are sluggish, 
and when it becomes encapsulated it divides into eight young entamoebae. 
The Entamoeba histolytica is a distinct parasite in the intestine of man, and 
produces there and in other organs most intense destructive changes. It 
is recognizable by its larger size (20-60 microns) and by the striking con- 
trast between its granular cytoplasm 
and its glassy, refractive, colorless 
ectoplasm. This latter is usually in 
active motion, throwing out and re- 
tracting pseudopods into which the 
remainder of the body streams. It 
multiplies also by fission, and when it 
undergoes encapsulation divides into 
four new amoebae. The Entamoeba 
tetragena is identical with this. 
The pathogenic amoebae are possibly 
introduced into the digestive sys- 
tem with uncooked vegetables or con- 
taminated water, although, as Walker 
and Sellards have shown, it must be 
remembered that the amoeboid, or 
vegetative form, is very little resist- 
ant to exposure to external conditions. 
The more resistant encysted form is, 
however, found in the stools of many 
apparently healthy carriers, and trans- 
mission is probably more easily ex- 
plained as the result of contamina- 
tion of food by these people. It has 
been shown by experiment that they 
are pathogenic for cats also. They 
have probably not been cultivated 
outside the body. 
Intestinal Infection.-In the intes- 
tine the amoebae find their way into 
the crypts of the mucosa of the colon 
and there produce small areas of necro- 
sis from which further invasion into 
the submucosa occurs. In most cases 
the mucosa of the colon is the only area affected, the invasion taking 
place especially in the upper part of the large intestine. It is rare to find 
any lesions in the lowermost part of the ileum or in the appendix. 
The earliest changes appear as elevations in the mucosa, with hyperemia 
or haemorrhagic halo and a central plug of yellowish, necrotic material. 
Fig. 377.-Amoebic colitis. There 
are numerous confluent and discrete 
elevated necrotic patches and many 
small ragged ulcerations. 772 
TEXT-BOOK OF PATHOLOGY 
Sometimes these elevations become quite large before the necrotic tissue is 
discharged, and I have seen cases in which the whole mucosa was covered 
with such patches without definite ulceration (Fig. 377). Usually, how- 
ever, the softened substance falls away and reveals ulcers which show a 
great tendency to undermine the mucosa and to coalesce with one another, 
leaving bridges of mucosa between them. This is not always the case: 
numerous large or small discrete ragged ulcers may be formed instead; 
but when it occurs extensively, as it does in some cases, the undermined 
mucosa dies and is found hanging in long shreds or sheets from the wall 
(Fig. 378). In one case observed recently at autopsy nearly the whole 
mucosa was thus destroyed, and great blackened, ragged films of mucosa 
were found hanging in the lumen. As a rule, the process is rather slow, 
and attempts at healing take place, so that the intestine tends to become 
greatly thickened by the formation of granulation tissue rather than to be 
perforated. Nevertheless, perforation does sometimes occur and is usually 
met by adhesions, so that only local abscesses are produced. Narrowing of 
the gut may follow such ulceration and healing. 
Microscopically one may find in the earliest stages minute ulcers involv- 
ing the mucosa alone, with amoebae in the margins of the tissue (Fig. 379), 
but more commonly the ulcer is found to extend in the submucosa and to 
Fig. 378.-Amoebic colitis. Two large ulcerated areas over which the mucosa has been 
undermined and hangs in necrotic shreds. 
be partly filled with disintegrated tissue with fragmented nuclei. On 
account of the exposure to the intestinal contents many bacteria are present 
and there is some inflammatory reaction, but this is by no means so promi- 
nent as in the case of the bacterial forms of dysenteric ulceration. In the 
edges of the necrotic tissue the amoebae are found lying in the crevices. 
Often they can be traced far into the submucosa or down into the interstices 
of the muscle or even into the subserous tissues, and when they are found, 
those in advance are usually not surrounded by any reaction nor by any AMCEBIC INFECTIONS 
773 
evident changes in the tissues. At times they are observed underneath 
the endothelium of the branches of the portal vein, and in many cases I 
have found them lying free in the lumen of such venules together with the 
blood-cells. This is important, since it explains readily their transportation 
to the liver. The reparative changes are quite like those seen in any other 
ulcer, but it is evident that they are frustrated by new necrosis of the tissue 
and must be repeated constantly. 
There is practically no difficulty in recognizing the amoebae which are 
found invading the tissue as the cause of the disease, although the clinician 
may run the risk, in the examination of the faeces, of mistaking the harmless 
and common E. coli for the pathogenic form. 
Such ulcerative dysentery causes diarrhoea, with much tenesmus or pain- 
ful straining, and the stools are made up of small amounts of mucus flecked 
with blood. The mucus may contain the amoebae, but they are found more 
abundantly after a saline cathartic is given. The infection is extremely 
persistent and often drags on for months or even years. 
Fig. 379.-Beginning amoebic ulceration of the mucosa of the colon. Amoebae (a) are 
seen in the crypts, in the stroma of the mucosa and submucosa, and in one case beneath 
the endothelium of a vein. 
Liver Abscesses.-Of the sequelae of amoebic dysentery, the commonest 
is the development of abscess of the liver. It is known that amoebae enter 
the branches of the portal veins in the intestine, and are swept into the liver, 
where they lodge in the capillaries and produce effects similar in principle 
to those set up in the intestine. The amoebae in the intestine take into their 
cytoplasm red corpuscles and bacteria as well as the debris of tissue-cells, 
and it is not surprising, therefore, that there are sometimes evidences of 
bacterial infection in the liver also. But usually it seems that these bac- 
teria are digested, for the abscesses are likely to be sterile except for the 
presence of the amoebae themselves. Although the lesions are commonly 774 
TEXT-BOOK OF PATHOLOGY 
called abscesses, they are really not quite like the abscesses produced by 
pyogenic bacteria, inasmuch as the amoebae cause the necrosis and liquefac- 
tion of tissue without any very pronounced inflammatory reaction. The 
contents of such abscesses, therefore, consist chiefly of the debris of liver 
tissue, with relatively slight admixture of leucocytes. Ordinarily only one 
such abscess is found, but in about one-third of the cases the abscesses are 
multiple, two or three rather large cavities being found in different parts 
of the organ (Fig. 380). Rarely there are hundreds of small foci. The 
drawing shows well the appearance of the rapidly forming fresh abscesses, 
of which there were several in this case, together with numerous very small 
ones. A description of the case may serve to present the fresher stages. 
The small abscesses (from which the contents can be squeezed out like 
paint) appear as opaque, yellowish-white areas occupying the space of one 
or two lobules. The large ones have a definite cavity lined with yellowish- 
Fig. 380.-Multiple amoebic abscesses of liver (Mense's Handb. d. Tropenkrank- 
heiten). 
white necrotic material resembling badly made custard. In the cavity one 
may find a similar substance or a turbid fluid with shreds of necrotic tissue 
hanging from the wall. In one abscess in this case there was a clear, straw- 
yellow fluid. The surrounding tissue ends abruptly in the necrotic lining 
of the abscess, but from the rapid extension of the cavity and the accumula- 
tion of fluid it becomes much compressed. The effect of this pressure is to 
stop the outflow of blood from regions drained by branches of the hepatic 
vein which pass by the abscess, and thus to produce local areas of passive 
congestion. The same thing is to be observed in the neighborhood of 775 
AMCEBIC INFECTIONS 
metastatic tumor nodules in the liver. Other areas become anaemic from 
the compression of branches of the portal vein. 
Far more commonly one finds the abscesses in a more advanced state in 
which it is no longer possible to recognize necrotic curdled liver tissue in the 
contents. Then they are filled with thick, creamy, gelatinous, purulent 
fluid or with a more pasty tenacious opaque material, which is often stained 
greenish from the admixture of bile from some duct which has been invaded. 
In these abscesses efforts at healing have been made in the adjacent liver 
tissue which result in the formation of a thick wall of granulation tissue. 
After that, the advance of the abscess through the liver tissue is far slower. 
Even when a distinct wall is formed, shreds and long strands of necrotic 
liver tissue may be found hanging in the cavity. Later still, the amoebae 
may die out, most of the fluid be absorbed from the pus, and the wall 
Fig. 381.-Subacute amoebic abscess of the liver. The amoebae are seen in the crevices 
of the loose connective tissue which is forming round the abscess. 
contract down around the mortar-like material which remains. Usually 
this becomes pigmented with an orange-yellow pigment derived from ex- 
travasated blood, finally the whole may be replaced by a pigmented scar. 
But although one occasionally sees this spontaneous healing, it occurs in 
my experience usually in those cases in which another abscess has formed 
elsewhere in the liver or in the lung, or in which rupture of the abscess has 
taken place either spontaneously or through surgical intervention. 
The affection is a very serious one, and the mortality is high even with 
modern treatment. The growth and extension of the abscesses often bring 
them to the surface of the liver, so that other tissues are invaded and rupture 776 
TEXT-BOOK OF PATHOLOGY 
occurs in one or other direction. The commonest site is in the dome of the 
right lobe, whence extension can occur through the diaphragm into the 
substance of the adherent lung, with rupture and discharge of the pus 
(now stained brownish-red, "anchovy sauce appearance") through the 
bronchus, so that it is coughed up and expectorated. This is the most 
frequent and favorable outcome. But extension and rupture may also 
occur into the free pleural cavity or the pericardium, into the peritoneal 
cavity or adherent colon or stomach or duodenum, or even through the 
outer skin. More rarely the portal vein or vena cava receives the con- 
tents of the abscess. 
Histologically the appearances vary with the age of the abscess. In 
the very fresh ones the form of many liver-cells can still be seen, there is 
oedema of the surrounding tissue, the amoebae are found in the edge of the 
living tissue, and there are a few mononuclear wandering cells whose nuclei 
are mingled with the fragmented nuclei of the tissue. Later the necrotic 
lining of the cavity loses its recognizable constituents and shows only a 
mass of nuclear fragments with a few leucocytes (Fig. 381). The amoebae 
are still found only in the margin of the living tissue unless the abscess has 
been opened to the air. This is because of their need of oxygen, and it is 
observed by surgeons that when an amoebic abscess is opened, no amoebae 
are to be found in the pus which escapes, but only in scrapings of the wall. 
Next day, however, after the cavity has been exposed to the air, the pus 
which escapes is full of active amoebae. When the dense connective tissue 
with its lining of partly necrotic granulation tissue is formed the amoebae 
wander in the crevices of that tissue. 
These abscesses may reach a great size before rupture or evacuation takes 
place and may contain several litres of pus. They consequently destroy 
much of the liver tissue and occasionally one may find efforts at its re- 
generation. 
Abscesses of the lung of quite the same character are produced by 
transportation of the amoebae from the liver, apparently by way of the he- 
patic veins rather than by direct extension. Indeed, Bunting was able to 
trace in one of our cases emboli containing amoebae from a thrombus in the 
hepatic vein which also contained them, and to show that this embolism 
of the pulmonary arteries had produced an amoebic abscess in the lung. 
By this time the original amoebic ulcers in the intestine were healed. 
In the so-called Rigg's disease, or pyorrhoea alveolaris, the Entamoeba 
buccalis has been thought to be the aetiological factor and is found in great 
numbers in the pus which forms in the cavities between the loosened gums 
and the roots of the teeth. Such cavities extend down into the alveolar 
process of the jaw, which is eroded away. The good effects of emetine in 
curing the disease seemed to show that the amoebae are responsible for its 
existence, but doubt has been cast upon this recently. 
LITERATURE 
Craig: American Medicine, 1905, ix, 854. Arch. Int. Med., 1914, xiii, 737. 
Schaudinn: Arb. a. d. Kais. Gesundheitsamte, 1903, xix, 547. MALARIA 
777 
Councilman and Lafleur: Johns Hopkins Hosp. Rep., 1891, ii, 395. 
Musgrave and Clegg: Bull. Gov. Laboratories, Manila, 1904, xviii. 
Sachs: Arch. f. kl. Chir., 1876, xix, 235. 
Kruse and Pasquale: Zeitsch. f. Hyg. u. Infektionskr., 1894, xvi, 1. 
MacCallum: Handb. d. Tropenkrankheiten, Mense, 1906, iii, 22. 
Bunting: Arch. f. Schiffs- u. Tropenhygiene, 1906, x, 73. 
Woolley and Musgrave: Bureau of Gov. Laboratories, Manila, 1905, xxxii, 31. 
Futcher: Jour. Amer. Med. Assoc., 1903, xli, 480. 
Bass and Johns: Jour. Amer. Med. Assoc., 1915, Ixiv, 553. 
Walker and Seilards: Philippine Jour, of Sci., B, 1913, viii, 253. 
James, W. M.: Ann. Tropical Med. and Parasitology, 1914, viii, 133. 
MALARIA 
Since the discovery by Laveran in 1880 of the protozoan parasites which 
cause this disease, it has been possible to give a precise reason for the ex- 
istence of three different types of malarial fever in man, since it is found 
that there are three different species of parasite. These can be recognized 
through differences in their morphology and by the differences in the time 
required for them to become mature, which decides the type of fever. 
Tertian malaria is that in which there is a chill every other day. In 
quartan malaria the chill comes on every third day, while in the sestivo- 
autumnal forms chills and the associated fever appear at irregular intervals. 
The tertian parasite (Plasmodium vivax) is found in the red blood-cor- 
puscles in the form of a pale, amoeboid body growing rapidly to a rather 
large size and accumulating yellowish-brown pigment in fine granules which 
dance actively. It causes swelling and pallor of the red corpuscle which 
contains it, and on reaching maturity divides into 18 to 20 segments leaving 
the pigment in the centre of the rosette. Flagellated forms are seen. It 
requires forty-eight hours to develop from the earliest small hyaline form 
without pigment to the point of segmentation. 
The quartan parasite (Plasmodium malarise) appears also as a small hya- 
line body in the red corpuscles; it grows more slowly, requiring seventy- 
two hours to complete its development up to the point of segmentation, 
and is throughout smaller and more dense and refractive than the tertian 
form. It produces blackish pigment in coarser granules and is more quies- 
cent than the tertian form. Finally it breaks up into a small rosette of 6 
to 12 segments, having at no time caused the corpuscle to swell or become 
pale, but leaving it rather shrunken and deeply colored. 
The cestivo-autumnal parasite (Plasmodium falciparum) is often at first 
ring-formed, but later becomes an amoeboid body with brownish pigment. 
It develops in twenty-four to forty-eight hours and forms 8 to 10 seg- 
ments, but these are rarely seen in the circulating blood, although they 
are to be found in the spleen and perhaps other internal organs. In its 
more mature form the organism is often found in the circulating blood in 
the shape of a rounded crescent, across the concavity of which the re- 
mainder of the corpuscle is seen to stretch. Such crescents may or may 
not give rise to the flagellated forms. 778 
TEXT-BOOK OF PATHOLOGY 
In studying the related forms, Proteosoma and Halteridium, in birds, 
and the sestivo-autumnal form in man, I was able to show that when these 
parasites were removed from the circulation the mature forms proceeded 
to enter upon a sexual cycle. During the existence of any of the types as 
parasites in the blood-corpuscles of the circulating blood, they merely con- 
tinue the asexual cycle, wherein they grow in the corpuscle for a certain 
time, after which they divide by fission into many small segments which 
burst out of the corpuscle and enter others, starting the cycle afresh. 
The sexual cycle has a different purpose. Under the microscope the 
mature forms are seen to break out of the blood-corpuscles into the plasma. 
Some remain quiescent; others, after violent convulsions of the proto- 
plasm, throw out long, active flagella which beat about and soon become 
separate free-swimming threads, like spermatozoa. These make their way 
to the quiescent forms, and of the little swarm which hovers about each of 
these female forms, or macrogametes, it is seen that one and only one buries 
itself in the protoplasm, while the rest perish. The flagella, or microga- 
metes, are really analogous to spermatozoa. A short time after the fertili- 
zation the zygote, or fertilized form, becomes very active and wanders about. 
At this point Ross, in India, discovered that there appeared pigmented cysts 
m the walls of the stomach of those mosquitoes which have bitten persons 
ill with malaria, and formed the idea that the process of fertilization and 
formation of a motile zygote described above must occur in the mosquito's 
stomach, and that the development of cysts in the walls of that organ must 
be due to the fact that this new active zygote could push its way into that 
situation and there become encapsulated. After that, Ross found that 
minute transparent spores were produced in great numbers in such cysts 
and liberated into the body cavity of the mosquito. Thence they wandered 
into the epithelial cells of the salivary gland of the mosquito, and were in- 
jected into the blood of the next person bitten, together with the salivary 
secretion. There the spores or sporozoites entered the red corpuscles 
exactly as did the hyaline segments from the rosette of the asexual stage. 
Hence, since an important part of the development occurs in the body of the 
mosquito, which is thus a host of the parasite, it seems certain that trans- 
mission to human beings must always occur in this way. Further, it is 
learned that while a form of culex transmits the proteosoma to birds, it is 
incapable of transmitting any human form of the parasite. For these 
another mosquito (anopheles) is the specific host and transmitting agent. 
To recapitulate briefly, the malarial parasite passes part of its existence 
in the blood-corpuscles of man, where it goes through a round of develop- 
ment ending in segmentation and the infection of other corpuscles by the 
segments which are set free. The other part of its existence is passed in 
the body of the mosquito. In the mosquito's stomach the elaboration of 
the sexual forms, conjugation, and the development of the actively motile 
zygote take place. There follows penetration of the stomach wall by the 
zygote, its encapsulation and the formation of tiny spores or sporozoites, 
which, wandering through the body cavity into the salivary glands, are MALARIA 
779 
injected by the bite of the mosquito into the human body, infect the cor- 
puscles, and start again the asexual cycle. 
Symptoms.-The evil effects of infection in the human being are there- 
fore dependent upon the asexual cycle alone. The liberation of the seg- 
ments involves the bursting and destruction of the red corpuscle, the spill- 
ing of the remaining haemoglobin and of the malarial pigment into the 
plasma, and the wandering of the motile segments to new corpuscles. 
This is accompanied by a sudden and extreme rise in temperature with a 
chill. According to the length of the cycle of development the chills are 
spaced twenty-four, forty-eight, or seventy-two hours apart. But this is 
Fig. 382.-Malaria. Capillary in the brain filled with parasites of the sestivo-autumnal 
type- 
only because large groups of parasites reach maturity at those moments. 
If, for example, in the tertian infection the parasites are not all of the 
same age, but fall into two groups which mature at different times, there 
may be a chill every day. The liberation of haemoglobin and of malarial 
pigment, which is a kind of melanin, results in the pigmentation of the or- 
gans with haemosiderin and melanin, and the associated destruction of red 
corpuscles produces an anaemia which may reach a profound degree. There 
is, as a rule, a marked diminution in the number of leukocytes, although 
there may at times be a leucocytosis during the chills. The relative num- 
ber of lymphocytes is increased. 
The severer symptoms of the disease, aside from the anaemia and general 780 
TEXT-BOOK OF PATHOLOGY 
evidences of poisoning which may constitute what is commonly spoken of 
as cachexia, are dependent upon the great accumulation of the parasites 
in the brain or in the gastro-intestinal mucosa. There are, of course, other 
phenomena due to injuries to the liver and kidneys, but the symptoms of 
general intoxication are sometimes combined with coma when the brain is 
especially affected, or with choleriform diarrhoea when the intestinal capil- 
laries are loaded with parasites. In all cases the spleen becomes enlarged, 
and when the infection has lasted a long time, it may be enormous and 
very hard. 
Fig. 383.-Malaria. Liver from a case of malaria of long standing. Endothelial cells 
and wandering cells in the capillaries are loaded with clumps of pigment. 
Pathological Anatomy.-At autopsy there is a distinct slaty or blackish 
pigmentation affecting especially the spleen, the liver, the brain, and some- 
times the intestinal mucosa. It is due not only to the parasites themselves, 
with their grains of pigment, but more especially to the quantities of pig- 
ment set free from other parasites and now held in innumerable phagocytic 
cells, both of the type of wandering macrophages and of the endothelial 
cells of the capillaries. This pigmentation is the most characteristic feature 
in the autopsies performed upon cases which have died after protracted 
infections. MALARIA 
781 
In the brain, the endothelial cells of the capillaries in the brain substance 
may show such pigment, but in intense infections one often finds that the 
capillaries are actually plugged with masses of corpuscles bearing parasites, 
together with phagocytic cells and occasional free parasites (Fig. 382). 
In the intestine the same condition may prevail, the capillaries of the 
mucosa being rendered impermeable by the mass of these cells. 
In the liver Barker has described focal necroses. I have not found these 
in other cases, but there are always parasites in the capillaries and much 
pigment is present, especially in the stellate cells of Kupfer and in the en- 
dothelial cells in general (Fig. 383). 
Fig. 384.-Malaria. Splenic pulp in sestivo-autumnal infection showing many pig- 
mented parasites either free or enclosed in large phagocytic cells. 
The spleen is particularly rich in the parasites and, indeed, in the case 
of the sestivo-autumnal form, the segmenting forms are to be found only 
there. The endothelial cells of the splenic sinuses are loaded with pigment 
and with fragments of cells and parasites (Fig. 384). These cells become so 
enlarged and so distended with this material that they finally burst, the 
debris being taken up by other phagocytic cells which are less engorged. 
Mononuclear wandering cells of other types take part in this process as 
well. Here, as in Hie liver, much of the pigment is the iron-containing 782 
TEXT-BOOK OF PATHOLOGY 
haemosiderin derived from the haemoglobin set free in the destruction of the 
red corpuscles. In later stages there is found a great increase in the amount 
of connective tissue throughout the organ, doubtless caused to grow by the 
presence of so much pigment and the long-continued infection. 
The bone-marrow is likewise pigmented, and while showing little new 
formation of polynuclear leucocytes, is rich in large phagocytic endothelial 
and reticular cells which have acted as macrophages. 
Many other changes in the organs, such as cirrhosis of the liver, chronic 
nephritis, etc., have been ascribed to the action of the malarial parasite, 
but it seems that the evidence in these cases is not quite decisive. 
LITERATURE 
Thayer and Hewetson: Malarial Fevers of Baltimore, Johns Hopkins Hosp. Rep., 1895, 
vol. v, 3 (Early literature). 
Thayer: Lectures on the Malarial Fevers, New York, 1897. 
Barker: Johns Hopkins Hosp. Rep., 1895, vol. v, 219. 
Laveran: Bull, de l'Acad. de med. de Paris, 1880, ix, 1268. Com pt. Rend, de l'Acad. 
des Sc., 1881, xlii, 627. 
Ross: Malaria, Nobel Lecture for 1902, Stockholm, 1904. 
MacCallum: Jour. Exp. Med., 1898, iii, 103. Lancet, 1897, ii, 1240. 
Elting: (Inoculation) Zeitschr. f. kl. Med., 1899, xxxvi, 491. 
Daniels: Proc. Roy. Soc., 1899, Ixiv, 443. 
Bastianelli and Bignami; Grassi; Celli: Ann. d'lgiene Sperimentale, 1899, ix, 245. 
(Beautiful plates.) 
Nuttall: Centbl. f. Bakt. u. Paras., I. Abth., 1899 and 1900, xxv-xxvii. 
Schaudinn: Arb. a. d. Kaiserl. Gesundheitsamt, 1904, xx, Heft 3. 
Ewing: Jour. Exp. Med., 1900, v, 419. 
In persons who have had malaria or who are still infected with the parasites there may 
occur a violent and rapidly fatal disease in which the most striking symptom is the 
passage of red or almost black urine, the color being due to the presence of haemoglobin. 
Diminution of the urine to complete anuria may follow. There are general evidences of 
intoxication, with the most rapid and extreme blood destruction, which quickly leads to 
profound anaemia. The spleen is greatly swollen and tender, there is vomiting and 
intense icterus and fever. Recovery may occur without conferring any immunity, but 
rather predisposing to another attack, or the patient may die from suppression of urine 
or from exhaustion. 
The condition has every appearance of being due to the action of some intense poison 
which produces haemolysis, but no such poison has been demonstrated. In some patients 
the administration of quinine will bring on an attack, but there are many cases in which 
it occurs although no quinine has been given. There are several hypotheses as to its 
nature: That it is an especially intense manifestation of malaria; that it is due to 
quinine and, lastly, that it is caused by some specific infectious agent as yet undiscovered. 
Most writers, failing to prove any of these theories, conclude that malaria produces a 
condition which predisposes to blackwater fever, which may at times be induced under 
the circumstances by quinine. In spite of the earnest endeavors of many investigators, 
the matter is no more cleared up than this. The advocates of the theory that there is a 
specific infective agent have not proven their point. 
At autopsy the spleen is found to be greatly swollen with many phagocytes and with 
extensive necroses. It is bright red and velvety on section, in contrast to the slaty or 
H^MOGLOBINURIC OR BLACKWATER FEVER TRYPANOSOME INFECTION 
783 
blackish spleen of chronic malaria. Necroses occur also in the lymphatic glands and in 
the liver. The kidneys are somewhat enlarged and flecked with red and black dots which 
are due to the haemoglobin in the tubules. The glomeruli are usually normal, the tubules 
filled with irregular clumps of haemoglobin, their epithelial cells slightly degenerated. 
Acute nephritis supervenes in some cases. 
LITERATURE 
Deaderick: Memphis Med. Monthly, 1907, xxvii, 637, et seq. 
Whipple: Malaria, 1909, i, 215. 
Deeks and James: Report on Haemoglobinuric Fevers in the Canal Zone: Isthmian 
Canal Commission, 1911. 
Various diseases of animals and at least one disease of man are caused by 
the invasion of the trypanosomes, which are large flagellated organisms of 
elongated form with an undulant membrane rising from the blepharoplast 
at the posterior end and terminating in the long flagellum at the anterior 
end. These multiply by fission in the circulating blood and invade all the 
tissues, being found especially in the lymph-glands and spleen and in the 
central nervous system and meninges. The intermediate host is some form 
of biting insect-in the case of Trypanosoma lewisi of the rat it is a louse, 
in the tsetse-fly disease of cattle (nagana) caused by T. brucei it is a fly 
(Glossind). In the sleeping sickness of human beings, caused by T. gam- 
biense and T. rhodesiense, it is also a Glossina, the G. palpalis being con- 
cerned in the first and G. morsitans in the second case. 
The organisms conjugate in the intestine of the fly, and smaller flagellated 
forms are produced in great numbers which enter the salivary glands and 
are inoculated into the new host by the next bite. 
The infection is extremely persistent and produces in man a disease 
which is fatal after a prolonged illness, or, at least, in spite of every effort 
at cure, drags on for a very long time. The sleeping sickness, a disease 
essentially of Africa, is characterized by swelling of the glands and fever, 
later followed by disinclination to work, rapid fatigue, and a soporous con- 
dition which may pass into almost continuous sleep. Occasionally there 
is agitation and delirium. The victims become greatly emaciated and lie 
helpless until they die, with or without the help of intercurrent infections. 
The organisms are found widely scattered in the tissues, and in the brain 
produce hyperaemia and infiltration of the meninges and perivascular tis- 
sues, somewhat resembling that in dementia paralytica. 
TRYPANOSOME INFECTION 
LITERATURE 
Laveran and Mesnil: Trypanosomes (Tr. by Nabarro, Chicago, 1907). 
Liihe: Mense's Handb. d. Tropenkrankheiten, 1906, iii, 69. 
Mense: Ibid., 617. 
Kinghorn, Yorke, Lloyd: Annals of Trop. Med. and Paras., 1913, vii, 183 (Rep. Sleep- 
ing Sickness Commission). 
Wolbach and Binger: Jour. Med. Research, 1912, xxvii, 83. 
Novy and McNeal: Jour. Infect. Dis., 1904, i, p. 1. CHAPTER XXXIX 
TYPES OF INJURY.-DISEASES DUE TO ANIMAL PARASITES 
(Continued) 
Cestode Infections: Tcenia and bothriocephalus; T. echinococcus; echinococcus cysts in 
man. Trematode infections: Bilharziosis; Paragonimus and Clonorchis Trichiniasis: 
Biology of the parasite, symptomatology, pathological anatomy. Uncinariasis: Symptoma- 
tology; life-history of parasite; pathological anatomy. Infections with ascaris, oxyuris, 
trichocephalus, and filaria. Elephantiasis. 
Four principal types of cestode worms are concerned in the infection of 
human beings, as follows: 
Tcenia saginata, or mediocanellata 
Tania solium 
Bothriocephalus latus 
Tcenia echinococcus 
Each of these worms requires an intermediate host for the development of 
its larval form, after which the ingestion of the tissues of that host allows 
the formation of the mature worm in the definite host. 
Taenia saginata is found in its mature form in the small intestine of man, 
whence ripe segments, loaded with eggs, are discharged. The eggs pass into 
the digestive tract of the ox, and the embryo penetrates through the in- 
testinal wall by the aid of six booklets at its anterior end. It is then swept 
everywhere by the blood-stream, and lodging in muscles develops into the 
cystic larval form which, if the beef be eaten uncooked, becomes the mature 
form once more in the human intestine. The mature tapeworm has a 
head with four suckers but no hooks. Its segments are characterized by 
having a great many lateral uterine diverticula filled with eggs. 
Taenia Solium.-The mature worm, which is provided with a circle of 
hooks as well as four suckers on its head, is rare in the human intestine in 
this country. It has segments which differ from those of T. saginata in 
showing relatively few lateral uterine pouches. The eggs get into the 
intestine of the pig, and exactly as in the case of the T. saginata, pass into 
the muscle and organs to produce cystic larvae (Cysticercus cellulosae). 
Occasionally by self-infection the eggs can reach the intestine of man, who 
then becomes also the intermediate host, allowing the development of the 
Cysticercus cellulosae in his organs. There is a specimen in the Baltimore 
museum which shows a human brain studded everywhere with cystic 
larval forms of the T. solium. 
CESTODE INFECTIONS 
784 CESTODE INFECTIONS 
785 
Bothriocephalus Latus.-The larval form of this worm is found in the 
muscles of several fish, including the salmon, trout, perch, ling, etc., upon 
the ingestion of which the mature worm develops in the human intestine. 
It is a large, broad worm with elongated lateral suckers and with a different 
arrangement of the geni- 
talia, the genital opening 
being on the face of each 
segment instead of at the 
edges, as in the taenia. Its 
presence in the intestine 
causes an intense anaemia 
which has already been 
mentioned. 
Taenia Echinococcus.-In 
the case of this worm, of 
which there are two varie- 
ties, man is the interme- 
diate host, while the mature 
form is a parasite of the in- 
testine of the dog. It is 
a very small worm, only 3 
to 6 mm. in length, in con- 
trast to those taeniae just 
described, which may reach 
the length of 30 to 40 feet. 
Many other animals can 
also act as the intermediate 
hosts. The adult is a worm 
with four suckers and two 
rows of hooks, which forms 
only three or four segments 
instead of many hundreds. 
From dogs, especially in 
such countries as Iceland, 
where men and dogs live in 
the same rooms, the eggs 
are transmitted to the hu- 
man digestive tract. The 
wandering of the embryos 
can take them to any organ 
of the body, and the devel- 
opment of the huge cystic larva is reported for every possible situa- 
tion. In the case of T. echinococcus, single cysts form, but in infection 
with the allied form, T. multilocularis, the larval cysts are like a ramifying 
spongy tissue full of small cavities. The parasite produces injury by the 
Fig. 385.-Echinococcus cysts in the liver. 
Daughter-cysts with chitinous wall are dislocated 
from the outer wall. 786 
TEXT-BOOK OF PATHOLOGY 
space it occupies (as in the brain), or by the toxic products or by the devel- 
opment of great numbers of secondary cysts through the rupture of the 
first and the liberation of the larvae. 
When the eggs hatch in the human intestine, the embryo bores through 
the intestinal wall and is transported by the blood-stream to its lodging 
place. There it grows and surrounds itself with a thin, chitinous membrane 
of pearly translucence which in turn is densely enclosed in a capsule pro- 
duced by the reaction of the surrounding tissue. Inside the chitinous mem- 
brane the embryonic tissue grows and separates in its central part to allow 
Fig. 386.-Chitinous wall of echinococcus cyst with lining membrane of the parenchyma 
of the worm and several daughter cysts with scolices. 
of the accumulation there of a clear fluid rich in salt and albumin. It 
thus becomes a lining of a cyst (Fig. 385). From this lining there spring 
up buds which may be extremely numerous as the cyst grows larger, and 
are finally recognizable as the heads of new worms. Some of the buds 
may, however, enlarge and themselves become hollow and constitute 
daughter cysts in whose lining once more there may spring up little buds 
which give rise to new heads (Fig. 386). Such buds in the main cyst or in 
the daughter cyst elevate themselves in bunches on little stalks and are now 
seen to be invaginated, so that what is to become the head of the adult 
worm is now turned inside out, so that in the dell at the tip of the bud one 
finds the crown of booklets and four suckers facing inward (Fig. 387). CESTODE INFECTIONS 
787 
Fig. 387.-Single scolex or head from echinococcus cyst cut in median line, showing in- 
verted suckers and rostellum of hooks. Two of the hooks are drawn separately. 
Fig. 388.-Old echinococcus cyst of liver with mortar-like contents. The chitinous 
lining is loosenod and thrown up in folds. TEXT-BOOK OF PATHOLOGY 
788 
With the liberation of such buds or scolices by the ingestion of the cyst 
material by a dog or other suitable host, the heads are quickly evaginated 
so that suckers and hooks present themselves in proper relations and fix 
themselves in the mucosa of the intestine, after which the worm proceeds 
to assume its mature form. 
Such cysts are quite common in the liver of the pig, where they are mul- 
tiple and cause huge enlargement of the organ. Later, in any organ which 
harbors such a cyst, if the opportunity for its ingestion by the definite host 
is postponed, the embryos may die and the fluid be absorbed. There 
remains what is easily recognizable as an obsolete echinococcus cyst, a 
rounded mass of mortar-like whitish material densely encapsulated with 
fibrous tissue, underneath which can still be discerned the wavy, lami- 
nated, translucent chitinous membrane which is in itself so peculiar as to 
be of diagnostic importance (Fig. 388). In the crumbly mass left after 
absorption of the fluid loose booklets can be found scattered about, de- 
rived of course from the armament of the dead scolices. 
The dissemination of some toxic material often gives rise to repeated 
attacks of urticaria and also to an alteration of the blood plasma, such that 
the presence of the echinococcus cyst can be recognized by complement 
deviation reactions. 
Stiles: Hygienic Laboratory, Marine Hosp. Service, Bulletins 25 and 28 (Cestode para- 
sites of man). 
Stiles and Hassal: Index catalogue of Medical and Veterinary Zoology, Washington, 
1908. 
Braun: Thierische Parasiten des Menschen, Wurzburg, 1903 (Transl. 1906, New York). 
Brumpt: Precis de Parasitologic, Paris, 1910. 
Marchand: Handb. d. allg. Pathologie, 1908, i, 340. 
Melnikow Raswedenkow: Echinococcus multilocularis, Ziegler's Beitr., 1901, iv, 
Suppl.-Heft, 5. 
LITERATURE 
Fluke worms rarely cause disease in man in this country, but there are 
several wide-spread types of human disease due to their invasion in 
Africa and Asiatic countries. 
Of these, the most important is the bilharziosis, caused by the various 
forms of Schistosomum. These are trematode worms in which the sexes are 
separate, the male being provided with a gynaecophoric canal in which the 
female is carried during conjugation. There are three known forms: 
S. haematobium, which is the common African form, producing eggs with 
a terminal spine; S. mansoni, found in the West Indies and South Amer- 
ica and probably also found in Africa, with eggs with a lateral spine, 
and S. japonicum, the Asiatic form, whose eggs are elliptical and with- 
out any spine. It has been shown by Leiper that the eggs set free in the 
water motile miracidia, which invade various snails, Bullinus, Planorbis, 
Blanfordia, Physopsis, Limnaeus, etc., in which they develop into active 
TREMATODE INFECTIONS TREMATODE INFECTIONS 
789 
cercariae, which escape into the water and can penetrate the skin of per- 
sons bathing. The eercarise wander in the body and become mature in 
the veins. The eggs are carried into various tissues and cause destruction 
and scarring. S. haematobium produces especially haematuria because of 
infection of the urinary tract with formation of polypoid granulation 
tissue in the bladder. There is prostatitis and intense cystitis, often with 
fistulous communications with surrounding tissues, renal infection, etc. 
Vesical calculi are frequently formed. S. mansoni causes chronic dysen- 
tery with tenesmus and the passage of blood. There is great thickening 
of the mucosa of the colon with the formation of polyps loaded with 
eggs. S. japonicum also produces dysentery, but no infection of the urinary 
tract. Later it gives rise to cirrhosis of the liver through the irritating 
deposit of its eggs in the tissues of that organ. In an autopsy which I 
saw recently the liver was hard and nodular, and in the depressions be- 
tween the nodules there were ochre-yellow patches which proved, when 
portions of the capsule were torn oft and examined with the microscope, 
to be full of eggs which gave the yellow color. On section, the same yellow 
discoloration was to be seen through many of the scarred areas. Similar 
patches of dull yellow were found in the mucosa of the colon, and in these, 
too, there were found thousands of eggs. 
Paragonimus westermanii is another trematode which causes in For- 
mosa, Japan, and Korea frequent infection of human beings. It gives 
rise to cough with haemoptysis and later to emaciation and anaemia. In 
some chronic cases epileptic seizures of Jacksonian type form the final 
symptoms. The worm is found in its mature form encapsulated in the 
lungs, where it sets up an inflammatory reaction. The capsules are always 
connected by channels with the bronchi, and often with one another. 
Indeed, the worms may lodge and form their capsule within the lumen 
of the bronchus. In any case the eggs are abundantly discharged in the 
sputum. Occasionally, however, they are carried in the blood-stream to 
the brain, and there they, or even mature worms which can pass into the 
brain in the same way, give rise to the injury and irritation which produces 
the epileptic attacks. Other organs may also become the lodging place 
for the worms and their eggs. 
The development has been worked out by Nakagawa and is essentially 
as follows: The eggs develop in water into free swimming miracidia, which 
penetrate into the body of snails, Melania, where they develop into 
cercariae and escape. The cercariae enter the tissues of freshwater crabs 
(Potamon, Eriocheir, etc.). These crabs when eaten raw or insufficiently 
cooked transmit the infection to man, in whom the encysted cercariae are 
set free when the cysts reach the intestine. They bore through the in- 
testinal wall, pierce the diaphragm, and enter the lungs through the pleura. 
There they form capsules and develop into adult forms. 
In the Chinese and sometimes in the Japanese there is another trematode, 
which in its mature form infests the gall-ducts and gall-bladder. This is 790 
TEXT-BOOK OF PATHOLOGY 
the Clonorchis (Opisthorchis) sinensis. The worms do not necessarily 
produce much change in the liver, but in a case recently seen at autopsy 
in Panama the liver showed many areas of atrophy and scarring of the 
tissue with inflammatory reaction about the bile-ducts. Kobayashi has 
shown that several cyprinoid fishes act as the intermediate host, including 
Pseudorasbora, Leucogobus, and Carassius, some of which are eaten raw, 
and thus readily transmit the infection. 
For descriptions of other trematodes which infect human beings, Fas- 
ciolopsis, Heterophyes, etc., works on parasitic diseases must be consulted. 
Schistosomum: 
Looss: Mense's Handb. d. Tropenkrankheiten, 2 Aufl., 1913. 
Reed: Amer. Jour. Trop. Dis., 1915-16, iii, 250. 
Leiper: Jour. Royal Army, M. C., 1915, xxv, 2, 148, 253; 1918, xxx, 235. 
Diamantis: Jour. d. Urol. med. et chir., 1917, vii, 9. 
Paragonimus: 
Nakagawa: Jour. Exp. Med., 1917, xxvi, 297. 
Yoshida: Jour. Parasitol., 1916, ii, 111. 
Clonorchis: 
Kobayashi: Mitth. a d. Med. Fachschule, Keijo, 1917, 251. Reviewed, Japanese 
Med. Literature, 1917, ii, 34. 
Refer also in general to- 
Fantham, Stephens, and Theobald: Animal Parasites of Man, N. Y., 1916. 
Brumpt: Precis de Parasitologic, Paris, 1910. 
LITERATURE 
TRICHINIASIS 
The trichina, or, as it is now called, Trichinella spiralis, was discovered by 
Owen in 1835 and has since been studied by Virchow, Zenker, Leuckart, 
and a host of others, the most compendious publication being that of 
Staubli. It is a nematode, or round worm, the anatomical structure of 
which will be found in any book on animal parasites. It carries out its 
whole life cycle in one animal, but it must then pass into the digestive 
tract of another animal to begin another cycle. The reason for this will 
be found in the following brief summary of its life-history. The worm is 
essentially a parasite of swine, but can live in rats, mice, guinea-pigs, 
rabbits, dogs, cats, and many other animals as well as man. It is from 
eating insufficiently cooked pork that man is infected, but the pigs them- 
selves are often infected through eating dead rats. The embryos, both 
male and female, are found in the muscle substance of the pig, and on 
being eaten by man quickly develop into mature forms when they reach 
the intestine. There the females penetrate into the substance of the villi 
and often actually enter the central lymphatic; the eggs hatch in the 
uterus of the worm, and the active embryos are set free from the genital 
opening, after which they bore their way into the lymphatics, if they are 
not actually deposited there by the mother. Thence they are swept in 
great numbers through the mesenteric lymph-glands and the thoracic 
duct into the blood, and are to be found there by centrifugalizing, after TRICHTNIASIS 
791 
treating the blood with 3 per cent, acetic acid, which dissolves away the 
red corpuscles. They are thus carried through the whole body but choose 
the voluntary muscles for their permanent abode. Doubtless they have 
to penetrate into them from the capillary by their own activity. They 
lodge in every other tissue, but appear to find conditions unsuitable and 
never develop there; indeed, they are rarely found anywhere else than in 
the skeletal muscles. They are not found in the heart muscle, but are 
occasionally seen in the mesenteric lymph-glands and for a time are abun- 
dant in the peritoneal cavity. 
Fig. 389.-Pectoral muscle with encapsulated and calcified trichinae. 
Having entered the muscle, each one penetrates into a muscle-fibre 
where it lies as a small, rod-like structure in the middle of the fibre. As the 
embryo grows the fibre loses its striations and becomes granular and 
swollen. The sarcolemma nuclei sink into the more or less homogeneous 
mass and surround the little worm. A little later the parasite, having 
developed until it shows the alimentary tract and a rudiment of the re- 
productive glands, coils itself up and becomes surrounded by a rather 
thick hyaline capsule which is usually elliptical (Fig. 389). There is a 792 
TEXT-BOOK OF PATHOLOGY 
dispute as to the origin of this capsule, but it seems most probable that it 
is formed by the worm, as Leuckart thought, although there are many 
who think it produced by the host. But the host does not produce such 
a peculiar capsule for any other foreign body, and it seems specifically a 
part of this parasite. Fat may collect at its poles outside, and within it 
there are usually found a few cells at each pole. These may be included 
parts of the group of sarcolemma nuclei. Later, the capsule becomes 
Fig. 390.-Larva of trichinae encapsulated in muscle. There is abundant infiltra- 
tion of leucocytes, most of which are eosinophiles, and many muscle-fibres are reduced 
to hyaline masses. 
partly or completely calcified, and then the worm is likely to die or has 
already died. Nevertheless, they live for years in the muscle, awaiting 
a chance to go through the development to maturity, in their turn, in the 
body of another animal. 
The disease trichiniasis is a serious one, and often ends fatally when 
much of the infected meat is eaten. Death is probably due to the in- 
tense injury produced by the penetration of the intestinal wall, although UNCINARIASIS 
793 
more rarely it may occur after the embryo has entered the muscle. Much 
care is taken by the German government to prevent the sale of infected 
pork, and Staubli's book is one long outcry against American pork. The 
frequency with which epidemics of trichiniasis occur in Germany is, how- 
ever, probably the outcome of the German habit of eating raw pork and 
blood sausages and makes the meat inspection futile. 
The disease may simulate typhoid fever. There is fever and malaise, 
often with diarrhoea when the infection is intense, with oedema of the 
tissue below the eyes and sometimes of other parts of the body and often 
with profuse sweats. There is no Widal reaction, and there is a marked 
leucocytosis with an extraordinary increase in the eosinophile cells (Brown). 
Later the muscles become stiff and painful, and in the effort to relieve 
them there is dyspnoea, aphonia, and general immobility. With the estab- 
lishment of the worms in the muscle and their encapsulation, the symptoms 
gradually disappear. 
If a person thus infected dies, the appearance of the organs varies with 
the stage of the disease. In the fresher stages the intestinal mucosa is 
said to be swollen and reddened but without definite haemorrhages. The 
lymph-glands are swollen in the mesentery and there is bronchitis, but 
there is usually no other organic change dependent upon the infection 
except, of course, the change in the skeletal muscles. The bone-marrow 
is hyperplastic and rich in eosinophile myelocytes. 
The muscle parasites are not visible to the naked eye and there may be 
no sign of any change. It is only much later when, after years, they become 
calcified that they are visible (Fig. 390). Then they look like tiny opaque 
yellowish-white flecks in the muscle. Their distribution has guided the 
meat inspection in Germany and the diaphragm or neck muscles are 
chosen for study, since those places seem especially favorable for their 
growth. 
LITERATURE 
Staubli: Trichinosis, Wiesbaden, 1909. 
Askanazy: Virch. Arch., 1895, cxli, 42. 
Brown: Jour. Exp. Med., 1898, iii, 315. 
Herrick and Janeway: Arch. Int. Med., 1909, iii, 263. 
UNCINARIASIS 
Through the work of Stiles in this country and Ashford in Porto Rico 
the enormous importance of this infection has been made clear and Stiles 
has shown that, in addition to the Anchylostomum duodenale or Uncinaria 
duodenalis, there is another form, called by him Necator americanus, which 
is the parasite especially concerned in America and the West Indies. 
All through the southern states and in tropical and sub-tropical countries 
around the world, the so-called "hookworm disease" is more or less pre- 
valent. Ashford's description of it as it occurs in the "jibaro" or laborer 
in Porto Rico is most vivid and gives a better idea of the ravages it causes 794 
TEXT-BOOK OF PATHOLOGY 
than any other I have read. The people who work in damp coffee planta- 
tions are especially affected there. Elsewhere, those who work in the soil 
are the ones to suffer, chiefly when they get into mud, although Stiles 
suspected especially the influence of sandy soils. After having walked 
barefoot in the mud, they have a peculiar eruption on the skin which 
burns and itches. Some time after that such people find themselves weak 
and easily tired and unable to work. They grow pale and the skin assumes 
a yellowish clay color. The digestion is disordered, there is constipation 
or diarrhoea with occasional periods of abdominal pain. The nervous 
system is often much affected, and in some cases actual maniacal attacks 
interrupt the usual stupid condition. The extreme anaemia, often with 
eosinophilia, becomes more profound and there is often associated with it 
oedema of the face or of the whole body. The patient becomes unable 
to walk or to help himself in any way and may die. The faeces contain 
numbers of the elliptical ova of the worm, but in Ashford's experience no 
blood. The whole affection can be cured with thymol. 
Most interesting is the pathogenesis of this disease which has been 
worked out by Looss in Egypt. The eggs passed with faeces develop, if 
they find themselves in a moist place, into small active embryos. Whole 
areas of moist ground can be thus infected. Ashford mentions the damp 
ground in the shade of coffee bushes, Looss the mud in which the fellaheen 
work after the Nile recedes. Looss' beautiful experiments showed that if 
water or mud containing larvae at this stage were applied to the skin there 
arose almost at once a burning and itching sensation, and by the time the 
water had dried all the larvae had bored their way into the skin, leaving 
their shed skins as empty shells on the outside. He repeated this with a 
leg about to be amputated and was able to trace the larvae into the hair 
follicle and thus through the skin. They do not enter sweat-glands or 
sebaceous glands, but Schuffner found that they could pierce the skin 
anywhere. Further experiments with dogs showed that they wander into 
the blood-vessels and are carried to the lungs, where they are too large to 
pass through the capillaries, but emerge into the air-cells. Thence, crawling 
up the bronchi, they get over into the oesophagus and reach the stomach 
and intestine, where after other moults they become mature worms. 
Of course, the irritation felt by Looss (who thus produced a general in- 
fection in himself and long harbored the worms in his intestine) was iden- 
tical with the ground itch or "mazamorra," which comes on after walking 
barefoot in infected mud or smearing the hands with it, and there seems 
no doubt that this is the ordinary mode of infection. Of course, the larvae 
may be swallowed if muddy water or mud-covered vegetables are taken 
into the stomach or if, as sometimes happens to these people, a craving 
for bulk in their food is satisfied by eating mud or clay. But although 
this infection by mouth has been regarded as the chief mode of entrance 
it seems now, in the light of Looss' work, to be less important and perhaps 
even uncommon. UNCINARIASIS 
795 
The mature worms attach themselves to the walls of the intestine and 
draw into their capacious mouths some part of the mucosa (Fig. 390A). 
They seem to be actual blood-suckers, although there is still difference of 
opinion about this. Sometimes haemorrhage can be found about the point 
at which they were applied, and it has been thought that much loss of 
blood might occur after they dropped off or changed to another place. 
But little blood is found in the stools, and it is not, as a rule, found in the 
Fig. 390A.-Head of ankylostome in section showing how the submucosa of the intes- 
tine is drawn up into the mouth cavity. 
intestine of the worm. The impression is, therefore, that they do not 
cause the profound anaemia by merely mechanically removing blood, and 
this is strengthened by the character of the anaemia, which is peculiar 
and marked by an outspoken eosinophilia. This, together with the nervous 
phenomena and the symptoms of general intoxication, point rather to a 
toxic substance produced by the worm as the cause of the anaemia. 
The worms are found hanging to the wall of the small intestine and are 
pretty tightly attached. Hundreds of them occur in one case. Aside TEXT-BOOK OF PATHOLOGY 
796 
from the pallor, changes in the other organs are not especially charac- 
teristic. The spleen is not enlarged. The bone-marrow shows a response 
to the anaemia. The kidneys are found to present some exudate of blood 
and epithelial degeneration. 
LITERATURE 
Ashford and Igaravidez: Uncinariasis in Porto Rico, U. S. Senate Document No. 
808, 1911, (Literature). 
Stiles: "Hookworm Disease," Hygienic Laboratory Bull., No. 10, Washington, 1903. 
Looss: Centbl. f. Bakt. u. Paras., Abth. i, 1901, xxix, 733. 
OTHER NEMATODE INFECTIONS 
Brief mention may be made of certain other very common infections 
with nematode worms. 
Ascaris lumbricoides is the common round worm found in the intestine 
of children, which, by its presence in numbers, exercises an irritating 
influence. It does not actually fix itself to the intestinal wall, but lies free 
or in convoluted masses in the lumen. The effects of its wanderings into 
other localities have been mentioned. Apparently it may secrete a toxic 
material, for there are general and nervous symptoms due to its presence. 
The life-history of the Ascaris has been shown more clearly in the recent 
work of Stewart, and of Ransom and Foster. Stewart found that when 
eggs were fed to rats and mice the larvae hatched in the intestine, reached 
the lung, and developed there, passing thence into the intestine, from which 
they were discharged. He thought that these animals must act as inter- 
mediate hosts, and that infection of the final host must arise from the 
ingestion of the partly developed worms thus excreted. Ransom and 
Foster show clearly, however, that these larvae are discharged from the 
intestine of the rat or mouse only because they are unsuitable hosts. In 
pigs and children, if young enough, larvae which are hatched in the intestine 
from ingested eggs wander into the lungs through the diaphragm and 
pleura. There they develop further, causing serious pneumonic phenom- 
ena, and later, passing up the trachea, they go down into the intestine, 
where they complete their development. The larvae, as shown also by 
Yoshida, have a remarkable power of wandering through all the tissues 
and can penetrate the skin. 
LITERATURE 
Stewart, F. H.: Brit. Med. Jour., 1916, ii, 474, 486, 753. Parasitology, 1917, ix, 213; 
1918, x, 189, 197. 
Ransom and Foster: Jour. Agric. Research, 1917, xi, 395. Jour. Parasitol., 1919, v, 93. 
Yoshida: Ibid., 1919, vi, 19. 
Oxyuris vermicularis, a small worm with pointed extremities, 3 to 
5 mm. long, is a frequent inhabitant of the colon, where it attacks the 
mucosa, and by its bites produces haemorrhagic points, and an inflam- OTHER NEMATODE INFECTIONS 
797 
matory reaction with intense itching of the anal region. Its eggs develop 
on vegetables, etc., or the embryos which quickly leave the shell may be 
transferred to the mouth and an extensive autoinfection produced. In- 
vasion of the oxyuris into the mucosa of the appendix has been shown to 
be responsible for a considerable number of cases of appendicitis (17 in 
a series of 129 cases, Cecil and Bulkley). 
The Trichocephalus trichiurus, or dispar, is a similar worm with long, 
thread-like anterior end. It buries this anterior end in the mucosa of the 
caecum and absorbs blood. No very marked symptoms are produced, but 
it can occasionally be the cause of appendicitis. More important than 
these is the Filaria Bancrofts, whose embryos are found in the circulating 
blood in the form of delicate, actively motile threads which appear there 
only at night. They are transferred by the mosquitoes (culex), in which 
they undergo a certain development, reaching the salivary glands or 
oesophagus, so that they are injected with another bite into another host. 
Fig 390B.-Elephantiasis affecting both legs (Singapore). 
The mature worm, developing in the human body, invades and lodges 
itself in the lymphatic channels, where it produces great distension, hsemor- 
rhage, and inflammation. Huge masses of lymphatic varicosities are the 
result and much obstruction to the flow of lymph. The effect of this is 
evident in nearly every tropical country in the occurrence of the so-called 
elephantiasis (Fig. 390B), which affects the legs or the scrotum, causing 
huge enlargements due to lymph stasis and new formation of tissue which 
are traceable to the presence of the worm. Chyluria, or milky urine, and 
chylous ascites are also characteristic features. In the Fiji Islands, where 
Bahr showed that the Stegomyia acts as intermediate host and carrier 
of the infection, I saw several cases of elephantiasis affecting the arms 
alone. The most frequently observed lesion in those islands is, however, 
a great swelling and induration of the lymph-nodes in the inguinal region TEXT-BOOK OF PATHOLOGY 
798 
or elsewhere, and in the disintegrated centre of each of these the filariae 
are to be found. Recently in Tahiti, where elephantiasis is common, I 
saw many cases with extremely advanced changes. Dr. Cassian, who has 
had long and varied experience with the disease, expressed the idea that 
it is due rather to a chronic bacterial infection, and there are many who 
hold this view. It is in accord with the observations of Dr. Halsted on 
surgical elephantiasis, which show that in an extremity from which the 
return of blood has been somewhat obstructed, repeated slight infection 
may produce a lasting swelling resembling elephantiasis. Even Manson, 
the discoverer of the mode of transmission of the filaria, now thinks that 
bacterial infection in addition to lymph stasis is necessary to produce 
elephantiasis. The student should read the paper of Halsted, Johns 
Hopkins Hospital Bulletin, 1921, xxxii, 309. 
LITERATURE 
Braun: Thierischen Parasiten des Menschen, Wurzburg, 4 Aufl., 1908. 
Cecil and Bulkley: Jour. Exp. Med., 1912, xv, 225. 
Opie: "Filarial Lymphatic Varix," Amer. Jour. Med. Sci., 1901, cxxii, 251. 
Manson: Tropical Diseases, London, 1903, 545. 
Looss: Mense's Handb. d. Tropenkrankheiten, 1914, ii, 312. 
Bahr: Jour. London School of Tropical Med., Suppl. i, 1912. CHAPTER XL 
THE EFFECTS OF INJURIES UPON THE BLOOD AND BLOOD- 
FORMING ORGANS 
Importance of changes in blood-forming organs. The bone-marrow: its regenerative 
changes. The spleen. The lymphoid tissues with the haemolymph nodes. Injuries of red 
corpuscles and erythrogenic tissue. Polycythaemia. Anaemia or oligocythoemia. Post- 
haemorrhagic and other secondary anaemias. Pernicious anaemia. Aplastic anaemia. 
Haemochromatosis. Haemolytic icterus. Osteosclerotic anaemia. Banti's disease. Spleno- 
megaly of Gaucher. 
The fact that in the many disorders of the blood and of the blood-forming 
organs we are as yet in most cases ignorant of the cause, makes it seem 
preferable to discuss these conditions together and quite objectively. It 
is true, of course, that nearly all of the injuries which have already been 
considered cause changes in the blood and its sources, and sometimes we 
can trace these effects with the greatest accuracy, so as to derive enlight- 
enment with regard to the principles which are probably concerned in the 
more obscure affections. 
The blood, in virtue of its rapid circulation and of the powerful sifting 
and cleansing effect exerted upon it by the very blood-forming organs 
which are its source, does not show the direct effect of local injury except 
after very gross damage by haemorrhage or by chemical agents. Then 
it becomes impoverished by the loss of cells, or, in the second case, it shows 
the effect of the chemical (as in the formation of carbon monoxide haemo- 
globin, methaemoglobin, etc.). Instead, the changes which appear in the 
circulating blood are essentially those which depend upon the activity 
of the blood-forming organs, and may consist in an incomplete new 
formation of cells of the same type as those which were lost, or in the 
introduction of greatly increased numbers of some of the cells (leuco- 
cytes), or even in the appearance of cells which are not normally pres- 
ent in the blood (erythroblasts, myeloblasts, etc.). Thus it is clear 
that we shall have to deal but little with the direct effects of injurious 
agents upon the blood itself. On the other hand, the changes brought 
about in the blood-forming organs by direct injury or through the neces- 
sity of restoring to normal the injured blood, must interest us quite as 
much as the remarkable changes in the blood which then follow. It is as 
though an army during the battle should rapidly circle back into the mother 
country carrying the dead and wounded, returning to the battle with ever 
799 800 
TEXT-BOOK OF PATHOLOGY 
new reserves. In time there would come a change in the character of 
the army, depending upon the ability of the mother country to recruit. 
BLOOD-FORMING ORGANS 
Leaving aside the conditions found in embryonic life, it is clear that the 
bone-marrow constitutes the essential seat of the formation of most of the 
elements of the blood, although, as we have seen in the outline given in 
Chapters IX and XII, the cells of the lymphoid series are furnished to 
the blood by the lymphoid tissues scattered everywhere throughout the 
body. Under stress of great need, tissue of the character of the bone- 
Fig. 391.-Bone-marrow from femur of normal adult, showing chiefly fat with very 
little myeloid tissue. 
marrow appears in situations far removed from the bones, and cells swept 
into the general circulation may settle as colonies in the capillaries of 
various organs and there multiply to some extent (Tanaka). The part BLOOD-FORMING ORGANS 
801 
played by the spleen in blood formation is still disputed, and although 
some writers assign to it a most important role, others regard it as 
chiefly concerned in the purification of the blood. This matter must for 
the present be left undecided. 
The Bone-marrow.-Throughout life the marrow of the cancellous 
framework of the short and flat bones maintains its cellular character and 
is active in blood formation. In childhood this is true of the marrow of 
the long bones too, but with advancing age fat increases in amount there 
and replaces the marrow, often even in the cancellous regions of the ends 
of the bone. The microscopical study of the marrow shows only a delicate 
framework with blood-vessels among the closely packed fat-holding cells. 
In the angles and crevices one may find a few cells of myelocyte or ery- 
Fig. 392.-Bone-marrow from normal infant. It shows quite well-defined blood- 
channels, neutrophile and eosinophile myelocytes, megalocaryocytes, etc. There are 
numerous normoblasts which do not show well in this drawing. 
throblast type (Fig. 391). It seems that these are the cells which multiply 
at an astounding rate when special activity of the bone-marrow is de- 
manded. In the marrow of the child's femur (Fig. 392) or in that of the 802 
TEXT-BOOK OF PATHOLOGY 
short cancellous bones a very different condition exists. There is relatively 
little fat, and the delicate vascular reticulum is loaded with loose cells. Of 
course, as mentioned before, the osteoblasts and osteoclasts which are 
closely applied to the bone hold aloof and are concerned only in bone for- 
mation and destruction. The capillaries are wide and variable in diameter, 
and it is frequently difficult to trace their endothelial outlines. Indeed, one 
does not receive the impression that they are stout-walled tubes capable 
of carrying blood safely at a considerable pressure, but rather that their 
walls are extremely thin if not actually lacking in places. At times it 
seems as though the mass of cells in the reticulum were continuous with 
those within the capillaries, and one must suppose that some such relation 
may exist, to explain the phenomenally rapid delivery of cells into the 
blood-stream. For a discussion of the histogenesis of the cells concerned 
the student is referred to the papers of Maximow, Jackson, and others. 
Fig. 393.-Bone-marrow of rabbit after long treatment with benzol. Practically all the 
blood-forming elements are destroyed. 
In such cellular marrow there are found, side by side, the following 
kinds of cells: BLOOD-FORMING ORGANS 
803 
1. Those concerned in the production of red corpuscles: Megaloblasts, 
normoblasts, and the erythrocytes themselves. 
2. Those concerned in the formation of the neutrophile, eosinophile and 
basophile granular leucocytes: Myeloblasts without granules, myelo- 
cytes with neutrophile, eosinophile and basophile granules, and the mature 
leucocytes themselves with these different types of granule. 
3. An indefinite but limited number of large and small lymphoid cells, 
situated usually about the blood-vessels and capable of giving rise to 
lymphocytes and to their derivatives, including plasma cells. 
4. Megalocaryocytes which, by constricting off portions of their granular 
cytoplasm, form blood-platelets, which they discharge into the blood. 
In ordinary sections these cells are so intermingled that one cannot 
make out their relations to one another, but Bunting puts forward the 
Fig. 394.-Bone-marrow of rabbit. Beginning regeneration after benzol poisoning; 
islands of myelocytes and normoblasts. 
statement that they occur in definite groups or colonies at the margins of 
which the perfected cells are set free. This he has found especially striking 804 
TEXT-BOOK OF PATHOLOGY 
in experimental anaemias in rabbits in which the bone-marrow had been 
injured by the injection of ricin or other substance used to produce the 
anaemia. So, too, Selling described the appearance of such colonies or 
pure cultures of the various cells in bone-marrow rendered practically 
cell-free (Fig. 393) with injections of benzol and then allowed to regenerate. 
These preparations I have studied and the truth of the statement is very 
striking. There are isolated groups composed in one case entirely of 
nucleated red cells (Fig. 394), in another entirely of myelocytes or of 
megalocaryocytes (Fig. 395), and in the later stages each of these comes 
to be accompanied by the mature cells which they produce (Fig. 396). 
Bunting explains that with further development the groups become so 
interwoven that it is impossible to outline them clearly, but in the bone- 
marrow of his rabbits made anaemic with ricin he finds such islands with 
a central group of megaloblasts surrounded by normoblasts and these in 
Fig. 395.-Bone-marrow of rabbit after benzol poisoning. Beginning regeneration; 
islands of megalocaryocytes. 
turn by ordinary red corpuscles. It is on the basis of these observations 
that he regards the megaloblasts as normal constituents of the bone-marrow BLOOD-FORMING ORGANS 
805 
and the immediate ancestors of the normoblasts. It is well known that 
this is not the view of German haematologists (Naegeli), who hold to 
Ehrlich's statement that megaloblasts are embryonic cells occurring only 
under pathological conditions in adult bone-marrow, and that therefore 
pernicious anaemia, in which they become abundant in the marrow, rep- 
resents a pathological return to embryonic conditions. It seems, however, 
that one may convince oneself of their common occurrence in normal and 
Fig. 396.-Bone-marrow of rabbit after benzol poisoning. Later stage of regeneration. 
Mixed islands of myelocytes, normoblasts, with occasional megalocaryocytes. 
regenerating bone-marrow and of the probability of Bunting's view that 
they represent the earlier stage in the formation of red corpuscles. The 
occasional sweeping of these nucleated cells into the blood will call for 
discussion below. 
In quite the same way the myeloblasts and myelocytes of each kind 
grow in colonies and shed into the blood their polymorphonuclear de- 
scendants. These cells, even in their earlier non-granulated stages, give 
an intense blue reaction with alpha-naphthol and dimethylparaphenylene 806 
TEXT-BOOK OF PATHOLOGY 
diamine, which in the presence of an oxydizing ferment produce indophenol 
blue (oxydase reaction). This reaction is also given by all the granulated 
leucocytes of the blood, including the large mononuclear and transitional 
forms of Ehrlich. The latter are thereby shown to be related to the my- 
elocyte group rather than to the lymphoid cells, since none of the lym- 
phocytes or related cells give the reaction. (The mast cells of the tissue 
fail to give it despite their basophilic granules.) 
Ordinarily the lymphoid cells of the bone-marrow form an inconspicuous 
element of the cell mass and are sometimes collected in groups or lymph 
nodules. In those cases in which the injurious agent causes the isolated 
overproduction of lymphoid cells they may, however, increase to such an 
extent as to crowd aside all the other cells. Theirs is probably under 
ordinary circumstances the least prominent role among the bone-marrow 
cells. 
The megalocaryocytes which maintain the platelet content of the blood 
are, like the other cells, vulnerable, and may be greatly reduced in number 
by toxic substances. They regenerate themselves in little colonies just 
as do the other cells (Fig. 395). 
The Spleen.-The studies of Weidenreich and Mollier have made clear 
the structure of the spleen as far as concerns its vascular arrangement, 
Fig. 397.-Diagrammatic drawing of splenic venule showing the elongated endothelial 
cells, the structureless membrane, and the circular reticulum fibres (Mollier). 
but there is still much to be learned with regard to the cellular structure 
of the splenic pulp. 
The smaller branches of the splenic artery are surrounded for some 
distance by mantles of lymphoid tissue which constitute the Malpighian 
bodies. These are in every respect like nodules of lymphoid tissue found 
elsewhere and show the same reactions. Aside from them the tissue 
between the fibrous trabeculae belongs entirely to the splenic pulp and BLOOD-FORMING ORGANS 
807 
into this the arteriole passes, to branch and empty into the wide venules, 
which form a sort of feltwork making up most of the pulp. In the inter- 
stices between these venules is the reticulum of the pulp, in which are 
held great numbers of free cells. For our purposes the most interesting 
features are the structure of the walls of the venules and the nature of 
the cells in the pulp reticulum. The walls of the venules (Fig. 397) are 
very loose in texture, so that it seems extremely easy for cells to wander 
in and out. The lining endothelial cells are quite unlike those seen else- 
Fig. 398.-Section of spleen showing venules with endothelial cells and network of pro- 
toplasmic and reticulum strands (Mollier). 
where, and instead of being flat and polygonal and uniformly adherent 
by their edges to the edges of the next cell, they are greatly elongated, 
thick, and pointed at each end, with a large and pointed nucleus which 
projects into the lumen of the venule. In many places the cells, which 
lie parallel to one another and lengthwise in the venule, have their nuclei 
side by side, so that between these rows of nuclei the wall is formed by 
the bodies only of the cells. A cross-section at that point shows only 808 
TEXT-BOOK OF PATHOLOGY 
the unstained bodies of the cells, like little cogs on the inside of the 
venule, while at another level the venule may be lined all round with 
the prominent nuclei (Fig. 398). Outside the venule there is a delicate 
cylindrical basket work of elastic fibrils; whether there is any other 
structureless membrane between is still disputed. 
The reticulum between the venules shows a few elongated nuclei which 
belong to the cells of the connective-tissue framework. In chronic passive 
congestion and similar conditions these are very conspicuously increased 
in number and the fibrous reticulum is correspondingly denser. In the 
meshes there are great numbers of red corpuscles, the actual quantity 
varying with different conditions, so that in the fibroid spleen of chronic 
passive congestion there are hardly any, while in the acute splenic tumor of 
typhoid fever they are present in overwhelming numbers. The majority 
of the other cells are lymphocytes, and these can be found wandering 
through the walls of the venules as well as within the venules themselves. 
There are other rather larger mononuclear cells ("pulp cells"), some of 
which reach the size of myelocytes. It is indeed not uncommon to find 
both eosinophile and neutrophile myelocytes in small numbers, but thia 
is not a feature of perfectly normal spleens. Plasma cells, polymorpho- 
nuclear neutrophile, and eosinophile leucocytes are occasionally present, 
but are in very small numbers. Thus under ordinary circumstances the 
cells seem to be essentially of the lymphoid type. One is especially im- 
pressed with the complete ease with which all these cells pass in and out 
through the walls of the venules, and it is easy to understand that, under 
these circumstances, modifications of the passing blood might readily change 
the character of the splenic tissue. 
As to the function of the spleen, it is even yet, after centuries of ex- 
periment and speculation (Malpighi attempted to discover this function 
by extirpating the spleen of a dog), impossible to say anything very defi- 
nite. It is generally supposed to be an organ active in destroying injured 
blood-corpuscles and sifting out of the circulating blood the debris of such 
cells, the haemoglobin of which it prepares for use by the liver in the for- 
mation of bile-pigments. This idea depends chiefly upon the finding of 
pigment in the spleen, but there is little to show that all of this cannot be 
equally well accomplished after the spleen is removed. It is stated by 
many that the spleen is an active blood-forming agent, and Pearce and his 
co-workers have shown, among others, that there is a temporary anaemia 
after splenectomy, apparently compensated for by hyperplasia of bone- 
marrow and lymphoid tissues. Lymphocyte production is perhaps de- 
creased for a time by splenectomy, but is soon reinstated (Murphy). 
Studies of the blood of the splenic vein as contrasted with that of the ar- 
tery have been referred to, but they are open to criticism and give very con- 
tradictory results. Since these methods are unsatisfactory, it is difficult to 
prove that the spleen actually contributes cells to the blood (although that BLOOD-FORMING ORGANS 
809 
seems probable), because new cells from any source added to the circulating 
blood tend to lodge in its pulp. 
The Lymphoid Tissue.-The lymphoid tissue is almost universally 
distributed, since it occurs in conspicuous accumulations throughout the 
whole digestive tract, in the walls of the respiratory tract, in lymph- 
glands in orderly arrangement everywhere throughout the body, in the 
Malpighian bodies of the spleen, and in inconspicuous nodules in the skin, 
bone-marrow, and other organs such as the thyroid, parathyroid, adrenal, 
kidney, liver, pancreas. The lymphatic channels lead its cells into the 
blood but are interrupted by others of its masses arranged as sieves to 
retain impurities. Everywhere the architecture of the lymphoid tissue is 
the same in principle although slightly more elaborate in those places where 
lymph sinuses surround the more compact masses of lymphoid tissue. 
There is in this tissue a reticulum with many associated cells of large size 
and pale vesicular nucleus and, very commonly, in the follicles a central, 
palely staining mass of large cells related to if not identical with the retic- 
ulum cells. These have been looked upon since Flemming's work as the 
direct antecedents of the lymphoid cells. The latter, which are identical 
with the lymphocytes of the blood, are accumulated in quantities in the 
meshes of the reticulum. The origin and relations of all those phago- 
cytic, mononuclear, wandering cells which appear in so many inflam- 
matory processes is discussed in an earlier chapter, where it is suggested 
that they are not so closely related to lymphoid cells as we at one time 
thought. 
EFFECT OF INJURIES TO THE RED CORPUSCLES AND THEIR FORMA- 
TIVE ORGANS 
It is naturally impossible that there should be any extensive alterations in 
the red corpuscles without some accompanying changes in the closely 
associated white corpuscles and vice versa; nevertheless the disturbances 
affect so predominantly one type of cell or the other that we may confidently 
speak of these diseased conditions with regard to the cells chiefly affected, 
referring to the changes in the others as accessory. 
In the normal blood the number of red corpuscles per cubic millimetre 
is about five million, while the number of white corpuscles taken together 
is about five or six thousand. Any great variation from these numbers 
usually indicates the influence of some abnormal condition. An increase 
in the number of red corpuscles or polycythcemia may occur, but is by no 
means so common as the opposite effect, a decrease in their number, 
oligocythcemia, loosely called ancemia. 
Polycythaemia.-The rapid loss of fluid from the body, such as may 
occur with severe diarrhoea or Asiatic cholera or even with profuse sweating, 
leads to such inspissation or concentration of the blood as to raise the 
number of red corpuscles per cubic millimetre to six or seven million. 810 
TEXT-BOOK OF PATHOLOGY 
This is naturally a transitory phenomenon if the patient survives, since 
with the absorption of water from the digestive tract the blood returns to 
its normal concentration. There are other conditions, however, such as 
chronic cyanosis from cardiac insufficiency or from emphysema, in which 
there is a lasting polycythsemia apparently due to the actual need for 
more blood to nourish and oxygenate the tissues properly. This is espe- 
cially marked when the chronic passive congestion has existed since in- 
fancy, as in congenital heart lesions. In persons who live at high 
altitudes there is a similar increase in the number of red corpuscles which 
appears after even a short stay in the mountains or, it is said, after or 
during a balloon voyage. More interesting still and more difficult to 
explain are those cases of polycythamia rubra (Osler), or erythrcsmia, in 
which the blood becomes actually thick and viscous from the presence 
of such enormous numbers of red corpuscles (10 millions or more). There 
is increase in the total volume of blood, cardiac hypertrophy, great en- 
largement of the spleen, and hyperplasia of the bone-marrow. The cause 
is quite unknown and the patients go on to die of haemorrhage or of some 
intercurrent infection. It is a very curious phenomenon, perhaps analogous 
to leukaemia, since in spite of the fact that the blood-vessels are everywhere 
turgid with blood, the erythroblastic tissues of the bone-marrow are found 
to be in process of active hyperplasia and blood formation, as though 
behaving quite independently of the needs of the blood which usually 
govern them. 
Anaemia.-On the other hand, agencies which destroy and diminish the 
red corpuscles are extremely common, and their action far more easily 
understood. 
Decrease in the number of red corpuscles in the blood may be brought 
about in a very great variety of ways which perhaps fall into the following 
divisions: 
1. Actual loss of blood through haemorrhage. 
2. Destruction of blood and injury of the bone-marrow by poisons 
which are often those produced by bacteria or other parasites, often 
chemical substances taken as drugs or absorbed by workers in certain 
industries. Long-continued infections and the presence of malignant 
tumors are factors especially likely to bring about such results. 
3. A peculiar, sharply defined disease known as pernicious anosmia, in 
which, despite the most active efforts toward regeneration, the red cor- 
puscles continue to decrease in number. 
4. Osteosclerotic Anosmia.-The attack may be more serious in that it is 
directed against the bone-marrow itself. While it is difficult to show 
that this is so in the case of poisons and infections which may also destroy 
the circulating red corpuscles, it is quite clear in those cases in which 
metastases from cancers of the prostate or breast occupy the whole 
marrow cavity of every bone to the mechanical exclusion of bone-marrow, 
or even in the cases of leukaemia in which the whole of the bone- BLOOD-FORMING ORGANS 
811 
marrow is given over to the production of the forerunners of white 
corpuscles, so that the erythroblastic tissue is crowded out of existence. 
In such cases there is extreme anaemia in spite of efforts toward extra- 
medullary blood formation. 
Secondary Anaemias.- 1. Post-hcemorrhagic anaemias depend in their 
severity upon the extent of the haemorrhage and upon the frequency with 
which it is repeated. A single great haemorrhage is followed by a series 
of symptoms due to the incomplete filling of the blood-vessels,-fainting, 
nausea, weakness, collapsing pulse, etc.,-but the concentration of the 
blood and the proportion of corpuscles immediately after the haemorrhage 
is naturally exactly what it was before. Very rapidly, however, fluid 
passes from the tissues or from the digestive tract to dilute the blood 
and make up its quantity. Within a few days after such haemorrhage 
the fatty bone-marrow of the long bones becomes so filled with newly 
formed cells that the fat is crowded out and the marrow assumes a red 
color and cellular consistency. In such marrow there are found abundant 
nucleated red cells rapidly giving rise to red corpuscles, and also quanti- 
ties of myelocytes; this is not followed, however, by the pouring out of 
any extraordinary number of leucocytes, although the proportion of these 
cells in the blood is somewhat increased. 
Such extensive haemorrhages occur, of course, in mechanical injuries 
in which large blood-vessels are cut or torn, but they also occur in advanced 
pulmonary tuberculosis from the erosions of a branch of the pulmonary 
artery, in ulcers of the stomach or in cases of cirrhosis of the liver in which 
there is a rupture of the dilated veins in the oesophagus, in the rupture of 
an extra-uterine pregnancy, or in ordinary pregnancy at childbirth. But 
even more profound degrees of anaemia may be produced by slighter but 
frequently repeated haemorrhages, such as those which come from re- 
current nose-bleed, bleeding haemorrhoids, and ulcerated submucous myo- 
mata of the uterus, and, possibly, in the case of certain intestinal para- 
sites which suck the blood, although, as has already been said, this is of 
somewhat doubtful occurrence in human beings and the anaemia caused by 
these parasites seems rather due to a poison which they produce. 
2. Destruction of the blood-corpuscles (haemolysis) may be caused by a 
great variety of chemical substances, of which ricin and benzol have already 
been mentioned. Nitrobenzol, toluylenediamine, lead, and a host of other 
substances have a similar effect. Particularly interesting are the specific 
haemolytic sera which have been experimentally produced, and we are 
even yet very imperfectly informed as to the part which similar elusive 
substances may play in human pathology. There are many bacteria 
which produce strong haemolytic poisons, and acute infections are there- 
fore common causes of intense anaemia. For example, the haemolytic 
streptococci can cause the destruction of a great proportion of the blood- 
corpuscles in a brief period, and even the less actively haemolytic 3. viridans 
produces an endocarditis and general infection which runs its course with 812 
TEXT-BOOK OF PATHOLOGY 
the development of extreme grades of anaemia. The anaemia which ac* 
companies typhoid fever, chronic tuberculosis, and syphilis is apparently 
due to similar processes, while in chronic nephritis and the cachexias which 
accompany the presence of tumors, especially perhaps when they are 
ulcerated, the nature of the poison is more difficult to ascertain. 
The extreme anaemia brought about by malaria is in great part due to 
the mechanical destruction of the corpuscles by the parasites, but in the 
case of bothriocephalus and uncinaria it appears that a recognizable 
haemolytic material can be extracted from the worms and that this is 
probably diffused into the blood and tissues. 
Such anaemias, which together with those caused by haemorrhage, are 
often called secondary, since their cause is known, resemble one another 
closely in the character of the blood changes. The red corpuscles may be 
reduced to less than a million per cubic millimetre, and tend to be rather 
small and pale, or poor in haemoglobin, and show some irregularities in 
size or form. Normoblasts are present in the circulation, often appearing 
in great numbers, at intervals corresponding with what seem to be crises 
of activity in the bone-marrow. Megaloblasts are seldom seen. There is 
nearly always an accompanying leucocytosis except in the case of such 
diseases as typhoid fever and malaria, in which the leucocytes are de- 
creased in number. 
The changes in the bone-marrow are those already described as charac- 
teristic of hyperplasia, which appears in response to the dearth of red 
cells, but associated with similar hyperplastic changes in the myelocytic 
group (Fig. 399). When, however, the anaemia is caused by some poison 
which attacks the bone-marrow itself, the reparatory changes are even 
more striking, as shall be detailed later. In the spleen, which may be 
somewhat enlarged, one finds no especial change in the Malpighian bodies, 
but in the splenic pulp, myelocytes, erythroblastic cells, and other elements 
corresponding to those of the bone-marrow are to be found. Similarly in 
the capillaries of the liver, and sometimes outside them in the liver sub- 
stance itself, such groups of cells may occur. The lymph-glands and 
lymphoid tissues are practically unaffected in secondary anaemias. Scat- 
tered haemorrhages are common, and oedema of the ankles or of the tissues 
under the eyes forms a characteristic accompaniment. Other anatomical 
changes, aside from the pallor of the organs in which little or no blood 
pigment is deposited, are inconstant. Very often there is an accumulation 
of fat globules in the heart muscle and in the kidneys. The disabilities 
produced by such anaemia are those consequent upon diminution of the 
bulk of the blood and of its oxygen-carrying capacity. Weakness, faint- 
ness, etc., have been mentioned, but, curiously enough, whether from the 
increased efforts of the heart and more rapid circulation, or other cause, 
the respiratory interchange is not decreased and the nitrogenous output 
not characteristically altered. 
A secondary anaemia is the banal result of all sort of injuries which BLOOD-FORMING ORGANS 
813 
destroy the blood-corpuscles, just as cardiac decompensation may arise 
from the most varied injuries to the heart. The changes in the bone- 
marrow are the ordinary or routine efforts of the body to repair this injury, 
just as new epithelium grows to cover a defect. We need not feel surprised, 
therefore, in finding the type of the reparatory reaction the same in all. 
If we can remove the cause by stopping haemorrhage, by expelling para- 
sites, by extirpating tumors or withdrawing chemical poisons, the rapid 
Fig. 399.-Bone-marrow in secondary anaemia, showing intense regenerative hyper- 
plasia: (a) Myelocytes; (b) normoblasts with occasional megaloblasts; (c) eosinophile 
myelocytes; (d) lymphoid cells. 
production of red corpuscles in the bone-marrow proceeds until the anaemic 
circulation once more has its normal amount of normal blood, after which 
it quiets down and the cellular marrow resumes its fatty character in the 
long bones. 
Pernicious Anaemia.-This, although so difficult to distinguish from other 
types of severe anaemia by any single criterion, is quite obviously an indepen- 
dent and definite disease which we recognize with certainty, and of which we 
can foretell the course as surely as we can in a case of typhoid fever. It 814 
TEXT-BOOK OF PATHOLOGY 
may be said that nothing is known of its cause although numerous theories 
have been put forward, but the complex of changes in the blood, the 
anatomical changes in the organs, and the symptoms and the course of the 
disease are monotonously uniform. From the fact that we have not dis- 
covered its cause it has often been called primary or essential anaemia, in 
contrast with secondary anaemias, but it seems by no means impossible 
that when we presently discover this cause and find that its removal 
allows the otherwise progressive anaemia to be repaired there will be no 
justification for such a name as primary anaemia. That it is different from 
the ordinary secondary anaemias is shown at once, however, by the con- 
dition of the blood, which is simulated closely only in the bothriocephalus 
anaemia. Briefly, there is extreme decrease in the number of red cor- 
puscles, each of which, however, contains an abnormally large amount of 
haemoglobin, so that, sometimes, in spite of the oligocythaemia, the haemo- 
globin of the whole blood is not greatly lowered. The corpuscles are very 
irregular in form (poikilocytosis) and in size (anisocytosis), there being 
not only small forms but very large or giant corpuscles, also tinged deeply 
with haemoglobin. The presence of these large forms together with the 
high color index is distinctive, since these do not occur in secondary anaemias 
where the color index is low. Nucleated red corpuscles are found some- 
times in large numbers and megaloblasts are often abundant. Indeed, 
the finding of megaloblasts in the circulating blood is much relied on in 
the diagnosis of this disease. The leucocytes are decreased in number 
and there maybe only 1500-2000 per cubic millimetre. Since the lymphoid 
structures in the body are unaltered, the percentage of lymphocytes rises 
and they may assume a proportion of as much as 60 per cent. The great 
decrease is in the polymorphonuclear neutrophiles. Myelocytes and 
myeloblasts are occasionally found. The decrease in the red cells is 
often such as to give the blood a peculiar watery appearance, although 
the high color index tends to keep it red. In actual numbers the red cells 
may sink far below one million. (For details of the blood changes consult 
the works of Cabot, Nsegeli, Lazarus.) This distinctive alteration of the 
blood is perhaps not enough to mark out pernicious anaemia as an inde- 
pendent disease, but the occurrence in middle-aged people, the complete 
lack of any recognizable cause, the continued good nutrition of the 
patient, the progressive deepening of the anaemia with intermissions during 
which great improvement occurs, the yellow pigmentation of the skin, and 
the practically uniform fatal outcome are enough to establish its identity. 
At autopsy the body is found well nourished, the subcutaneous fat and 
indeed all the fat tinged a rather deep yellow. The muscles are dark red. 
The diminution in the amount of blood is striking, and there may be found 
minute ecchymoses and local oedemas, especially in the lungs. The heart 
is soft, and through the myocardium there shines the yellow streaking 
which indicates the presence of much fat in the muscle-fibres. The 
liver, cortex of the kidneys, heart muscle, and the lungs are pigmented BLOOD-FORMING ORGANS 
815 
with iron-containing blood-pigment, even to the extent of assuming a 
rather distinct chestnut-brown color. Immersed in ferrocyanide of potas- 
sium and weak hydrochloric acid, they become gray-blue in color. The 
mucosa of the stomach is often atrophic and smooth and there may be 
achylia. Indeed, many writers have thought this to be in some way the 
cause of the disease, but the evidence is insufficient to uphold this view. 
In the mouth, too, there are often lesions of the mucosa of an inflammatory 
character associated with haemorrhages which cause pain, especially when 
acids are taken into the mouth. On the tongue there are brownish patches 
Fig. 400.-Bone-marrow in pernicious anaemia. Normoblasts and numerous mega- 
loblasts occur, together with many neutrophile myelocytes. There are phagocytic cells 
and some finely granular pigment. 
at the site of haemorrhages. Hunter has especially emphasized this glossitis 
and regards it as the primary lesion, or portal of entry of the causative 
agent of the disease. The blood-forming organs show changes which are 
primarily distinctive of the reaction to a severe anaemia. 
The bone-marrow is dark red and rather gelatinous. Its fat is replaced 
by the abundant hyperplastic tissue which in general resembles that found 
in secondary anaemias. The character of this can be conveyed better by 
a drawing than a description (Fig. 400). There is extensive new formation 
ofimyelocytes and myeloblasts. Newly formed lymphoid cells are present, 
and there are abundant groups or islands of erythroblastic cells among 816 
TEXT-BOOK OF PATHOLOGY 
which megaloblasts are conspicuous. Ehrlich made the statement that 
the presence of megaloblasts in the hyperplastic bone-marrow was peculiar 
to pernicious anaemia and that it indicated a return to a distinctly em- 
bryonic type of erythrocyte formation, in sharp contrast with the normal 
formation, which is by way of the normoblasts. The appearance of megalo- 
blasts in the blood and of megalocytes or large, deeply colored, non-nucleated 
red corpuscles was equally characteristic, and one must regard pernicious 
anaemia as a condition in which there was being formed a different sort of 
blood derived largely from abnormal cells, the megaloblasts, proper to 
embryonic life but obsolete in adult life. Naegeli and Lazarus and most 
Fig. 401.-Bone-marrow in pernicious anaemia. An island or group of megaloblasts 
with adjacent myelocytes and a few normoblasts. 
German writers have accepted this view of the obsolete nature of megalo- 
blasts and the consequent peculiarity of the bone-marrow in pernicious 
anaemia. Certainly the presence of megaloblasts in the circulating blood 
is indicative of very severe anaemia, and although these cells occur in 
other forms of anaemia, they are far more common in pernicious anaemia. 
But any one can convince himself of the presence of megaloblasts in any 
hyperplastic bone-marrow, and the experiments of Bunting, in which, by 
repeatedly injuring the bone-marrow with ricin, he produced an anaemia 
practically identical with pernicious anaemia, showed further that in the 
bone-marrow there were quantities of megaloblasts which formed the BLOOD-FORMING ORGANS 
817 
centres of erythrogenetic islands. They formed red corpuscles by de- 
velopment through the intermediate normoblasts which lay peripherally. 
It is Bunting's idea that this is practically the normal relation, and that 
the erythrocytes are given off peripherally, but that in the case of such 
serious injury to the bone-marrow as may be produced with ricin or as 
exists in pernicious anaemia, not only the more peripheral normoblasts, 
but the central megaloblasts themselves, may be hurriedly discharged. 
It is quite true that in the bone-marrow of pernicious anaemia it is ex- 
ceedingly difficult to outline any such groups of cells, since they are in- 
timately intermingled with adjacent groups of other sorts of cells. Never- 
theless, the relative concentration which can be made out, and the analogy 
with the perfectly clear-cut islands of regenerating cells in bone-marrow 
made aplastic with benzol, leads us to believe that Bunting's conception 
Fig. 402.-Pernicious anaemia. Lymph-gland with phagocytes in the peripheral sinus, 
containing red corpuscles. 
is a true one (Fig. 401). Numerous large phagocytic cells are found in 
the sections, loaded with red corpuscles and with the shadows of such 
corpuscles, together with occasional fragments of nucleated cells. These 
have been described by Sternberg and are conspicuous also in the spleen 
and in the haemolymph glands (Fig. 402). They at least indicate the 
activity of blood destruction. 
The spleen is usually slightly enlarged, and in some cases, but by no 
means all, shows a rusty tint on its cut surface. The Malpighian bodies 
can be seen plainly and the splenic pulp is not very greatly increased 
in bulk. Occasionally the organ is larger and firmer than normal, the 
increase being evidently in the splenic pulp. Microscopically there is 
strikingly little change from the normal (Fig. 403). The venules are 
clearly outlined with intact endothelial cells; the intervening reticulum of TEXT-BOOK OF PATHOLOGY 
818 
the pulp is more abundantly loaded with red corpuscles than in the normal, 
and many of these appear to be disintegrating. The lymphoid cells which 
normally occupy this position seem to be relatively few. Both within and 
between the venules there are moderate numbers of large phagocytic cells 
with debris of red corpuscles in their protoplasm. The myeloid change 
described by Meyer and Heineke and others is by no means so conspicuous 
as one might be led to expect from the severity of the anaemia; indeed, 
it is necessary to search through the sections to find any myelocytes, and 
Fig. 403.-Pernicious anaemia. Spleen showing distorted red corpuscles between the 
venules and small group of myelocytes in the reticulum of the pulp. 
then they occur only in small groups of two or three, both inside and out- 
side the venules. Many of them are found in the margins of the Mal- 
pighian bodies or in the walls of the larger blood-vessels. Nucleated red 
cells are also inconspicuous, but are occasionally found in the splenic pulp. 
In reality, the alterations of the spleen in severe secondary anaemias may 
be much more marked than in this condition, both with regard to the 
increased number of wandering cells in the pulp and the accumulation of 
myeloid cells, but that is probably to be explained by the influence of the 
infectious or toxic process which stands as the cause of such secondary BLOOD-FORMING ORGANS 
819 
anaemia and which in itself may produce changes in the spleen (c/. acute 
splenic tumor in infectious diseases). 
The lymph-glands show no striking alterations, but, as stated above,, 
the haemolymph glands contain in their blood-filled sinuses many of the 
large phagocytic cells loaded with red corpuscles. The immunity of the 
lymphoid tissue from alteration in pernicious anaemia is evident in some 
cases in the presence of a slight degree of lymphoid hyperplasia in the 
bone-marrow and in the relative increase in the numbers of lymphoid 
cells in the blood. 
The liver is said by Meyer and Heineke to show accumulations of 
myelocytes and erythroblastic cells. Much more striking is the fine, dust- 
like sprinkling of iron-containing pigment in the liver-cells themselves 
(Fig. 52, page 124). This pigment, which is readily colored blue by the 
ferrocyanide method, lies about the fine bile canaliculi in the centre of 
each strand of liver-cells. There is some pigment also in the Kupffer 
cells of the capillaries, but it is far less noticeable. 
Another lesion characteristic of pernicious anaemia is found in the 
white matter of the spinal cord. Especially in the posterior tracts there 
occur focal areas of degeneration of the nerve-fibres and neuroglial scar- 
ring which, by interrupting these tracts, produce irregular, ascending, sec- 
ondary degenerations. These, described by Lichtheim, Minnich, Nonne, 
Milne, and others, bring about very distinct sensory disturbances during 
life, sometimes amounting to ataxic phenomena closely resembling those 
of tabes. 
On the whole, taking into consideration the various lesions here de- 
scribed, it appears that the autopsy findings in pernicious anaemia are so 
constant and peculiar that a diagnosis can be made with security from 
them alone, but when taken together with the typical course of the disease 
and the alterations of the blood, there remains no doubt as to the inde- 
pendence of the disease. It seems reasonably certain, too, that before 
long some simple explanation of the pathogenesis of this disease will be 
found. 
Some mention should be made of the rather rare cases of aplastic ancemia 
which runs a more precipitate downward course to a fatal result because no 
effort toward regeneration of the blood takes place in the bone-marrow. 
Instead, the marrow of the long bones is found at autopsy, in spite of the 
most profound angemia, to be entirely yellow and fatty without any of 
the cell hyperplasia seen in the ordinary cases. 
In some degree allied to pernicious anaemia, although in most respects essentially 
different, is the curious affection hemochromatosis. This has been referred to in connection 
with pigmentation and perhaps also in other associations. Inasmuch as it is not a 
form of anaemia it has no place here, but the deposition of blood pigment is so striking 
that it is unconsciously associated with that just described in pernicious anaemia. As 
a result of some process of unknown nature, and without great blood destruction, the 
organs become laden with haemosiderin and haemofuscin. Incidentally there is injury 820 
TEXT-BOOK OF PATHOLOGY 
and scarring of the liver and pancreas, and usually diabetes. All these organs assume 
a bright chestnut-brown color. Whether the accumulation of iron is due to some in- 
ability of the mucosa of the colon to excrete the usual excess, remains to be determined. 
Another form of anaemia which may be touched upon is that which 
accompanies the so-called hoemolytic icterus. It is either congenital or 
arises later in life and appears to be associated with an excessive fragility 
Fig. 404.-Myeloid alteration of the splenic pulp in osteosclerotic anaemia from 
destruction of bone-marrow by metastases from a carcinoma of the prostate. N. M., 
Neutrophile myelocytes; E. M., eosinophile myelocytes; Ph., pigment holding phagocytic 
cells. 
of the red corpuscles as tested with hypotonic solutions. These, in liberat- 
ing their hsemoglobin, furnish the material for the production of jaundice. 
There is no obstruction of the bile-passages, but the spleen becomes greatly 
enlarged and filled with red corpuscles. It is said that removal of the spleen 
brings the disease to a stop and that the corpuscles recover their normal 
resistance. No adequate explanation is offered for this. BLOOD-FORMING ORGANS 
821 
Anaemia Following Mechanical Destruction of the Bone-marrow.- 
Although the technically impossible experimental destruction of all the 
bone-marrow has often been discussed, some light on such a condition 
is furnished by those cases in which a tumor, such as a carcinoma of the 
prostate or breast, metastasizes to the marrow cavity of practically every 
bone in the body, and there, by occupying space in the rigidly enclosed 
Fig. 405.-Osteosclerotic anaemia following destruction of bone-marrow by metastatic 
carcinoma. Clumps of myelocytes in the liver capillaries. The endothelial cells are 
intact. 
cavity, destroys the bone-marrow. There is much uniformity in these 
cases, and we have recently studied two in which literally every bone was 
found to be completely occupied by the tumor. The cavities of all the 
long bones were filled with a solid tissue, for these tumors cause the forma- 
tion of enormously thick laminae of new cancellous bone which lie in a 
close network and contain in their meshes only the epithelial cells of the 
tumor. The ribs, vertebrae, pelvic and other bones were also solidly in- 
filtrated by the bone-forming tumor. The effect was to produce the most 
profound anaemia in which the red blood-corpuscles sank to 600,000 per 822 
TEXT-BOOK OF PATHOLOGY 
c.mm. There was a parallel reduction of the granular leucocytes. It is 
in such cases that the greatest need arises for extramedullary blood for- 
mation and, indeed, they furnish the best and least complicated examples 
of myeloid change in the spleen and liver. The development of blood in 
the spleen and liver in one of these cases is shown in Figs. 404 and 405. 
A similar effect, as far as the red corpuscles are concerned, is produced 
by the crowding out of the erythrogenic tissues by the enormous over- 
growth of myeloid cells in myeloid leukaemia and of the lymphoid cells 
in lymphoid leukaemia. Of course the destruction is by no means so com- 
plete in these cases, and the existence of the myeloid change in other 
Fig. 406.-Spleen in Banti's disease. 
tissues is less clearly defined since they are already overwhelmed with the 
hyperplastic elements from the bone-marrow itself. 
Banti's Disease.-There is a form of anaemia with great swelling of the 
spleen and usually accompanied by haemorrhages which has long been 
described by clinicians as anaemia splenica. Banti has studied these cases 
anatomically and his name is associated with the complex of lesions, al- 
though it is claimed by others that not all the cases progress, as Banti 
describes them, to a stage in which cirrhosis of the liver and ascites are 
features. Nothing is known of the cause: the spleen becomes greatly 
enlarged and there is a secondary type of anaemia intensified by haemor- . 
rhages from the stomach. There may or may not be cirrhosis of the liver, 
but there is a peculiar and specific type of alteration in the spleen which is 
not like that due to chronic passive congestion nor even like the one asso- BLOOD-FORMING ORGANS 
823 
ciated with forms of cirrhosis of the liver which do not obstruct the portal 
blood-stream (Fig. 406). It may reach a weight of 1 to 3 kg., and during 
life is distended with blood. The veins are enormously enlarged and 
numerous huge collateral channels appear, especially in adhesions between 
the spleen, the stomach, and the diaphragm. There is often thrombosis 
of the main splenic vein, a condition which I have seen three times. When 
the spleen is extirpated, it shrinks and collapses with the escape of blood 
Fig. 407.-Portion of spleen and liver from case of Banti's disease. Spleen fibrous and 
elastic. Extreme cirrhosis of the liver. 
and becomes a rather flabby elastic mass which, on section, shows a grayish- 
pink translucent cut surface that sinks a little below the capsule (Fig. 
407). The Malpighian bodies are not visible. Microscopically there is 
found to be moderate atrophy and scarring of the Malpighian bodies, and 
in the pulp the venules are separated by quite abundant loose fibrous 
tissue in which there remain very few of the original pulp cells. The whole 
spleen is thus impoverished in cells and has assumed an empty appearance, 824 
TEXT-BOOK OF PATHOLOGY 
being composed essentially of fibrous tissue in which the venules are em- 
bedded. The liver, in the late stages, is said by Banti to become distinctly 
cirrhotic. In our rather numerous cases it has frequently appeared normal 
and in few instances has shown advanced cirrhosis. The bone-marrow is 
moderately hyperplastic. We are thus very ignorant of this condition, 
but it is quite clear that it is a definite and constantly recurring disease 
and that it is easy to recognize the typical anatomical changes. Ex- 
tirpation of the spleen appears to cure the whole malady, if it does not 
kill the patient through uncontrollable haemorrhage at the operation. 
There is another type of splenomegaly known as Gaucher's splenomegaly 
in which a totally different condition exists. Details must be read in the 
papers of Bovaird, Brill, Mandelbaum, Risel, and others, but the essential 
facts are that it occurs in families, affecting several children, that it pro- 
duces great enlargement of the spleen and sometimes of the lymph- 
glands, without jaundice or ascites. There is no change in the blood, but 
in the spleen, lymph-glands, bone-marrow, and liver there are giant, multi- 
nuclear, phagocytic cells the origin of which has been much disputed. 
Marchand and Risel think they arise from the reticulum cells through the 
absorption of a hyaline, foreign, protein-like substance. A case studied 
recently by Rich showed an extreme enlargement of the long bones which 
were occupied by the tumor-like mass of tissue composed of the large cells. 
Elsewhere this tissue behaved like a tumor invading the organs. 
LITERATURE 
General-Paltauf, Freund, and Sternberg: Handb. allg. Path., Krehl and Marchand, 
1912, ii, 1. 
Naegeli: Blutkrankheiten u. Blutdiagnostik, Leipzig, 1907. 
Bone-marrow-Maximow: Arch. f. mikr. Anat., 1910, Ixxvi, 1. 
Jackson: Arch. f. Anat. u. Phys., Anat. Abth., 1904, 33. 
Bunting: Johns Hopkins Hosp. Bull., 1905, xvi, 222. Jour. Exp. Med., 
1906, viii, 625. 
Myeloid metaplasia-Tanaka: Ziegler's Beitr., 1912, liii, 338, Lit. 
Meyer and Heineke: Verb. Dtsch. Path. Gesellsch., 1906, ix, 224- 
Sternberg: Ziegler's Beitr., 1909, xlvi, 586. 
Domarus: Arch. f. exp. Path. u. Phar., 1908, Iviii, 319. 
Morris: Johns Hopkins Hosp. Bull., 1907, xviii, 200. 
Benzol ancemia-Selling: Ziegler's Beitr., 1911, li, 576. 
Oxydase reaction-Loele: Ergebn. d. allg. Path., 1913, xvi2, 760. 
Schultze: Ziegler's Beitr., 1909, xlv, 127. 
Anatomy of spleen-Weidenreich: Arch. f. mikr. Anat., 1901, Iviii, 247. 
Mollier: Ibid., 1910-11, Ixxvi, 608. 
Pearce, Austin, Krumbhaar, Eisenbrey: "Spleen and Blood De- 
struction," Jour. Exp. Med., 1912, xvi; ibid., 1913, xviii; ibid., 
1914, xx, et seq. 
Lymphocytes-Marchand: Verh. Dtsch. Path. Gesellsch., 1913, xvi, 5. 
Polycythcemia rubra-Osler: Amer. Jour. Med. Sci., 1903, cxxvi, 187. Brit. Med. Jour., 
1904, 1, 121. 
Lucas: Arch. Int. Med., 1912, x, 597. 
Typhoid bone-marrow-Longcope: Bull. Ayer Clin. Lab., 1905, ii, 1. BLOOD-FORMING ORGANS 
825 
Haemolymph nodes-Warthin: Amer. Jour. Anat., 1901, i, 63. 
Pernicious anaemia-Cabot: Osler and McCrae's Modern Medicine, 1915, iv, 619. 
Lazarus: Die Ansemie, Wien, 1913. 
Sternberg: Verh. Dtsch. Path. Gesellsch., 1907, x, 114. 
Ziegler: Dtsch. Arch. f. kl. Med., 1910, xcix, 431. 
Aplastic anaemia-Lavenson: Amer. Jour. Med. Sci., 1907, cxxxiii, 100. 
Stone: Ohio State Med. Jour., 1907, iii, 243, Lit. 
Osteosclerotic anaemia-Assmann: Ziegler's Beitr., 1907, xli, 565. 
Askanazy: Verhandl. Dtsch. Path. Gesellsch., 1904, vii, 58. 
Haemolytic jaundice-Guizzetti: Ziegler's Beitr., 1912, lii, 15. 
Primary splenomegaly-Banti: Riforma Medica, 1901, xvii, i, 590. 
Rolleston: Practitioner, 1914, xcii, 470. 
Leon-Kindberg: Annales de Medicine, 1914, i, 189. 
Gaucher's splenomegaly-Bovaird: Amer. Jour. Med. Sci., 1900, cxx, 377. 
Brill and Mandelbaum: Pbid., 1909, 1913, cxlvi, 863. Jour. 
Exp. Med., 1912, xvi, 797. 
Marchand: Munch, med. Woch., 1907, liv, 1102. 
Risel: Ziegler's Beitr., 1909, xlvi, 241. CHAPTER XLI 
EFFECTS OF INJURIES TO THE BLOOD AND BLOOD-FORMING 
ORGANS (Continued) 
Leucocytosis; Leucopenia. Lymphocytosis. Eosinophilia: Corresponding changes of 
hcematopoietic organs. Independent disease of the blood-forming organs: General characters; 
Classification in lack of information as to aetiology. Chronic lymphoid leukaemia. Acute 
lymphoid leukaemia. Leucosarcoma, or chloroleucosarcoma (chloroma). Lymphoid 
myeloma. Pseudoleukaemia. Lymphosarcoma. Status lymphaticus. 
The blood-forming organs respond promptly in the production of white 
corpuscles when the occasion demands it, just as they do in the case of 
red corpuscles. But in this case the causes of their activity are different 
and it is toward the flooding of the blood with abnormally great numbers 
of these white corpuscles that their efforts tend, rather than to the mere 
replacement of those which have been destroyed in the circulation. 
The appearance of an excessive number of white corpuscles in the 
circulation is called hyperleucocytosis, commonly shortened to leuco- 
cytosis, while their decrease is known as leucopenia. So specific are the 
different types of white cell of the blood that each may separately be thus 
affected, and it is necessary, in order to understand the nature of the change, 
to know not only how many white cells are present in each cubic milli- 
metre of the blood, but in what proportion the different cells are present. 
Through common use the far more frequent excess in the absolute number 
of polymorphonuclear neutrophile leucocytes has come to be spoken of 
loosely as " leucocytosis " par excellence. But the terms lymphocytosis, 
eosinophilia, myelocytosis, etc., are also used to express the predominant 
increase in the corresponding cells, and these terms may be properly used 
even though the total number of leucocytes is not increased. In the fol- 
lowing we shall use the term leucocyte to refer to any of the circulating 
white cells of the blood, specifying in each case the particular type meant. 
The details of the changes in the relative proportions and absolute num- 
bers of leucocytes must be studied in the special works on the clinical 
examination of the blood, and only an outline shall be given here in con- 
nection with the description of the changes in the blood-forming tissues. 
Neutrophile leucocytosis is the common outpouring of polymorphonuclear 
neutrophiles into the blood, so familiar in almost every sort of acute in- 
flammatory process. These cells have to a great extent the function of 
attacking and engulfing bacteria and other injurious substances and of 
LEUCOCYTOSIS AND LEUCOPENIA 
826 LEUCOCYTOSIS AND LEUCOPENIA 
827 
producing a proteolytic ferment which acts best in an alkaline medium. 
They appear in increased numbers in the course of digestion after the use 
of certain drugs (quinine, etc.), after hsemorrhage, during some forms of 
toxic injury to the tissues, but especially and in greatest abundance as a 
response to the invasion of bacteria. Thus in pneumonia, endocarditis, 
septic infection, and in nearly every sort of acute inflammatory process, 
the neutrophile leucocytes rise in number until the white corpuscle count 
reaches 20,000 to 30,000 or 40,000, or in some cases as much as 150,000, 
per c.mm. In such cases the other leucocytes are not correspondingly 
increased, and the neutrophile cells assume a proportion of 90 or 95 per 
cent. There are notable exceptions to this in the case of typhoid fever, 
measles, tuberculosis, and protozoan infections, such as malaria, in which 
the leucocyte count does not rise, or in the case of trichiniasis and allied 
parasitic infections in which the eosinophile cells are especially increased. 
Lymphocytosis.-The lymphocytes are relatively and sometimes ab- 
solutely increased in number in typhoid fever and several other infections, 
and the important work of Murphy* has recently shown that their presence 
is really of the very greatest value in antagonizing such infections. Animals 
deprived of their lymphocytes by exposure to x-rays, etc., are much more 
susceptible to tuberculosis than normal animals, and the zone of lympho- 
cytes which is so constantly found gathered about growing tumors is 
evidently of great importance, for in animals without lymphocytes im- 
planted tumors grow rapidly, although they are destroyed in the controls. 
Hence we must assume that the so-called round-cell infiltration which is 
so striking a feature of the late stage of an inflammatory reaction and 
predominant in the more chronic forms, is an expression of the ability of 
the lymphocytes to act in the process of warding off and annulling injuries. 
Relative lymphocytosis occurs not only in typhoid fever but in malaria, 
small-pox, exophthalmic goitre, and in many affections of childhood. 
Eosinophilia has been mentioned as occurring in trichiniasis, uncin- 
ariasis, and other infections with parasitic worms, in asthma, in various 
skin diseases, in scarlet fever, etc. Other cells, such as myelocytes, myelo- 
blasts, and mast cells are found at times in the circulating blood but 
usually only in connection with leukaemias, except in certain severe in- 
fections in which myelocytes are swept into the blood in the wake of 
the leucocytes. 
The changes in the blood-forming organs in these states of the blood are 
not so satisfactorily studied as one could wish. Descriptions of the spleen 
and bone-marrow are particularly meagre except in a few instances. 
In neutrophile leucocytosis there is a strong hyperplastic reaction in 
the bone-marrow, which naturally consists essentially in a great new 
production of neutrophile myelocytes, which leads to the formation of the 
leucocytes. As a rule, the leucocytes are discharged so rapidly that the 
* Murphy and Ellis: Jour. Exp. Med., 1914, xx, 397. 828 
TEXT-BOOK OF PATHOLOGY 
myelocytes become the most prominent feature of the bone-marrow section 
(Fig. 408). Undoubtedly the spleen is deeply affected in this process and 
commonly assumes the peculiar softness and richness in cells which has 
already been described as the acute splenic tumor of infectious or septic 
diseases. It appears that in such spleens there is a form of myeloid meta- 
plasia combined with an accumulation of the debris of cells, and phagocytes 
loaded with such fragments. The lymph-glands and lymphoid tissues are 
Fig. 408.-Bone-marrow from a case of staphylococcus septicaemia with leucocytosis. 
Myelocytes are abundant, but there are few leucocytes in the marrow. 
not necessarily much affected except by local conditions in which they 
take up the products of inflammation. 
The cause of the changes in the bone-marrow in inflammatory leuco- 
cytosis has been much discussed. It is evident that the appearance of 
such great numbers of leucocytes must depend upon the ability of the 
bone-marrow to produce them rapidly. The idea that the leucocytosis 
is a response to the need caused by the destruction of many of their number 
is scarcely different from the idea that they are drawn to the general cir- 
culation and thence to the site of the inflammation by a chemotactic 829 
LEUCOCYTOSIS AND LEUCOPENIA 
substance which itself gains entrance into the circulation. That some such 
chemical stimulant must not only attract the leucocytes but also stir the 
bone-marrow to increased formation of these cells seems to be clearly 
shown by the extremely rapid and ready increase which takes place in 
infections as contrasted with the much less striking leucocytosis which 
appears after a severe haemorrhage, that is, after the actual mechanical 
removal of the leucocytes. It is most important to realize the fact that 
an extremely violent poisoning, such as occurs in many severe infections, 
Fig. 409.-Bone-marrow in typhoid fever. 
may not be followed by any leucocytosis. On the contrary, the bone- 
marrow seems to be so injured by the strong stimulus as to be incapable of 
producing the cells. It is probably exactly the same thing on a somewhat 
different plane when, in a debilitated old person, there is no leucocytosis 
in pneumonia or other infection, for then a degree of poisoning which 
might be readily met by a leucocytosis in a young and strong person is 
sufficient to paralyze the feebly reacting bone-marrow of the old man. 
Clearly then the prognosis in any infection may be judged to some extent 
by the efficiency of the leucocytic response; when there is a failure on the 830 
TEXT-BOOK OF PATHOLOGY 
part of the bone-marrow to produce abundant leucocytes the disease is 
likely to prove fatal. 
In lymphocytosis of infectious diseases the spleen and lymph-glands are 
usually enlarged, but this enlargement is generally due to local causes, as 
in typhoid fever, and not especially to their participation in the production 
of lymphocytes, although the lymphoid tissue is undoubtedly active in 
this way. In the bone-marrow there is very definite hyperplasia and the 
bone-marrow of the femur becomes red or grayish-red and cellular. Here, 
however, the new formation of myelocytes and neutrophile cells is found 
to have sunken to a relatively far less important position. It is true that 
the typhoid marrow still shows numerous myelocytes, but the striking 
feature, as Longcope has shown, is the relatively abundant new formation 
of lymphoid cells there. A comparison of Figs. 408 and 409 will show 
this. In typhoid fever the myelocytes seem unable to respond to such 
stimuli as usually produce neutrophile leucocytosis. The advent of 
pneumonia or other similar infection in the course of the disease does not 
necessarily bring out the corresponding leucocytosis, and, indeed, those 
things which usually produce an abscess have failed to do so in a person 
sick with typhoid fever, although the occurrence of furunculosis with 
typhoid fever is familiar. This, however, comes on in a late stage, and cor- 
responds with the experiment of Bauer who could produce no abscess by 
injecting turpentine subcutaneously during the height of the typhoid fever, 
although when the fever disappeared in convalescence the belated abscess 
appeared at the site of the injection. 
In eosinophilia there is a relative and absolute increase in the eosinophile 
myelocytes of the bone-marrow. This statement is made without hesitation 
since it has been shown experimentally by Opie to be so, although there 
are as yet no conclusive reports as to the appearance of the bone-marrow 
in human beings in those infections (trichiniasis, etc.) in which the eosino- 
philes are so abundant in the blood. With regard to the analogous con- 
ditions in leukaemia we shall speak presently. 
INDEPENDENT DISEASE OF THE BLOOD-FORMING ORGANS 
We approach in this section a series of extraordinary affections involving 
the blood-forming organs, and consequently the blood, in which the morpho- 
logical changes from normal are very minutely studied, but in no single 
one of which we know anything of the cause. The study of these diseases 
is made more difficult by the fact that while there are type forms which 
are fairly distinct, one meets with many individual cases in which there 
are wide variations from these types. They are affections of the lymphoid 
tissue on the one hand, or of myeloid tissue on the other, and such is the 
specific distinction between these tissues that we find no mixture of the 
two. They are essentially hyperplasias of the blood-forming tissues, and 
while in some cases this does not involve any striking change in the cir- 
culating blood, in others such quantities of new cells are emptied into the INDEPENDENT DISEASE OF THE BLOOD-FORMING ORGANS 
831 
blood-stream as to be completely subversive of its ordinary composition.* 
Perhaps this should not be regarded as a distinction of importance between 
these cases, because it is said to happen that in some forms the blood, 
after having been normal through a long period in which disease of the 
myeloid or lymphoid tissue was well developed, may suddenly be flooded 
with an excessive number of cells representing the particular hyperplastic 
element. Such cases, however, are rare, although great modifications in 
the quantity of cells poured into the blood occur from time to time in 
those in which the blood shows distinct changes. It is probably correctly 
claimed that the classification of such diseases should be based not upon 
the number of cells swept into the blood, but upon their character and 
therefore upon the character of the hyperplasia in the blood-forming organ 
concerned. Still, the setting free of the cells or their retention in the place 
of their formation is so nearly a constant feature of each form that we 
must assume that there is something peculiar about the way these cells 
are held together in the tissue, which brings about these different results. 
It is difficult, if not impossible, to see in the sections of bone-marrow or 
lymphoid tissue anything which in one case would make the escape of 
cells impossible, in another facilitate it; but perhaps with finer technique 
this may be discerned. 
In some types it appears that the hyperplasia of one sort of cell occurs 
strictly within the normal limits of the myeloid or lymphoid tissue, as 
the case may be, even though these cells may escape into the blood. In 
others the hyperplastic tissue extends like a tumor, so as to invade and 
destroy adjacent tissue, even breaking through the cortex of the bone or 
spreading far and wide from the normal limits of the lymphoid tissue. 
On account of this many authors have looked upon these hyperplasias 
as tumor growths. Indeed, even when there is no obvious tumor but 
great quantities of cells are found circulating in the blood, it seems that 
these cells may form colonies in other organs and there give rise to new 
cells of the same sort. This is the point in dispute in the question of mye- 
loid metaplasia, other investigators holding that such colonies of cells are 
formed in situ by a true metaplasia, and not derived from the usual site 
of their formation in the blood-forming organs. The question is hard 
to settle satisfactorily, but in the one case the new formation of cells 
in an unaccustomed organ, such as the liver, would resemble the mode of 
distribution and proliferation of a tumor; in the other we must assume 
that the tissues of the capillary walls of the liver, the splenic pulp, etc., 
are capable of reacquiring the power of blood formation which, as all agree, 
they possessed during embryonic life. To me the idea of the transplant- 
* Leukaemia, or leucocythaemia, was first observed almost simultaneously by Bennet 
in Scotland and by Virchow in Germany (1848). Virchow recognized the lymphoid 
nature of the cells in one type and their granular character in the other, and called them 
lymphatic and lienal forms. Neumann first pointed out the importance of the bone- 
marrow in their production. TEXT-BOOK OF PATHOLOGY 
832 
ation and growth of cells seems more plausible, although there is some 
good evidence in favor of the idea of metaplasia. 
It appears, then, that if we know accurately all the cellular types existent 
in the bone-marrow and in the lymphoid tissue, which are the blood- 
forming tissues concerned, and if we assume that each is capable of under- 
going an independent hyperplasia, we should be able to construct a tabu- 
lation of all the possible diseases arising in this way. This has indeed 
been done, just as it was possible for Rokitansky to foretell what types 
of malformation of the heart might occur on the basis of the embryo- 
logical development of that organ and then years later to meet with cases, 
hitherto unknown, which realized each member in his scheme. The 
possible existence of unknown tumors has been foretold in the same way 
on a histogenetic basis. 
Sternberg has made such a table, which I shall quote in brief: 
A-Local limited homologous hyperplasias: 
a-With escape of cells into the blood 
(1)-of the lymphatic tissue Lymphatic leukaemia. 
(2)-of the myeloid tissue Mixed-cell leukaemia. 
b-With slight or no escape of cells 
(3)-of the whole lymphatic tissue (diffuse) Pseudoleukoemia. 
(4)-of lymphatic tissue of bone-marrow (tumor- 
like) Lymphatic myeloma. 
(5)-of myeloid tissue of bone-marrow (tumor-like).Myeloid myeloma. 
B-Atypical growths invading surrounding tissue with 
heterotopic or distant nodules: 
a-With escape of cells into the blood 
(6)-of the lymphatic tissue Leucosarcoma or chloro- 
leucosarcoma. 
(7)-of the myeloid tissue Chloromyelosarcoma. 
b-Without escape of cells into the blood 
(8)-of the lymphatic tissue Lymphosarcoma. 
B-b-(9) which would be an atypical growth of myeloid 
tissue, invasive but without escape of cells, has not 
yet been observed. 
While this classification seems logical, it is not an setiological classification, 
and therefore open to criticism. I should prefer another division, perhaps 
equally open to criticism, but separating as the main groups the affections 
of the lymphoid from those of the myeloid tissue. The subordination of 
the main basis of Sternberg's grouping is made for reasons explained above. 
A-Hyperplasia of lymphoid tissues: 
a-With leukaemic blood-- 
(1)-with swelling of lymphoid tissue and lymphoid 
infiltration of organs Chronic lymphoid leukaemia; 
Acute lymphoid leukaemia. 
(2)-with tumors originating in various situations 
and invading tissues Leucosarcoma; Chloroleuco- 
sarcoma (Chloroma). 833 
INDEPENDENT DISEASE OF THE BLOOD-FORMING ORGANS 
b-Without leukaemic blood- 
(3)-with tumors involving bone-marrow Lymphoid or plasma-cell 
myeloma. 
(4)-with general swelling of lymphoid tissue Pseudoleukoemia, aleukcemic 
lymphadenosis. 
(5)-with regional invasive tumor-like growth Lymphosarcoma. 
(6)-with stigmata of general maldevelopment... .Status lymphaticus. 
B-Hyperplasia of myeloid tissue: 
a-With leukaemic blood- 
(7)-with myeloid infiltration of organs Myeloid leukcemia; Myelo- 
blastic leukcemia. 
(8)-with tumors of the myeloid tissue Chloromyelosarcoma (Mye- 
loid chloroma). 
b-Without leukaemic blood- 
(9)-with tumors of the myeloid tissue Myeloid myeloma. 
C-(Included here though probably not related.) Tumor- 
like swelling of lymph-glands with nodules in spleen, 
liver, lungs, etc., granulomatous alteration of lymphoid 
tissue of specific morphology, apparently infectious in 
origin . . Lymphogranulomatosis or 
Hodgkin's disease. 
Chronic Lymphoid Leukaemia.-The onset is insidious, with painless 
enlargement of some of the lymph-glands and occasionally with haemor- 
rhages from the mucosae. Examination of the blood shows an increase 
in the leucocytes without necessarily any change in the red corpuscles. 
Among the leucocytes the small lymphocytes occupy the important place 
and are proportionately greatly increased. This state may continue for 
years with gradually progressing anaemia, continuous intermittent increase 
in the number of white cells, and slow enlargement of the lymph-glands, 
spleen, and sometimes of the liver. The leucocytes may constitute 90 
or 95 per cent, of all the white cells and there may be several hundred 
thousand of these per c.mm. Naegeli mentions one case in which the haemo- 
globin was 25 per cent, and there were 621,000 leucocytes, of which 99.6 
per cent, were lymphocytes with only 0.14 per cent, of neutrophiles. The 
symptoms are due chiefly to the presence of infiltrations of these lympho- 
cytes in various places where they often produce pressure phenomena, 
and to haemorrhage. In the nervous system and eyes, destructive changes 
may occur in this way. Dyspnoea follows similar obstruction in the lungs, 
which, together with the changed character of the blood, makes aeration 
difficult. In the skin there are sometimes tumor-like masses. Death 
follows from the cachectic condition itself or from acute exacerbation or 
intercurrent bacterial infection. 
At autopsy the lymph-glands are found enlarged and converted into 
homogeneous masses of soft, grayish-white cellular tissue, without any 
marks remaining to indicate their structure. In one case which I watched 
for several years the axillary, inguinal, and retroperitoneal glands finally 
formed huge masses in which the separate glands had grown to the size 
of apples. They were so large as to hold the arms away from the sides, 834 
TEXT-BOOK OF PATHOLOGY 
but showed no tendency to invade the surrounding tissue. In that case 
the spleen was large and hard and there were scattered infiltrations of the 
lymphoid cells along the portal branches in the liver (Fig. 410). The 
tonsils and pharyngeal lymphoid tissue may become enlarged late in the 
disease, but this is not invariable. The intestinal lymphoid tissue is aston- 
ishingly little affected. The spleen is generally enlarged, although not to 
the maximum degree. It may still show Malpighian bodies on section 
Fig. 410.-Chronic lymphoid leukaemia. Infiltration about the gall-ducts and portal 
vessels. 
or these can become so indistinctly outlined as to merge in the rest of the 
tissue which is of a grayish or brownish red. The bone-marrow is no longer 
fatty in the shaft of the long bones, but forms a solid cellular tissue of 
gray or grayish-red color, often with patches of dark red. The liver, 
which is usually rather swollen, shows grayish lines accompanying the 
bile-ducts and portal veins. Gray infiltrations are found elsewhere too, 
as in the thymus, which may be markedly enlarged, or in the kidneys, INDEPENDENT DISEASE OF THE BLOOD-FORMING ORGANS 
835 
adrenals, testes, etc. Following the blood-vessels in the retina are sheaths 
of lymphocytes with which haemorrhages are often associated. 
The histological changes are all occasioned by the extraordinary over- 
production of lymphocytes from the lymphoid tissue, wherever that occurs, 
in the lymph-glands, lymphoid apparatus of the respiratory or digestive 
tracts or skin, or in the bone-marrow. It is impossible, as a rule, to make 
out just where it started to undergo hyperplasia in these chronic cases, 
although there is a better opportunity in the acute cases to be described later. 
Fig. 411.-Chronic lymphoid leukaemia. Spleen showing a Malpighian body and part 
of the pulp in which there is much induration and infiltration with lymphoid cells. 
Nsegeli makes a special point of saying that such hyperplasia cannot 
occur in the bone-marrow lymphoid tissue alone, but that all the lymphoid 
tissue is equally involved. 
The cells, in most of the chronic cases, are small lymphocytes. Never- 
theless, in the lymphoid tissue in which they are being formed one finds 
almost always a mixture of these with rather larger lymphoid cells. 
In the lymph-glands all signs of the original architecture with lymph- 
nodules and sinuses have disappeared, being swamped and covered in or 
pushed aside by the overwhelming growth of one kind of cell, so that the 836 
TEXT-BOOK OF PATHOLOGY 
tissue appears as a solid, uniform mass of lymphocytes. In the spleen, at 
first sight, it seems that the same thing is true, as though the Malpighian 
bodies had spread to occupy everything, but closer examination shows that 
the structure of the pulp is still discernible and the venules and interspaces 
are found filled with lymphocytes. In the older cases, in which the spleen 
is hard, there is much new fibrous tissue between the venules. This was 
true in the very chronic case mentioned above and is shown in Fig. 411. 
In the bone-marrow there is usually almost complete replacement of the 
ordinary cells by spreading masses of lymphoid tissue, but in many cases 
there are areas of myeloid tissue left unchanged with erythroblastic and 
myeloblastic cells. These appear to be the dark-red patches which are 
visible in the gross and are no doubt responsible for the relatively good main- 
tenance of the red cell content of the blood. 
Acute Lymphoid Leukaemia.-In our experience this is a more common 
affection than the chronic form, and must be distinguished from it because 
of its more violent and severe symptoms and rapid course, and also because 
the cells concerned are in most cases larger. In relatively few cases only 
are they of the same small size as in the chronic forms. It must be noted 
here that certain of the cases which were formerly classed as acute lymphoid 
leukaemia are now known to be not lymphoid leukaemia at all, but myeloid 
leukaemia in which the non-granular myeloblast is the cell that is especially 
abundant. 
In contrast to the chronic form of lymphoid leukaemia this one begins 
suddenly with intense symptoms: fever, haemorrhages from the mucosae, 
and rapidly developing anaemia. Haemorrhages in the retinae are almost 
constant, while those in the conjunctivae, over the face and over the whole 
body, are often very extensive and gradually pass through the ordinary 
changes of color to become pigment spots that finally disappear. The 
haemorrhages in the mouth, vagina, and digestive tract often become con- 
verted into gangrenous areas which leave deep ulcers. The tonsils and 
the rest of the pharyngeal adenoid tissue frequently become greatly enlarged 
and deeply ulcerated. The lymph-glands may, in some cases, even in a 
rather advanced stage, be relatively slightly enlarged, but usually they are 
palpable or even form prominent packets. In a case now under observa- 
tion what seems to be the thymus has become greatly enlarged in the course 
of a few days. A radiograph reveals the fact, however, that this is a 
retrosternal mass of lymph-glands. The spleen is generally enlarged but 
does not reach as a rule the huge dimensions seen in some other forms. 
The blood in some instances shows no decrease in red corpuscles but usually 
the anaemia advances rapidly and in the case mentioned is already under 
1,000,000. Occasionally such blood shows regenerative forms resembling 
those of pernicious anaemia, but often there seems to be no attempt at 
regeneration. The leucocytes reach high numbers, ranging from 50,000 to 
250,000 or more, and the increase is represented by the lymphocytes, which 
may constitute 98 or 99 per cent, of the cells. As stated above, these INDEPENDENT DISEASE OF THE BLOOD-FORMING ORGANS 
837 
lymphocytes are in most cases larger than those of normal blood. Death 
results from a terminal infection, from haemorrhage, or from the disease 
itself. 
At autopsy the lesions are found to resemble those of the chronic form 
except that since the course of the disease is so much briefer, there is not 
time for the development of such great accumulations of lymphoid tissue. 
The lymph-glands are nevertheless enlarged, and show on section a homo- 
Fig. 412.-Splenic pulp in acute lymphoid leukaemia. The cells of the pulp are practi- 
cally entirely replaced by large lymphoid cells. 
geneous, grayish-white cellular tissue rather softer than that found in the 
chronic cases. The presence of haemorrhages in these glands is very 
characteristic. Microscopically one may find the architecture still rec- 
ognizable although the sinuses contain great quantities of lymphocytes. 
Occasionally, however, the whole structure appears as a mass of lymphoid 
cells. There are usually similar changes in the adenoid tissues of the 
throat, and sometimes in those of the digestive tract, so that swellings com- 
parable to those in typhoid fever are found in the solitary nodules and 838 
TEXT-BOOK OF PATHOLOGY 
Peyer's patches. Since, with haemorrhages, these may become ulcerated, 
the resemblance may be close. 
The spleen is fairly firm, moderately enlarged, and dark grayish-red in 
color. Sometimes one can see the Malpighian bodies distinctly, but in 
other cases they are not to be outlined. There are occasional infarctions. 
Microscopically it is difficult to outline the Malpighian bodies because the 
splenic pulp is filled with quite similar cells. These lie in great numbers 
between the venules, to the exclusion of most of the other cells (Fig. 412). 
Fig. 413.-Spleen in acute lymphoid leukaemia. The splenic pulp and blood-vessels 
are filled with large lymphoid cells contrasting with the lymphocytes of the Malpighian 
bodies. 
It is noteworthy that in this, as in other forms of leukaemia, the endothelium of the 
venules of the spleen to which so many functions have been ascribed is perfectly intact 
and shows no evidence of playing any part in the extraordinary changes going on round 
about. 
In a case before me, however, the Malpighian bodies do stand out with 
fair distinctness because their cells are rather smaller and more closely 
packed than those in the pulp (Fig. 413). In the bone-marrow (Fig. 414), INDEPENDENT DISEASE OF THE BLOOD-FORMING ORGANS 
839 
which is gray or grayish-red and cellular, often with red, gelatinous 
patches, the conditions vary. Usually practically all the myeloid elements 
are crowded out of existence, except perhaps in the red patches just men- 
tioned, by the great compact swarms of lymphoid cells. Nevertheless, 
there are some cases in which these lymphoid cells occur at the time of 
death in patches only, as though they were still in process of aggression. 
Naegeli is very dogmatic in stating that there are, and can be, no cases in 
which this process begins in the bone-marrow alone-that it is essentially 
a systemic disease affecting all the lymphoid tissue. Nevertheless, in one 
Fig. 414.-Bone-marrow in acute lymphoid leukaemia. 
such case reported by Dr. Reed we found the lymphoid tissue throughout 
the body entirely unaffected except that, in the manner of a sieve, it had 
retained many of the circulating lymphocytes in its vessels. The bone- 
marrow was practically entirely composed of lymphocytes. Ehrlich, in 
studying the preparations from that case, expressed his opinion (1902) 
that such a leukaemia might originate from any substratum of lymphoid 
tissue, such as that in the skin, in the intestinal wall, or in the bone-marrow. 
The other changes are the effects of infiltration and localization of large 
quantities of lymphocytes in the organs. In the liver this deposit does not, 840 
TEXT-BOOK OF PATHOLOGY 
in the brief span of the disease, reach macroscopical dimensions, but in the 
kidneys there have been cases in which such quantities of cells have 
gathered in the interstices as to enlarge the organ greatly and give it the 
appearance of a huge white kidney. In the nervous system and retinae 
similar accumulations accompanied by haemorrhages cause functional and 
anatomical disturbances. It is important to note that in neither of the 
forms of lymphoid leukaemia do the circulating lymphoid cells, or the cells of 
this sort in the tissues, give the oxydase reaction which is shown by Schultz 
to be characteristic of the myeloid cells. Nor, according to Longcope, 
are they capable of producing a proteolytic ferment. The contrast in the 
case of other forms of leukaemia, to be described later, is very striking. 
Leucosarcoma or Chloroleucosarcoma.-This term, introduced by Stern- 
berg, is meant to designate those cases in which a definite, tumor-like mass 
is developed in some organ or tissue and is composed of lymphoid cells 
which seem to escape into the blood-stream, giving rise to leukaemic altera- 
tions of the blood. Naegeli and others refuse to recognize this as anything 
distinct from lymphoid leukaemia, in which, as they say, there may be 
extensive, tumor-like infiltrations of the tissues. Sternberg, who finds the 
tumors in the dura mater, in the mediastinum, in the breast or in connec- 
tion with the tissues of the orbit, denies that such growths occur in ordinary 
leukaemia and brings forward the cases studied by Paltauf and by Buschke 
and Hirschfeld in which the tumor was well developed before any changes 
occurred in the blood. Several cases which we have studied, even though 
this very point was neglected, have seemed to me to occupy so distinct a 
position and to begin so definitely with the formation of a localized tumor- 
like mass that I am inclined to accept Sternberg's nomenclature. In one 
of these cases there were two circumscribed " lymphomatous " nodules in 
the breast, which were removed by the surgeon. It was only after their 
removal that examination of the blood was made and revealed the presence 
of 250,000 lymphocytes per c.mm. Another case showed a lymphoid nod- 
ule in the cervix uteri (Fig. 415) extending to the vagina, with ulceration 
and bleeding. It was at first thought to be a carcinoma, but the autopsy 
revealed areas of infiltration of lymphoid cells in many of the organs in 
association with the leukaemic condition of the blood. The cells in this 
form also fail to show the oxydase reaction. 
Intimately related to this, if not identical with it, is one of the forms of 
chloroma, so named for the green color which the tumor-like nodules show 
when first exposed at autopsy. There are two sorts of chloroma, one com- 
posed of large lymphoid cells, the other of myeloid celjs. The lymphoid 
type differs in no important particular from the leucosarcoma except in its 
green color, and perhaps in its arising usually in connection with the peri- 
osteum, and especially with that of the bones of the face and head. The 
green color is inconstant, failing in some parts of the same nodule, and is 
not to be regarded as sufficient basis for the separation of these cases; hence 
Sternberg classifies them as chloroleucosarcoma. No good explanation of INDEPENDENT DISEASE OF THE BLOOD-FORMING ORGANS 
841 
the jade green color has been found, and efforts at the isolation of the 
pigment have failed, perhaps partly because it fades very quickly on 
exposure and disappears. The myeloid form is named by Sternberg on the 
same basis chloromyelosarcoma; it will be referred to later. 
Lymphoid or Plasma Cell Myeloma.-A myeloma is a growth springing 
up in the bone-marrow and evidently occurring as a systemic affection of 
the marrow-cells, since it appears simultaneously in many bones and nowhere 
else. Unless we assume the existence of cells which can grow only in bone- 
marrow, it is hard to imagine such wide-spread multiple growths as due to 
Fig. 415.-Leucosarcoma. Tumor-like nodule in the substance of the cervix uteri. 
This was associated with lymphoid leukaemia. 
transportation of cells. There are again two kinds, this one composed of 
lymphoid cells and another, to be described later, composed of myeloid 
cells. In their biological behavior they are almost exactly alike. The 
lymphoid myeloma is gray or reddish-gray on section, while the myeloid 
form is deep red and soft, but both encroach upon the cortex of the bone 
and erode it, causing fractures at such weakened spots. In both types 
there occurs in the urine a peculiar albumose (Bence Jones protein), the 
mode of formation of which is much debated. In neither form is there any 
constant or characteristic alteration of the blood in the sense of a leukaemic 842 
TEXT-BOOK OF PATHOLOGY 
flooding with lymphoid or myeloid cells, but in one of the three cases 
of the lymphoid form which we observed this winter there were excessive 
numbers of large lymphoid cells with the morphology of plasma cells, in 
the circulating blood. 
In two of these cases there were prominent tumors projecting from the 
ribs, vertebrae, and long bones. On sawing through the bones it was found 
that the involvement of the marrow was far greater than could be realized 
from the surface. Where the tumors showed, the enlargement was partly 
due to lifting up of the cortex, partly to its actual erosion and the protrusion 
Fig. 416.-Lymphoid myeloma. The cells closely resemble plasma cells. 
of the tumor. There were several fractures of the weakened bones. In the 
third case, in which the albumosuria was absent, there were no tumors 
springing from the bones, but nearly all the ribs were broken and the thorax 
collapsed. The marrow was entirely replaced by masses of lymphoid 
cells and the same was true of the marrow of the long bones where the bony 
cortex had become greatly thinned. There was no leuksemic change in the 
blood. The cells (Fig. 416) are non-granulated mononuclear cells with 
basophilic protoplasm, and are very similar to the plasma cells, with which 
they are regarded by most writers as identical. INDEPENDENT DISEASE OF THE BLOOD-FORMING ORGANS 
843 
Pseudoleukaemia.-Cohnheim employed this term to describe a case in 
which there was marked lymphoid hyperplasia in the lymph-glands and 
other lymphoid tissue but no leukaemia; in other words, a condition identical 
with lymphoid leukaemia, but without the blood changes. Since that time 
every sort of obscure affection of the lymph-glands has been called by this 
name, usually in the lack of any clear idea of the nature of the case, and it 
has been particularly confusing in the case of Hodgkin's disease. At the 
1912 meeting of the German Pathological Association in Strassburg this 
was made the subject of discussion. Fraenkel and Sternberg agreed that 
such a condition as Cohnheim described existed, and that it differed from 
lymphosarcoma and Hodgkin's disease, but that in some cases there arose a 
sublymphsemic condition of the blood or even a leukaemic condition, after 
which it could no longer be distinguished from leukaemia. In the long dis- 
cussion which followed no one referred specifically to any case of this dis- 
ease nor did any one seem familiar with it. It is unquestionably a very 
uncommon affection, and the instances which are referred to are usually 
those in which there has been clinical study only. Nevertheless, one does 
meet with cases in which there is swelling of the glands wdiich form bulky 
packets, enlargement of the spleen, and no blood change. If such cases at 
autopsy prove to be due to a true hyperplasia of lymphoid tissue without 
leuksemia and without invasion of the tissues, they will fulfil the definition 
of pseudoleukaemia, or aleukaemic lymphadenosis. 
Lymphosarcoma.-Kundrat was the first to give a clear description of the 
disease which he outlined as lymphosarcomatosis. In this he recognized a 
more or less wide-spread growth arising from a group of lymph-glands (more 
rarely from a single one) or from a tract of lymphoid tissue such as occurs in 
the intestinal wall, pharynx, etc. Such a growth is composed of a delicate 
reticulum in the meshes of which lie cells of a lymphoid character. It fails 
to respect the capsules of the lymph-glands but grows rapidly and invades 
and infiltrates adjacent tissues. Isolated metastases in distant organs are 
rare, but the adjacent lymph-glands may be involved; otherwise the growth 
tends to spread in loose tissue and in film or plate form over serous surfaces. 
Throughout, Kundrat recognized the regional character of the growth. 
Where the tumor appears in the form of a metastatic nodule in such organs 
as the heart or kidney, the sharply outlined nodule seen with the naked 
eye proves to be a localized infiltration of cells between the muscle-fibres 
or tubules (Fig. 417). Eight cases which I was able to study seemed 
to fall into two groups. Three showed thoracic masses apparently derived 
from mediastinal lymph-glands and limited in their extension to the thorax, 
while five were equally limited to the abdominal cavity. They differed 
slightly in the form of the cells, which in the thoracic type were small 
(4-6 n), while in the abdominal type they measured 8-12 /i and were 
associated with a few scattered phagocytic cells of large size. The thoracic 
type formed great masses of solid tissue surrounding the heart and com- 
pressing the lungs. In one case these had actually penetrated the heart-wall 844 
TEXT-BOOK OF PATHOLOGY 
and hung in polypoid lobules in the cavity of the right ventricle. The abdom- 
inal or intestinal type, as already mentioned, either formed great ring-shaped 
masses at intervals along the intestine, penetrating into its lumen and 
obstructing it until ulceration again opened the channel, or else they 
infiltrated the whole wall diffusely for a long way, and by making it 
rigid and inactive might have caused a so-called paralytic ileus. The 
intestine comes to look like a stiff piece of garden hose, and the folds of 
mucosa are all greatly swollen and stand up stiffly (Fig. 418). In such 
Fig. 417.-Lymphosarcoma. Infiltrating mass appearing as a quite sharply outlined 
nodule in the kidney. This was a case in which the intestine was probably the point 
of origin. 
intestinal cases it is not uncommon to find organs such as the adrenal and 
pancreas completely buried in an infiltrating mass of the tissues. The 
mesenteric glands are usually greatly enlarged by a similar infiltration. 
The spleen shows no especial alteration in either of these types, nor do the 
more distant lymph-glands. It is generally stated that the bone-marrow 
is quite unaffected and that there are no alterations of the blood. In two 
of our cases there was hyperplastic bone-marrow in the long bones and 
there were many cells which resembled precisely those of the tumor growth, INDEPENDENT DISEASE OF THE BLOOD-FORMING ORGANS 
845 
and formed solid masses of tumor tissue. Further and more modern 
study of the bone-marrow in such cases must be made. Lymphosarcoma 
arising from other groups of lymph-glands occurs as mentioned above and 
presents similar characteristics. 
The characters which distinguish a lymphosarcoma from other condi- 
tions which resemble it in a confusing way may be best set down in a com- 
parative form. From a single section it would probably be impossible from 
a study of the cells to distinguish between an involvement of a gland by 
chronic lymphoid leukaemia, leucosarcoma, lymphosarcoma, and small 
round-cell sarcoma. In chronic leukaemia the glands become enlarged 
but remain discrete, there is dissemination of lymphoid cells in the capil- 
Fig. 418.-Lymphosarcoma. Infiltration of valvulae conniventes of the jejunum. 
laries of organs otherwise practically unchanged, and there is the leukaemic 
state of the blood. In leucosarcoma there is an invasive lymphoid tumor 
and there may be nodular infiltrations, but once more there is the leukaemic 
state of the blood. In lymphosarcoma there is an invasive or infiltrating 
lymphoid growth which has a peculiar regional way of spreading and is 
rather limited either to the thorax or the abdomen. It is much like leuco- 
sarcoma except that there is no leukaemic change of the blood. Round- 
cell sarcomata offer much less difficulty: they start anywhere in the con- 
nective tissue (not in the lymph-glands especially) as a single tumor nodule 
which invades the surroundings and metastasizes by way of the blood- 
stream, forming new discrete nodules in distant organs, such as the lungs, 846 
TEXT-BOOK OF PATHOLOGY 
Fig. 419.-Intestine in status lymphaticus, showing great enlargement of lymphoid 
nodules. INDEPENDENT DISEASE OF THE BLOOD-FORMING ORGANS 
847 
liver, etc. When they lodge in a lymph-gland they produce a solid nodule 
with an outline, outside which some remnant of the gland may be found 
unchanged. All the others cause a complete replacement of the gland, 
although occasionally a localized lymphosarcomatous infiltration may leave 
the rest of the gland intact. With round-cell sarcoma there is no leukaemia. 
Status Lymphaticus or Thymico-lymphaticus.-In many young persons 
and children who have died suddenly after some slight shock or infection 
which seemed insufficient to cause death, there is found, at autopsy, a general 
swelling of the lymphoid structures and persistence or enlargement of the 
thymus. Paltauf was the first to 
point out clearly that this lym- 
phoid hyperplasia is only part of a 
general constitutional abnormal- 
ity which amounts to a physical 
inferiority of the persons affected. 
The whole complex is best seen in 
young persons, since only part of 
it is as yet evident in children, 
while the lymphoid changes fade 
in old people. In men there is 
an incomplete development of the 
secondary sexual characteristics 
with a tendency toward the femi- 
nine type-the hair on the face is 
scanty or lacking, the pubic hair 
has the feminine distribution, 
being sharply limited toward the 
abdomen, the external genitals 
are small, the thighs round and 
arched anteriorly, and the skin 
smooth and velvety. In women, 
thorax and extremities are slen- 
der, the genitals are hypoplastic, 
menstruation is irregular or ab- 
sent, and there may be a tendency 
to growth of hair on the face. In such persons the musculature may be 
flabby and weak, though sometimes well developed, but the heart is weak 
and soft and the large blood-vessels are relatively narrow and thin walled. 
It appears that failure of this inadequate circulatory mechanism may be 
one at least of the causes of sudden death and probably the most impor- 
tant. Emerson finds such cases most common among alcoholics and drug 
habitues, but it is by no means limited to mental degenerates. Persons 
with this constitutional abnormality are evidently far more exposed than 
others to destruction by the injuries and infections incidental to life, and 
if they reach mature age, it is through especial care or good fortune. 
Fig. 420.-Status lymphaticus. Enlarge- 
ment of tonsils and lymphoid nodules at the 
root of the tongue. 848 
TEXT-BOOK OF PATHOLOGY 
At autopsy one finds the lymphoid nodules throughout the digestive 
tract especially enlarged and prominent (Fig. 419). In the throat and at 
the base of the tongue the adenoid tissue is swollen too (Fig. 420), although 
Emerson makes little of this point. The lymph-glands in general may be 
larger than normal, although this is not constant. The spleen is not 
particularly affected except that the Malpighian bodies are enlarged. 
There is often red bone-marrow. The thymus is commonly persistent and 
often greatly enlarged, so as to weigh forty to fifty grams and extend far 
down over the pericardium. The narrowness and delicacy of the aorta and 
the smallness of the heart are striking. Wiesel has described in many 
cases hypoplasia of the adrenals and chromaffin system and thinks that 
the condition of the circulatory apparatus is connected with that. The 
lymphoid tissue shows no such hyperplasia as is seen in leukaemia, but 
maintains its architecture and the relations of lymphoid cells to germinal 
centres. Details of this affection should be read in the papers of Neusser, 
Bartel and Bauer, and others. It may be interesting to quote Neusser's 
division of constitutions into two categories. One, the bearer of a 
good heart, good blood-vessels, good bone-marrow, good sympathetic 
and chromaffin system, and good genitals, is like a folio edition of the 
genus Homo; while the other shows just the opposite, with its poor heart, 
poor hypoplastic vessels, poor bone-marrow, poor genitals, poor chromaffin 
and sympathetic system. 
LITERATURE 
General-Sternberg: Ergebnisse d. allg. Path., 1903, ix, Hte Abt., 360. 
H. Hirschfeld: Ztschr. f. Krebsforschung., 1923, xix, 269. 
Leukaemia-Naegeh: Leukaemia u. Pseudoleukaemia, Wien, 1913. 
Sternberg: Ztschr. f. Heilkunde, 1904, xxv, Path. Abth., 170. 
Reed: Amer. Jour. Med. Sci., 1902, cxxiv, 653. 
Leucosarcoma-Sternberg: Wien. kl. Woch., 1908, xxi, 475. Ziegler's Beitr., 1915, 
Ixi, 75. 
Myeloma--Christian: Jour. Exp. Med., 1907, ix, 325. 
Shennan: Edin. Med. Jour., 1913, n. s. x, 321. 
Hoffman: Ziegler's Beitr., 1904, xxxv, 317. 
Sternberg: Ztsch. f. Heilk., 1904, xxv, Path. Abth., 89. 
Hedinger: Frankf. Ztsch. f. Path., 1911, vii, 343. 
MacCallum: Jour. Exp. Med., 1901-05, vi, 53. 
Pseudoleukoemia--Fraenkel: Verh. d. Dtsch. Path. Gesellsch., 1912, xv, 5. 
Sternberg: Ibid., 22; discussion, 82. 
Lymphosarcoma-Kundrat: Wien. kl. Woch., 1893, vi, 211. 
Paltauf: Ergebn. d. allg. Path., 1896, iii, 652. 
MacCallum: Johns Hopkins Hosp. Bull., 1907, xviii, 337. Trans. 
Assoc. Am. Phys., 1907, xxii, 350. 
Status lymphaticus-Neusser: Diagnose des Status Thymico-lymphaticus, Wien, 1911. 
Bartel: Status Thymico-lymphaticus, Leipzig, 1912. 
Paltauf: Wien. kl. Woch., 1889, ii, 876; 1890, iii, 172. 
Emerson: Arch. Int. Med., 1914, xiii, 169. 
Zellweger: Ztsch. f. angew. Anat. u. Konstitutionslehre, 1913, 
i, 192. 
v. Werdt: Berl. kl. Woch., 1910, xlvii, 2383. CHAPTER XLII 
EFFECTS OF INJURIES TO THE BLOOD AND BLOOD-FORMING 
ORGANS (Continued) 
Chronic myeloid leukaemia. Acute myeloid leukaemia, myeloblastic leukaemia. Myeloid 
chloroma or chloromyelosarcoma. Myeloid myeloma. Hodgkin's disease or lympho- 
granulomatosis . 
CHRONIC MYELOID LEUKAEMIA 
The beginning of this disorder is usually gradual and unnoticed, with 
weakness and loss of weight, after which anaemia and slight haemorrhages 
appear. Many of the patients suffer no particular discomfort and show no 
anaemia until late in the disease, but apply for relief from a large abdominal 
tumor which proves to be the enormously enlarged spleen. Examination 
of the blood shows a very great increase in the number of white cells which 
are easily seen to be large granular cells. They may reach a count of over 
1,000,000 per c.mm. More careful study reveals the fact that while at 
first the polymorphonuclear neutrophiles are still the predominant cells, 
there is later a great increase in the neutrophile myelocytes which usually 
become the most numerous cells. Eosinophile myelocytes also appear in 
great numbers, while eosinophile leucocytes, though absolutely increased, 
like the neutrophile leucocytes, do not attain to any great proportion among 
all the cells. Mast leucocytes with their basophile granulations and 
basophilic myelocytes are abundant and conspicuous. Lymphocytes are 
present in small numbers and form a very small proportion of the total. 
Normoblasts and rarely megaloblasts appear in later stages when the 
anaemia becomes more marked. The appearance of such blood with its 
huge numbers of large granular myelocytes is most astonishing even when 
compared with the much altered blood of the lymphoid forms of leukaemia. 
In late stages when the alterations have become most intense, non-granular 
myeloblasts may appear in considerable numbers. These, like the granular 
cells just mentioned, give the oxydase reaction most brilliantly, and, as 
might be expected, the blood in these cases is rich in proteolytic ferments. 
There may be no reduction in the red corpuscles until quite late in the 
disease. Then, partly as a result of the haemorrhages, their number sinks 
and normoblasts appear in the circulation. In some cases megaloblasts 
are found and the form of the red corpuscles (anisocytosis, poikilocytosis) 
recalls that seen in pernicious anaemia. Megalocaryocytes are sometimes 
found. 
With the advance of the disease there often occur rather extensive 
haemorrhages from the mucosa or into the retinae or other organs. Death 
849 TEXT-BOOK OF PATHOLOGY 
850 
from apoplexy seems to be relatively common. Extensive necrotic and 
gangrenous processes sometimes appear here just as in the lymphoid cases. 
There have been reported a few instances, such as those of Thompson 
and Ewing, Burckhardt, and others, in which such myeloid leukaemia 
with predominant myelocytes in the blood has arisen acutely and quickly 
led to sudden death, and in these cases evidences of haemorrhage and 
necrotizing processes are most striking. 
They are mentioned here because there is 
another group of acute myeloid leukaemias 
to be discussed later in which myeloblasts 
form the predominant cell in the blood. 
At autopsy, in cases of chronic myeloid 
leukaemia, the blood is found clotted in the 
heart and large vessels and is so peculiar in 
appearance that it suggested to Virchow 
the name leukaemia or white blood. When 
it clots slowly, as in the heart, the upper part 
of the clot is whitish or greenish and rather 
opalescent on account of the great number 
of leucocytes. In a typical case which we 
have studied, the clots evidently formed 
more rapidly for they were of a quite uni- 
form pale chocolate color. The most strik- 
ing phenomenon at autopsy is the great 
enlargement of the spleen (Fig. 421), which 
is smooth and firm and often deeply notched 
at its edge. In some cases it is adherent 
to the diaphragm and abdominal wall. It 
stretches downward toward the right and 
may reach the symphysis pubis, filling a 
great part of the abdominal cavity and ap- 
pearing to rest on the right ilium. In the 
case just mentioned it weighed 1550 grams 
but it may weigh as much as 10,000 grams. 
On section it is grayish-red and finely gran- 
ular and opaque; the Malpighian bodies 
have disappeared but the trabecula? can 
usually be fairly clearly seen. Sometimes, however, in the later stages it 
is very fibrous and dense and the whole structure assumes a rather uni- 
form appearance. Infarcts are quite common. The bone-marrow in the 
long bones is no longer fatty but firm, opaque yellowish gray or pinkish- 
gray, and homogeneous. It can be cut out in blocks and is evidently a solid 
mass of cells. The liver is enlarged and rather pale but usually without 
any grossly visible change in the structure. However, in the case men- 
tioned there were several opaque grayish nodules embedded in its sub- 
Fig. 421.-The spleen in chronic 
myeloid leukaemia. CHRONIC MYELOID LEUKEMIA 
851 
stance and reaching 5 to 8 mm. in diameter, which proved to be masses of 
myeloid tissue. The other organs show no characteristic gross changes 
except the effects of the anaemia, which are seen in the general pallor of 
the organs and in accumulations of fat in the heart, kidneys, etc. The 
lymph-glands are not enlarged and with the rest of the lymphoid tissue 
appear to play no part in the process. Apoplectic haemorrhages in the 
brain have already been mentioned. Thrombosis of various veins is not 
uncommon. When complicating infections occur the leucocytosis which 
attends them may be quite normal and the reaction about the bacteria 
and injured tissue typical. In such cases the whole blood picture can 
change so that the leukaemic character disappears, and in place of the 
Fig. 422.-Bone-marrow in chronic myeloid leukaemia. There are very abundant 
neutrophile (B) and eosinophile (C) myelocytes, megalocaryocytes (A), and a few 
normoblasts (D). 
horde of myelocytes there are found the neutrophile leucocytes. Such a 
change does not last, however, and when the occasion for leucocytosis is 
over the leukaemia returns. I have not seen such a case but it would 
appear to offer an interesting field for study of the nature of leukaemia. 
Microscopically the bone-marrow is the tissue of prime interest. It 
appears as a solid array of cells among which the capillary vessels can be 
made out with some difficulty (Fig. 422). Within these vessels there are 
great numbers of neutrophile myelocytes, eosinophile myelocytes, leucocytes 
of all kinds, and red corpuscles. Outside, but evidently able to enter the 
blood-channels pretty easily, are masses of neutrophile myelocytes with 
somewhat smaller numbers of eosinophile myelocytes. Basophile myelo- 852 
TEXT-BOOK OF PATHOLOGY 
cytes are also present in great numbers, and there are other non-granular 
mononuclear cells of rather large size which are probably myeloblasts. 
Neutrophile leucocytes are there in rather large quantities too, but there is 
not much to be seen of red blood-cells or of erythroblastic tissue. Normo- 
blasts are present here and there in small groups but must be searched for. 
From this it seems that the progressive anaemia in this, as in other types of 
leukaemia, may be due to the actual crowding out of the erythroblastic tissue 
Fig. 423-Spleen in chronic myeloid leukaemia. Space between two adjacent 
venules, showing numerous myelocytes of neutrophile and eosinophile type. Many 
cells, emigrating from the venules, of which some appear to be nucleated red corpuscles. 
rather than to the haemorrhages, which are not always very evident. In 
this respect it would resemble the osteosclerotic anaemia mentioned above. 
The spleen (Fig. 423) in this disease, has almost the same composition in 
respect to the cells present as the bone-marrow; it resembles in an exagger- 
ated way the myeloid spleen found in the osteosclerotic anaemia. As shown 
in the drawing, the venules of the splenic pulp (Malpighian bodies are not 
found) are intact and in themselves unaffected. They are full of myelo- 
cytes and in the intervening spaces myelocytes of all kinds are crowded CHRONIC MYELOID LEUKAEMIA 
853 
together with some red corpuscles and a few nucleated red cells. Myelo- 
blasts, nucleated red cells, and even lymphocytoid cells are constantly 
found passing through the walls of the venules which seem to be as open as 
so much mosquito netting. 
In all the other organs the microscopical alterations consist essentially 
in the filling of the capillaries with myelocytes, etc., from the leukaemic 
blood (Fig. 424). In the liver the capillaries may be hugely distended 
Fig. 424.-Myeloid leukaemia. General infiltration of the liver with myeloid cells. 
with clumps and masses of these cells. It is interesting to note that 
no necroses occur in the liver-cells or even among the packed myelocytes 
themselves. In this the myelocytes differ from the cells found distending 
these capillaries in typhoid fever, which seem unused to life within the 
vessels and in addition carry seeds of death with them. In the nodules 
mentioned above there are huge pools of myeloid cells and the liver-cells 
are compressed into flattened rows or squeezed out of existence entirely. 854 
TEXT-BOOK OF PATHOLOGY 
Some of the wide capillaries contain megalocaryocytes in groups, and the 
whole area has assumed the exact appearance of bone-marrow (Fig. 425). 
Other organs are also thickly infiltrated with myelocytes (Fig. 426), but 
as a rule show little of actual myeloid colonization. The lymph-glands 
Fig. 425.- Myeloid leukaemia. Myeloid area in the liver, showing displacement of 
liver-cells by the abundant myelocytes, and in the endothelium-lined capillaries many 
megalocaryocytes. 
merely participate passively in this process-occasionally their sinuses are 
stuffed with the cells of the blood. 
The nature of the process is quite obscure as in the other forms, but it 
seems clear that the changes are primary in the bone-marrow, and that 
those of the spleen and other organs are secondary. Nevertheless it is also 
pretty clear that new formation of cells goes on in the myeloid accumula- ACUTE MYELOID LEUKEMIA.-MYELOBLASTIC LEUKEMIA 
855 
tions of tissue in spleen and liver, although not, it seems to me, as the result 
of activity on the part of splenic or hepatic endothelium. 
We have already mentioned the existence of cases in all respects like the 
chronic myeloid leukaemia except that their fatal course is very rapid and 
marked by the occurrence of more extensive haemorrhages and ulcerations of 
mucosae. In another and larger group of these acute cases whose symptoms 
ACUTE MYELOID LEUKAEMIA.-MYELOBLASTIC LEUKAEMIA 
Fig. 426.-Myeloid leukaemia. Heart showing the overfilling of the capillaries with mye- 
loid cells. 
are not to be easily distinguished from those of acute lymphoid leukaemia, 
the differences lie in the fact that the non-granular mononuclear cells which 
are predominant in the blood and tissues are not lymphocytes, but myelo- 
blasts, as shown by their possession of a proteolytic ferment action in an 
alkaline medium and by their positive oxydase reaction. In these cases 
there is a great overflooding of the blood with white cells, most of which are 
myeloblasts; the bone-marrow shows a myeloid hyperplasia in which they 
are prominent, and there are myeloid changes in the spleen and liver. 
Haemorrhages, necrotic and ulcerative stomatitis, etc., are common. 856 
TEXT-BOOK OF PATHOLOGY 
Lymph-glands may be enlarged, but commonly are not. The whole condi- 
tion has the appearance of an acute infectious process, and indeed infections 
often exist, but whether as cause or as incidental accompaniment it is difficult 
to say. Sternberg, however, is so impressed by this that he proposes to 
exclude the myeloblastic leukaemia completely from the group of leukaemias 
and to regard it as an infectious process-the more so since it has been 
shown that a number of extremely severe infections can cause the appear- 
ance of huge numbers of myeloblasts or myelocytes in the circulating blood. 
These, however, are not progressive processes, and the myeloid cells dis- 
appear with recovery from the infection. 
The question of the relation of infection to the whole group of leukaemias 
is one which we can hardly discuss as yet with profit. All of them have 
something of the character of infections and although we have no facts to 
go on it seems impossible to single out one form as definitely infectious on 
such inadequate evidence. Only when we have a firmer knowledge of their 
aetiology shall we be able to make a rational classification. 
MYELOID CHLOROMA. CHLOROMYELOSARCOMA 
The justification for the isolation of this group is_much the same as in the 
case of the lymphoid chloroma or chloroleu^osarcoma and the same argu- 
ments have been raised against it. The peculiar feature consists in the 
formation of tumor-like growths within the bone-marrow or extending 
through the cortex of the bone to spread over the periosteal surface. Some 
of them spring apparently from the periosteum. They may or may not 
have a bright grass green color, and, as in the lymphoid chloroma, the in- 
constancy of this color makes it seem anmadequate basis of classification. 
The tumors allow the myeloid cells to escapq in great numbers into the 
circulation and are thus accompanied by a leukaemic state of the blood. 
The bone-marrow, in Meixner's case, was partly red, partly occupied by 
masses of myelocytes which in the gross looked green. The lymph-glands 
were unaffected; the spleen much infiltrated with myelocytes. J 
MYELOID MYELOMA 
In the previous chapter we spoke of multiple, rather invasive, tumor-like 
growths springing from the bone-marrow and composed of mononuclear 
cells which have been regarded as plasma cells. There are other cases, 
however, in which the tumors have in general the same distribution but 
differ in appearance, being very soft and deep red in most parts. They 
infiltrate and destroy the bones and give rise to repeated fractures. As in 
the other type there is found the Bence-Jones albumose in the urine. 
Boggs and Guthrie have shown that this albumose is by no means limited to cases 
of myeloma, and even that it may be absent in some well-defined cases of this affection. 
On the other hand it is present in cases of carcinomatous invasion of the bone-marrow 
and in cases of chronic myeloid leukaemia. The mechanism of its production is as yet 
too uncertain to discuss here. hodgkin's disease or lymphogranulomatosis 
857 
The cells which form these tumors have occasionally been demonstrated 
to be myelocytes or even erythroblasts (Ribbert), but in most cases they 
correspond with myeloblasts. In a case which I studied ten years ago 
I thought that their identity with myeloblasts was proven (Fig. 427). 
It is to be hoped that in future the oxydase reaction will be applied to these 
cases to settle this point definitely. No leukaemic changes occur in the 
blood. . _ 
Fig. 427.-Myeloid myeloma. The cells are larger than those of the lymphoid 
myeloma (Fig. 416), which are drawn to the same scale. They show no definite granules, 
but would probably give the oxydase reaction. 
While not an example of the hyperplasia of either myeloid or lymphoid 
tissue, the clinical and gross anatomical difficulties in diagnosis make it 
desirable that Hodgkin's disease should be considered in this connection. 
Described by Hodgkin together with a number of other conditions in 1832, 
much confusion existed as to the nature of the process until the work of 
Sternberg, Reed, Longcope, Ziegler, and others established the fact that 
there is a peculiar and specific histological picture which sets it apart as a 
separate disease. 
The affection is commonly found in rather young persons and far more 
frequently in men than in women. Beginning with painless swelling of the 
superficial lymph-glands, it progresses with gradual enlargement of these 
HODGKIN'S DISEASE OR LYMPHOGRANULOMATOSIS 858 
TEXT-BOOK OF PATHOLOGY 
glands and signs of similar enlargement of others within the thorax or ab- 
domen, and usually with increase in size of the spleen. Anaemia appears 
and may reach a profound degree. There may be evidences of mechan- 
ical pressure exerted by the enlarged glands upon the veins, producing 
oedema of the face or other regions, upon the trachea, leading to emphysema 
in some cases, or upon some part of the alimentary tract, causing character- 
istic effects. Death is the result of one of these mechanical influences, of 
some intercurrent infection, or of the anaemia and cachexia produced by the 
disease itself. It may be well to describe the peculiar change in the tis- 
Fig. 428.-Hodgkin's disease; early stage. Lymphoid and epithelioid cells with 
scattered eosinophiles and large multinuclear cells. 
sues, which is the same wherever it occurs, before discussing in detail the 
distribution of the lesions. The lesion is best seen (Fig. 428) in the lymph- 
glands where, in different nodules, it may be followed through the changes 
which it undergoes in the course of its development. In the smaller nodes 
the beginning of the process, as Dr. Reed pointed out, consists in a prolifera- 
tion of the lymphoid cells, which is soon followed by the appearance of a 
coherent tissue formed of larger and paler cells with elongated vesicular 
and rather palely staining nucleus. These resemble the reticulum cells 
and have been called endothelioid cells. They lie in no particular order hodgkin's disease or lymphogranulomatosis 
859 
but they, together with the lymphoid cells and others to be described, 
soon spread so as to replace the normal tissue of the whole gland, obliter- 
ating the distinction between lymph-cords and sinuses. Among these cells 
there are found much larger ones which constitute the most characteristic 
feature of the lesion. These are really quite large cells, and while they vary 
greatly, are many times the size of the lymphocytes. Their protoplasm is 
clear except for scattered, irregular stainable shreds, and their outline is 
rather ragged. They contain one or two or several large nuclei which are 
rounded or indented or lobed and usually lie close together. These nuclei 
Fig 428A.-Hodgkin's disease; early stage. 
are very sharply outlined with a deeply staining chromatin membrane 
within which the nuclear substance is relatively sparsely granular. In 
each nucleus there is a large nucleolus, sometimes two, and these nucleoli 
stand out very clearly with a deep stain. Besides the lymphoid, epithelioid 
(or endothelioid) cells and these large cells there are usually found many 
eosinophile leucocytes. Dr. Reed made much of their presence, but later 
agreed that they might be absent without lessening the certainty with 
which one might recognize the tissue. Occasionally, but in my experience 
rarely, there are found giant-cells of another type with many rather small 
nuclei arranged in a ring or horseshoe. These are much closer to the sort 860 
TEXT-BOOK OF PATHOLOGY 
found in foreign body giant-cells or even to those of the tubercle. The 
reticulum, in the meshes of which these cells lie, is of extreme delicacy and 
the whole mass thus forms a soft, rather translucent grayish tissue, which is 
Fig. 429.-Hodgkin's disease. Partly scarred mass in which there are still areas of the 
characteristic tissue. The large nodule has undergone partial hyaline change. 
Fig. 430.-Hodgkin's disease. Multiple irregular nodules of specific tissue in the spleen. hodgkin's disease or lymphogranulomatosis 
861 
quite elastic and in appearance quite homogeneous (Fig. 428A). This cel- 
lular condition is found in the earlier stages, but after a time there appears a 
progressive scar formation throughout the gland coincident with the dis- 
appearance of the cells. Every step in the development of this change can 
be followed until finally there is left a dense mass of fibrous tissue in which, 
here and there, are to be found pockets or nests of such cells as have been 
described (Fig. 429). It should be noted that this change in the gland is 
one which even in the earlier stages involves the whole gland and obliterates 
its architecture by replacing the lymph-cords and sinuses with a uniform 
cellular tissue. In the neighborhood of such glands tiny new glandular 
clumps of lymphoid tissue are formed by a regenerative process, but these 
are no sooner developed than they are transformed into the same new tissue. 
The glands first affected are usually those at the root of the neck just above 
the clavicle, where they form a nodular mass almost like a sort of collar. 
Thence those higher in the neck are quickly involved; axillary and inguinal 
glands are only less frequently concerned. Sometimes they are extirpated 
at operation, and it is then found that in the early stages they are oval or 
round, discrete nodes which, unlike tuberculous glands which adhere and 
tend to bind themselves together in a solid mass, can be easily pulled apart. 
The smooth glands on section show the grayish gelatinous elastic tissue 
described, but in the somewhat later stage one very frequently finds in 
them dry, opaque, firm, yellowish-white areas of necrotic tissue with occa- 
sional hsemorrhages. The old cases still show the glands in packets, loosely 
bound together, but as time passes there is more tendency to adhesion. 
The capsule and adjacent tissue may be especially thickly infiltrated with 
eosinophiles in these advanced cases. In the interior of the body the 
bronchial, peritracheal, and mediastinal glands are extensively involved and 
form such masses as to compress the trachea or impede the heart-beat. I 
saw one case in a woman in which huge masses existed in the place of the 
bronchial glands at the bifurcation of the trachea. From these the tissue 
extended into the lungs and there were numerous large discrete nodules 
scattered in the lung tissue. In another, a negro boy, one lung was con- 
verted into a solid gray translucent mass closely bound by the much 
thickened pleura and showing no air-containing lung tissue, but only 
patches of collapsed alveoli in which the epithelial cells were loaded with 
fat. All the gray tissue was of the character just described and though 
already rather fibrous, showed very distinctly all the types of cells. In the 
abdomen, the retroperitoneal glands and perhaps more especially the peri- 
pancreatic and periportal glands are likely to be involved. The periportal 
glands may be large enough to compress and obstruct the common bile- 
duct and produce jaundice. In the liver Dr. Reed describes the wide- 
spread occurrence of perivascular and interlobular accumulations of the 
typical tissue, with its specific large cells, in strands and small nodules. 
This seems to be rather infrequent. On the other hand the spleen is 
pretty regularly involved, sometimes with mere swelling and with diffuse 
infiltration of the pulp; at other times, as shown in Fig. 430, with 862 
TEXT-BOOK OF PATHOLOGY 
great enlargement and with numerous gray nodules composed of the char- 
acteristic tissue and pretty sharply marked off from the deep red pulp. 
Occasionally such foci are found in the bone-marrow, which otherwise 
shows no change except the hyperplasia due to secondary anaemia. Never- 
theless, I have recently found at autopsy in a man, who had been ill for a 
long time, a tumor-like invasion of many bones, including ribs and verte- 
brae, with extensive destruction of the cortex and pathological fractures. 
Longcope describes the invasion of the Hodgkin's tissue through the 
walls of the blood-vessels so as to penetrate the intima. There is, however, 
no leukaemic change in the blood from such invasion; instead there is a 
decrease in the red cells and usually a moderate increase in the leucocytes 
without much disturbance of their relative numbers. On the whole we find 
in this disease an affection principally of the lymph-glands, which become 
greatly enlarged by the development in them of a peculiar tissue which 
rather rapidly takes the place of the original structure. Cellular and soft 
at first, this tissue in the course of time loses most of its cells and becomes 
scarred and hard. Hence the recognition of soft and hard forms of lymph- 
gland involvement. The growth is not limited to the lymph-glands but 
may extend into the adjacent tissues, such as the lung and pleura, or ap- 
pear separately as a sort of metastasis in the spleen beginning perhaps 
in the Malpighian bodies and extending to the pulp. 
It is evident that this is not a hyperplasia of the essential lymphoid cells 
of the gland, nor is it anything like the myeloid hyperplasias described 
above. It has some of the characters of a tumor growth, but by far the 
greater weight of evidence is in favor of its being an infectious process 
involving simultaneously much of the lymphatic gland system. As to the 
portal of entry of the infectious agent nothing can be said. The tonsils 
are most often unaffected. 
Nor can anything definite be said as to the nature of the causative agent. 
Sternberg maintained for a time that this is a peculiar form of tuberculosis, 
but all efforts to demonstrate tubercle bacilli or to infect guinea-pigs with 
the tissue were in vain, unless, of course, as was true in Dr. Reed's first case, 
there was a coincident infection with tuberculosis, and tuberculous lesions 
and those of Hodgkin's disease lay side by side. Afterward Sternberg and 
others thought it due to a weakened tubercle bacillus but this seems un- 
likely in view of the case just cited and also because a weakened tubercle 
bacillus ought to produce injuries less destructive than those caused by a 
virulent one and not necessarily fatal. Hodgkin's disease produces lesions 
quite unlike those of tuberculosis but is always fatal. Fraenkel and Much 
have described certain granular Gram-positive rodlets which they find fre- 
quently and consider that they have found the cause of the disease. On the 
other hand, Bunting and Yates have found a pleomorphic diphtheroid 
bacillus which they think is the cause. It is too early to decide as to the 
merits of these different organisms, but the impression is strong that- 
Hodgkin's disease is an infectious process. hodgkin's disease or lymphogranulomatosis 
863 
Myeloid Leukcemia-Naegeli: Leukamie, Wien, 1913. 
Sternberg: Wien. kl. Woch., 1911, xxiv, 1623. 
Herxheimer: Munch, med. Woch., 1913, lx, 2506. 
Burckhardt: Frankf. Ztsch. f. Path., 1911, vi, 107. 
Sternberg: Ziegler's Beitr., 1915, Ixi, 89. 
Myeloid Chloroma : Wien. kl. Woch., 1907, xx, 593. 
^Sternberg: Ziegler's Beitr., 1904, xxxvii, 437. 
'Roman: Ibid., 1913, Iv, 61. (Lit.) 
Myeloid Myeloma..-Shennan: Edinb. Med. Jour., 1913, x, 321. 
MacCallum: Jour. Exp. Med., 1901, vi, 53. 
Boggs and Guthrie: Johns Hopkins Hosp. Bull., 1912, xxiii, 353; 
1913, xxiv, 368. 
Hodgkin's Disease.-Sternberg: Ctbl. f. d. Grenz, d. Med. u. Chir., 1899, ii, 641. 
Ztsch. f. Heilk., 1898, xix, 21. 
Reed: Johns Hopkins Hosp. Reports, 1902, x, 133. 
Longcope: Bull. Ayer Clin. Labty., 1903, i, 4. 
K. Ziegler: Hodgkin'sche Krankheit, Jena, 1911. 
Bunting and Yates: Jour. Amer. Med. Assoc., 1913, Lxi, 1803; 
1914, Ixii, 516. 
Discussion to Sternberg: Verb. d. D. Path. Gesellsch., 1912, xv, 22. 
LITERATURE CHAPTER XLHI 
DISEASES DUE TO INJURIES OF THE ORGANS OF INTERNAL 
SECRETION 
Pancreas. Diabetes mellitus. General character of process. Pathological anatomy. 
Nature of disturbance of carbohydrate metabolism. Relation of other organs. Diabetic 
acidosis. Resume: Thyroid: anatomy and physiology. Myxoedema, effects of extracts. 
Cretinism, goitre, exophthalmic goitre, general symptoms, pathological nature of disease. 
In considering the diseases which depend upon disturbance of the activities 
of the organs of internal secretion we must usually speak of a disease in 
which one of these organs is most prominently affected, because it is known 
that they seem to cooperate in such a way that the disabling of one disturbs 
the others. 
Diabetes mellitus is an example of this, for while we find the pancreas 
most prominently concerned, we are not yet sure of the part played by 
adrenal, thyroid, hypophysis, etc. Nor are we sure in the case of exoph- 
thalmic goitre whether thyroid or thymus or some other organ is chiefly 
responsible for the disease. 
The Pancreas 
DIABETES MELLITUS 
Diabetes mellitus is a disease occurring at almost all ages and usually 
more severe and quickly fatal in young persons. It is peculiar in that 
the carbohydrate metabolism is deranged in such a way that sugar ab- 
sorbed from the intestine is no longer stored in reserve in the form of gly- 
cogen in the liver and body muscles, but circulates in the blood and is 
excreted in the urine. The excess of glucose in the circulation probably 
causes the continuous thirst, the satisfaction of which brings about poly- 
uria. Since sugar ordinarily forms the great source of energy for the 
muscles and is now scarcely used by them, great changes in the general 
metabolism arise. Protein substances, even including those of the tissues, 
are consumed in an unaccustomed way to develop the necessary energy, 
and a part split off from them in the form of sugar becomes useless be- 
cause of its carbohydrate nature and is excreted with the rest in the 
urine.* In severe cases, in spite of enormous quantities of food consumed 
usually with great amounts of water (polyphagia, polydipsia), the protein 
becomes inadequate to supply the energy demands and the fats are at- 
* That this is only partly true is shown by experiments with depancreatized animals 
in which the high sugar content of the blood is greatly decreased by muscular work. 
864 865 
DIABETES MELLITUS 
tacked. Being incompletely oxidized, these give rise to intermediary prod- 
ucts, $-oxybutyric acid, aceto-acetic acid, and acetone, which are excreted 
in part, but which also act as poisons, producing the diabetic coma that so 
commonly leads to death. Peripheral neuritis and various trophic dis- 
turbances, sometimes with gangrene of the extremities, are met with, 
and the patients show such an extraordinarily lowered resistance to bac- 
terial infection that rapidly progressing tuberculosis or generalized and 
local infections of other sorts may become the actual cause of death. 
Pathological Anatomy.-The nature of this process is not made clear 
by anatomical study at autopsy, for in most cases no gross changes are 
found in any of the organs which seem capable of explaining the complete 
upset of the general metabolism. Study of the blood reveals an increased 
amount of blood sugar. The liver is devoid of glycogen, or nearly so. 
That usually found in globules or granules in the protoplasm of the liver 
cells is gone, and the nuclei of the cells, which are swollen, now contain 
whatever glycogen remains in the organ. The muscles have also lost their 
reserve of glycogen, and this is true of all the tissues except the heart 
muscle, the leucocytes, and the renal epithelium, particularly, as pointed 
out by Baehr, that in the terminal part of the first convoluted tubules. 
Since the time of Claude Bernard who produced glycosuria and hyper- 
glycaemia by injuries to the brain (piqure) it has been known that this 
disease is in some way associated with disturbances of the central nervous 
system, and indeed, various lesions of the brain and spinal cord have been 
found in cases dying after prolonged glycosuria. But they are very variable 
lesions and although they seem to cause glycosuria, they do so by no means 
constantly. It is quite possible that their effects are due to changes in the 
hypophysis. On the other hand, most cases of outspoken diabetes present 
no recognizable alterations of the nervous system. 
Mering and Minkowski showed that extirpation of the pancreas is 
followed regularly by all the phenomena of diabetes, and this led to the 
prevailing view of the predominant importance of the pancreas in this 
disease. That it was really the loss of the pancreas that produced these 
results and not injury to the intestine or to the nerves has been proven 
by the most severe tests. So long as a part of the pancreas remains 
well supplied with blood, even separated from all its original connections 
with the intestine, no diabetes appears, but as soon as that fragment is 
removed from the circulation, even, in suitable experiments, by a single 
ligature placed on its blood-vessels, hyperglycsemia and glycosuria appear 
at once. 
Lesions may, therefore, be sought in the pancreas in cases of diabetes. 
It must be said that while various changes are found it usually requires a 
certain complaisance to ascribe the extreme diabetic symptoms to them 
because they are practically never destructive enough to be compared with 
the extirpation of the gland. Nevertheless, as we shall see, there are other 
things which enhance the effect of a partial destruction of the gland. 866 
TEXT-BOOK OF PATHOLOGY 
Further, it may well be that the destruction of an inconspicuous constituent 
of the gland will be followed by results out of proportion to the change in 
its gross appearance. It is well known that while the acinar parts of the 
pancreas secrete the pancreatic juice into the intestine by way of the duct, 
the islands of Langerhans have no direct connection with them or with the 
ducts, but are isolated groups of cells with very rich blood-supply scattered 
through the organ. The cells do not resemble those lining the acini in 
Fig. 431.-Hyaline island of Langerhans from a case of diabetes. 
form or arrangement. Their protoplasmic grannies are quite different and 
much finer and the cells are connected in an irregular network. 
By special stains one may even recognize two kinds of cells in these islands 
distinguished by their different types of granules. The names of Opie, 
Schaefer, and Ssobolew are connected with the idea that these islands are 
responsible for maintaining at least one part of the chain of events in the 
metabolism of carbohydrates, and that they may be regarded as the 
structures in the pancreas which produce an internal secretion which is 
liberated into the blood. Opie described a case of severe diabetes in which DIABETES MELLITUS 
867 
practically all of the islands of Langerhans were converted into hyaline, 
inert masses in which living cells could no longer be seen (Fig. 431). The 
rest of the pancreas was normal, and naturally such an inconspicuous lesion 
produced no change in the gross appearance. Were this a constant finding 
there would be little difficulty in establishing this plausible theory of the 
relation of the islands to diabetes, but there are many cases of diabetes in 
which no such universal destruction of the islands is found. Instead, one 
finds very often a fine scarring of the organ analogous to cirrhosis of the 
liver or sometimes no recognizable change at all. Hence there are many 
who refuse to believe in the specific relation of the islands of Langerhans to 
diabetes and think rather that the whole glandular substance of the pan- 
Fig. 432.-Pancreas of guinea-pig one year after ligation of the ducts. The islands of 
Langerhans alone remain, embedded in fat. 
creas is concerned. Nevertheless Cecil, in studying a large number of 
cases of diabetes, found pancreatic lesions in more than 87 per cent, and 
showed that in these the islands of Langerhans were always affected; in 
about 12 per cent, the islands alone were injured. 
Certain experimental studies furnish, it seems, the only unassailable evi- 
dence in this connection. The ligature of the pancreatic ducts results in 
atrophy of the acini, but since the islands of Langerhans have no connec- 
tion with these they do not suffer and no glycosuria results. In one type 
of experiment, half of the pancreas was thus ligated off, and the animal 
survived perfectly well. After a year such an animal (dog or guinea-pig) 
showed the complete reduction of the ligated part to a thin, transparent 868 
TEXT-BOOK OF PATHOLOGY 
film in the mesentery; extirpation of the remaining intact half of the pan- 
creas was followed in such an experiment by transient glycosuria, but after 
one day of this the animal showed no symptoms whatever and could 
assimilate large amounts of glucose or starch. After a month, the trans- 
parent film which represented the other half of the pancreas was extirpated, 
and then the animal was plunged into the severest diabetes. This film 
contained only islands of Langerhans, as was proved in the case of the 
guinea-pig at least by the special stain of Bensley (MacCallum: Johns 
Hopkins Hosp. Bull., 1909, xx, 222;' Kirkbride: J. Exp. Med., 1912, xv, 
101) (Figs. 432, 433). 
Other investigators have sometimes found destructive changes in the 
Fig. 433.-Island of Langerhans enlarged from Fig. 432. The sharp differential stain- 
ing of the granules shows that the cells are intact. 
islands after such obstruction of the ducts, but it seems that the weight 
of evidence is at present in favor of the belief that the islands are the 
specific organs of internal secretion. 
Dr. Winternitz has told me of a case in which steatorrhoea had existed 
since birth. On the death of the child no pancreas was found, but only 
a thin strip of tissue which contained nothing but islands of Langerhans. 
No diabetes had existed. 
It is true that in many cases of diabetes it is difficult, if not impossible, 
to demonstrate any lesion in the pancreas, and then it may be necessary to 
assume that some extrapancreatic cause has brought about the disease, 
but, in such studies as that of Cecil, changes in the islands are found in an 
overwhelming proportion of the cases. DIABETES MELLITUS 
869 
Bensley and Lane have discovered that in the islands of Langerhans 
some of the cells have a type of granule which they designate A, the rest, 
another type, B. Homans, in studying the condition of islands in portions 
of pancreas left after extirpation of the rest, finds that the evidences of 
their inadequate function shown by glycosuria are parallel with loss of 
B granules in the swollen islands. 
Thus, while it is not invariably possible to demonstrate the existence of 
lesions of the pancreas in cases of diabetes, they are usually found; on the 
other hand, the whole symptom-complex can be produced by extirpation 
of the organ and not in any other way, although transient glycosuria may 
have many other causes. The role of the pancreas in diabetes must there- 
fore be regarded as very important. 
Nature of Disturbance of Carbohydrate Metabolism.-Experimental 
and physiological studies have thrown more light on the nature of the 
disease than has anatomical investigation. 
Carbohydrates are transported in the body to the tissues, which need them as energy 
producers, in the form of grape-sugar or dextrose. Only monosaccharids, such as dex- 
trose, maltose, and levulose, can be consumed by these tissues; others, such as cane- 
sugar, if injected into the blood are excreted unchanged. Therefore starch and allied 
substances and cane-sugar are hydrolyzed by the action of ferments in the intestinal 
tract, beginning with the ptyalin of the saliva and ending with the diastase of the 
pancreatic secretion, into one of these simpler sugars. Starch acted upon by diastase 
passes through dextrine to maltose, which is converted into dextrose by another ferment, 
maltase. Arrived by way of the portal vein in the liver, the dextrose is polymerized, 
by the action of the liver-cells, into glycogen. Doubtless the liver-cells, like the muscle 
cells and others capable of elaborating and storing up glycogen from dextrose, do so 
by the aid of a ferment, but although this may perhaps be a diastase reversing its action, 
the actual ferment has not been demonstrated. As far as experimental study goes it 
seems that only living cells are able to bring about this change. 
The glycogen is set free from the liver and poured into the blood through the action 
of a diastatic ferment, glycogenase, which apparently occurs in all the organs and is 
able to convert glycogen into dextrose through several steps, in the last of which maltose 
becomes dextrose through the agency of the ubiquitous maltase. 
Liberated in this way, the dextrose is used by the muscles as a source of energy, 
though the steps of this process are yet shrouded in mystery. In the end it is an oxida- 
tion, although the sugar may at first be decomposed into various intermediary sub- 
stances. Taylor suggests glyoxal, lactic acid, and alcohol, as the successive steps, but 
this is not established. Much ingenuity and labor has been spent in the attempt to 
elucidate this process of "glycolysis," and the theory of O. Cohnheim is especially 
well known although not now generally accepted. He seemed to prove that muscle 
juice could cause glucose to disappear only when activated by pancreas extract, but it 
has been shown that this disappearance is not really oxidation of the sugar but only 
the assumption of another form in which it will no longer reduce copper salts. 
But if we do not know the steps in the process, it is fairly clear that sugar is finally 
oxidized in the working muscles to carbon dioxide and water, and we can recognize 
the effect of this combustion in the amount of carbon dioxide exhaled as compared 
with the amount of oxygen consumed in the respired air. 
It is well known that this "respiratory quotient" gives some idea of the character 
of the materials undergoing combustion, for the oxidation of carbohydrate results in 
CO 
the proportion = 1, while the combustion of proteins and fats gives a lower figure 870 
TEXT-BOOK OF PATHOLOGY 
Upon extirpation of the pancreas this whole chain of events is at once 
disarranged. Probably the sugars are sufficiently well prepared in the 
intestine and absorbed, although the amylolytic ferment of the pancreas is 
no longer furnished there. 
But when the sugar reaches the liver, it is not stored up as glycogen. 
Either the loss of the pancreas makes it impossible for the liver-cells to 
form and store glycogen from the sugar presented, or it allows the diastatic 
ferment, the glycogenase, to run riot, decomposing at once all the glycogen 
already lodged in the liver and forestalling the formation of any more. 
Since, after the complete destruction of the pancreas, the glycogenase is so 
active, it seems necessary to conclude that the internal secretion of the 
pancreas and the glycogenase are very different things. 
Set free from the liver, the dextrose circulates in excess (hyperglycaemia), 
and much is excreted by the kidneys (glycosuria), but none or very little is 
oxidized in the muscles. This is shown by the lack of any heightening of 
the respiratory quotient when sugar is fed to such a diabetic, and also by the 
fact that the amount fed reappears almost quantitatively in the urine. 
This would suggest that the tissues had lost their power to consume 
dextrose for the liberation of energy, and indeed this is a view long held and 
supported by much evidence. Recent work of Knowlton and Starling, 
McLeod, Liithje, and others shows, however, that the tissues of depan- 
creatized animals if perfused with Locke's solution containing dextrose are 
quite as able to consume the sugar as those of normal animals. The original 
experiment of Starling and Knowlton with perfusion of normal and diabetic 
hearts seemed to show that the diabetic heart consumed less sugar than the 
normal. This, however, was corrected later, since it proved to be due to 
the increased store of glycogen in the diabetic heart, which was used instead 
of the sugar of the perfusion fluid. 
We are left then with the problem as to whether the hyperglycaemia 
and glycosuria arise because there is an overliberation of sugar into the 
blood or because the tissues are unable to consume it. 
Hedon states that the introduction of the blood of the pancreatic vein 
of a normal dog into the portal vein of a depancreatized dog will reduce 
very greatly the amount of sugar in the urine and also in the blood, as though 
a necessary ferment were secreted by the pancreas into the blood. 
If this be true, it still remains to determine whether the ferment forms 
glycogen, prevents the dissolution of glycogen into sugar, or causes the 
more distant glycolysis. The statement that it has no effect except when 
injected into a branch of the portal vein so as to reach the liver directly 
suggests that its influence is in connection with the two earlier proc- 
esses. 
Admont Clark has furnished definite evidence in this connection by 
his skilful perfusion experiments, in which Locke's solution containing 
known amounts of sugar and kept free from bacteria was passed through DIABETES MELLITUS 
871 
the pancreas alone, through the beating heart alone, and through pancreas 
and heart in series. The pancreas alone causes no disappearance of the 
sugar, very little is lost from the perfusate which passes through the heart 
alone, but when the fluid is passed first through the pancreas and then 
through the beating heart there is a great consumption of sugar. A sugar- 
free solution which has passed through the pancreas alone contains some- 
thing of ferment nature which, when added to a sugar-containing solution 
used to perfuse the beating heart, enables the heart to consume much 
sugar. It is true that the pancreas by itself can change the optical rotat- 
ing power of dextrose to some extent when perfused through it, but it is 
most important to have shown thus for the first time that the pancreas 
actually produces a ferment-like substance which is essential for the proper 
consumption of sugar by the muscles. 
Many observations tend to show that other factors than these fer- 
ments are concerned in the control of the carbohydrate metabolism, 
for hyperglycaemia and glycosuria can be induced in a variety of 
ways. The whole mechanism of carbohydrate control seems to be, to 
some extent at least, under the influence of the nervous system, 
especially the sympathetic system. Injury to the brain and especially 
the so-called piqure of Claude Bernard produces glycosuria, usually at- 
tended, however, by symptoms of asphyxia and circulatory disturb- 
ances which in themselves may have similar effects. Stimulation of the 
splanchnic nerves causes glycosuria without the other phenomena, but 
fails to do so when the adrenal glands are extirpated. From various 
experiments it seems that this sympathetic innervation of both adrenals 
comes from the left splanchnic. Massage of the adrenals or the injection 
of adrenaline causes glycosuria without stimulation of the nerves, and 
stimulation of the hepatic sympathetic plexus also does so as long as the 
adrenals are present, but not when they are extirpated (Nishi, McLeod). 
It seems, therefore, that the secretion of the adrenal is a necessary part of 
the mechanism through which the impulses from the sympathetic passing 
to the liver promote the setting free of sugar. We may ask then whether 
the pancreatic ferment opposes the action of adrenaline, since in its absence 
the sugar is quickly set free, and still more quickly if adrenaline be injected. 
Interesting relations exist between the secretions of other related organs 
and this condition of hyperglycsemia and glycosuria, for in the absence of 
the thyroid it becomes difficult to produce it in any way, while it may 
appear spontaneously when an excess of the secretion of thyroid or hypophy- 
sis is thrown into the circulation. In slighter degrees such modification of 
the sugar metabolism may be tested for by determining the sugar tolerance, 
that is, the amount of sugar which may be injected without producing 
glycosuria, or by the respiratory exchange. These relations and others 
have been much discussed by Eppinger, Falta, and Ruclinger, who have 
constructed a sort of formula which expresses them, but which ascribes all 872 
TEXT-BOOK OF PATHOLOGY 
the effects to influences exercised upon one organ by another rather than to 
the chemical antagonisms of their secretions. 
Glycosuria may also be produced by caffeine, strychnine, sensory stimuli, 
and asphyxia (which in its turn may be brought about by various narcotics, 
ether, chloroform, morphine, etc.), and by curare (Pollak). In other cases 
(renal poisons or phloridzin poisoning) it seems that there is no hyper- 
glycaemia and that glycosuria arises as a result of renal changes. For 
information concerning the complex effects of phloridzin poisoning, Lusk's 
paper may be consulted. 
It must not be inferred from what has been said that the carbohydrates 
alone are disturbed in diabetes nor that sugar is produced from carbohy- 
drates only. Indeed, it has been shown that proteins are split up in such 
a way in the liver as to liberate certain molecules of sugar, and further it 
has been possible to determine that certain of the amino-acids which go to 
build up these proteins are far more capable than others of liberating sugar. 
Consequently some forms of meat (chicken) are found to furnish more 
sugar in a diabetic organism than others (beef) (Janney). Many other sub- 
stances, such as glycerin, glycolaldehyde, glyceric acid, dioxyaceton, have 
been found to produce sugar in the perfused liver (Emden, Barrenschein). 
In pancreatic diabetes when carbohydrates are quite withdrawn from 
the food sugar may still be excreted, and the amount of this sugar bears a 
constant relation to the amount of nitrogen excreted. This D:N ratio is 
thought to represent the relation between the amount of sugar liberated 
from the protein of the food or of the wasting tissues and the nitrogen of 
that protein. It is evident that this indicates at least a considerable waste 
in the proteins, inasmuch as the carbohydrate portion is excreted as such. 
Although certain authors, Forges and Salomon, V. Noorden, Raubit- 
schek, and others, claim a formation of sugar from fats, the weight of 
evidence does not seem to favor this idea. Lipsemia during diabetes 
is common, fat streaming in visible form in the blood in such a way as 
to make the serum milky, and accumulating in large cells in the spleen. 
The origin of this fat is not clearly known, but at first there is a great in- 
crease in lecithin, and throughout a still greater increase in cholesterol. 
In the absence of carbohydrate utilization there occurs a peculiar im- 
perfect consumption of fats which is analogous to that seen in the course of 
starvation, where for another reason no carbohydrate is supplied for energy 
production to the tissues. For some reason the oxidation of carbohydrates 
renders easier the complete combustion of fats, and in their absence this 
is imperfect, oxidation of the fatty acids, at any rate those with an even 
number of carbon atoms, takes place by the oxidation of the third carbon 
atom (that is, in the /3 position) and the splitting off of the terminal carbon 
atoms. In this way /3-oxybutyric acid can be formed from all of these 
fatty acids, including palmitic, stearic, and oleic (Knoop). But for some 
time the /3-oxybutyric acid does not appear in the urine, but, instead, DIABETES MELLITUS 
873 
diacetic acid and acetone, which are successive oxidation products derived 
from it. Their formulae are as follows: 
/3-oxybutyric acid CH3-CH OH-CH2-CO OH 
Diacetic acid CH3-CO-CH2-CO OH 
Acetone CH3-CO-CH3 
These are the so-called acetone bodies, which tend to appear more readily 
in herbivorous and omnivorous animals than in the purely carnivorous. 
Diacetic acid and acetone rarely occur in any great amount in the urine, 
but the ^-oxybutyric acid may reach 50 to 100 grams a day or more. 
With such disordered fat combustion, toxic phenomena appear which are 
known as the symptoms of acidosis or acid intoxication. They are quite 
similar to those produced by the feeding of inorganic acids to rabbits or 
other herbivorous animals, and consist in a peculiar violent deep respiration 
or air hunger and coma. These symptoms may be much relieved by the 
introduction of large quantities of an alkali, such as sodium bicarbonate. 
During the gasping for breath the blood is bright red and contains very 
little carbon dioxide; instead, the tissues are loaded with carbon dioxide 
which the blood is unable to remove, presumably because the acid injected 
has combined with the sodium of the blood so that it is no longer able to 
aid in the transport of the carbon dioxide to the lungs. Ordinarily (Wells) 
it passes to the lungs as bicarbonate, where it is decomposed into the car- 
bonate, liberating CO2, and returns to the tissues for more. Exactly the 
same preemption of the alkali of the blood results from the presence of the 
organic acids that arise from the decomposition of the fatty acids, and the 
diabetic dies in coma largely as a result of this kind of asphyxia, unless 
the alkali is supplied rapidly from the outside. 
Since the last edition of this book the preparation of insulin, the active 
principle or secretion of the islands of Langerhans by Banting and Best, 
has stirred an even greater interest in diabetes. Insulin is an extract of 
the pancreas made by digesting it in acidulated alcohol and has the won- 
derful power of causing the excess of sugar in the blood and the con- 
sequent glycosuria to disappear at once. It further restores at once the 
storage of sugar in the form of glycogen in the liver, brings back to normal 
the distribution of fat, so that the liver and blood are no longer over- 
loaded with it, and finally stops the production of oxy butyric acid, diacetic 
acid, and acetone from fat with its accompanying poisonous action. Per- 
sons in coma from this acidosis are marvelously brought back to a normal 
state, and the whole disordered metabolism is restored to the normal 
course as long as the insulin lasts. Too large a dose removes all the car- 
bohydrate from the blood and the patient or animal in this extreme hypo- 
glycaemia sinks into another sort of coma identical with that which Mann 
has shown to follow extirpation of the liver. A dose of glucose intra- 
venously, or of adrenaline, which stirs up the liberation of sugar into the 874 
TEXT-BOOK OF PATHOLOGY 
blood, brings such a patient back to consciousness and well-being with a 
miraculous suddenness equal to that seen when insulin stops the coma of 
acidosis. 
The mechanism of all this action of insulin is not yet perfectly clear. 
McLeod states that the storage of glycogen in the liver reaches an almost 
abnormal degree under its influence, and that the respiratory quotient 
promptly rises to unity from having been about 0.7 in the depancreatized 
animal. He thinks that since insulin has no effect upon glycolysis in the 
circulating blood, it must cause removal of the sugar to the tissues, and 
since the respiratory quotient quickly reaches the figure characteristic 
of the oxidation of carbohydrate it must indicate that the sugar is oxidized 
there. He states, however, the possibility that it may be converted into 
a fat-like substance. Geelmuyden argues that there is no binding evidence 
that the sugar is oxidized and that the increase in the R. Q. can be explained 
by the cessation of formation of sugar from fat. He thinks that the rise 
of the R. Q. above unity indicates the formation of fat from sugar or 
glycogen-that is, a complete reversal of the diabetic, metabolic anomaly. 
His discussion and that of Laufberger would lead us to believe that the 
action of insulin is essentially upon the fat metabolism changing the dis- 
tribution of fat and inhibiting the formation of sugar from the fat which, 
according to them, is the striking feature of the metabolism of diabetes. 
Insulin seems to act especially in the liver, both on the fat metabolism and 
in restoring the glycogen formation there. Especially emphasized is the 
fixation of glycogen because otherwise it is difficult to understand the 
further effect of large doses of insulin in producing a serious hypoglycaemia. 
LITERATURE 
Banting and Best, McLeod, and others: Jour. Lab. Clin. Med., 1922, vii, 251; Trans. 
Assoc. Amer. Physicians, 1922; Amer. Jour. Physiol., 1922, Ixii, 162, 559. 
Ceelmuyden: Ergebn. d. Physiol., 1923, xxii, 292. 
Laufberger: Klin. Woch., 1924, iii, 264. 
McCann, Hannon, and Dodd: Johns Hopkins Hosp. Bull., 1923, xxxiv, 205. 
McLeod: Brit. Med. Jour., 1922, i, 833. 
Resume.-The loss of the function of the pancreas thus precipitates a 
condition in which carbohydrates are not normally utilized. They are 
absorbed, but neither stored in the form of glycogen nor readily dissociated 
in the tissues to supply energy. Proteins supply whatever is possible of 
the needed energy, but they too liberate from certain of their amino-acid 
fractions the material for sugar, which promptly becomes useless and 
circulates until it is excreted. Fats aid in furnishing energy to the tissues, 
but they too are imperfectly used and become dissociated in the process of 
oxidation to liberate the series of acetone bodies of which /3-oxybutyric 
acid is the most toxic, and this, evincing part at least of its injurious action DISTURBANCES OF THE FUNCTIONS OF THE THYROID GLAND 
875 
in preempting the blood alkalies, and thus causing tissue asphyxia, brings 
about the characteristic air hunger and coma in which many of the victims 
of severe diabetes die. 
Where the pancreas exerts its function, and precisely what are its rela- 
tions with the nervous system and the other organs of internal secretion is 
even yet very obscure, although the discovery of insulin furnishes a 
method for experimental study which cannot fail to be fruitful. 
LITERATURE 
Cecil, R. L.: Jour. Exp. Med., 1909, xi, 266. 
Lusk: Erg. d. Physiol., 1912, xii, 315; Science of Nutrition, Phila., 1909. 
McLeod: Diabetes, London, 1913. Harvey Lectures, 1913-14, ix, 174. Amer. Jour. 
Physiol., 1916, xlii, 193, 460. 
Allen: Glycosuria and Diabetes, Cambridge, 1913. Harvey Lectures, 1916-17, xii, 42. 
Benedict and Joslin: Metabolism in Diabetes, Trans. Assoc. Amer. Physicians, 1910, 
xxv, 172; 1912, xxvii, 93. 
Wells: Chemical Pathology, Phila., 1914. 
Bensley: Harvey Lectures, 1914-15, x, 250. 
Homans: Proc. Royal Soc. Biol., 1913, Ixxxvi, 73. Jour. Med. Research, 1914, xxx, 49; 
1915, xxxiii, 1. 
Lane: Amer. Jour. Anat., 1907, vii, 409. 
Woodyatt: Jour. Biol. Chern., 1915, xx, 129; 1916, xxiv, 327, 343; 1917, xxx, 155. Jour. 
Amer. Med. Assoc., 1916, Ixvi, 1910. Tr. Assoc. Amer. Phys., 1916, xxxi, 12. 
Murlin and others: Jour. Biol. Chern., 1916, xxviii, 261, 289. 
Joslin: Harvey Lectures, 1914-15, x, 290. Johns Hopkins Hosp. Bull., 1918, xxxix, 
80. 
Clark, A.: Jour. Exp. Med., 1916, xxiv, 621; 1917, xxvi, 721. 
Disturbances of the Functions of the Thyroid Gland 
The thyroid, arising from a median and two lateral rudiments from the 
fifth branchial arch, is composed finally of two lateral masses in some 
animals, of a fused organ in others, the isthmus of connection in man 
crossing in front of the trachea. The original duct opening at the root of 
the tongue is interrupted by the growth of the hyoid bone, but occasion- 
ally there are remnants of glandular tissue left about the foramen caecum, 
which represents its outlet. The alveolar structure of the mature gland, 
its relation to blood-vessels, and its colloid secretion, and the surmises 
about the fate of that secretion, are discussed in all text-books of his- 
tology and physiology. 
So, too, for that matter, are most of the dramatic effects of the loss of 
its function or its overactivity, and every one knows of its iodine content. 
But even so we are very ignorant of most of its relations to other organs, 
and the actual nature of its function is still rather obscure. 
In early infantile life the alveoli are small and contain very little colloid; 
later they show the homogeneous colloid which may at times become inspis- 
sated into an almost solid mass, floating in the more recently secreted fluid. 
How the colloid leaves the alveoli and enters lymphatics or veins has not 
been determined, although there are many theories. 876 
TEXT-BOOK OF PATHOLOGY 
Physiology.-Destruction of the thyroid gland in animals by operative 
extirpation is not easy, because there are practically always numerous 
minute accessory nodules of thyroid tissue scattered in the neck, in the 
thymus, and inside the pericardium (Halsted). On this account it is diffi- 
cult to produce experimentally the effects of the loss of the gland. The 
difficulty is increased by the fact that in some animals (cat, dog, etc.) 
the parathyroid glands are very closely associated with the thyroid, and if 
they be destroyed in the operation, the slowly developing effects of thyroid- 
ectomy will never really appear because the animal dies quickly from the 
loss of the parathyroids. 
It is in very young animals that careful removal of the thyroids, leaving 
some of the parathyroids intact, produces the most remarkable changes, 
changes which are the counterpart of those observed in children in whom 
some disease has destroyed the thyroid leaving the other glands unaffected. 
But in adult human beings and animals similar, if less extreme, changes are 
also brought about. 
MYXCEDEMA 
The child devoid of thyroid tissue begins to show symptoms after it has 
ceased to nurse, and these consist essentially in the practical cessation of 
growth and development. The rate of metabolism is greatly decreased, 
the temperature is low, relatively little food is taken, and all the functions 
of the bodily organs are retarded. Mentally the child remains at the stage 
at which the destruction of the thyroid found it. Sexually it ceases to 
develop, and after twenty or thirty years of life it is still an infant in 
these respects, although the skin may be wrinkled and the hair sparse. 
Nothing expressed the situation better than the phrase "a sad old child" 
which some one has used. 
Such children may become very obese, but they do not grow in stature, 
because the process of bone formation is retarded, not merely at the epi- 
physes, as in chondrodystrophy (q. v.), but throughout, so that a delicate 
small skeleton is produced in which all the cartilaginous epiphyseal lines 
and junctions remain as cartilage until very late in life. 
In one case dissected some years ago a few of the permanent teeth had 
appeared, crowding inside the milk teeth, all of which were still present. 
The sternum was in several parts at fifteen years of age, and the three 
pelvic bones were still joined only by cartilage in the acetabulum. The thy- 
roid was reduced to a minute mass of distorted alveoli about the foramen 
csecum, and two extremely small cystic nodules somewhere in the position 
of the lateral lobes. These were smaller than the parathyroid glands, 
which were perfectly well preserved, and this is a common finding. The 
hypophysis was rather large, and gave the impression of being in process of 
hypertrophy. 
Such a state might well be the end result of a destructive infection, such 
as is known to occur, without actual abscess formation, in the thyroid, or it MYXCEDEMA 
877 
might possibly be thought of as a congenital defect, but even then it seems 
more plausible to regard it as the outcome of some intra-uterine disease. 
This girl was an idiot with the intelligence of a young infant. 
In adults the thyroid may be destroyed by operation or by disease, to a 
degree sufficient to produce a condition which closely resembles that seen 
in children, in so far as the already attained development will allow. Any 
further growth is stopped, and mental and sexual activity rapidly recedes, 
so that these people quickly becomes sexually impotent and mentally 
dulled. They grow sluggish and cold, appetite fails, metabolism is de- 
creased, the skin becomes dry and scaly, and in a curious way thickened 
and dense. Heavy pads form in a characteristic way below the clavicles 
and elsewhere, and over the face and forehead the skin may feel as though 
there were a thick, pasty elastic infiltration in its deeper layers, so that it 
cannot be easily pinched up into a fold. Actually, there is said to be an 
accumulation of a bluish-staining semifluid material there, which was 
thought to have a mucoid character, and hence the name myxcedema, which 
was given long ago by Gull. The patients may or may not become very 
fat, heart-beat and respiration are slowed, and the carbon dioxide output is 
lowered. 
There are all imaginable grades of this thyroid insufficiency, and the 
slighter ones are difficult to recognize, but in the more complete degrees the 
effects are overwhelming. In a relatively short time if there is no ther- 
apeutic intervention the patient sinks into a state of idiocy and physical 
torpor such that one is reminded rather of the life of a vegetable than that 
of a human being. 
The proof that all this is due to the loss of the thyroid lies in the fact that 
the daily long-continued administration by mouth of an extract of the thy- 
roid of some animal will restore such an inert being to life and activity. 
The child grows and develops and brightens into a normal person. The 
adult is transformed to his old self, the whole machinery quickens its rate, 
the skin becomes thin and moist, and the hair grows. The face loses its 
dull, bloated appearance, and the tongue its thickness and sluggishness, 
and words and ideas come back. It is as though the regulator of an engine 
were reset at the normal point. The same effect has sometimes been 
attained by the transplantation of thyroid tissue into the patient, or has 
appeared gradually with the increase in size through compensatory hyper- 
trophy, of some fragment or accessory nodule left intact, or even with the 
growth of a metastasis from a malignant tumor of the thyroid, through the 
surgical extirpation of which the myxcedema arose. 
In these persons, as in animals, it is found, by studying the metabolism, 
that the output of nitrogen in the urine is greatly decreased, that the intake 
of oxygen and the discharge of carbon dioxide are similarly on a lower level. 
Unless the appetite is greatly decreased, there is apt to be a gradual in- 
crease in weight under these circumstances, and most of this is in the form 878 
TEXT-BOOK OF PATHOLOGY 
of fat. Since the oxidation is thus decreased in the restricted metabolism 
of the muscles and other organs, the production of heat is diminished, 
and this may reach the point where the regulatory mechanism is unable to 
maintain the normal standard of bodily temperature, so that it falls even 
several degrees. 
Carbohydrate metabolism is affected in such a way that it becomes 
practically impossible to produce an alimentary glycosuria, that is, to 
cause the elimination of sugar in the urine by feeding it in excessive amounts. 
Even those drugs and nervous disturbances which ordinarily produce 
glycosuria fail to do so, or succeed only when pushed to extremes. Adrena- 
line, which in relatively small doses produces hyperglycsemia and glycosuria, 
fails to do this in the absence of the thyroid, or does so only when given in 
far larger doses. Even the glycosuria of depancreatized animals is greatly 
modified by the loss of the thyroid, although not entirely abolished. It is 
difficult to give a satisfactory explanation of this. Falta, Rudinger, and 
Eppinger regard it as the effect of the loss of the promoting influence of the 
thyroid upon the chromaffin system, and at the same time the loss of the 
normal antagonistic effect of the thyroid upon the pancreas. It seems more 
simple, though, to think of the thyroid secretion as something which plays a 
role in the final processes of oxidation of the sugar, acting in a sense as an 
antienzyme. Here, however, we tread on uncertain ground, not yet sup- 
ported by enough experimental results. 
CRETINISM 
In certain districts, especially in the high valleys of the Alpine region, and 
in similar mountainous parts of other countries, a considerable proportion 
of the inhabitants are defective in a way very like that of the sporadic or 
scattered cases of myxoedema. 
Unlike the myxoedema cases which occur anywhere and everywhere, 
regardless of environment or hereditary taint, these people, known as 
cretins, are found in regions where the condition seems to be endemic or 
inherent in the environment, and we can usually trace in their parents or 
ancestors some similar thyroid defect. 
In the cases of myxoedema one may often determine the cause of the 
destruction of the gland, and find minute remnants of it at autopsy. In 
the cretins there is commonly a great enlargement of the thyroid, which 
none the less seems to be deficient in its function. Every grade of severity 
in the physical and psychical disturbance is found here also. Some cretins 
are able to earn a living and procreate children, others are stunted idiots. 
Thyroid treatment seems far less brilliant in its results with them than with 
the cases of myxoedema, but still accomplishes something. 
The nature of this process has been earnestly studied, since it affects 
thousands in France, Italy, Switzerland, and Austria, but as yet without 
any clear result. GOITRE 
879 
Bircher thought it occurred in people who live in a country formed by 
strata which had once been submerged under the ocean, and not in those 
living on strata formed under fresh water or on volcanic formations. The 
introduction of a new water supply from a district of different character into 
one of these foci (Aarau) seemed to bring with it a great decrease in the 
number of new cases and improvement in the old. 
Bacteria have been sought in the drinking-water and found, together with 
many other forms of life, but it could not be proved that they bore any 
relation to the disease. Still the goitre could be produced, even in animals, 
by giving them the water from wells and springs in the affected districts, 
and so firmly fixed is the idea of this connection, that some of these springs 
are called " Kropf brunnen, " or goitre springs. But animals fed on im- 
ported food and water and kept in the district also acquire goitres. The 
water will produce goitre in animals kept in another country; the agency, 
whatever it is, will not pass through a dialyzing membrane, and therefore 
it must be of colloid character, but it will withstand temperatures up to 
75° to 80° C. Wherefore it is agreed that it cannot be a living thing, and 
the problem is still to be solved. Nevertheless there are those who main- 
tain stoutly that it is an infection (McCarrison) 
GOITRE 
Something has been said of goitre, which is the term long used in general to 
indicate an enlargement of the thyroid gland. It is not only in cretins that 
such enlargement occurs. There are various forms, and while one gains the 
impression that they are more frequently found in certain districts, such as 
the shores of the Great Lakes in this country, they do appear elsewhere in 
people and animals which have not been exposed to any recognizable 
peculiarity of environment. What it is in these goitre districts which pro- 
duces goitre without especial signs of thyroid deficiency is as obscure as 
in the case of the cretins. Perhaps it is the same influence, since in the 
Alpine regions there are many persons afflicted with goitre who are not 
cretins. About Kingston, in Ontario, and about Cleveland it is especially 
common, and Marine states that 80 per cent, or more of the stray dogs near 
Cleveland have enlarged thyroids. Possibly, as he thinks, it may be due 
to a lack of assimilation of iodine from the food, since iodine has long been 
known as a remedy in this disease which is more or less efficient in diminish- 
ing the size of the gland. 
There are many variations in the anatomical character of these enlarge- 
ments, many combinations and progressive alterations, but there seem to 
be two essentially different forms which constitute the basis for all these 
variations. 
In one of these, the so-called colloid or gelatinous goitre, the gland is fairly 
uniformly enlarged, because every alveolus is increased in size and dis- 
tended with colloid, even to such a degree that the lining epithelium is 880 
TEXT-BOOK OF PATHOLOGY 
flattened to a scale-like form. Such a goitre, on section, is rather soft and 
translucent, like amber, and uniform in appearance throughout, although 
there are often haemorrhages or necroses, or the scars which result from 
these. The alveoli filled with clear 
colloid are often so large that they are 
visible to the naked eye. 
The other form, frequently combined 
with this, but also occurring alone, 
seems to begin in young persons about 
the time of puberty, and to progress 
very slowly. It is not a diffuse en- 
largement, but is produced by the 
presence of one or many circumscribed 
nodules made up of a tissue different 
in appearance from the surrounding 
thyroid, which becomes greatly com- 
pressed by the sharply outlined nod- 
ules. In their fresher state these nod- 
ules are elastic, and on section show a 
smooth swelling, finely granular, or 
velvety surface, which is grayish white 
or flecked with small diffuse haemor- 
rhages (Fig. 434). Microscopically, it 
is seen to be made up of many small 
round alveoli lined with rather high 
cubical epithelium, inclosing a small 
lumen which usually contains little or 
no colloid (Fig. 435). The alveoli are 
not, as a rule, closely packed together, but are separated by an abundant, 
rather oedematous looking stroma, rich in blood-vessels, from which inter- 
alveolar haemorrhages are often seen to have arisen. In some cases the 
alveoli are larger and more irregular in form and filled with colloid. Indeed 
one occasionally finds nodules of almost the character of the colloid goitre. 
After they have existed for a time necroses arise in the central portion and 
appear as opaque yellow areas. They may become calcified, or they 
soften so that the nodule becomes a cyst, with turbid and blood-stained 
liquid contents, which in time may become, in turn, a clear yellow fluid. 
The rind of the nodule persists, often with extensive calcification, and is 
deeply pigmented with haemosiderin from the blood which was extravasated 
in the interior. 
These seem to be tumor-like growths or adenomata. It is true that 
their structure bears a faint resemblance to that of the foetal thyroid in the 
lack of colloid, but I do not think it justifiable to call them, as Wolfler does, 
foetal adenomata, since there is no evidence whatever that there is any- 
Fig. 434.-Large adenoma of thy- 
roid. The nodule is sharply outlined 
and surrounded by compressed thyroid 
tissue. Necroses, haemorrhages, and 
areas of calcification in its substance. GOITRE 
881 
thing foetal about them. Instead, the condition might be called adenoma- 
tous or nodular goitre. 
Both of these forms, or combinations of them, even when considerable 
Fig. 435.-Circumscribed adenomatous nodule of the thyroid. The surrounding 
tissue is somewhat compressed. The alveoli of the nodule are small and round, and are 
embedded in abundant stroma. 
scarring has taken place, seem to be compatible with practically normal 
life, without any evidences of deficiency or excess of thyroid function. 
If anything, it would seem that the error would be on the side of defi- 882 
TEXT-BOOK OF PATHOLOGY 
ciency, since the colloid is found on analysis to be relatively poor in iodine 
(which may perhaps be taken as an indication of the efficiency of the gland), 
but the quantity of colloid is so increased in the first form that the total 
amount of iodine may exceed the normal. It leads one to the idea that the 
enlargement may be a compensatory phenomenon, an attempt to make up 
in bulk what is deficient in quality of the colloid. 
It has long been recognized that there is some connection between iodine and the 
thyroid; poultices of burnt seaweed which contains iodine were long ago applied with 
effect in the attempt to reduce the size of goitres, and in a similar way iodine has been 
painted on the skin over them. Baumann isolated an iodine-containing protein ma- 
terial which he regarded as a characteristic constituent of the thyroid, while Oswald 
later determined that this substance is a globulin, and named it thyreoglobulin. Its 
iodine content varies in different glands, and indeed may be changed at will by the ad- 
ministration of iodine, much as the iodine content of other organs is affected, but in a 
far more striking degree. The lipoid contents of the gland, while showing a certain 
avidity for iodine, seems to play no important part in the actual iodine interchange of the 
gland (Howe). Kendall has isolated in a substance with an oxyindol nucleus the 
active principle of the thyroid, and has even synthesized it (Tr. Assoc. Amer. Phys., 
1918, xxxiii, 324). It produces the same physiological effects as extract of the gland. 
Marine has shown that the iodine content of the thyroid is in inverse proportion to the 
activity of its efforts at hyperplasia. This hyperplasia involves the new formation of epi- 
thelium, which is thrown up into folds, and usually the diminution or disppearance of the 
colloid. The administration of iodine has the remarkable effect of checking the hyper- 
plastic epithelial growth and restoring the gland to its colloid-filled state. When the hy- 
perplasia is already advanced, the nearest approach to the normal gland attained by giving 
iodine is seen in an organ whose alveoli are rather overstretched with colloid. Marine 
therefore looks upon such epithelial hyperplasia as a normal effort to compensate for an 
insufficiency due to inability to absorb or assimilate sufficient iodine. Probably the long- 
recognized reduction in the bulk of colloid goitres upon the application of iodine may be 
due to the concentration of the iodine content of the dilute colloid, and a consequent re- 
duction in its amount. 
Although the functional activity of such enlarged and distorted thyroid 
glands may not be strikingly disturbed, the mechanical effects upon 
the neighboring organs are often serious. The goitre may be so large as to 
be very unsightly, and impede the movements of the head, but more impor- 
tant than this are the results of pressure upon the trachea, the oesophagus, 
and the circulatory organs. 
Lateral pressure upon the trachea frequently reduces its calibre to a 
narrow slit, with distortion and softening of the cartilages, so that extreme 
dyspnoea, emphysema of the lungs, etc., may ensue. Dysphagia from 
compression of the oesophagus is far less common, but the circulation is 
sometimes embarrassed, so that palpitations and tachycardia and finally 
cardiac hypertrophy are brought about. 
Minnich, who has made a study of such goitre hearts, points out the 
mechanical strain offered in the lesser circulation by the effects of dysp- 
noea, but thinks that even more frequently the circulation is disturbed by 
alterations in the secretions of the thyroid, which affect the nervous 883 
EXOPHTHALMIC GOITRE 
regulators of the heart, diminishing especially the action of the depressor 
and allowing the heart to be overworked. 
An interesting if rare form of enlargement of the thyroid is the so-called 
plunging goitre, which hangs down behind the sternum and moves up and 
down, in and out of the thorax, with respirations. 
Most interesting of all the diseases which affect the thyroid is this so-called 
Graves' or Basedow's disease, in which, at least, there are active symptoms 
EXOPHTHALMIC GOITRE 
Fig. 436.-Exophthalmic goitre. The patient shows a goitre of moderate size; great 
exophthalmos, smooth forehead, and abnormal expression. 
in place of the sluggish effects met with in the diseases following upon 
deficiencies in the thyroid glands. But here the nature of the relation of 
the symptoms to the thyroid is not so clear, although it is commonly looked 
upon as the effect of overactivity of the gland. 
The disease is common, occurring sporadically everywhere without 
recognizable relation to any particular district, and much more frequently 
in women than in men. Extremes of age have been reported, but it is 
essentially an affection of young and middle-aged adults. It begins with- 
out any very obvious causes, after recovery from some infection or often 
after some violent emotional disturbance or fright, sometimes appearing 
suddenly in its full intensity, more frequently developing gradually. The 
more prominent disturbances of function are briefly as follows: there are 
nervousness and irritability, the patient being agitated and perturbed by 
occurrences which would produce little impression on a normal person; 
the skin is flushed and moist, and the patient feels hot; the heart beats 884 
TEXT-BOOK OF PATHOLOGY 
very rapidly ond forcibly, and the peripheral vessels are distended and 
thump. There is tremor; the eyes protrude abnormally, so that the 
eyelids may fail to cover them properly; there are disturbances in the 
motility of the eyelids and of the forehead (Fig. 436). There is often, 
though not always, enlargement of the thyroid, and finally, in spite of the 
good appetite, the patient wastes away. Nitrogenous metabolism is 
increased, as judged by the excretion of nitrogen in the urine; the calor- 
Fig. 437.-Exophthalmic goitre. Gross external appearance of the thyroid. 
imeter shows an increased dissipation of energy. The tolerance for sugar is 
lowered, and glycosuria is readily brought about or occurs spontaneously, 
since the storage of carbohydrate is so unstable. 
After operation, especially when the thyroid has been much handled, 
the patients sometimes show great intensification of the symptoms for a 
short time. Holman has recently described a case in which there de- 
veloped after operation instead of hyperglycaemia a severe hypoglycaemia 
with coma, which was relieved by injection of glucose. 
Such patients are more or less incapacitated, but some of them go on for 
years and die of an intercurrent affection. Others develop symptoms of 
such intensity that they die from the disease itself, often with mental 
derangement, with cardiac dilatation, with excessive vomiting, or with 
exhaustion from any of these. 
At autopsy fairly constant changes are found in the thyroid, in the 
thymus, and in the lymphoid structures. The heart is frequently hyper- 
trophied, but there are no very obvious changes in the other organs. The 
brain, in spite of most diligent search, has shown nothing constant. EXOPHTHALMIC GOITRE 
885 
The Thyroid.-Many descriptions of the thyroid alterations have been 
given and many subdivisions made, but it is doubtful whether these classi- 
fications have any great significance. Many stages or degrees of altera- 
tion are found in the gland, and these must be studied in detailed reports 
on this subject (A. Kocher, etc.). There is not always a great enlarge- 
ment of the gland, and sometimes it cannot be palpated. When the thy- 
roid is exposed at operation, it is found to be very richly supplied with 
blood, and over the surface course huge distended veins whose walls tear 
Fig. 438.-Exophthalmic goitre. Alveoli are irregular in form, lined with columnar 
epithelium, and almost devoid of colloid. The stroma is increased in quantity. 
readily, so that the risk of haemorrhage is great in these operations. After 
removal, when the blood runs out, the gland appears pale, dense, and 
hard, and on section its cut surface is both finely and coarsely lobulated, 
opaque, and of a pale, grayish-pink color (Fig. 437). Little or no colloid 
can be found. On the other hand, there are some cases in which colloid 
is abundant, so that the characteristic gross appearance of opacity is not 
produced. 
Microscopically, there is found in the most typical cases an alteration of 
the gland (Fig. 438) which closely resembles that recognized as a com- 886 
TEXT-BOOK OF PATHOLOGY 
pensatory hyperplasia in the remnant of the thyroid of a normal animal, 
some time after a large part of the gland has been extirpated. The alveoli 
are no longer uniform in size or shape, and contain little or no colloid. 
What they do contain is no longer homogeneous or refractive, but granular 
or shreddy, like a thin, coagulated fluid. The epithelium, instead of being 
flattened or low cubical, is high and often distinctly columnar, and is so 
increased in amount that it is thrown up into folds, giving to the alveolus 
an irregular outline, with papillary ingrowths encroaching greatly upon 
the cavity. Commonly many very small alveoli are associated with each 
larger one, and one sometimes receives the impression that many of these 
are merely cross-sections of the bays which project from the larger ones. 
The stroma is frequently but not always fortified by scar tissue, sometimes 
to such an extent as to suggest a cirrhotic condition. Definite lymphoid 
nodules are often found scattered through the gland, an appearance which, 
while fairly characteristic of this disease, is rarely if ever seen in the normal 
thyroid. 
These changes may sometimes be recognized as beginning in patches 
scattered through the normal gland or in adenomatous nodules, but in 
most cases they appear gradually and diffusely throughout the organ. 
They are constantly found, in some stage of development, although in 
any large series one finds several cases in which, although the symptoms 
are definite and intense, the alveoli of the thyroid are still large and fairly 
uniform in outline and filled with colloid. The various modifications of 
this anatomical picture which involve reduplication of the epithelial 
lining, distortion and irregularity in the form of the cells, desquamation 
of the epithelium, etc., must be read in such papers as that of Kocher. 
The thymus, which is ordinarily atrophied in adult life except for micro- 
scopical remnants, is found to be greatly enlarged. This has been con- 
stant in the autopsies which I have seen, and in some cases it has presented 
itself as an organ almost the size of one's hand. Hassal's bodies persist, 
and the small cells are in such excess that the ordinary distinction between 
medulla and cortex is obscured. Dr. Halsted discusses its importance in 
connection with the symptoms and the favorable effect of its extirpation. 
The lymph-glands, especially in the neck, are often markedly enlarged. 
In some cases this increase in the bulk of the lymphoid tissue occurs 
throughout the body, even the solitary nodules in the intestine projecting 
as gray prominences. Together with this, which corresponds with the 
finding of new lymph-nodes in the substance of the thyroid, there is a dis- 
tinct lymphocytosis (Kocher), which is reduced to normal when the thy- 
mus is removed (Capelie and Bayer). 
Conceptions of Nature and Cause of the Disease.-In spite of all investi- 
gation, the nature of this disease is still in doubt. Since the statements of 
Mobius it has been most commonly thought of as the effect of hypersecre- 
tion or perhaps an altered secretion on the part of the thyroid, without any 
further curiosity being shown as to what might cause this altered activity EXOPHTHALMIC GOITRE 
887 
of the thyroid. The main support for this lies in the recognition (by the 
acetonitrile method of Hunt) of excess of thyroid secretion in the circulating 
blood, in the increased nitrogenous metabolism during the disease, in the 
harmful effects of thyroid extract, and in the peculiar hypertrophic changes 
in the thyroid itself. The lack of colloid there is ascribed to the rapidity 
of its removal by the passing blood. Further, the view is supported by the 
beneficial effects of removing part of the thyroid or of ligating the thyroid 
arteries. 
Opposed to this view are the following facts: the thyroid gland and the 
colloid contain less iodine than the normal gland; after extensive operative 
extirpation, or even in the natural course of the disease, symptoms of 
myxcedema which surely indicate insufficiency, may arise, while the symp- 
toms of exophthalmic goitre are still present and intense. Nor do the 
symptoms of exophthalmic goitre disappear with any precision upon the 
removal of half or more of the gland, as they should if they were merely 
the result of an excessive secretion. What actually happens is that 
the recognized influence of the thyroid in promoting nitrogenous katabol- 
ism is halted by the loss of the gland, and for a time the patient, in spite of 
her other symptoms, gains weight. Nevertheless, with the compensatory 
growth of the thyroid the weight sinks again. Further, it is impossible 
to reproduce exactly the whole symptom complex by administering an 
excess of thyroid secretion, although some of the phenomena can thus be 
brought about. 
On the whole, it seems clear that while the thyroid is profoundly affected, 
and through the disturbance of its function does cause many of the symp- 
toms, it is not alone responsible, but forms part in a chain or circle in which 
notably the sympathetic system and probably the other organs of internal 
secretion, perhaps especially the thymus, are concerned. This is true, as 
we have seen, in most of the diseases which involve these organs, and in 
their study we are more and more impressed with their close interrelation. 
Cannon has recently reported an ingenious experiment which may shed 
much light on the affection, although in itself it must be regarded as a purely 
artificial imitation of the disease. He anastomosed the phrenic nerve, 
which sends an impulse with every breath to the diaphragm, with the 
cervical sympathetic, which gives sympathetic fibres to the thyroid. 
After the time necessary for the functional union of the two nerves had 
passed, he found that the animals (cats) showed practically all the symp- 
toms of exophthalmic goitre, tachycardia, diarrhoea, greatly increased appe- 
tite, emaciation, an increase of 150 per cent, in the nitrogenous metabolism, 
exophthalmos, and, while in the dark, a rhythmic expansion and contrac- 
tion of the pupil with each breath. 
On the basis of such experiments he thinks that in exophthalmic goitre 
there may be a lowering of the threshold which normally limits the passage 
of sympathetic stimuli to the organs, and that the overactivity of the thy- 
roid and the consequent symptoms are due primarily to a disturbance of 888 
TEXT-BOOK OF PATHOLOGY 
the central nervous system and the preponderance of the sympathetic 
over the autonomic stimuli. (For a discussion of the relation of sympa- 
thetic to autonomic nerve influences see Barker, Trans. Assoc. Amer. 
Phys., 1912, xxvii, 491.) 
THYROID LITERATURE 
Halsted: Jour. Exp. Med., 1912, xv, 205. 
v. Eiselsberg: Krankh. d. Schilddriise, Dtsche. Chirurgie, 1901, 38. 
Marine: Arch. Int. Med., 1909, iv, 440; 1911, vii, 506. 
Oswald: Chemische Beschaffenheit d. Schilddriise, Strassburg, 1900. 
Minnich: Das Kropfherz, Leipzig, 1904. 
Mobius: Die Basedow'sche Krankheit, Wien, 1906. 
A. Kocher: Virch. Arch., 1912, ccviii, 86. 
MacCallum: Jour. Am. Med. Assoc., 1905, xlix, 1158. 
Halsted: J. H. H. Bull., 1914, xxv, 223; Harvey Lectures, 1913-1914, ix, 224. 
Capelle and Bayer: Beitr. z. klin. Chir., 1913, Ixxxvi, 509. 
Holman: Johns Hopkins Hospital Bulletin, 1923, xxxiv, 69. CHAPTER XLIV 
DISEASES DUE TO INJURIES OF THE ORGANS OF INTERNAL 
SECRETION (Continued) 
The parathyroid: Anatomy, physiology. Tetany, hyperexcitability of nerves. Relation to 
calcium metabolism, pathological anatomy. Other types of tetany. Thymus: Anatomy, 
evolution, and involution. Hyperplasia. Thymus in exophthalmic goitre, in myasthenia 
gravis, in status thymico-lymphaticus; accidental involution. Adrenal: Anatomy. 
Function of medulla, functions of cortex. Addison's disease. 
DISTURBANCES OF FUNCTION OF THE PARATHYROID GLANDS 
The parathyroid glands arising from the walls of the third and fourth 
branchial clefts come to lie in man in various situations along the posterior 
edge of the thyroid, and are usually four in number. They are brown 
and soft, with conspicuous peripheral veins, and are composed of anastomos- 
ing strands of cells many of which have a very clear protoplasm in early 
youth, while in later life the predominant cells have a slightly granular 
cytoplasm, a few' groups standing out by reason of their small dark nuclei 
and their bright eosinophile protoplasm. Differences in the function of 
these cells are not understood. 
Experimental study has shown convincingly enough the complete inde- 
pendence of these organs, although there are still writers who claim that 
they are merely undeveloped portions of thyroid tissue. That they are 
intimately related functionally in the community of organs of internal 
secretion is, however, pretty certain, although it is not yet possible to out- 
line precisely the part that they play. 
Physiology.-When the parathyroids are completely extirpated, a period 
of twelve hours to several days elapses during which there are no symptoms, 
but then there appear the evidences of the so-called tetany, which may 
quickly reach the greatest intensity. Twitchings of various muscles 
appear, and soon there is a continuous quivering or vibration of the tense 
muscle, which can be felt as a thrill interrupted by violent convulsive 
jerks. The whole body becomes rigid, the jaws snap, and every muscle 
is thrown into violent clonic convulsions. Smooth muscle is said to be 
affected also, but its participation is inconspicuous. Such convulsions 
involve the most extreme labor on the part of the muscles, and the tempe- 
rature rises to fever heat because the dissipation of heat cannot proceed 
rapidly enough. In the dog respiration becomes very rapid, because that 
is its way of dissipating heat. Death may occur in such a convulsive 
seizure, or the tetany may pass off for a time and recur until death follows 
from complete exhaustion. Sometimes a sort of continuous milder twitch- 
889 TEXT-BOOK OF PATHOLOGY 
890 
ing persists for a long time, the animal rapidly wastes and becomes infected, 
and dies in a kind of cachexia. 
All this depends upon the most striking and constant feature of tetany, 
the hyperexcitability of the motor nerves, with which there appears to be 
associated a similar hyperexcitability of the sensory nerves. 
This hyperexcitability is easily shown, in that a muscular jerk is elicited 
by a galvanic shock applied over the motor nerve, so weak that it would have 
no effect under normal conditions. The direction of the current and the 
character of the shock, whether due to opening or closing of the circuit, 
must be considered, and the following table will give an average comparison 
between the shocks necessary to produce a visible muscular contraction in 
a normal and a tetanic animal. 
Normal 
Milliamperes 
Tetany 
Milliamperes 
Kathode closing 
0.3 
0.05 
Kathode opening 
6.0 
0.6 
Anode closing 
1.8 
0.8 
Anode opening 
2.0 
0.8 
It will be seen that the greatest and most characteristic change is in the 
reaction to the kathode opening shock; that is, where the kathode of the 
battery is put on the nerve and the current broken. Practically all the 
other symptoms seem to depend upon this hyperexcitability of the nervous 
system. 
It was found (MacCallum and Voegtlin) that injection of a salt of calcium 
would abolish the hyperexcitability and cure all symptoms of tetany, even 
to the extent of keeping the animal alive and well for months if regularly 
administered, and it was suspected that a lack of calcium in the circulating 
fluids and tissues might explain the hyperexcitability of the nerves. As a 
fact, the blood and nerve tissues of animals in tetany contain a decreased 
amount of calcium. It was shown (MacCallum) that if an isolated 
extremity of a normal animal be perfused with blood from another in the 
height of tetany, the excitability of its nerves would be increased to the 
tetany level, returning to normal when again perfused with normal blood. 
Conversely, if one extremity of a dog in tetany be perfused with normal 
blood, the excitability of the nerves of that leg becomes normal, and that 
leg ceases to twitch, although the excitability rises and the twitchings begin 
again if the femoral vessels are reanastomosed with their stumps, so that 
the leg is again flooded with its own "tetany blood." This blood is poor 
in calcium, and it seems that the hyperexcitability of ganglion-cells of the 
central nervous system throughout, as well as the nerve endings, is pro- 
duced by this, for if one remove calcium from the blood by dialysis (Mac- 
Callum and Lambert), and then perfuse an extremity with that blood, 
exactly the same hyperexcitability is produced. Further evidence in 
favor of the conception of the parathyroid as an organ presiding in some 
sense over the calcium metabolism is presented by Erdheim, who finds 
that in chronic tetany in rats, produced by extirpating almost all of the DISTURBANCES OF FUNCTION OF PARATHYROID GLANDS 
891 
numerous scattered glands, calcium fails to be deposited in the constantly 
growing teeth, so that they become soft and break off. Fractured bones 
heal with only a soft callus, and thus fail to unite firmly. Reimplantation 
of parathyroid tissue restores the ability of the dentine to calcify and 
harden, and reestablishes the ossification process as long as the graft lives. 
The influence upon the sympathetic system is not yet worked out, 
although there are vague indications of hyperexcitability of those nerves 
after the destruction of the glands. 
Tetany in Human Beings.-Tetany may be produced by the injection 
of alkaline phosphates or carbonates and by the removal from the body 
of carbon dioxide or hydrochloric acid. In every case it appears to be a 
reduction in the available or ionized calcium salts which is brought about 
by these procedures, and in all cases the symptoms can be promptly made 
to disappear by the injection of calcium. 
Aside from the postoperative tetany following upon destruction of the 
parathyroid glands in operations for removal of tumors of the thyroid, 
which then resembles experimental tetany, there occur several types of 
spontaneous tetany in human beings. Howland and his assistants have 
studied the tetany of infants and find that it is always associated with 
rickets and is characterized by great reduction in the calcium content of 
the blood. It is cured by cod-liver oil or exposure to ultraviolet rays, 
which cure the rickets by improving the absorption of calcium, etc. 
When the pylorus is obstructed there is a great loss of hydrochloric acid, 
the alkali reserve of the blood is greatly increased, chlorides disappear 
from the urine and are reduced in the blood, and it seems probable that 
the ionization and availability of calcium are reduced. In lactation there 
is a direct loss of calcium which would intensify any influence already 
present to produce tetany. Tetany from various poisonings, such as 
ergot, phosphorus, etc., and among certain workmen, such as shoemakers, 
.are not so easily explained. 
LITERATURE 
Erdheim: Mitth. Grenz, d. Med. u. Chir., 1906, xvi, 632. 
Escherich: Tetanie d. Kinder., Wien, 1909. 
Frankl Hochwart: Tetanie d. Erwachsenen, Wien, 1909. 
Kramer, Tisdall, and Howland: Amer. Jour. Dis. Child., 1921, xxii, 431. 
MacCallum: Ergebn. d. innere Medizin, 1913, xi, 569 (Lit.); Jour. Amer. Med. Assoc., 
1912, lix, 319. 
MacCallum: Ibid., 1913, xxv, 941. Pathogenesis of Tetany, Medicine, 1924, iii. 
MacCallum and Lambert: Jour. Exp. Med., 1914, xx, 149. 
MacCallum and others: Johns Hopkins Hospital Bulletin, 1920, xxxi, 1. (Gastric 
Tetany.) 
MacCallum and Voegtlin: Jour. Exp. Med., 1909, xi, 118. 
MacCallum and Vogel: Jour. Exp. Med., 1913, xviii, 618. 
The recent literature on the whole subject of tetany is reviewed in Medicine, 1924, iii, p. 892 
TEXT-BOOK OF PATHOLOGY 
DISEASES DUE TO THE DISTURBANCES IN THE FUNCTION OF THE THYMUS 
The thymus arises in man as a paired ventral outgrowth from the entoderm 
of the third and fourth branchial clefts, the main portion of the gland being 
derived from the third cleft. 
Its original form is that of a flat pouch. With the gradual thickening of 
the walls of the sac the original lumen is obliterated, but vestiges of the 
original canal may be found even in the fully developed organ. In embryos 
of 30 to 40 mm. the rapid increase in size leads to great convolution of the 
surface, but although the form of the gland becomes more complicated, the 
parenchyma maintains its continuity. The right and left lobes remain 
separate, but there is no formation of isolated lobules. 
Two types of cells are distinguishable in the thymus-one, resembling 
the lymphocyte, being concentrated in especial abundance in what thus 
becomes the cortex of the organ, while the other, recognized as epithelial 
in nature, occurs throughout, but is less masked in the central or medullary 
part. 
Long dispute has occurred as to the nature of these cells and their origin, 
and the controversy is not yet finished. For many years the lymphocytic 
nature of the small cells was unquestioned, but their origin was attributed 
by one school (His, Stieda, etc.) to an early invasion of the epithelial ele- 
ments by wandering mesenchymal cells, by another to a direct differentia- 
tion of the epithelial cells into lymphocytes identical with those of the blood- 
stream and lymphatic tissues (Beard, Kblliker, Prenant, etc.). 
Stoehr, in 1906, declared that the small thymus cells were neither genet- 
ically nor functionally lymphocytes, but true epithelial cells, while more 
recently Hammar and Maximow have demonstrated an early invasion of 
the epithelial cells by migrating lymphocytes which accompany the in- 
growing blood-vessels. 
Morphologically and biologically the small cells resemble in almost 
every respect the lymphocytes. 
The greater portion of the medulla and the reticular framework of the 
cortex are formed of derivatives of the original epithelial cells. They tend 
to arrange themselves in concentric fashion to form the Hassal bodies, 
which are not vestigial structures, but are constantly being newly formed 
from hypertrophic epithelial cell complexes. The protoplasm of the epi- 
thelial cells has a fibrillary character, and gives rise in places to intracellular 
fibrils resembling neuroglia fibrils. 
There is no fibrous reticulum within the substance of the organ, and only 
a delicate sheath accompanying the blood-vessels. Opinion is divided as 
to the significance of the thymus as a blood-forming tissue, aside from its 
importance as a site for the production of lymphoid cells. 
The thymus is thus, if we accept the prevailing view as to the lympho- 
cytic nature of the smaller thymus cells, an organ composed of two genet- 
ically distinct types of tissue. These twTo types of cells, lymphoid and 
epithelial, are intimately commingled, and in the normal gland there con- DISEASES DUE TO DISTURBANCES IN FUNCTION OF THYMUS 
893 
stantly occurs a destruction of the lymphoid cells and phagocytosis of the 
degenerating cells and pyknotic nuclear fragments, by the larger epi- 
thelial cells. 
Normal Evolution and Involution.-The thymus reaches its maximum 
development coincidentally with the maturation of the sexual organs, and 
then gradually atrophies. This is the normal involution, but since the 
work of Waldeyer it has been known that even in senescence there are 
regularly found the strands of thymic tissue containing presumably func- 
tioning thymic cells. 
In early childhood cortex and medulla cannot be distinguished, as the 
lymphoid cells are predominant throughout. In later childhood the differ- 
entiation between cortex and medulla becomes more pronounced, but 
from adolescence on there is a progressive reduction in the amount of the 
parenchyma, the Hassal bodies are brought together, and the interstitial 
tissue and fat form a large part of the volume of the organ. 
Hammar gives a table of normal weights at various ages, from which the 
following may be extracted: 
Grams 
New-born 13.26 
6-10 years 26.1 
11-15 years 37.52 
21-25 years 24.73 
56-65 years 16.08 
66-75 years 6.0 
Effects of Extirpation.-Many efforts have been made to show the 
nature of the function of the thymus by extirpating the organ, but these 
have given variable and unsatisfactory results. Probably most, if not all, 
were really incomplete extirpations, and while some authors describe re- 
tardation of growth and rachitic changes in the bones, Park, in his recent 
review of the literature and description of his own experiments upon 
guinea-pigs, concludes that results such as his own, which were quite 
negative, are most trustworthy, and that developmental anomalies in the 
dog after such operations are not due to the loss of the thymus, but to con- 
finement, unsuitable food, etc. 
For a discussion of this whole question the reader is referred to the paper 
of Park and McClure in the American Journal of Diseases of Children. 
"Hyperplasia," "Abnormal Persistence" of the Thymus.-Since thymic 
tissue can be demonstrated in normal individuals at any age, the term ab- 
normal persistence should be dropped, but there are cases in which the 
thymus fails to undergo involution at the proper time, and others in which 
there is a renewal of growth after involution has been established. In these 
latter cases it may attain a weight several times that of the normal organ. 
Such hyperplastic glands are found in infants usually unassociated with 
general lymphoid hyperplasia, in older individuals in connection with vari- 
ous derangements of the organs of internal secretion, particularly thyroid, 
adrenals, hypophysis, and genital organs, in the so-called myasthenia 894 
TEXT-BOOK OF PATHOLOGY 
gravis, and finally in individuals presenting the anatomical features in- 
cluded under the conception of status thymicolymphaticus. 
In the form found in infants the thymus may reach a weight of 60 grams 
at birth, and may actually constitute an obstruction to the respiratory 
passages or great veins. In older persons the evidence is against the 
possibility of any such mechanical obstruction, although the literature is 
full of contradictory statements concerning thymic asthma and other 
effects of pressure. Nevertheless, the immediate relief of the suffocative 
attacks which follows the partial removal by the surgeon of the enlarged 
gland is pretty strong evidence in favor of the idea. There is no evidence 
that the enlarged thymus yan interfere with the function of the vagus,, 
phrenic, or recurrent laryngeal nerves. 
The Thymus in Exophthalmic Goitre.-Reference has already been made 
to the enlargement of the thymus which, according to Capelle and Matti, 
occurs in 75 to 79 per cent, of the cases. That it is an actual enlargement 
is clear from the fact that its weight may greatly exceed the normal limits 
at the height of development. The descriptions of the histological changes 
are most contradictory, but it seems that they may represent an accentua- 
tion of the condition corresponding to the age at which the disease de- 
veloped. In a young person (twenty-three years) the appearance was that 
of a child's thymus, the hyperplasia being essentially in the lymphoid 
elements. The interpretation of the role it plays and of the beneficial 
effects of its operative removal is as yet entirely speculative. 
Hyperplasia of the thymus in Addison's disease and acromegaly and in 
genital hypoplasia or eunuchoidism has been frequently observed and it 
has been experimentally proven that the involution of the thymus is greatly 
delayed after castration at an early age. 
Myasthenia Gravis.-In about 90 per cent, of the cases of this peculiar 
disease the thymus is enlarged into a bulky mass, variously regarded as a 
new-growth or as a simple hyperplasia. There are found lymphoid infiltra- 
tions in the skeletal muscles and sometimes in the myocardium, adrenal, 
and liver. 
The Thymus in Status Thymico-lymphaticus.-This condition (already 
mentioned in Chapter XL), difficult to recognize before puberty, is more 
definite in adults. There is at least a certain group of individuals who are 
characterized-(1) By anomalies in the hair distribution; (2) by the 
rounded conformation of the limbs; (3) by the smooth texture of the skin; 
(4) by a general lymphatic hyperplasia; (5) by hypoplasia of the aorta 
and other arterial trunks, and (6) by hypoplasia of the adrenals and the 
entire chromaffin system. 
It is generally assumed that enlargement of the thymus forms a part of 
this rather vaguely outlined condition, but it requires further study to be 
sure of this. Pappenheimer, analyzing 28 cases of sudden death in sub- 
jects up to thirty-five years of age with the anatomical features of status DISEASES DUE TO DISTURBANCES IN FUNCTION OF THYMUS 
895 
lymphaticus, found that the beginning of involution of the thymus is de- 
layed to the third decade. The histological picture is in no sense char- 
acteristic, although Schridde claims that there is hyperplasia of the medulla 
with underdevelopment of the cortex. The possibility that there may have 
been previous involutional changes, thinning the cortex, must be remem- 
bered. 
There is no proof that the thymus is concerned in the development of 
status lymphaticus or in the sudden death which sometimes occurs in these 
persons. It is more logical to believe that it is the incomplete differentia- 
tion of secondary sexual characters, which causes the failure of the thymus 
to undergo involution, and possibly all the other features of status lymphati- 
cus may be best explained in this way too. Nor is there convincing evi- 
dence that the sudden death, increased susceptibility to acute infections, 
trauma, emotional stress, and anaesthesia, is in any way due to hyperfunc- 
tion or disordered function of the thymus. 
Accidental Involution.-Starvation, acute and chronic wasting disease, 
infections, and exposure to x-rays produce rapid degenerative changes in 
the thymus, leading often to extreme atrophy. 
The histological picture produced in this condition, which Hammar has 
called " accidental involution," varies with the acuteness and severity of the 
injury and the previous state of involution of the gland. The small thymus 
cells suffer first, being most susceptible to injurious influences; their nuclei 
become pyknotic and fragmented, and the debris is taken up by the active 
phagocytic epithelial elements. The depletion of the cortex may lead to 
an inversion of the normal picture, the medulla now becoming packed with 
small cells or their remains. The reticular cells lose their protoplasmic 
connections, become rounded and vacuolated, and may contain fat-drop- 
lets. The Hassal bodies are resistant, and because of the rarefaction of the 
intervening parenchyma, they become concentrated together. There may 
occur a sort of sclerosis in this rapid destruction, in contrast to the condi- 
tion seen in normal involution, in which the parenchyma merely disappears 
without stirring up the production of any scar tissue. 
Otherwise, except in the rate of development, the accidental involution 
is in principle the same as the normal process. 
LITERATURE 
Hammar: "Fungfzig Jahre Thymus Forschung," Ergeb. d. Anat. u. Entw., 1909, xix, 1; 
also Zentralbl. d. exp. Med., 1912, i, 23; Ibid., 1913, iii, 109; Ibid., 1914, v, 55. 
Ziegler's Beitr., 1919, Ixvi, 37. Ztschr. f. Angew. Anat., 1918, iii, 314; iv, 1. 
Wiesel: Ergebn. d. allg. Path., 1911, xv, 416. 
Stohr: Anat. Hefte, 1906, xxx, 407 
Maximow: Arch. f. mikr. Anat., 1909, Ixxiv, 525. 
Pappenheimer: Jour. Med. Res., 1910, xviii, 1. Jour. Exp. Med., 1914, xix, 319; xx, 477. 
Matti: Mitth. a. d. Grenzgeb. d. Med. u. Chir., 1912, xxiv, 665. 
Capelie: Munch, med. Woch., 1908, lv., 1826. 
Park: Jour. Exp. Med., 1917, xxv, 129. Amer. Jour. Dis. Child., 1919, xviii, 317. TEXT-BOOK OF PATHOLOGY 
896 
In the adrenal glands we have organs of complex character long recognized, 
but only recently known to be intimately related to many other similar 
organs which are scattered chiefly along the course of the chains of sympa- 
thetic ganglia, and known as chromaffine bodies. These chromaffine 
bodies are of the same character as the medulla of the adrenal glands, 
which is itself enveloped in a cortical covering of very different nature. 
In children the so-called Zuckerkandl organ is a mass of medullary or 
chromaffine substance situated near the bifurcation of the aorta. The 
carotid glands are said to have the same chromaffine quality, absorbing 
chrome salts and thereby stained brown, but it is not known that they 
actually belong to this system. Practically the same relations exist in 
other animals lower than man, but in some fishes, such as the sharks and 
rays, the two types of tissue are not so intimately intermingled; instead, 
the cortical substance forms one mass between the kidneys (interrenal 
body), while the other tissue (the adrenal bodies) is distributed in a series 
of nodules with the sympathetic ganglia. On this account it is feasible 
to carry out on these animals isolated extirpations not possible in the 
higher animals, where cortex and medulla or interrenal and adrenal sub- 
stances are too inextricably entangled. 
In the early development the cortex arises as a new formation from a 
portion of the mesodermal ridge, while the medulla appears in the form of 
tiny groups or balls of cells which arise with the sympathetic ganglia and 
from common forerunners. These cells wander into the substance of the 
cortex and take up a central position, where they constitute the medulla. 
They retain the most abundant and intimate connections with the 
sympathetic system, receiving quantities of fibrils from the coeliac ganglia. 
Accessory or aberrant masses of adrenal character occur frequently 
in man, as well as other animals; indeed, they are practically constant 
in the rat. They are usually composed of cortical material, sometimes 
of cells resembling the outermost or glomerular layer, sometimes and most 
often of cells such as form the fasciculate zone. It is rare to find an 
aberrant adrenal containing medullary substance. They occur in the kid- 
ney, liver, retroperitoneal tissues, ovary, testis, in the tissues accompany- 
ing the spermatic cord, and elsewhere, and are conspicuous on account 
of their bright yellow color. 
The normal histology of the adrenal need not be described here, but 
attention should be called to the peculiar involution through which it 
passes in early life. It is a relatively large organ in the new-born infant, 
and in the first two weeks during which the medulla, which is then an 
extremely inconspicuous collection of cells, begins to grow, the innermost 
zone of the cortex is destroyed and converted into a highly vascular and 
often haemorrhagic connective-tissue layer which collapses. Consequently 
it requires some time for the adrenal to reach again the size it had at birth, 
and this growth is partly effected by the extension of the medulla into this 
DISTURBANCES IN FUNCTIONS OF THE ADRENAL GLANDS DISTURBANCES IN FUNCTIONS OF THE ADRENAL GLANDS 
897 
collapsed framework which represents the inner layer of the original cor- 
tex (Thomas, Pappenheimer, and Lewis). 
The medullary cells, while they are in themselves colorless and appear 
gray and translucent in mass, have, as stated above, the property of absorb- 
ing chromium salts and assuming a bright chestnut-brown color. The 
peculiarities of granule staining in the various zones are complicated, and as 
yet very inadequately studied. 
The cortex is particularly rich in globules of anisotropic lipoids (cho- 
lesterine esters), as well as ordinary fats, which, however, as the experiments 
of Landau, Hueck, and Rothschild show, cannot be taken as evidence that 
these organs produce the lipoids, nor even that they affect the combina- 
tion of cholesterine with fatty acids. Cholesterine fed to herbivorous 
animals is stored in quantity in the adrenal cortex. It is abundant there 
normally, and especially so in pregnancy, but tends to disappear with 
infections, narcosis, delirium tremens, etc. 
Functions.-It is even yet impossible to separate accurately the func- 
tions of the cortex and medulla, and still more hopeless to distinguish 
the activities of the layers of the cortex. Doubtless both cortex and medulla 
are vitally important organs, but there seems to be evidence that the rap- 
idly fatal effects of extirpation of the whole organ are chiefly due to the loss 
of the cortex, since animals survive which possess accessory masses of 
cortical material. 
At any rate, death follows quickly the loss of both adrenals, and it is 
certain that this is not due to the severity of the operation. Dogs die 
usually within forty-eight hours, and so indeed do cats and other animals, 
with symptoms of profound depression, weakness, low temperature, and 
low blood-pressure. It is thought, however, that the low blood-pressure 
is only that which is to be found in any moribund animal, and appears 
just before death. Stewart showed that these phenomena were much post- 
poned in pregnant or lactating animals, and that this might possibly be due 
to the excess of cholesterine in their blood, since the injection of cholesterine 
esters before and after the operation seemed to prolong life. Extirpation of 
one adrenal only has no especial effect, except that the remaining organ 
hypertrophies, the hypertrophy affecting especially the cortex. Upon the 
loss of both adrenals the cholesterine content of the blood increases at 
once. If the animal lives long enough, glycogen disappears from the liver 
and sugar is decreased in the blood. The fat of the body is mobilized and 
wasted, and the animal rapidly loses weight. Whether the change in dis- 
tribution of the cholesterine causes this is uncertain, but Landau suggests 
that cholesterine is just as necessary to the functioning of the adrenal cor- 
tex in its relation to the medulla as the cortex is in its regulating effect 
upon cholesterine. It may be gathered from these vague statements that 
little is known even about the mechanism of the symptoms and death 
following adrenal extirpation. Even in the case of the rays, where the 898 
TEXT-BOOK OF PATHOLOGY 
interrenal body has been extirpated alone by Biedl and Hueck, there is 
no agreement as to the symptoms that lead to death. 
It has, of course, been suggested that death may be due to lack of 
adrenaline, and it is true that adrenalectomized animals may be revived 
repeatedly by injections of adrenaline, but nevertheless they die almost as 
quickly as though they received nothing. 
Function of the Medulla.-Massage of the adrenal evidently forces out 
into the circulation some of the medullary secretion, for the effects are those 
of a small dose of adrenaline. This extract, presumably derived from the 
medulary substance, is most remarkable in its effects, which are well 
known (Biedl, Meyer, and Gottlieb). Injected subcutaneously or intra- 
venously, it stimulates the heart to violent activity and raises the blood- 
pressure also, by causing an intense contraction of the smaller peripheral 
blood-vessels. It acts upon the sympathetic nerve-endings, or perhaps 
rather upon the substance of the neuromuscular junction, and not directly 
upon the muscle itself. The coronary arteries it causes to dilate. In the 
same way it relaxes the intestinal wall. In the eye, separated from its 
nervous connections, it produces, in extremely small doses, dilatation of the 
pupil, but has no effect in the intact eye except that after pancreatec- 
tomy it dilates the pupil when dropped on the conjunctiva. 
It causes quite violent contractions of the uterus, and may produce mis- 
carriages in animals, but this action is greatly modified or even reversed 
by other drugs, such as ergot. In all these cases it is evident that its 
effect is upon smooth muscle innervated by the sympathetic system, and 
in all a striking peculiarity is the transitory character of the effect of a single 
dose. A violent rise in blood-pressure, with constriction of the vessels and 
energetic heart-beat, soon passes off, possibly because adrenaline is quickly 
destroyed in the organism. 
Perhaps the most interesting and important effects of the secretion of the 
chromaffine tissue, which we believe to be essentially adrenaline, are those 
which it exerts in connection with the organs of internal secretion. They 
are probably simple enough, but in the present state of our knowledge 
appear extremely complicated. Injections of adrenaline as well as the 
original application of adrenaline to the pancreas (Herter and Wakeman) 
produce hyperglycsemia and glycosuria. The same thing results from 
massage of the adrenals or from stimulation of the splanchnic nerves. 
There is some difference of opinion as to whether it follows splanchnic 
stimulation after adrenal extirpation. McLeod and others speak of the 
splanchnic impulses as going to the liver via the adrenals, and think that 
the presence of adrenal secretion is necessary to their effectiveness in 
liberating sugar. Freund and Marchand, however, produced hypergly- 
csemia by piqure, or by splanchnic stimulation after adrenalectomy, and 
think the splanchnic fibres go direct to the liver. It must, of course, be 
remembered that there exists much other chromaffine tissue which could 
furnish adrenaline. DISTURBANCES IN FUNCTIONS OF THE ADRENAL GLANDS 
899 
Evidently the adrenaline so acts upon the liver-cells as to cause them 
to bring about the rapid depolymerization of their glycogen, and does 
this independently of the pancreas, since the hyperglycaemia following 
pancreatectomy is even accentuated by injection of adrenaline. 
The relation of other organs of internal secretion to this function of the 
adrenal is not yet entirely cleared up. In the absence of the thyroid it is 
less easy to produce hyperglycaemia with adrenaline, although pancreatec- 
tomy still produces it. In exophthalmic goitre, on the contrary, glycosuria 
is apt to occur spontaneously. Thus it appears that, with certain con- 
trolling mechanisms, this particular activity of the adrenal which brings 
about the pouring of immediately available carbohydrate into the blood is 
regulated by the nervous system through the splanchnic sympathetic nerve. 
Cannon has shown that, in fear or rage or pain, strong impulses are sent to 
the gland, and that the mechanism is well adapted to such situations, since 
under those conditions there is an immediate supply of dextrose to the 
muscles, which act violently without fatigue, the blood-pressure being at 
the same time correspondingly heightened, so that the animal can fight 
or run to the best advantage. The influence of the medulla is in all these 
ways so important that we are not surprised that the chromaffine tissue is 
scattered so widely and is so well protected. But Stewart and Rogoff 
show in a careful experimental study that by extirpating one adrenal and 
cutting the nerves to the other the liberation of epinephrin into the blood 
is stopped. This does not affect the health of the animal, and all those 
procedures which cause hyperglycsemia, such as asphyxia, piqure, etc., still 
do so in the lack of any secretion of epinephrin into the blood. They 
find no definite production of hyperglycsemia by fright or other emotional 
disturbances, and no increase in epinephrin output under these conditions. 
Functions of the Cortex.-It is evident that not much more can be stated 
definitely as to the functions of the cortex in the present state of our knowl- 
edge. As a storehouse of cbolesterine esters, and possibly in some sense 
a controller of the metabolism of these bodies, it seems to play a role, but 
there is practically nothing else to impute it to except a vague "vital im- 
portance." In a number of cases in which tumors have occupied the 
adrenals, composed usually of tissue resembling the cortex rather than the 
medulla, and containing no adrenaline, there have been signs of a peculiar 
precocity in sexual development. Children with such tumors (Fig. 439) 
may appear as mature sexually as adults. When the tumor developed in 
late life (after the menopause), as in a case described by Tuffier, the woman 
assumed male characters, heavy beard, baldness, ability to perform heavy 
labors without fatigue, etc. On the other hand, the gradual atrophy of 
the adrenal is thought to be associated with a condition of premature 
senility called progeria. In anencephalic monsters in which the med- 
ullary groove remains open and the brain remains in a rudimentary state, 
aplasia of the adrenals is a fairly regular accompaniment. This was ob- 
served also in a recent case in which, although the skull was well formed, it 900 
TEXT-BOOK OF PATHOLOGY 
contained a large quantity of fluid with only a small mass of nervous tissue 
to represent the brain. 
Addison's Disease.-Addison described in 1855 a symptom complex 
which is now known by his name, and found to depend upon chronic 
destructive disease of the adrenals. The patients become gradually weak 
and easily fatigued, the circulation is enfeebled and the blood-pressure 
low, the heart beats rapidly, irregularly, and feebly, there are vomiting 
and anorexia, and the skin becomes pigmented at first only about the usual 
areas of greatest pigmentation; later the whole skin may become brownish 
or deep bronze in color. In a state of the most extreme weakness and 
prostration the patient dies. The autopsy reveals most commonly a 
Fig. 439.-Tumor of adrenal cortex from a female child who showed masculine characters. 
tuberculous infection which has attacked especially the adrenals and con- 
verted them into necrotic caseous masses, but there are other cases in which 
some other destructive process has so injured the adrenals as to leave 
only scars or calcified nodules in their places. In a few cases the adrenals 
appear normal, while there are others more numerous in which they are DISTURBANCES IN FUNCTIONS OF THE ADRENAL GLANDS 
901 
apparently entirely destroyed or converted into caseous material, although 
there have been no signs or symptoms of Addison's disease. To explain 
these things is not easy, and the attempt leaves us with the conviction that 
we are still ignorant of the exact relation of the adrenals to the disease. 
Wiesel, who sees in the chromaffine tissue the first part affected, although by 
no means denying the important role that the cortex may play, recalls the 
fact that outside the adrenal there is much chromaffine tissue in the 
paraganglionic nodules, so that the destruction of the adrenals does not 
mean the destruction of all the chromaffine tissue. In several fatal cases of 
outspoken Addison's disease he found that these paraganglionic masses 
had disappeared. If the symptoms were really due to the loss of the 
chromaffine tissue alone, might not Addison's disease exist with only very 
inconspicuous changes in the adrenals themselves, and, on the contrary, 
might not that portion of the total chromaffine tissue which is in the ad- 
renals be destroyed without symptoms? 
Others have found lesions in the sympathetic ganglia and in the splanch- 
nic nerve supply, and suggest that these may occasion a cessation of the 
activity of the gland, just as the destruction of a motor nerve does that of 
its muscle. Still others (Scott, Karakascheff) have found the destructive 
change chiefly in the cortex of the adrenal. Discussion of all these argu- 
ments will be found in the works of Biedl, Neusser, Wiesel, Bittorf, and 
Bayer. 
With regard to the pigmentation of the skin, the ideas are vague. Furth 
has found that the ferment, tyrosinase, will produce a black pigment from 
adrenaline, but it is difficult to understand how, in the absence of the 
adrenal, such a reaction could aid in the enormous production of pigment 
seen in Addison's disease. Bauer thinks it a derivative of uric acid. 
Two other questions may be briefly discussed in this place: first, the idea of Schur 
and Wiesel that the high blood-pressure and cardiac hypertrophy which are so common in 
cases of chronic nephritis are due to a coincident hypertrophy of the adrenal and espe- 
cially of the chromaffine tissue. This has been supported by many who think they have 
been able to observe such hypertrophy and hyperadrenalinaemia, but contradicted by 
many others who find no evidence in favor of it, and who point out that Schur and Wiesel 
themselves fail to find the hypertrophy in many forms of nephritis in which the blood- 
pressure is high and the heart enlarged. It must await further investigation, although 
at present the weight of evidence is rather against this explanation. 
The second question is that of the production of arteriosclerosis in the aorta of rabbits 
by the repeated injection of adrenaline. The lesions can apparently be produced only 
in rabbits, in which spontaneous lesions of the same kind are not infrequent. At any 
rate, dogs and other carnivorous experimental animals seem quite unsuited to this ex- 
periment, possibly just as they are for the production of arteriosclerosis by the feeding 
of cholesterine. The aorta in the rabbit becomes greatly deformed by the dilatations 
and areas of calcification. The lesion appears with necrosis and calcification in the 
media, and later extends to involve the intima, although some writers state that they 
have found primary accumulations of fat in the intima. At first it was thought that this 
might be due to the mechanical effect of the high blood-pressure, but the same effect is 
produced if another drug is given to counteract the high pressure, and thereupon the 
idea was adopted that a toxic action of the adrenaline was responsible for the injury. TEXT-BOOK OF PATHOLOGY 
902 
The application of these findings to the explanation of human arteriosclerosis has not 
yet been successfully carried out. 
At the same time destructive lesions of the walls of the heart, with necrosis of the 
muscle and later extensive scarring and compensatory hypertrophy, are produced 
(Stewart). 
Neusser and Wiesel: Erkrank. d. Nebennieren, Wien, 1910. 
Bittorf: Pathologic der Nebennieren, Jena, 1908. 
Elliott: Quarterly Journal of Medicine, 1914-15, viii, 47-89. 
Biedl: Innere Secretion, Berlin, 1913. 
Bayer: Ergeb. d. allg. Path., 1911, xiv, 1. 
Stewart; Journal of Pathology and Bacteriology, 1912, xvii, 64. 
Landau: Verh. Dtsch. Path. Gesell., 1914, xvii, 573; Die Nebennierenrinde, Jena, 1915. 
Stewart and Rogoff: Jour. Pharm. and Exp. Therap., 1916, viii, 205, 479. Jour. Exp. 
Med., 1916, xxiv, 709; 1917, x, 1, 49; 1917, xxvi, 613, 637. Amer. Jour. Physiol., 
1917, xliv, 149, 543; 1918, xlvi, 90. 
Bauer: Virch. Arch., 1918, ccxxv, 2. 
LITERATURE CHAPTER XLV 
DISEASES DUE TO INJURY TO THE ORGANS OF INTERNAL 
SECRETION (Continued) 
Hypophysis. Structure. Properties of extracts of different lobes. Experimental extirpa- 
tion. Effects of hyperactivity and hypoactivity at different periods of life. Gigantism. 
Acromegaly. Frohlich's syndrome. Adiposity. Relation of genital function. Diabetes 
insipidus. Histological changes in hypophysis in pregnancy, acromegaly, etc. Hyper- 
trophic pulmonary osteoarthropathy. 
THE EFFECTS OF INJURY TO THE HYPOPHYSIS 
Structure.-The hypophysis is a complex organ, formed, in part, of an up- 
growth of the epithelium of the pharyngeal vault, in part of a downward 
prolongation of the floor of the third ventricle of the brain. The epithelial 
part becomes constricted off (although remnants are often found along the 
tract of a perforation in the sphenoid bone, the so-called canalis cranio- 
pharyngeus), and constitutes eventually the anterior lobe of the gland. 
It retains a cleft or cavity at its juncture with the posterior lobe, which is 
lined by epithelium and is the pars intermedia. This anterior portion is 
composed of strands and networks of cells which are often so loosely 
arranged that they seem to be in masses. But they are held in a reticulum 
which bears adequate blood-vessels. Many of the cells are relatively 
small and show no especial granulation or staining affinity (chromophobe 
cells), while others are granular and reveal either eosinophile or basophile 
granulations (chromophile cells). The cells of the pars intermedia are more 
apt to form alveolar cavities which often contain a colloid material. They 
also produce hyaline droplets, which are seen to spread into the posterior 
lobe. The posterior or infundibular portion, also sometimes called pars 
nervosa, has, in lower animals, a wide-open cavity, but in man there is 
none, or only a scarcely perceptible canal which extends along the stalk to 
the third ventricle. The structure of this lobe seems not thoroughly well 
known. It is said to be composed mostly of neuroglia. No distinct nerve 
elements are described, but there are a few cells scattered here and there. 
As mentioned, the hyaline soluble droplets from the pars intermedia pass 
readily into its meshes, and indeed Herring, whom Cushing warmly sup- 
ports, declares that he can trace the passage of these hyaline droplets to 
their escape into the cerebrospinal fluid in the third ventricle, and thinks 
that this is the mode of delivery of the secretion of the gland. Cushing has 
demonstrated, by means to be discussed, the existence of the specific 
secretion of the hypophysis in the cerebral fluid. 
Properties of Extracts of Different Lobes.-Extracts from the anterior 
lobe seem quite inactive when injected into animals. On the contrary, 
903 904 
TEXT-BOOK OF PATHOLOGY 
extracts of the posterior lobe have striking effects (Schafer, Howell). 
They depress and then raise the blood-pressure, constrict the coronaries, 
and dilate the renal vessels, thus causing diuresis. They cause contractions 
of smooth muscle, as in the uterus, and give rise to a temporary increase 
in the production of milk. They also cause glycosuria by lowering the 
glucose tolerance. Dr. Abel has recently purified and concentrated such 
extracts, showing that their activity in infinitesimal doses is almost incred- 
ible. Such is the astonishing series of properties of extracts of the inert- 
looking neuroglial mass, while the extracts of the active-looking epithelial 
part of the gland do none of these things and seem to be perfectly without 
effect. 
Experimental Extirpation.-Extirpation of the whole gland causes death 
in a few days with symptoms of collapse, extreme lowering of the temper- 
ature, apathy, etc. These symptoms appear to depend upon the loss of 
the anterior lobe. Perfectly clear experiments with the extirpation of each 
lobe alone seem not to have been accomplished, and one cannot give a clear- 
cut idea of their separate functions. Removal of the posterior lobe alone 
seems to give rise to no recognizable symptoms although, as was said, its 
extract is the only one with obviously active properties. Most of the 
experiments in which animals have remained alive were those in which the 
posterior lobe and a large part of the anterior lobe were removed. Such 
animals grow fat, become stupid, retrogress sexually, or, if very young at the 
time of the operation, never develop sexually beyond the infantile stage. 
They fail to grow like the controls, their temperature is low, they often 
have a transient polyuria, secreting five times as much as normal, and they 
develop an extraordinary sugar tolerance, so that it is practically impos- 
sible to produce alimentary glycosuria. 
Apparently, then, most of the serious symptoms following destruction 
of the gland are due to the loss of the anterior lobe, although the posterior 
lobe seems responsible for the disturbances of carbohydrate metabolism 
and the consequent adiposity or obesity. Unsatisfactory as the experi- 
mental work is in sharply separating the functions of the parts of the gland, 
it will be seen that the effects of disease in human beings, which on account 
of the wealth of rather contradictory details we must present rather 
dogmatically, throw a good deal of light upon it. 
Disease of the gland may be produced by primary changes in its own 
tissue, or through its compression or destruction by a tumor or gumma or 
other pathological process, or by its compression through the presence 
within the rigid cranial cavity of a distant lesion which heightens the 
pressure. In the contracted limits of the sella turcica even the growth 
of the anterior lobe, which might cause its hyperactivity, can in time, by 
compressing the posterior lobe and the outlet of the secretion, cause an 
insufficiency. 
It is thought that the anterior lobe has an important influence upon the 
growth of the skeleton and upon other organs of internal secretion, but THE EFFECTS OF INJURY TO THE HYPOPHYSIS 
905 
especially upon the genital organs. If it is deficient in its activity, growth 
is stunted and sexual development is stopped. If its activity is excessive, 
growth passes all normal bounds and precocious sexual development 
occurs. Most of the actual observations fit with this hypothesis and sup- 
port it, but it must nevertheless be regarded as a mere hypothesis, since 
prolonged administration of extracts of the anterior lobe have not been 
found capable of producing any such striking effect on growth nor on sex 
manifestations. Possibly, therefore, it is a qualitative change in the func- 
tion of the gland which is responsible for the remarkable growth phenom- 
ena, etc., rather than a mere quantitative one. The hypothesis goes on to 
state that if the gland is excessively active it is not constantly so, but with 
irregular remissions, perhaps only for one short period. If this occurs 
before the ossification at the epiphysis is complete, the individual grows 
to giant proportions; if it takes place after ossification is complete and the 
epiphyseal line of ossification has disappeared, then the bones enlarge and 
become curiously deformed in the fingers and toes and in the face, but the 
height is not necessarily increased. Hence the conditions gigantism and 
acromegaly (enlargement of the tips of the extremities). Further, the 
idea is of importance that while this hyperactivity leads to such astonishing 
results which remain as permanent changes, it may pass into a state in 
which the gland is inactive and supplies too little secretion for the body. 
Then development stops and retrogression begins. 
Hyperactivity and Hypoactivity.-The following paragraphs are meant 
to recount in more detail the conditions illustrative of the effects of hyper- 
activity or insufficiency of each part of the gland. It must be remembered, 
however, that hyperactivity may give place to inactivity, and that signs of 
both may remain. 
1. Hyperactivity of the anterior lobe before epiphyseal ossification 
is complete. 
2. Hyperactivity of anterior lobe beginning after epiphyseal ossifica- 
tion is complete. 
3. Inactivity of anterior lobe beginning before puberty. 
4. Inactivity of anterior lobe beginning late in life. 
1. When the gland is excessively active or enlarged and still active 
in the period of epiphyseal growth, its effect is to exaggerate the growth 
of the skeleton and of the other tissues at the same time. As a result the 
individual becomes a giant. An illustration taken from Cushing's work 
will convey more than any description (Fig. 440). This one, aged thirty- 
six, was rather weak, had a high sugar tolerance, was sexually impotent, 
and showed at autopsy a much reduced hypophysis converted into a cyst. 
Evidently the activity of growth under the influence of the hypophysis, 
which began to increase at the age of fifteen, gave place, after the ossifica- 
tion was complete, to glandular insufficiency. Such gigantism (Figs. 441, 
442, 443) is not entirely limited to those in whom the activity of growth 
stops with the completion of ossification, but may be combined with the 906 
TEXT-BOOK OF PATHOLOGY 
effects of overgrowth which occurs after the epiphyseal lines are ossified, 
and thus may play a part in the changes in cases of group 2. 
2. When the anterior lobe, through hyperplasia or increased activity, 
causes excessive growth in adult life, the result is acromegaly (Marie, 1886). 
Again an illustration of a typical case will convey more than a description 
(Fig. 444). The bones of the face and those of the hands and feet become 
Fig. 440.-Note the narrow chest; large joints; hypotrichosis. Also the large size 
of the hands compared with those of Dr. Crowe, whose height is 5 feet 8 inches (Harvey 
Cushing). 
enlarged, the jaw projects, and the soft parts of the face, hands, and feet 
become greatly thickened (Fig. 445). For a time there may be glycosuria, 
or at least a lowered sugar tolerance. The sexual function is not impaired 
in this stage. Some acromegalics are also giants, evidently because the 
stimulus to growth existed before ossification was complete, although there 
may have been a long interval after the increase in stature before the dis- 
torting growth of the facial bones and extremities took place. Such THE EFFECTS OF INJURY TO THE HYPOPHYSIS 
907 
remissions in the activity of the gland are recognized. The condition, 
acromegaly, is permanent, but in most cases, owing to subsequent impair- 
ment of the hypophysis, symptoms of insufficiency (obesity, impotence, 
high sugar tolerance, etc.) appear. 
Fig. 441.-Gigantism. Man with evidences of hypophyseal disturbance, shown in 
contrast with a normal negro man, 5 feet 8 inches tall. Hands and feet are shown for 
comparison (Figs. 442 and 443). 
3. Inactivity of the hypophysis beginning before puberty causes the 
changes observed in puppies after hypophysectomy, namely, stunting 
of growth, great obesity, high sugar tolerance, and failure in the develop- 
ment of the sexual glands and in the appearance of secondary sexual 
characters. Mental dullness is a frequent accompaniment. 908 
TEXT-BOOK OF PATHOLOGY 
Fig. 442.-Hand of patient in Fig. 441 compared with that of a normal negro. 
Fig. 443. Foot of the patient in Fig. 441 compared with that of a normal negro. 909 
THE EFFECTS OF INJURY TO THE HYPOPHYSIS 
Fig. 444.-Acromegaly. Great enlargement of face, with heavy features. Great increase 
in size of hands, with thickening of the fingers. 
Fig. 445.-Acromegaly. This man was an acromegalic giant aged thirty-five, with 
blindness and large tumor of the hypophysis (Cushing). 910 
TEXT-BOOK OF PATHOLOGY 
Frohlich's Syndrome.-These are the fat boys that one sees so fre- 
quently, fairly bursting from their clothes. They have a peculiar feminine 
habitus (Fig. 446), with wide hips, knockknees, and especial collections or 
pads of fat in the pectoral regions and on the hips (Fig. 447). Even in 
adult life there is no beard, and hair is scanty over the body. If there is 
any pubic hair, it has the feminine distribution (Fig. 449).* 
4. If the deficiency of the hypophysis begins late in life, there is an 
approach to this condition. Naturally 
there is no retrogression of anatomical 
features of the skeleton already estab- 
lished, nor even of the distribution of the 
hair and development of the genitalia, but 
obesity comes on with the great heighten- 
Fig. 446.-Frohlich's syndrome. Preadolescent 
pituitary insufficiency in a male (Cushing). 
Fig. 447.-Preadolescent hy- 
pophyseal insufficiency in a male 
(Cushing, after Neurath). 
ing of the sugar tolerance, and there is gradual or rapid loss of sexual 
functions. It is apparently among these cases that we should class those 
extraordinary instances of adiposis dolorosa, or Dercum's disease, multiple 
lipomatosis, etc., although the relation is not clearly established (c/. Lyon). 
These are people in whom there are huge irregular accumulations of adipose 
* I am indebted to Dr. Harvey Cushing for allowing me to use the photographs of 
his cases. THE EFFECTS OF INJURY TO THE HYPOPHYSIS 
911 
tissue, or in whom with neuralgic and joint pains the whole adipose tissue 
is greatly increased (Figs. 450, 451). 
The peculiar anatomical conditions which surround the hypophysis 
are responsible for much of the confusion which still prevails as to the part 
played by each division of the gland in these lesions. If the hypophysis 
were an organ like the thyroid, situated in loose tissue, and able to grow 
without compressing itself, or so placed that one part might grow without 
Fig. 448.-Preadolescent pituitary in- 
sufficiency in a female aged sixteen. 
Skeletal and sexual infantilism. Con- 
genital pituitary tumor. The child was 
formerly extremely fat (Cushing). 
Fig. 449.-Adult pituitary insuffi- 
ciency with hypophyseal tumor. Femi- 
nine habitus (Cushing). 
destroying the other, it might be easier to recognize the role of each lobe. 
Furthermore, the fact that the functions of all the organs of internal secre- 
tion seem so closely interrelated makes it difficult to outline the part of 
each. The hypophysis seems especially closely related to the genital 
glands, and its destruction brings with it the loss of function of those 
glands, amenorrhcea, and cessation of spermatogenesis. The thyroid and 
adrenals are vaguely associated also, and changes are likely to be found in 
their structure and function when there are hypophyseal disturbances. 912 
TEXT-BOOK OF PATHOLOGY 
In these diseases of the hypophysis, except when atrophy leads to its 
diminution in size, there are mechanical effects produced by the enlarge- 
ment of the gland itself or by the tumor which causes its destruction. 
These are found to be associated with either the signs of hyperactivity or 
those of insufficiency, but since hy- 
peractivity is a relatively transient 
phenomenon and usually passes 
over into insufficiency, even through 
the very agency of the tumor for- 
mation, the mechanical effects are 
most commonly found in the stage 
of insufficiency. They are, as a con- 
Fig. 450.-General extreme adiposity prob- 
ably due to late hypophyseal disease. 
Fig. 451. - Multiple lipomatosis. 
There are symmetrical fatty tumors 
about the neck, arms, hips, and femoral 
regions. 
sideration of the anatomical relations of the hypophysis would show, usually 
caused by pressure upon the optic tracts or upon the brain as a whole as it 
lies within the rigid cranium, or upon the hypophysis itself. There is pro- 
gressive narrowing of the field of vision, hemianopsia passing on to com- THE EFFECTS OF INJURY TO THE HYPOPHYSIS 
913 
plete blindness, choked disc and retinal changes, violent headache, etc. 
Hydrocephalus may be the cause of hypophyseal insufficiency, just as any 
distant intracranial tumor may, in the limited space, give rise to slight 
evidences of hypophyseal impairment. 
Diabetes insipidus, which is a name given to a symptom complex in which 
extreme thirst and polyuria form the most striking features, is probably in 
most instances due to an injury of some sort to the hypophysis, causing its 
insufficiency, although it is difficult to explain why the insufficiency of the 
posterior lobe should cause such diuresis when the injection of its extract 
has exactly that effect (Berblinger). 
As to the nature of the changes in the hypophysis itself, much more study 
is required. It has been stated that in the anterior lobe there are neutro- 
phile or chromophobe cells which form a great proportion of the tissue, 
but that there are also many eosinophile and basophile cells. Erdheim and 
Stumme have shown that there are remarkable changes in the gland during 
pregnancy. It becomes much enlarged, and the chromophobe cells, which 
they call chief cells, are greatly enlarged and increased in importance, push- 
ing aside the eosinophiles, which shrink, and the basophiles, which become 
very pale. Indeed, as the great mass of 11 pregnancy cells" these altered 
chief cells occupy practically the whole field. With the end of pregnancy 
and during lactation the gland undergoes gradual involution to the normal 
condition. 
In the various phases of the hypophyseal hyperactivity or insufficiency 
mentioned above, it is evident that the destructive effects of tumors, cyst 
formation, haemorrhages, tuberculosis, gumma formation, anaemic infarcts 
have nothing especially peculiar about them. They cause insufficiency by 
destruction of the tissue or by pressure. The cause of hyperactivity is 
more interesting and not yet clearly determined. Usually there is an exces- 
sive growth of the tissue of the anterior lobe in the form of a sort of tumor 
or glandular hyperplasia often spoken of as an adenomatous growth. Great 
variety exists among these. Erdheim has described eosinophile adeno- 
mata and Nothdurft a basophile one. Benda pointed out that in the cases 
of acromegaly the new growth found in the anterior lobe is rich in eosino- 
phile cells, and others have agreed with him, while Cushing, in the strumas 
or adenomata found in cases of hypophyseal insufficiency, has found only 
the chief or chromophobe cells. Nevertheless it would be hazardous to 
state definitely that the acromegalic changes depend upon the eosinophile 
cells. 
A sharp distinction must be drawn between acromegaly and the other 
condition described by Marie as hypertrophic secondary pulmonary osteoar- 
thropathy, which also results in elongation of the bones of the extremities 
and in the formation of a rather thick periosteal new bone formation. In 
this the hands and feet may be greatly enlarged, but they are quite different 
in form from the short thick extremities of acromegaly. It is supposed to 
be due to the absorption of some toxic substance, since it accompanies 914 
TEXT-BOOK OF PATHOLOGY 
chronic bronchiectasis, tumors of the lung and thorax, and other analogous 
affections. 
LITERATURE 
Benda: Dtsch. med. Woch., 1901, xxvii, 513, 536, 564. 
Cushing: The Pituitary Body and its Disorders, Phila., 1912. Also Jour. Amer. Med. 
Assoc., 1909, liii, 249. With Crowe, Quart. J. Exp. Physiol., 1909, ii, 389. With 
Goetsch, Amer. Jour, of Physiol., 1910, xxvii, 60. 
Pick: Dtsch. med. Woch., 1911, xxxvii, 1930, etc. 
Erdheim: Frankf. Ztschr. f. Path., 1910, iv, 70. 
Kraus: Ziegler's Beitr., 1914, Iviii, 159. 
Lyon: Archives of Int. Med., 1910, vi, 28. 
Erdheim and Stumme: Ziegler's Beitr., 1909, xlvi, 1. 
Wurmbrand: Ibid., 1910, xlvii, 187. 
Berblinger and Goldzieher: "Diabetes Insipidus," Verh. Dtsch. Path. Gesellsch., 
1913, xvi, 272. 
Simmonds and others: Verh. Dtsch. Path. Gesellsch., 1914, xvii, 184-231. 
Swale Vincent: Practitioner, 1915, xciv, 147. 
Marie: Rev. de Med., 1886, vi, 297; 1890, x, 1. 
Thayer: New York Med. Jour., 1896, Ixiii, 33. CHAPTER XLVI 
INJURIES WHICH CAUSE METABOLIC DISTURBANCES AND 
CONSEQUENT DISEASE OF THE BONES 
Chemical interchanges in growth of bone. Importance of calcium. Relation of internal 
secretions to bone formation. Normal ossification. Rickets. Osteomalacia, chondro- 
dystrophia foetalis. Scurvy and Moller-Barlow's disease; osteogenesis imperfecta; osteo- 
psathyrosis; Paget's disease. 
The structure of the bones is so complicated, and their mode of growth 
involves so many chemical interchanges, that it is not surprising to find 
them extremely sensitive to disturbances of metabolism. In most cases we 
are ignorant of the ultimate causes of those disorders of the chemical inter- 
changes of the body which bring with them visible alterations in the bones, 
but in some we understand at least the principles which are immediately 
concerned. Since mineral substances make up so great a part of the weight 
of the bones, we naturally turn at once to them. It is well enough known 
that attention to the food of horses and other domestic animals, and care 
that they receive enough lime and phosphorus, is necessary that their grow- 
ing bones be well formed and strong. If we deprive an animal of the lime 
which should be in its food, its bones become porous and weak, or even quite 
soft, and it may be rendered helpless by the giving way and bending which 
can occur (Pexa, Dibbelt). 
Dibbelt found that for a growth of 100 grams, a dog uses 2.2 grams of CaO. In his 
experiments with calcium-poor food, the deposit of lime was | to of the normal, 
and the bones became extremely light and porous. The epiphyseal cartilages grew 
large and broad, and the cortex everywhere became rarefied by the enlargement of the 
Haversian canals into considerable cavities. The broadening of the epiphyseal line is 
due to the lack of provisional calcification of the cartilage and the consequent inability 
of the marrow capillaries to convert it into bone. In spite of the lack of calcium, how- 
ever, there was abundant formation of a tissue morphologically like bone, but devoid of 
lime salts (osteoid tissue). Stoeltzner thinks that the formation of this osteoid tissue is 
dependent upon a stimulus furnished by calcium, and that osteoid tissue remains so 
only because it is unable to take up the calcium. He is supported by Lehnerdt, who 
substituted the closely allied strontium for calcium, in the food, and found, just as did 
Dibbelt in the extreme lack of calcium, that the cartilage cells being unchanged, were not 
normally invaded by marrow capillaries, and that the underlying spongy bone was re- 
placed by a thick zone of osteoid tissue. This latter formation he states is due to a 
power of stimulation possessed by strontium equally with calcium, but that since stron- 
tium cannot replace calcium as a hard deposit in the new-formed tissue, it remains 
osteoid tissue and not bone. Dibbelt's observation seems to disprove the idea that the 
stimulus of calcium or strontium is necessary for the growth of the osteoid tissue. 
Phosphorus, which, with carbonic acid, is found in the normal lime and magnesia com- 
binations which make up the hard part of bone, is naturally of great importance for 
proper bone formation. Some authors have looked upon it as a special stimulus to bone 
formation too, but whether it is in that role, or merely in its obvious part in furnishing 
material for the ultimate phosphates, remains to be determined. Magnesium salts are 
915 916 
TEXT-BOOK OF PATHOLOGY 
present in a much smaller proportion than those of calcium, but nevertheless play a part 
to which it seems not enough attention has yet been paid. 
Importance of Calcium.-Direct abstraction of lime from the food does 
not ordinarily occur, and one must, if a disease appears which points 
toward an insufficiency of calcium, determine whether the failure is not 
Fig. 452.-Senile osteoporosis. Section of rib showing great thinning of the cortex 
and atrophy of the lamellae. With the disappearance of calcium, the lattice figures 
become evident in the Haversian systems. 
rather in the ability of the body to absorb, retain, and deposit the calcium. 
It is known, of course, that, in the period of growth, and especially in child- 
hood, the deposition of lime salts is abundant, and that the bones become 
progressively firmer, while in old age the reverse is true-more lime salts are 
absorbed from the bone than are deposited there afresh, so that the lamellae 
become thinner and disappear, and in the Haversian systems of the cortex 
so much of the solid material is lost that the laminae of bone assume a 
reticulated appearance and become relatively weak (Fig. 452). This is the 
senile osteoporosis which is to be regarded as a more or less normal process, 
but which leads to obvious atrophic changes in some bones, such as the 
skull and jaw bones, and to such rarefaction of the others that fractures RELATION OF INTERNAL SECRETIONS TO BONE FORMATION 
917 
occur with comparatively slight occasion. This is an expression of the 
preponderance in old age of the process of absorption of the bone over that 
of apposition, two processes which go on side by side through life, even 
during the period of most rapid growth. 
Relation of Internal Secretions to Bone Formation.-We have a certain 
amount of vague information regarding the influence which the organs of 
internal secretion exert over the interchange of calcium and the other con- 
stituents of bone, and over the growth of bone itself, and much of this has 
already been detailed. Its vagueness consists largely in the fact that while 
metabolism and growth in general are largely influenced by these glands, 
it is more difficult to ascribe specific changes in the bones to their activity or 
lack of activity. Acromegaly and gigantism, in which there is such an 
excessive growth of bone (together with that of the soft parts), is fairly 
clearly associated with excessive activity of the anterior lobe of the hypo- 
physis. Klose and Matti find that the destruction of the thymus causes 
great defects in bony growth, but Pappenheimer and many others dispute 
this. Defective metabolism and stunted growth follow destruction of the 
thyroid, but there is no specific or especially pronounced change in the bones 
except general retardation of their development. Loss of the parathyroid 
is thought to disturb the calcium metabolism and to allow the tissues to 
become impoverished. The dentine of the teeth fails to become calcified, 
and the callus formed in the healing of fractures remains soft, but it has not 
yet been made clear that the processes of bone formation in general are 
characteristically affected. Still less definite statements are made about the 
part played by the chromaffine system and by the ovaries and testes on the 
course of ossification. This is one of the most obscure but also one of the 
most interesting chapters of human pathology, and as yet we possess only 
the beginnings of information on the subject. We may examine the facts, 
however, which are afforded by study of the several diseases in which the 
growth and structure of the bones are peculiarly affected (together with 
many changes in other organs), and attempt to realize at least where the 
problems lie. 
Normal Ossification.-A few words as to the tissues concerned may recall what is 
necessary to the understanding of the pathological changes. Bones are formed either 
by ossification of connective-tissue membranes or by the replacement of cartilage 
by bone tissue. Membranous bones seem to be produced by a change in the func- 
tion of certain cells which acquire the power of laying down an intercellular matrix 
in which they bury themselves, and which in time becomes calcified. In the car- 
tilages of the foetus which are covered with a layer of such altered or osteoblastic 
connective-tissue cells there comes a time when blood-vessels (later the nutrient 
vessels) push into the substance of the cartilage, carrying the perichondrial osteoblasts 
before them. They hollow out the cartilage, and the osteoblasts, after destroying the 
cartilage cells, deposit further formless material upon the remains of the matrix, bury 
themselves in it, and promote its calcification. Thus bone is formed. It can be most 
clearly studied along the line of demarcation between the epiphyseal cartilage and the 
advancing marrow cavity, because there the process persists for a long time, with the 
formation and ossification of ever new cartilage, as is necessary for the growth of the 918 
TEXT-BOOK OF PATHOLOGY 
bone in length. Growth in thickness is by this time carried out by the persistent per- 
iosteal and endosteal cells in the diaphysis, which add to the mass of the cortical bone 
and to the lamellae of the cancellous bone. In the epiphyseal ossification zone the process 
is clearly seen as follows. The most distal of the cartilage cells near the joint surface 
are flattened; next is a great quiescent mass of small elongated cells lying in every 
direction; toward the marrow cavity there is a broad belt in which they begin to be 
more deeply stained and to be arranged with their long axes more transversely to the 
long axis of the bone. Still nearer to the border zone they form straight, closely arranged 
columns, like grains of corn on a cob, separated by the alternating and more irregular 
columns of the blue-staining matrix. Quite at the line of ossification these cells swell 
and become large, rounded, or irregular structures (c/. Fig. 44). A whole phalanx of cap- 
illary loops from the bone-marrow presents itself along this row of cartilage cell columns, 
and each capillary, covered loosely with a mantle of osteoblasts, tends to push itself into 
or alongside of a column of cartilage cells. Here, in the matrix of the border zone of 
cartilage cell columns, there is a provisional or preliminary deposit of calcium salts in 
very fine granules. This calcification seems to offer some obstacle to the invasion of the 
vessels since in its absence blood-vessels penetrate far into the cartilage and branch there 
in a way which we shall discuss presently in connection with rickets. 
When the conditions are all favorable, the cartilage cells themselves are broken in 
upon and set free from their nests in the matrix (c/. Fig. 44). They may be destroyed 
or they fall into the marrow cavity and are thought to take no further part in actual 
bone formation. The invading osteoblasts range themselves along the jagged remnant 
of matrix and once more begin their process of burying themselves in a hyaline substance 
which forms around and beneath them. After a time they show clearly, as they lie in 
the little cavity which they form for themselves, their numerous long thin processes 
which extend out in all directions in minute canaliculi in the homogeneous matrix. 
The tissue at this stage is osteoid tissue. Quickly, however, there occurs a deposit of 
calcium throughout and it becomes hard bone. Ordinarily there is no considerable 
amount of osteoid tissue at any time, but, as we shall see, there are diseases in which it 
persists as such. Thus finished, this cancellous bone is left behind and the capillaries 
with more osteoblasts advance to meet new cartilage cells. The epiphyseal bony centre 
is formed later in exactly the same way by the invasion of another vessel into the epi- 
physeal cartilage, and bone formation spreads from this centre through the cartilage in 
all directions. Perichondral blood-vessels invade the cartilage only rarely, except in 
the direct process of entering to form the epiphyseal ossification centre (and to some ex- 
tent along the plane between resting and actively growing cartilage), but that too is 
much modified by disease. Along the epiphyseal line the process is actually maintained 
for many years until the bone has reached its full length, when with a final replacement 
of the remnant of cartilage the line is merged into the cancellous bone. 
RICKETS OR RACHITIS 
The weakened condition of the bones probably gave rise to the old name, 
rickets, for this disease, and rachitis is only a high-sounding Latinization of 
the English word. It is an astonishing condition which is seen at its height 
in children, beginning usually at the sixth month and lasting sometimes for 
several years, with remissions and final healing. The disease may, never- 
theless, leave behind it very obvious traces of the deformities which are 
produced when the bones are soft and fragile. It is often remarkable to 
observe how completely the healing process, by the aid of the mechanical 
agencies which normally act on the skeleton, can restore to the normal form, 
bones which at one time were greatly deformed. The signs of rickets in 
adults are rarely very disfiguring, although in the case of the pelvis the 
deformity may have far reaching consequences in the obstruction of child- 
birth. RICKETS OR RACHITIS 
919 
The disease is commonly said to pass through three stages which can be 
distinguished as the beginning, the florid stage, and that of healing. Dif- 
ferent conditions with regard to the metabolism prevail in these stages. At 
the height of its development the following may be observed. The child is 
pale and sickly, the anaemia being sometimes quite profound. Such children 
show a lowered resistance and are prone to infections of all sorts. The 
lymph glands are usually enlarged, and tonsils and other adenoid tissues are 
everywhere swollen. The abdomen protrudes, and in many cases, if not in 
all, the spleen is enlarged and fairly firm. The distension of the abdomen 
may be in part due to atony of the intestinal walls. Flabbiness and softness 
of the skeletal muscles are most striking. The epiphyses, especially those 
of the wrists, ankles, and knees, are much enlarged. At each costochondral 
junction there is a hard swelling which can be felt through the skin, and the 
row of these nodules on each side of the sternum is often spoken of as a 
rickety rosary. The enlargement is especially prominent on the inside of 
the thorax and may be due in part to the angular inward dislocation of the 
bony end of the rib through respiratory efforts which are often made diffi- 
cult by adenoid growths in the upper air-passages, associated with the 
general lymphoid swelling. Skoliosis, or curvature of the spine, bending or 
fracture of the long bones, and a peculiar flattening or contraction of the 
pelvis are due to the general softening of the bones. The anterior bowing 
of the tibiae (sabre tibia), and the consequent flat foot, are particularly strik- 
ing features in those children who walk about. 
The skull is made square, and the forehead very prominent, by the growth 
of convex spongy thickenings over the frontal and parietal bosses. There 
is often an actual erosion deep into the bone of the skull over the back of 
the head as the child lies on the pillow, but Ziegler regards this "osteotabes" 
as a totally different affection, and he is probably right. 
Most cases, if the child survives, end with the gradual restoration of the 
normal consistency of the bones and afterward with the far more gradual 
rearrangement of the bony structure and readaptation to the mechanical 
needs and normal form of the bones. There are some, however, in which 
such extreme distortion of the whole skeleton takes place in the florid stage 
that the deformity is never really overcome, and the patients remain per- 
manently disabled. Such skeletons are seen in European museums showing 
extreme bending and twisting of the long bones, but the extremely severe 
cases seem at least very rare in this country. M. B. Schmidt thinks that 
different forms occur in different regions, those seen in Zurich having large 
epiphyses with straight hard diaphyses, while those seen in Strassburg have 
large epiphyses also, but show bent and deformed or fractured diaphyses 
with a thick covering of soft periosteal new bone. In this country we occa- 
sionally see the latter type, but the former is more common. 
At autopsy it is rather easy to cut with a knife down through the epi- 
physeal end of the bone deep into the shaft, and the cut surface presents an 
extraordinary contrast with the normal bone (Fig. 453). It is seen that in 920 
TEXT-BOOK OF PATHOLOGY 
the normal bone the line of ossification is perfectly sharp, even, and really 
a narrow line. In rickets it is replaced by a wide irregular band of rather 
Fig. 453.-Rickets, a, Normal bone with clear line of ossification, b and c show 
broad bands of osteoid tissue instead of this line; their diaphyses are firm, delicate, and 
straight, d, Form of rickets in which the diaphysis is weakened, covered with perios- 
teal new bone, and fractured. 
soft gray translucent tissue, in which white opacities and gritty particles 
represent the calcified lamellae, but throughout which islands of bluish 
cartilage can also be seen. The cortex of the shaft often shows soft, spongy 
growths both inside and outside. These changes are especially well seen in 
the lower end of the femur, the upper end of the tibia, etc., but to a slighter 
degree they are found in every bone and are very prominent in the costo- 
chondral junction of the ribs. A section through the epiphysis and shaft of 
such a bone shows (Fig. 454), on analysis of the confusing scene, that the 
border zone of the cartilage where it should abut on the advancing marrow 
vessels has failed to undergo the usual provisional calcification or is calcified 
in irregularly scattered places only. Where there is no calcification, the 
marrow vessels push far into the cartilage and branch here and there, leav- 
ing long tongues of the calcified cartilage projecting toward the marrow 
cavity. So sluggish is the process of invasion of the cartilage cells that 
much uncalcified cartilage is also left in these tongues or islands of tissue. RICKETS OR RACHITIS 
921 
Where the capillaries do lay open the cartilage cells and spread their osteo- 
blasts on the remaining cartilage matrix, the result is the formation of 
Fig. 454.-Rickets. Rib at site of line of ossification. The preparatory zone of 
cartilage is irregularly invaded by perichondral and marrow vessels. Calcification of 
cartilage lacking, except in two or three foci. Invading blood-vessels surrounded by 
osteoid tissue. Lamellae of bone remain partly covered with osteoid tissue. 
highly irregular, thick laminae, morphologically like bone (though much 
more bulky), but not calcified. This is the osteoid tissue described before, 
and this it is which makes up practically all of the thick grayish band which 922 
TEXT-BOOK OF PATHOLOGY 
lies where the line of ossification should be. Where the capillaries grow far 
into the cartilage, they may surround themselves with zones or mantles of 
osteoid tissue. So too the margins of the cartilage masses left behind in the 
Fig. 455.-Periosteal osteoid formation about a rib in rickets. 
advance of the growth become changed into osteoid tissue, and -when, in 
healing, this becomes bone, the rest remains as a cartilage island enclosed in 
bone. There is much of this osteoid tissue in the shaft of the bone also, 
making up the superficial layers of the laminae of the cancellous bone and of 
the periosteal exostoses (Fig. 455). Even in the denser bone of the cortex 
one finds osteoid tissue, especially about the vessels, which lie in the so- 
called perforating canals, but also at times occupying a quadrant or more of 
an otherwise well-calcified Haversian system. The point most disputed in 
the recent discussion of rickets and osteomalacia before the German Patho- 
logical Society was the question whether this calcium-free bone should be 
regarded as the result of the absorption of lime from old bone previously 
calcified (halisteresis), or new bone laid down calcium free. The strongest 
evidence seemed to be in favor of the wide-spread existence of halisteresis, 
although, of course, it is clear that much osteoid tissue is newly formed. 
Another process characteristic of rickets is the abundant ingrowth of 
blood-vessels into the epiphyseal cartilage from the perichondrium. These 
split up the resting cartilage in every direction, and end in a network of 
small vessels parallel with the transverse plane of ossification. Several 
such layers or "stages" of vessels may be formed, and may be visible at RICKETS OR RACHITIS 
923 
once, although as the irregular region of ossification advances they become 
in turn confluent with the vessels from the marrow cavity and lose their 
identity. As they lie in the cartilage ("cartilage marrow canals") the 
matrix round them loses its blue stain and assumes the power of staining 
with eosin. This collagenous material soon becomes converted by the 
accompanying osteoblasts into osteoid tissue, which finally adds itself to the 
mass of osteoid tissue formed by the marrow vessels. 
The marrow is in itself changed into a tissue much more fibrous than 
normal ("endostitis fibrosa"), and laminse of bone or osteoid tissue may be 
formed in this fibrous marrow. It is easy to see that an extremely compli- 
cated condition can be produced in this way, especially when it is remem- 
bered that similar processes in modified form occur in the shaft of the bone 
as well. It is remarkable that any adequate return to the normal architec- 
ture of the line of ossification is possible in the course of healing. The 
enlargement of the epiphyses is due, not so much to any excessive produc- 
tion of cartilage, as to the fact that ossification is extremely sluggish and the 
cartilage does not become converted into the calcified and less bulky bone. 
The exostoses on the skull are soft, spongy masses of lenticular form com- 
posed of porous osteoid tissue which becomes partly calcified and later may 
be absorbed in large part or completely converted into bone. 
The spleen is often enlarged, and shows an increase in the reticulum 
fibres without any parallel increase in connective tissue. Giant-cells occur, 
the Malpighian bodies are small, and the pulp hypersemic (Hayaski). In 
our cases the condition is variable, and in some there is a distinct induration 
from an excess of connective tissue. There is atony or hypotony of the skele- 
tal muscles, as well as of the smooth muscles of the intestines and arteries. 
Great advance in the understanding of rickets has been attained in the 
last years. The approach has been so complicated by the maintenance of 
fixed ideas, however, that the literature is very extensive. The student 
may find the details in the review of Park and should certainly read that 
of Howland. Briefly summarized, the course of the investigation has 
been as follows: It was found possible to produce rickets regularly in rats 
and other animals by certain diets in which there was a deficiency either 
in calcium or phosphates. The significant thing about such diets is, how- 
ever, the disproportion between these substances. Howland and Kramer 
show that rickets is invariably present when there is a reduction of the 
product of the concentration of calcium and inorganic phosphorus in the 
blood to a point below 30 to 40 mgm. per 100 c.c. Apparently two sorts 
of rickets may be thus produced-those with low phosphorus and those 
with low calcium, but the unbalanced state is especially important. If, 
however, cod-liver oil is given, or if the animals are exposed to sunlight 
or to ultraviolet rays of 300 wave length, no rickets ensues, or, if already 
advanced, it is cured, because these influence the economy of the use of 
calcium and phosphorus, or their absorption from the intestine in such a 
way that a proper balance is maintained or reestablished. For a time it 
was thought to be the fat-soluble vitamine A, which is abundantly present 924 
TEXT-BOOK OF PATHOLOGY 
in cod-liver oil, which is effective, but McCollum and his associates have 
destroyed that in cod-liver oil and found that something still remains which 
they call X, which is perfectly efficient. What there is in common between 
this substance X and the light of short wave lengths it is hard to imagine. 
(I have found that the vapor arising from cod-liver oil will produce a 
picture on a photographic plate exposed to it in the dark, if the plate is 
partly protected by some pattern, but this is definitely due to direct 
chemical contact with the vapor and not to radiations, because there is 
no effect if a quartz plate is interposed.) 
Even hunger alone will in some way restore the appropriate balance 
between calcium and phosphorus and allow ossification to take place 
normally again. It is thought that this may be due to the liberation of 
substances, perhaps like X, from the breaking down of tissues, and, since 
there is no unbalanced diet, equilibrium may be reestablished. 
Rickets, then, is apparently caused by deficiencies in diet both in the 
calcium and phosphorus content and in the peculiar substance or sub- 
stances which control their equilibrium, but also by the withholding of 
the child from the influence of sunlight which can replace in this regard 
the controlling substance in the food. Even in breast-fed infants the lack 
of some of these factors in the diet or secretions of the mother may be of 
great importance in bringing about the disease. 
Osteomalacia is a very similar disease which occurs in adults, especially 
in women, with exacerbations during pregnancy and lactation. It is 
thought by many to be practically identical with rickets, except in occurring 
in persons whose endochondral ossification is complete. Otherwise the 
histological modifications of the bones are nearly identical. Here the 
softening of bones which were quite calcified and hard a short time before 
must be due to halisteresis, and in section the bones show clearly the osteoid 
margin along each lamina of bone, covering in the still calcified central part. 
The most extraordinary deformities through bending of the soft bones are 
produced during the florid stages, when the decalcification is at its height, 
and this is accentuated by the greater weight of the adult body. The pres- 
sure of the heads of the femora flattens the pelvis laterally and forces the 
symphysis pubis forward into a sort of beak. With returning rigidity such 
a pelvis is, of course, incompatible with childbirth. The loss of calcium 
may be relatively high in each day's excreta (Holtz' case, 0.1809 gm. daily; 
Sauerbruch's, 0.07 to 0.17 gm. daily). 
Adrenal insufficiency and ovarian hyperactivity have been looked upon 
as the cause of the affection, and adrenaline treatment or castration carried 
out with alleged good effect. But the matter is still debated. Erdheim 
found lesions of various sorts in the parathyroid glands, and calls attention 
to the parallelism between this condition and the escape of calcium in 
parathyroid insufficiency. 
LITERATURE 
Rickets.-Schmidt, Stoeltzner, Dibbelt, Schmorl: Verh. Dtsch. Path. Gesellsch., 1909, 
xiii, 1-54. 
Ziegler: Ctbl. f. allg. Path., 1901, xii, 865. RICKETS OR RACHITIS 
925 
Rickets.-iSchmorl: Ergebn. d. inn. Med. u. Kinderh., 1909, iv, 403. 
See various papers of Mellanby, Telfer, Hess, and Unger, Pappenheimer and 
others, McCollum, Simmonds, Shipley and Park, all referred to by Park 
in his review. 
Park, E. A.: Physiological Review, 1923, iii, 106. 
Howland: Medicine, 1923, ii, 349. 
Osteomalacia.-Marinesco, Parhon, and Minea: Nouv. iconogr. de la Salpetriere 1911 
xxiv, 1. 
Erdheim: Sitz. d. k. Akad. d. Wiss., Wien, Math. Naturw. KI., 1907, 
cxvi, Ab th. iii, 311. 
Bauer: Frankf. Ztschr. f. Path., 1911, vii, 231. 
Chondrodystrophia foetalis is a disease of the cartilage occurring in foetal 
life, and leading to a partial or complete cessation of the endochondral ossifi- 
cation, while periosteal bone formation proceeds vigorously. The result of 
this is that the infant is brought into the world with extraordinarily short- 
ened arms and legs and with other deformities, among which are distortion 
of the pelvis, malformation of the vertebral column and thoracic skeleton, 
and great enlargement of the skull, with retraction of the nose. Every one 
is familiar with the peculiar short-limbed dwarfs, with their large heads and 
characteristic faces, in which the nostrils seem directed almost straight 
forward. They are intelligent, active, and strong, and make their way in 
life, often as clowns in circuses, where their strength and agility find them 
occupation. They may reach an advanced age and bear children, although 
on account of the deformity of the pelvis these must be removed by Caesa- 
rean section. That the disease is hereditary is seen from the fact that these 
are commonly also dwarfs, but cases of chondrodystrophia occur often 
enough in families in which no other instances are known. 
The cause of the disease is quite unknown. The organs, including all the 
glands of internal secretion, are found to be quite normal, and all the 
changes are explained on the basis of the disturbances in the cartilages. 
Kaufmann distinguishes chondromalacic, hyperplastic, and hypoplastic 
alterations of the cartilage, but, as Siegert points out, all these may occur 
together in the same case. The epiphyseal cartilages are found abundantly 
penetrated by blood-vessels from the perichondrium (Fig. 456). The carti- 
lage cells may be very small and widely separated by a rather soft fibrillar 
intercellular substance. Often they lie in great spaces which produce a 
spongy appearance. Along the line of ossification there is in patches a col- 
umnar arrangement of cells, while for the rest the cells are enlarged and to- 
tally irregular in their arrangement. In other instances the zone of columnar 
arrangement of cartilage cells is separated from the marrow cavity by other 
cartilage cells arranged in a network. Often, but not always, a lamella of 
periosteum with blood-vessels extends across the epiphyseal cartilage, just 
above the line of ossification, and causes a complete cessation of that process. 
Invasion of the cartilage by marrow capillaries is almost at a standstill, and 
usually the spaces are limited by a film of completed bone. Calcification of 
the cartilage is rather slight, but some remnants of blue-staining material 
are found in the centres of the terminal bone lamellae. In spite of these 
anatomical conditions, which express the result, it is hard to say exactly 926 
TEXT-BOOK OF PATHOLOGY 
why such slight obstacles are not overcome, so that growth of the cartilage 
into orderly columns and consequent ossification may proceed. Periosteal 
growth, building up and 
breaking down of the la- 
mellae of the diaphysis, and 
bone-marrow formation are 
normal. Premature synos- 
tosis of the portions of the 
sphenoid with one another 
and with the basilar por- 
tion of the occipital bone 
is common, and in sharp 
contrast with the condition 
in myxoedema or cretinism, 
in which this connection re- 
mains cartilaginous a very 
long time. It may be re- 
sponsible in part for the re- 
traction of the nose. Dandy 
has recently observed that 
there is a distinct hydro- 
cephalus in these cases. 
There is a lumbar lordosis, 
and the promontory of the 
sacrum projects into the up- 
per strait of the pelvis, so 
as to make it very narrow. 
In adults of this type, as in 
the case of a woman aged 
seventy-five seen at au- 
topsy recently, ossification 
is quite complete, and no 
trace of intermediary car- 
tilage remains. Endochon- 
dral ossification with some 
growth does, therefore, go 
on to completion, but with- 
out adding much to the 
length of the bones. This condition is not to be confused with cretinism, 
in which the whole process of ossification is retarded, nor with rickets, in 
which there is a period during which osteoid tissue, and not bone, is formed 
abundantly. 
Fig. 456.-Chondrodystrophy in an infant. Me- 
dian section of the femur, showing softening and 
displacement of the epiphyseal cartilage. 
LITERATURE 
Kirchberg, Marchand: Ziegler's Beitr., 1889, v, 183. 
Kaufmann: Die sog. foetale Rachitis, Berlin, 1892. 
Siegert: Ergeb. d. inn. Med. u. Kinderh., 1912, viii, 64. 
MacCallum: Johns Hopkins Hosp. Bull., 1915, xxvi, 182. SCURVY AND MOLLER-BARLOW's DISEASE 
927 
SCURVY AND MOLLER-BARLOW'S DISEASE 
Prolonged subsistence upon such food as salted meats, canned meat with 
biscuits or bread, and boiled or condensed milk, without fresh fruits, milk, 
vegetables, or fresh meat, is known to produce a complex disease charac- 
terized by anaemia, swelling and infection of the gums, painful haemorrhages 
in the joints and under the periosteum, and purpuric haemorrhages in the 
skin. This may lead to death, but can be cured by giving the so-called 
Fig. 457.-Infantile scurvy. Line of ossification of the lower end of the femur: (a) 
Calcified cartilage; (b) haemorrhage in the fibrous bone-marrow. The process of ossifi- 
cation in almost entirely interrupted. 
antiscorbutic substances which are contained in fresh fruits and vegetables 
and in fresh meat and milk. It is a disease which raged among sailors in 
times when it was difficult to carry these things, and voyages were of longer 
duration. In adults it is now rather rare, and occurs only among the very 
poor, or in conditions of isolation where fresh food is not obtainable. It is 
still observed in children, especially when they must be artificially fed. The 
scurvy or scorbutus of adults seems to be identical with the infantile scurvy 928 
TEXT-BOOK OF PATHOLOGY 
or Moller-Barlow s disease of children, except in some trifling details which 
depend upon anatomical differences. It may be experimentally produced 
in animals by intentional feeding with a ''scorbutic" 
diet, and prevented or cured by giving the antiscor- 
butic substances. The lesions in animals are iden- 
tical with those in man. 
Among antiscorbutic substances, lemon- and lime- 
juice are well known. They resist heating, are acid, 
and keep well. Extracts of vegetables, such as cab- 
bage and potatoes, or dandelions are effective, but 
deteriorate on standing, are alkaline, and are de- 
stroyed by heating. The beneficial properties of 
milk are destroyed by heat. Attempts to isolate 
the active substance have as yet led to no clear re- 
sult. 
The lesions, which develop in the course of a few 
weeks or months of the unfavorable diet, affect chiefly 
the bones. The bone-marrow loses its blood-forming 
elements and becomes converted into an oedematous 
fibrous tissue in which the blood-vessels and osteo- 
blastic cells seem relatively few. As a result, bone 
formation becomes almost stagnant everywhere, and 
since the resorption of bone goes on normally, the 
whole structure shortly becomes rarefied. At the 
epiphyseal line the lack of proper and orderly inva- 
sion of the cartilage columns is very marked (Fig. 
457). Sometimes there is irregular or oblique inva- 
sion, and the zone of osteogenesis becomes broad- 
ened where there is a network of capillaries, but this 
is also an ineffectual method of bone formation. 
Usually only scattered laminae are produced, and in 
some cases a sort of bony wall is formed transversely 
which obstructs further ossification. Haemorrhages 
occur as elsewhere in the body, in the joints, under- 
neath the periosteum, and in the substance of the 
bone-marrow. The periosteum may be elevated 
from a large part of the shaft of the bone by the effu- 
sion of blood (Fig. 458). Periosteal growth of bone 
tends to replace the clot, but the cortex continues to 
be rarefied. The disturbances of ossification do not 
depend on the haemorrhages, since they precede 
them (Ingier). 
Healing takes place after the proper food is once more given by the 
rearrangement of the disturbed cartilage cells in their columnar order, by 
the reappearance of blood-forming cells and abundant capillaries with osteo- 
Fig. 458.-Infantile 
scurvy. Section of fe- 
mur showing subperi- 
osteal haemorrhages 
with periosteal bone 
formation. There are 
haemorrhages in the 
bone-marrow and dis- 
tortion of the line of 
ossification at the 
lower end. paget's disease (osteitis deformans) 
929 
blasts in the impoverished bone-marrow, which then go on to the normal 
processes of ossification. The disease is quite different from rickets, in 
which the chief feature is the absence of calcification of the cartilage, and 
the consequent rapid ingrowth of capillaries which form osteoid tissue, in 
the lack of calcium. 
Aschoff and Koch, W.: Skorbut, Jena, 1919. 
Schmorl: Ziegler's Beitrage, 1901, xxx, 215. 
Holst and Frohlich: Ztschr. f. Hyg., 1912, Ixxii, 1. 
Ingier: Frankf. Ztschr. f. Path., 1913, xiv, 1. 
Hess and others: Proc. Soc. Exp. Biol, and Med., 1914, xi, 130; 1916, xiii, 145; 1918, 
xv, 74, 141. Amer. Jour. Dis. of Child., 1914, viii, 386; 1916, xii, 152; 1917, xiii, 
98; 1917, xiv, 337. 
LITERATURE 
OSTEOGENESIS IMPERFECTA 
Osteogenesis imperfecta is a condition in which, in infants and young chil- 
dren, multiple fractures of the ribs and long bones occur. Niklas, in describ- 
ing a still-born infant in whom there were more than 60 fractures, most of 
them produced some time before birth, regards the process as different from 
osteopsathyrosis or osteogenesis imperfecta tarda, which occurs in adult life 
and the nature of which is still doubtful. Study of the bones in osteogenesis 
imperfecta shows normal cartilage with normal preparatory calcification, a 
normal line of ossification, with normal-looking osteoblasts. These, how- 
ever, must function imperfectly, since the lamellae of bone are extremely 
delicate and thin. Periosteal bone formation is greatly reduced, and many 
lamellae of the cortex are disconnected and run transversely. Resorption of 
bone is normal in the presence of this faulty or deficient apposition-hence 
the numerous fractures. Niklas found a hyperplastic thyroid and ovaries, 
and suggests the possibility that disturbances of internal secretion may be 
concerned. 
LITERATURE 
Bamberg and Huldschinsky: Jahrb. f. Kinderheilk., 1913, Ixxviii, Ergnzngsheft., 214. 
Hart: Ziegler's Beitrage, 1914, lix, 207. 
Niklas: Ibid., 1915, Ixi, 101. 
PAGET'S DISEASE (OSTEITIS DEFORMANS) 
In 1876 Paget described a disease in which the bones of the extremities and 
of the skull became greatly thickened, and to some extent softened, so that 
bowing of the legs occurred. The enlargement of the head was extreme, 
and the person sank in stature. Many cases of this disease have been 
studied, and although the cause is still unknown, the anatomical changes 
are fairly clear. It begins usually after the age of forty, and progresses 
slowly with some pain and tenderness in the altered bones. In some cases 
the changes are unilateral or limited to one or two bones. In those in which 
the skull and facial bones alone are affected the condition is spoken of as 
leontiasis ossea. In them the softened bone may later assume an ivory-like TEXT-BOOK OF PATHOLOGY 
930 
hardness. The tibiae and femora commonly become thickened and bent 
forward. The skull (Fig. 459) may reach a thickness of two or three or even 
four centimetres, and, as a rule, the bone is easily cut with a knife. Since it 
is a disease of advanced life, there is no question of disturbance of ossifica- 
tion along the epiphyseal line. Instead, there are concerned especially 
extensive resorption of the normal bone by osteoclasts, and the excessive 
Fig. 459.-Paget's disease, or osteitis deformans. Thickened skull and cross-section 
of femur. Marrow cavity filled with osteoid tissue. 
new formation of irregular bony lamellae by the osteoblasts which accompany 
the fibrous marrow. The marrow actually loses its blood-forming elements 
and becomes converted into a vascular fibrous tissue which produces much 
soft, bone-like tissue. The architecture of the bone is disorganized, and the 
cortex loses its dense character and sharp outline. The marrow cavity is 
encroached upon or filled completely, and a thick subperiosteal layer is 
formed (Fig. 459). In this new tissue the lamellae run in every direction. paget's disease (osteitis deformans) 
931 
Occasionally there are cysts or spaces in it filled with fluid, or tumor-like 
growths may appear. There is no halisteresis, as in osteomalacia. 
Various theories have been proposed as to the causation, and many 
infectious agents have been held responsible, including syphilis. There is 
little evidence for these views. Others have thought of it as an effect of the 
disturbance of some internal secretion. DaCosta and his coworkers find 
that there is a retention of calcium, magnesium, and phosphorus, with 
excessive excretion of sulphur, and state that there have been analyses 
which show that, in spite of their softness, the bones are especially rich in 
calcium. 
Paget: Medico-Chir. Transactions, 1877, lx, 37; 1882, Ixv, 225. 
Higbee and Ellis: Jour. Med. Research, 1911, xxiv, 43. 
Watson: Johns Hopkins Hosp. Bull., 1898, ix, 133. 
Hurwitz: Ibid., 1913, xxiv, 263. 
DaCosta and others: Publications of Jefferson Med. College, Phila., 1915, vi, 1. 
LITERATURE CHAPTER XLVII 
ARTHRITIS DEFORMANS 
Confusion as to classification; infectious, traumatic, neuropathic, and gouty forms. Ar- 
thritis deformans: terminology. 1. Proliferative arthritis deformans or progressive poly- 
arthritis; clinical and gross pathological characters; histology. Spondylitis of Bechterew 
and Marie. 2. Degenerative arthritis deformans. Clinical and gross pathological changes; 
histology. Malum coxce senile; spondylitis deformans. 
The recent discussion of chronic affections of the joints at the International 
Congress of Medicine in London showed how confused our ideas are as to 
the classification of these affections. We have learnt that there are many 
infections in the course of which recognizable organisms lodge in the tissues 
of the joints and produce acute or chronic forms of arthritis and periarthri- 
tis. This is particularly true of the pyogenic micrococci, and perhaps 
especially of the gonococcus. There are also, as is well known, articular 
and periarticular inflammations due to the unknown infectious agent cf 
rheumatism (and to avoid confusion we shall use the term rheumatism fcr 
that affection only in which fever, arthritis, and peri-, endo-, and myocardi- 
tis are found, often associated with tonsillitis and chorea). 
The part played by the tubercle bacillus in producing destructive and 
reactive changes in joints has been dwelt upon, and there are other cases in 
which the Spirochaeta of syphilis plays a similar role. 
These are, with many others, the infectious forms of arthritis usually 
easily recognized to be the sequelae of the existence of a focus of similar 
infection elsewhere. While this primary infectious lesion may sometimes 
be very evident, it is less so at other times, as, for example, those cases in 
which pyorrhoea alveolaris, or some nasal suppuration, is the real, though 
unsuspected, source of the spread of bacteria. The lesions of the joints are 
sometimes suppurative inflammations; sometimes there are only effusions 
of fluid; adhesions and even complete ankylosis of fibrous or bony character 
often occur. Traumatism, especially when bacteria are introdued into the 
joint cavity, is naturally often productive of an arthritis, and in haemophilia 
and allied conditions there arises haemorrhage into the joints which may 
simulate in its effects those of an inflammation. 
In the course of some diseases of the spinal cord, notably tabes dorsalis 
and syringomyelia, there occur curious changes in some of the joints, caus- 
ing complete disorganization not only of the joint structures themselves, 
but of the neighboring bones, with the most deforming dislocations. The 
tabetic arthropathies have already been mentioned, and one of them at 
least represented in an illustration (Fig. 365). 
932 933 
ARTHRITIS DEFORMANS 
A fourth type is that already described and figured in speaking of gout, in 
which the deposition of crystalline masses of urates in the joint cartilages 
and in the periarticular tissues is the cause of intense inflammatory reac- 
tions (Fig. 34). 
When all these forms of arthropathy have been considered, there still 
remain many which cannot be regarded as definitely belonging to any of 
those groups. These are commonly chronic and extremely persistent affec- 
tions, which, although they may sometimes begin suddenly enough with 
pain and fever, and even in quite young people, drag on through years, and 
cause the most extreme deformities and disabilities, which are permanent. 
Indeed, they appear to be gradually progressive during all that time in 
producing atrophy and disorganization of the cartilages and of the bone 
itself, accompanied by extraordinary new formations both of cartilage and 
bone, as well as of scar tissue, in and about the joint. 
It may as well be admitted at the beginning that, since every author who 
writes upon the subject seems to use a different terminology, it is extremely 
difficult to compare their results and to decide upon the limits of the disease 
and its most satisfactory subdivision. Barker has reviewed the subject, 
and in his tabulations he separates osteoarthritis deformans from chronic 
progressive polyarthritis (the rheumatoid arthritis of Garrod). German 
writers, such as M. B. Schmidt and Kaufmann, divide arthritis deformans 
into three groups: (1) A. ulcerosa sicca, which is often monarticular and is 
essentially a degenerative and destructive process; (2) Arthritis adhcesiva, 
in which many joints are involved, and while destructive in a sense, is espe- 
cially characterized by the growth of granulation tissue forming adhesions 
and even a firm fibrous ankylosis; and (3) Arthritis deformans, in which 
atrophic or degenerative changes in the cartilage and bone are accompanied 
by extraordinary new formation of both bone and cartilage in such a way 
that the ends of the bone forming the joint become profoundly deformed 
and often dislocated. Nichols and Richardson regard all the cases as 
examples of one disease, but recognize an essentially degenerative form in 
contrast with another in which proliferation of connective tissue, cartilage, 
or bone is predominant. It seems that their proliferative form must cor- 
respond with the A. adhsesiva, while their degenerative form comprises the 
other two classes. In the same way in comparing their terminology with 
that of Barker it seems that the proliferative form is the same as the chronic 
progressive polyarthritis or rheumatoid arthritis, while the degenerative 
form is co-extensive with osteoarthritis deformans. 
Proliferative Arthritis Deformans.-The first part of these, the prolifera- 
tive form of arthritis deformans of Nichols, or progressive polyarthritis of 
other writers, begins often with fever and sudden pain in the joints, almost 
as in an attack of rheumatism. It affects young people as well as old, and 
quickly leads to lameness, disability, and stiffness of the joints. It affects 
many joints, including those of the knees, shoulders, etc., as well as those of 
the hands and feet. The joints become enlarged, but remain soft and 934 
TEXT-BOOK OF PATHOLOGY 
doughy, without any irregular nodules (Fig. 460). X-rays show rarefac- 
tion of the bone, which may be due to a withdrawal of calcium salts, but no 
exostoses. If such a joint be opened, its articular surface is found partly 
covered with red granulation tissue and the synovial membrane generally 
thickened. At a later stage the cavity may be partly or completely obliter- 
Fig. 460.-Proliferative arthritis; soft swelling of the joints of the hand. 
ated by adhesions, and the cartilages partly replaced by new bone or by 
fibrous tissue. Fibrous or even bony ankylosis may occur, and in extreme 
cases the two bones become united with continuous marrow cavity. 
Partial dislocations are sometimes found, but even in such late stages there 
is no new formation of bony nodules about the joints. 
Fig. 461.-Proliferative arthritis with ankylosis of phalangeal joint. Spongy bone 
of the phalanx (1). Growth of fibrous tissue and fibrocartilage (2) has almost entirely 
obliterated the joint cavity (3) (Nichols and Richardson). 
Histologically, the following is found to occur. As a result, no doubt, of 
some primary injury, there is formed a layer of granulation tissue on the 
surface of the synovial membrane and spreading over the cartilage of the 
articular surfaces. This reduces the extent of exposure of the cartilage, and 
through adhering to the similar granulation tissue of the opposite side, ARTHRITIS DEFORMANS 
935 
causes partial obliteration of the joint cavity (Fig. 461). The granulation 
tissue also extends into the substance of the underlying cartilage and tends to 
destroy it. The bone beneath shows, for a time at least, no morphological 
evidence of rarefaction, but the bone-marrow becomes converted into an 
mdematous fibrous tissue with many osteoblasts and capillaries. This 
invades the cartilage from below, causing its ossification as it goes, and may 
penetrate to join the overlying layer of granulation tissue. The activity of 
the osteoblasts may cause much condensation of the bone beneath the carti- 
lage, but it also causes much new bone formation within and overspreading 
the cartilage, often with new cartilage formation as well, so that Nichols 
even pictures a bone in which, while part of the original cartilage remains, 
there is a layer of bone surmounted by cartilage covering it. All these 
things explain the tendency to the formation of dense fibrous ankylosis 
which may be more or less complete. One type of this disease which in- 
volves fibrous or bony ankylosis of the articular processes of the vertebrae, 
including the costovertebral articulations, is particularly striking. Occasion- 
ally the ligaments are ossified also. The result is the solidification of the 
Fig. 462.-Degenerative arthritis; characteristic deformities of the hands with nodular 
enlargements of the joints. 
spinal column into a rigid curved structure, concave throughout on the 
anterior aspect. In the so-called Bechterew's disease the ankylosis is limited 
to the spine or part of it, beginning above, but in other cases the hip- and 
shoulder-joints are also involved (spondylose rhizomelique of Marie-Striim- 
pell). 
Degenerative Arthritis Deformans.--The second group, the degenerative 
form of Nichols or osteoarthritis deformans of others, is more particularly 
found in elderly people, and is often an affection of fewer joints. It usually 
begins insidiously, without fever, and progresses slowly to extreme deformi- 
ties and disabilities of the joints. These become enlarged by the appear- 
ance of firm or hard nodules, and are tender and painful. The joints of the 
hands and feet often show the most striking changes, although the knees 
and hips and other large joints are equally characteristically affected (Fig. 
462). The hands of these patients present an especially remarkable appear- 
ance. There is flexion of the fingers, as a rule, with deflection to the ulnar 
side. Great knobby enlargements of the knuckles and of the terminal 
phalangeal joints are often associated with relatively slight enlargement of 936 
TEXT-BOOK OF PATHOLOGY 
the middle joints of the fingers, so that these tend, on account of the relaxa- 
tion or atrophy of their ligaments, to bend backward (Fig. 463). Between 
the knuckles and the wrist-joint the back of the hand over the metacarpal 
bones sinks into a hollow over which the skin is extremely thin, like crinkled 
tissue paper, shiny and translucent, so that the veins show through dis- 
tinctly. 
On opening one of these joints no new growth of granulation tissue is 
Fig. 463.-Degenerative arthritis; typical deformity of the hands, with ulnar deflection. 
found, nor any tendency to ankylosis. Instead, the changes are predomi- 
nantly in the cartilage and secondarily in the bone. The cartilage is at 
first fibrillated and plush-like, so that its shaggy surface can be smoothed 
over from one side to the other. This causes such softening and disintegra- 
tion that it is readily eroded away, leaving deep ulcers and sometimes expos- 
ing the bone (Fig. 464). In the gross specimen this uncovered bone is in 
most cases found to be smooth and hard. Opposite such an ulceration of 
Fig. 464.-Degenerative arthritis. Phalangeal joint, showing irregular joint surface, 
(1) with exposed eburnated bone (2, 2) (Nichols and Richardson). 
the cartilage the cartilage of the other joint surface tends to thicken itself 
and fill up the space, often becoming partly or completely ossified in this 
process. But sometimes both of the opposed surfaces are denuded of carti- 
lage and bone grinds against bone. Ordinarily this sets up the formation 
of much new bone in the substance of that which is exposed, and the surface 
layers become very compact and hard. In such joints as move like hinges ARTHRITIS DEFORMANS 
937 
these opposing surfaces of dense bone grind upon one another until they 
become brilliantly polished. Sometimes this condition arises only after 
inequalities in one surface have been filled up by overgrowths from the other 
which have become bony. Then the grinding produces parallel grooves, 
Fig. 465.-Arthritis deformans (degen- 
erative form). Head of femur showing 
erosion and marginal osteophyte forma- 
tion. 
Fig. 466.-Arthritis deformans (de- 
generative form). Extreme erosion of 
the head of the femur, with polishing 
and exostosis formation. 
which are fitted by ridges of the opposite side. In joints which work in 
many directions these parallel grooves do not appear (Fig. 465). Where 
the bone is very atrophic and unable to respond, or in retired places where 
the pressure is insufficient to stimulate much new bone formation, the sur- 938 
TEXT-BOOK OF PATHOLOGY 
Fig. 467.-Arthritis deformans (degenerative form). Acetabulum with marginal osteo- 
phytes. 
Fie. 468.-Arthritis deformans (degenerative form). Shallow acetabulum surrounded 
by marginal osteophytes. (Another view of Fig. 467.) ARTHRITIS DEFORMANS 
939 
face does not become smooth and shiny, but remains porous, as though one 
had tried to polish pumice stone (Walkhoff). 
All round the margin of the joint (Fig. 466), which is much enlarged 
thereby, there is usually formed a series of cartilaginous or bony nodular 
outgrowths. These may interlock in such a way as to limit the motion of 
the joint very seriously. From the capsular synovial membrane there often 
hang villous, branched, fat-containing masses which are spoken of as lipoma 
Fig. 469.-Arthritis deformans (degenerative form). Erosion of head of femur with 
dislocation to a new flattened joint surface on the ilium. 
arborescens. In this capsule, also calcified or cartilaginous masses of tissue 
may form and become pedunculated. Through constriction of their stalk 
they may come to be free in the cavity, where they cause much disturbance 
(joint mice). 
Histologically the first changes are found in the cartilage, which loses its 
normal elasticity and homogeneous character and becomes vertically split 
into fine fibrillae. The cartilage cells degenerate and disappear. The 
■whole layer may be ground away, exposing the bone, which has in the mean- 940 
TEXT-BOOK OF PATHOLOGY 
while, by the activity of the subchondral osteoblasts, become eburnated or 
condensed, so that the cancellous laminae lie close together in a compact 
mass. Great proliferation of the remaining cartilage around the margin of 
the joint occurs, and into this cartilage the blood capillaries of the osteo- 
genic marrow grow, converting it into bone. There is little or no formation 
of granulation tissue from the synovial membrane or perichondrium over 
the surface of the joint, and ankyloses do not occur. The erosion can go 
Fig. 470.-Spondylitis deformans, showing fusion of the bodies of the vertebrae by 
exostoses which stretch across the intervertebral discs. The smaller articulations show 
no ankylosis, in which this condition differs somewhat from the spondylose rhizomelique. 
much further than the mere thickness of the original layer of cartilage. 
The exposed bone is worn away deep into the head of the epiphysis until the 
most extreme deformity is produced, constantly made up in a futile way by 
the growth of the marginal osteophytes (Fig. 467). In the hip such changes 
produce a flattening of the head of the femur into a mushroom-like mass 
fringed with hanging osteophytes which plays in the partly filled-up and 
very shallow acetabulum (Fig. 468), or the erosions may be more lateral and 
the head of the femur, now a laterally flattened mass, becomes' dislocated to ARTHRITIS DEFORMANS 
941 
some point on the ilium where it lies against a new-formed acetabulum 
(Fig. 469). In all the more advanced cases of this type there is much rare- 
faction of the bones, and a dried femur is extraordinarily light as compared 
with one from a normal person. In one case which I observed for a long 
time the bones were so fragile that one of them broke on lifting the body of 
the woman from the bed after death. A section showed the cancellous bone 
to be extensively atrophied and the cortex greatly reduced in thickness. 
This group comprises, beside the forms in which the joints of hands and 
feet are affected together with other larger articulations, those in which 
erosion of the cartilage and atrophy of the bones found in one hip-joint 
(malum coxae senile), and those in which the cartilaginous intervertebral 
discs form the starting-point, and in which the production of exostoses and 
ecchondroses round the centre of the vertebrae results in a rigidity of the 
spinal column not dependent upon ankylosis of its smaller articulations 
(spondylitis deformans) (Fig. 470). 
LITERATURE 
Pommer: Mikr. Befunde bei Arthritis deformans, Wien, 1913. 
Pribram: Spez. Path. u. Therapie v. Nothnagel, 1902, 7ver Theil, v. 
Kimura: Ziegler's Beitrage, 1900, xxvii, 225. 
v. Stubenrauch: Munch, med. Woch., 1914, Ixi, 1494, 1565. 
Barker: XVII. Internat. Cong, of Med., London, 1893, vi, Part I, 253. 
Nichols and Richardson: Jour, of Med. Research, 1909, xxi, 149. 
Walkhoff: Verh. Dtsch. Path. Gesellsch., 1906, ix, 229. CHAPTER XLVIII 
TUMORS 
General nature of tumors; difficulty of classification. Fibromata. Neurofibromata,, 
keloids. Lipomata. Chondromata. Osteomata. (Xanthomata.) Myomata; leiomyomata, 
rhabdomyomata. 
General Nature of Tumors.-It seems quite impossible to discuss the gen- 
eral nature of tumors or to attempt any definition of a tumor until after 
some survey of their varying anatomical characters and modes of growth 
is made. In the meanwhile it may be said that they are masses of tissue 
resembling, but not perfectly identical with, the normal tissues, which grow 
without any regard for the laws which govern and restrain the growth of 
normal tissue. They are supplied with blood-vessels and a sufficient sup- 
porting framework by the host, and derive their nourishment from the 
circulation of the host. Therefore, like any parasite, they are harmful to the 
person in whose body they grow, but the injury which they do becomes 
intolerable when they not only absorb this essential nourishment, but also 
invade and destroy the normal tissues. In olden times they were actually 
looked upon as parasites foreign to the body, but such a vague idea was 
forced to disappear when Johannes Muller showed that they were always 
composed of tissue of their host. If, now, we speak of a fibrous tumor as a 
fibroma, a fatty tumor as a lipoma, and cartilaginous or bony tumors as 
chondromata or osteomata, it is rather because their tissues closely resemble 
fibrous, fatty, cartilaginous, or bony tissue, than that we can actually trace 
their origin to these tissues. Our classification is, therefore, rather a tissue 
of assumptions than one formed on a true histogenetic basis. Probably it 
is true that an epithelioma is definitely derived from the epithelium in 
which it began, and a fibroma from the preexistent connective tissue. It 
would be difficult to conceive of any other explanation, but the absolute 
proof is not at hand. Classification is at best unsatisfactory on a histo- 
genetic basis, since so often we cannot make a good guess at the tissue which 
the tumor most resembles, and since then, in so many cases, we have no 
clue as to the point from which it actually sprang. It is greatly aided by 
observations on the histological characters of the new-growths, and in our 
ignorance of their aetiology, we adopt a subdivision in which the type of the 
tissue and the mode of growth form the main lines upon which separation 
into classes is carried out. Such a classification will be given (p. 1096) after 
we have examined the tumors themselves. 
942 FIBROMATA 
943 
FIBROMATA 
A fibroma is a tumor composed of tissue which resembles more or less 
closely one of the many types of normal connective tissue. There is such 
variety in the relations of intercellular substance and cells in these normal 
types (tendon, fascia, areolar tissue, dermis, etc.) that it is not surprising 
that the fibrous tumors, which can diverge in every way from the character 
Fig. 471.-Types of fibroma. C, Nasal polyp or oedematous fibroma. The others 
(A, B, D, E) are fibromata of different consistence, formed in various situations in the 
body. 
of the tissue from which they may be supposed to arise, may show a much 
greater variety. In every case one is impressed by the purposeless arrange- 
ment of the fibres, which stand in no especial relation to adjacent tissues, as 
they do in normal connective tissue, but are merely woven together in a 
mass. Some fibromata are extremely soft and loose in texture-others are 
dense and hard (Figs. 471 and 472). When the intercellular fibres are little 944 
TEXT-BOOK OF PATHOLOGY 
developed and the tumor is made up chiefly of closely packed cells, it may be 
found that its growth is rapid and invasive, and that the tumor should really 
be called a sarcoma. This is one of the points at which mere histological 
examination may fail to afford a correct interpretation and the biological 
characters must be known. To coin for such tumors the name fibrosarcoma 
is probably only to add to the difficulties of classification. 
Fig. 472.-Types of fibroma: (a) Cellular fibroma resembling a spindle-cell sarcoma, 
but benign; (d) keloid. 
Fibromata occur almost anywhere in the body and are frequently mul- 
tiple. They arise most commonly in the skin, the fasciae, and the inter- 
muscular tissues, about the joints or in connection with nerves. In the 
internal organs they are found in the submucosse, in the kidney, ovaries, 
etc., but in many cases, especially in the breast and uterus, the excessive 
growth of fibrous tissue accompanies that of other cells, such as epithelium 
or smooth muscle, and although such tumors are commonly spoken of as FIBROMATA 
945 
adenofibromata or fibromyomata, it seems probable that they are rather to 
be regarded as tumors of epithelium or muscle with merely a very abundant 
stroma. Fibromata of the skin are sometimes hard, solid tumors embedded 
deep in the skin and extending into the subcutaneous tissue (Fig. 473). 
One which was studied after its removal by operation formed a thick cap 
over the whole scalp, projecting down with thick rounded edges as far as 
the ears. It was so rigid and so densely connected with the skin that much 
Fig. 473.-Subcutaneous hard fibroma. 
skin had to be grafted to cover the skull after its extirpation. Others are soft 
and project above the skin surface, often hanging by a relatively thin stalk 
(Fig. 474). Occasionally very large tumors composed of soft fibrous tissue 
are found hanging by a long stalk from the labium majus or from some other 
site about the external genitalia. Single tumors of this sort occur, but the 
most characteristic form is that described as fibroma molluscum, in which 
great numbers of soft, partly pedunculated nodules are scattered over the 946 
TEXT-BOOK OF PATHOLOGY 
whole body (Fig. 475). This condition is often called von Recklinghausen's 
disease, and it has been learned that it is a more complicated condition than 
might appear at first sight. It is congenital or hereditary, although the 
nodules may become conspicuous only in later life. There are areas of 
pigmentation scattered among them, and the nodules themselves are devel- 
oped around nerves in the substance of which fibrous masses also appear. 
Dissection of such a mass will often reveal a cutaneous nerve embedded in 
loose fibrous tissue and beaded along its course by small denser fibromata 
which spread apart its fibres. There 
is also in some cases a peculiar re- 
laxation of the skin, usually over 
the scalp, which allows great folds to 
hang down over the ears or over the 
face. In such folds similar nerves 
beaded with fibromata have been 
found. Fabyan found no nerves in 
the tumors in his case. 
Keloids are extremely dense, scar- 
like tumors which appear in some 
people (especially in negroes) in the 
scars of wounds. Even when the 
wound has been very slight great 
nodules may result. I have seen one 
or two negresses in whom puncture 
of the ear-lobes for earrings had set 
up the formation of great lobulated 
keloids. In other cases scratches, 
burns, or even healed acne pustules 
seem sufficient to start the growth. 
Extirpation leaves another scar in 
which, of course, the process may 
repeat itself. It seems that there 
must be some individual predisposi- 
tion in such cases for, of course, this 
does not happen in every one. The 
tumors are composed of very dense 
fibrous tissue in which blood-vessels and cells are far apart (Fig. 472, d). 
In the nose fibromata grow in clusters from the nasal septum, pushing up 
the Schneiderian membrane to cover them. These become extremely oede- 
matous since they are loose in texture and hang in the cavity of the nose as 
translucent, rather turgid rounded bodies almost like white grapes (nasal 
polyps). They cause obstruction of the air-passage and are exposed to 
trauma. Microscopically they are found to show sparsely arranged con- 
nective-tissue cells, but are infiltrated with all sorts of wandering cells, 
Fig. 474.-Small soft pedunculated fi- 
broma of the skin. FIBROMATA 
947 
including many eosinophiles and the most beautiful mast cells (Fig. 471, c). 
In connection with fasciae, ligaments, and periosteum there are found 
larger, dense fibrous tumors in which the cells and their abundant inter- 
cellular fibres are closely packed together in a hard mass which, on section, 
shows a shining, pearly white surface. These too may present softer areas, 
but usually the consistence is 
pretty uniform. Sometimes the 
fibres are gathered into interlacing 
bundles, an arrangement which is 
particularly common in those which 
are associated with the sheaths of 
the nerves. These tumors, often 
mistakenly called neuromata, are 
sometimes found in large numbers 
even along the course of the larger 
nerves, and not only, as in the case 
of von Recklinghausen's disease, 
as small nodules near the termin- 
ation. Dr. Prudden has described 
one case from which specimens are 
preserved in the museum, and his 
illustrations show the extraordin- 
arily wide distribution of the tu- 
mor masses. Here the nerve-fibres 
are stretched out over the nodules 
so as to enclose them. Such rela- 
tions with the nerves seem com- 
moner than with the blood-vessels, 
although there are found, in the 
nose and elsewhere, fibromata of 
extraordinary vascularity. 
Pure fibromata are rare in the 
uterus and in the mammary gland. 
In the ovary they occur in the form 
of hard nodules which may reach 
a great size. These show micro- 
scopically closely arranged spin- 
dle-shaped connective-tissue cells 
with compact intercellular fibres. 
In the kidney there are often seen 
rather small, round, grayish white 
glistening nodules embedded in the cortex or pyramids and crowding aside 
the tubules. These on section show an atypical fibrous tissue with vary- 
ing proportions of cells and fibrous material. So too in the submucosae 
Fig. 475.-Multiple neurofibromatosis 
(von Recklinghausen's disease). Observe 
the great relaxed mass of skin which hangs 
from the side of the head. 948 
TEXT-BOOK OF PATHOLOGY 
of the alimentary tract firm gray nodules are found lifting up the mucosa. 
While some of these are true fibromata, most of them are made up of 
smooth muscle with a fibrous stroma. 
Mention is usually made in this connection of elephantiasis and of 
localized giant growths, although it seems that they have little to do with 
tumor formation. Many of these conditions seem to be caused by inflam- 
matory processes, while others are related to von Recklinghausen's mul- 
tiple neurofibromatosis and occur with it. Partial gigantism, in which 
one extremity is merely developed on a larger scale than the rest, is evi- 
dently the result of disturbances of embryonic development. 
LITERATURE 
Fibroma.-Gergo: Virch. Arch., 1913, ccxiii, 317. 
Neurofibromata.-Harbitz: Arch. Int. Med., 1909, iii, 32. 
Helmholtz and Cushing: Amer. Jour. Med. Sci., 1906, cxxxii, 355. 
These are tumors composed of fat tissue and occurring in the form of 
circumscribed and sometimes lobulated flattened or rounded masses. Since 
fat tissue is not very sharply characterized histologically, it is difficult to 
make out differences between that which occurs in tumors and the normal 
fat. In some cases, however, the fat is associated with such a dense fibrous 
growth that the name fibrolipoma may be appropriate. In others an exces- 
sive vascular supply may suggest the name angiolipoma. 
The tumors occur most commonly in the subcutaneous tissue, and especi- 
ally over the back, the neck and shoulders, and the buttocks. They project 
as rather soft, lobulated masses which are sometimes quite tender or even 
spontaneously painful. They can be shelled out of their bed in the tissue 
and do not tend to recur. Microscopically there is merely fat in hugely 
dilated cells, arranged in compact lobules held together by the fibrous 
stroma. Coalescence of fat-cells with loss of their walls so that pools of oil 
are formed is an uncommon occurrence. Calcification or even ossification 
in necrotic areas is sometimes observed. 
Other sites for lipomata are in the mesentery, the submucous and sub- 
serous tissues of the whole alimentary tract, in the kidney, heart, uterus, 
and even in the meninges. In the kidney the lipomata are usually rather 
small, but a few larger ones have been studied and have shown, beside the 
fat, an admixture with muscle and other elements, often with nodules of 
adrenal-like tissue. 
Very interesting are the symmetrical multiple lipomata which have been 
mentioned before as related somehow with the irregular adiposis dolorosa of 
Dercum. The figure (Fig. 451) gives the impression better than any des- 
cription. These are often tender or painful, and are associated with mental, 
motor, sensory, and trophic disturbances of various sorts. Lyon thinks 
LIPOMATA CHONDROMATA 
949 
they shade off into the more general adiposis and may prove to be due to 
some disturbance of internal secretions. 
Lipomata are practically invariably slow-growing tumors which increase 
from within themselves, expanding so as to compress surrounding tissues or 
to project on the body surface. 
LITERATURE 
Lipoma.-Lyon: Arch. Int. Med., 1910, vi, 28. 
Keenan and Archibald: Jour. Med. Research, 1907, xvi, 121. 
Ebner: Beitr. z. kl. Chir., 1913, Ixxxvi, 186. 
Schridde: Ergebn. d. allg. Path., 1906, x, 674. 
CHONDROMATA 
Tumors composed of cartilage of a somewhat irregular and atypical charac- 
ter occur in connection with preexisting cartilage in the joints, in the bones, 
or occasionally in the bronchi. 
Those which spring from the 
bone or skeletal cartilage 
appear as nodular tumors 
(Fig. 476) composed of elastic, 
pale-bluish cartilage which is 
covered with a fibrous envel- 
ope and divided, as a rule, 
into lobules by a framework 
of connective tissue which 
bears blood-vessels. They 
are broadly connected with 
the bones or cartilage, or 
are partly embedded in the 
bone, occupying much of its 
marrow cavity and extending 
through the cortex to project 
upon the surface. The bone 
is often greatly distended by 
such a mass, and especially 
in the case of the fingers be- 
comes greatly distorted (Fig. 
477). Large tumors of this 
kind are not uncommon in 
the hand, where several fin- 
gers may be converted into unwieldy lumps which become absolutely 
useless. In the pelvis enormous cartilaginous masses have been seen, 
projecting from the symphysis pubis or from the sacro-iliac synchondrosis, 
and so occupying the cavity of the pelvis as to obstruct childbirth. Simi- 
lar tfimors are described for the scapulae, the ribs, the hyoid bone, etc. 
Fig. 476.-Chondroma of phalanx. 950 
TEXT-BOOK OF PATHOLOGY 
Chondromata arising in the trachea or bronchi are often flattened clumps 
of tissue which, even though they lie in the spaces between the cartilaginous 
rings, are found to have a connection with them or with the perichondrium. 
In other cases large nodules have been observed blocking the bronchus or 
extending into the lung tissue. 
Since normal cartilage is not vascular and depends for its nutrition upon 
the absorption of fluid from the vessels of the perichondrium, no great bulk 
of it can maintain itself alive. In the cartilaginous tumor, however, the 
tissue is in relatively small districts well supplied with nourishment from 
abundant blood-vessels which accompany its fibrous stroma. The inter- 
cellular substance is more variable in consistence and less dense than that 
of normal cartilage, and often shows a distinctly fibrillar structure. The 
cells vary greatly in size, and in their arrange- 
ment in groups, and thus differ markedly from 
those of normal cartilage (Fig. 478), but, on 
the whole, the resemblance is very close, and 
as a rule it is not easy to be sure of their tumor 
nature without recourse to information about 
the general features of the growth. Blood- 
vessels sometimes grow into the cartilage, as in 
normal endochondral ossification, and convert 
it into bone, so that the chondroma eventually 
becomes a kind of osteoma. Usually a layer of 
cartilage remains over the surface. In other 
cases extensive calcification occurs in patches, 
or the tumor may undergo a softening which 
leaves a cavity filled with a gelatinous, semi- 
fluid material in which large radiating cells are 
found. Actual cysts are formed finally if the 
liquefaction continues. 
Virchow and others have attempted to show 
that since these tumors are commonly found 
in young people, they may have arisen from congenitally misplaced carti- 
lage or from disarranged cartilage islands cut off in the ordinary process 
of endochondral ossification. Such little islands do occur and remain un- 
ehanged. Virchow thought for a time that rickets, with its exaggerated 
and disorderly process of ossification, might present an especially favor- 
able condition for such displacement of cartilage, but the cases seldom, 
if ever, show signs of healed rickets. It seems hardly necessary to 
insist upon the existence of such latent displaced cartilage islands, however, 
since periosteum and endosteum are so readily capable of producing carti- 
lage whenever, as in a fracture, the new formation of tissue is required. 
Since we have other atypical tumor growths arising everywhere without 
special preparatory displacement of the tissue which exactly corresponds 
with them, it is not difficult to imagine the growth of a cartilaginous tumor 
Fig. 477.-Chondroma of 
phalanx. The tumor appears 
to begin in several places, 
perforating the cortex and 
lifting up the periosteum. OSTEOMATA 
951 
from the cells which form bone by the way of cartilage. So, too, in the lung 
the new cartilage growths, which are often called ecchondroses, when they 
seem to represent a mere hyperplasia, are easily derived from the peri- 
chondrium. 
Combination of cartilage with other tumor elements is frequently found. 
Fig. 478.-Chondroma with irregular blood-vessels and atypical bony areas 
LITERATURE 
Chondroma.-Ribbert: Geschwulstlehre, Bonn, 1904. 
Ehrenfried: Jour. Amer. Med. Assoc., 1915, bdv, 1642. 
Boggs: Johns Hopkins Hosp. Bull., 1913, xxiv, 210. 
OSTEOMATA 
It has already been stated that at many points throughout the body ossifica- 
tion of tissue may take place if degenerative changes and deposition of 
calcium salts have occurred. At points in relation with cartilage and bones, 
instances have already been met with in which, as, for example, in the case 952 
TEXT-BOOK OF PATHOLOGY 
of arthritis deformans, rather extensive new bone formation occurs. Inj uries 
to muscles and fasciae and inflammations of various sorts seem capable of 
giving rise to some change which finally leads to bone formation. Thus it 
is said that cavalrymen acquire bony plates in the muscles of the insides of 
their thighs, and soldiers and others, similar plates in their deltoid muscles 
where gun or heavy burden rests. It is difficult to regard such things as 
tumors, since they seem to be merely an osteoplastic healing process which 
follows upon injury to the 
tissues. The so-called pro- 
gressive myositis ossificans 
which, after inflammatory 
stages, ends in the forma- 
tion of extensive bony shells 
in the muscles is doubtless 
similar in character. 
More difficult to interpret 
properly are the multiple ex- 
ostoses which appear about 
the epiphyses in young per- 
sons and are left along the 
shaft as the bone grows. 
They are often partly carti- 
laginous for a time, but in 
the end are bony. They 
can stretch some distance, 
and sometimes interarticu- 
late in a way, with one an- 
other, or, by fusing, limit 
the motion of the extremi- 
ties. These growths are 
often observed to occur in 
one family and seem to have 
an hereditary element. Of 
course, any collection of 
bones will be found to pre- 
sent at least a few examples 
in which extensive exostoses 
are found in the form of 
irregular, rather thin, sharp outgrowths, but these are usually recognized 
to be the accompaniments of an old fracture or of some long-standing 
inflammatory disease. Growths of this kind from the surface of a bone 
are called exostoses; those which appear in the interior of a bone, enostoses, 
while a diffuse thickening of the bone is called hyperostosis. 
The nodules of bone found in the lungs sometimes reach a considerable 
size. They are thought by many to depend upon preexisting inflammatory 
Fig. 479.-Large osteoma of very dense texture 
surrounding the elongated optic nerve, and dislo- 
cating the eye by extending into the orbit. The 
tumor bulged into the cranial cavity, and over it 
the brain was adherent. OSTEOMATA 
953 
processes, and so too are those tiny bone masses which form in the trachea 
and roughen its mucosa. These are not in direct connection with the 
tracheal cartilage rings. 
Tumor-like growths of bony consistence, usually masses more or less 
closely connected with the bones, may be very compact and hard, "ebur- 
nated, " or soft and spongy. Much has been said of such bony growths in 
other connections, and it will suffice to recall attention to the rounded masses 
of osteoid tissue which appear on the skull in rickets and later become hard- 
ened into bone; to the extensive new bone formation in chronic osteomyeli- 
tis around the areas of infection and in the neighborhood of ulcers which 
overlie such bones as the tibia. Chronic syphilitic forms of periostitis in 
the same way lead to 
the production of rough 
periosteal growths which 
deform the bone. Men- 
tion may also be made of 
the so-called osteophytes 
of pregnancy, which are 
thin, white, chalk - like 
deposits on the inner sur- 
face of the skull. These 
seem to be reabsorbed or 
merged with the cranial 
bones later, and are prob- 
ably the result of changes 
in the distribution of cal- 
cium which characterize 
the altered metabolism 
of pregnancy. 
Osteomata or bony tu- 
mors in which the bone 
is growing independently 
and without a limited aim 
are rare. They some- 
times occur in connection 
with the long bones and sometimes with pelvis, shoulder-girdle, etc. Occa- 
sionally they are more independent of the skeleton and arise in tendons or 
muscles as actual growing nodules. It appears that the bones of the skull, 
especially about the nose and orbit and middle ear, offer the most favorable 
chance for their development, and it is not infrequent to find rounded 
masses developing in the nasal cavity from the ethmoid or other bones or in 
the accessory nasal sinuses. These sometimes become loose and are known 
as dead osteomata. One which we studied last year showed a compact, 
extremely hard mass, which had grown to occupy the upper maxilla, and 
part of the temporal bone, projecting far into the orbit so as to displace the 
Fig. 480.-Ivory-like exostosis or osteoma of skull. 954 
TEXT-BOOK OF PATHOLOGY 
eye. When sawed through (with great difficulty), it presented a perfectly 
smooth, ivory-like surface, and was seen to project in all directions so as to 
occupy space in the cranial and other cavities (Fig. 479). There are other 
ivory-like tumors which occur like buttons on the skull, and sometimes form 
hemispherical masses of considerable size. They are usually a little separated 
from the skull around the edges so as to appear pedunculated. These cause 
no especial inconvenience (tig. 480). 
LITERATURE 
Osteoma.-E. Bruckmann: Virch. Arch., 1910, cc, 433. 
Heymann: Virch. Arch., 1886, civ, 145. 
Zimmermann: Dtsch. Ztschr. f. Chir., 1900, Ivii, 354. 
Fischer: Ergebn. d. allg. Path., 1906, x, 678. 
XANTHOMA 
Although commonly described with tumors, the forms of xanthoma seem hardly to be 
true tumors, but rather the result of local or wide-spread accumulations of lipoid sub- 
stances in degenerated cells. Although this suspicion is not justified entirely by the 
histological study, it does seem to be upheld by the transient character of many of these 
growths and by their usual association with jaundice, diabetes, pregnancy, etc., all 
conditions in which the lipoid content of the blood is altered. 
There are found-(1) xanthoma palpebrarum, in which flat, slightly elevated yellow 
patches are developed on the eyelids. These contain cholesterine esters with other 
lipoids in large cells in the cutis. These are thought by Pollitzer to be degenerated 
muscle cells; (2) multiple xanthoma which resembles (3) xanthoma diabeticorum in 
forming nodules in various places in the body, composed of somewhat similar large 
lipoid-laden cells, together with connective-tissue cells and a fibrous stroma. These 
nodules occur also in the internal organs, and are in most cases associated with jaundice. 
LITERATURE 
Pollitzer: N. Y. Med. Jour., 1899, Ixx, 73. 
Sikemeier: Frankfurter Zeitschr. f. Path., 1913, xiv, 428. 
MYOMA 
The term myoma is applied to tumors which are composed largely of muscle, 
those in which smooth muscle or non-striated muscle constitutes the pre- 
dominant tissue being called leiomyomata, while the rather more compli- 
cated tumors, which contain striated muscle, are spoken of as rhabdomy- 
omata. Since these types of tissue are not very closely related, it is not 
surprising to find that the corresponding tumors stand very far apart. 
Leiomyomata 
Tumors composed of smooth muscle occur very commonly in the walls of 
the uterus. Although they are found elsewhere, as in the walls of the 
stomach and intestine, in the bladder, kidneys, skin, etc., they are only 
rarely encountered in those situations and constitute a group of little impor- 
tance as compared with those of the uterus. 
Myomata (or fibromyomata) of the uterus, often loosely spoken of as MYOMA 
955 
fibroids, appear as rounded or nodular tumors situated in the uterine wall, 
although they frequently project from the outer surface in such a way that 
they seem to be attached to the uterus by a slender peduncle only. The 
thin layer of uterine muscle which envelopes them becomes more and more 
inconspicuous as they project in their growth from the uterine surface. On 
the other hand, there are also fibromyomata which project into the cavity 
of the uterus, carrying with them a very thin layer of the uterine muscula- 
ture and the mucosa. They, too, become pedunculated and hang by this 
Fig. 481.-Subperitoneal, submucous, and intramural myomata of the uterus (Kelly- 
Cullen) . 
stalk in the cavity, sometimes projecting from the external os uteri. In 
these three positions the tumors are given the epithets intramural, sub- 
serous, and submucous. 
Uterine myomata vary greatly in size, some being found embedded in the 
wall, and no more than 2 or 3 mm. in diameter, while others reach enormous 
dimensions. Often several tumors of different sizes are found in the same 
uterus, and these may occupy all three situations (Fig. 481). In the cases 
in which large submucous myomata are found, the cavity of the uterus is 956 
TEXT-BOOK OF PATHOLOGY 
greatly enlarged and distorted by the presence of the mass, and indeed this 
is true also in those cases in which large tumors occupy an intramural 
position. 
They are dense, hard, pearly-white masses, which on section are found to 
be sharply marked out from the surrounding uterine musculature by pro- 
jecting above its cut surface. They are further distinguished from it by 
their greater density and by their poverty in blood-vessels, for whereas the 
uterine wall is rather reddish-gray and vascular, the tumor is usually com- 
posed of whorls of fibres intimately woven together so as to shine with a 
tendon-like lustre, reflected separately from each bundle, and is much more 
rigid than the surrounding tissue. Its blood-vessels, although sometimes 
rather large in the superficial zone, are quickly reduced to a very small 
calibre as they penetrate into the interior. Clarke has shown that this 
vascularization often becomes quite inadequate to nourish with blood the 
innermost parts, so that most extensive necroses appear, recognizable as 
hyaline areas or patches in which calcification or even bone formation has 
occurred. Great cyst-like cavities filled with brownish, turbid fluid are 
also found as a result of the disintegration of the tissue. 
Such tumors grow by new formation of tissue from within, expanding and 
compressing adjacent structures, but showing no tendency to invade nor to 
set up, by metastasis, similar growths in distant organs. Nevertheless, 
they may cause great distortions in the uterus and interfere seriously with 
its function. Although childbirth may be possible when the tumor is not 
too large, or when it is situated high in the fundus of the uterus, it may 
readily be understood that a large tumor, especially when situated low in 
the uterus, can effectively obstruct parturition. Submucous myomata 
tend also to interfere with pregnancy and may, in case pregnancy does 
occur, offer a serious obstacle to the birth of the child. 
The submucous myomata are especially productive of serious symptoms 
at all times, since the uterus tends to expel them into the vagina, exposing 
the surface to infection. Circulatory disturbances aid in causing the mass 
to soften and disintegrate, and from the putrefying tissue absorption of 
poisonous substances soon leads to a cachectic condition in the woman who 
bears such a tumor. In addition, these growths usually cause frequent 
haemorrhages from the uterus, which may bring about extreme anaemia. 
The many other details in the biology of these tumors may be read in the 
book of Kelly and Cullen on Myomata of the Uterus, in which a great wealth 
of material is described. One of the most interesting phenomena is the 
formation of vascular adhesions between large subperitoneal uterine myo- 
mata and the omentum or intestine, or other abdominal organ, after which 
the tumor becomes dependent upon that organ for its blood supply and may 
even be separated finally from all connection with the uterus (parasitic 
myoma). 
Microscopically, fibromyomata are found to be composed of smooth 
muscle-fibres arranged in parallel rows in bundles which interlace in every MYOMA 
957 
direction. These are embedded in an abundant stroma of connective tissue 
which bears the blood-vessels. According to the proportion of muscle to 
fibrous stroma, the consistence of the tumor varies, increase in the fibrous 
tissue adding to its hardness. The muscle-fibres are recognizable by their 
rod-shaped nuclei and by their relatively plump cell-body, which takes a 
greenish color with Van Gieson's stain, in contrast with the bright red 
fibrous stroma. Of course, the actual bodies of the connective-tissue cells 
stain greenish yellow also, but they are rather sparsely scattered in the 
stroma. 
Several theories as to the origin of these tumors have been advanced, but 
none are as yet firmly established. While it seems probable that they 
arise from abnormal portions of the uterine musculature itself, there are 
those who assert their origin from the musculature of the walls of the blood- 
vessels. The fact that myomata relax and soften during pregnancy, recover- 
ing their hardness afterward, seems to point to their relation to the uterine 
musculature. 
The greatest interest has been roused by certain rather diffuse myoma- 
tous tumors which occur in the uterine wall, especially at the angle where 
the Fallopian tube enters, and also in the tube itself and in the round liga- 
ment. These are peculiar in containing epithelium-lined, gland-like cavi- 
ties scattered in the mass of smooth muscle. They were called adenomy- 
omata by von Recklinghausen, who ascribed them to misplaced rudiments 
derived from the mesonephros or Wolffian body. This view has been 
widely accepted. The proof is not complete, however, and R. Meyer, 
Lockstaedt, and others bring forward arguments against it showing that it 
is quite possible that such glandular tumors might arise from inclusion of 
uterine glands in a muscular mass. Cullen, in his volume on the subject, 
has shown, by careful study of 73 cases, that in 56 it was possible to trace 
the uterine mucosa directly into continuity with the glands of the tumor, a 
finding which seems to decide the matter definitely. 
Myomata of the stomach and intestine are usually small nodules lying 
beneath the mucosa or projecting on the peritoneal surface. They show 
no degenerative changes, and are, as a rule, too small to cause any symp- 
toms. Those in the vagina and in the urinary bladder are sometimes much 
larger, while nodules of smooth muscle in the kidneys are usually quite 
small. In the skin, myomata develop as subcutaneous or intracutaneous 
nodules arising probably from the tissue of the arrectores pilorum, although 
other explanations have been given. 
Malignant tumors composed of smooth muscle occur. Ghon and Hintz 
described one which arose from the intestinal tract with secondary growths 
in pancreas, liver, heart, etc., and give references to the literature which 
show that many cases have been observed. The development of such 
malignant characters is most important in the case of the common uterine 
myomata. In those tumors there are observed changes in the microscopi- 
cal appearance of the cells, leading to their extreme irregularity in size and 958 
TEXT-BOOK OF PATHOLOGY 
form. Corresponding with these peculiar appearances it has been found 
that the tumors assume a rapid and irregular growth and give rise to 
secondary growths or colonies in other organs or in adjacent tissues. It 
seems clear that malignant tumors spring out of benign myomata which 
have already existed for a long time, but the question remains as to their 
exact origin. They may be due to the acquisition of malignant powers of 
growth by the smooth muscle-cells, in which case we should speak of them 
as malignant myomata, or the invasive tumor may be the offspring of the 
Fig. 482.-Rhabdomyoma beginning in the vaginal wall in a child, and extending 
into the bladder. Grape-like polypoid masses hang from the infiltrated vaginal walls 
(Dr. C. Cone's case, from Kelly-Noble). 
stroma of the myoma, and then it would be justifiable to call the tumor a 
sarcoma. It is only in the latter case, in which there is a true sarcoma 
mixed with the muscle tissue of the myoma, that such a term as myosar- 
coma is justifiable. A sarcoma is not a tumor derived from muscle, but 
rather one arising from connective tissue. 
Leiomyomata.-Kelly and Cullen: Myomata of the Uterus, Phila. 
Cullen: Adenomyoma of Uterus, Phila., 1908. 
LITERATURE MYOMA 
959 
Leiomyomata.-Ghon and Hintz: Ziegler's Beitrage, 1909, xlv, 89. 
Lubarsch: Ergebn. d. allg. Path., 1895, i, 330; 1897, ii, 574. 
Aschoff: Ibid., 1900, v, 97. 
Zieler u. Fischer: Ibid., 1906, x, 700. 
Rhabdomyoma 
In these tumors, which are found usually in young persons or children in 
such positions as the heart-wall, bladder and vagina, kidney, oesophagus, 
etc., the tissue frequently contains cells of various kinds, among which 
there are found striated muscle-fibres. It seems to be rare to find a whole 
Fig. 483.-Rhabdomyoma, from same case as Fig. 482; long, ribbon-like, striated 
fibres (c) are mingled with round- and spindle-shaped cells (a, d). There are some wan- 
dering eosinophiles (e) (from Kelly-Noble). 
tumor made up of muscle-fibres, and the admixture is often with such ele- 
ments as cartilage, loose cellular connective tissue, and even epithelial 
structures. The suspicion is, therefore, aroused that rhabdomyomata are 
closely related to the mixed tumors or teratomata. 
These are usually benign tumors, but in many cases they develop invasive 
characters and may metastasize widely. Those in the heart-wall form 
single or multiple nodules which often project into the cavity of the heart. 
Those in the bladder, of which we were able to study one case, hang in 
polypoid masses which often appear in the vagina as well and protrude from 
its orifice (Fig. 482). 960 
TEXT-BOOK OF PATHOLOGY 
Microscopically, these are soft, often oedematous tumors, which show 
numerous small, irregular, and spindle-shaped cells which make up a con- 
siderable part of their bulk, but scattered among these, and sometimes in 
compact masses, are larger elements in whose protoplasm a delicate striation 
is visible (Fig. 483). These do not resemble muscle-fibres closely, but show 
transitions to other greatly elongated cells which do resemble the earlier 
developmental stages of striated muscle. These are narrow, ribbon-like 
cells with a central space which may contain many nuclei. The proto- 
plasm is not only longitudinally striated, but shows distinct transverse stri- 
ations. The rhabdomyomata usually have an abundant content of glyco- 
gen. They are regarded by most writers as arising from a rudiment derived 
from an early embryonic stage, which, displaced in the course of develop- 
ment, has grown in its unusual situation. 
LITERATURE 
Seiffert: Ziegler's Beitrage, 1900, xxvii, 145. 
Stumpf: Ibid., 1911, 1, 171. CHAPTER XLIX 
TUMORS (Continued) 
Tumors derived from elements of the nervous system: General relations to various stages in 
development of the nervous system. Neurocytoma, neuroblastoma, chromaffine tumors. 
Gliomata. Angiomata: hemangiomata, lymphangiomata. Sarcomata: General charac- 
ters. Spindle-cell, mixed-cell, round-cell, and alveolar sarcomata. Giant-cell sarcomata. 
Osteosarcomata. Myxomata. 
The interpretation of tumors of the nervous system has recently undergone 
many changes, and certain tumors growing in other parts of the body and 
formerly regarded as peculiar sarcomata, have been recognized as belonging 
to this group. 
Tumors are found composed of neuroglia in its various modifications; 
others contain certain ganglion-cells, often with abundant nerve-fibres, others 
are composed largely of antecedents of these structures capable sometimes 
of forming in the tumor ganglion-cells or fibres, elements of the type of the 
chromaffine tissue or any of the modifications of neuroglia. The type of 
tumor finally evolved seems to depend upon the stage in embryonic develop- 
ment at which the formative cells were diverted to the formation of a tumor. 
Originally, the epiblastic cells which line the medullary groove are capable of develop- 
ing into nervous elements or into supporting glial cells. The production of the peri- 
pheral nervous system is due to the outgrowth of nerve-fibres from this central region, but 
in addition to this, many of the neuro-epithelial cells wander into the interior of the 
body and assume certain positions in relation to the organs where they give rise to the 
cells and fibres of the sympathetic system. Their invasion into the interior of the rudi- 
ments of the adrenal glands results in the formation of the medulla of those glands in 
close relationship to the adjacent sympathetic ganglia. Similar modifications of some 
of these invading neurocytes in other situations lead to the formation of the analogous 
chromaffine bodies which are found in close association with the sympathetic ganglia 
in the thorax and retroperitoneal tract. It is necessary to believe that these cells may 
also give rise to less specialized attendant or supporting cells in each of these situations. 
The relations to one another of the elements derived from the original medullary 
groove may be expressed as follows in a table which is partly derived from Wahl and 
Landau: 
TUMORS DERIVED FROM ELEMENTS OF THE NERVOUS SYSTEM 
N euro-ectoderm 
Sympathetic formative cells 
Sympathogonia or neurocytes 
of the sympathetic system 
Neurocyte (neuroblast?) 
the cerebrospinal system 
Neurogliocytes (spongio- 
blasts?) of the cerebro- 
spinal system 
Sympathoblasts, 
transitions to 
Phseochromoblasts 
Ganglion-cells 
Neuroglial cells 
Ganglion-cells 
Sheath cells 
Peripheral 
glial cells 
Phaeochromocytes 
or chromaffine cells 
Sympathetic system 
Chromaffine system 
961 TEXT-BOOK OF PATHOLOGY 
962 
The known limitation of the power of mature nerve-cells and fibres to 
reproduce themselves has made it seem probable that those tumors which 
contain ganglion-cells and nerve-fibres must have arisen from some less 
differentiated stage. Indeed, since the weight of evidence is distinctly 
opposed to the idea that the cells of the sheath of Schwann, even if they do 
prove to be of nervous origin, can give rise to a new axis-cylinder, little 
credence is given to any report of tumors composed solely of tangles of 
nerve-fibres. There is probably no such tumor. 
Tumors of Nerves.-The tumors which actually appear in the course of 
the nerves are usually derived from the supporting structures and are some- 
times called false neuromata or neurofibromata. They have already been 
described in connection with fibromata. Those which show a cirsoid 
arrangement under the skin of the scalp or face are also of epineural or 
perineural origin, but do involve a great elongation of the nerve-fibres. 
Similarly the so-called amputation neuromata, which are round or nodular 
masses of whorled nerve-fibres, developing at the ends of nerves severed 
in the course of an amputation, are not tumors in the true sense. They 
are merely masses of twisted nerve-fibres frustrated in their attempt to 
grow down to the end-organ. Having excluded these growths from the 
group of tumors belonging strictly to the nervous system, it is found that 
nearly every stage in the table given above is represented by tumor for- 
mation. Wahl has discussed all these forms in an able paper in which he 
tabulates clearly all the tumors which have as yet been described and 
which can now be recognized as belonging to this group. 
Neurocytoma.-Marchand has described a small tumor composed of cells 
resembling lymphoid cells, with fine fibrillar ground substance, which he 
regarded as a neurocytoma, or tumor derived from the undifferentiated 
neuroectoderm. This tumor was found in the Gasserian ganglion, and no 
similar growth has as yet been discovered in the sympathetic system. 
Neuroblastoma.-J. H. Wright was the first to recognize clearly the 
existence of a group of tumors originating from the sympathetic formative 
cells or sympathogonia, and to these he gave the name neuroblastoma. 
These are growths which appear, as a rule, in infants and young children, 
although occasionally in adults, and in most cases arise from the adrenals, 
with abundant metastases in the liver. When they spring from other 
situations, such as the retroperitoneal or pelvic region, they are found to be 
associated with the sympathetic nervous system, and thence metastasize 
with great malignancy. They are often very extensive tumors, composed 
of small cells which are frequently arranged in characteristic rosettes, and 
the processes of these cells form a fine fibrillar intercellular stroma which 
gives none of the staining reactions of neuroglia or connective tissue. 
Sympathoblastoma.-Martius has described one case in which, side by side 
with ganglionic elements, the tumor which lay at the root of the neck con- 
tained cells transitional in appearance between those of the neuroblastoma 
and ganglion-cells. He thinks, therefore, that this tumor represents Poll's 
sympathoblast or transitional stage. 963 
TUMORS DERIVED FROM ELEMENTS OF THE NERVOUS SYSTEM 
Ganglioneuroma.-Many tumors containing ganglion-cells have been 
described from all parts of the body, but most often from some situation 
such as the retroperitoneal or pelvic or retrocervical regions, where they 
might have arisen in connection with the sympathetic system. These con- 
tain nerve-fibres also, though chiefly those of the non-medullated sort. The 
ganglion-cells are usually imperfectly developed and irregular in form, and 
the fibres are twisted and irregular in appearance, with, of course, no proper 
connection with any end-organ. While most ganglioneuromata are 
thought to be derived from the later developmental stages of the sympa- 
thetic system, there are some which arise in the same way in connection 
with the ganglia of the cerebrospinal system (Risel) or even in the brain 
itself. They are usually benign tumors, but a few, such as the second of 
Beneke's cases, show numerous metastases which seem to be derived from 
the smaller and less differentiated cells. 
In connection with these there is sometimes a marked new formation of 
neuroglial elements which spring from the peripheral glial-cells, and such 
tumors have been called ganglioglioneuromata. 
Neurinomata.-Verocay has recognized the origin of certain neuro- 
fibroma-like tumors which occur about the roots of spinal nerves and 
elsewhere in connection with nerves, from neurogenic tissue capable of 
forming ganglion cells, glia, and nerve-fibre cells. Antoni has collected 
and described minutely a number of such tumors often pressing on the 
spinal cord and composed of closely packed cells in palisade arrangement 
in bundles, but with many modifications in form and arrangement. For 
these he accepts Verocay's name multiple neurinoma. Masson has des- 
cribed tumors found in obliterated, vermiform appendices as neuromata 
of sympathetic origin. These too have something of the character of 
nerve sheath cells, but may contain distinct nerve-cell elements. Schweizer 
suggests that they, too, be called neurinomata. 
Certain tumors known as acusticus tumors or at times as cerebello- 
pontine tumors invade the internal auditory canal with the eighth nerve, 
compressing and destroying it and eroding the bone. These tumors have 
a structure resembling that of Verocay's neurinomata, and are composed 
of densely packed, elongated spindle-shaped cells. 
Chromaffine Tumors, Paragangliomata.-Benign and solitary tumors 
have been found in old people, arising usually in the adrenal medulla and 
containing, as a rule, sympathetic formative cells. These are composed 
largely of masses of cells which are sufficiently developed to give the brown 
staining reaction with chromic salts. No one has yet discovered a tumor 
which could be assigned to the earlier stage in the development of these 
cells (phseochromoblasts). 
It is seen that practically all these active tumors are derived from 
some stage in the development of the sympathetic system and its allied 
tissues, only rare examples of ganglioneuromata derived from develop- 
mental stages of the cerebrospinal system being mentioned. In contrast 
with this the tumors arising from the neuroglia of the cerebrospinal sys- 964 
TEXT-BOOK OF PATHOLOGY 
tem are relatively common and occupy an important place in the surgery 
of the nervous system. 
Gliomata.-From the neuroglia there develop tumors in the brain, in 
the spinal cord, and in the eye. These are benign growths in the sense 
that they give rise to no distant colonies or metastases, but they are 
extremely destructive, inasmuch as they grow 
expansively, and in an infiltrating way, into 
the important structures of the nervous sys- 
tem. Since they are confined in the bony 
cavities of the skull and spinal cord, they soon 
cause the most serious symptoms through the 
pressure on the brain or cord. Even though 
a glioma embedded in the brain may not it- 
self increase the intracranial pressure enough 
to cause these well-known symptoms, it is con- 
stantly liable to sudden extravasations of 
blood into its substance, which are followed 
by apoplectiform attacks, with loss of con- 
sciousness, high blood pressure, choked disc 
(Fig. 484), and even generalized paralysis. 
The gliomata of the brain may be situated 
at any point in the cerebrum, cerebellum, 
pons (Fig. 485), etc., and vary in size from very small nodules up to 
huge masses which occupy nearly the whole of a hemisphere. They 
Fig. 484. -Choked disc 
with small haemorrhages, from 
a case in which a glioma of 
the cerebellum produced hy- 
drocephalus and increased in- 
tracranial pressure. 
Fig. 485.-Glioma of pons with moderate haemorrhage. 
are rarely sharply outlined, either by their color or their consistence, but 
shade off insensibly into the surrounding brain substance (Fig. 486). Their TUMORS DERIVED FROM ELEMENTS OF THE NERVOUS SYSTEM 
965 
position can be made out in the cut surface fairly well, however, by the 
swelling, the increased vascularity and translucence, and by the haemor- 
rhages and necroses which are usually present. There are some forms, 
indeed, which are so diffused through the brain substance that it is difficult 
to determine their outline even with the microscope. The adjacent tissue 
is pushed aside, and is much torn by the growth of the tumor. Neverthe- 
less, gliomata do not, as a rule, extend to the surface of the brain and never 
pierce the meninges. A small group of these tumors presents an appearance 
Fig. 486.-Glioma of brain with haemorrhage. 
very different from that of the common ones. Instead of being gray, 
translucent, soft, and rather cedematous, they are small, compact, and even 
quite hard. These generally project in relation to the ependyma. 
Under the microscope most gliomata present a fairly uniform mass of 
cells of rather small size, with numerous protoplasmic processes which extend 
into a tangle with those of other cells and thus produce a feltwork of delicate 
filaments (Fig. 487). The question as to the independence of some of these 
neuroglia fibres seems to be unsettled in the minds of some writers, but 
Mallory has shown by special stains that the neuroglia fibres bear the same 
relation to the neuroglia cells as the collagen fibres to the cells of the con- 
nective tissue. They are differentiated products sometimes still traversing 
the edge of the body of the cell, sometimes lying free. Nevertheless, the 
actual protoplasmic processes of the cells play a considerable part in forming 
the fine intercellular network. 966 
TEXT-BOOK OF PATHOLOGY 
Great variety is seen in the form and arrangement of these cells. They 
are frequently found to have a rather abundant cytoplasm, with many long 
processes extending in all directions, so that they have acquired the name 
astrocyte or spider cell. Others are much simpler in outline and may have 
Fig. 487.-Glioma of the cerebrum composed of loosely arranged neuroglia cells and 
fibres. 
very few prolongations (Fig. 488). In many gliomata they are especially 
condensed about the blood-vessels; in others there are minute spaces about 
which cells are arranged radially with a fiat or curved foot at the edge of the 
space, and a long, frayed-out cell-body extending peripherally to become 
entangled with the other cells. About larger spaces the same presentation 
of a smooth surface to the cavity is seen. Ganglion-cells and other nerve- 
cells of smaller size are quite frequently found in the substance of a glioma. 
It seems clear that these must be remnants of the original nervous tissue 
which have been caught in the advance of the tumor and surrounded. 
The degenerative changes, haemorrhages, and necroses which are so fre- 
quent in these tumors have already been mentioned. They may lead to 
such wide-spread destruction of the tumor that only a thin rim of tumor 
tissue is left. It is not infrequent in such cases to find that the debris of the TUMORS DERIVED FROM ELEMENTS OF THE NERVOUS SYSTEM 
967 
tumor-cells and blood has been replaced by a clear fluid, so that the whole 
area appears as a thin-walled cyst with only some pigment and fast vanish- 
ing traces of tumor tissue in its walls to indicate its original nature. I have 
seen two cysts of this kind in the cerebellum which had had time to reach 
this state in spite of the great destruction of the cerebellar tissue. 
Fig. 488.-Glioma of cerebrum. 
Gliomata developing in the pons or in the medulla may cause even more 
serious and quickly fatal destruction than those embedded in the brain. In 
the spinal cord these tumors are less common. They may exist in the form 
of a nodular mass, but are usually centrally placed and much elongated, 
forming, in the midst of the cord, a pencil-like growth which pushes aside 
all the nervous elements and compresses them. Many of these central 
tumors have a lumen and then appear as tubes. While an overgrowth of 
neuroglia or gliosis may occur in the cord from other causes, the presence of 
such a tubular glioma can give rise to one, at least, of the forms of syringo- 
myelia. 
Syringomyelia is a curious affection of the spinal cord in which, as its name implies, a 
pipe or tube of neuroglia is embedded in the cord, and extends, sometimes, upward into 
the medulla. The most extraordinary symptoms follow: loss of temperature sense, and 
later of tactile sense, extreme contractures and deformities of the extremities and thorax, 
etc. 968 
TEXT-BOOK OF PATHOLOGY 
In the eye, gliomata arise from the glial constituents of the retina, or from 
some earlier developmental stage of the cells of the retina which can give 
rise to glial tissue, and grow out into the vitreous humor, pushing the retina 
forward. Frequently they begin near the anterior margin of the retina, 
and extend thence so as to occupy much or all of the cavity of the eye. 
Necroses are extremely frequent in the tissue, and the whole tumor may be 
reduced to a non-staining debris, except for the cells which immediately 
surround the blood-vessels. In other cases, in which there is no such necro- 
sis, the nodular mass pushes through the sclera or through the cornea and 
appears in the orbit or on the surface of the eyeball. When removed by the 
enucleation of the eye, it tends to recur and to spread rapidly in the orbit 
and backward into the brain. The opposite eye is commonly involved. 
The tumor itself .is usually composed of small cells with little protoplasm 
and very few inconspicuous fibrils. There is another type first described, 
as far as I can determine, by Flexner, in which the cells are frequently ar- 
ranged in rosettes. This tumor, he thought, should be designated neuro- 
epithelioma, since it apparently arose from an undifferentiated element 
of the retinal neuro-epit helium. 
Ependymal Gliomata.-Several authors have described gliomatous 
tumors in which, on account of the presence of peculiar gland-like spaces 
lined with cells resembling epithelium, they have traced a relationship to 
the ependymal cells. Mallory was able to show that these peculiar cells 
have in their protoplasm certain small rodlets or granules which are charac- 
teristic of the ependymal cells, and therefore had no hesitation in regarding 
them as ependymal gliomata. Saxer described other tumors in which the 
ependymal elements occupy the predominant place and grow up into papil- 
lary masses resembling those seen on mucous surfaces. These cells are, 
however, of the same origin as the neuroglial elements in general. 
J. H. Wright: Jour. Exp. Med., 1910, xii, 556. 
Landau: Frankfurter Ztschr. f. Path., 1912, xi, 26. 
Wahl: Jour. Med. Research, 1914, xxx, 205. 
Herde: Archivf. kl. Chir., 1912, xcvii, 937. 
Weglein: Verh. Dtsch. Path. Gesellsch., 1912, xv, 225; Frankf. Ztschr. f. Path., 1909, 
ii, 485. 
Symmers: Jour. Amer. Med. Assoc., 1913, lx, 337. 
Harbitz: Archives of Int. Med., 1915, xvi, 312. 
Glioma.-Landau: Frankfurter Ztschr. f. Path., 1910, v, 469. 
Mallory: Jour. Med. Research, 1902, viii, 1. 
Stroebe: Ziegler's Beitrage, 1895, xviii, 405. 
Saxer: Ibid., 1902, xxxii, 276. 
Flexner: Johns Hopkins Hosp. Bull., 1891, ii, 115. 
Verocay: Ziegler's Beitrage, 1910, xlviii, 1. 
Masson: Bull, et Mem. Soc. Anat, de Par., 1919, Ixxxix, 405. 
Guirin: Sympathomes Embryonnaires, Trav. de 1'Inst. and Anat. Pathol, de Stras- 
bourg, 1921. 
Cash: Jahrb. f. Psych, u. Neurol., 1923, xlii, 185. 
Cushing: Acusticus Tumors, Saunders, 1917. 
LITERATURE ANGIOMATA 
969 
ANGIOMATA 
Haemangioma.-A haemangioma is a tumor composed essentially of 
blood-channels, in contradistinction to a lymphangioma, whose cavities 
contain lymph instead of blood. A true haemangioma is distinguished from 
a mere dilatation of capillaries or venules belonging to the general circula- 
tion by the fact that its blood-channels grow independently, without regard 
to the laws which govern the distribution of such vessels. It thereby 
forms a mass which is somewhat withdrawn from the general circulation, 
and although supplied with artery and vein, does not stand in any intimate 
anastomotic relations with the adjacent circulation. Ribbert lays great 
stress upon this lack of communication between the capillaries of an 
angioma and those of the contiguous tissue, and has proved his point by 
injections. Further, he insists that such tumors grow from their own vas- 
cular substance and not through the widening and assimilation of adjacent 
vessels. There are some border-line forms in which it is difficult to say 
whether one is dealing with a tumor or not, such as the plexiform or cirsoid 
angiomata of the scalp, which are made up of tangled masses of pulsating 
arteries, and others of even less tumor-like nature, such as the bluish vas- 
cular flecks seen in the skin of old people. True haemangiomata are most 
commonly divided into a simple or telangiectatic form, in which the abun- 
dant capillaries, though widened, maintain fairly well their form as tubes 
with parallel walls, and the cavernous form, in which the character of erec- 
tile tissue is approached, with large, irregular blood -spaces opening abun- 
dantly into one another. It is not very apparent, however, where the line 
of division can be sharply drawn between these groups. Certainly it is 
difficult to determine from sections in some cases whether one should regard 
the tumor as verging on the cavernous or not. Doubtless if the channels 
were injected and a slice of the tumor rendered transparent, a most beautiful 
proof of this distinction might be obtained. 
These tumors occur most commonly in the skin, especially on the face 
and scalp, but also in all other parts of the body. The more definitely 
simple forms through which blood runs fairly rapidly present themselves as 
flat or slightly elevated, bright-red patches from which the blood may be 
squeezed out (naevus flammeus). Many of these are found in the neighbor- 
hood of angles or fissures about the face and neck so that they have been 
thought to be congenital displacements. Hanes has recently reviewed the 
history of a peculiar hereditary form of multiple telangiectasis with num- 
erous bluish nodules in the skin and nose from which any trifling injury 
would serve to start a profuse haemorrhage. In these, the irregularly 
widened capillaries lay just under the thin smooth skin. Other examples 
of simple angiomata are found in the muscles, where they reach a con- 
siderable size. In the tongue, nose (Fig. 489), and lips they are also found, 
but in all these latter situations the tumor is likely to have more of the 
cavernous character. 970 
TEXT-BOOK OF PATHOLOGY 
Cavernous angiomata are also common in the skin, where they form 
most of the so-called birthmarks which are so frequently seen on the face. 
These are usually dark purple, and are often covered with rough, nodular 
skin (naevus vinosus). They are, as a rule, distributed over the region of 
one or more divisions of the fifth cranial nerve and seldom cross the mid- 
line of the face. It is said that they sometimes appear in the meninges in a 
Fig. 489.-Angioma from the nose. The blood-channels are of fairly uniform calibre. 
corresponding distribution, and that they may give rise to haemorrhage 
there (Cushing). In the lips or tongue they form large, nodular, purple 
masses very prone to injury and haemorrhage and very distorting. I have 
seen one or two cases of multiple cavernous haemangiomata in the walls of 
the intestine (Fig. 490). Haemorrhage may occur from these, although it 
had not done so in my cases. In the muscles, masses of spongy vascular 
tissue are found, extending between the fibres and into the intermuscular 971 
ANGIOMATA 
spaces. In these, too, the blood-channels are frequently irregular in form, 
with wide communications. 
The cavernous angiomata of the liver constitute perhaps the best studied 
type (Fig. 491). They are found, as a rule, at autopsy, without having 
given rise to any symptoms, and may be very small or reach a diameter of 
several centimetres. Frequently there are four or five in the same liver, of 
rig. 490.-Cavernous haemangioma of the small intestine. 
which some may be visible through the capsule, while others are buried deep 
in the substance. On section, they appear as deep, purplish-red, sharply 
outlined areas, from which dark blood can be squeezed or washed out, leav- 
ing a grayish-white, spongy framework. We have recently seen at autopsy 
a huge angioma of the liver which was only partly surrounded by liver 
tissue, and hung as by a stalk from the right lobe. It measured 24 cm. in 
diameter, and corresponded in structure with the smaller ones. Micro- 972 
TEXT-BOOK OF PATHOLOGY 
scopically, this framework is seen to inclose quite large spaces which open 
into one another, and which are evidently interposed between artery and 
vein. They are lined with endothelium and do not seem to communicate 
with the adjacent capillaries, although some of them occasionally extend 
into the adjacent liver substance as though forming an outpost of growth. 
Liver-cell strands are often found to lie in the connective tissue of the 
angioma, practically surrounded by it. Nevertheless, as Ribbert points 
out, an injection of the angioma passes very little, if at all, into the circula- 
tion of the liver. 
In all these angiomata circulatory disturbances can occur. Infection may 
cause an inflammatory reaction in their substance, thrombosis of the blood- 
channels is common, and phleboliths may be formed. It is not infrequent 
to find parts of them scarred and obliterated by such processes with abun- 
dant pigmentation. 
Ribbert's idea of their origin from a rudiment which is destined to form 
blood-vessels, from which they grow independently, is generally accepted, 
and the ideas as to their being due to mere dilatation of capillaries, or to the 
Fig. 491.-Cavernous haemangioma of the liver. 
organization of haemorrhages, should be abandoned. That they may be the 
result of foetal displacement of tissue is, of course, prominent in all discus- 
sions, and applies here just as it does in the case of most other tumors. These 
are among the displacements or perverted formations of tissue which 
Albrecht separates as "Hamartomata." 
In the edges of the heart valves of infants there are frequently seen 
minute, tense, deep-red nodules which project like tiny red berries. On 
section they look like cavernous haemangiomata, but they persist only a 
short time, and are probably not to be regarded as tumors (Fig. 492). 
Lymphangioma.-Quite analogous tumors, except that they are composed 
of spaces and channels containing lymph, are the lymphangiomata. They 
are telangiectatic or simple, cavernous, and cystic. Of these, the first type 
is especially common in the skin, lips, tongue, and subcutaneous or inter- 
muscular tissue. They form nodular masses or diffuse enlargements which, 
on injury, may allow the escape of lymph. In the case of the tongue, they 
cause an enlargement which constitutes one of the forms of macroglossia, 
and in the extremities the diffuse distribution of such a cutaneous and sub- 
cutaneous tumor may give rise to a great enlargement which constitutes 973 
ANGIOMATA 
one of the numerous divergent forms of elephantiasis. In section such 
tumors are found to be made up of anastomosing channels or spaces lined 
with thin endothelium and filled with clear fluid with a few lymphoid cells. 
Naturally haemorrhages into these spaces may confuse the picture and sug- 
gest the existence of a haemangioma, but the history of the case will prevent 
such an error in diagnosis. In these tumors, as in the haemangiomata, the 
interstitial connective tissue grows, together with the lymph-channels, to 
Fig. 492.-Angiomatoid nodule upon the heart-valve of an infant. 
produce the tumor which again is more or less independent of communica- 
tion with adjacent lymphatics. In the intestinal wall one may observe 
nodules of considerable size filled with clear or with milk-white fluid, and 
composed of cavernous arrangements of lymph-channels. It is important 
here to distinguish between true cavernous lymphangiomata and mere 
dilatations of the chyle-ducts. 
The cystic lymphangiomata are, as a rule, still more circumscribed, and 
are composed of masses of rounded or irregular cystic structures with the 
same thin endothelial lining. They occur sometimes in the internal organs, 974 
TEXT-BOOK OF PATHOLOGY 
as in the liver, spleen, adrenals, etc., where they are usually pretty sharply 
marked out from the organ itself. In the neck and sacral regions the so- 
called cystic hygromata are found, and are especially easily recognized as 
the results of developmental disarrangements of tissues. They are cystic 
lymphangiomata which are less circumscribed, and in the neck form large, 
ramifying masses which extend far up behind the ear and down between the 
muscles of the thorax and in the soft tissues of the shoulder. One, which 
we saw recently in a child, had become infected, so that all the cavities were 
filled with a purulent exudate which infiltrated the tissue between them. 
Another showed, in addition to the large tumor in the neck, a mass as large 
as an apple projecting into the pleural cavity. When, as in the so-called 
lymphangioma tuberosum multiplex of Kaposi, there are more complex 
strands of endothelial cells in place of simple, endothelial-lined channels, 
it is better to speak of the tumor as an endothelioma. 
Haemangioma.-Ribbert: Virch. Arch., 1898, cli, 381. 
Hanes: Johns Hopkins Hosp. Bull., 1909, xx, 63. 
Roggenbau: Ziegler's Beitrage, 1910, xlix, 313. 
Fischer and Zieler: Ergebn. d. allg. Path., 1906, x, 815. 
Lymphangioma.-Sick: Virch. Arch., 1902, clxx, 9; 1903, clxxii, 445. 
Fischer and Zieler: Loc. cit., 842. 
Paltauf: Verh. d. Dtsch. Path. Gesellsch., 1908, xi, 255. 
LITERATURE 
A sarcoma is a tumor arising from connective tissue and retaining most of 
the general characteristics of connective tissue, but endowed with the new 
power of invading and actively destroying adj acent structures and of form- 
ing colonies of its own tissue in distant organs. In this respect sarcomata 
are typically malignant tumors. 
It has been shown that benign tumors may be derived from any of the 
various forms of connective tissue which make up the framework of the 
body, and that they depart somewhat, in each instance, in the character of 
their cells, from the normal standard. All this is equally true of the sar- 
comata, and while they, too, may originate in any kind of connective tissue, 
their cells are far more unlike those of the normal tissue in appearance and 
totally unlike them in their biological characters? 
It is scarcely possible to decide from the study of a microscopical prepara- 
tion as to the point of origin of any sarcoma, since almost any region may 
be the starting-point for any type of tumor. When the tumor contains 
bone or cartilage, it is fairly safe to say that it sprang from some part of the 
skeleton, although this, too, would be indiscreet, since such tumors occasion- 
ally arise elsewhere. 
The sarcomata are tumors preeminently characterized by the energy and 
rapidity of growth of their cells, and this in itself brings about the striking 
morphological differences between them and the corresponding benign 
tumors arising from similar situations in the connective tissue. It would 
SARCOMATA SARCOMATA 
975 
doubtless be quite misleading to describe the lack of a capsule or of a dense 
stroma as mechanical factors favoring their rapid growth. On the con- 
trary, they grow so quickly and irresistibly that there is no time for the 
formation of a dense stroma nor any opportunity for their encapsulation. 
There may be differences between these cells and those of a fibroma with 
regard to the process of mitosis. It is possible that irregularities in mitosis 
are associated with their precipitate growth, and that this explains the 
irregularities in the form of the cells sometimes met with, but in general 
they grow and develop in much the same way. Cultures in vitro from nor- 
mal connective tissue and sarcoma tissue are almost indistinguishable from 
one another, except by most careful comparison of such things as the mitotic 
figures just mentioned. In both cases the cells grow out in scattered 
strands or isolated groups, quite unlike epithelial cells, and through their 
power of stretching themselves along a support and responding to tactile 
stimuli make considerable progress away from the point of origin. In the 
tumors, as they occur in the body, the impression is given in many cases that 
such cells form the whole compact mass, but in every case it is found that in 
addition there is a distinct framework of ordinary connective tissue with 
very abundant blood-vessels and some nerve-fibrils. Just as in all other 
tumors, the sarcoma elements demand this service of the normal tissues, and 
force the development of a mechanism for support and blood supply. Some- 
times the framework is extremely delicate and seems to consist of little 
beside thin-walled blood-vessels (Fig. 493, c). In other cases it is very abun- 
dant and dense, so that the tumor-cells are separated into strands and 
compact masses which anastomose with one another, but appear in sections 
as the contents of alveolar spaces. (Fig. 493, 6) There are also types of 
sarcoma in which the tumor cells themselves have the power of producing 
abundant intercellular fibres. 
The malignant character of the tumor is evident in the infiltrating, 
destructive manner of its growth when it is well established, but in the 
beginning it may be difficult to recognize this. Nevertheless, unless the 
tumor is extirpated it soon reveals its true nature, and even if it is removed 
at operation, the tendency to recur in the same place from traces of the tissue 
left behind is associated with other evidence of its malignancy. Above all, 
the appearance of colonies of the same tissue elsewhere in the body leaves 
no room for doubt. It appears, then, that in order to decide upon the 
nature of a connective-tissue tumor which, as far as its microscopical mor- 
phology is concerned, might be a benign fibroma or a malignant sarcoma, 
it is necessary to know the history of the growth and its gross relations to 
the adjacent tissues. Even then it may be impossible to be completely 
sure until recurrence or metastases have appeared. It is at this point that 
the greatest uncertainty may exist, but ordinarily, as will be explained, the 
morphology of the tumors has become sufficiently well known in connection 
with the history of their growth to allow one to foretell the progress of the 
growth and to decide upon its nature. 976 
TEXT-BOOK OF PATHOLOGY 
There are great difficulties in outlining this group of tumors, since there 
are so many malignant growths composed of ill-characterized cells upon 
whose origin it is almost impossible to decide exactly. Many authors are 
willing to speak of malignant tumors arising from muscle, neuroglia, etc., 
by such names as myosarcoma and gliosarcoma. Ribbert is among those 
Fig. 493.-Several types of sarcoma: (a) Spindle-cell sarcoma from chest-wall; 
(b) alveolar sarcoma of mesentery; (c) spindle-cell sarcoma; the blood-vessels are in- 
jected and are seen to be very numerous; (d) mixed-cell sarcoma of leg metastasizing 
to the mediastinum; (e) osteosarcoma with calcified areas and cartilage. 
who prefer, as it seems to me correctly, to call them malignant myomata 
and malignant gliomata, reserving the term sarcoma for malignant tumors 
clearly of connective-tissue nature. Such names can be used, however, to 
indicate a sarcoma in which the type of connective tissue from which it 
originated is still evident, as osteosarcoma, chondrosarcoma. Recently, too, SARCOMATA 
977 
there has been a tendency to treat separately, on account of their peculiar 
character, tumors thought to be derived from endothelium, and that group 
of pigmented tumors long known and still generally spoken of as melanosar- 
comata. In addition to these there are numerous tumors which arise from 
somewhat specialized cells belonging to the blood-forming apparatus and 
Fig. 494.-Several types of sarcoma: a, Mixed-cell sarcoma; b, coarse spindle-cell 
sarcoma; c, metastatic round-cell sarcoma; d, sarcoma of thyroid with giant-cells; e, 
sarcoma of ovary. 
which, under various names (lymphosarcoma, leucosarcoma, myeloma, etc.), 
have, rightly or wrongly, been considered in connection with the diseases of 
that apparatus, since it is by no means quite clear that they are tumors at 
all. Finally, there are tumors, usually of rather complicated structure and 
often occurring at birth, or in the very young, which have long been desig- 978 
TEXT-BOOK OF PATHOLOGY 
nated sarcomata, but which appear to be rather of the nature of the so- 
called mixed tumors, which are referable to the aberrant growth of tissue 
displaced in the course of embryonic development. In this group there 
may be mentioned especially many of the malignant tumors of the testicle 
and the sarcomata of the kidney which grow during infancy and childhood. 
Nevertheless, in spite of the nebulous state of our knowledge as to the 
real relations of these questionable growths, there remain many well- 
Fig. 495.-Sarcoma of tissues of the axillary plexus. The cells of the tumor are long 
and fusiform, and there are many wandering cells. 
defined sarcomata which, in any series of cases, stand out sharply as easily 
recognized representatives of certain groups. They are distinguished from 
one another chiefly by the form of their cells and by the character of their 
intercellular substance, as well as their energy of growth, but there are so 
many transitional forms and combinations that I do not wish to draw very 
sharp lines between them (Fig. 494). 
Of these, the commonest are the spindle-cell sarcomata, which originate SARCOMATA 
979 
in almost any situation. In the series which I have for study spindle-cell 
sarcomata arose in the breast, hand, mesosalpinx, vulva, wall of ovarian 
cyst, leg, liver, etc., but any connective tissue, such as fasciae, subcutaneous 
tissue, or the framework of organs, may be their starting-point. They are 
white or gray-white, rather firm, shining, and somewhat circumscribed 
masses which have perhaps less tendency to metastasize widely than some 
of the other forms. Microscopically, they are found to be composed of 
smoothly arranged, elongated or spindle-shaped cells, very uniform in size 
and general appearance, 
and supported in bundles 
or whorls by the most 
delicate stroma, with wide 
and very thin-walled 
blood-vessels. The inter- 
cellular substance of the 
tumor itself is usually ex- 
tremely scanty, so that 
the cells lie close together. 
In some cases, however, 
there is a good deal of fib- 
rillar intercellular sub- 
stance, the cells are less 
uniformly arranged and 
tend rather to a branched 
form (Fig. 495). To such 
tumors the name fibrosar- 
coma may be fittingly 
applied. The secondary 
growths or metastases may 
occur in the lymph-glands, 
which drain the area of 
the tumor, but they are 
more frequently found in 
the lungs (Fig. 496) and 
later in other internal or- 
gans which would indicate 
that the cells of the tumor were transported by way of the venous blood- 
stream (c/. Fig. 28). Borst emphasizes the idea that such spindle-cells 
are especially immature, approaching in this respect embryonic cells.- It 
seems to me, however, that this is based merely upon the general resem- 
blance in form to the cells of embryonic connective tissue. Their biolog- 
ical characters, which should be of greater weight in deciding such a 
question, are totally abnormal, and they have acquired powers which 
might distinguish them very sharply from even the most immature of 
embryonic cells, since they are such as to enable them to grow indefinitely 
Fig. 496.-Metastatic sarcoma in the lung. Nod- 
ules are found in various parts of the pleura, but 
especially along the margins of the lobes. TEXT-BOOK OF PATHOLOGY 
980 
without at any time differentiating themselves into any finite tissue which 
obeys the normal laws of growth. The resemblance to embryonic tissue is, 
therefore, most superficial, and they are rather cells which have no true 
analogue in the body at any stage of its development. 
Nearly as common as the spindle-cell sarcomata are those in which cells 
of many forms and sizes occur, with many bizarre modifications of their 
nuclei. For want of any better term, these may be called mixed-cell sarco- 
mata (Fig. 494, a). They arise anywhere, too, but perhaps most commonly 
in connection with the internal organs. I have seen them especially in the 
retroperitoneal region, apparently springing from the lymph-glands there, 
and forming huge masses, but there are before me examples from the thy- 
roid, from the ovary, periosteum, etc. The cells are in general fusiform, 
but are somewhat irregularly arranged and form by no means so compact 
and orderly a tissue as in the pure spindle-cell type. Among these are 
many of much larger size, with several nuclei or one very large and deeply 
stained nuclear mass. 
Round-cell sarcomata are in our experience relatively rare as long as we 
separate from them the lymphosarcomata and leucosarcomata, which have 
distinctive features, as already mentioned. They are tumors composed of 
small round cells held in a most delicate vascular stroma which in any single 
microscopical preparation might be difficult to distinguish from lymphosar- 
comata. They arise, however, as single, rather circumscribed masses spring- 
ing from the connective tissue of the skin or fascise or intermuscular septa 
or elsewhere, and, aside from their local invasion and destructive growth 
spread, not in a regional way, as lymphosarcomata do, but exactly as other 
sarcomata, by the transportation of their cells, usually by the blood-stream 
to the distant lungs, where they form once more circumscribed and solid 
nodules (Fig. 497). When a regional lymph-gland is involved, it usually 
presents a more or less definitely outlined tumor mass embedded in its sub- 
stance, and is not itself at first completely replaced by the new tissue. These 
round-cell sarcomata are extremely malignant, and give rise to wide-spread 
metastases, often passing through the lungs into the general circulation. 
There are some with small and some with relatively large cells. 
Other distinctly sarcomatous tumors of equally cosmopolitan origin are 
composed of cells uniform in type, but not definitely round nor spindle- 
shaped. They are rather polygonal or plump cells, which form a compact 
tissue with abundant ramifying blood-vessels. 
In these especially, but also in the other forms already described, there 
often occurs what seems to me to be a local necrosis of the tumor cells from 
lack of sufficient blood supply. This leads to a curious condition in which 
only those cells which are close to the blood-vessels remain alive and the 
rest fade into a pale-pink staining debris (Fig. 498). Consequently the 
tumor appears to be made up of blood-vessels each with a thick mantle of 
cells, and such tumors have been described as a separate type under the 
name angiosarcoma. The cells about the blood-vessels have been regarded 981 
SARCOMATA 
as arising from a hypothetical tissue spoken of as perithelium, and the tu- 
mor, therefore, called a perithelial angiosarcoma. It is possible that tumors 
with this structure really exist, to which the explanation just given will not 
apply, but I have not seen them. The appearance is common enough, 
but in itself does not seem sufficient to warrant the use of a special name. 
Alveolar sarcomata are those in which the tumor-cells are rounded or 
polygonal, rarely fusiform, and grow in groups or strands which lie in the 
Fig. 497.-Round-cell sarcoma primary in the testicle. There are several large cells 
which show irregular mitotic figures. 
meshes of a fairly dense stroma (Fig. 493, c). In a single section the cells 
appear to be inclosed in alveolar spaces and indeed they then resemble very 
closely some kinds of carcinoma. At times it is difficult if not impossible to 
distinguish between them from a single section, although the distribution of 
the tumors and the history of the case will usually decide. Efforts have 
been made to state histological criteria, by which it is made to appear that 
the cells of the sarcoma are in more intimate relation with the stroma and 
often pervaded by fine fibrillae of stroma, while the carcinoma cells lie 982 
TEXT-BOOK OF PATHOLOGY 
isolated in spaces lined by endothelium. I am sure that this is all based on 
hypothesis made to suit the case for the relation of the epithelial cells of the 
cancer to the connective tissue may in point of space be just as close as that 
of the sarcoma cells; moreover, the fibrillae of stroma are not evident, and 
the cancer cells do not restrict themselves to endothelial-lined channels, but 
push into any cranny or crevice of the fibrous tissue. The form of the 
Fig. 498.-Sarcoma springing from the pelvis and showing disintegration of the cells, 
except in the neighborhood of the blood-vessels. 
tumor cells is of no help because sarcoma cells and epithelial cells may look 
exactly alike. But an epithelial origin is soon found for the cancer in one 
or other characteristic site, whereas the alveolar sarcoma begins its 
growth, not in an epithelial organ, but in some such place as the dermis 
or the fascia or the skeletal tissues. It is quite common to find very 
numerous subcutaneous or intracutaneous nodules scattered over the body 
which reveal themselves as alveolar sarcomata, and appear to grow simul- 
taneously. They are usually secondary to some original growth of ear- 
lier formation. SARCOMATA 
983 
Giant-cell Sarcomata.-Although large irregular protoplasmic masses 
with several nuclei occur at times in many of the mixed cell sarcomata, there 
is a group of tumors in which typical multinucleated giant-cells form so 
constant and characteristic a feature that they are classed by themselves 
under this name. 
They arise usually in connection with bone, and although many of them 
Fig. 499.-Giant-cell sarcoma springing from a bone. 
are otherwise composed of spindle-shaped cells showing no tendency to 
cartilage or bone formation (Fig. 499), there are also tumors containing 
such giant-cells which definitely belong to the group of osteosarcomata. 
For this reason, the idea has been suggested that the giant-cells may be 
identical with the osteoclasts of the bone which are endosteal or periosteal 
cells modified by their phagocytic function. Others have thought that 
since giant-cell sarcomata occur also in other places, such as the breast, far 
from any connection with bone, the giant-cells might be regarded as com- 
parable to the ordinary foreign body giant-cells. There is perhaps no 
fundamental difference between the giant-cell character of osteoblasts and 
that of foreign-body giant-cells, and in both cases it seems to be a morpho- 984 
TEXT-BOOK OF PATHOLOGY 
logical modification dependent upon the function of the cells and perhaps 
only temporary. It is, therefore, difficult to decide upon the relation of the 
cells of the tumor to such cells and probably dangerous to assume that any 
of these types of giant-cells could transmit their giant-cell character to 
their offspring. 
Fig. 500.-Giant-cell sarcoma (epulis) from the jaw. 
The most common giant-cell sarcomata are those which grow from the 
alveolar process of the jaw and hang as pedunculated tumors in the cavity 
of the mouth. These growths, which are known by the name epulis, are 
covered for a time with the mucosa of the mouth, but tend to become 
ulcerated. They are usually rather small, but occasionally, as in one case 
which I saw, reach such a size as practically to fill the mouth. When 
removed, they show little tendency to recur and there are no metastases. 
Microscopically the dense, hard tumor is found to be composed of inter- 
laced spindle-cells with numerous large multinucleated giant-cells (Fig. 500). 
Other giant-cell sarcomata, closely related to these, spring from the peri- 
osteum of long bones, or, still more commonly, from their endosteal lining. SARCOMATA 
985 
Expanding and eroding the cortex of the bone, they form large masses which 
are kept covered by a constantly new formed shell of periosteal bone. The 
central part may, through haemorrhage or other disturbances of circulation, 
Fig. 501.-Periosteal osteosarcoma of the humerus. The marrow cavity is not invaded, 
become necrotic and softened, and there may be formed a cyst-like swelling 
in or about the bone, in the walls of which little or no tumor tissue is left. 
There is a tendency among surgeons to insist that such are not tumors 
at all, that they never metastasize, and that the giant-cells are merely 
foreign-body phagocytes associated with a granulation tissue which en- 
capsulates the central haemorrhage and necrosis. It will require further 
study to reach a decision on this question. 
Osteosarcoma, Osteochondrosarcoma. - There are other sarcomata, 
usually forming large nodular masses about the bones, which are developed 
from the periosteum or from the endosteum. These, while showing to some 
degree the capacity of sarcomata to metastasize, have retained the power of 
the bone-forming cells to elaborate all the types of connective tissue con- 986 
TEXT-BOOK OF PATHOLOGY 
cerned in the formation of bone. Hence the tumors are found to contain 
cartilage, osteoid tissue, and definite bone, as well as the less specialized 
cellular or fibrous tissue. 
Those which arise from the periosteum form spindle-shaped or irregular 
nodular masses around the bone (Fig. 501), often with beautiful, glistening, 
radially arranged spicules of bone which give the tumor great rigidity. 
Those which start in the endos- 
teum fill the marrow cavity, erode 
through the cortex of the shaft of 
the bone, and finally spread out- 
side as expanding nodular tumors 
(Fig. 502). In either case there 
may be great irregularity in the 
form of the growth and in the 
character of the tissue of which it 
is composed. In all these tumors 
which arise from bone-forming 
cells the new-formed tissue usu- 
ally presents a ground-substance 
of irregular or spindle-shaped 
cells, among which certain groups 
give rise to areas of cartilage or 
cartilage - like tissue. This be- 
comes calcified, and, by a proc- 
ess resembling that of normal 
ossification, lamellae of bone are 
formed, usually in the most ir- 
regular arrangement. In other 
cases, or even in the same tumors, 
osteoid tissue is usually formed 
without the intervention of carti- 
lage, and later becomes calcified 
into true bone. Many tumors, 
however, remain as osteoid sar- 
comata, composed largely of os- 
teoid tissue with relatively little 
bone formation. The cortex of 
the original bone may remain vis- 
ible in the midst of such tumors, 
but usually shows much erosion and one or more fractures. In other cases, 
with the growth from inside, the dense cortex is eroded away and replaced 
on the outer surface of the advancing tumor. Since the replacement is less 
rapid than the erosion, a thin-walled dilatation of the cortex is produced 
and finally broken through. 
Osteosarcomata and the allied chondrosarcomata form metastases in 
Fig. 502.-Osteosarcoma involving the 
marrow of the humerus, piercing the cortex 
in many places, and growing out radially 
under the periosteum. MYXOMATA 
987 
distant organs, such as the lungs, and, in those new situations, the secondary 
nodules usually show the same atypical cartilage and bone formation. They 
are, in general, less malignant than other sarcomata, but are by no means 
entirely innocent. 
Sarcomata of other types may also arise in the interior of the bones, and, 
having eroded their way through the cortex and spread outside into a large 
tumor, metastasize extensively elsewhere. These appear not to grow from 
the active bone-forming endosteum, since they form little or no bone or 
cartilage, but are composed of soft cellular tissue. In one which we studied 
recently there had been a tumor springing from the femur for which the leg 
had been amputated several months before death. At autopsy enormous, 
soft, partly necrotic tumor masses were found in the lungs and mediasti- 
num. These were composed of variegated cells without the least evidence 
•of any tendency to bone formation (Fig. 493, d). 
Sarcoma.-Borst: XV. Cong. Internal, di Med., Lisbonne, 1906, Section iii. 
Ackermann: Volkmann's kl. Vortrage, 1883, Nr. 233, 234. 
Coenen: Beit. z. kl. Chir., 1909, Ixiii, 337. 
Monckeberg: Ergebn. d. allg. Path., 1906, x, 730. 
LITERATURE 
MYXOMATA 
This term is used to indicate tumors which are composed of a loose connec- 
tive tissue with branched cells widely separated by a viscid, opalescent, 
mucoid fluid, which actually contains mucin. While such tissue is not 
found in the adult body, it does exist in the Wharton's jelly of the umbilical 
cord, which tissue, therefore, stands as the prototype of the myxoma. 
These tumors are found in various situations in the subcutaneous and 
intermuscular tissues in connection with tendons, periosteum, and joints, 
and especially in the heart. 
Ribbert makes a point of declaring that in those frequent cases in which 
a complex or teratomatous tumor presents patches of mucoid tissue here 
and there, the myxomatous part is not to be regarded as a secondary degen- 
eration of some other part of the tumor. In other words, he maintains the 
independence of the myxoma as a distinct tumor which may be combined 
with cartilage or with bone, etc., to form a myxochondroma or myxo- 
osteoma. 
In the heart the soft tumor is in most cases found to hang in polypoid 
form from the wall of the left auricle, more rarely arising from the septum 
or other situation. It is covered with endothelium and composed, as in 
other cases, of the mucin-containing loose tissue. 
In most instances myxomata are benign and well-outlined tumors, but 
occasionally they evince signs of malignancy and invade widely and metas- 
tasize to other organs. On the whole, they are rare tumors. 
There is a form of myxomatous tumor which grows in great nodular masses 
in the retroperitoneal region at the root of the mesentery, and pushes aside TEXT-BOOK OF PATHOLOGY 
988 
the abdominal organs, although it does not become closely adherent to 
them. The nodules are encapsulated, and may be as large as a cocoanut. 
On removal they tend to recur, and even to produce metastases in the liver 
and other organs. Such tumors are not rare, and we have had an oppor- 
tunity to study one of them from the Mount Sinai Hospital material, where 
Dr. Mandlebaum has seen four. In this case there were five large masses, 
one of which seemed almost entirely composed of fat. The others were 
elastic, translucent, and gelatinous, with little admixture of fat. Micro- 
scopically the lipoma-like tumor showed some areas of the same translucent 
Fig. 503.-Myxoma from retroperitoneal region. 
tissue. The larger gelatinous tumors were composed of an extremely loose 
vascular tissue in which the cells were rather small, provided with a rounded 
or oval vesicular nucleus, and long branching protoplasmic processes by 
which they held together (Fig. 503). The intercellular fluid was extremely 
abundant, and it was necessary to examine frozen sections, since any 
attempt to make a paraffin section resulted in great shriveling of the tissue. 
With haematoxylin the fluid assumes a bluish stain. 
Ribbert: Frankfurter Ztschr. f. Path., 1910, iv, 30. 
LITERATURE CHAPTER L 
TUMORS (Continued) 
Pigmented tumors: Noevi. Their relation to epithelium and connective tissue. Melano- 
mata or melanotic sarcomata. Tumors of adrenal origin: Hypernephromata. Rela- 
tion to aberrant adrenal tissue. Endotheliomata: difficulty of establishing their relation 
to endothelium. Endotheliomata from lymphatic endothelium; cylindromata. Pleural 
and peritoneal tumors. Endotheliomata of the meninges. Tumors derived from endothelium 
of the blood-vessels. " Perithelial" tumors. 
Tumors which show the presence of brown or black pigment, and which in 
some cases develop an extreme malignancy, form a group whose position in 
the general scheme of tumors is still extremely debatable, because it is 
impossible to decide as to the nature of the cells from which they arise. 
Since they behave more in the manner of sarcomata than in that of other 
tumors, they may be described here, although it must be borne in mind that 
there is no good proof of their right to this place. 
N^VI 
The simplest of these are the pigmented moles or nsevi, which are flat or 
slightly elevated, gray or brown or almost black patches in the skin. Some- 
times they are quite prominent, roughened, and irregular, and may be marked 
by the growth of coarse hairs (Fig. 504). There are many varieties in so far as 
the intensity of pigmentation and the bulk of the tumor tissue are concerned, 
but the structure is, in its essentials, similar in all. Occasionally, however, 
the tumors are exceedingly rich in blood-vessels, so that they have then the 
character of superficial angiomata. The overlying skin is slightly irregular in 
thickness and sends down quite long interpapillary processes of epithelium. 
The papillae of the corium are enlarged by the presence of compact or loose 
masses of cells, commonly called naevus cells, which are sometimes quite 
colorless (Fig. 505) and sometimes deeply pigmented. It is with regard to 
the nature of these cells that discussion has been carried on for years, since 
it is most desirable that we should know whether they are derived from the 
epithelium or not. The following table from Dalia Favera shows fairly well 
the position taken by various authors on this point. 
1. They arise from the epidermis (Unna, Kromayer, Marchand, 
Gilchrist, and many others). 
2. They are of mesodermal origin, and are- 
(a) Young connective-tissue cells (Simon, Virchow, Riecke). 
989 990 
TEXT-BOOK OF PATHOLOGY 
(b) They arise from proliferation of the lymphatics (v. Reckling- 
hausen, Lubarsch, Herxheimer, and others). 
(c) They spring from the endothelium and perithelium of blood- 
vessels (Pick, Jadassohn). 
(d) They originate in the sheaths of nerve-fibres (Soldan). 
3. They are specially characterized cells of mesodermal origin-chro- 
matophores (Ribbert). 
From this it will be seen what divergent views have been held by the best 
observers. Dalia Favera, in a paper from Marchand's institute, presents 
the study of 30 naevi, and brings very convincing histological pictures to 
Fig. 504.-Small pedunculated naevus of skin showing the relation of the naevus cell 
strands to the epidermis. 
prove that naevus cells originate in direct continuity with the epithelial 
cells, forming in little nests in cavities among those cells, and later becoming 
loosened and separated. Ribbert is quite as emphatic in his claim that 
these cells are not epithelial cells, since the character of their nuclei and 
protoplasm, and especially the possession of numerous long processes, makes 
that practically impossible. As chromatophores they are mesodermal cells 
whose duty it is to carry pigment. Similar cells are found in many lower 
animals, where they lie in the skin, and by changes in their form are instru- 
mental in producing changes in its color. MELANOTIC SARCOMA 
991 
Such pigmented and colorless naevi may remain for many years without 
much increase in size and without producing any ill effects. Through trau- 
matism or for some other more obscure reason they may, however, begin to 
grow and produce a definite tumor. The pigmented tumor thus formed is a 
melanoma or melanotic sarcoma. 
Fig. 505.-Non-pigmented naevus of skin of the shoulder. The papillae of the corium 
are hypertrophied. Large masses of "naevus cells" lie in its deeper parts. 
MELANOTIC SARCOMATA 
These tumors cannot always be shown to have originated in a well-defined 
mole, and there are many cases in which the cutaneous manifestations 
remain inconspicuous while large internal metastases develop. Doubtless 
it could be said that the origin was really from some small mole in such 
cases, but in one which was seen in the Presbyterian Hospital recently there 
was only a bluish stain above the knee which could not be felt with the 
finger, and yet the adjacent inguinal lymph-nodes were greatly enlarged 
and the man actually coughed or spat up a piece of tissue, which on section 
showed the typical structure of a melanosarcoma. No autopsy was obtain- 
able to reveal the position of the growth from which that piece came. 
Another case may be recalled in which a melanosarcoma apparently arose 992 
TEXT-BOOK OF PATHOLOGY 
in a healing haematoma under the thumb-nail and caused death from nu- 
merous metastases some months after the first injury. 
Usually it is possible to trace the black tumor-mass which develops in the 
skin to a preexisting naevus at the same spot. That naevi are not essential 
is shown, however, by the growth of quite similar tumors from the choroid 
of the eye, from the brain and meninges, from the conjunctiva, the nasal 
mucosa, the adrenal, ovary, intestine (ampulla of Vater), the rectum, 
urethra, etc. 
For those who hold to the ectodermal or epithelial origin of the tumors, 
Fig. 506.-Primary melanoma of the choroid. There was relatively little pigment in 
this tumor. The retina is dislodged and stretches through the middle of the vitreous 
humor at b. The outer layer of the retina passes over the tumor at a. 
it would seem that some of these sites could hardly be explained. Never- 
theless, the invasion of ectodermal sympathetic cells in the adrenal is ad- 
duced to explain the tumors of adrenal origin, while in other cases the par- 
ticipation of displaced embryonic remains in the form of teratomata may 
afford a source of epithelial cells. It is not possible to form a definite opinion 
as to the true nature of the pigmented cells from the evidence now available. 
Naturally, there is no fundamental reason why mesodermal cells should not 
form pigment from materials supplied by the blood, although in general we 
are more accustomed to find the pigments of the body produced by cells of 
epithelial origin. Whatever is ultimately determined to be their true rela- MELANOTIC SARCOMA 
993 
tion, it is clear that these cells do not merely receive pigment transferred to 
them from other cells, but maintain throughout their existence the ability 
to form pigment and transmit that ability to their offspring. 
The melanosarcomata of the skin are composed of compact masses of 
cells which in section have an irregular polygonal form or are more often fusi- 
form (c/. Fig. 49), although Ribbert shows that in fresh teased specimens 
they possess numerous long processes which are pigmented to their ends. 
The pigment is in fine granules and clumps and is yellowish brown or dark 
brown in color. Much of it is scattered free in the crevices of the tissue 
and is taken up by various phagocytic cells. The stroma is sometimes very 
Fig. 507.-Melanoma. Multiple small metastatic nodules in the liver. The primary 
tumor was in the choroid of the eye. 
delicate, but often coarse enough to divide the tumor into an alveolar 
arrangement. 
In the eye these tumors spring from the choroid either as a flat, lamellar 
plate, or as a nodule which may be distinctly pedunculated. They grow up 
into the vitreous humor, pushing the layers of the retina before them, and 
finally filling the whole eye or bursting outward to invade the orbit (Fig 
506). 
In the other sites in which primary melanomata occur their mode of 
growth and histological structure are similar. Melanomata grow with great 
rapidity and spread their metastases by way of the blood-stream with 
extraordinary effect, producing secondary growths in great numbers in all 
the organs (cf. Fig. 48). These vary in size from minute groups of cells so 
small as to be visible only when they stand out by their black color against TEXT-BOOK OF PATHOLOGY 
994 
such a tissue as the white matter of the brain, up to enormous masses which 
occupy a great part of the liver. There are usually many nodules scattered 
in each organ, and in the case of the liver it is common to find hundreds 
of rounded tumors which are embedded everywhere in the tissue (Fig. 507). 
Most of these are very deeply colored, but some of them may be perfectly 
unpigmented. Frequently a single nodule shows both black and white 
portions. In the heart-wall one may find several coal-black nodules or a 
whole sprinkling of small black points. 
In all these positions necrosis and disintegration of the tumor occur, and 
much of the pigment thus released is taken up by the endothelial cells and 
wandering phagocytes or remains scattered free in the crevices of the tissue. 
It seems to be carried in the blood-stream to the kidneys, and is decolorized 
in this transit, but appears again in its black form in the urine, especially 
after exposure to air. The pigment itself is one of the melanins, and con- 
tains sulphur, but no iron. 
Dalla Favera: Ziegler's Beitrage, 1903, xliii, 43. 
T. C. Gilchrist: Jour. Cutaneous and Genito-Urinary Diseases, 1899, xvii, 117. 
Ribbert: Ziegler's Beitrage, 1897, xxi, 471. 
Geschwulstlehre, Bonn, 1904, 255. 
Wolfrum: Ergebn. d. allg. Path., 1914, xvi, Ergnzbd., 660. 
Kyrle: Arch. f. Dermatol, u. Syphilis, 1913, cxviii, 319. 
Pinkus: Dermatol. Ztschr., 1908, xvi, 483. 
Maclachlan: Jour. Med. Research, 1914, xxix, 433. 
Winternitz: Johns Hopkins Hosp. Bull., 1909, xx, 314. 
LITERATURE 
TUMORS OF ADRENAL ORIGIN (HYPERNEPHROMATA) 
This is a group of tumors of such common occurrence as to be familiar to all 
pathologists, but yet so peculiar in their histological characters and location 
as to have given rise to differences of opinion with regard to their origin, 
which are even yet unsettled. 
They are nodules of soft, opaque, yellow tissue, sometimes very small, 
sometimes growing to a great size, and situated in the adrenal gland, in the 
kidney, or just beneath its capsule, or in any one of many other positions, such 
as the liver, pancreas, retroperitoneal tissue, spermatic cord, epididymis, 
etc. The tumors may be multiple, and while the small multiple nodules 
appear to remain localized, the larger ones may exhibit an extreme malig- 
nancy, forming metastases in the lung, bones, and other distant organs. 
Attention was directed to the probability of their origin from the adrenal 
by Grawitz, who referred those occurring in the kidney to the overgrowth of 
small misplaced masses of adrenal tissue embedded in the substance of that 
organ. It is found that accessory nodules of adrenal tissue are actually 
distributed quite widely in the body, and are found not only in the immedi- 
ate neighborhood of the adrenal itself, or embedded in its cortex, but also in 
the liver, kidney, and in the other situations mentioned, broad ligament, 
spermatic cord, epididymis, etc. These are often of microscopic dimen- TUMORS OF ADRENAL ORIGIN (HYPERNEPHROMATA) 
995 
sions, may be present in considerable numbers, and are usually composed of 
tissue identical with that of the cortex of the adrenal. There are found 
occasionally accessory adrenals which contain medullary elements also, and 
a few have been described which were said to be composed entirely of 
medullary tissue. The most common are those in which cortical cells are 
arranged radially to form a small rounded nodule. 
Such nodules appear not to grow to any great size. They contain the 
same abundant lipoids as the adrenal cortex, but do not produce adrenaline, 
since that is, of course, a function 
of the medulla. 
The larger tumors are most com- 
monly found embedded in the kid- 
ney, the tissue of which they push 
aside or destroy (Fig. 508). They 
usually grow in the cortex, bulging 
under the capsule, which they may 
perforate, but in many cases they 
extend through the pyramidal re- 
gion so as to approach the pelvis. 
The best preserved part of the tu- 
mor is yellow or reddish-yellow, 
often interspersed with gray, trans- 
lucent areas, but in practically every 
case there are found extensive areas 
of necrosis with wide-spread haemor- 
rhage, which gives the cut surface 
an extremely variegated appearance. 
In the further course of their de- 
velopment these tumors metastasize 
sometimes by way of the lymphatic 
channels, but more often through 
the venous blood-stream. I have 
seen one case in which the lymph- 
atics in the walls of the blood-vessels 
in the lungs were filled with the 
yellow tumor mass, in such a way 
that all these vessels stood out 
prominently as thick-walled tubes 
composed of a soft yellow material. In this case the primary transpor- 
tation may well have taken place by way of the circulating blood, the 
filling of the pulmonary lymphatics being a secondary phenomenon. On 
the other hand, Oberndorfer, Ribbert, and others describe extraordinary 
invasions of the branches of the renal vein, with continuous extension of the 
tumor through the vena cava into the heart. We saw such a case at 
autopsy in which the main tumor was situated in the left kidney. The 
Fig. 508.-Hypernephroma embedded in 
the substance of the kidney. 996 
TEXT-BOOK OF PATHOLOGY 
veins draining it were completely occluded by moulds of tumor tissue which 
extended to fill the left renal vein, and reached across to ramify in the right 
renal vein far into the right kidney. In the vena cava it proceeded upward, 
forming a cylindrical mass 3 cm. in diameter, which completely blocked and 
distended the vein up to a point just below the entrance of the hepatic veins. 
On looking down into the vena cava it could be seen as a rounded mass partly 
covered with fresh thrombi. Metastases were found in the lungs and in 
various bones, those in the skull being especially striking since their growth 
Fig. 509.-Hypernephroma showing characteristic large clear cells. 
from the diploe was accompanied by the formation of sharp spicules of bone 
which projected about each nodule. 
When studied microscopically, these tumors are found to present a great 
variation in structure, but those arising from the kidney resemble closely 
those derived from the adrenal itself. The most common microscopical 
picture is that in which wide strands of cells anastomose freely with one 
another and are cut at various angles (Fig. 509). These are supported by a 
delicate stroma with thin-walled blood-vessels. The cells are large, cylindri- TUMORS OF ADRENAL ORIGIN (HYPERNEPHROMATA) 
997 
cal, or cubical, and extremely pale and transparent, recalling in their appear- 
ance the cells of a growing plant tissue. Glycogen is found in these cells, 
together with abundant droplets of cholesterine esters and other lipoids, 
such as are normally found in the adrenal cortex. The resemblance of the 
tumor-cells to those of the adrenal cortex has always been emphasized, but 
it must be admitted that they are far more transparent than the cells of the 
gland. In many cases the tumor-cells are arranged not in strands, but as 
the lining elements of tubular spaces. These canals may anastomose 
widely or become distended into spaces of considerable size. Frequently 
they are filled with blood, which appears to be in a good state of preservation, 
so that the idea has arisen that these may be tumors in which the typical 
cells are really endothelial cells lining blood-channels, and that they should 
be regarded rather as endotheliomata. In other cases still the necrosis of 
the tumor tissue leaves nothing but mantles of cells about the blood-vessels, 
and these have been looked upon by some authors as peritheliomata. This 
peculiar condition has been mentioned elsewhere in connection with other 
tumors, and it was said that it seems quite wrong to assign to these rem- 
nants of tissue a name which suggests that they, as " perithelial " cells, had 
given rise to the tumor. 
Not all these tumors are even as simple as this, for there are some in which 
large cavities occur and others in which the epithelial cells are thrown up 
into most complicated papillary folds which may almost fill the cavities. In 
these cases the cells are usually more granular and less like vegetable cells. 
Since the assertion of Grawitz that such tumors, even when they occur in 
the kidney, arise from misplaced bits of adrenal tissue, there has been a 
great deal of discussion of their origin and true relations. Sudeck, Stoerck, 
and others contest their relation to the adrenal, and claim that there is strong 
evidence that they are really derived from the tissue of the kidney, and that 
they are renal rather than adrenal tumors. In the lack of any perfectly 
decisive proof it seems to me that their arguments are weak, and that the 
evidence which Grawitz himself brought forward to show their relation to 
the adrenals is stronger. These arguments, which deal with the lipoid and 
glycogen content, with the formation of spaces or lumina in the tumors, etc., 
may be read in the papers of Stoerk, Sisson, Sabolotnow, and others. 
Wells has analyzed the lipoid content, and has found that it approaches 
that of the normal adrenal cortex and far exceeds that of other tumors. He 
could demonstrate no adrenaline-like substance in any of the tumors. 
LITERATURE 
Stoerk: Verh. d. Dtsch. Path. Gesell., 1908, xii, 123. 
Grawitz: Arch. f. kl. Chir., 1884, xxx. 
Sabolotnow: Ziegler's Beitrage, 1907, xli, 1. 
Wells: Arch. Int. Med., 1909, iv, 291; Jour. Med. Research, 1908, xvii, 461 
Sisson: Ziegler's Beitrage, 1910, xlix, 476. 
Davis: Arch. Int. Med., 1911, viii, 60. 
Kostenko: Dtsch. Ztschr. f. Chir., 1911, cxii, 284. 
Rosenfeld: Frankfurter Ztschr. f. Path., 1913, xiv, 151. 998 
TEXT-BOOK OF PATHOLOGY 
ENDOTHELIOMATA 
The tumors so far discussed have been described as though they were com- 
posed of elements whose relationship to some tissue which gave them origin 
is so readily recognizable as to rouse no doubts. Further, they have been 
spoken of as though in every part they presented the same characteristic 
appearance. In many cases these things are true, and we have no hesita- 
tion in assigning a definite source for a tumor which is quite uniform in 
structure throughout, and whose cells are, as in the case of a fibroma or 
chondroma, obviously of the same general character as those of the tissue 
in which they develop. More emphasis should have been laid, however, 
upon the frequent admixture of other tissues, and especially upon the modi- 
fications which the essential tissue of the tumor undergoes. Thus nothing 
is commoner than to find, instead of a pure chondroma, an osteochondroma 
or a myxochondroma or a myxochondrosarcoma. In these cases it must be 
decided whether the tissues are of equal dignity in the tumor growth, or 
whether one or two of them represent metaplasia or degenerative changes in 
the other. In most of the cases already considered we have dealt with 
tissues so closely related that, as in the case of cartilage, bone, and connec- 
tive tissue, we are not surprised to find one assuming the character of the 
other or giving rise to the other in its further growth. We realize that many 
of these changes are due to the infiltration of fluid or of mucin or to some 
other mechanical or chemical change which can produce an alteration in the 
appearance of the interstitial substance or of the cells themselves. 
In spite of some difficult feats of tracing the cells to unfamiliar stages in 
the embryonic development of their parent cells, we have found it possible 
to feel pretty sure of the point of departure of the tumor elements. Of 
course, a rigid criticism might show that we are by no means possessed of 
proofs of these histogenetic relations, but, on the whole, there is so much 
evidence that the tracing seems safe enough. 
There are, however, many tumors whose origin and histogenetic relations 
are difficult, if not impossible, to trace. They are never the familiar tumors 
which occur in dozens of cases in practically the same form and situation, 
but odd growths which appear in some unusual site or in tissues where any 
one of several origins might be assigned to them. In structure they are 
unlike any known tissue, and offer no suggestion as to their nature from the 
non-committal arrangement of their cells. Of course, it must occur to 
every one that in time these tumors will be recognized in spite of their lack 
of resemblance to known mature tissues, just as the neuroblastomata were 
finally recognized, although they had long been contemplated without 
understanding. But the stumbling-block is that a name has been dis- 
covered under which all these difficult tumors can be conveniently classed, 
and thus pigeonholed and withdrawn from further study. Every unusual 
tumor which lacks characters that will permit its ready recognition stands 
an excellent chance of being labeled endothelioma and relegated to oblivion. ENDOTHELIOMATA 
999 
Still more disturbing is the fact that certain well-known groups of tumors, 
such as the mixed tumors of the salivary glands, have been declared by 
some one to be endotheliomata, and have, therefore, been classed in that 
capacious group by every one. Happily, in that particular type of tumor 
there has been sufficient interest to bring forth further study with more 
accurate results. 
In practically no case has the origin of a tumor from endothelium been 
proven. As Ribbert points out, the mere continuity of the tumor-cells with 
endothelium at the margin of the tumor is no proof of their identity. Borst 
has shown that tumor-cells may grow into lymphatic channels and cause the 
endothelial cells to proliferate, but that even when the proliferation is suffi- 
cient to close the channel, it is only a normal reaction to the presence of a 
foreign tissue and not a participation by the endothelial cells in the tumor 
growth. Ribbert thinks that proof of the endothelial nature of a tumor 
will require the study of that tumor at its inception, which is impossible. 
Much confusion has arisen because of the uncertainty as to what should 
be called endothelium, and many different standpoints have been taken. 
All agree that the lining cells of blood- and lymph-vessels and the lining 
of the cerebrospinal spaces must be accepted as endothelium. Disputed 
tissues are the lining-cell layers of pleura, peritoneum, etc. According to 
the coelom theory, these cells must be epithelial (hypoblastic and epiblastic) 
in origin. Some other characteristics, such as the possession of cilia, etc. 
make them seem more allied to epithelium, and indeed there are many now, 
including Ribbert, who regard the serosa cells as epithelial in nature and the 
tumors derived from them as epithelial tumors. 
Even yet, in spite of all the work on the relation of the lymphatics to the 
connective tissue, much is written of the endothelial cells which line or 
partly line the indefinite lymph-spaces or crevices in the tissue, and what is 
written is used as a complete explanation of the origin of certain obscure 
tumors. Since it appears that the lymphatics are complete blind-ending 
tubes lined with endothelium, such tumors would have to be derived from 
their walls. 
There is no reason that endothelial tumors should not arise from the 
endothelium of the lymphatics or blood-capillaries. No doubt they do and 
possibly some of the tumors described as endotheliomata really have this 
origin, but it is far from proven or even plausible in most cases, and in many 
the essential cells of the tumor, though flattened and stretched out, are 
easily shown to be epithelial cells. Indeed, in most of these tumors which 
arise in the skin, in the mouth, or nasal sinuses, in connection with bones, 
or in less characteristic situations, it is found that the tumor-cells are flat- 
tened, rather deeply staining cells, arranged in strands which anastomose 
and give off long-pointed processes which extend into crevices of the con- 
nective tissue. The cells do not resemble any normal type closely, and 
since no primary growth is found in any of the usual epithelial organs, and 
since further the cells stand out too distinctly from the stroma to be accepted 1000 
TEXT-BOOK OF PATHOLOGY 
as connective-tissue cells, it is rather feebly assumed that they must be 
endothelial cells. The proof is not much stronger than that, and is rather a 
process of exclusion than a positive tracing of a relation to endothelium. 
Even though every one must admit the possibility and even the probability 
of the existence of tumors derived from endothelium of the lymphatics, this 
kind of reasoning is most unsatisfactory. 
In the following, the types of tumors which have been looked upon as 
derived from endothelium may be given briefly and discussed. It will be 
found that the evidence of their relation to endothelium is thought to be 
satisfactory in the cases of endothelioma of the dura, and in a very small 
number of tumors derived from capillary blood-vessels, but that in the 
others it is either disproven or very doubtful. New tumors are constantly 
being described in which an attempt is made to establish an endothelial 
origin, and the matter may soon reach a state of greater clearness. 
Endotheliomata Derived from Lymphatic Endothelium.-Tumors of the 
skin are described by Borst and others as composed of nodular masses of 
rather dense tissue in which anastomosing strands of flattened smooth cells, 
sending off pointed processes, are embedded in connective tissue. Similar 
tissues are found elsewhere, and may be really endotheliomata or derived 
from much altered epithelium. 
Cylindromata or tumors in which hyaline cylindrical strands or balls are 
interspersed with strands of flattened cells were described by Billroth, and 
have been much discussed in later years. They are usually tumors which 
occur in the mouth, near the salivary glands, or in the nasal sinuses, but 
may be found elsewhere. They are generally benign, but may metastasize. 
Histologically the cylindrical hyaline structures (which are not peculiar to 
these tumors, but may occur in sarcomata and carcinomata) are seen to be 
formed by modification of the connective-tissue stroma or of the walls of 
the blood-vessels (Fig. 510), although in some cases such hyaline masses 
appear to be formed in the middle of a strand of tumor-cells. The name is 
given on account of this anatomical peculiarity, and should not distinguish 
a special type of tumor. While it is difficult to decide upon the actual origin 
of the tumor-cells, Ribbert has brought strong evidence that they are 
epithelial and that they arise from the glands or surface epithelium of the 
mouth and nasopharynx. 
Pleural or peritoneal tumors have given rise to much difference of opinion. 
They are apparently primary in the lining cells of the pleura or peritoneum, 
and can be distinguished from those which occur as metastases from pri- 
mary tumors situated elsewhere. The latter are usually in the form of 
small lenticular or rounded nodules, which extend into the underlying 
lymphatic channels, while the primary tumors of the pleura are most com- 
monly seen as thick white layers of dense tissue covering the lung and 
containing in the meshes of the connective tissue simple or very complicated 
arrangements of cells whose nature cannot be positively stated from a study 
of their morphology. There are some investigators who insist that they are ENDOTHELIOMATA 
1001 
derived from the endothelium of the underlying lymphatic channels, but 
the majority, including Ribbert, refer them to the serosa cella and consider 
them epithelial tumors. They may metastasize to lymph-glands or extend 
into the lung. Those arising in the peritoneal cavity are more likely to 
occur in nodular form. They too may invade, and, penetrating the dia- 
phragm, spread over the pleura. 
Fig. 510.-Cylindromatous tumor. 
Endotheliomata of the Dura Mater.-There seems to be a general agree- 
ment of opinion as to the endothelial character of the lining of the dura. 
The cells of this lining are often thrown up into minute solid masses which 
can be recognized with the naked eye and which seem to foreshadow the 
possibility of tumor formation. Tumors attached to the dura and pressing 
into the surface of the brain are quite common. They may reach such.a 
size as to compress the brain seriously and to cause death by occupying the 
limited space of the cranium. In one case we observed a tumor of the size 
of an egg lying on the convex surface of the cerebrum, in which it had 
pressed a deep groove for its own accommodation. This was a stalked 1002 
TEXT-BOOK OF PATHOLOGY 
growth hanging from the dura along the median longitudinal sinus. Others 
(as in Fig. 511) embed themselves deeply in the cerebral substance and 
may appear as though derived from the brain. They are sharply limited, 
however, and readily fall out of the depression in which they lie. They 
are not malignant and do not recur when removed. In section they are 
firm tumors which show a peculiar whorled arrangement, somewhat like 
that of a uterine myoma. This appearance is seen under the miscroscope 
to be due to the concentric arrangement of the flattened cells which may 
also form interlacing strands (Fig. 512). Occasionally the flattened 
cells are closely wrapped around a central grain of calcified material, and 
Fig. 511.-Endothelioma of the meninges lying in a deep depression in the surface of 
the cerebral hemisphere. 
this arrangement may be repeated throughout the tumor, giving rise to 
the so-called psammoma. Connective tissue may be associated with the 
"endothelial" cells and contributes a greater firmness to the tumor. 
The term "psammoma" is another descriptive name, and is applied to any tumor 
which contains many tiny concretions or rounded grains of calcified material enwrapped in 
concentric layers of cells. Such concretions occur in the choroid plexus, in the hypoph- 
ysis, in the pineal gland, and elsewhere in the body, as well as in the endotheliomata of 
the dura. 
Tumors Derived from the Endothelium of the Blood-vessels.-A few 
tumors have been described which appear to represent this group, but they ENDOTHELIOMATA 
1003 
seem to be very rare. Borrman, for example, has described two tumors 
composed of long strands and channels composed entirely of endothelium 
and connected with the blood-capillaries. These he calls tubular capillary 
endotheliomata, and in so far as the relation to the capillary endothelium 
can be proved, the name is well chosen. Colmers has also described a tumor 
of the penis, metastasizing into the internal organs, which was composed of 
blood-channels lined by tumor-cells, which he regarded as endothelial cells. 
Fig. 512.-Meningeal endothelioma. The tumor is made up of long, fusiform cells 
arranged in whorls. 
The endothelial cells were much changed in form, and greatly enlarged, and 
sometimes occluded the wide blood-channels of the corpora cavernosa into 
which they grew. B. Fischer describes another peculiar tumor situated 
in the liver, most of which it occupied. In the outlying parts of the many 
nodules this was seen to be a mere widening of the capillaries with thick- 
ening of the endothelium, but in the centre of each nodule the change in 
the endothelium became more striking, producing great widening of the 
capillary, often with occlusion and disappearance of the liver-cells. Most 
active blood formation was found to be going on in the capillaries of these 
areas, and one is led to speculate as to whether this may have been an 
exaggerated myeloid alteration rather than a tumor. We have, how- 1004 
TEXT-BOOK OF PATHOLOGY 
ever, recently met with an exactly similar tumor arising in the small 
intestine where it was constantly injured and bled a great deal. It pro- 
duced hundreds of metastases in the liver and these are found to be made 
up of wide blood-channels the living cells of which are the tumor cells. 
One tumor which I studied microscopically seemed to fall into this group. 
It was a pulsating mass in the region of the left scapula in a boy, and was 
incompletely removed at an operation, which had to be stopped because of 
the excessive haemorrhage from the tumor. There was a recurrence which 
grew rapidly until the boy's death, when metastases were found in the lungs. 
In the metastases, as well as in the primary growth, the whole tumor was 
composed of delicate canals lined with high swollen cubical cells with very 
clear protoplasm, quite like those in a hypernephroma. Each canal was 
filled with blood, which seems to have been in circulation and to have given 
rise to the extensive haemorrhages at operation. This tumor reminded us 
of a hypernephroma, and it is possible that it may have been a secondary 
growth, although no tumor was found in the adrenals or kidneys or else- 
where, except the pulmonary nodules, which were numerous and all about 
the size of peas. 
"Perithelial" Tumors.-Many tumors have been described as composed 
of matted strands of blood-vessels, each of which is surrounded by a mantle 
of tumor-cells supposed to be derived from certain adventitial cells of the 
vessel-wall, the so-called perithelium. Such tumors have been named 
peritheliomata or perithelial angiosarcomata, and are said to be malignant 
growths metastasizing rapidly. It seems that the conception of perithelium 
is accepted passively by every writer and transferred from text-book to 
text-book. I have searched in vain for perithelium, or even for any clear 
description of it, and do not believe such cells exist. Of course, there are 
accompanying lymphatics in the walls of the blood-vessels, and there are 
the vasa vasorum, and it is conceivable that a tumor might arise from either 
of these. The cells described in such tumors have no resemblance to endo- 
thelium, but nothing can be concluded from that. In all the descriptions 
some mention is made of hyaline and necrotic changes in the stroma between 
the vascular strands, and this, it seems, affords the explanation of the ap- 
pearance. Only those parts of a sarcoma remain alive which immediately 
inclose the blood-vessels, and hence become isolated in necrotic ground 
substance as mantles of cells around blood-vessels. There may be real 
peritheliomata, but it seems improbable, and I have not been able to find 
them. 
LITERATURE 
Borrmann: Ergebn. d. allg. Path., 1902, vii, 870; Virch. Arch., 1898, cli, Suppl., 151; 
ibid., 1899, clvii, 297. 
Monckeberg: Ergebn. d. allg. Path., 1906, x, 789. 
Volkmann: Dtsch. Ztschr. f. Chir., 1895, xli, 1. 
Hinsburg: Dtsch. Ztschr. f.'Chir., 1899, li, 281. 
Lubarsch: Ergebn. d. allg. Path., 1897, ii, 592. 
Colmers: Ziegler's Beitrage, 1903, xxxiv, 295. 
B. Fischer: Frankfurter Ztschr. f. Path., 1913, xii, 399. CHAPTER LI 
TUMORS OF EPITHELIAL ORIGIN 
Relation of epithelium to stroma. Papillomata: Origin from skin and mucosae. Papil- 
lomata of bladder and ovary. Adenomata: Origin from skin, salivary glands, gastric and 
intestinal mucosae, kidney, liver, adrenal, hypophysis, and prostate. Adenomata of the 
breast. Intracanalicular forms. Cystadenomata of ovary: Their origin and form; 
papillomatous types. Adenomata of the uterus. 
In the tumors hitherto discussed cells evidently derived from the connec- 
tive tissue or some other mesoblastic structure have in most cases formed 
the essential feature of the growth, although in every instance these have 
been supported and supplied with nutrition by a vascular connective-tissue 
stroma. It has been made clear that in these tumors, as in the growth of 
organs in the embryo or in the Pew formation of tissue in the healing of a 
wound, the supporting framework and the vascular supply are called for 
and made to serve the ends of the more important specific tissue. This 
becomes even more apparent in the case of the great group of tumors in 
which epithelial cells play the leading part in the constitution of the growth. 
Although there are some authors, such as Hibbert, who hold to the idea, 
expressed by Virchow, that the new-growth of epithelium is initiated by an 
atypical growth of the underlying connective tissue, the opposite view is 
maintained by the majority, and seems to me to be supported by far greater 
weight of evidence. Nevertheless it will be necessary to weigh this matter 
in each case, and in some it may be found difficult to decide. 
Very convincing proof of the mastery of the epithelium seems to be furnished by those 
papillary epithelial tumors of the ovary which grow both from the inside and the outside 
of cysts in that organ. If minute clusters of the epithelial cells which cover the branches 
of these growths as they project into the peritoneal cavity are broken off and scattered 
over the loops of the intestine and on the surface of the other abdominal organs, they 
take root and grow, not merely into masses of epithelium, but into new branched forma- 
tions which are supported by connective tissue springing from the peritoneal tissue, and 
supplied by branches of the blood-vessels of the organ on which they grow. Even if a 
bit of connective tissue be implanted with the group of epithelial cells, we must admit 
that the new blood-vessels and probably the new stroma are commandeered from the 
underlying tissues. 
Although we may agree that epithelium growing so abundantly on a surface 
as to be forced up into folds demands a vascular stroma for each fold, and 
that epithelium growing in the form of a gland demands the formation of 
vascular connective tissue enough to surround it, there are instances in 
which the epithelium assumes a growth so rapid that it far outstrips the 
1005 1006 
TEXT-BOOK OF PATHOLOGY 
connective-tissue formation, and abandons the ordinary relation which it 
regularly bears to that tissue, in the formation of an organ or in the normal 
covering of a surface. Then the epithelial cells in solid strands push their 
way lawlessly into any crevice in the tissue. Even then, however, when 
muscle, organ tissue, or bone is destroyed by the advance of these cells, there 
is never formed any considerable mass of epithelium alone, but the connec- 
tive tissue follows with its blood-vessels, though often in an irregular and 
inadequate way, and forms a support for the epithelium in its new position. 
Should the epithelial cells be set free in the lymph- or blood-stream and 
lodge in the capillaries of a distant organ, their multiplication in that new 
site is at once assisted by the ingrowth of fibroblasts and capillaries which 
quickly organize a stroma. These are the malignant epithelial tumors, and 
it is seen that the difference which exists between their structure and the 
more orderly form of the benign ones depends upon the headlong irregular- 
ity of their growth, with which the stroma can scarcely keep pace. 
We may consider first the benign epithelial tumors, in which the relation 
between the epithelium and its stroma or supporting framework is main- 
tained nearly as it is in normal tissues, and afterward the malignant or 
cancerous form, in which this relation is disturbed. It must be remembered, 
however, that the difference between a malignant and a benign tumor con- 
sists not merely in this morphological manifestation, but in the overwhelm- 
ing energy of growth of the epithelial cells of the cancer against which the 
normal tissues can set up no effective barrier. 
Benign Epithelial Tumors.-Those epithelial growths which maintain, at 
least in principle, the normal relations between epithelium and stroma fall 
into several groups, according to their general form, although these groups 
overlap in the sense that combinations or transitions from one form to 
another are found. The types are as follows: 
IZA papilloma is a tumor of lobulated, branched, or papillary form, in which 
each fold or offshoot of the epithelial layer has a central core of connective 
tissue with blood-vessels. 
An adenoma is a tumor composed of glands of tubular, acinous, or other 
form, embedded in a vascular stroma. Such a tumor may exist as a nodule 
in the substance of a solid organ, or it may project as a polypoid growth on a 
mucous surface. Since the glands are often without connection with the 
efferent ducts, many of them may become cyst-like. Indeed, there is no 
sharp line between these tumors and cysts, which may be multilocular or 
unilocular. Within such cysts the epithelium may be thrown up into papil- 
lary growths, so that a combination of cystoma or cystadenoma with papil- 
loma occurs. 
PAPILLOMATA 
The term is applied on the basis of their form to tumors composed of 
branching, cauliflower-like, or finely lobulated growths of epithelium, with a 
stroma which branches to carry blood-vessels into each prolongation. Some- 
times these branches are so small that only single capillary loops supply 1007 
PAPILLOMA 
them with blood. Although this general principle of formation is carried 
out throughout the group, there are great differences in their form and con- 
sistence, which depend upon the character of the epithelium from which 
they rise, since those which occur upon the skin are usually rough and hard, 
while those growing from the mucous membranes in the interior of the body 
are more commonly very soft, with loose, cedematous stroma. In the skin, 
papillomata may appear anywhere on the surface of the body, but are some- 
what more common on the face and in the anal and genital region, than 
elsewhere. They are often mulberry shaped on a short stalk, and rather 
soft, often more deeply indented, rough, and horny. These, especially in 
some cases in which they are situated on the penis or labia, may grow to a 
Fig. 513.-Papilloma of cheek. 
considerable size. Being exposed to constant traumatism, they are fre- 
quently inflamed or ulcerated. Fig. 513 shows the structure of such a 
tumor which was found growing on the cheek, and corresponds almost 
exactly with the appearance of others found on the lips, margin of the anus, 
and elsewhere. 
Less complex are the common warts, which are small papillomata, most 
frequently seen on the hands and composed of elongated papillae covered 
with thick epithelium. In many of them the skin is merely thickened and 
deformed, although continuous, while in others the main mass of the wart 
seems to break through the surrounding skin, to protrude as a brush of fine, 
stiff, epithelium-covered papillae. Section shows the continuity of the TEXT-BOOK OF PATHOLOGY 
1008 
deeper layers of the epidermis with this papillary growth. Wile states that 
these warts are infectious in character and may be produced by inoculation 
of a cell-free extract from other warts. In other cases the keratinization 
of the thick epithelial covering is so extensive that an actual horn-like 
outgrowth may be formed, and such horns, growing usually on the face 
or scalp, may reach a length of several centimetres. 
Many pedunculated papillary tumors are pigmented or bear long hairs, 
and these on section are found to be made up largely of the peculiar cells 
described as characteristic of pigmented moles. They are, in fact, naevi 
which have assumed a papillary form, and although to this degree they are 
papillomata, the fact that they are only thinly covered with stretched-out 
epidermis and that the cells which take the initiative are naevus cells, and 
not epithelium proper, justifies the distinction. They are extremely com- 
mon, and when not deeply pigmented, may resemble the ordinary papil- 
lomata very closely. 
Besides these, there are many small, pedunculated fibromata which im- 
pose themselves as tumors resembling papillomata. They have been referred 
to in an earlier section, where their relation to the nerves was discussed. 
The fact that they are essentially newT growths of connective tissue with 
only a thin covering of normal epidermis serves to distinguish them from 
the present group. 
In the stratified epithelium which lines the mouth and nasopharynx 
papillomata spring up from the tongue, the nose, and elsewhere, which 
resemble those of the skin. Irritation and trauma may cause modification 
in the epithelium, so that the more exposed parts are denuded. Similar 
tumors are found in the larynx and trachea, often attached by stalks to the 
vocal cords, where, of course, they interfere greatly with phonation. These 
are fairly hard, and although in the trachea rising from cylindrical epithe- 
lium, may be covered with stratified epithelium. 
In the urethra, vulva, and vagina similar growths occur. In these regions 
care must be taken to distinguish from true papillomata the flat and pointed 
condylomata, which are not tumors, but peculiar hyperplastic growths of 
epithelium caused by infection, with inflammatory reaction. The flat 
condylomata are of syphilitic origin, while the pointed or irregular ones are 
formed in the course of chronic gonorrhoea, chancroids, or other long-stand- 
ing infectious processes about the genitalia. They even occur in pregnancy, 
and disappear after childbirth, although here the participation of an infec- 
tion is not to be excluded. Apparently the gonococcus is not directly 
responsible for them. Such condylomata show on section (Fig. 514) an 
intensely inflamed tissue with distinct papillary new-formation of epithe- 
lium, so that without the clinical history it might be rather difficult to draw 
a sharp line between them and papillomata. 
In the stomach and intestine papillomata occur, but they are by no means 
so frequent as the more polypoid glandular tumors, which will be referred to 
under Adenomata. This is probably because of the tendency of the cylin- 
drical epithelium of the digestive tract to form tubular glands, rather than PAPILLOMA 
1009 
to throw itself up into papillary processes. Nevertheless, there are some 
such tumors which hang like great tassels in the cavity of the stomach, or 
less commonly in the colon. Those which I have seen in the stomach were 
associated with other tumors of a cancerous nature, but this is probably a 
coincidence. They are so soft and fragile that losses of substance fre- 
quently occur with haemorrhage from the remaining surface. 
The papillomata of the bladder are very similar in appearance, being 
extremely soft, tassel-like, stalked masses of thread-like papillae which float 
about in water. They show in section a delicate stroma covered by thick, 
stratified epithelium, the surface layers of which are usually lost. From 
being caught in the urethral orifice in the contraction of the bladder the 
papillae are often torn and portions are discharged in the urine, together with 
blood. These tumors tend to recur when they have been removed by 
Fig. 514.-Acuminate condyloma from a case of chronic gonorrhoea. 
operation, and in most cases, whether interfered with by operation or not, 
they finally invade and destroy the bladder-wall, revealing themselves as 
carcinomata. They should doubtless be regarded from the first as papillary 
carcinomata of the bladder. 
From the surface of the ovary, and usually simultaneously from both 
ovaries, richly branching papillomatous tumors are found to grow, extending 
into the peritoneal cavity. They appear to arise from the epithelial cover- 
ing of the organ, and are supported by the usual vascular stroma derived 
from the ovary. In their biological characters they resemble those which 
occur in the walls of ovarian cystadenomata. 
In all these tumors the extensive growth of the epithelium, which casts 
it into folds and projecting papillae, is, nevertheless, governed by a certain 1010 
TEXT-BOOK OF PATHOLOGY 
obedience to the normal laws of growth, which maintains a smooth line of 
demarcation between the epithelium and the underlying stroma. The 
whole tumor may become infiltrated with leucocytes during inflammation, 
and these cells wander readily from the stroma into the epithelium, but it 
is possible to trace round every projection and into each bay and indenta- 
tion the distinct, regular line of separation between epithelium and stroma. 
The usefulness of a recognition of this line in diagnosis is realized daily. 
In a case observed recently there was a mass extending from the tonsil and 
pillars of the fauces downward on the epiglottis, in a man of middle age. 
Sections of an excised portion showed everywhere a typical papilloma with 
perfectly even, thick, stratified epithelial covering, uniformly marked off 
from the stroma. Doubts as to the nature of a tumor in that situation 
prompted the excision of another fragment, which in general showed the 
same structure, but at several points it was possible to see that an excessive 
and lawless growth of epithelium had burst the barrier, and had invaded 
the stroma in the form of long strands of cells. The malignant nature of 
the tumor was at once clear, and the diagnosis is being substantiated by the 
clinical course of the growth. 
ADENOMATA 
Epithelial tumors of glandular origin and retaining in general a gland-like 
structure are extremely common, and occur in practically every situation 
where there are glands. They may present themselves as nodules embedded 
in the substance of solid glandular organs, or as polypoid masses projecting 
on the surface of a mucosa. The stroma is sometimes dense and hard, 
often soft and gelatinous, so as to give the tumor a polypoid character. The 
epithelium-lined spaces may become enlarged to form cysts, and these may 
be partly occupied by papillary ingrowths of the same epithelium. It is as 
well to consider the cysts with the adenomata, since those cysts which are 
not modifications of these tumors are of a quite different nature, and are 
due either to obstruction and dilatation of the ducts of glands or to the 
congenital misplacement of embryonic tissues, under which headings they 
may be discussed. 
Adenomata of the skin may arise from the sweat-glands or from the 
sebaceous glands. Such tumors are rare and must be distinguished from 
the vesicles which result from obstruction of the ducts of the sweat-glands 
and the so-called milia or comedones, which are due to the accumulation of 
sebaceous material in obstructed sebaceous glands. 
In the digestive tract small adenomata may spring from the mucus- 
secreting glands, or occasionally appear in the salivary glands. The so- 
called ranula is a cystic tumor which forms in the frenulum of the tongue, 
and is derived from the sublingual ducts, especially from Nuhn's glands. 
In the salivary glands themselves there occurs not only a form of " cylin- 
droma, " but also and more frequently composite tumors containing several 
types of tissue. These may be discussed later. ADENOMA 
1011 
In the stomach and intestine adenomata usually project or hang by a 
stalk as soft, polypoid tumors made up of abundant, irregular, and partly 
cystic glands, of much greater length than the normal glands, and embedded 
Fig. 515.-Tip of polypoid adenoma of the intestine. 
in a loose stroma which, on account of the traumatism to which it is exposed, 
is constantly inflamed. Sometimes these polyps reach a considerable size, 
and may offer a certain obstruction, or be seized by the intestinal wall in its 1012 
TEXT-BOOK OF PATHOLOGY 
peristaltic contraction and dragged on into a lower part of the gut. In this 
process the wall of the intestine may be invaginated by the tension on the 
stalk of the tumor, and an intussusception started. 
Microscopically, such adenomata are in continuity with the rest of the 
mucosa, but there is a sudden transition from the normal into the large 
distorted glands, lined with cylindrical epithelium, which may stain more 
deeply than the normal cells. The muscularis is not affected, but the sub- 
mucosa is greatly thickened at this point and extends upward into the 
tumor (Fig. 515). 
Polypoid adenomata are often multiple, and sometimes so numerous and 
so small as to give the intestinal mucosa a shaggy appearance. When they 
are larger (Fig. 516), they project into its lumen at every level as rounded, 
soft, velvety masses, varying in diameter up to one centimetre or more. 
Figs. 516.-Multiple polypoid adenomata of the mucosa of the colon. 
They must be distinguished from the irregular, polypoid masses of mucosa 
which are often formed at the margins of ulcers in the process of healing, or 
by the undermining of part of the mucosa in old dysentery. In the latter 
case the isolated mucosa breaks free at one end and hangs in the intestine 
as a polypoid mass. 
Adenomata in the kidney are grayish-red nodules lodged in the cortex, 
usually small, but sometimes attaining a great size. They are composed of 
ramifying or twisted glandular or tubular epithelial structures in which the 
cells are much smaller than those of the convoluted tubules (Fig. 517). It 
seems probable that the tumor-cells are the offspring of cells destined to 
form kidney substance, but diverted to the formation of a tumor at a rela- 
tively early stage of development. 
In the liver, as in other solid glandular organs, it is sometimes difficult to ADENOMA 
1013 
determine whether the nodular growths of the parenchyma of the organ 
should be looked upon as tumor formations, or as the result of a compensa- 
tory hyperplasia. It has been made clear in discussing cirrhosis of the liver 
that the destruction of a portion of the liver tissue causes the great over- 
growth of the remaining fragments, so that the organ assumes a rough, 
nodular arrangement, in which the nodules are sometimes quite large. 
Fig. 517.-Adenoma of the kidney. 
Microscopical study shows, however, that the strands of cells which make 
up these nodules, though disarranged from the normal order, are still in con- 
nection with the bile-ducts and actively functioning. It is probable that 
this is the nature of the circumscribed and irregularly arranged nodules of 
liver tissue which are sometimes found embedded in a Ever which is other- 
wise almost normal looking. At least this explanation seems safest so long 
as the cells of the nodule closely resemble the normal liver-cells. Occasion- 1014 
TEXT-BOOK OF PATHOLOGY 
ally, however, there are seen nodules composed of irregular strands or 
tubules of cells which no longer stain as do the normal cells, and these must 
be regarded as adenomata representing less highly differentiated liver-cells 
or derivatives of the bile-duct epithelium. 
The adenoma-like nodules of the cortex of the adrenal have been des- 
cribed elsewhere, and mention has been made of those of the thyroid. The 
thyroid adenomata are extremely common, and here again it is sometimes 
difficult to feel sure that we are dealing with actual tumors, and not with 
hyperplasia of the functioning gland. This is especially the case in the 
rather indistinctly outlined nodules of thyroid tissue in which the alveoli 
are distended with clear colloid and lined with thin, flat epithelium. In 
these cases the rest of the thyroid is frequently distended with colloid, in 
the same way, evidently, as the result of some abnormality in its function. 
Fig. 518.-Adenomatous nodules in the thyroid. Some of these contain abundant 
colloid. 
It is much easier to feel sure of the tumor character of the more common 
nodules which make up the bulk of the adenomatous or nodular goitres 
(Fig. 518), since they are sharply outlined and are composed of a quite 
abnormal tissue, in which the alveoli are often extremely small and lined with 
relatively large cuboidal cells. These cells occupy so much of the whole 
diameter of each alveolus that the lumen is often lost, and the tumor is 
found to be made up of narrow anastomosing strands or clusters of cells. 
Occasionally the larger alveoli contain distinct colloid secretion, but often 
there is none to be seen. The stroma is very abundant and becomes more 
conspicuous with the degeneration and disappearance of the alveoli, after 
which haemorrhages and wide-spread necroses occur, followed by liquefac- 
tion of the tissue, with the formation of cyst-like cavities full of bloody or 
brown turbid fluid. Extensive calcification may occur in the walls of the 
cysts or in the substance of such adenomata (cf. Figs. 434, 435). ADENOMA 
1015 
Tumors of the hypophysis, composed of a gland-like growth of one or 
other of the elements of the organ, have been much studied of late, and have 
been mentioned in connection with acromegaly. They are most commonly 
composed of the chromophobe cells, which are arranged in solid strands or 
alveoli. Adenomata of the eosinophile cells have also been observed. 
Adamantine Epitheliomata or Adamantinomata.-These are tumors 
which develop in the substance of the jaw bone at the base of a tooth, and 
Fig. 519.-Adamantinoma. Each mass of cells presents a central cavity filled with fluid. 
push their way out, displacing the tooth and causing the wasting away of 
the bone until they emerge as nodular, hard masses which may reach the 
size of a grape-fruit. The tumors, which are usually quite small, are de- 
rived, according to the general opinion, from the enamel organ, which is 
an epithelial structure at the base of the tooth concerned in the formation 
of enamel. Malassez regards them as derived from certain paradental 
remnants of epithelium, but the evidence for the other origin seems 
stronger. TEXT-BOOK OF PATHOLOGY 
1016 
The strands of epithelium are broad and anastomose irregularly (Fig. 
519). They are hollowed out centrally into cavities which are seen to be 
due to the gradual separation of the cells and the accumulation of fluid. 
The cells ramify somewhat, and are connected by very distinct intercel- 
lular bridges. The most peripheral cells abutting on the connective tissue 
are almost cylindrical in form. A characteristic appearance is produced 
by this arrangement, and it is very easy to recognize these tumors. The 
stroma is dense and fibrous and sometimes contains bone. 
LITERATURE 
Adamantinoma.-Krompecher: Ziegler's Beitrage, 1918, Ixiv, 165. 
Tumors arising from the remaining rudiment of the connection of the 
infundibulum with the roof of the pharynx (hypophyseal duct) have 
been described by Erdheim, Haberfeld, Duffy, and others. They are by 
no means uncommon benign tumors, behaving as destructive growths 
largely from the position they occupy in the sphenoid or in the sella turcica, 
which allows them to encroach upon the hypophysis, and further, upon 
the brain. Their structure is almost identical with that of the adaman- 
tinoma (Fig. 519), although the epithelial cells form, as a rule, smaller 
strands with less extensive rarefaction in the centre. 
LITERATURE 
Duffy: Annals of Surgery, 1920, Ixxii, 537. 
Erdheim: Sitzungsb. b. d. k. Akad. d. Wiss. Math. Natura. kl. Wien, 1904, cxiii, 537; 
Ctbl. f. Allg. Path. u. Path. Anat., 1906, xvii, 209. 
Haberfeld: Ziegler's Beitrage, 1909, xlvi, 133. 
Husten: Virch. Arch., 1923, ccxlii, 222 (Lit.). 
Krompecher: Ziegler's Beitrage, 1918, Ixiv, 165. 
There remain the most common and important adenomatous growths, 
namely, those of the breast and the ovary. The adenomata of the prostate 
have been discussed elsewhere. 
The adenomata of the breast, often called adenofibromata on account of 
their dense stroma, are very common, and assume a great many different 
forms. They are benign tumors, limited in their outline, and growing 
expansively so that they can sometimes be shelled out of the remaining 
breast tissue. This is not always the case, and if they are examined in a 
section through the breast, they are found to appear as grayish-white, 
rather translucent nodules, or indistinctly localized areas of dense consis- 
tence. There is one group which in such a cut surface shows a peculiar 
structure, as though many small papillary or cauliflower-like masses were 
inclosed in cysts. These can indeed be partly turned out of such cavities, but 
are attached at some point by a stalk. They are the intracanalicular 
fibroadenomata, and their peculiar appearance will be recognized by the 
description of their microscopical structure. ADENOMA 
1017 
The more homogeneous adenomata of the breast show on section many 
epithelial structures in the form of acini, canals, or small cysts surrounded 
by an abundant stroma which is usually rather lax immediately about the 
glands and denser in the broad intervening strands (Fig. 520). In some 
cases the whole stroma is cellular and rather oedematous, without any dense 
bands or areas of fibrous tissue. This is so, especially in the cases in which 
the epithelium-lined spaces have the character of long tubules (Fig. 521). 
Fig. 520.-Adenofibroma of breast. The acini are very uniform in size, and are often 
lined with two layers of epithelial cells. 
In every case, whether the epithelial structures have the arrangement of 
acini or tubules or are in the form of cysts, the lining epithelium, which 
may be in two layers, is sharply bounded by a hyaline basement membrane. 
In some tumors this membrane is very broad and thick. When the cells 
are able to disregard the barrier and burst through to grow at large in the 1018 
TEXT-BOOK OF PATHOLOGY 
crevices of the stroma, the tumor must be recognized as a cancer. While 
it is not easy to show histologically that an adenoma can change its char- 
acter and assume that of a carcinoma, the clinical history of these tu- 
mors gives much support to the idea that this change may occur. 
The formation of cysts is of very frequent occurrence (Fig. 522), and 
although in most instances they never reach any great size, there are occa- 
Fig. 521.-Adenofibroma of the breast. The epithelial structures resemble ducts in 
many places. 
sionally seen adenomata in which nearly the whole tumor is occupied by a 
cyst. Distinction must be drawn between the cyst formation in actual 
adenomata and the development of many minute cysts scattered diffusely 
through the breast in the so-called chronic mastitis, which will be described 
later. In the adenomata the cysts are found to contain clear fluid, or fluid 
rendered turbid by the presence of many desquamated cells, or blood- 
stained fluid which may become thick and deeply pigmented with blood- 
pigments. In some cases the cysts contain a butter-like material produced ADENOMA 
1019 
by the epithelium. The epithelium may be reduced to a thin layer of 
flattened cells, or it may be lost entirely. On the other hand, it is frequently 
proliferated and thrown up into folds and papillae (cf. Fig. 522). Distinct 
papillomatous outgrowths may press into the cyst so as to fill it completely. 
Such intracystic papillomata are of quite frequent occurrence. 
Intracanalicular Adenomata.-Closely related to these are the intracanal- 
icular forms described above. In microscopic sections even the smaller 
Fig. 522.-Adenoma of breast. Some of the acini are lined with high cubical or cylin- 
drical epithelium, and such acini are sometimes dilated into cysts. 
epithelial structures may show the curious appearance in which isolated 
masses of connective tissue covered with epithelium lie packed together 
inside an irregular, epithelium-lined cavity or canal as though they were 
really free within the canal. The canal itself is thus reduced to a series 
of branching slits (Fig. 523). In truth these are sections of polypoid in- 1020 
TEXT-BOOK OF PATHOLOGY 
growths which press into the cyst or canal and are cut at a point away from 
their stalks. Sections in another direction would show them as stalked 
polypoid masses. The question once more arises as to whether they are 
initiated by the growth of epithelium or by an excessive growth of connec- 
tive tissue which pushes the epithelium into the cavity. In all probability 
it must be answered, as in the case of the papillomata, that the evidence is 
in favor of the primary activity of the epithelium. Such intracanalicular 
growths have a stroma which is loose and mucoid in the neighborhood of 
Fig. 523.-Intracanalicular adenofibroma of breast, showing numerous apparently free 
epithelium-covered masses packed together. 
the glands; dense and firm in the intervening areas. The denser fibrous 
tissue stains red with eosin, while the mucoid tissue assumes a blue stain. 
On this account they are often called intracanalicular myxofibromata. 
Cystadenomata of the Ovary.-In the ovary the epithelial growths are 
very commonly cystic. It is true that there are rare instances in which a 
papillomatous tumor springs from the surface of the ovary, and we shall see 
later that there are other solid ovarian tumors of a malignant character. 
The common adenomatous ovarian tumors are, however, cystic and are 
spoken of as cystadenomata. There are several varieties: ADENOMA 
1021 
1. Simple ovarian cysts-the so-called hydrops folliculi. 
2. Pseudomucinous cystadenomata. 
3. Serous cystadenomata. 
The division is not important since it is evident that it is based on no essential 
difference. The first type has long been supposed to arise from the Graaf- 
ian follicles through mere accumulation of fluid in their cavities, and this 
view was supported by the finding of ova in the walls of the cysts (Roki- 
tansky and others). Although rigorously upheld by Pfannenstiel, it has 
been practically abandoned by most writers since the work of Nagel, v. 
Kahlden, and others, who have shown that these cysts are not derived from 
Fig. 524.-Large multilocular cystadenoma of the ovary. The Fallopian tube on 
that side is greatly elongated and stretched out over the tumor. 
Graafian follicles, but from ingrowths of the germinal epithelium of the 
surface of the ovary, v. Kahlden traced this clearly in many cases and 
showed that the ova seen by several investigators were really protoplasmic 
masses somewhat resembling ova, but produced by the epithelial cells, per- 
haps as a futile effort on the part of those cells to carry out the function for 
which they were originally intended. 
The cystadenomata are also derived from solid or tubular ingrowths of 
the superficial germinal epithelium, and not from the Graafian follicles nor 
from the so-called Pfluger's cords, which are groups of ova and epithelial 
cells. They are frequently single, but often arise from both ovaries simul- 
taneously and are formed of one large cyst or of a great number of smaller 1022 
TEXT-BOOK OF PATHOLOGY 
ones (simple and multilocular cystomata). At one time much attention was 
devoted to the chemical study of the contents of these cysts, and they were 
grouped on this basis although it is not a distinction of great importance. 
There are some which contain pseudomucin, a substance allied to mucin but 
easily split by boiling with acids so as to produce a carbohydrate which will 
reduce copper. This fluid may be slightly viscid or thick and gelatinous, 
Fig. 525.-Multilocular cystadenoma of the ovary. The cysts are lined with high 
columnar epithelium. 
sometimes dense enough to cut. I remember well one such cyst of 
enormous size from which, at operation, a whole tubful of yellowish brown, 
gelatinous, semifluid material was evacuated. The others, which may be 
called serous cysts, contain a fluid rich in albumin but not gelatinous and 
containing no glycoproteid. 
The cystadenomata are sometimes quite small, and may at times push 
their way into the substance of the ovarian and broad ligament. Usually 
they occupy most of the substance of the ovary, which is spread out on the ADENOMA 
1023 
surface, and press up into the peritoneal cavity attached only by the stalk 
which contains the ovarian blood-vessels. In this way they may reach the 
most enormous size, producing a colossal distension of the abdomen where 
they are carried like a tremendous burden held in front. Their operative 
removal after the fluid is withdrawn through a cannula is often an extremely 
easy feat, since it consists merely in cutting through the stalk of the vessels. 
The pseudomucinous cysts frequently develop many daughter cysts in 
their walls, or they may be definitely multilocular or composed of a great 
Fig. 526.-Portion of a papillomatous growth springing from the wall of an ovarian 
cystadenoma. 
mass of small cysts (Fig. 524). These are lined with columnar or high 
cuboidal epithelium, which produces the fluid contents. They are by far 
the commonest of the cystadenomata (Fig. 525). 
The serous cysts are also usually unilateral, but are very often multi- 
locular, each small cyst being lined with high columnar epithelium which 
is often ciliated. We have recently observed, in two cases, bilateral 
multilocular ovarian cystadenomata composed of such small cysts that 1024 
TEXT-BOOK OF PATHOLOGY 
the very large tumors appeared to be almost solid. In such cases there 
is frequently a great accumulation of fluid in the peritoneal cavity. 
Both pseudomucinous and serous cystadenomata may thus be multiloc- 
ular, or in the form of a single cyst, although even then the remnants of 
broken partitions are usually evident. Both types show, as a rule, some 
infolding or papillary growth of their epithelium, and this may proceed to 
the formation of highly complex papillomatous ingrowths (Fig. 526). These 
are sometimes small and uniformly scattered over the wall; more often 
they arise from the wall in branching masses, leaving much of the lining 
smooth. Such masses may completely fill the cyst. The papillomatous 
growths may also appear on the outside of the cyst, so as to hang in the 
peritoneal cavity, and then they resemble the papilloma of the ovary already 
described. Fragments are broken off and swept into all parts of the peri- 
toneum, where they adhere and grow, forming new papillomata wherever 
they lodge. This may take place, also, in the edges of an operative wound 
in the abdomen. In this sense the papillomatous cystoma partakes of the 
character of malignancy, but it goes no further and there are no metastases 
outside of the peritoneal cavity nor is there any destructive invasion of the 
underlying tissue. A somewhat analogous process follows the rupture of a 
pseudomucinous cyst, with extravasation of the contents into the peri- 
toneum. The gelatinous material is spread everywhere over the wall and 
becomes partly organized by the upgrowth of granulation tissue. Some 
writers have thought that epithelial cells are implanted and continue the 
production of the pseudomucin, but the evidence for this is insufficient. 
The result is that the whole peritoneal cavity is lined with a thick, translu- 
cent layer, often spoken of as pseudomyxoma peritonei. A similar process 
may take place in connection with certain epithelial tumor growths of the 
appendix vermiformis. 
Cysts of the parovarium are generally unilocular, thin walled, and filled 
with clear fluid. They are derived from the parovarian remnants which 
lie in the mesosalpinx and the cyst is found in that situation. 
Adenomata of the Uterus.-From the uterine mucosa there are formed 
polypoid adenomatous growths comparable to those of the intestine. They 
are soft, broad masses, sessile on the mucosa of the uterus, and usually sit- 
uated in or near one of the cornua, although they sometimes occur in the 
cervix and may contain small cysts. On section they are found to be com- 
posed of enlarged and distorted glands embedded in a cellular stroma. 
Aschoff: Ergebn. d. allg. Path., 1897, ii, 456. 
Simpson: Jour. Med. Research, 1913, xxvii, 269. 
Lincoln Davis: Annals of Surgery, 1906, xliii, 556. 
Pfannenstiel: Veit's Handb. d. Gynakologie, 1908, iv, 107. 
Olshausen: Billroth-Lucke, Handb. d. Frauenkr., ii, 308. 
Waldeyer: Arch. f. Gynak., 1870, i, 252. 
Seydel: Ergebn. d. allg. Path., 1901, vi, 805. 
Williams: Johns Hopkins Hosp. Rep., 1892, iii, 1 
v. Kahlden: Ziegler's Beitrage, 1900, xxvii, 1. 
LITERATURE CHAPTER LII 
CARCINOMATA 
General characters, grouping. Flat-cell carcinomata. Epitheliomata of lip, skin, etc. 
Mode of growth and metastasis. Epitheliomata of tongue, tonsils, bronchi, (esophagus, 
gall-bladder, urinary bladder. Epitheliomata of the vaginal portion of the cervix uteri. 
Their frequency and importance. Adamantinomata. Basal-cell carcinomata. Their 
relatively benign character. Distribution, peculiar morphology. Relation to ncevi. Other 
tumor assigned to this group. Analogous tumors of intestine and appendix. 
General Characters.-The jcarcinomaia or cancers' are tumors composed 
essentially of epithelium, although they, like other tumors, are supported 
or surrounded By a vascular stroma, which they exact from the neighboring 
tissue. They are quite analogous to the papillomata and adenomata except 
in the fact that their epithelial cells are possessed of the enormous vigor of 
growth, which breaks through every barrier, and enables them to grow into 
new colonies when they are transported by the lymph- and blood-streams 
and lodged in distant organs. It is this character of malignancy which 
marks them out from other epithelial tumors, and even in the earliest stages 
gives them an anatomical form different from that of the benign growths. 
It is not possible with the means now at our command to distinguish with 
certainty a cell of the epithelium which has this exaggerated power of 
growth from a cell of the epithelium of a benign tumor or even a normal cell. 
But it is quite possible to distinguish these cells by their behavior, not only 
in the distribution of the tumor throughout the body, but in the minuter 
relations which, in microscopical section, the epithelial cells are seen to bear 
to the surrounding tissues. It is true that the cells themselves are usually 
different from normal cells, and in some cases extremely different. No 
doubt, in time we shall have a reliable morphological criterion by which 
we may say definitely that an isolated cell is a cancer-cell or a normal cell, 
but at present no such criterion exists, and we rely upon the arrangement 
of the cells and their relation, in their growth, to the surrounding tissues, 
because there are many instances in which the individual tumor cells look 
so precisely like the normal cells. 
Practically the same distribution and architectural plan found in the 
papillomata and adenomata is repeated in distorted fashion in the carcino- 
mata. We may, therefore, expect to find a great variety of cancerous 
tumors; nevertheless, by divergence from the original form, epithelial cells 
from the most widely different sources often approach a common nonde- 
script type so that the tumors which they produce finally resemble each 
other. 
1025 TEXT-BOOK OF PATHOLOGY 
1026 
We may distinguish the following groups of carcinomata: 
1. Squamous or Flat Cell Cancers.-These arise in the skin, oesophagus, 
etc., or wherever there is stratified epithelium, and are commonly known as 
epitheliomata. 
2. Basal-cell Cancers.--These arise chiefly in the skin, but analogous 
tumors are found elsewhere. They are relatively non-malignant and are 
the basis of the so-called rodent ulcers. 
3. Cylindrical-cell Cancers.-These are analogous to the polyps or poly- 
poid adenomata of mucosse which have glands lined with columnar epithe- 
lium. They retain the tendency to form gland-like structures lined with 
cylindrical epithelium and are hence called adenocarcinomata. 
4. Cancers Derived from Acinous Glands.-These are analogous to the 
solid adenomata and are the commonest cancers, since they include the can- 
cers of the breast. In them the epithelium usually grows in solid strands. 
No very appropriate name has been given them and none is in common use. 
They are gland-cell cancers so non-committal in appearance as not to sug- 
gest a definite morphologically descriptive name. The term carcinoma 
simplex which was at one time applied to them is misleading and useless 
since they are in no sense more simple than the others. Of the various 
metamorphoses of these tumors which change their consistence or give 
them peculiar characters, almost constant enough to stamp some of them 
as another type of carcinoma, we shall speak later. The most striking of 
these is the formation of a gelatinous or colloid material either in the 
cells themselves, in cystic spaces lined by columnar cells, or in the stroma. 
Such colloid cancers fall readily enough into the different groups already 
given, but on account of this common peculiarity it might be tempting to 
class them together as a distinct type. 
FLAT OR SQUAMOUS CELL CARCINOMATA 
There is extraordinary similarity among these tumors from whatever point 
in stratified epithelium they arise. Those which spring from the skin show 
as a rule a greater tendency to keratinization than those derived from such 
epithelium as that of the oesophagus, but this is not invariably so and does 
not constitute a reliable distinction between the two. 
Epitheliomata of the lip (Fig. 527) begin in persons of rather advanced 
age, most commonly in men, in the form of a slight scaly roughness with 
little or no underlying induration. After some slight traumatism which 
may cause the place to bleed, a crust forms, but there is no healing, and if it 
is pulled off, an ulcer is left upon which another crust forms. By this time 
thickening of the skin in that area is palpable. The growth of this thick- 
ened area proceeds until there is a considerable mass, which extends quite 
far into the substance of the lip. Usually there is repeated uncovering of a 
superficial ulceration, which quickly becomes overlaid with a dry crust, but 
it sometimes happens that this destruction of the surface is very slight 
indeed. On the other hand, the ulceration may go very deep and cause FLAT OR SQUAMOUS CELL CARCINOMATA 
1027 
great distortion of the lip, hollowing out a great cavity which exposes the 
teeth. A firm nodule may be felt by this time in the position of the sub- 
mental lymph-gland, and there may even be similar firm masses replacing 
the cervical lymph-glands. If operative extirpation of the primary tumor, 
together with the glands which may be involved, be delayed beyond the 
early stages, death follows after long delay, from the development of 
metastases in more distant organs, among which the liver is most promi- 
nent. As a rule, however, in all such neglected cancers which are allowed 
to metastasize, death is actually the immediate result of lobular pneu- 
monia or other similar terminal in- 
fection. 
When cut through, the tumor and 
its metastatic growths appear as 
grayish, translucent masses of tissue 
closely flecked with opaque yellow 
spots. These become more conspicu- 
ous as the tumor grows older and 
are scarcely to be found in the per- 
fectly fresh margins where growth is 
proceeding. Slight pressure will ex- 
press little masses or cylinders from 
the cut surface, and these are found 
to be composed of necrotic and kera- 
tinized cells. 
Microscopical study of a section 
through an epithelioma of the skin 
(Fig. 528) reveals the existence of a 
mass of growing strands of epithe- 
lium which extend far down into the 
thickened dermis and subcutaneous 
tissue. These are solid columns of 
epithelial cells which frequently anas- 
tomose with one another and branch. 
They are several cells broad or may 
expand into much wider or bulbous masses in which there is evident a 
tendency to a concentric arrangement of the cells, which become more 
and more keratinized toward the centre. Sometimes these concentric 
horny masses are relatively large, and are often spoken of as cancroid 
pearls, cancroid being an old name for this type of epithelioma. All the 
stages in keratinization are seen plainly in passing from the outer layer 
of cells which lies next the connective tissue in toward the centre of such 
a pearl. The cells become thickly studded with black staining droplets of 
eleidin, which in turn fade as the nucleus and' cell-body shrink into the 
horny scale of the innermost layers. The most extraordinary enlargement 
and deformities of the epithelial cells appear in such areas and all sem- 
Fig. 527. -Epithelioma of lip with begin- 
ning ulceration. 1028 
TEXT-BOOK OF PATHOLOGY 
blance of the regularity with which the process goes on in the normal skin 
may be lost. 
The margin of the tumor is usually continuous with the normal skin- 
occasionally there is a break between the epithelial masses of the tumor and 
the edge of the normal epidermis, as though the tumor had burst up through 
the skin. When the two are continuous, there is not a perfectly abrupt 
transition, for the epidermis becomes thickened and sends down some rather 
irregular prolongations just before it joins the tumor. Even then it is quite 
possible that the epithelium of the tumor has healed to the epidermis after 
having burst up through it. It is not believed that the epidermis is con- 
verted into tumor tissue as the tumor spreads, but that all tumor epithelium 
arises from that which first began to grow. Therefore, the epidermis must 
Fig. 528.-Epithelioma of penis showing atypical hyperplasia of adjacent epithelium 
and downgrowth of the tumor-cell strands. 
be pushed aside or burst through in order to allow the tumor to grow. In 
the first case it might retain its continuity with the tumor throughout; 
in the second there must be a secondary healing together. 
The stroma runs everywhere among the strands of cells, carrying blood- 
vessels. It is new tissue, of course, different in arrangement from the 
surrounding dermis and subcutaneous tissue, but in itself there is nothing 
peculiar to be seen. It has no recognizable tumor character, but is rather 
thickly infiltrated with polynuclears and especially mononuclear leucocytes 
or lymphocytes. It is encroached upon by the epithelial cells at every 
point, and if we follow the coarse strands downward, we find that at their 
termination they frequently narrow themselves to single rowrs of cells or 
even isolated groups of cells with advancing prolongations which are FLAT OR SQUAMOUS CELL CARCINOMATA 
1029 
obviously insinuating themselves into crevices of the tissue (Fig. 529). 
In this way they invade not only the stroma, whose formation they have 
enforced, but also the deeper connective tissue and muscle. Any crevice 
or intercellular space is seized upon for their invasion, and they are by no 
means limited to the endothelium-lined lymphatic channels, although they 
also enter these. At the surface, where ulceration has taken place, the epi- 
Fig. 529.-Portion from tumor (Fig. 528) more highly magnified, showing extensive 
keratinization, invasive growth of epithelium, and inflammatory reaction. 
thelial strands are interrupted, and their broken ends exposed in the base 
of the ulcer or covered by an ordinary granulation tissue. Where the 
strands are intact, there may be excessively thick layers of keratinized or 
horny cells. In the deeper strands, too, instead of compact pearls, there 
are often found cavities lined with keratinized cells and filled with a soft 
debris of desquamated scales (Fig. 528). 1030 
TEXT-BOOK OF PATHOLOGY 
The living cells of these strands are obviously unlike the cells of the 
normal epidermis in many respects, although since other conditions may 
produce similar morphological alterations, it is not possible to recognize 
them by these abnormalities as definitely cancerous cells. They are 
usually rather enlarged and polygonal, or irregular in outline, and are ir- 
regularly arranged with regard to one another. Their protoplasm takes a 
rather deep pink stain with eosin in many cases, and their nuclei seem 
especially rich in chromatin and consequently deep stained. There may 
be two or more nuclei in a single cell and the mitotic figures which are 
abundant may be irregular or multipolar. The cell strands are often 
invaded by leucocytes, and fragments of these cells may even be found 
embedded within the cancer cells. Other cell inclusions of various forms 
occur, and have been studied with great care, because it was thought 
that they might be parasites causing the growth of the tumor. These must 
be discussed later. 
The most important point for consideration, however, is the relation of the 
tumor-cells to the adjacent tissue. They are not definitely and smoothly 
bounded by a line of demarcation from the connective tissue. Instead, it 
is constantly to be observed that the cells grow out irregularly at any 
point in the course of the strand, and push their way into that tissue in a 
way totally foreign to the normal epidermis. This process, which, as we 
have said, is most striking along the advancing margin of the tumor where 
it encroaches upon the underlying tissue, is the visible sign of the malig- 
nancy of growth which gives the tumor its peculiar character. 
It has been said that the tumor-cells sometimes push their way into 
the lymph-channels, and it is probable that in doing this they are aided 
by a certain degree of amoeboid activity, which they have been shown to 
possess in tissue cultures (Hanes and Lambert). In those channels they 
are swept along with the stream whenever they break loose, and lodge in 
the next lymph-gland, which acts as a sieve. There, instead of disinte- 
grating and being devoured by phagocytes as other cells would be, they 
are often able to establish themselves in the lymph-sinus and grow rapidly, 
filling up all the sinuses between the lymph-cords and beneath the capsule 
of the gland with a solid injection of epithelial cells, or else spreading from 
the sinus in which they lodge to produce a nodule of tumor tissue which 
extends radially to occupy a large part of the gland. In this process the 
epithelium at once causes the formation of a new vascular stroma for its 
cells at the expense of the gland, and in its growth separates and destroys 
the normal tissue of the gland which it replaces. The structure of this new 
nodule is finally in every respect similar to that of the original tumor and 
all the processes of keratinization and other changes described for that 
situation are repeated here. This is true, too, for further metastases even 
when the renewed transportation of cells from the first metastasis gives rise 
to secondary or tertiary colonies in distant organs. 
Epitheliomata may occur in many situations in the skin, although it FLAT OR SQUAMOUS CELL CARCINOMATA 
1031 
seems that places at which two types of epithelium come together are rather 
predisposed to the development of these tumors. The lip, the edges of the 
nostrils, the eyelid, the penis and vulva, the margin of the anus are places 
where they most frequently occur. In the margins of old varicose ulcers 
they may develop, apparently stimulated or possibly even caused to grow 
by the long-continued irritation to which the skin in exposed in a site 
where it is continually endeavoring to grow and being as constantly frus- 
trated. 
Epitheliomata are by no means limited to the skin, but occur very fre- 
quently in mucosse which are covered with stratified epithelium. 
Thus such tumors may originate at almost any point in the interior of 
the mouth. Although they sometimes occur in the cheek or gums, epi- 
theliomata of the tongue are far more common. They may occupy any 
situation from the tip to the extreme base of the tongue, and grow in such a 
Fig. 530.-Epithelioma of tongue with ragged ulceration. 
way as to form a dense mass extending far into its substance and becoming 
deeply ulcerated (Fig. 530). There is little or no keratinization, and the 
superficial layers readily become macerated. Metastases may appear in 
the regional lymph-glands and internal organs. In one case in which we 
found a great solid mass embedded in the root of the tongue, with only slight 
superficial ulceration, there were enormous nodular masses in the cervical 
lymph-glands throughout the whole chain, and other nodules in the liver. 
In another case in which the deeply ulcerated tumor had extended so as to 
approach the internal carotid artery, it finally eroded that vessel some 
weeks after a partial extirpation of the tumor tissue. A formidable haem- 
orrhage was stopped by ligature of the artery, but the man died ten days 
later. There were no metastases, but there was a large abscess in the 
cerebral hemisphere of that side. This case is cited merely as an example TEXT-BOOK OF PATHOLOGY 
1032 
of the unexpected sequelae which may complicate the course of a tumor of 
this kind, developed in the immediate neighborhood of important structures. 
Epitheliomata may develop from the surface epithelium or crypts of 
the tonsils, and are often particularly destructive. Laryngologists meet 
with similar tumors involving the vocal cords, the arytenoid folds, or the 
epiglottis. They are quickly ulcerated, and lay bare the cartilages of the 
larynx after having destroyed the soft tissues. One case has already been 
mentioned in which a tumor assumed the form of a papilloma, although 
spreading over the arytenoid folds and epiglottis on both sides and extend- 
ing to the pillars of the fauces. In most cases, however, the tumors are not 
elevated, but appear as flattened, rough thickenings of the tissue, soon 
hollowed out into ragged ulcers. 
Tumors of the trachea and large bronchi are rare, and not ordinarily of 
the type of flat-cell epithelioma, as is natural from the fact that those 
canals are lined with cylindrical ciliated epithelium. Nevertheless in the 
substance of the lung tumors, which are definitely squamous, epitheliomata 
do arise from the branches of the bronchi. We have recently observed 
a whole series of these tumors of the lung, among which there were several 
instances in which a great cavity in the upper part of the lung was found on 
incision to be lined with opaque, yellowish-white, friable, crumbling tissue. 
In some of these the bronchus could be traced directly into the cavity, 
its walls becoming thickened by a great new-growth of the mucosa, which 
became continuous with the margins of the lining of the cavity. Micro- 
scopical sections show in these cases that most of the tumor is made up of 
strands of atypical stratified epithelium showing all the characters of those 
seen in the cutaneous cancers. The cells are held together by very distinct 
intercellular bridges (prickle cells) and undergo keratinization. In the 
bronchus one may trace the transition of cylindrical into squamous epi- 
thelium. It is perhaps an example of metaplasia which converts one kind 
of epithelium into another, although it is conceivable that some other 
explanation, depending rather upon embryonic displacement of cells 
destined to become squamous epithelium, might be offered instead. Dr. 
Adler has reviewed these tumors of the lung, and in his book it may be 
learned that there are many other types in which cylindrical cells play the 
important role. There are also some derived from the flattened alveolar 
epithelium, although their cells scarcely retain that form. 
To return to the digestive tract, epitheliomata are common in the 
oesophagus, where they occur at almost any level, but most frequently 
opposite the cricoid cartilage, the bifurcation of the bronchi, and at the 
cardiac orifice of the stomach. Whether the explanations given for these 
traditional sites are satisfactory, must be left to the future to determine. 
It has been thought that the oesophageal mucosa at these points is irritated 
by passing food, since a certain projection into the lumen is caused by the 
firm structures which touch the outside. 
The epitheliomata are usually broad, flattened masses which nearly FLAT OR SQUAMOUS CELL CARCINOMATA 
1033 
encircle the oesophagus, and, by encroaching upon its lumen, obstruct it 
greatly. The starvation caused by this obstruction hastens the decline 
in health of the affected person. We have been repeatedly struck by the 
fact that the tumor may not extend all the way around the wall of the 
oesophagus, but leaves intact a narrow band of normal mucosa which joins 
the unaffected mucosa above and below the tumor. On section, the cut 
surface of the tumor is quite like that of other epitheliomata, except that it 
is perhaps less closely flecked with necroses. Nevertheless, ulceration 
does occur rapidly and at the same time the tumor extends through the 
muscular and connective-tissue coats. Usually adhesions of dense fibrous 
tissue form between the diseased oesophagus and neighboring structures, 
so that further growth of the tumor extends through the adhesions into 
those organs. Thus a main bronchus or the trachea may be invaded and 
perforated so that there is formed a definite fistula between the bronchus 
and oesophagus. In that case bronchopneumonia rapidly follows the 
leakage of oesophageal contents into the bronchus. The lung may be 
invaded directly, or an opening be formed into the pleural cavity. In 
rare cases the aorta or inferior vena cava are eroded and death may follow 
from haemorrhage. Occasionally the tumor recedes in its growth and under- 
goes a partial healing, with the formation of scar tissue which contracts 
about the oesophagus, forming a narrow stricture. Metastases are found 
in a rather small proportion of the cases and are then in the pericesophageal 
lymph-glands, in the lungs, in the liver, or in other more distant situa- 
tions. I saw a case in which the tumor had invaded a pulmonary vein, 
producing infarcts in the kidneys and intestines and emboli surrounded 
by haemorrhages in the liver and meninges. Another projected, in the 
form of nodules, into the lumen of the trachea, while there were secondary 
nodular growths in the parietal pleura. Microscopically these tumors, 
like those of the skin, grow in the form of solid branching strands of 
cells which readily invade the muscularis. They are rather less regular 
in form, and in the character of their nuclei, than the cells of the skin 
cancers and do not become keratinized. Nevertheless, the same con- 
centric arrangements may be found with flattening and degeneration 
of the central cells. 
The tumors of the gall-bladder are usually of the cylindrical cell type, 
but they may sometimes, as in the case of the lung, show themselves to be 
composed of squamous epithelium, a character which is maintained in 
all the metastatic nodules. 
In the urinary bladder there appear papillomatous tumors which have 
already been described, and these, as it was then said, are probably from 
the beginning malignant in character and merely impose themselves for a 
time as benign growths. At the bases of the tassel-like papillomatous 
growths the thick stratified epithelium is found to invade the underlying 
tissue in the form of solid strands (Fig. 531). Usually after a time ulcera- 
tion may destroy most of the papillomatous growth, leaving only a ragged 
area in the bladder-wall lined by rough masses of growing epithelium. 1034 
TEXT-BOOK OF PATHOLOGY 
Another type of carcinoma of the bladder does occur, however, in which the 
wall is infiltrated and invaded widely without having lodged at any time a 
papillomatous growth. I saw one case, however, in which there were many 
small polypoid tumors scattered over the bladder-wall and concentrated 
Fig. 531.-Papillomatous tumor of bladder, showing invasive growth of some strands 
of epithelial cells. 
especially about one ureteral orifice. That ureter was greatly dilated and 
was lined with similar tiny papillomata which extended up into the pelvis 
of the kidney. It was difficult to be sure whether the primary growth was 
in the ureter or bladder. Single carcinomatous nodules sometimes occur FLAT OR SQUAMOUS CELL CARCINOMATA 
1035 
in the ureter, causing its great obstruction, and giving rise to metastases 
in neighboring lymph-glands. In these one finds very delicate narrow 
strands of epithelial cells which no longer resemble closely the large cells 
of the typical epitheliomata. 
The epitheliomata of the cervix uteri and adjacent vaginal wall are per- 
haps the most important of all, on account of their extreme frequency, 
their malignancy and rapid growth, and their fatal effects. 
Fig. 532.-Epithelioma of vaginal p ortion of cervix uteri, invading uterine and vagi- 
nal wall. There is great ulceration, which approaches bladder and rectum without ac- 
tually perforating them. 
Another type of carcinoma of the uterus derived from the tubular glands of the body 
of the organ, and maintaining the character of an adenocarcinoma, will be described 
later, but it is of much less importance, since it is relatively rare and by no means so 
malignant. 
These tumors (Fig. 532) develop in the portio vaginalis of the cervix 
uteri, near the line of transition of the stratified epithelium into the 
cylindrical mucosa, and appear at first as rough erosions with a surface 
which bleeds easily and is almost papillary in form. Growing into the 
substance of the cervix the tumor may surround the external os with a 
dense ring of friable epithelium. The further growth is usually accom- 1036 
TEXT-BOOK OF PATHOLOGY 
panied by ulceration, which hollows out a funnel-shaped or irregular 
aperture. A longitudinal section of the uterus at this stage shows that 
much of the cervical wall is occupied by a gray, solid tissue with numerous 
opaque flecks of white. The growth extends irregularly into the muscle 
above and extension outside on the vaginal portion of the cervix and over the 
vault of the vagina is common; later more of the vagina may be involved 
in the continuous growth. Metastases to the inguinal lymph-glands and 
Fig. 533.-Epithelioma of cervix uteri with many multinucleated cells. In the centre 
there is an epithelial cell showing multipolar mitosis. 
later to those of the retroperitoneal region may occur at this stage, and 
there may even be nodules in the liver or lungs. The further growth of the 
tumor extends into the parametrium, forward into the wall of the bladder, 
and backward to involve the wall of the rectum. Ulceration takes place 
rapidly, and it is not uncommon to find a great, ragged perforation between 
the vagina and bladder or between vagina and rectum. I have seen one 
case in which, from such ulceration, bladder, uterus, and rectum all opened BASAL-CELL CARCINOMATA 
1037 
in common into a great ragged cavity. Infection of the bladder and 
ureters is sure to follow, and death may be immediately due to an ascending 
suppurative nephritis. The tumor is composed of thick, irregular strands 
of stratified epithelium, which is not keratinized, but in which the most 
extreme irregularities in the form of the cells may be observed. In one 
such case (Fig. 533) there were cells of all sizes, even including huge proto- 
plasmic masses containing as many as 12 nuclei irregularly placed through- 
out the cell-body. Multipolar mitotic figures, in which several centrosomes 
and achromatic spindles could be seen in relation to a very much branched 
arrangement of chromosomes, gave the explanation of the formation of 
these multinucleated cells. Other tumors of this type are less atypical 
and merely present irregularly branching cords of cells, which ramify and 
spread freely in any direction to invade the uterine muscle. Necroses are 
frequent in such tissue, involving the broader bands of epithelial cells. 
The stroma which is formed in association with them is much infiltrated 
with wandering cells, and it may happen that, at the surface of the tumor, 
only those epithelial cells which are immediately around the blood-vessels 
remain alive and project as papillary remnants. 
The remote metastases which may be in the peritoneum or omentum, in 
the liver, kidneys, etc., as well as in the regional lymph-glands, often reach 
a considerable size, although in the cases which I have seen they have been 
relatively small. They maintain the type of tumor tissue seen in the origi- 
nal growth. 
Tumors which belong in this general class are the cancers of aniline 
workers, of chimney-sweeps, of betel chewers, and of those in whom x-ray 
burns have long persisted. It will be more useful to describe them in con- 
nection with the general discussion of carcinoma and other tumors. 
LITERATURE 
Skin.-Janeway: Ztschr. f. Krebsforschung, 1910, viii, 403. 
Dittrick: Amer. Jour. Med. Sei., 1905, cxxx, 277. 
Penis.-Patterson: Univ. Penna. Med. Bull., 1901, xiv, 157. 
(Esophagus.-Sakata: Mitth. a. d. Grenzgeb. d. Med. u. Chir., 1903, xi, 634. 
Cummins: Proc. Path. Soc. Phila., 1908, xi, 44. 
Tongue.-Kuttner: Beitrage z. kl. Chir., 1898, xxi, 732. 
BASAL-CELL CARCINOMATA 
Krompecher has pointed out the fact that many of the tumors which grow 
in the skin and are distinctly derived from the epithelium are quite different 
in structure from the epitheliomata just described and quite as different in ( 
their biological characters. These comprise, in addition to many flattened 
irregular nodular masses, the so-called rodent ulcers, which have been long 
known to differ from the ordinary epitheliomata in that they are relatively 
benign and rarely show any tendency to metastasize rapidly. Krompecher 
regards these tumors as growths derived from the lowermost or basal layers 
of the epidermis, for which reason they show no tendency to keratinization 1038 
TEXT-BOOK OF PATHOLOGY 
or to pearl formation. Indeed, he is willing to ascribe certain tumors to the 
cylindrical or Malpighian layer, others to the rete layer with cuboidal cells, 
and the highly malignant epitheliomata 
to the more superficial or spiny layer. 
This seems open to question, and it is 
conceivable that, while the more inno- 
cent basal-cell cancers may, in truth, be 
derived from these lower layers, the 
malignant epitheliomata may represent 
a different biological alteration of any 
or all cells of the epidermis, so that their 
malignancy is not merely the effect of 
their being derived from a somewhat 
more differentiated layer of the same 
cells. 
The basal-cell cancers appear most 
frequently on the face, being especially 
common in the upper part, about the 
forehead, the cheek, the nose, and the 
eyelids (Fig. 534). They are also to be 
found on the back or abdomen, or in 
any other region of the body, and it is 
to be observed that they do not, like 
the ordinary epitheliomata, arise at the 
margins of the skin and mucosae, where 
complexities in development occur. 
Krompecher gives diagrams which show 
how they grow from the lower layers of 
the epidermis, forming masses of solid 
strands or complicated formations of 
ramified epithelial structures in which 
the cells maintain themselves in single layers. In these cases the super- 
ficial layer of the epithelium persists as a smooth sheet of cells, although 
occasionally it may dip down into the middle of each downgrowth of the 
basal epithelium. 
On section through such tumors (Fig. 535) one is impressed with the fact 
that, in spite of the complexity of the downward-growing strands, all reach 
to about the same level. Further, it is seen that they are very sharply 
outlined against the stroma, and show little inclination to strew their cells 
into the irregular crevices of that tissue. Doubtless this morphological 
character is an expression of their benign type of growth. The cells are 
rather small and compact, with deeply staining nuclei and relatively 
scant protoplasm, which also takes a rather dark stain. There is little or 
nothing of the pallor, the inflation, and the nuclear irregularities which are 
so common in the cells of the more malignant epitheliomata. Necrosis and 
Fig. 534.-Basal-cell epithelioma or 
rodent ulcer of eyelid. BASAL-CELL CARCINOMATA 
1039 
ulceration are common, however, and the tumors often present them- 
selves as advancing ragged ulcers with only a very thin wall of tumor 
tissue. Upon extirpation they show little tendency to recur, but even if 
there is a recurrence, it is exceptional to find metastases in the regional 
lymph-glands or in more distant situations. 
Fig. 535.-Basal-cell epithelioma of the skin, showing peculiar limitation of the down- 
ward growth. 
It will at once suggest itself that the naevi bear a considerable resemblance 
to these tumors, since they are composed of small, compact cells which lie 
in the papillae of the dermis, and are thought by many to be connected with TEXT-BOOK OF PATHOLOGY 
1040 
the epidermis itself. It is true that, in naevi, the connection of the tumor- 
cells with the epithelium must be sought for with great care, and is fre- 
quently impossible to find, that the cells have little histological resemblance 
to those of the epithelium, and that their great tendency to form or to 
accumulate pigment in their cell-body marks them out from those of the 
basal-cell tumors. There the tumor-cell strands are everywhere continu- 
ous with the epithelium; they are not merely isolated groups of cells lying 
in the substance of the dermal papillae: they are typically epithelial in 
character, and seldom contain any considerable amount of pigment. They 
have little energy of growth and rarely metastasize, while from the naevi 
there arise the most malignant of all tumors, the melanomata, which may 
scatter secondary nodules in thousands in every tissue of the body. Never- 
theless, there are many who regard the naevi and the melanomata as tumors 
of epithelial origin, and Krompecher identifies them more or less closely 
with his basal-cell cancers. A decision is difficult in this matter, but it 
seems that there are sufficient points of distinction to warrant the separa- 
tion of the groups. The tumors which were referred to as endotheliomata 
of the skin by Braun, and accepted as such by Borst, were mentioned under 
that heading as possibly derived from the endothelium of the lymphatic 
channels in the skin. Such tumors are, of course, possible, but Krompecher 
unhesitatingly ascribes to them an epithelial origin and regards them as 
identical with the basal-cell cancers. This identification he pushes further 
to include many tumors which arise from the glands which open upon sur- 
faces of stratified epithelium, and even the mixed tumors of the salivary 
glands, which we shall discuss in the next chapter. He finds that basal-cell 
cancers arise in ovarian tumors, in dermoid cysts, and other tumors of 
teratomatous origin. This can, of course, never be contradicted, since 
those tumors have such manifold possibilities. Finally, the neuroepithelio- 
mata of the retina described by Flexner, and later by Wintersteiner, seem 
to him to have similar characters. 
In the intestine Krompecher describes no analogues of his tumors, but 
other authors have found curious carcinomata in the small intestine, usually 
occurring as multiple nodules, and often causing stricture or obstruction of 
the gut, which, from their structure and behavior, seem to resemble these 
basal-cell cancers quite closely. They are dense masses which partly 
encircle the intestine at several points or project into its interior and are 
made up of rather narrow strands of cells in a dense stroma. One tumor 
apparently of this character occurring in our material was called an intesti- 
nal adenoma. It is composed of broad, solid strands of cells, with rounded 
nuclei, which extend down into the muscularis and show little connection 
with the overlying mucosa. The cells of these strands are frequently col- 
lected into rosettes or interlacing strands, which look like tubules, but are 
solid and closely packed together to form the main masses. In this respect 
they remind one of the neuroepitheliomata. Similar tumors of relatively 
benign character are found in the appendix. There, too, the tumor tissue BASAL-CELL CARCINOMATA 
1041 
is composed of narrow, irregular, solid strands of small cells, in no place 
reproducing the crypts or glands of the appendix, as would be the case in an 
adenocarcinoma. Implantations in the peritoneum may occur, but metas- 
tases are rare. Masson regards them as derived from an endocrine tissue 
which exists in relation with sympathetic nerve-fibres. 
In spite of the numerous papers which have appeared recently with regard 
to these tumors, it seems that there remains much to learn as to their rela- 
tions. 
LITERATURE 
Krompecher: Ziegler's Beitrage, 1900, xxviii. 1. Der Basalzellenkrebs, Jena, 1903. 
Bunting: Johns Hopkins Hosp. Bull., 1904, xv, 389. 
Oberndorf er: Frankfurter Ztschr. f. Path., 1907, i, 426. 
Burckhardt: Ibid,., 1912, _xi, 219. 
Dietrich: Ibid., 1913, xiii, 390. 
Masson: Bull, et mem. Soc. anat. de Par., 1919, Ixxxix, 405. CHAPTER LIII 
CARCINOMATA (Continued) 
Adenocarcinomata: General characters and distribution. Carcinomata of the stomach: 
polypoid, solid, and scirrhous forms. Their histology and mode of growth; metastasis. 
Colloid forms, their somewhat different mode of growth. Carcinomata of the gall-bladder 
and ducts; carcinomata of the pancreas, of the colon, of the prostate. Metastasis into bones 
from prostatic tumors. Adenocarcinomata of the uterus and of the ovary. 
From all mucosae in which the epithelium is cylindrical in form, and from 
glands and ducts lined with cylindrical epithelium, there may be derived 
adenocarcinomata or cylindrical-celled cancers. These are malignant tu- 
mors which give rise to extensive metastases, often far larger than the 
primary growth. They maintain in irregular fashion the arrangement of 
tubular glands, transmitting this mode of growth to the primary metas- 
tases, but sometimes losing it in secondary metastases which arise from the 
transportation of cells from the primary ones. This modification of the 
architecture of tumors in secondary or tertiary metastases is not uncom- 
mon, and will be discussed later in a more general way. 
While adenocarcinomata may thus appear in situations almost as numer- 
ous as those which form the point of origin of epitheliomata, there are cer- 
tain sites which become important from the fact that they are so frequently 
the starting-point of these tumors-the stomach, the gall-bladder, and bile- 
ducts, the pancreas, the large intestine, the body of the uterus, and to a less 
extent the prostate and the bronchial mucosa. Of course, tumor tissue of 
this structure may also occur in teratomata, where there are abundant 
opportunities for its development. Except for the exaggerated energy of 
growth of their cells, they are quite comparable to the adenomata and poly- 
poid glandular tumors. 
Carcinomata of the Stomach.-The extreme prevalence of carcinoma- 
tous tumors of the stomach, their disabling effects, and fatal outcome cause 
them to occupy a very prominent place among tumors. There are many 
varieties, and many situations in the stomach may be occupied, so that the 
symptoms vary greatly. A cancer at the cardiac orifice, by obstructing the 
entrance of food into the stomach, may, like the epitheliomata of the oesoph- 
agus, result in starvation and extreme emaciation. A cancer in the 
fundus of the stomach or on any part of the wall away from the orifice may 
exist a long time without causing any symptoms, while such a tumor at the 
pylorus or encircling the pyloric ring is sure to cause stagnation of the 
gastric contents and dilatation of the stomach. Absorption of poisonous. 
ADENOCARCINOMATA 
1042 1043 
ADENOCARCINOMATA 
decomposition products must then occur, and the gastric juice loses its 
antiseptic qualities with the loss of its high content of hydrochloric acid, in 
place of which lactic acid often appears. Bacteria or moulds may thrive 
in considerable quantities in the accumulated material, particularly the 
large Oppler-Boas bacillus. Vomiting is frequent, and gastric tetany may 
appear just as it does when the pylorus is obstructed by the scar of an old 
ulcer. -«p 
The following types of cancer of the stomach are met with and are 
Fig. 536.-Large fungus-like carcinoma near fundus of stomach. 
sufficiently different morphologically to fall into groups, although doubtless 
in principle they are alike. 
Carcinomata about the cardiac orifice may be derived from the prolonga- 
tion of the stratified epithelium of the oesophagus and may therefore have 
the anatomical characters of the epitheliomata. The others derived from 
the cylindrical epithelium usually maintain that type of cell, although in 
many instances in which fine strands of cells are found scattered through the 
musculature, the cylindrical character is lost. 
Polypoid Carcinomata.-These occur anywhere on the stomach-wall and 
project into the lumen as broad, pedunculated, fungus-like masses, which 
are rather soft and easily torn or broken apart. In Fig. 536 there is 1044 
TEXT-BOOK OF PATHOLOGY 
shown an example of this type, in which the tumor is situated very near the 
cardiac orifice, and doubtless projected in front of it, without, however, 
causing any marked obstruction. Quite similar tumors are found near the 
pylorus. In this case there were no discoverable metastases, and it is my 
impression that these tumors do not form metastases as rapidly as do the 
other types. The normal mucosa passes upward to the overhanging edge 
and gives place to the most complex arrangement of gland-like structures 
lined with cylindrical epithelium. In places there appear to be papil- 
lomatous areas; in others through the whole depth of the tumor the tissue 
is made up of a delicate stroma, supporting wide and narrow ramifying 
tubular epithelial structures. There is surprisingly little downgrowth into 
the muscular wall in this case, but in others of the same type it is far reach- 
ing and destructive. Necrosis and sloughing of the exposed tumor is of 
almost regular occurrence. 
Solid carcinomata of more sessile form are much denser than these 
fungating types. They, too, may grow anywhere in the stomach, but 
appear most frequently about the pylorus and the lesser curvature. Va- 
rious stages may be found, from a beginning adenoma-like growth of small 
size to the huge, crater-like, excavated masses which occupy a great part 
of the wall of the stomach. I remember one such tumor as large as a child's 
head, composed of dense, elastic, yellowish-white tissue, which projected 
into the stomach and was hollowed out so that the cavity extended far into 
the liver, to which the outer surface of the stomach had become densely 
adherent. Ordinarily, such tumors are found as rounded or irregular ulcers 
with thick, elevated, rounded edges which can be felt to project a short 
distance beneath the adjacent mucosa (Fig. 537). One may pick up and 
move the mucosa almost as far upward on this ridge as its crest-beyond 
that, although the mucosa looks smooth and velvety for a short distance 
further, it is adherent and immovable. There follow a roughening and 
irregularity of the surface which then drops precipitously into the ulcer. 
On cutting through the margin of the tumor the transition of the normal 
mucosa into the greatly thickened epithelial mass of the tumor can be seen. 
Here as in the epitheliomata of the skin, the significance of this continuity 
may be questioned and it seems probable that in spite of the intermediate 
zone of modified mucosa, the unbroken epithelium may be maintained 
by repeated healing together. It is, however, possible that the normal 
mucosa is merely pushed back by the increase in size of the tumor. It 
does not seem probable that normal mucosa is converted into tumor as the 
growth advances. 
It is rare to see a gastric carcinoma which is not ulcerated, although the 
tumor itself may be far larger than the area occupied by the ulceration. 
The cut surface reveals a white or grayish-white or yellowish tissue which 
interrupts the muscularis mucosse, and passing through the submucosa, 
interrupts and penetrates the muscular coat of the stomach. At the 
margin the muscular coat may be traced for some distance into the tumor, ADENOCARCINOMATA 
1045 
and then it is found that the tumor has grown in thousands of fine strands 
between the fibres of the muscle, leaving it otherwise intact for a long time. 
In the subserous tissue it again becomes a solid mass. On the outer surface 
the site of the cancer is readily made out by the rigidity of the wall, and 
usually by the appearance of whitish, flattened nodules which cover the 
peritoneal surface. Dense adhesions to surrounding organs are very 
common, and the stomach is, in consequence, often kinked and distorted 
by being drawn up against the liver or pancreas. Metastatic nodules are 
usually found in the neighboring lymph-glands, which may be greatly 
Fig. 537.-Carcinoma of stomach with ulceration and thickened, elevated margin, 
enlarged. On section, they show a white tissue, usually with yellowish 
necrotic flecks in every way similar to that in the gastric wall. The omen- 
tum is studded thickly, in many cases, with minute nodules of the same 
tissue and is drawn up into a dense prismatic mass which lies transversely 
in the abdomen and can be felt through its wall. There may be more 
distant metastatic nodules in the peritoneum, but it is more common to 
find them rather limited to the region of the stomach. The occurrence of 
metastatic nodules in the fiver is extremely frequent and these may reach 
a very great size and be very numerous. The most remarkable variation 1046 
TEXT-BOOK OF PATHOLOGY 
occurs in this respect, for while some large tumors show only a few small 
metastases, others of less extent are found to have given rise to enormous 
growths in the liver sufficient in number to occupy most of its substance. 
The occurrence of metastases in other situations will be referred to later. 
It has long been thought that these tumors may develop in the edge of a 
round ulcer of the stomach, and there is much clinical and pathological evi- 
dence to support this view. The transformation of symptoms of long- 
standing gastric ulcer into those of a gastric carcinoma may not be very 
convincing, nor even the discovery of an ulceration in the middle of the 
tumor, with such induration of its base as to suggest the existence of a 
primary chronic gastric ulcer. But when the tumor develops on one side 
of a typical round ulcer, the conclusion is more difficult to escape. We 
Fig. 538.-Dense carcinoma of stomach surrounding the whole pyloric region and 
narrowing the channel. There is diffuse infiltration of the whole thickness of the wall 
with the tumor-cells. 
have seen two typical round ulcers of the stomach, in the margins of which 
carcinomatous growth of epithelium of unmistakable character was found, 
although in neither case had the tumor developed sufficiently to disturb 
the characteristic appearance of the ulcer. 
Other solid gastric cancers grow as in Fig. 538, without such extensive 
ulceration and produce a great thickening of the mucosa and of the sub- 
mucosa, infiltrating the muscle layer and the subserous tissue. Such a 
tumor does become ulcerated, but its earlier growth forms an extremely 
dense, resistant mass, which may completely surround the pyloric portion 
and render it quite rigid. 
Occasionally there is found a peculiar thickening and induration of the 
whole stomach-wall, which causes it to shrink to a small size. There may ADENOCARCINOMATA 
1047 
be no prominent tumor nodule and little ulceration, but the mucosa is 
roughened and wrinkled, and not readily movable upon the underlying 
tissue. A section shows that the whole wall is infiltrated with a tumor in 
which the epithelial cells are relatively sparsely scattered in an abundant 
and dense stroma. This is the so-called diffuse scirrhous carcinoma of 
the stomach (Fig. 539). 
Microscopically, various appearances are met with in these forms of 
more solid carcinomata. In most cases the normal mucosa, in approaching 
the tumor, becomes infiltrated with lymphocytes and other wandering cells, 
and its glands are lengthened and become tortuous, often with dilatation 
of the lowermost part. Nevertheless, they retain the smoothness of their 
Fig. 539.-Scirrhous cancer with very slight ulceration occupying whole wall of stomach 
and causing its great contraction. 
outline. Suddenly as the surface layer of the epithelium reaches the crest 
of the marginal ridge of the tumor, the whole arrangement changes and 
the cells themselves assume a different character (Fig. 540). The glands 
become exceedingly irregular, with numerous branches, or are greatly 
enlarged and partly or completely filled with epithelial cells. It is now very 
difficult to determine just how much of the epithelial mass belongs to each 
gland, for their identity as glands is lost, and instead there are ramifying 
cavities lined with several rows of cells among which are other cavities, or 
there are solid groups of cells. The cells lose their regular arrangement 
and to a great extent their uniform cylindrical shape. They no longer 
range themselves on a smooth basement membrane, but grow at will in 1048 
TEXT-BOOK OF PATHOLOGY 
any direction into the stroma. The sudden change from the moderately 
infiltrated and loose stroma of the mucosa, to the much denser stroma 
of the tumor which is thickly infiltrated with leucocytes, is very striking. 
Still, in other cases, the disarrangement of the glands in passing over from 
the mucosa into the tumor is by no means so great, and the whole tumor is 
Fig. 540.-Carcinoma of stomach showing sudden transition of glands into the carcino- 
matous distortion. 
found to be made up, even in its distant extensions through the muscle and 
into the subserous tissue, of long tubules which are coarse and deeply 
stained and variable in calibre, but which do not seem to fray out into the 
tissue, or to grow into more solid masses. At these extreme ends there is 
generally an indication of the invasive freedom of their cells. Usually, ADENOCARCINOMATA 
1049 
however, even in those in which the glandular or tubular arrangement is 
best preserved, there are parts of the tumor in which the tubules appear 
as solid strands with numerous spaces lined with cylindrical cells, which 
keep up the glandular appearance. 
In the denser tumors, such as that shown in Fig. 538, it is common to 
find the glands of the mucosa, as one passes into the tumor, changing into 
extremely long narrow tubules which are lost in a dense and greatly 
thickened submucosa. Between these glands, the tissue is packed with 
Fig. 541.-Margin of a secondary nodule in the liver derived from an adenocarcinoma 
of the stomach. 
cells, many of which are clearly wandering cells, while great numbers are 
loose epithelial cells. It is difficult to trace the exact source of these cells, 
although they may sometimes be obviously derived from the lowermost 
ends of the glands. Deeper in the submucosa and far into the muscle they 
assemble themselves into more definite groups, which arrangement they 
retain wherever they are found. This is practically the character of the 
growth in the scirrhus cancers, in which very small solid groups of cells are 
set free from the ends of the glands, and grow into the submucosa. The 
extreme growth of connective tissue in response to this causes the mucosa, 1050 
TEXT-BOOK OF PATHOLOGY 
submucosa, and muscularis to become matted together into a leather-like 
mass, in which tumor-cell strands are sparsely scattered. 
Occasionally there are observed several carcinomatous nodules projecting 
from the mucosa of the stomach, and the explanation is to be found in 
Fig. 542.-Metastatic cancerous nodule in the liver from a primary carcinoma of the 
stomach. The section shows the central necrosis and scarring of the tumor, with retrac- 
tion and dell formation. 
the fact that in these cases the network of lymphatic channels in the sub- 
mucosa and in the subserous tissue is filled solidly with tumor-cells, which 
enter at the primary growth and grow along until they form a sort of injec- 
tion of the whole network. The accessory nodules appear to be eruptions 
of tumor growth from those underlying lymphatics. This mode of growth ADENOCARCINOMATA 
1051 
was studied by Borrmann, whose illustrations correspond well with the 
condition found in several of our cases. 
With regard to metastasis from the carcinomata of the stomach, a brief 
statement was made above. It is true that the adjacent lymph-nodes 
and the adjacent peritoneum are usually primarily involved, and also 
that numerous nodules are frequently formed in the liver (Fig. 541). 
These vary greatly in size and evidently in age, and while there are small, 
Fig. 543.-Invasion of lymphatics in the walls of a bronchus extending from pleural 
metastases. 
translucent, grayish-white nodules of smooth, globular form, there are also 
very large masses of similar form, but showing the well-preserved tumor tis- 
sue only in their marginal portions. The whole central part of such nodules 
usually presents necroses, which may affect only small groups of cells here 
and there, so as to produce the familiar yellow flecks on a gray surface, or 
may be complete, so that nothing remains alive except the connective-tissue 
stroma. When the nodule lies at the surface of the liver, it at first presents 1052 
TEXT-BOOK OF PATHOLOGY 
a convex or flattened face, but with the liquefaction and absorption of this 
central necrotic part and the contraction of the stroma which remains 
behind, there comes a sinking of the centre. Every secondary cancer 
nodule of any age which projects from the surface of the liver shows this 
central depression, and on section the reason is plainly seen (Fig. 542). 
Doubtless insufficient blood supply is the cause of such necrosis. The 
nodules press upon the blood-vessels and bile-ducts and cause local areas of 
anaemia and chronic passive congestion, and also jaundice. The jaundice 
may be extreme, 'but it must be remembered that there are often opportu- 
nities for its production by 
the compression of the large 
bile-ducts outside the liver 
by the main tumor or by its 
intraperitoneal metastases. 
The metastases are not 
confined to the abdominal 
organs, but are found in the 
pleural cavities on the cos- 
tal pleura, or on the surface 
of the lung. There one ob- 
serves peculiar minute, len- 
ticular flecks of gray, trans- 
lucent tissue, which look 
almost like tubercles. They 
are larger and flatter, how- 
ever. On section, the lung 
is air containing, but is 
roughened by the projection 
of the interlobular septa, 
blood-vessels, and bronchi, 
all of which stand up a little 
from the cut surface as gray, 
translucent, rough ridges. 
This is due to the filling 
up of the lymphatics in the 
walls of vessels and bronchi 
and in the interlobular septa with an injection of epithelial cells (Fig. 
543). Occasionally larger lymphatic trunks can be seen branching over 
the pleural surface, and made conspicuous by the grayish-white injec- 
tion of tumor-cells. In other cases the secondary growths are in the form 
of button-like nodules on the pleura. In the lung itself the tumor may 
metastasize, with the formation of large, discrete nodules which push aside 
the tissue or, as in a case which we saw recently, with the production of a 
pneumonia-like process. Each alveolus over a large area of the lung was 
filled -with tumor-cells, and since the alveolar walls and vessels were intact 
Fig. 544.-Colloid carcinoma of the stomach. 
Secondary nodule in the liver, showing the tumor- 
cells separated from one another, and each contain- 
ing a globule of colloid. ADENOCARCINOMATA 
1053 
and undisturbed, the patch had almost exactly the appearance of a pneu- 
monic consolidation. 
Metastases in the brain, kidneys, spleen, and other organs occur, but are 
not especially common. Numerous metastases in the bones have been 
found, and I have seen one case in which these growths produced rarefac- 
tion with fractures of the bones. 
Another form of carcinoma of the stomach which is peculiar in many of 
its characters is the colloid cancer. There are at least two types in which 
the accumulation of a gelatinous colloid material is found: one in which the 
Fig. 545.-Colloid cancer of the stomach with large alveoli filled with colloid material and 
only partly lined with the remains of the epithelium. 
glands or tubules of the tumor are made up of spaces in which the epithelial 
cells lie quite loose, are rounded or spherical, and contain each a large globule 
of clear fluid (Fig. 544); the other, in which the tubules are distended into 
cyst-like cavities lined with a single layer of cylindrical epithelium, and filled 
with glairy fluid (Fig. 545). The first of these appears as a diffuse thicken- 
ing of the mucosa and of the whole wall of the stomach, with a gelatinous, 
yellowish, translucent tissue, which accumulates in soft nodules over the 
outer surface of the stomach and spreads quickly into adjacent glands and 
over the peritoneal surface. The second usually causes a far greater thick- 1054 
TEXT-BOOK OF PATHOLOGY 
ening of the stomach-wall, with a large ulcerated area in the mucosa and 
with great layers of new tissue on the outer surface (Fig. 546). The omen- 
tum is converted into a huge mass of friable gelatinous material, and the 
whole peritoneum may be lined with a thick layer of it. On cutting through 
any of this tissue the cavities filled with fluid are quite visible to the naked 
eye, so that this type was once called alveolar cancer. It has the appear- 
ance of sago pudding, and 
one may scrape off a tena- 
cious glutinous fluid from 
the surface. In one case 
which I saw at autopsy all 
the abdominal organs and 
the parietal peritoneum 
were covered with a layer 
more than a centimetre in 
thickness, which was quite 
brittle, although fairly firm. 
It was so transparent that 
one could see the blood- 
vessels in its depth. Metas- 
tases, if they occur, have 
the same structure (Fig. 
547), but while the tumor 
easily penetrates the stom- 
ach-wall and spreads im- 
plantations throughout the 
abdominal cavity, it is not 
strikingly capable of pro- 
ducing metastatic nodules 
in other organs. 
Carcinomata of the Gall- 
bladder and Ducts.-These 
tumors may be described 
much more briefly since 
their general behavior re- 
sembles that of the adeno- 
carcinomata of the stom- 
ach. It has been stated 
that epitheliomata may 
arise in the gall-bladder especially when there are incarcerated gall- 
stones there which have long caused irritation. One sees them sometimes 
accurately moulded round the gall-stones, and extending only so far as it 
lies in contact with the mucosa. Adenocarcinomata may spring from the 
mucosa of the gall-bladder even in the absence of inciting gall-stones, and 
usually metastasize quickly to the liver. As a rule, the primary tumor is- 
Fig. 546.-Colloid cancer of the stomach. There 
is great thickening of the stomach-wall, so that the 
pylorus is almost occluded. The colloid-filled alveoli 
of the tumor are visible to the naked eye. ADENOCARCINOMATA 
1055 
Fig. 547.-Secondary nodules in the lung from a colloid cancer of the stomach. 
Fig. 548.-Adenocarcinoma of the fundus of the gall-bladder with metastases in the liver 
compressing and obstructing a large bile-duct and producing jaundice. 1056 
TEXT-BOOK OF PATHOLOGY 
found to invade the liver in such a way that there is only a remnant of the 
gall-bladder wall which stretches over a large, ulcerated tumor mass em- 
bedded in the liver. Rupture of this into the peritoneum or into the ad- 
herent colon may occur. Metastases resemble those from the carcinoma 
of the stomach, and usually cause jaundice, occasionally, as in Fig. 548, by 
obstructing one of the larger ducts. Quite similar carcinomatous tumors 
may spring from the bile-ducts at any point, from the ampulla of Vater to 
the branches high in the liver. They often appear to be multiple in origin, 
although that is by no means certain. They almost invariably produce 
jaundice, which may be very deep. These tumors form a large proportion 
of the primary cancers of the liver and may grow to enormous masses in one 
or other lobe of the liver (Fig. 549). 
Fig. 549.-Primary carcinoma of liver springing from bile-ducts. Numerous secondary 
nodules in the liver. 
Adenocarcinomata of the pancreas are most frequently situated in the 
head of the gland, near the duodenum, and form large, irregular masses 
invading and compressing the adjacent structures with various results. 
One or both of the pancreatic ducts may be compressed, and the pancreatic 
tissue drained by the obstructed duct becomes atrophic. The tumors have, 
as a rule, a complex tubular arrangement with high cylindrical epithelium. 
Metastases have the same distribution as in the carcinoma of the stomach. 
Adenocarcinomata of the Intestine.-In the small intestine adenocarci- 
nomata are quite uncommon if we except the multiple, relatively benign 
tumors which were described in connection with the basal-cell cancers. On 
the other hand, those of the colon are especially common, and therefore ADENOCARCINOMATA 
1057 
important. They may occur at the ileocaecal region (Fig. 550), or anywhere 
in the course of the colon or in the rectum. In nearly all cases the tumor 
springs up from the mucosa as a projecting mass which encroaches upon the 
lumen of the colon and usually encircles it. Great obstruction may be 
produced in this way, not only by the actual bulk of the mass, but more 
especially by the contraction of those tumors which, in their late stages, 
become extensively degenerated and scarred. In these cases the lumen of 
the intestine may be reduced to the diameter of a few millimetres, so that 
the contents stagnate above the 
obstruction, remain fluid, and es- 
cape continuously in small quan- 
tities. As stated in a previous 
chapter, muscular hypertrophy ap- 
pears above the obstruction, often 
accompanied by ulceration of the 
mucosa. 
The carcinomata of the colon 
are nearly always composed of 
irregular, tubular downgrowths of 
epithelium lined with high cylin- 
drical cells (Fig. 551). In the 
deeper portions, these may, of 
course, become more atypical in 
appearance and more confused in 
their order. 
The intestinal wall is often pene- 
trated by the growth, and exten- 
sive adhesions and excavations 
into adjacent organs occur. Re- 
gional metastases into neighboring 
lymph-glands are common, perito- 
neal implantations occur, and there 
are metastatic nodules in the liver 
in many cases, resembling closely 
those derived from tumors of the 
stomach. I recall one case in 
which there was a very small nodule of hard tumor tissue surrounding the 
colon and drawing it into an extremely narrow stricture. The whole 
mass was not more than 3 cm. in diameter, and yet there were many 
metastatic nodules in the liver, one of which reached the size of a man's 
head. 
Carcinoma of the prostate is most commonly of the adenocarcinomatous 
type, although there are some cases in which the tumor-cells present them- 
selves in broad, solid strands. The tumors are capable of penetrating into 
the bladder or into the rectum, with resulting ulceration and infection. 
Fig. 550.-Adenocarcinoma at the ileo- 
csecal valve causing almost complete ob- 
struction. 1058 
TEXT-BOOK OF PATHOLOGY 
Metastases are usually abundant in the lymph-glands of the pelvis and 
retroperitoneal tissue, in the liver, lungs, and other organs, but particularly 
in the bones. In two of our recent cases in which the primary growth was 
inconspicuous and microscopically showed the complex glandular arrange- 
ment of an adenocarcinoma, there were a few internal metastases, but on 
examining the skeleton, it was found that practically every bone was in- 
volved. The cancellous marrow of such bones as the vertebrae, sternum, 
Fig. 551.-Margin of an adenocarcinoma of the rectum showing a transition from 
slightly modified mucosa to the tumor growth, which maintains a gland-like arrange- 
ment of the epithelium. 
ribs, and clavicles was completely replaced by the tumor, which had stimu- 
lated an excessive new formation of bone, which was very dense and 
hard. In the long bones the marrow cavity was entirely filled with a yel- 
lowish, opaque, ivory-hard tissue, so that the bone seemed to be quite solid. 
It is so evident that much new bone is formed in such cases that these 
metastases are called osteoplastic. Microscopically it is found that every 
lamella of the cancellous bone is enormously thickened, and that the marrow 
spaces are correspondingly narrowed. All these spaces are filled with tumor 
tissue which completely excludes the marrow. The layer of osteoblasts is 
preserved in apposition to the bone, and it seems probable that the tumor 
exerts its osteoplastic effect by stimulating those cells to increased activity. 
Wide-spread necrosis, which involves a great part of such cancerous bone,, 1059 
ADENOCARCINOMATA 
Fig. 552.-Carcinoma of the prostate extending into the bladder so as to overhang 
the urethra. The urethra is distorted and the seminal vesicles somewhat encroached 
upon. 1060 
TEXT-BOOK OF PATHOLOGY 
seems to be of very frequent occurrence. The almost complete destruction 
of the bone-marrow leads to an extreme anaemia, and to efforts at blood 
formation in other organs, which have been referred to elsewhere in discuss- 
ing osteosclerotic anaemia. The carcinomata of the prostate are well 
known for this peculiarity of metastasizing into the bones, a property which 
is shared to some extent by the carcinomata of the breast, stomach, and 
thyroid. 
Adenocarcinomata of the Uterus.-These tumors, already referred to in 
contrast with the epitheliomata of the cervix, are developed from the tub- 
ular glands of the fundus uteri or the more complex glands of the cervix. 
In some cases their growth seems associated with the previous existence of 
an adenoma of the uterus, but this is by no means a regular occurrence. 
Since they appear to grow rather slowly, many cases have been observed in 
Fig. 553.-Adenocarcinoma of the uterus. The tumor is a mere ragged thickening of 
the mucosa at the fundus. There is a fibromyoma lodged in the substance of the uterine 
wall. 
which extirpation of the uterus was performed at a time when the carcinoma 
was still small (Fig. 553). In such a case the mucosa is found thickened and 
rough, with many papillary projections. The growth extends into the 
musculature, but for some time is fairly evenly outlined against it. Never- 
theless, it is not long before the invasion of the musculature occurs by the 
downgrowth of some of the glandular elements which may be found deep in 
the uterine wall. Ulceration may occur, and the cavity of the uterus 
becomes enlarged by the excavation of the tumor in its wall. Even then 
the outer surface of the uterus may show no evidence of the presence of the 
tumor other than the enlargement. ADENOCARCINOMATA 
1061 
Metastases are slow to form, and appear in the retroperitoneal lymph- 
glands. I have seen a few cases, however, in which the secondary growths 
were very widely disseminated, involving the peritoneum, liver, and other 
organs. Microscopically, the tumor is made up of tubular epithelial 
growths resembling in all their complex modifications those already des- 
cribed for other adenocarcinomata, although seldom showing any such 
Fig. 554.-Adenocarcinoma of ovary. There are numerous mitoses in the epithelial 
cells and many multinucleated cells. 
orderly columnar cells with globules of mucus as are usually found in the 
rectal carcinomata. 
The tumor is to be sharply distinguished from the squamous cell epitheli- 
omata of the cervix, not only through its histological characters, but through 
its original site, its mode and rate of growth, and its much slighter malig- 
nancy. 
Adenocarcinomata in general, similar in character to these, develop in 
many other places, and mention may be made of the kidney, breast, 
ovary, and thyroid as points of origin. 1062 
TEXT-BOOK OF PATHOLOGY 
Adenocarcinomata of the ovary are quite common, and assume many 
puzzling forms, sometimes appearing as solid tumors which may occupy 
both ovaries, and metastasizing widely into distant organs. The gland- 
like spaces in such a tumor are lined with cells which are very unlike the 
epithelial cells derived from the skin or mucous surfaces (Fig. 554). In other 
cases the tumor develops in a cystadenoma of the ovary and causes great 
Fig. 555.-Metastasis in lymph-gland from colloid carcinoma of ovary. Many of the 
epithelial cells are seen to be isolated in the colloid material. 
thickening of the wall of one or more of the cysts. These tumors are fre- 
quently colloid cancers, and even in their distant metastases maintain the 
power of forming blue-staining colloid material (Fig. 555). In one which 
we studied recently there was a huge cyst with thick walls which, on section, 
showed a sticky, gelatinous material in the substance of the walls. Metas- 
tases in the abdominal and retroperitoneal lymph-glands showed the tumor 
to be composed of small cysts lined with cylindrical epithelium, which was ADENOCARCINOMATA 
1063 
frequently thrown up into folds. The content of these cysts was, how- 
ever, not like the colloidal material mentioned above, but resembled the 
pseudomucinous content of some adenocystomata. 
LITERATURE 
Stomach.-Ebstein: " Magenkrebs," Volkmann's kl. Vortrage, 1875, No. 87. 
Verse: Arbeiten a. d. Path. Inst. Leipzig, 1908, i, Heft 5. 
Borrmann: Mitth. a. d. Grenzgeb. d. Med. u. Chir., 1901, Suppl. Bd. 1. 
Lewis: Surg., Gyn. & Obst., 1914, xix, 757 (Pseudomyxoma). 
Hauser: Cylinder-Epithel Karzinom des Magens, Jena, 1890. 
Gall-bladder.-Laspeyres: Centralbl. f. d. Grenzgeb. d. Med. u. Chir., 1901, iv, 10. 
Zenker: Deut. Arch. f. kl. Med., 1889, xliv, 159. 
Miodowski: Virch. Arch., 1902, clxix, 117. 
Uterus.-Hitschmann: Arch. f. Gynakologie, 1903, Ixix, 629. 
Lehman: Ibid., 1900, Ixii, 439. 
Cullen: Carcinoma of the Uterus, New York, 1900. 
Pancreas.-Hulst: Virch. Arch., 1905, clxxx, 288. 
Rectum.-Harrison Cripps: Cancer of the Rectum, London, 1890. CHAPTER LIV 
CARCINOMATA (Continued) 
Gland-cell carcinomata: Carcinomata of the breast; epitheliomata, tumors derived from 
the acini (general form, mode of extension and metastasis, histology, relation to adenomata 
and chronic cystic mastitis, scirrhous forms), tumors derived from the ducts, colloid cancers. 
Carcinomata of the ovary; carcinomata of the thyroid; primary carcinomata of the liver 
with cirrhosis. Chorionic epitheliomata: Histogenesis of chorionic epithelium, its normal 
invasive growth. Hydatidiform mole. Chorionic epithelioma; gross appearance, metastasis, 
histology, and histogenesis; relation to corpus luteum. 
GLAND-CELL CARCINOMATA 
There is probably little justification for the separation of cancers derived 
from the cuboid al or polygonal cells of the solid glands from the others 
which have just been described, because the division is made on a purely 
morphological basis, and it is not always easy to distinguish them in this 
way. Nevertheless, the division is convenient and serves a useful purpose. 
Such tumors are extremely common in the breast. Elsewhere they play 
a less important part, but they are to be found in the thyroid, the liver, 
the ovary, the prostate, and in some other glands. 
The Carcinomata of the Breast.-There is so great a variety of these 
tumors that the experience of any one is scarcely sufficient to cover the 
whole range. They are extremely common and fatal in their effects, and 
the efforts to extirpate them completely and to understand and frustrate 
their extension affords much work to the surgeon. It is difficult to make 
any short classification, but there may be distinguished the following: 
1. Tumors of stratified epithelium, which are either those beginning in 
an eczema-like alteration of the nipple and adjacent skin (Paget's disease), 
or those which arise in the substance of the breast and are, nevertheless, 
composed of squamous epithelium (Troell and others). 
2. Tumors Derived From the Cells of the Acini of the Gland.-These 
may be made up of abundant ramifying masses of cuboidal cells, with 
relatively little stroma, so that great, soft, cellular masses are formed 
(medullary cancer), or there may be less abundant cell strands, with 
a relatively greater amount of stroma, so that the tumor area is composed 
of firm whitish tissue, or finally the epithelial structures may be greatly 
reduced, so that only small groups and thin strands of cells are formed, 
embedded in a dense, scar-like mass of fibrous tissue (scirrhous cancer). 
3. Tumors Derived From the Ducts and Their Branches.-These 
approach more nearly the cylindrical cell cancer, and are often in the form 
of tumor masses made up largely of tubular epithelial structures. There 
1064 GLAND-CELL CARCINOMA 
1065 
are usually cysts associated with this form, and these may have a thick lin- 
ing of several layers of cells. There is another type, of relatively benign 
character, in which every section shows canals or cavities lined with a 
thick layer of many rows of irregular cells. These have been called 
adenocarcinomata by Halsted, and have also been referred to as comedo 
cancers, on account of the fact that cells can be squeezed out like the 
material from a comedo or blackhead in the skin. 
4. Colloid Tumors.-Tumors derived from the epithelium of the acini, 
but presenting an extraordinary colloid or gelatinous metamorphosis of the 
stroma. 
Of these, the most important by far are those derived from the cells of 
the acini. The tumor appears as a hard nodule in the substance of the 
Fig. 556.-Carcinoma of the breast showing retraction of the nipple and limited inva- 
sion of the fat. 
breast, and later often forms adhesions with the skin or causes a retrac- 
tion of the nipple (Fig. 556). The extension to the skin may be followed by 
ulceration. A wealth of detail has been worked out by surgeons as to the 
mode of growth and extension, and an interesting series of observations has 
been made upon the more local spread by Handley. As described by Borr- 
mann, in the spread of carcinoma of the stomach through the stomach-wall, 
there is in the breast a radiating growth of the carcinoma in the lymphatic 
plexus which extends outward in connection with the deep fascia. The lym- 
phatic channels distended with tumor-cells become obliterated and disap- 
pear as the tumor growth passes outward, so that it is only in a zone, like 
the spread of a ringworm, that one finds these lymphatics actually , filled 
with the tumor-cells. New nodules spring up into the skin from various 
points in their course, but by that time the channels much farther out are 
filled. In rare cases the skin of the whole chest-wall may be involved in a 
layer of cancer growth which ulcerates at many points {cancer en cuirasse). 1066 
TEXT-BOOK OF PATHOLOGY 
Handley's ideas as to the further spread into lymph-glands and distant 
organs are not so convincing. 
It is known that in nearly every case metastatic nodules are formed in 
the axillary lymph-glands, and that somewhat later the subclavicular and 
cervical glands may be involved. Deep invasion through the pectoral 
muscles and extension along fasciae at that plane are common, and one not 
infrequently traces extension through the intercostal muscles to the pleura 
and finally to the lung. 
Fig. 557.-Secondary nodule from a tumor of the breast, involving upper end of femur, 
and producing a pathological fracture. 
While extension thus occurs by way of direct growth through connective- 
tissue spaces and along fasciae, as well as by continuous growth in the lym- 
phatics or the transportation of isolated groups of cells in the lymph-stream 
to the axillary glands, there is also the possibility that further dissemination 
may occur by way of the blood-stream, and the metastases in the liver, 
bones (Fig. 557), ovaries, and other distant organs seem explicable only 
on this basis. Handley's statement that emboli of tumor-cells in the blood- 1067 
GLAND-CELL CARCINOMA 
vessels are destroyed by the formation of a thrombus may be true for the 
majority of tumor-cell emboli, but I think we have good evidence that it is 
not true for all, and that it is probably no such mechanical influence which 
destroys any of them. Out of great numbers of such emboli, it seems that 
almost all persist, but a few only take root and grow, producing the dis- 
tant metastases. 
Microscopically, these tumors are found to resemble rather closely in 
Fig. 558.-Medullary cancer of the breast with necrosis in some of the epithelial strands. 
their general arrangement the softer forms of epithelioma, since they are 
composed of ramifying solid strands of epithelial cells which push their way 
into the crevices of the stroma. Their appearance is seen in Figs. 558, 559, 
560. The striking feature in all is, of course, the unbridled growth of the 
cells, which is so energetic that no basement membrane can restrain them 
and they penetrate along the lines of least resistance everywhere. 
An interesting point lies in their relation to the adenomata of the breast 
and to the so-called cystic mastitis of old people. It is not uncommon to 1068 
TEXT-BOOK OF PATHOLOGY 
find in sections of a breast tumor taken for diagnosis that the tissue has 
almost everywhere the appearance of a typical benign adenomatous growth. 
Indeed, it is surprising to learn how frequently those specimens which 
offer any difficulty in diagnosis are of this character. It is necessary then 
to determine whether in all places the epithelial strands and tubules main- 
tain strictly their orderly form and their sharp outline which is produced 
Fig. 559.-Carcinoma of the breast showing area of hyaline degeneration with advanc- 
ing strands of epithelial cells. 
by the basement membrane. In true innocent adenomata this basement 
membrane is often exaggerated, so that it appears as a broad, pink-staining 
hyaline membrane, which, of course, leaves no doubt as to the benign 
nature of that particular area of the growth. With the beginning of a 
cancerous growth, which one may often detect in very early stages, the cells 
evidently grow so rapidly as to burst through this membrane and spread 
rapidly without it. Their contact with the connective tissue immediately 1069 
GLAND-CELL CARCINOMA 
becomes far more intimate, and they are found lying loose, strewn in con- 
tinuous or broken strands through the spaces in the stroma (Fig. 561). 
This seems to be the crucial test of carcinoma growth, for while the cells 
do assume an appearance different from that of the normal, it is not a change 
definite enough to afford any chance for a decision as to the carcinomatous 
nature of the tumor. 
Fig. 560.-Carcinoma of breast. The epithelial cells are growing almost in single file 
into every crevice of the stroma. 
In such cases it seems necessary to conclude that the carcinoma has 
developed from an adenoma, but there is no more difficulty in this assump- 
tion than in the more usual one that it develops from the normal epithelium 
of the gland. 
Carcinoma growth seems especially common as a sequel of the senile 
hyperplasia with cyst formation, which is often referred to as chronic 1070 
TEXT-BOOK OF PATHOLOGY 
cystic mastitis. This condition comes on with the menopause or later, and 
leads to the formation of rather dense fibrous tissue throughout the gland, 
with hypertrophy of the acinous tissue into adenomatous structures, often 
with the formation of many cysts. It is not thought to be due to any 
infectious or traumatic injury, and the scarring is really a normal process at 
the time of menopause, but the formation of cysts, adenomata, and papil- 
lomatous growths must be considered as abnormal. 
The scirrhous tumors, the arrangement of which is shown in Fig. 562, 
grow and metastasize much more slowly than do the softer forms, so that 
such a tumor may exist for many years without producing a fatal extension. 
Nevertheless Bloodgood finds, by statistical study of the hospital cases, that 
Fig. 561.-Development of a carcinomatous nodule in an adenofibroma of the breast. 
The invasive character of the carcinoma cells is apparent. 
these are the most tenacious, and finally lead to the most unfavorable 
results. 
The adenocarcinomata derived from the ducts or from adenomatous 
nodules are, in some instances, as in the form described by Halsted, relatively 
benign. My father extirpated such a tumor from each breast of an old 
woman who has survived many years without lymph-node metastases or 
local recurrence. 
In other cases, however, there may be found a very large tumor mass 
composed chiefly of cysts filled with glairy fluid, and lined with high 
columnar or cubical epithelium. Between these are dense adenomatous 
masses. From the walls of such cysts an invasion may take its origin. GLAND-CELL CARCINOMA 
1071 
The colloid tumors are uncommon, but Lange collected 75 cases, and 
from their study learnt that metastases were rare, and that the tumors 
grow very slowly and are relatively benign (Fig. 563). 
Carcinomata of the ovary may be primary or secondary. Although tumors 
distinctly secondary to mammary, gastric, or intestinal carcinomata have 
been found in this organ, their occurrence is rare and most of the ovarian 
Fig. 562.-Scirrhous cancer of the breast. The epithelial cells are greatly reduced in 
number and scattered in an extremely dense hyaline stroma. The blood-vessels show 
thick hyaline walls. 
cancers are primary. It is difficult to explain why they so frequently 
occur simultaneously in both ovaries. They are solid tumors, tumors 
combined with cystomata, or papillomatous growths, and almost every 
type of cancer observed elsewhere seems to be represented here. When 
the carcinoma is cystic or develops in connection with a small cyst, it may 
be surmised that the tumor began as a carcinoma. When, however, the 1072 
TEXT-BOOK OF PATHOLOGY 
malignant growth appears in the wall of a large cystadenoma of long stand- 
ing, it must be supposed that its relation to the cystadenoma is analogous 
to that of the carcinoma of the breast to the adenoma within which it 
develops. 
Metastases (Fig. 564) vary with the character of the tumor, and may 
be confined to intraperitoneal implantations in the papillary forms. In 
one which we studied recently both ovaries were replaced by cysts of about 
Fig. 563.-Colloid carcinoma of the breast. The colloid appears to be developed in the 
stroma in which the epithelial cells are isolated. 
orange size, in the walls of which there were thick, yellow masses of solid 
tumor. There were metastases in the liver, and especially interesting was a 
continuous chain of white nodules along the round ligament extending into 
the substance of the liver. It is possible that further study may reveal an 
unusual method of invasion of the liver by extension along the lymphatics 
of that cord. Handley discusses a similar occurrence in connection with 
mammary carcinomata. GLAND-CELL CARCINOMA 
1073 
Krukenberg described as a form of sarcoma a tumor which is obviously 
carcinomatous and which often involves both ovaries. These nodules are 
rather dense and infiltrated with loosely arranged epithelial cells, each of 
which is swollen with a globule of colloid or gelatinous fluid. They are 
relatively benign growths. 
The carcinomata of the ovaries, like the cystadenomata, are evidently 
Fig. 564.-Metastasis from carcinoma of the ovary in an axillary lymph-gland. The 
lymph-sinuses are filled with epithelial cells. 
derived from invaginations of the surface epithelium, although many other 
hypotheses have been offered as to their source. There seems to be no 
good evidence that they arise from the Pfliiger's cords or from Graafian 
follicles. 
Carcinomata of the Thyroid.-These tumors have been studied especially 
by v. Eiselsberg, Kocher, and Langhans, who find that they can distinguish 1074 
TEXT-BOOK OF PATHOLOGY 
several groups, among which a form of adenocarcinoma or proliferating 
struma is especially common. These occur as single nodules containing 
every transition between solid strands of cells and colloid-containing 
alveoli, closely resembling those of the normal gland. They are not very 
malignant, but occasionally metastasize in distant organs or bones. The 
second group, called by Langhans carcinomatous struma, has the arrange- 
ment in irregular solid strands of epithelial cells seen in many carcinomata 
of the breast. These quickly burst through the capsule of the gland and 
metastasize abundantly. Metastasizing colloid struma forms the third 
group, with numerous secondary nodules, composed of colloid-holding 
vesicles in which no striking morphological signs of its malignancy are 
to be seen. The tumors of the fourth group, named alveolar large-cell 
struma, are also malignant, and give rise to numerous metastases. 
They are composed of large cuboidal or cylindrical cells, arranged 
in small alveoli or in tubular or strand-like structures. The cells in 
these tumors are occasionally very large, with deeply stained nuclei. 
The other groups comprise the papillomatous tumors of the thyroid, in 
which branching processes grow into cysts or cavities in the thyroid, and 
squamous cell epithelioma, which may occur in the substance of the gland 
and must be ascribed to a congenital displacement of cells. 
Primary Carcinoma of the Liver.-Reference has already been made to 
the cylindrical cell cancers of the liver which originate in the epithelium 
of the bile-ducts, and appear as solid white masses in the substance of the 
organ. There is another type quite different from this, which is so char- 
acteristic and constant in form that, once seen, it can never be forgotten or 
mistaken for any other tumor. This is the primary cancer which originates 
from the liver-cells themselves, and occurs in multiple nodules closely set 
throughout the whole liver. Whatever remains of liver tissue is profoundly 
scarred, as in the most advanced cirrhosis. The liver is greatly enlarged, 
and dark green or grayish, rounded nodules project everywhere. On sec- 
tion nearly the whole cut surface is occupied by these velvety green or gray 
rounded masses which stand up from the remaining liver substance (Fig. 
565). There is usually quite deep jaundice, and often a terminal haemor- 
rhage from the rupture of some softened nodule which projects into the 
peritoneal cavity. There are generally no metastases, but branched 
emboli of tumor-cells may be found plugging the terminal twigs of the pul- 
monary artery in the lung. In the last case we have seen, however, there 
were many metastases as large as marbles in the lungs and all the adjacent 
pulmonary arterioles were full of the tumor. There were also pleural and 
diaphragmatic nodules. On opening the portal and hepatic veins masses 
of the tumor are often found projecting into the lumen of one or other of 
these veins. 
Microscopically, it is found that the liver tissue between the nodules and 
in areas unoccupied by them presents the irregular masses of distorted liver- 
cell strands and the broad bands of collapsed framework and scar tissue, GLAND-CELL CARCINOMA 
1075 
with numerous bile-ducts which are seen in the ordinary nodular cirrhosis. 
The tumor nodules are composed of anastomosing strands of rather large 
cells, corresponding fairly closely with the liver-cells, but with larger nuclei 
rich in chromatin, and with swollen cell-bodies which take a rather deep 
stain. Great irregularities occur, and there are many huge cells with 
several nuclei. There is a tendency toward an arrangement in broad 
strands of cells separated by narrow capillaries, and in many places it is 
seen that these strands hang in the lumen of a blood-vessel, where they are 
surrounded by blood and everywhere covered with endothelium. It is 
extremely common to find blood-vessels thus packed with bunches of 
Fig. 565.-Primary adenocarcinoma of the liver, with cirrhosis. There are multiple 
nodules, and the portal vein with its branches is filled with the tumor. 
strands of tumor-cells which, on account of their endothelial covering, 
cause no thrombosis. The larger invasions of the branches of the veins 
seem to maintain this characteristic growth. Quite apart from the well- 
formed tumor nodules, there may be found in the cirrhotic liver tissue 
minute groups of tumor-cells recognizable by their abnormal form, but 
standing in direct continuity with the surrounding liver-cells, which 
they compress by their rapid growth. These seem to be beginning tumor 
nodules. 
The multiplicity of these growths and their lack of power to form 
metastases have caused much speculation. They have been thought 1076 
TEXT-BOOK OF PATHOLOGY 
to arise simultaneously in many situations in the liver as the result of an 
over-stepping of the bounds of what might be regarded as normal in 
the compensatory hyperplasia of the liver-cells in an advanced cirrhosis. 
Winternitz advanced the idea that they are really metastatic nodules, 
secondary to an original growth near the hilum of the liver, which invades 
the portal vein and scatters its cells through the whole liver. If such 
exquisite power of metastasis exists in the liver, it is difficult to under- 
stand why these same cells should be completely incapable of growing else- 
where, although they can be found as emboli in the capillaries of the lung 
in great abundance. It must be admitted that, whatever explanation is 
accepted, the behavior of this tumor is peculiar and unlike that of the 
other carcinomata. 
LITERATURE 
Breast.-Fr. Lange: Bruns, Beitrage z. kl. Chir., 1896, xvi, 1. 
v. Winiwarter: Beitrage z. Statistik der Carcinome, Stuttgart, 1878. 
Greenough and Hartwell: Jour. Med. Research, 1903, ix, 416. 
Bloodgood: Kelly and Noble, Gynecology and Abdominal Surgery, 1907, ii, 180. 
Halsted: Trans. Amer. Surgical Assoc. (Adenocarcinoma), 1898, xvi, 144. 
Ovary- Pfannenstiel: Veit's Handb. d. Gynakologie, Wiesbaden, 1908, i. Halfte, 177. 
Glockner: Arch. f. Gynakologie, 1904, Ixxii, 410. 
Thyroid.-Langhans: Virch. Arch., 1907, clxxxix, 69. 
Th. Kocher: Deut. Ztschr. f. Chir., 1907, xci, 197. 
Diver.-v. Heukelom: Ziegler's Beitrage, 1894, xvi, 341. 
Travis: Johns Hopkins Hosp. Bull., 1902, xiii, 108. 
Wegelin: Inaugural Dissertation, Bern, 1905. Virch. Arch., 1905, clxxix, 95. 
Winternitz: Virch. Arch., 1913, ccix, 239. 
In the study of the formation of the placenta there has never been complete 
unanimity of opinion as to the origin of the syncytial layer which covers the 
chorionic villi. The other cells which cover these villi and which are 
arranged in a more sharply defined layer (Langhans' cell layer) are uni- 
versally recognized as the foetal ectoderm, but for the syncytium, at least 
three ideas have been expressed: (a) That it is derived from the maternal 
uterine epithelium; (b) that it is a modification of maternal endothelium, 
and (c) that it belongs, like the Langhans' layer, to the foetal ectoderm. 
The weight of evidence seems to be in favor of the last view. 
During pregnancy there is normally a curious invasive growth of the 
chorionic villi into the uterine wall, and it is by no means uncommon to find 
masses of syncytium-like giant-cells with many nuclei lodged in the 
interstices of the muscle, quite deep down in the uterine wall. Indeed, 
such masses have been found to invade blood-vessels and to be carried as 
emboli into distant organs. Nevertheless, this invasive growth ends harm- 
CHORIONIC EPITHELIOMATA CHORIONIC EPITHELIOMATA 
1077 
iessly, and the cells presently disappear from the tissue as though 
the body had some mechanism for destroying them when pregnancy 
is over. 
Two curious abnormal conditions may arise during pregnancy which 
bring about a result quite different from the usual normal ending. One 
of these is the development of the hydatidiform mole, the other the growth 
and metastases of the chorionic epithelioma. In the case of the hydatidi- 
form mole it is found that, when pregnancy approaches its termination, 
there may be expelled from the uterus, not a child with the cord and placenta, 
but a great mass of polypoid, gelatinous structures, which hang together 
like a huge bunch of grapes. There may be no foetus at all, or the shrunken 
remnants of one, and the placenta is converted into the villous mole, which 
receives its name from its resemblance to the clusters of hydatids or cysts 
of the taenia larvae which are sometimes seen. (Mole is used here in the 
old sense-mass.) Microscopically, these polypoid blebs are swollen 
chorionic villi enormously enlarged and covered with greatly proliferated 
epithelium. It is rare to see such a mass in situ, but in the uterus removed 
after the expulsion of the mole it is found that the villi grow into the 
uterine musculature and sometimes give rise to malignant, tumor-like 
extension and metastasis. Nevertheless, such invasive growth is by no 
means constant, and the woman may recover her health perfectly and even 
give birth to a second or third hydatidiform mole. I 
This has intimate relations, as will be seen, with the chorionic epithe- 
lioma. The pregnancy may be interrupted by the development of a 
haemorrhagic tumor in the uterine wall, or after pregnancy is over such a 
tumor may develop even several months later. Curettings have the 
appearance of placental tissue, except that the cells are more profuse 
in these growths and are much better preserved than those found in curetted 
remnants of retained placenta. Still, it is only through determining the 
relation of the tissue to the uterine muscle, together with the alarming 
clinical symptoms of haemorrhage, that a diagnosis can be made with any 
certainty. Frequently there is found a conspicuous haemorrhagic tumor 
in the vaginal wall which will make the diagnosis clear. 
With such partial removal of the tumor as is possible by curettage com- 
plete recovery occurs in some cases, and all traces of tumor growth dis- 
appear. In other cases the patient coughs up blood and bleeds from the 
uterus, and at the autopsy there is found a tumor invading the uterine wall 
and growing in metastatic nodules in the lungs, liver, brain, and elsewhere. 
The tumor in the uterine wall is a soft, ragged, intensely haemorrhagic 
mass, variegated in color by gray or whitish areas, and by brownish patches 
in which the blood has undergone decomposition, with the formation of 
pigment. The metastases in the lungs are often round nodules, of about the 
size of a cherry, scattered abundantly through the organ. They, too, are 
deep red from haemorrhage. There may be large, more ragged, and pig- 1078 
TEXT-BOOK OF PATHOLOGY 
mented masses. In the brain the metastatic tumor may produce apoplecti- 
form symptoms from haemorrhage and compression. 
Microscopically, these tumors are found to be made up almost entirely 
of broad, irregular, and ragged anastomosing strands of the two types of 
chorionic epithelium, in which the Langhans' cells can be readily dis- 
tinguished by their smaller and more regular form, with pale or almost 
clear protoplasm, and fairly sharp cell outline, while the syncytial material 
spreads over them or forms solid areas of protoplasm which stains much 
Fig. 566.-Chorionic epithelioma, metastatic nodule in the lung, showing Langhans' 
cells and syncytium. 
more deeply, and in which numerous nuclei, often of great size, are 
embedded. The stroma and blood-vessels are inconspicuous or entirely 
lacking, since the tumor seems to grow into blood-channels, and every- 
where the tissue is torn and disarranged by extensive hsemorrhages (Fig. 
566). 
It was thought for a long time that these tumors were of sarcomatous 
or endothelial nature, and that they had preceded pregnancy and were 
stimulated by it to more rapid growth. It was thought by others that CHORIONIC EPITHELIOMATA 
1079 
they were derived from the decidua, and they were, therefore, spoken of 
as malignant deciduomata, but the work of Marchand cleared up the 
whole situation by showing clearly that none of these theories had any 
foundation, and that the tumor originates in the chorionic epithelium or 
foetal ectoderm of the placenta, and that both layers of this epithelium 
are involved. 
The tumors are especially interesting from the fact that a somewhat 
analogous growth and invasion of the chorionic epithelium occurs normally, 
and that an exaggeration of the development of the villi, often ending in 
the formation of a malignant tumor, is found in the hydatidiform mole. 
The fact that definite chorionic epitheliomata seem to retrogress sometimes 
and disappear completely is also peculiar, and has led to speculation 
(Fleischmann) as to whether there is some substance formed in the maternal 
blood at the end of pregnancy, which, like the experimentally produced 
syncytiolysin of Scholten and Veit, has the function of destroying the 
syncytial elements which remain buried in the uterine wall or lodged in 
distant organs. The failure of this substance might allow the unchecked 
development of the tissue into a destructive tumor, while its late formation 
might account for the disappearance of the tumor. 
On the other hand, it is found that in a large proportion of cases the 
development of a hydatidiform mole or a chorionic epithelioma is accom- 
panied by a peculiar enlargement of the ovaries, sometimes to the size of a 
large grape-fruit. This is due to the formation of numerous cysts, most of 
which are, like the cysts derived from corpora lutea, lined with several 
layers of yellow lutein cells. The well-known theory of Fraenkel and Born, 
according to which the corpus luteum is an organ of internal secretion con- 
trolling and forwarding the embedding of the ovum and the development 
of the placenta, is brought into play by Runge, Pick, and others as a ready 
explanation of this association. If there is a great overgrowth and excessive 
activity of the corpus luteum tissue, it may produce excessive growth of the 
chorionic villi over which its secretion is supposed to preside. Dunger 
reverses the idea and suggests that the excessive growth of the chorion 
requires the development of additional corpus luteum tissue. L. Loeb 
finds that irritation and injury of the mucosa of the uterus in guinea-pigs 
after coitus will, under certain conditions, produce very large growths of 
tissue, which he calls placentomata. In his papers he emphasizes the 
alteration in environmental conditions of the mucosa, and recognizes in 
these and other papers the importance of the influence of the corpora 
lutea. 
The matter requires further study, and it seems to offer an extremely 
interesting border-line condition the comprehension of which might throw 
much light upon tumor growth in general. 1080 
TEXT-BOOK OF PATHOLOGY 
Risel: Ergebn. d. allg. Path., 1907, xi2, 928. 
Gaylord: Amer. Jour. Obstetrics, 1902, xlv, 465. 
Marchand: Monatsschr. f. Geburtsh. u. Gynak./1895, i, 419. Ztschr. f. Geburtsh. u. 
Gynak., 1895, xxxii, 405. Ibid., 1898, xxxix, 173. 
Fleischmann: Monatsschr. f. Geburtsh. u. Gynak., 1905, xxi, 353. 
Runge: Arch. f. Gynak., 1903, Ixix, 33. 
R. T. Frank: New York Med. Jour., 1906, Ixxxiii, 793. 
L. Loeb: Arch. f. Entwicklungsmech. d. Organismen, 1911, xxxii, 67. Ztschr. f. Krebs- 
forschung, 1912, xi, 259. 
LITERATURE CHAPTER LV 
TERATOMATA; COMPOSITE TUMORS 
Chorionic epithelium in tumors of the male. Teratomata. Early development of the ovum, 
potency of blastomeres. Their inclusion in the formation of double monsters. Formation 
of solid teratomata. Dermoid cysts. Cutaneous and branchial cysts. Cholesteatomata. 
Mixed tumors of salivary glands; of the kidney. Congenital cystic kidney. Mixed tumors 
of the breast and of the testicle. Chordoma. 
In the last pages there has been given a description of the hydatidiform 
mole and of the chorionic epithelioma which may develop in connection 
with pregnancy, and it was pointed out that these are tumors of a more 
suggestively parasitic nature than the others which have been considered 
in previous chapters, since they are composed of the tissue of a different 
individual. This is not enough to shake our faith in the belief that the 
ordinary tumors are composed of the tissue of the same individual, but at 
least it causes us to reflect upon this question. 
The existence of tumors morphologically identical with the chorionic 
epithelioma of women, but growing in the testicle of men, is especially 
calculated to rouse our interest in this question. These tumors belong to 
the composite type called teratomata, which contain tissue of many sorts, 
representing all of the three germinal layers, and give rise to metastases 
which are composed of Langhans' cells and syncytium. Chorionic epi- 
thelium occurs also in the tumors themselves, and may, indeed, be the only 
tissue found, in which case it is thought that the other types have been 
overgrown and obliterated by it. Scott and Longcope described a tumor 
of the testicle composed entirely of chorionic epithelium, and Frank had a 
similar case, but most of these tumors have contained a mixture of other 
tissues as well, which often resemble disorted organs in such a way as to 
suggest an abortive attempt at the formation of a foetus. 
We have recently seen a beautiful example of this type of tumor in which 
metastases in the brain, lungs, omentum, and elsewhere had all the char- 
acteristics of a chorionic epithelioma. The original tumor in the testicle 
showed, however, cartilage, various gland-like epithelial structures, and 
other tissues of a complex foetal inclusion. Of all the tissues concerned 
in the abortive growth of an included foetus, only those of the rudimentary 
chorion metastasized. 
It is to be observed that in this case the tumor belongs to the same 
generation as the host, while in the chorionic epithelioma in a woman it 
is derived from the foetal tissues, and therefore belongs to an individual of 
the next generation. 
1081 1082 
TEXT-BOOK OF PATHOLOGY 
Such a suggestion of the formation in a man's testicle of a foetus with 
chorionic epithelium, however abortive, demands explanation, and numer- 
ous hypotheses have been put forward. Schlagenhaufer points out, first of 
all, the value of such an observation in settling the origin of the syncytial 
Fig. 567.-Teratomatous tumor of testicle invading vena cava through spermatic 
and renal veins. Hydatidiform, grape-like structures hang free in the circulating 
blood. 
layer of the chorion. It must be derived from foetal ectoderm, since in this 
situation there is no uterine mucosa to give it origin. He regards the 
tumor as an imperfect foetus which has formed about itself foetal membranes 
which spread into the tissue of the host, and metastasize to distant organs. teratomata; composite tumors 
1083 
Risel insists, however, that it is unnecessary to assume the formation of a 
chorionic membrane with villi, since the foetal ectoderm can produce such 
chorionic epithelium easily enough. 
Schlagenhaufer, finding that the tumors occasionally grow into large 
veins in polypoid clusters of translucent, grape-like bodies, suggested that 
this was analogous to the formation of a hydatid mole. I have studied 
one of the four or five tumors of this nature, and find that the villus-like 
bodies (Fig. 567) are not covered with chorionic epithelium. It is, there- 
fore, as Risel explains, only an accidental resemblance. 
Teratomata.-While such fcetus-like tumors with chorionic epithelium are 
rare, there are others in which rudimentary, organ-like masses of tissue are 
mingled together as though in an unsuccessful attempt to form a foetus, but 
without any development of chorionic elements. These are the solid terato- 
mata or embryomata which are not very uncommon, and may occur in the 
ovary or testicle, or in almost any other situation in the body. They are es- 
pecially frequently found at the poles of the body, springing from the roof 
of the mouth or from the sacrum, or, in somewhat different form, in the 
brain, in the orbit, in the mediastinum, or abdomen. Some of them project 
outwardly and are covered with skin, even presenting at times a vague 
resemblance to limbs or other parts of the body: others are completely 
inclosed within the body cavity, where they may be connected by a stalk 
with surrounding organs, or enveloped in a capsule. 
Dissection of such masses shows that they are not like ordinary tumors, 
inasmuch as they are not merely composed of one type of tissue, but con- 
tain representations of all three germinal layers. There are structures of 
every degree of complexity, composed of skin and its appendages; mal- 
formed teeth are found sometimes in connection with bony structures, 
sometimes embedded in soft tissues. Misshapen eyes or masses of brain 
tissue, portions of intestinal mucosa or convoluted canals resembling the 
intestines alternate with cysts lined with epithelium difficult to recognize, 
and masses of cartilage or thyroid tissue (Fig. 568). There is no tissue 
which may not be represented, although liver and pancreas, testicle and 
ovarian tissue and chorionic epithelium are usually absent. Ganglion- 
cells are abundant, as a rule, embedded in a connective tissue which may 
assume almost any form. More detailed description of any one case would 
hardly repay us, because in the next a different set of tissues might be repre- 
sented. But it is evident that the whole mass represents in some sense a 
frustrated attempt at the formation of a human body in which the whole 
plan has failed through the lack of the necessary parts, and the distortion 
and disarrangement of those which were available. It is obvious that, for 
an explanation, we must go back to the beginnings of embryonic develop- 
ment, in the hope that at some point a mechanism may be recognized by 
which it is possible for one individual or a rudiment of an individual to be 
inclosed within another. 1084 
TEXT-BOOK OF PATHOLOGY 
In the beginning the ripening ova cast off some of their chromatin in the form of 
polar bodies, after which they are ready for fertilization. There are vague and unsatis- 
factory statements that the polar bodies may be fertilized by spermatozoa and undergo 
Fig. 568.-Teratoma of testicle with cartilage, (a) nerves, striated muscle, and cavi- 
ties (5) lined with various kinds of epithelium. 
cleavage to a certain extent in insects, but not, so far as I can learn, in higher animals. 
Upon fertilization the ovum divides into two segments, and these again divide into two 
until there is a rounded mass of blastomeres. By invagination or gastrula formation teratomata; composite tumors 
1085 
ectoderm and entoderm are distinguished, and from them there is formed the mesoderm, 
which at first consists of two layers of cells, later dividing into the myotome and another 
mass which, by division, forms the middle plate, and the splanchnopleure and somato- 
pleure, which enclose the coelom. From the middle plate there arise the Wolffian body, 
the kidney, and the genital glands. The original Wolffian duct comes into very close 
relationship with the ectoderm at this point, a fact which is of interest in connection with 
the development of certain tumors. 
The genital cells at first contain somatic material, but they lose this in the course of 
division and become purely sex cells at a very early stage. Since they retain their 
chromatin tenaciously they appear as deeply stained cells. 
The power of development of the cells in each stage is of especial interest 
in any attempt to explain the formation of tumors. Much has been said 
of the possibility of the growth of the original sex cells, or of the ripening 
ovum, into differentiated tissues, but there is no real evidence that such 
parthenogenetic development can occur within the body, and any idea of 
internal fertilization in the tissues rests upon no support. There is no 
reason to deny the possibility of the fertilization and development of polar 
bodies, but although that idea has been put forward by Marchand, there is 
practically no evidence in its favor, and it has been pointed out that there 
may be multiple teratomatous tumors which could not be explained on this 
basis, since at most there are two polar bodies. The fertilized ovum is 
totipotent; that is, it is capable of giving rise to all the tissues of the 
body. So, too, are the first segmentation spheres, as is proven by the 
development of twins from a single ovum. These twins are always of the 
same sex, and resemble each other very closely-they are more nearly 
related than other brothers and sisters. 
In later stages of segmentation the blastomeres remain multipotent or 
capable of producing several tissues, but probably not a perfect individual. 
Still later, the destiny of the cells becomes much more rigidly prescribed, 
and they are limited to the formation of certain tissues. When the germ 
layers are defined, elements from each of these layers have the power of 
producing ectoderm, entoderm, or mesodermal structures only, and are 
even more closely confined, according to their point of origin in the layer. 
Nevertheless, it is obvious that there is a chance for the development of a 
mass of tissue of almost any degree of complexity from a blastomere, if we 
are willing to assume that it may become independent of the others at some 
stage in the segmentation. This idea involves the further assumption that 
this independently growing blastomere may remain attached to the main 
embryo, or become partly or completely surrounded by it in its growth, so 
as to be finally included in its body. 
There is such abundant material illustrating every stage of attachment, 
inclusion, and final complete enclosure of one body in the other, that no 
assumption is required and the story is practically complete. It has been 
said that the complete separation of the first two segmentation spheres 
results in the so-called single ovum twins. The developing segments may, 
however, remain attached or fuse in the course of their development, as we 1086 
TEXT-BOOK OF PATHOLOGY 
see in the case of the well-known Siamese twins, and in hosts of other double 
monsters in which the two bodies are united by their sternal, sacral, or 
cranial regions. While these individuals seem to be more or less inde- 
pendent, there are important structures common to the two bodies, and 
other double monsters are not wanting in which the fusion becomes much 
more complete. When the isolated blastomere or group of blastomeres is 
derived from a somewhat later stage, so as to be incapable of producing a 
whole body, or when a totipotent blastomere in its development is out- 
grown by the other, there results a parasitic monster; that is, an incomplete 
individual attached to its brother or partly embedded in his body and deriv- 
ing all its nutrition thence. Such an abortive individual may project in 
the form of incomplete arms or legs from the epigastric or pubic or other 
region of the host or "autosite." From this it is but a short step to the 
still more rudimentary organ masses, which are completely inclosed within 
the abdomen or thoracic cavity, and which, while maintaining a degree of 
independence, draw their blood supply from the adjacent tissues of the 
host. The solid teratomata, with their cysts and aimless organ rudiments, 
are practically of this nature. Of course, if the isolated blastomere and 
the main group of segmentation spheres begin to develop at the same time, 
we should expect the tissues of host and teratoma to appear to be of the 
same age or maturity, while if the isolated blastomere should remain stag- 
nant during the growth of the host, it might be expected to produce by 
later growth a teratoma composed of embryonic tissues. It is said that 
this distinction can be made. No one has found and recognized such 
latent blastomeres, and the tissues of all teratomata are often so abnormal in 
appearance that it'is difficult to judge of their maturity, so that this state- 
ment about the age of the growth is somewhat speculative. 
It seems that the evidence in favor of the isolation of a blastomere as the 
origin of teratomatous tumors is incomparably stronger than that for any 
of the other modes of formation which have been suggested. With this 
explanation there is no difficulty whatever in understanding the localiza- 
tion of a teratoma in the testicle or in the brain, while with the others, 
which involve fertilization and development of ova, etc., insuperable 
obstacles are met with in many cases. With this explanation, too, there 
is no difficulty in comprehending the formation of teratomata of all degrees 
of complexity down to the simplest cysts, composed of only one or two 
types of tissue, whereas if they arose from fertilized polar bodies, primary 
sex cells, etc., we should expect in every case growths more closely sim- 
ulating complete individuals. The formation of teratomata with chorionic 
epithelium becomes intelligible, since a blastomere in its development is 
like a growing embryo, capable of forming certain tissue, whatever its own 
situation. It becomes clear that there is a difference between the metasta- 
sizing chorionic epithelioma of women, and that which occurs in the testicle, 
in that the former is tissue of the offspring of the woman and belongs 
to another generation, while the latter belongs to the individual himself, 
and therefore is co-aetaneous, or pertaining to the same generation. teratomata; composite tumors 
1087 
The solid teratomata may grow to a great size, especially when they are 
enclosed in the abdominal cavity and attached to the retroperitoneal tissue 
or sacrum, but they are, as a rule, in themselves quite benign masses with 
no capacity for unlimited growth. Nevertheless they produce extra- 
ordinary mechanical disturbances at times. I remember one case especially 
well in which a great mass appeared in the abdomen of a man and grew 
slowly. It was found impossible to extirpate it, and after some months he 
died with signs of the presence of a tumor in the lung. At the autopsy there 
was found a huge mass, in- 
extricably entangled in the 
intestines, and springing 
from the retroperitoneal re- 
gion. It contained con- 
voluted, intestinelike chan- 
nels and several large cysts, 
in the walls of one of which 
a carcinoma had developed. 
All the rest of the mass 
showed only an organ-like 
arrangement of tissues, and 
the metastases in the man's 
lungs were from this car- 
cinoma. While it is true 
that the teratoma itself is 
benign, it is not at all un- 
common to find the devel- 
opment of a distinct car- 
cinoma at some point in its 
epithelium, exactly as we 
find it in the body in gen- 
eral. 
Dermoid Cysts.-A sim- 
pler form of teratoma is that 
which is known as a der- 
moid cyst. These may oc- 
cur almost anywhere, but 
are perhaps most common in the ovary, where there may be several. They 
are, as the name implies, composed essentially of derivatives of the ecto- 
dermian layer, but there is no line between them and the more complex 
teratomata-indeed, all dermoids on closer examination prove to have a 
more complicated structure than is apparent at first sight. A dermoid cyst 
is round or irregularly multilocular, and on incision is found to have a 
tough, hard wall and to be filled with a soft, greasy mass of granular, but- 
tery consistency, in which there are often tangles of hair (Fig. 569). Some- 
times the hair may be extremely long and abundant. It does not spring 
Fig. 569.-Dermoid cyst of ovary, showing sebaceous 
material and hair. 1088 
TEXT-BOOK OF PATHOLOGY 
evenly from the whole wall, but has its roots in a thickened patch which is 
constantly present in the wall of such cysts (Wilms). The thick area pro- 
jects into the lumen of the cyst, and is sometimes very irregular and rough. 
It is covered with thick epidermis, and bears the roots of the hairs and an 
exaggerated array of sebaceous glands (Figs. 570 and 571). It is from these 
sebaceous glands that the buttery contents of the cyst are secreted. They 
may open in the hair-sheaths, but most commonly open directly into 
the cyst. There are sebaceous glands around the whole wall of the cyst, 
quite away from the hair-bearing patch. Opposite this patch the dis- 
tal ends of the hairs may become buried in the wall and encapsulated by 
granulation tissue, so that they seem to have taken root there. In the 
mass of tissue which projects into the cavity there may be smooth muscle, 
Fig. 570.-Wall of dermoid cyst, showing solid projection covered with epidermis. 
There are many hair and sebaceous glands on the surface. 
like the arrectores pilorum, and fat and dense connective tissue. That 
these dermoid cysts verge on the more solid teratomata is seen from the 
fact that some of them have teeth in their walls often set in connection with 
a bony mass which lies deeper in the wall (Fig. 572). If there are pig- 
mented rudiments of an eye or elements of the central nervous system, 
the approach to the complexity of the more solid teratomata is even 
closer. Wilms points out the fact that most of the structures seen in der- 
moid cysts are such as might be developed from the head, that part of the 
embryo which develops most rapidly. Various degenerative changes occur 
in such cysts, the walls become calcified, their epithelium disappears and 
is replaced by granulation tissue, the sebaceous contents shrink and become 
solidified, and in some cases carcinomatous tissue develops in the wall. 1089 
Still simpler cysts occur in which the origin from a misplaced blastomere 
is not so evident. These are the wens or epidermoid cysts, which are found 
in the scalp, and are lined with stratified epithelium which grows in quan- 
tity and is desquamated into the interior to form a soft, flaky substance. 
They may perhaps be explained as displacements of ectoderm at a much 
later stage. So, too, with the atheromatous cysts or branchial cysts, which 
are developed from an imperfectly obliterated and isolated part of a branch- 
ial cleft. Either cylindrical or squamous epithelium may form their lining, 
and they sometimes grow in a ramifying way far up behind the ear and 
teratomata; composite tumors 
Fig. 571.-Wall of teratomatous cyst of the ovary. There is an epidermal lining with 
sebacous glands. In the deeper portions there is a mass of cartilage and structures 
resembling salivary glands. 
down into the neck. In one which we have recently studied the epithelial 
lining was very thick, and had desquamated enough of its cells to produce 
a soft, yellowish material like the caseous centre of a tubercle. They are 
hard to extirpate and tend to recur. 
Cholesteatomata.-Another teratoid growth which may occur in the 
brain in connection with the meninges, or about the hypophysis, is a thin 
epidermal sac, which, from its abundant content of cholesterine crystals 
mixed with epidermal scales, is called a cholesteatoma. Such growths 1090 
TEXT-BOOK OF PATHOLOGY 
which are lined with skin-like epidermis, and distended with desquamated 
epidermal cells, may occur in the orbit, or at times in the middle ear, where 
they do harm by occupying space. 
Mixed Tumors.-This leads us to the composite or mixed tumors, which 
represent the teratomata derived from the isolation of cells already in an 
advanced state of differentiation, whose capabilities are therefore limited 
and pretty strictly determined. There is much dispute as to their nature 
and origin, but this explanation seems to me most acceptable and credible. 
Fig. 572.-Teratomatous cystoma of the ovary, containing teeth and a tongue-like 
structure covered with hair. 
Such tumors are found in immediate connection with the salivary glands, 
in the kidneys in children, in the breast, in the testicle, and elsewhere, but it 
must not be supposed that they resemble each other in these different situa- 
tions. All they have in common is the principle upon which they are 
formed. 
Mixed Tumors of the Salivary Glands.-In their gross appearance these 
tumors resemble one another very closely-they are rounded or nodular, teratomata; composite tumors 
1091 
elastic masses, which grow, as a rule, not in the gland, but in close proximity 
to it, being generally attached to its capsule. They spring in this way from 
the parotid or submaxillary, and may reach a very great size. On extirpa- 
tion they may recur, but even then they run a benign course. On section 
such a tumor presents extensive, rather translucent, areas, with occasional 
patches of denser opaque tissue and rare points of calcification. Micro- 
Fig. 573.-Mixed tumor of the parotid gland, showing cartilage and narrow strands of 
epithelial cells. 
scopically, the most varied appearances are seen (Fig. 573). The stroma is 
hyaline or like the matrix of cartilage; there may be true cartilage, mingled 
with dense fibrous tissue. Everywhere there are masses of cells arranged 
in tubules or cysts, or in long tapering strands which anastomose and 
finally fade into the crevices of the stroma. In some cases, but not in all, 
there are patches of this cellular tissue which are distinctly and unmis- 1092 
TEXT-BOOK OF PATHOLOGY 
takably composed of stratified epithelium with concentric epithelial pearls. 
These were recognized by Landsteiner, who declared the tumors to be of 
epithelial origin. Volkmann had studied many cases, and had decided 
that the narrow strands of cells were derived from endothelium, and indeed 
these parotid tumors make up a great part of the material for his mono- 
graph on endotheliomata. Krompecher thinks of them as basal-cell 
tumors. Marchand, Wilms, and others regard them now as composite 
tumors in which epithelium plays the most prominent part, and trace them 
to an origin analogous to that of the teratomata, except in that the embry- 
onic rudiment is separated at a later stage. 
Composite Tumors of the Kidney.-In infants and children there occur 
tumors of the kidney which grow to an enormous size, and metastasize 
into distant organs. They may appear as congenital growths in new-born 
infants, and are composed of a mixture of tissues in which cartilage, fat, 
smooth muscle, and myxomatous connective tissue, together with complex 
arrangements of epithelium, take part. Unlike the hypernephromata, they 
cause no hematuria, and are recognized by their growth to a great mass in 
the abdomen. Wilms, Busse, Hedren, and others discuss their origin at 
length. While Busse thinks they may be derived from the kidney, or at 
least from its embryonal rudiment, Wilms places their origin farther back, 
in the middle plate, after its separation from the myotome. This tissue 
might well furnish all the elements which are found in such tumors. Stri- 
ated muscle does not occur, and hence the myotome is not involved, but 
stratified epithelium does occur, and offers difficulties to Wilms' view. 
Nevertheless the intimate relation of the anterior end of the Wolffian duct 
to the ectoderm-possibly a remaining trace of its old arrangement as a 
nephridial tube opening on the skin-may account for this epithelium. 
The morphology of these tumors is so variable that no single description 
will apply. The student is referred to the paper of Hedren, in which the 
literature is reviewed and in which there are many illustrations. In general, 
the epithelial cells are small and are arranged in irregular, gland-like tubules, 
interspersed with solid cords. 
Congenital Cystic Kidney.-There is no good place in which to mention this condi- 
tion, since our knowledge of its nature is so unsatisfactory, and for that reason a brief 
space may be devoted to it here. 
This is a peculiar affection of the kidneys which leads, during embryonic development, 
to the formation of cysts throughout both kidneys, and frequently to the formation of cysts 
in the liver as well. Most of the substance of the kidneys is occupied by these cysts, and 
there is extremely little functional tissue left between them. Yet such people may grow to 
adult life without knowing that there is anything amiss with their kidneys. In later 
life they may die of renal insufficiency after the injury of the scarcely sufficient tissue. 
In infancy the kidneys form huge masses of gelatinous cystic tissue, so large in one case 
which I studied that they had to be removed before birth was possible. This child was 
otherwise extensively malformed. Reconstruction (Meader) shows that the cysts may 
be in immediate relationship with the glomeruli, or may be developed in the first part 
of the convoluted tubule and connected by a narrow canal with the glomeruli. teratomata; composite tumors 
1093 
Ribbert puts forth a theory that the cysts are caused by interference with the union 
of the glomerular part of the tubule with the other rudiment, which grows up from the 
ureter to join it. Hence the glomerular portion dilates into a cyst. The end of the 
ureteral portion may also become cystic. Others regard the whole process as an ade- 
nomatous growth, which it is said might account for the similar growth of cysts in the 
liver. It seems to me more plausible to base the change on anomalies of embryonic de- 
velopment. 
In the adult the cystic kidneys may form two huge tumors occupying the whole 
abdominal cavity on each side (Fig. 574). At autopsy they are found to be no longer 
gelatinous, but made up of cysts about the size of a cherry or larger, filled with clear, 
or dark brown, or turbid fluid. Between these cysts, which are lined with low cubical 
epithelium, there are scattered normal tubules and glomeruli. 
In infants one may occasionally see another type of cystic dilatation of the tubules 
which occupies the pyramid and leads to the fusiform widening of the conducting tubules. 
Fig. 574.-Congenital cystic kidney. Remnants of a pelvis are seen in the centre at 
the lower part of the figure. 
Composite tumors of the breast are rare and are made up of stratified 
epithelium, together with various types of connective tissue. They are of 
less importance than the- 
Mixed Tumors of the Testicle.-Perhaps these should not be referred 
to again, since they are undoubtedly of teratomatous character, but it is 
intended to emphasize the point that in many of these tumors, whether 
because of their late origin in the course of embryonic development, or 
because one tissue has outgrown the others, the structure is relatively 
simple. The most common tumor of the testicle is that in which in most 
parts the cells are uniform in appearance and are large round cells, arranged 
in irregular masses or strands, with a stroma which is infiltrated with 
lymphocytes (Fig. 575). These are commonly called round-cell sarcomata 
of the testicle, and possibly this is correct in some cases, but in many others 
there are transitions to other forms of tissue and admixtures of epithelium 1094 
TEXT-BOOK OF PATHOLOGY 
which indicate the more complex character of the tumor. Other tumors 
of the testicle contain cartilage and cysts. Their main tissue is arranged 
like epithelium, in complex, gland-like structures often resembling an 
adenocarcinoma. Still other more complicated forms occur, and we find 
ourselves once more approaching the the solid teratomata. Still it is the rule 
for these testicular tumors that they grow with extreme malignancy, and 
extend into the spermatic cord and metastasize by way of the veins with 
great rapidity. In this respect they are unlike the ordinary teratomata* 
Fig. 575.-Teratomatous tumor of the testicle composed largely of tissue like that of a 
round-cell sarcoma. 
and we must assume that if they began as teratomata they have acquired 
the character of malignant tumors. 
Chordomata.-Mention may be made here of a rather rare tumor which 
usually springs from the body of the sphenoid bone, and projects into the 
cranial cavity, compressing the brain and the cranial nerves. Similar 
tumors may arise from the sacrum and other parts of the vertebral column. 
They are shown to be malignant by their invasive mode of growth, which 
allows them to destroy the bone extensively and to penetrate into veins. 
Nevertheless, no metastases in other organs have been found. The tumor 
is lobulated, the lobules being composed of groups and strands of large and teratomata; composite tumors 
1095 
small cells in a homogeneous ground-substance which takes a bluish stain 
with haematoxylin. They are rich in glycogen. The work of various 
authors, and particularly that of Marchand's pupil, Nebelthau, has shown 
that these growths are derived from remnants of the chorda dorsalis. 
LITERATURE 
Chorionic Epithelioma of Testicle.-Scott and Longcope: Proc. Path. Soc. Phila., 1909, 
xii, 8. 
Frank: Jour. Amer. Med. Assoc., 1906, xlvi, 248. 
Schlagenhauf er: Verh. d. Dtsch. Path. Gesellsch., 
1902, v, 209. 
Risel: Ergebn. d. allg. Path., 1906, xi, 929. 
Teratomata in General.-Seydel: Ergebn. d. allg. Path., 1901, vi, 858. 
Wilms: Die Mischgeschwiilste, Leipzig, 1899. 
Marchand: Missbildungen: Eulenberg's Realencyklopadie, 
1897, xv, 503. 
Dermoid Cysts.-Saxer: Ziegler's Beitrage, 1902, xxxi, 452. 
Katsurada: Ibid., 1901, xxx, 179. 
Salivary Tumors.-Landsteiner: Ztschr. f. Heilkunde, 1901, xxii; Abth. f. path. Anat., 1. 
Hinsberg: Dtsch. Ztschr. f. Chir., 1899, li, 281. 
Wood: Annals of Surgery, 1904, xxxix, 57. 
Mixed Tumors of Kidney.-Hedren: Ziegler's Beitrage, 1907, xl, 1. 
Busse: Virch. Arch., 1899, clvii, 346. 
Wilms: Loc. cit. 
Congenital Cystic Kidney.-Ribbert: Verh. d. Dtsch. Path. Gesell., 1900, ii, 187. 
Busse: Virch. Arch., 1904, clxxv, 442. 
Meader: Johns Hopkins Hosp. Bull., 1907, xviii, 354. 
Mixed Tumors of Testicle.-Debernardi: Ziegler's Beitrage, 1908, xliii, 89. 
Chevassu: Tumeurs du testicule, Paris, 1906. 
Chordoma.-Jelliffe and Larkin: Ztschr. f. d. ges. Neurol, u. Psychiat., 1911, v, 590. 
Wegelin: Atti del I Congresso Internaz. dei Patologi, Torino, 1911, 70. CHAPTER LVI 
CLASSIFICATION OF TUMORS 
The only satisfactory classification of tumors would be on the basis of 
their aetiology. Since we know nothing of this, they are classed very much 
as animals or plants would be, on the basis of their most striking char- 
acters. The most fundamental available characteristics are: (1) The 
type of tissue which they resemble, and from which we suppose them to be 
derived; (2) the degree in which they diverge from the type, and the 
extent to which they have acquired the power of invasion and coloniza- 
tion, and (3) the form which the tumor assumes, that is, its architecture 
as a papillary, cystic, glandular, or solid growth. 
In other words, we have tumors derived from one or more of the three 
germ layers, or more specifically from a tissue originating from one of these 
layers. They may be benign or malignant, and may grow in one or other 
of the many arrangements adopted by normal tissues, or in combinations 
or perversions of these forms. Rather than assume too accurate a knowl- 
edge of the ultimate derivation of the tumors, I have preferred to arrange 
them according to the general character of their tissues, both anatomical 
and biological, and their form. 
Other classifications as given in the various text-books and treatises on the 
subject should be consulted. The following list is mainly for convenience 
in summarizing the various forms as they have been considered here. It is 
an arrangement, not a classification. 
1. Benign tumors of connective-tissue character: 
Fibroma. 
Lipoma. 
Chondroma. 
Osteoma. 
Xanthoma. 
2. Tumors composed of tissue of muscular character: 
Leiomyoma. 
Rhabdomyoma. 
3. Tumors composed of tissue of nervous character: 
Neurocytoma, neuroblastoma, sympathoblastoma. 
Ganglioneuroma, neurinoma. 
Paraganglioma. 
Glioma. 
4. Tumors composed of blood and lymph channels-angiomata: 
Haemangioma. 
Lymphangioma. 
1096 CLASSIFICATION OF TUMORS 
1097 
5. Malignant tumors of connective-tissue character-sarcomata: 
Spindle-cell sarcoma. 
Mixed-cell sarcoma. 
Round-cell sarcoma. 
Alveolar sarcoma. 
Giant-cell sarcoma. 
Osteosarcoma. 
Myxoma. 
6. Pigmented tumors: 
Naevus. 
Melanotic sarcoma or melanoma. 
7. Tumor composed of tissue resembling adrenal cortex: 
Hypernephroma. 
8. Tumors thought to originate from endothelium-11 endotheliomata" 
Lymphangioendothelioma. 
Cylindroma. 
Pleural and peritoneal tumors. 
Meningeal tumors. 
Haemangioendothelioma. 
9. Benign epithelial tumors: 
Papilloma. 
Adenoma. 
Adamantinoma. 
Cy stadenoma. 
10. Malignant epithelial tumors-carcinomata. 
Flat-celled epithelioma. 
Basal-cell cancer. 
Cylindrical-cell cancer or adenocarcinoma. 
Gland-cell cancer. 
11. Chorionic epithelioma. 
12. Mixed tumors and teratoma. CHAPTER LVII 
GENERAL DISCUSSION OF TUMORS 
General character of tumors; relation to tissues of host. Their independence of the laws 
governing the growth of normal tissues; consequent abnormal architecture and metabolism. 
Distinction between tumors and infectious processes. Nature of cells of tumors; specific 
relation to those of host; relation to embryonic stages of cell development; atypical character. 
Growth; implantation, extension, metastasis, recurrence. Contributory causes of tumor 
growth: injury and irritation {physical, chemical, parasitic; Rous' filterable tumor}; in- 
ternal secretions; malformations; disposition; senility; heredity. 
Resistance and immunity. 
Theories as to the (etiology of tumors: Theory of parasitic origin of tumors; theory of tumor 
growth as the effect of irritants; theories emphasizing a disturbance of equilibrium of tissues; 
Cohnheim's theory; Ribbert's theory; theories of tumor growth depending upon changes in 
the cells. 
General Character of Tumor.-Up to this point we have considered the 
characters of tumors as though they were plants in a garden, observing 
their general structure and their mode of growth in individual cases. It is 
necessary now to make an attempt to learn whether there are common 
features in these respects, and whether we can discover the causes of 
their appearance and growth and of their peculiar relations to the host. 
Otherwise it must remain extremely difficult to give a definition of what a 
tumor really is. 
It is clear from what has been said of all these tumors that they are 
composed of the tissue of the host. This was recognized by Johannes 
Muller, and in spite of Virchow's rather generous idea that carcinomata, 
as well as other tumors, might be formed in a connective-tissue matrix, 
Waldeyer insisted that the specific relation was closer and that cancers 
which are composed of epithelium could arise only from epithelium. After 
that the intimate relationship of each tumor to one form or other of normal 
tissue was looked for and usually found, although we are still puzzled to 
trace this relationship in many cases. 
But if it is possible to feel sure that a given tumor is of epithelial or 
connective-tissue origin, or even that it belongs to the stratified or cylin- 
drical epithelium, it is nevertheless equally certain that it does not resemble 
that tissue precisely. 
The laws which govern the growth of normal human tissue and organs 
are very rigid. The form of the normal cells is so constant, and their 
relations to one another in the architecture of the organ so fixed, that we 
become familiar with their appearance, and instantly recognize any 
divergence from the accepted form. We know well too what changes 
1098 GENERAL DISCUSSION OF TUMORS 
1099 
occur in the morphology of normal cells as the result of variations in their 
functional activity, and, above all, we know the plan upon which they 
grow. Their reactions in all these respects, to a great variety of recogniz- 
able injuries and pathological disturbances, are very familiar, and we realize 
that under those circumstances the cells and tissues still obey the laws 
which govern their growth under normal conditions, and strive to restore 
as quickly as possible *the forms and relations which have been established 
by ages of evolution. 
In tumors we find the cells abnormal in form, in their relations to one 
another, and in their relation to surrounding tissues. They are abnormal 
in every functional activity, and in many cases in their increased vigor of 
growth. Great stress is usually laid upon this increased energy of growth, 
although in many tumors it is at a very low ebb, and in the most rapidly 
invading forms is not to be compared with that of the growing embryo. 
The really essential difference between tumors and normal tissue is not 
the increased energy of growth, but the emancipation of the tissue from 
obedience to the laws which govern the growth of normal tissues. That 
this is closely related to the abnormality in the form of the cells is probable. 
It is as a direct expression of this complete lawlessness that the tissue pro- 
duced by these cells has no regular architectural arrangement, that it never 
forms organs that could be of any possible use, and that it pays no regard 
to the rights of other organs, but bursts its way recklessly through their 
boundaries and their tissues, destroying their cells as it goes. Its behavior 
is like a complete disregard of international law, which has been established 
for the welfare of the whole world. 
In the development of the body some people may hold that the equilib- 
rium which is maintained between various tissues depends entirely upon the 
power of each to grow, but it is evident enough that a balance is maintained 
by a higher law than this, and that such an organ as the liver does not main- 
tain a precise number of cells, because it has not the power to form more, but 
because the law of the general welfare demands that many, and no more. 
If some are destroyed, or if the general situation is changed, the liver will 
form more cells to restore precisely the balance. Hence even though it 
■can be defined only vaguely, we are aware that there is a delicate but effec- 
tive power which controls, possibly by way of the nervous system, the rela- 
tions of tissues to one another. They are disciplined, and grow when 
they are required, but not of their own initiative. 
It is far otherwise with tumors. No tumor of glandular character has a 
duct, nor have its glands any such arrangement that they could effectively 
discharge a secretion. It is true that tumors of the organs of internal secre- 
tion may sometimes form a useful secretion, but one has the impression 
that this is a rare occurrence and inadvertent on their part. No tumors are 
known to be under the control of the nervous system. They seem to have 
no nerves except those accidentally enclosed in their growth and possibly 
vasomotor nerves in their blood-vessels. It is true that Young was able 1100 
TEXT-BOOK OF PATHOLOGY 
to demonstrate the nerve-fibres in a number of tumors by staining with 
methylene-blue, but he could not show that they really belonged to the 
tumor tissue, and, as far as I can learn, no one has been more successful. 
Tumors are not even subject to the normal conditions of nutrition, and 
withstand in the most surprising way starvation which causes the rest of 
the body to waste. A lipoma in a starving animal remains a plump tumor, 
distended with fat when all the other fat has disappeared. It is true that 
Moreschi found that, by starving mice inoculated with a tumor, he could 
inhibit its growth, but Rous found that if the tumor were well established, 
it continued to grow. In human beings the contrast between the appear- 
ance of huge cancerous growths in full progress, and extreme emaciation of 
the rest of the body, is often very striking. 
Thus the isolation and independence of the tumor form the essential 
difference between its nature and that of the normal tissues. In virtue 
of this it behaves in such a way as to be, in nearly every instance, harmful 
to its host, either through occupying space and requiring nutrition, or by 
actually invading and destroying useful tissues. Since tumors are com- 
posed of human tissues, however, we cannot accept this inimical attitude 
as a natural thing as we would in the case of an animal parasite, and every 
effort has been directed toward learning why and how such independence 
has been attained. 
Notwithstanding this general statement that a tumor is a growth of 
abnormal tissue which is largely independent of the laws governing and 
controlling the growth of normal tissues, it is often very difficult to decide 
what is, and what is not, to be called a tumor. Histological study often 
leaves us uncertain, and some growths are so sluggish that even a survey of 
their whole biological relations is hardly sufficient to inform us as to 
whether they have arisen as a response to some injury, or are really inde- 
pendent and transgressing the regulations which govern the normal tissues. 
Indeed, we not infrequently discover that something which has long been 
regarded as a tumor is really the slow product of a chronic infection, and 
Virchow's great book, Die krankhaften Geschwiilste, is, perhaps inten- 
tionally, full of such examples. Tumors are simulated, on the one hand, 
by the reactions of the body to infection and injury, which often produce 
considerable masses of new and peculiar tissue; on the other hand, by mal- 
formations and displacements of tissue, with which, as has already been 
shown, their relations are especially intimate. Whether we can draw a 
boundary line to separate sharply the group of tumors from these is doubt- 
ful. It is relatively easy in the case of such typical malignant tumors 
as the carcinomata, but not easy when we consider such processes as Hodg- 
kin's disease, leukaemia, leukosarcoma, lymphosarcoma, and round-cell 
sarcoma. In the case of x-ray burns, psoriasis, xeroderma, etc., it is not 
even easy to say when the normal reaction ceases and tumor growth begins; 
nor at the other extreme is it easy to determine when a mixed tumor becomes GENERAL DISCUSSION OF TUMORS 
1101 
a teratoma, or where the term teratoma should be given up and reference 
be made to an imperfect or abnormal foetus, or even to a twin brother. 
It seems, however, that if we were able, in each instance, to decide 
accurately as to whether the normal laws of growth had been broken or not, 
we could outline sharply the whole group of tumors. The independence of 
tumors involves the progressive and unlimited character of their growth. 
They never reach any goal and are never complete, nor do their cells ever 
reach any stage comparable to maturity and functional perfection. The 
reaction to infection and mechanical or chemical irritation keeps pace with 
the injury; it exists only so long as the injury persists, and then, in complete 
obedience to the laws of growth and the regulation of the internal relations 
of the tissues, returns as quickly as possible to the normal. Misplaced 
embryonic tissues, no matter how complicated, proceed to the ordinary 
maturity of the tissue, and then remain as stationary as normal tissues. 
They are still abnormal and harmful to the host because they are out of 
place, but not because they are actively transgressing the law of the inter- 
relation of organs. Of course, many teratomata show themselves ulti- 
mately to be malignant tumors, but these are instances in which a tumor 
has developed in the tissues of a teratoma and grown to invade the tissues 
of the host. Such a tumor grows usually from only one of the types of tis- 
sue which make up the teratoma, and is precisely comparable to a tumor 
which develops anywhere else in the host. So too after long irritation or 
infection the reacting tissue may reveal itself as a carcinoma, but it is a 
tumor which has freshly developed in pathological tissue, just as it might 
anywhere else. Far more often the reacting tissue does not give rise to a 
tumor growth. 
If in such an obscure condition as Hodgkin's disease we were able to 
remove or destroy an infectious agent and to observe thereupon the im- 
mediate retrogression of the tumor-like nodules, we might conclude at 
once that they were not true tumors. Since we have not definitely rec- 
ognized an infectious agent, we are not quite sure whether Hodgkin's disease 
is a tumor or not. How, then, one may well ask, can we be sure that 
cancers and sarcomata are not infectious processes, since we do not know 
their cause? We are not sure, and although every bit of evidence points to 
their being of a different character, we cannot be absolutely sure until some 
other cause of their growth is definitely demonstrated. 
In this state of knowledge it seems best to hold to the one striking 
feature of tumor growth as contrasted with that of other tissue growth- 
its independence of the mechanical laws which govern the hereditary form 
of the body. 
Of course, we must some day discover the cause of this alteration in the 
behavior of the tumor-cells, and it is conceivable that it may prove to be 
some parasite which accompanies or lives in the cells, perverting their course 
of life from that which is normal, and keeping them forever growing and 
dividing to produce new cells. It is difficult to imagine, however, what 1102 
TEXT-BOOK OF PATHOLOGY 
kind of parasite that could be. One may implant a carcinoma of a mouse 
into a normal mouse and from that, after it has grown, transplant a frag- 
ment to another mouse, and repeat this for hundreds of generations until 
the mouse from which the tumor was originally taken, and all its contempo- 
raries and their offspring, have been dead for years of old age, and still the 
tumor-cells are alive and thriving with exactly the same anatomical and 
histological characters that they possessed at first. It is a kind of arti- 
ficial immortality that seems to require only nutrition, and none of the 
reinvigoration which other living things usually gain from a sexual union 
with their kind. Nevertheless, it is not yet proved that unicellular organ- 
isms die after long periods of multiplication by fission without sexual con- 
jugation, and Woodruff seems to hold that they may go on indefinitely in 
this way. Plants, such as banana trees, have in the same way been culti- 
vated for hundreds of years from cuttings without any recourse to fertiliza- 
tion and seed planting. 
We may pause here to review the general character of tumor growths 
before discussing the theories which have been proposed as to their causa- 
tion. 
GENERAL CHARACTERS OF TUMOR GROWTH 
Tumors are composed of the tissues of the host, as has long been agreed, 
in spite of such efforts as those of Kelling, who attempted to prove that 
they are made up of the tissues of cows, pigs, or chickens which had been 
used for food. By the enormous amount of work which has been done in 
the last ten years in transplanting tumors from one animal to another it 
has been shown that their tissues are exquisitely specific and will grow con- 
tinuously only in another animal of the same species. Thus a carcinoma 
of a white mouse will grow in another white mouse, but fails to reach any 
considerable size in a gray, or wild mouse, or in a rat, and finally undergoes 
retrogression. This explains easily the complete failure of those experi- 
ments in which it has been attempted to transplant human tumors to dogs, 
rabbits, and other animals. Even in monkeys such transplants have failed. 
Resemblance to Normal Cells. -We have observed in previous chap- 
ters the extent of the resemblance of tumors to normal tissues both in 
appearance and in histological characters, and have realized that there 
are extreme variations, so that, while the cells of some tumors are almost 
precisely like the normal cells, even in their arrangement (thyroid tumors, 
etc.), others depart very widely from this form and become quite unrecog- 
nizable. We have learned that many tumors are composed of cells which 
seem to belong unquestionably to the same stage of development as those 
of the surrounding tissues, while others are made up of tumor-cells which 
have the morphology and arrangement, and possibly also the biological 
characters of the cells of some tissue in the early stages of its development. 
Examples of the latter condition are found in the neuroblastomata, in which 
cells belonging to an early stage in the development of the sympathetic GENERAL CHARACTERS OF TUMOR GROWTH 
1103 
nervous system persist in that stage, and multiply excessively to form a 
tumor, and in rhabdomyomata, which contain cells resembling embryonic 
muscle-cells. Nevertheless, I have never used the expression "return to 
an embryonic state" in speaking of such tumors as sarcomata, which are 
commonly spoken of as composed of "undifferentiated" or "unripe," con- 
nective tissue, because I do not believe that there is evidence to show 
that there is anything embryonic about that tissue. It is true that the cells 
are unlike the normal cells, but they do not especially resemble the con- 
nective-tissue cells of the embryo, and are often extremely unlike them. It 
seems far more plausible that they are cells so modified that their sole func- 
tion is to reproduce themselves rapidly, for which reason they never assume 
the form of the normal cells, nor lie dormant in abundant intercellular 
substance. It is conceivable that they are cells which have, like the neuro- 
blasts, never passed the embryonic stage of development, but this is a diffi- 
cult explanation which is neither required nor supported by any facts. 
It does not seem at all probable that any cell of a mature animal can ever 
return to the embryonic condition. Even those cells of the blood-forming 
organs which continually produce new blood-cells, and the cells of the epi- 
dermis, which form new epithelial cells, are in no true sense embryonic cells. 
They have retained the function of becoming differentiated into one 
type of cell, but are even then far advanced from the condition of embryonic 
cells. The idea that cells may in tumor formation return to the embryonic 
state is based no doubt upon the desire to explain their new energy of growth, 
but this new character of their growth is not at all like that of embryonic 
cells. In the embryo, the cells pass through a definite development to 
become mature. If they grow rapidly, it is only in this respect that the cells 
of a tumor resemble them, because tumor-cells pass through no such regular 
development but merely continue to grow and divide. They do not ap- 
proach the character of the embryonic cells, but assume a totally new 
character, in which they only roughly resemble the cells of the embryo in 
form and in the rate at which they grow. It is difficult enough to believe 
that embryonic cells can be isolated and remain latent for years embedded 
in the normal growing tissues, but far more difficult to believe that normal 
cells, once matured, can return to the embryonic state. For the former 
possibility we have proofs; for the latter we have no evidence whatever, 
so far as I can see. 
Although we speak so easily of deriving tumor-cells from tissue of one 
type or another, we really depend largely upon their morphological re- 
semblance for our proof of the relation. It is possible that we are often 
wrong in this, but, on the whole, the chance of error seems relatively 
slight. 
Dependence upon Host for Nutrition.-Tumors, whatever the inde- 
pendence of their cells, are dependent upon their host for their nutrition. 
If the host dies, the tumor dies too. If a blood-vessel is plugged in a tumor, 
the area which should be supplied with blood becomes an infarct, just as it 1104 
TEXT-BOOK OF PATHOLOGY 
would in the kidney. Bashford has compared the mouse, in which a huge 
tumor larger than itself is growing, to a sort of nutritive machine engaged 
in feeding the tumor. Its heart hypertrophies to keep up the pumping of 
blood through the enormous mass of new tissue. Its liver and sometimes 
its kidneys enlarge. Price Jones found no great modification in the differ- 
ential count of the bone-marrow of these animals, but states that there was 
great enlargement of the spleen. Studies of the vascular supply of tumors 
by methods of injection show that great numbers of blood-vessels run 
to the rapidly growing tumor-numbers far in excess of those which supply 
normal tissues. These are new formed at the demand of the growing tumor, 
and carry with them the supporting stroma of connective tissue. Bash- 
ford and his co-workers make much of the importance of the stroma, which 
they think is specifically adapted to each type of tumor. It is their belief 
that it is only in animals which respond by the production of an adequate 
stroma and blood supply that an implanted tumor can succeed in growing. 
Others lay much less stress upon the importance of the stroma. 
When a tumor is implanted in a susceptible animal, its stroma and part 
of its specific cells undergo necrosis, but the surviving tumor-cells grow and 
are quickly invaded by a new stroma formed from the host, with new blood- 
vessels. It seems clear that the tumor-cells act as a dominant tissue, con- 
trolling and stirring up the development of the vascular stroma, practically 
as epithelial cells do in the development of an organ in the embryo. Sub- 
servient as this stroma is, it does not always remain so. Ehrlich and others 
have found that, after a time, when a carcinoma has been implanted, the 
stroma itself may assume the characters of tumor tissue, and grow vigor- 
ously as a sarcoma, oppressing and finally destroying the epithelial cells. 
Such a tumor, when transplanted, may continue its growth as a sarcoma, 
extorting now the new formation of another vascular stroma from its 
host. 
Still, nothing has been observed as to the ingrowth of nerves into such a 
tumor, although this would seem to be a matter of the utmost importance. 
Little is written of the formation of lymphatic channels, although we know 
by injection experiments (Evans) that lymphatics are present in abundance 
in human tumors of many sorts. 
Atypical Character of Tumor-cells-Adaptation.-All the tumor-cells are 
atypical in the ways mentioned. They are characterized not only by their 
powers of growth, but especially by their tendency to continue indefinitely 
to divide and produce new cells, regardless of any need or of any plan for the 
arrangement of these new cells or even of the existence of any space in which 
they can be lodged, and these new cells proceed in the same aimless way to 
produce others. That they are specifically related to animals of their own 
species is shown by their ability to grow indefinitely, in contact with the 
tissues of that species only. But the adaptation can be intensified by 
repeated transplantation into animals of the same species, for at first it is 
necessary to transplant a great number of pieces from a spontaneous FORM OF GROWTH, EXTENSION; IMPLANTATION; METASTASIS 
1105 
tumor into as many mice in order to obtain one successful implantation. 
After that, however, with repeated transplantations the tumor acquires 
the power to grow in practically every mouse. This does not necessarily 
mean that it grows more rapidly, or more destructively, or to a larger size. 
It is merely a matter of adaptation to its surroundings, and whether we 
regard the cell as independently originating the growth, or as impelled by 
some parasite, the explanation of the adaptation must be the same. 
FORM OF GROWTH, EXTENSION; IMPLANTATION; METASTASIS 
The form of the growth is, as we have learned, extremely variable, and 
there are all gradations between tumors which surround themselves 
with a smooth capsule and grow expansively, and those which scatter 
their isolated cells like spray in every direction, or send out long threads 
of cells which insinuate themselves between the cells and fibres of the 
tissues, and even into the walls of blood-vessels and lymphatics. The 
former mode of growth usually appears in a benign tumor, the latter in a 
malignant tumor. These two forms are doubtless in large part the ex- 
pression of differences in the rate and continuity of multiplication of the 
cells. The encapsulated benign form is far less exposed to the action of the 
cells and fluids of the organism than the spreading malignant form. Through 
this very fact the latter seems to become adapted to existence anywhere in 
the body, and is thereby aided in spreading and even in establishing colonies 
in distant organs. 
As to the spread or extension, we have already described several forms. 
Implantations.-In the older literature there were many descriptions 
of instances in which a carcinoma was thought to be transmitted by con- 
tact to another person. Some of these were cases in which, through 
intimate contact, as in the transfer of a genital carcinoma from husband to 
wife or the reverse, there was a semblance of probability, but in others, 
in which, for example, a nurse contracted a carcinoma of the breast from 
tending a patient with a similar carcinoma, there was unquestionably only a 
coincidence. Recent reports of such occurrences are rare. There are, 
however, instances of implantation of a tumor upon contiguous epithelial 
surfaces in the same individual, as, for example, the formation of a car- 
cinoma of the vagina opposite the ulcerated surface of a carcinoma of the 
cervix uteri. These, too, seem questionable, and it is perhaps more 
probable that such tumors are really due to transportation by way of the 
lymph-channels, although theoretically there is no reason why some abra- 
sion of the opposite mucous surface should not allow the implantation of 
cancer-cells. 
Much more familiar is the implantation of the cells of a tumor in the 
raw edges of a wound made for the extirpation of the growth, with the 
development of nodules in the resulting scar. Even this is a rather un- 
common occurrence, however. Within the body, the implantation of free 
fragments of tumor or tumor-cells is frequently seen in the peritoneal 1106 
TEXT-BOOK OF PATHOLOGY 
cavity and other serous cavities. It is especially common with papil- 
lomatous cystadenomata of the ovary and with colloid carcinomata, but 
it occurs also with various other tumors. Whether the nodules so often 
found on the surface of the lungs as growths secondary to a carcinoma, or 
sarcoma situated elsewhere are produced by implantation from the pleural 
cavity or by extension from the substance of the lung is rather difficult to 
tell. They occur as large, button-like nodules, or as smaller masses like 
beads, or even as tiny, flattened, confluent, or discrete thickenings of the 
pleura, and in every case they are continuous with growths of tumor-cells 
in the underlying lymph-channels. Sometimes these extend in the inter- 
lobular spaces or in the walls of blood-vessels or bronchi quite through the 
lung to the hilum, where the lymph-glands are generally involved. Thus 
it is possible that the tumor may have grown from the hilum or any part 
of the lung through the lymphatics to the surface, spreading out and 
developing there, and, indeed, in the absence of a tumor mass invading 
the pleural cavity this seems the more probable course. In other cases in 
which a tumor of the stomach or gall-bladder has distributed metastases 
on the under side of the diaphragm, the course of its extension to the pleural 
cavity and the surface of the lungs can be readily traced through the dia- 
phragmatic lymphatics. 
Extension.-The actual extension of an invasive tumor occurs, as we 
have seen, through the growth of strands of tumor-cells into the interstices 
of the surrounding tissue. These cells may become really isolated, but, as 
a rule, the strands or threads of cells maintain their continuity for a long 
time. With the widening of the strands the peripheral parts of the tumor 
become more condensed and the intervening normal tissue is destroyed. 
Frequently the advancing margin is much more compact, and the normal 
tissue is largely pushed aside and compressed, so that the tumor grows by 
the invasion of coarse projecting masses. In many instances these, as well 
as the finer strands, are guided by meeting with a dense fascia or other 
resistant tissue, and spread along its surface. 
Far more commonly, however, the cells break through the walls of 
lymphatic channels and spread themselves like an injection mass along 
their lumina so as to fill them completely. This is particularly character- 
istic of the carcinomata, and has been studied carefully for such cancers as 
are of common occurrence (breast, uterus, etc.). Handley finds that the 
extension in carcinoma of the breast is through the plexus of lymphatic 
channels which accompany the fasciae, and that these may become obliter- 
ated after the tumor has moved along their course. Thus in a wide halo 
around the tumor there are lymph-channels full of tumor-cells ready to 
grow into nodules or to wander farther, although the obliterated channels 
by which they reached that point are no longer visible. That this net- 
work of lymphatics in the deeper part of the skin and in the fasciae may act 
in this way is shown by the numerous small tumor nodules which often 
appear in these regions, quite far from the original tumor. Handley, FORM OF GROWTH, EXTENSION; IMPLANTATION; METASTASIS 
1107 
therefore, suggests that an extremely wide area of skin should be removed 
in order to extirpate the tumor completely. 
Metastasis.-Even more familiar and common is the transportation of 
loose clumps of tumor-cells, or even single cells, by the stream of lymphatic 
fluid along the course of the channel until they are caught and held in the 
complex sinuses of a lymph-gland. Since the distribution of the lymphatics 
is well known, one may foretell easily which gland is likely to receive the 
first emboli of this nature. There the tumor-cells develop into a new tumor 
which gradually invades and replaces the tissue of the lymph-gland. Other 
emboli of the cells may pass to more distant lymph-glands, or the process 
may be repeated with the metastatic nodule as the source for new emboli. 
If such floating cells reach the thoracic duct, they may lodge in its walls 
and there grow, but they are far more likely to be swept on into the blood- 
stream, whence they are caught up in the capillaries of the lungs. 
While such metastasis by way of the lymphatic channels is very common 
for carcinomata, it is somewhat less common for sarcomata and some other 
malignant tumors. These tend to grow in such a way as to penetrate the 
walls of the veins and discharge themselves directly into the blood-stream. 
Carcinomata do this also and it is by no means uncommon to find meta- 
static nodules which could be explained in no other way than by a trans- 
portation of the carcinoma cells by way of the blood. The invasion of 
sarcomata is frequently a very gross process, so that great masses of the 
tumor hang in the vein, or fill it completely. This is especially true of the 
hypernephromata, and we have already described a case in which the 
whole vena cava was filled with a tumor mass. The carcinomata primary 
in the liver exhibit the same tendency. 
The transportation of liberated cells proceeds, of course, with the 
stream of blood, and we should expect to find them lodged, first of all, in 
the lungs. That this is commonly the case is shown by the development of 
numerous tumor nodules in the lung tissue, but it is quite common to find 
metastases only in the liver, or in some other organ in the systemic circula- 
tion. Of course, if the primary tumor is situated in the intestinal tract, it 
is easy to comprehend that the tumor-cells carried by the portal blood 
should lodge and grow in the liver, but in other cases we must assume that 
the floating cells have passed through the wide capillaries of the lung to 
reach the other organs, unless there are also large metastases in the lungs 
themselves from which a secondary embolism might occur. 
Distribution of Metastases.-Numerous curious distributions of metas- 
tases occur, as when a neuroblastoma beginning in the adrenal gives rise 
to multiple secondary growths which are confined to the liver, or when a 
carcinoma of the prostate establishes practically all its secondary growths 
in the marrow of the bones. Virchow made the statement that in those 
organs in which tumors are commonly primary, metastases rarely occur, 
while primary growths are rare in those situations which seem to form the 
best soil for secondary nodules. Thus the stomach and uterus are common 1108 
TEXT-BOOK OF PATHOLOGY 
sources of primary tumors, but rarely the seat of metastases, while the 
reverse is true of the liver. Although this cannot be said to be universally 
true, it introduces the suggestion that certain tissues form an especially 
suitable ground upon which the tumor-cells may take root and thrive, 
and, further, that this is not the same for all types of tumors. Indeed, there 
are many tissues, such as the pancreas, thyroid, heart-wall, muscle, etc., 
which seem especially unsuited to support the growth of the tumor-cells, 
although these tissues must receive many emboli. There is no difficulty 
in accepting the idea that the tumor-cells may slip through the capillaries 
of the lungs, for in many cases they are not much larger than the blood- 
cells and ought to pass readily. It should be realized, however, that 
many emboli must pass into the organs and even into those most favorable 
to their growth, without ever developing into tumor-nodules. Instead, as 
M. B. Schmidt has shown, they are surrounded by minute thrombi and 
later destroyed. 
The secondary growth may far outstrip in size the primary tumor: 
As a rule, it reproduces the histological structure of the primary nodule 
with considerable fidelity, so that one may often form an idea of the posi- 
tion of that tumor by examining the secondary growth. Nevertheless, as 
Hansemann points out, the metastasis tends to diverge further from the 
normal architecture than did the primary growth. A tertiary nodule, 
derived by metastasis from the secondary one, might show an even greater 
departure from the normal. Hansemann describes this as an increase in 
anaplasia, by which he means a peculiar divergence from the normal mor- 
phology and functional nature which is characteristic of tumor-cells and 
which is often associated with irregularities in the process of mitosis. 
Nature of Metastasis.-The phenomena of metastatic growth show that 
the formation of a tumor in a distant organ depends upon the transporta- 
tion of the cells of the original tumor to a new site, and the secondary nodule 
is seen to develop from these cells, and to reproduce the type of tissue which 
makes up the original growth. This is a totally different process from the 
metastasis which occurs in infections, in which we can recognize the causa- 
tive agent, since there the infective agent alone is transported, and any 
nodule of new tissue which it may produce in the new situation is seen to 
be derived entirely from the tissue of the organ in which it lodges. It is 
the result of the reaction of those tissues to injury, and proceeds according 
to the well-known laws which govern the behavior of normal tissues when 
they act in unison to combat an injury. In the tumor-nodule one tissue 
opposes another-the local tissue antagonizes the immigrant tissue. If we 
assume that a parasite is the cause of the growth of tumor-cells, we have no 
evidence that it can exist without them, for we never find secondary tumors 
derived from the tissues of the organs in which they form. Since such 
hypothetical parasites must be so closely dependent upon the cells originally 
affected as to be practically an inseparable constituent of them, it is quite CONTRIBUTORY CAUSES OF TUMOR GROWTH 
1109 
as easy to assume that the cells themselves take the initiative in the 
abnormal process. 
Recurrences.-Tumors removed at operation may recur in the same 
place, or in the neighborhood, and from this it must be assumed that, in the 
field of operation, particles or cells have been left in the tissues which may 
grow again after the wound has progressed toward healing. This may be 
because the excision was not extensive enough to include in the extirpation 
all the prolongations of the tumor, or because, in the course of the manipu- 
lations, loose cells were strewn in the exposed wound surface. Regional 
recurrences which appear in the skin or deeper tissues at a little distance 
from the site of the original tumor are explained as growths from those 
lymphatics filled with tumor-cells which have been shown to radiate from 
the original growth. 
CONTRIBUTORY CAUSES OF TUMOR GROWTH 
It may be said in advance that nothing is known of the actual cause of 
tumor growth. Nevertheless, there are several things which must be 
seriously considered as bearing some relation to the development of tumors, 
since they have long been known to be intimately associated with the begin- 
ning of their growth, and have been regarded as predisposing or con- 
tributory causes. These are as follows: injury or irritation of physical or 
chemical nature with chronic inflammation; the effect of disturbances of 
internal secretions; malformations and displacements of tissue, and such 
general predisposing conditions as senility and inherited tendencies. 
As causes of irritation, numerous parasites of all kinds have been 
described, but in no case has a definite causal relation been proven. 
Injuries and Irritation.-Single severe injuries, such as blows or fractures, 
have frequently been followed by the development of a sarcomatous tumor, 
although rarely by a carcinoma. Thousands of such injuries have no such 
result, however, and it may well be questioned whether the connection 
is not an accidental one. Injuries which produce scars have sometimes 
resulted in a very striking way in the formation of a cancer in the scar. 
Thus a girl was burnt from shoulder to hip and recovered with a scar cover- 
ing that whole area. Years later, a huge carcinoma appeared occupying 
the site of the scar (v. Bergmann). 
Chronic or repeated mechanical irritation, the changes produced by light, 
x-rays, and radium, and by chemical irritants and bacteria, are more 
generally associated with the development of carcinoma. After explaining 
that they lead to chronic inflammatory processes and scar formation, 
which forms a transition between trauma and tumor formation, Borst sum- 
marizes the well-known examples of such tumors as follows: 
Carcinoma occurs in the penis in cases of phimosis, in the tongue and 
cheek in association with the irritation of a carious tooth, in the mammary 
gland from pressure of a corset. There are the lip cancer of pipe-smokers, 
cancers of the gall-bladder, renal pelvis, and urinary bladder in connec- 1110 
TEXT-BOOK OF PATHOLOGY 
tion with stone formation, the cancers of the ostia of the body and the 
normally narrow passages in the digestive tract, the occupational cancers, 
paraffin, tar, and chimneysweep's cancers, cancer of the bladder and kidney 
in aniline workers, pulmonary cancer of metal workers, workers in spinning 
mills and cigar factories, the carcinoma on the basis of chronic eczema 
(Paget's, Darier's diseases), on the basis of ulcerations (ulcer of leg, ulcer of 
stomach), carcinoma developing in fistulse and scars, carcinoma following 
chronic endometritis,,cystitis, chronic syphilis, and tuberculosis of the skin, 
cirrhosis of the liver, chronic nephritis, and various skin diseases, such as 
leucoplakia, hyperkeratoses, polyps, and condylomata. 
In this heterogeneous collection the common principle appears to be the 
long-standing irritation which brings about inflammatory reaction, destruc- 
tion and replacement of tissue, with distortion and disarrangement of 
cells. 
B. Fischer found that the injection into the skin of Scharlach R or Sudan 
III, dissolved in oil, would, if the solution were injected with force, result 
in the production of an extraordinary tumor-like growth of epithelium. 
Others have confirmed this, and Helmholz was able to produce in this way 
a tumor composed of cartilage. With the absorption of the stain and 
the oil these growths gradually recede and disappear. They never form 
metastases. 
Certain aniline bases had a similar but much less marked effect, and a 4 
per cent, solution of ether in water was found by others to accelerate 
greatly and intensify the growth of tissues. Askanazy found that implanted 
embryonic tissue, if first treated with ether water, would grow into a large 
teratoma, more bulky than those which grew without this treatment. 
Loeb and others have pointed out that these are all lipoid solvents, and 
that their effect is in some way related to the existence of a lipoid capsule 
about each cell. 
Yamagiwa and Ichikawa have found it possible to produce abundant 
nodular growths of epithelium on the skin of rabbits by rubbing in crude 
tar for a long time. These growths have all the appearances of epitheli- 
omata and, indeed, metastasize into the regional lymph-glands. Never- 
theless in many if not in most cases they tend to undergo retrogression, 
and are healed by scar formation and new growth of epithelium over the 
ulcer left by their necrosis and disintegration. This has been repeated by 
many workers and very extensive and widely distributed tumors produced. 
Dr. Maislin tells me that the application of tar has a general effect in re- 
ducing resistance to the growth of tumors and, in such animals as have 
received this treatment for a time, but have not developed tumors, the 
inoculation of transplantable tumors is more successful than in untreated 
controls, and metastasis occurs in a way not seen in normal animals in- 
oculated with the same tumor. 
It has already been stated that carcinomata have been found to develop 
in the scars and eczematous areas produced by the action of x-rays and CONTRIBUTORY CAUSES OF TUMOR GROWTH 
1111 
radium. No good explanation is offered for this, but it seems that this is 
one method by which it might be attempted to produce malignant tumors 
by experimental means with some chance of success. 
The part played by parasites has been studied at enormous length, and 
every conceivable sort of parasite has been described, both such as resemble 
known organisms and such as have no resemblance to any recognized 
living thing. Bacteria of several sorts have been incriminated, and the 
Micrococcus neoformans of Doyen is perhaps the one most widely known. 
Erwin Smith's researches on the crown gall of various plants show that 
these tumor-like growths are independent of the ordinary laws of growth 
and atypical in the arrangement and form of the cells. They are the result 
of infection with the Bacillus tumefaciens, and can be produced at will 
by inoculation of this organism. He claims no relation between the or- 
ganism and tumors of animals or man, but suggests that there are certain 
analogies in the methods or mechanisms of tumor production in plants and 
animals. Blastomyces and yeasts have been cultivated from many tumors, 
and have been inoculated into animals with various results, sometimes pro- 
ducing tumor-like nodules. But none of these has stood before the ordinary 
tests which are applied to the recognition of the causal relation of bacteria in 
infectious diseases. Borrel has tried to show the intimate relationship 
between certain acarians, including the Demodex folliculorum, and epi- 
thelial tumor growth, and has insisted that, even though they may have no 
power in themselves to cause the growth of the tumor, they may transfer 
the unknown virus from one animal to another. The number of spon- 
taneous tumors in mice kept in cages infected with these mites is very strik- 
ing. Somewhat similar is the observation of Fibiger, who found that 
a type of flat-cell epithelioma of the stomach and oesophagus occurs in 
rats in which a peculiar nematode worm, a species of spiroptera which 
passes its larval stage in the cockroach, is found embedded among the cells 
of the tumor. Such tumors could be produced in normal rats by feeding 
with cockroaches containing the larvse. Metastases are found in distant 
organs in which no nematodes or their eggs are discoverable. Fibiger 
thinks that the tumor is produced by the irritating action of some poison 
formed by the nematode, and states that this is the first instance of the 
experimental production of a metastasizing tumor. 
Bullock, Rohdenburg, and Curtis, working with F. C. Wood, have re- 
ported the production of a sarcoma of the liver in rats about the cysts 
formed by the larvse of the Taenia crassicollis of the cat which grow in the 
rat as Cysticercus fasciolaris. The tumors begin about these cysts in a 
)arge proportion of the infected rats and are capable of extensive growth, 
invasion and metastasis, and easy transplantation to other rats. 
Analogous to this are the numerous observations of the development of 
carcinomata in the bladder-wall in Bilharzia infection, in the liver in infec- 
tion with other trematodes (Opisthorchis, Distomum Japonicum, etc.), 
and in the neighborhood of cysticerci from tsenise in various situations. 1112 
TEXT-BOOK OF PATHOLOGY 
Most interesting in this and other connections are the studies of Rous, who 
discovered a peculiar tumor of a hen which he was able to transplant to 
other hens of the same breed. 'The tumor in the course of repeated trans- 
plantation acquired an astounding power of growth and adaptation and 
could be successfully inoculated by the mere introduction into tissues of a 
needle which had been plunged into the growth. It was, then, possible 
to transplant it to fowl of other breeds. The tumor has the form of a 
sarcoma with long, spindle-shaped, and branched cells, and produces huge 
tumor masses in the connective tissues of the fowl. Most significant, how- 
ever, is the fact that this tumor can be successfully transmitted by the 
inoculation of dried and powdered material, or even by the injection, into 
the tissues, of a clear, cell-free fluid, obtained by filtering a suspension 
through a Berkefeld filter. Naturally, there has been much difference of 
opinion as to whether this is a true tumor or the reaction of connective 
tissue to some extraordinary infection. The fact that it may be trans- 
mitted by a cell-free filtrate seems to indicate that it is caused by an ex- 
tremely minute living organism. 
Effects of Internal Secretions in Relation to Tissue and Tumor Growth.- 
There are many examples of the extraordinary growths of tissues which 
appear to be associated with activity of the organs of internal secretion, 
and most of these have been mentioned elsewhere. The growth of the 
breasts during pregnancy, of the antlers of the deer during the season of rut, 
of various transitory tissue masses in frogs and salamanders, and fishes 
during the analogous period, are instances in point. The theory of Fraenkel 
and Born, which is to the effect that the secretion of the corpus luteum is 
necessary to the proper progress of pregnancy, may throw some light 
on the development of malignant growths from the chorionic epithelium, 
since masses of persistent corpus luteum tissue are found in the enlarged 
ovaries in many of those cases. L. Loeb has even suggested that the 
internal secretion of the ovary or some of its derivatives has an influence 
upon the growth of mammary cancer, for mice castrated at an early age 
were found to develop cancer in far fewer cases than those not castrated. 
Malformations.-The relation of tumor growth to malformation has 
already been discussed in describing teratomata, and will be referred to 
again in connection with theories of the causation of tumors. It is of 
interest here, as an example of the ^contributory causes of tumor growth, to 
recall the fact that malignant tumors frequently develop from one tissue 
of a teratomatous growth and metastasize alone, although in the absence 
of this specific change such teratomata are benign. The mere displace- 
ment and subsequent development of embryonic tissue does not lead to 
true tumor growth. 
Disposition; Senility; Heredity.-We have some vague information with 
regard to these predisposing causes of tumor growth, but it is unsatisfactory. 
That there may be a constitutional tendency to the development of a tumor 
may easily be said, but it is, after all, a matter about which only a general CONTRIBUTORY CAUSES OF TUMOR GROWTH 
1113 
impression can be gained. Hereditary transmission of tumor growth or 
rather of susceptibility to tumor growth should be accessible to more 
exact investigation. Bashford, in analyzing English statistics, concludes 
that there is no evidence whatever to show the existence of any such heredi- 
tary taint, and states that in his thousands of experimental animals there 
has been nothing to show that it occurs. Even when carcinoma animals were 
intentionally inbred, so as to increase the chance of inheritance, no larger 
number of spontaneous tumors was found than occurred in normal [mice. 
Murray shows, however, in a later paper from Bashford's laboratory, that the 
incidence of spontaneous cancer is much higher in mice, whose immediate 
ancestors developed cancer, than in those in whose pedigree only remote 
ancestors were cancerous. Tyzzer found that the susceptibility of a parent 
mouse to inoculation with a certain tumor may be transmitted to its off- 
spring even though the other parent be insusceptible, and Maud Slye, 
from a large experience with mice, states that spontaneous tumors occur in 
the offspring of those which have had tumors, in accordance with Mendel's 
law. In her more recent experiments she has been able to mate animals, 
on the basis of her knowledge of this Mendelian heredity, in such a way as 
to bring about the appearance of tumors in the offspring, and even to plan 
for the development of a known type of tumor in a particular organ or 
location. Much remains to be learned in this matter. 
Morgan and his students have done something similar in flies, in which 
both malignant lethal and benign tumors develop. Their work has been 
especially concerned with the recognition of the particular chromosome 
with which this hereditary growth is associated. These studies appear to 
offer a whole new conception of the nature of tumor growths, but it is 
scarcely yet possible to interpret them with certainty. 
The incidence as affected by age is more clearly recorded. It is a matter 
of general experience that carcinomata tend to appear in persons who have 
reached or passed middle age and are rare in young people. On the con- 
trary, many sarcomata and those mixed tumors which sometimes occur 
congenitally, are more frequent in young people. It is possible that some 
of the contributory causes which favor tumor growth are really necessary 
in the case of cancerous tumors, for it is known that, while cancers originate 
in old persons and old animals which have long been exposed to those 
influences, young mice are far more susceptible than old ones to the artificial 
implantation of these tumors. 
LITERATURE 
Yamagiwa and Ichikawa: Mitth. d. med. Fakultat d. k. Univ, zu Tokyo, 1915, xv, 295; 
1917, xvii, 19. Japan. Ztschr. f. Krebsforschung, 1916, x, Heft 4; 1917, xi, Heft 2. 
Erwin Smith: Jour, of Cancer Research, 1916, i, 231. Jour. Agricult. Research, 1917, 
viii, 165. 
T. H. Morgan and others: Jour. Cancer Res., July, 1918; Jour. Exp. Zodl., Feb., 1919; 
Proc. Nat. Acad, of Sciences, 1919, v, 573. 1114 
TEXT-BOOK OF PATHOLOGY 
RESISTANCE AND IMMUNITY 
Only the briefest outline of this subject can be given here, although an 
enormous amount of labor has been devoted to it in recent years. 
Undoubtedly, many persons are highly resistant or incapable of harbor- 
ing certain forms of tumor growth, although they may be susceptible enough 
to the growth and extension of another form. We have no way of deter- 
mining this accurately, but we do know that when a tumor is already 
established in the body and is discharging into the circulation many emboli 
of its cells, most of these may be destroyed by the activities of the tissue 
fluids. Much light has been shed upon the question by the experimental 
study of tumors in animals. In mice, for example, malignant tumors which 
are transplanted from spontaneously developed nodules to normal mice 
fail to take at first, except in a very small percentage of the experiments. 
Later, with increasing adaptation to the conditions met with in the body 
of the mouse, the tumors, after repeated transplantation, acquire the 
power of growing in nearly every inoculated mouse. Nevertheless, there 
are some mice which show themselves refractory to the best adapted 
tumors. This is a natural immunity. If a mouse recovers spontaneously 
by destroying the tumor growth already begun in its tissues, or even if the 
tumor is completely extirpated after growing for a time there, it becomes 
immune and cannot be again inoculated successfully with that tumor. 
It is even immune with respect to other tumors, and Ehrlich has named 
this condition panimmunity. In this respect immunity from experimental 
tumors differs from the more specific immunity against infections. Even 
the inoculation of tissue or blood from another normal animal of the same 
species will confer an immunity from tumor inoculation. In all cases the 
immunity is dependent upon the inoculation of living cells, whether they 
be tumor-cells or those of the normal tissue. Ehrlich has offered an 
explanation of immunity which rests on the idea that a tumor requires for 
its growth a certain specific substance. He found that, by inoculation of a 
rapidly growing tumor, he could render impossible the growth of a second 
tumor, and, thinking that the first tumor had used up all this specific 
food substance, called this condition athrepsia. There have been many 
attacks on the validity of this theory, and it is not yet decided whether it 
will hold, since many investigators have found it possible to implant a 
second tumor in an animal already bearing one. The well-known zigzag 
transplantation from mouse to rat and back formed the strongest element 
of Ehrlich's proof. A mouse tumor implanted in a rat grows for a few 
days, but then regresses and dies, unless it be retransplanted into a mouse, 
where it once more thrives. Ehrlich thinks that the tumor must have 
lacked a particular food-stuff in the rat, necessary for its growth. 
These principles have not been applied to any great extent to the study 
of human tumors, and little is known of the conditions of immunity in the 
human body. 
Histological Character of the Immunity Reactions.-Several writers, THEORIES AS TO THE .ETIOLOGY OF TUMORS 
1115 
among whom da Fano may be mentioned, have studied the histological 
reaction to the invasion of tumors and have found that lymphocytes and 
plasma cells are especially concerned in this reaction. Murphy and his 
associates have found, quite recently, that the susceptibility to tumor im- 
plantation is enormously increased by the destruction of the lymphocytes 
by exposure to the x-ray or by the administration of benzol. They look 
upon the accumulation of lymphocytes about a tumor, for this reason, as 
a protective or combative reaction. These views are supported by others 
of their experiments which show that an embryo in which no lymphocytes 
have yet appeared is extremely susceptible to tumor inoculation, while the 
implantation of a fragment of lymphoid tissue from an adult into the body 
of the embryo confers upon it a resistance practically equal to that of the 
adult. 
Shirai (Japan Med. World, 1921, i, 14) has shown that, if the inocula- 
tion be made into the substance of the brain, a tumor can be transplanted 
from one animal to another of quite different species and will grow to a 
large size. Mouse tumors thrive in the brain of a rat or of a pigeon. 
Murphy and Shurm have confirmed this, except that they have not suc- 
ceeded in so implanting a spontaneous tumor, and they show further that 
the transplantation of a tumor already long adapted to experimental 
inoculation will thrive in the brain of the heterologous animal only if it 
be completely buried in brain tissue. If the graft extend into the ven- 
tricle or is in contact with the meninges it is soon destroyed. They also 
show that the growth of the foreign tissue in the brain may be completely 
inhibited by the simultaneous inoculation of a small bit of autologous 
but not by a bit of homologous spleen tissue. Mice highly immune to 
subcutaneous transplants of mouse cancer show no resistance to such tu- 
mors when the inoculation is made into the brain. 
The explanation of this is not easy, but it would appear that, as in the 
case of the embryo, which is so susceptible to the implantation of any tumor, 
the interior of the brain tissue is a place protected from the advent of 
lymphocytes which seem so important in the protection of the animal 
against tumor growth. 
THEORIES AS TO THE ^ETIOLOGY OF TUMORS 
We are as yet quite ignorant of the actual cause of tumor growth. It is a 
question which has occupied the minds of pathologists and clinicians for 
many years, and theories in incredible numbers have been proposed. Some 
of these theories, put forward by men who had worked very intimately 
with tumors, have survived to this day, but it is rather discouraging to 
find that most of the modern theories are merely fantastic inventions of a 
philosophic character, proposed by men who do not seem to have lived 
with tumors, nor even to have been particularly familiar with them. They 
always introduce many new terms and a new classification of tumors, with 
specially constructed Greek names, and the whole merely adds to the con- 1116 
TEXT-BOOK OF PATHOLOGY 
fusion and reminds one of the writings of the scholastics of the middle ages. 
We are quite ignorant of the real cause of tumor growth, and therefore the 
theories may all be wrong. In the meanwhile, until the real cause is ascer- 
tained, we may learn along what lines these attempts at explanation have 
been made. 
Theory of Parasitic Origin of Tumors.-The most obvious explanation 
would lie in the existence of a living organism, continually stirring the tis- 
sues to grow, but in that case it would, as we have explained, be necessary 
for the parasite to associate itself indissolubly with the cell, and accompany 
it in all its wanderings and divisions. No such minute organism has been 
found, and the gross parasites which have been described seem quite 
incapable of such subtle and constant relations, for it is not a reaction of 
any contiguous tissue that they provoke, but the irresistible growth of one 
sort of tissue, which wanders into new situations and maintains an inde- 
pendent existence. If there are parasites, we must be prepared to find 
them quite different from any which we now know, and capable of produc- 
ing tissue reactions quite at variance with all the laws of normal growth 
and normal reaction to injury. They must be so included in the growing 
cells as to multiply with them and accompany them wherever they go, 
since otherwise it seems impossible that they could maintain their stimu- 
lating effect upon cells which had been transplanted to a distant organ. 
If the parasite never shows itself alone or through its effects on tissues in 
general, but only in this intimate relation with its own tumor-cells, it must 
remain difficult to distinguish it from an acquired quality of the tumor-cells 
themselves. There must be a different parasite for each of the many sorts 
of tumors, and every one of these parasites must have these characters 
of intimate affinity for the special cells which it chooses to stimulate. It 
must merge its ability to produce antibodies in the affected animal in that 
of the cells, since that immunity seems to be of cytotoxic character and not 
very specific. Lambert has shown that tumor-cells will grow in vitro in the 
plasma of an animal insusceptible to the growth of that tumor, but are 
injured or destroyed by the plasma of an animal immunized against it. 
Since a cytotoxic immunity can be produced against the implantation of 
the tumor by the introduction of normal tissues of an animal of the same 
species, the parasite must be killed, too, and must, therefore, have acquired 
the specific character of the cells. It really seems that it must have become 
identical with the cell. 
Theories of Tumor Growth Based on the Effect of Irritants.-Numerous 
instances of tumor growth following upon irritation or injury with inflam- 
matory reaction have been mentioned, and there has long been a desultory 
argument tending toward the emphasis of their importance as causes of 
tumor growth. Bashford lays stress upon the direct connection which is so 
often observed, and although it fails in most cases, it is very striking when 
it does occur. Only yesterday, while writing somewhat skeptically of this 
relation, a man aged seventy showed me his leg, which he had struck against THEORIES AS TO THE ^ETIOLOGY OF TUMORS 
1117 
a bath-tub some months before, producing an abrasion which had failed to 
heal. He had no suspicion that anything had happened except that it had 
not healed, but covering the site of the injury there was actually a rough, 
flattened tumor, which appeared to be of the nature of a basal-cell car- 
cinoma. Most of these tumors appear after the irritation has existed a 
long time and has produced extensive inflammatory infiltration and re- 
paratory changes in the underlying connective tissues, as well as in the 
epithelium itself. No one has succeeded in producing them experimentally, 
except perhaps by the use of x-rays or the introduction of certain 
gross parasites, and the question arises as to whether a predisposition 
through senile changes or otherwise may not be necessary for their initia- 
tion. 
The idea of the influence of irritants recalls to our attention the whole 
question of the action of stimuli upon the growth of tissue, which has been 
so long discussed. Many investigators accept the existence of direct stim- 
uli to growth, and bring forward numerous instances in the history of tuber- 
culosis, syphilis, and a host of other infectious diseases and banal injuries. 
Others hold that the tendency to grow is roused only indirectly through 
functional needs, and Weigert has claimed that new-growth is essentially 
a reparatory process, attempting to make up for tissue which has been 
destroyed, thereby restoring the disturbed equilibrium of the tissues. In 
ordinary circumstances it is usually possible to explain the new growth of 
tissue as the effect of reparatory processes, even though in the cases of 
excessive growth it often appears that it is the response to repeated 
injuries which may affect the repairing tissue itself. Nevertheless, this 
explanation is complicated, and it is much easier to assume that injuries 
or irritants may directly stimulate the tissues to grow. In any case the 
new tissue remains subject to the general laws which govern the archi- 
tecture of the body, and tends to return to the normal relations when the 
irritation ceases. 
In the case of a tumor, a new element is introduced by the failure of the 
tissue to evince this general tendency to return to the normal relations after 
the irritation has ceased. The finality of its departure from the laws of 
growth is as though a train suddenly ran off the track, and careered through 
the neighboring streets and houses. Even though we accept the idea that 
irritation may directly stimulate tissue to grow, our explanation of the 
history of a tumor must really begin with its continuous independent and 
unlimited growth, which might be initiated, but not maintained in distant 
situations, by such irritants as are usually discussed. 
Theories of Tumor Growth Depending upon Disturbance of the Equi- 
librium of Tissues.-So firmly established is the evidence of mutual support 
and restraint among the tissues, that many writers have sought, in a dis- 
turbance of this equilibrium, the explanation of the unlimited growth of 
tumors. Thiersch thought that, with senility, the energy of growth of the 
connective tissue failed, so that the epithelium could invade it and grow TEXT-BOOK OF PATHOLOGY 
1118 
at will, while Waldeyer offered the reverse explanation, stating that the 
failure of the epithelium to maintain its ranks enabled the connective 
tissue to surround and isolate some of it, which then grew in its new situa- 
tion. The inadequacy of these explanations is evident, and Hanseman 
pointed out at once the fact that tumors occur in the young and are es- 
pecially malignant. Ribbert has pursued these ideas, explaining the in- 
growth of epithelium as dependent upon primary changes in the underlying 
connective tissue, which becomes relaxed and infiltrated with leucocytes, 
so that it is exposed to the invasion of the epithelium, which it surrounds 
and isolates, thereby allowing unlimited growth through the disarrange- 
ment of equilibrium. The inflammatory infiltration of lymphocytes, upon 
which Ribbert lays stress, appears now to be the protective reaction which 
Murphy has shown to be so important in preventing the extension of 
tumors. While Ribbert's theory involves the primary activity of the 
altered connective tissue, it does not rest solely on that basis, but is related 
in certain ways to other theories, so that it must be referred to again. 
Theories of Tumor Growth Depending upon Displacement of Embry- 
onic Cells.-Cohnheim's Theory.-Another theory, associated especially 
with the name of Cohnheim, assumes that since certain tumors which occur 
congenitally are traceable to congenital maldevelopment, it is possible, or 
even probable, that a disarrangement of cells in the course of embryonic 
growth may lie at the root of tumor growth in general. Cohnheim's idea 
was that at some stage of embryonic life cells might become isolated while 
still possessed of great energy of growth and potentialities which would 
have carried them on to the development of some specific tissue of the body, 
had they remained in their normal connection with the rest of the cells of 
the embryo. These cells are conceived of as lying dormant among the 
growing tissues, and showing no tendency to unfold their own powers of 
growth during years. Then, when the other tissues have become organs 
of an adult man, and commonly late in the life of this man, the hidden 
group of cells, still endowed with embryonic vigor, begins to grow. Cohn- 
heim did not think that these cells would begin their growth without some 
stimulus, but that, once started, they would exhibit a capacity for growth 
comparable only to that of the embryo. 
Numerous criticisms have been made, of course. It is difficult to believe 
that such misplaced cells or groups of cells could remain latent for many 
years and still maintain their youthful vigor. Further it is known that 
when such displacements of tissue obviously occur, the cells tend to pro- 
ceed through their allotted course of maturation and development, to pro- 
duce finished tissue, rather than to continue as embryonic cells, although 
there are some teratomata in which the peculiar form of cells has been 
interpreted, rightly or wrongly, as embryonic. Since tumors may occur 
anywhere, and are frequently initiated by irritation, it is necessary to 
assume an extremely wide distribution of displaced cells if a group of them 
is to be ready wherever the irritation may act. While Cohnheim's theory 1119 
THEORIES AS TO THE ETIOLOGY OF TUMORS 
may explain perfectly the teratomata and other growths which are obviously 
related to foetal inclusions, it does not explain the malignant type of 
growth, since it does not explain why the cells of a tumor behave differ- 
ently from those of an embryo, in that they continue to grow in the same 
atypical form and never proceed to anything resembling the end-product of 
tissue growth. 
Ribbert's Theory.-Ribbert also assumes that the most important and 
indispensable basis for the origin of a tumor is the independence of a tissue 
germ, attained through isolation of the cells, through which the always 
adequate capacity for growth of the cells is liberated. Not every isolated 
group of cells forms a tumor, and those which do are dependent upon 
favorable conditions of development, nutrition, etc. The character of the 
tumor depends upon the type of tissue in the rudiment, its degree of inde- 
pendence, and its energy of growth at the time of its isolation from the sur- 
rounding cells. This isolation occurs most frequently in embryonic life, 
but may also occur in adults, and is produced by abnormal processes of 
growth. Another tissue may grow in such a way as to cut off a group of 
cells from its normal relations with its own tissue. The growth of the 
other tissue is in a sense a preliminary stage, which ends in the initiation of a 
tumor, when it has isolated a group of cells which act as the germ of the 
tumor. Tumor-cells are not biologically different from normal cells, and 
only the conditions under which they find themselves decide them upon 
tumor formation. 
When Ribbert accepts in its general principle the Cohnheim theory, he 
modifies it by the statement that the isolation of the cells which are to 
produce the growth may occur in adult life, and that this isolation is brought 
about by the irregular growth of other tissues. Ribbert's other contention 
is that tumors are in a sense unicentric, that they grow out of their own 
material, invading the other tissue, it is true, but not infecting it or stim- 
ulating it to grow. He emphasizes particularly the statement that it is 
wrong to regard the growing margin of an epithelial tumor as a transi- 
tional zone between normal and tumor tissue, in which the normal tissue is 
being converted into tumor tissue. Instead, the tumor is entirely depen- 
dent upon its own dividing cells, which may burst through and upheave 
the adjacent epithelium or even heal together with it, but which do not 
convert it into tumor tissue. Borst and many others accept this statement, 
but Hauser and several more recent writers question its truth. It is well 
known that there is commonly a modification of the epithelium in the 
neighborhood of a primary epithelial tumor which resembles that at the 
edge of an old ulcer. The epithelial downgrowths between the papillae 
may be exaggerated, and are surrounded by an exudate of lymphocytes. 
Whether this is capable of being shown to be a preliminary to actual con- 
version into cancer tissue remains to be determined. Lubarsch points out 
the fact that the epithelial tissue adjacent to a metastasis in an internal 
organ from an epithelioma of the skin is very much less distinctly changed 
than that which adjoins the primary growth. 1120 
TEXT-BOOK OF PATHOLOGY 
Somewhat analogous to these theories which invoke the aid of the 
embryonic energy of growth are those more faintly expressed ideas whicn 
depend upon the possibility of a new fertilization. J. Loeb has shown that 
the eggs of some animals may be stirred to parthenogenetic development 
by the action of chemical substances. The disturbance of the lipoid sheath 
by some solvent, allowing the oxidative processes to go on, appears to be 
the mechanism concerned, and this explanation has been transferred to 
those experiments in which the introduction of scharlach oil, ether-water, 
etc., have stirred up a new growth of cells. There have, indeed, been efforts 
to show that an actual conjugation of adjacent cells may take place after a 
preliminary heterotypic division, with reduction of chromosomes to half 
their normal number (Farmer, Moore, and Walker). Such conjugation 
ought to confer a new impulse to growth, exactly as in the fertilization of 
the ovum. Rotter has elaborated on this idea in that he recalls the pos- 
sibility that primitive sex cells, in their wandering into the tissues of the 
embryo, may accidentally lodge anywhere outside the ultimate sex glands. 
Such cells, through a stimulus to parthenogenetic development, might be 
thought of as an origin for tumor growth. The idea is a most tempting 
one at first sight, but the proofs of the actual existence of this process 
have not been satisfactorily brought forward. 
Theories of Tumor Growth Depending upon Changes in the Cells.- 
Hauser was among the first to insist that tumor growth could be explained 
only on the assumption of a profound change in the character of the cells 
of which it is composed. He speaks of new cell races, and recognizes 
especially their independence and their arrogance in overcoming other 
tissues and cells. Marchand, Beneke, and Ziegler hold somewhat similar 
views. Hansemann has elaborated the idea by attempting to define the 
character of this change in the cells, which he describes as anaplasia, an 
alteration in the cell not always easily recognizable by its form, but con- 
sisting in changed histological characters which allow it to proliferate rather 
than to functionate. This, in its more intense degrees, is accompanied 
by changes in form and arrangement of the cells, and is associated with 
atypical or asymmetrical mitoses. Anaplasia is not the cause of tumor 
growth, but the term is descriptive of the changes which occur in the cells. 
Borst, recalling the infinite complexity of the process of distribution of 
parental characters to all the cells of the developing body, regards the change 
in the cells which leads to tumor growth as due to some irregularity in the 
formation of their "idioplasm," which one-sided development does not 
necessarily incapacitate them for an ordinary function in the ranks of other 
cells, but leaves them capable of independent and atypical growth. 
Schwalbe adheres to this idea, which he expresses differently, inasmuch as 
he speaks of congenital pathological abnormality of the cells, or cell mal- 
formation. 
It was said in the beginning that we do not know the cause of tumor 
growth, and it seems quite unprofitable to attempt new theories except on THEORIES AS TO THE /ETIOLOGY OF TUMORS 
1121 
the basis of adequate new facts. Those at our disposal have been so well 
pondered over that the newer theories prove to be merely the invention of 
new terms to express the old vague ideas. 
Nevertheless, I must express my own impressions of what has been 
learned and written of tumor growth without advocating any new theory. 
We have a fairly clear conception of the laws of normal growth from the 
beginning to the end of life. Those laws apply equally well to the growth 
of the embryo and to the growth of the adult. Tumor growth does not 
obey these laws, but transgresses them in every direction. It seems idle, 
therefore, to attempt its explanation by assuming that embryonic cells per- 
sist and grow in the adult body. That may explain teratomata very well, 
since they are essentially finite growths that obey the normal laws, as well 
as they can with their incomplete tissues and in their cramped situations. 
But it does not explain the growth of tumors. 
On the other hand, we are quite familiar with the effects of every sort of 
injurious influence in disturbing temporarily the normal growth of tissue, 
and can formulate general laws for these effects which are found to be always 
respected. But tumors do not respect them at all. For that reason I 
have written of tumor-growth separately from all the rest of pathology as 
a thing apart, not to be dealt with according to the laws of reaction of normal 
tissues. Although we discuss every sort of injury as a possible cause of 
their growth, we cannot conceive of one which would have this result with- 
out assuming some abnormal character in the tissue itself. No known 
injury can elicit such a reaction in normal tissue, and it must be a parasite 
of a totally unimagined kind which could do it. 
We are left with the impression that there is somehow produced a 
sudden, profound, and permanent change in the character of the cells 
themselves, and that other tissues which are invaded or form the stroma are 
affected by their activity; but although we realize this irrevocable change, 
we cannot assign a reason for it, nor even tell precisely in what structural 
alteration it may be recognized. 
LITERATURE 
Only such treatises as are of general character and give further references to the 
literature are given here: 
Virchow: Die krankhaften Geschwiilste, Berlin, 1863-1867. 
Borst: Die Lehre von den Geschwiilsten, Wiesbaden, 1902. Wiirzburger Abhand- 
lungen, 1906, vi, 221. (Excellent paper.) Ziegler's Beitrage, 1910, xlix, 638. 
Aschoff: Pathol. Anat., 1913, i, 51. 
Ribbert: Geschwiilstlehre, Bonn, 1904, with Supplements. Das Carcinom des Menschen, 
Bonn, 1911. (c/. Orth, Ztschr. f. Krebsforsch., 1913, xiii, 566, for a criticism of this 
work and Ribbert's theories.) 
Ewing, J.: Neoplastic Disease, 1919. 
E. Albrecht: Verh. d. Dtsch. Path. Gesellsch., 1904, viii, 89. Monatsschr. f. Geburtsh. 
u. Gynak., 1904, xx, 123. 
v. Dungem and Werner: Wesen der bosartiger Geschwiilste, Leipzig, 1907. 
Israel: Berl. kl. Woch., 1000, xxxvii, 608, 644, 667. 1122 
TEXT-BOOK OF PATHOLOGY 
Schwalbe: Verb. Naturh. Mediz. Verein zu Heidelberg, 1906, N. F. viii, 337. 
M. B. Schmidt: Verbreitungswege der Karzinome, Jena, 1903. 
Apolant and Ehrlich: Genese des Carcinoms, Verh. Dtsch. Path. Gesellsch., 1908, xii, 
3. 
Verse: Problem des Geschwulstmalignitat, Jena, 1914. 
Lubarsch: Pathol. Anat. u. Krebsforschung, Wiesbaden, 1902. 
Wolff: Lehre von der Krebskrankheiten, Jena, 1911. 
Da Fano: Ztschr. f. Immunitatsforschung, 1910, v, 1. 
Murphy and others: Jour. Exp. Med., 1913, xvii, 482; 1914, xix, 513; 1915, xxii, 204; 
1921, xxxiii, 299; 1923, xxxviii, 183. 
Rous: Jour. Exp. Med., 1910, xii, 696; 1911, xiii, 397; 1912, xv, 119, etc. 
Apolant: Ztschr. f. allg. Physiologie, 1909, ix, 63, Ref. (Review of experimental work.) 
Hansemann: Anaplasie, bosartigen Geschwiilste, Berlin, 1893-1897. 
Borrel: Probleme du Cancer, Paris, 1907. Bull. Inst. Pasteur, 1907, v, 206. Ann. de 
1'Inst. Pasteur, 1909, xxiii, 97. 
Fibiger: Ztschr. f. Krebsforschung, 1913, xiii, 217. 
Herxheimer and Reinke: Ergebn. d. allg. Path., 1910, xiii2, 356; 1913, xvi2, 1. 
Bashford and others: Publications Imperial Cancer Research Fund, 1904-1912. 
Woglom: Studies in Experimental Cancer, Crocker Research Fund, New York, 1913. 
Levin, Lambert, Hanes, and others. MacCallum, General Introduction: Experimental 
Studies in Cancer, Crocker Research Fund, N. Y., 1912. 
Bullock and Rohdenburg: Jour. Med. Research, 1913, xxviii, 477; Proc. N. Y. Pathol. 
Society, 1920, xx, 149. 
Rotter: Ztschr. f. Krebsforschung, 1921, xviii, 171. INDEX 
Note.-Page references to illustrations appear in italics. In cases where there 
are several references to discussions of the same subject, the more important refer- 
ences are printed in heavy type. 
Abscess, 221, 222, 227, 264, 510 
amoebic, of liver, 773, 774, 775 
of lung, 776 
cold, 687 
liquefaction of, 154, 263 
of brain, 517, 540 
of heart, 465 
of intestine, 263 
of kidney, 261, 455, 535 
of liver, 262 
amoebic, 773, 774, 775 
in suppurative cholangitis, 41®, 412 
of lung, 257, 536 
amoebic, 776 
pyaemic, 263 
of pancreas, 417 
of pericardium, 533 
of skin, 261 
psoas, 222 
Acapnia in shock, 378 
Acetone bodies in diabetes, 873 
Acidosis, 170 
in diabetes, 173, 873 
in infectious diseases, 173 
in other conditions, 173 
Acromegaly, 185, 906, 906, 907, 908, 909 
relation of hypophysis to, 905 
Actinomyces bovis, 630 
relation of, to streptothrix, 630 
Actinomycosis, 629, 632 
amyloid in, 633 
character of lesions, 630 
localization of, 631 
mode of infection, 630 
of bones, 632 
of Fallopian tubes, 632 
of intestines, 632 
of jaw, 631 
of liver, 633, 633 
of lung, 632 
of ovary, 632 
of spleen, 633 
Actinomycosis, references to literature, 
633 
sinuses in, 222 
Acusticus tumors, 963 
Adamantinoma, 1015, 1015 
Adaptation of growth to function, 177 
Addison's disease, 900 
chromaffin tissue in, 901 
pigmentation of skin in, 900 
references to literature, 902 
Adenine, 88 
Adenocarcinoma, 1026, 1042 
common sites of origin, 1042 
of breast, 1070 
of ovary, 1062, 1062 
of rectum, 1058 
of uterus, 1035, 1059, 1061 
Adenofibroma of breast, 1016, 1017, 1018 
Adenoids, obstruction of nose by, 428 
Adenoma, 1006, 1010 
differentiation of, from carcinoma, 1068 
intracanalicular, of breast, 1019, 1020 
of adrenal, 1014 
of breast, 1016, 1019, 1020 
of hypophysis, 1015 
of intestine, 1012, 1011, 1012 
of kidney, 1012, 1013 
of liver, 1012 
of skin, 1010 
of stomach, 1011 
of thyroid, 880, 880, 881, 1014, 1014 
of uterus, 1024 
polypoid, 1012 
references to literature, 1024 
Adenomyoma, 957 
Adiposis dolorosa, 910, 912 
Adrenaline, 898 
arteriosclerosis produced by, 901 
effect of, on blood-vessels, 898 
on organs, 899 
on uterus, 898 
glycosuria produced by, 898 
1123 1124 
INDEX 
Adrenaline, myocardial injury produced 
by, 470 
oedema of lungs produced by, 46 
Adrenals, accessory, 896 
amyloid infiltration of, 100 
chromaffin tissue in, 896 
disturbances in function of, 65, 896 
extirpation of, 897, 899 
cholesterinaemia from, 80 
function of cortex, 899 
function of medulla, 898 
in chronic nephritis, 901 
influence of, on carbohydrate metabo- 
lism, 871, 898 
on sexual development, 899 
in shock, 379 
in status lymphaticus, 848 
lipoids in, 897 
normal involution of, 896 
pigments of, 125 
references to literature, 902 
relation of cholesterine to function of, 
897 
transplantation of, 210 
tuberculosis of, in Addison's disease, 900 
tumors of, 994 
adenoma, 1014 
hypernephroma, 994 
relation to sexual precocity, 899 
Adventitial cells, 150 
staining, 150 
Agglutination, 165 
in dysentery, 620 
in typhoid fever, 165 
Agglutinins, 169 
Aggressins, 162 
Alastrim, 765 
Albuminuric retinitis, 305 
Albumosuria in myeloma, 87, 841, 856 
Alcohol poisoning, 400 
Alcoholism, chronic, 400 
degeneration of nerves in, 81 
haemorrhagic pachymeningitis in, 
122 
Alexin, 169 
Alimentary tract, obstruction of, 405 
references to literature, 427 
syphilis of, 713 
Alkali reserve of body, 170 
Alkalosis, 173 
relation to pyloric obstruction, 173 
Alkaptonuria, 87 
Alopecia, syphilitic, 706 
Amboceptor, 169 
Amino-acids in urine in diseases of the 
liver, 314 
Ammonia poisoning, 399 
Amoebae, pathogenic, 771 
Amoebic abscess of liver, 773, 774, 775 
dysentery, 771 
infections, 770 
references to literature, 776 
Amyloid, 98 
chemistry of, 101 
degeneration, 61 
experimental production of, 103 
deposits in adrenals, 103 
in bronchi, 103 
in intestine, 100 
in kidney, 99, 296, 297, 298, 299 
in liver, 99 
in lymph-glands, 100 
in spleen, 99, 99, 101 
in actinomycosis, 633 
in chronic nephritis, 298, 298 
references to literature, 103 
staining properties of, 100 
Amyloidosis, diseases associated with, 99 
actinomycosis, 633 
chronic nephritis, 298, 298 
Anaemia, 2 
aplastic, 206, 819 
references to literature, 825 
bone-marrow changes in, 206 
causes of, 810 
experimental, changes in bone-marrow, 
804 
from benzol poisoning, 206 
in lead poisoning, 401 
in mechanical destruction of bone-mar- 
row, 821 
local, 16, 18, 25, 27 
osteosclerotic, 810, 1059 
references to literature, 825 
pernicious, 810, 813 
aetiology of, 81 
blood changes in, 814 
deposits of iron pigments in, 815 
from Bothriocephalus latus infection, 
81 
hyperplasia of bone-marrow in, 815, 
815, 816 
liver in, 819 
phagocytosis of red corpuscles in, 817 
pigmentation of organs in, 124 
references to literature, 825 
spleen in, 817, 817 
regeneration of blood in, 205 INDEX 
1125 
Anaemia, secondary, 811 
blood changes in, 811 
bone-marrow in, 813, 813 
changes in organs in, 812 
from blood destruction, 811 
in malaria, 812 
splenic, 822 
Anaesthesia, Overton's theory of, 50 
Anal fistula, tuberculous, 674 
Anaphylaxis, 166 
relation to bronchopneumonia, 516 
Anaplasia of tumor cells, 1120 
Anasarca, 44 
Anchylostoma duodenale, 793 
head of, in intestinal wall, 795 
Aneurysms, 355, 361, 362 
aetiology of, 359 
arteriovenous, 358 
cirsoid, 356 
dissecting, 356, 374 
of aorta, 356, 357 
erosion of bone by, 69, 70, 360 
false, 359 
fusiform, 355 
mechanical effects of, 68, 359, 368 
multiple, 363 
of aorta, 359, 360, 361, 363 
of small arteries, 363 
racemose, 356 
references to literature, 363 
rupture of, 361 
saccular, 359, 361 
Angina, scarlatinal, 761 
Angioma, 969. See also Haemangioma and 
Lymphangioma. 
Angiosarcoma, 980, 1004 
Anisocytosis, 814 
Ankylosis in arthritis deformans, 934 
Anorexia nervosa, 63 
Anthracosis, 129 
of lungs, 130 
of lymph-glands, 129, 130 
Anthrax, 589 
bacillus of, importance of capsule for- 
mation, 162 
carbuncle in, 590 
haemorrhagic meningitis in, 591, 591 
lesions of organs in, 590 
portals of entry, 590 
references to literature, 592 
Antithrombin, 7 
Antitoxins, 167 
Antrum, infection of, 534 
in influenza 598 
Aorta, aneurysm of, 359, 360, 361, 363 
dissecting, 356, 357, 374 
saccular, 355, 359, 361 
arteriosclerosis of, 334, 337, 339 
fatty patches in intima, 84, 334, 335 
structure of, 333 
syphilis of, 252, 348, 349, 350 
thrombi in, 11 
Aortic insufficiency, 251, 350, 360, 475 
cause of collapsing pulse in, 476 
references to literature, 492 
stenosis, 350, 476, 477 
Aortitis, syphilitic, 252, 348, 349, 350 
aneurysms in, 359 
references to literature, 351 
Apoplexy, cerebral, 364, 364 
references to literature, 366 
pancreatic, 417 
Appendicitis, 236 
acute, 237, 237, 238 
perforating, 239, 239 
phlegmonous, 238, 240 
suppurative, 239 
aetiology of, 224 
bacteriology of, 237 
chronic, 237 
complications and sequelae of, 241 
haematogenous, 236 
healed, 241 
healing of, 237 
peritonitis in, 239 
references to literature, 243 
Appendix, concretions in, 238 
histology of, 236 
Aqueduct of Sylvius obstruction of, 505 
Archoplasm, 50 
Arcus senilis, 64 
Argyria, 130 
Arhythmias, 498 
due to heterogenetic impulses, 498 
to homogenetic impulses, 497 
Arsenic compounds, resistance of try- 
panosomes to, 162 
increased tolerance of, 162 
poisoning, 401 
acute, 401 
blindness in, 402 
chronic, 401 
degeneration of nerves in, 81 
Arterial hypertension, 304 
experimental production of, 305 
Arteries, fatty infiltration of, 84 
obstruction of, 18, 26 
structure of, 333 INDEX 
1126 
Arteries, thrombi in, 11 
Arteriosclerosis, 19, 333 
aetiology of, 346 
blood-pressure in, 347 
calcification in, 339, 340, 340 
cholesterine in, 338, 339 
circulatory disturbances in, 463 
early stage of, 334, 335, 336 
elastic tissue of vessels in, 337 
experimental, 347 
adrenaline, 901 
late stage of, 336, 339 
lipoids in lesions of, 336, 338 
Monckeberg type, 343, 344, 345 
of aorta, 334, 335 
of coronary arteries, 343, 465 
of femoral artery, 344 
of mesenteric artery, 338, 342 
of pulmonary artery, 347 
of renal artery, 341, 342 
of renal vessels, 286. See also Chronic 
nephritis, arteriosclerotic. 
ossification of, 340 
pathogenesis of, 346 
proper, 334 
references to literature, 348 
syphilitic, 348, 349, 350 
Arteriosclerotic kidney, 296 
Artery of cerebral hemorrhage, 395 
lenticulo-striate, 395 
lenticulo-optic, 395 
Arthritis deformans, 932 
degenerative, 935, 935, 936, 937, 938, 
939 
disturbances in bone formation in, 105 
proliferative, 933, 934 
references to literature, 941 
types of, 933 
gonococcus, 565 
in dysentery, 619 
infectious, types of, 932 
pneumococcus, 552 
rheumatic, 568 
Arthropathy, tabetic, 738, 739 
types of, 933 
Arthropods, pathogenic, classification, 770 
Ascaris lumbricoides, 796 
Aschoff bodies in heart, 465, 466, 568, 570, 
571 
Ascites, 43 
chylous, 797 
Asthma, pulmonary emphysema in, 437 
Atelectasis, 430 
Atheroma, 337. See also Arteriosclerosis. 
Atheromatous cysts, 1089 
Athrepsia, 1114 
Atmospheric pressure, effect of increased, 
368 
Atrophy, 62 
acute yellow, 313 
brown, of heart, 63, 64 
of liver, 63 
from disease, 62, 65 
from insufficient blood supply, 62 
from old age, 63 
from pressure, 62 
from starvation, 63 
of bones in leprosy, 628, 628 
of brain, senile, 64 
of fat, serous, 64 
of kidney after obstruction of ureter, 178 
of liver, senile, 63, 64 
of muscles, 63, 66, 67 
in acute poliomyelitis, 691 
senile, 63 
of skin, senile, 63 
progressive muscular, 66 
Attraction sphere, 50 
Auditory canal, tumors of, 963 
Auricle, thrombus in, 10 
Auricular fibrillation, 499 
Auto-intoxication, 395 
Autolysis, 58 
of liver, 58 
of lung, 58 
Axone reflex in inflammation, 143 
Azoospermia following gonorrheal epi- 
didymitis, 561 
Bacillus aerogenes capsulatus, 22 
in puerperal infections, 257 
anthrax, 589 
botulinus, 580 
infection, 395 
dysenteriae, types of, 616 
enteritidis infection, 395, 615 
leprse, 625 
mallei, 587 
paratyphosus, types of, 615 
pestis, 585 
tuberculosis, types of, 634 
effects of, on tissues, 642 
excessive repair following injuries by, 
186 
fats of, 80 
Bacteria, changes in virulence of, 508 
emboli of, 22 
portals of entry of, 160, 508 INDEX 
1127 
Bacteria, toxins of, 509 
Bacterial action, nature of, 509 
Bacteriolysins, 164 
specificity of, 168 
Bacteriotropins, 164, 169 
Banti's disease, 822 
cirrhosis of liver in, 822, 823 
spleen in, 822, 822, 823 
Basedow's disease, 883. See also Goitre, 
exophthalmic. 
Bechterew's disease, 935 
Bed-sores, 42 
Bence-Jones protein in urine in myeloma, 
841, 856 
Benzol poisoning, anaemia in, 206 
changes in bone-marrow in, 802, 803, 
802, 803, 8O'h 805 
references to literature, 824 
relation of lipoids to, 81 
Beri-beri, neuritis in, 81 
Beta-imidazolethylamine, 380. See His- 
tamine. 
Bile pigments, 113, 121 
elaboration of, by Kupffer cells, 127 
Bile-ducts, carcinoma of, 1054 
obstruction of, 406 
Bilharziosis, 788 
Bilirubin, 113, 121 
Blackwater-fever, 120, 782 
references to literature, 783 
Bladder, calculi in, 444 
dilatation of, paralytic, 449 
hypertrophy of, 44^, 560 
tumors of, carcinoma, 1033 
myoma, 957 
papilloma, 1009, 1033, 1034 
rhabdomyoma, 959 
Blindness from arsenic poisoning, 402 
Blood, calcium excess in, 110 
diminution of, in body, 69 
effects of injuries upon, 799 
fat in, 77 
in syphilis, 713 
in typhoid fever, 610 
of different species, precipitation test 
for, 165 
quantity of, in body, 2 
Haldane-Smith method for esti- 
mating, 2 
red corpuscles of, effect of injury to, 
809 
formation of, 148 
regeneration of, 204 
after hemorrhage, 205 
Blood, regeneration of, in anaemia, 206 
test for, 165 
Blood-clots, 3 
chicken-fat, 4 
cruor, 4 
in healing of wounds, 212 
postmortem, 4, 5 
structure of, 4 
varieties of, 4 
Blood-clotting, 3, 6, 7 
appearance under ultramicroscope, 7 
delayed, 7 
in haemophilia, 7 
in jaundice, 7, 126 
rapid, 7 
references to literature, 14 
Blood-crises, 206 
Blood-formation, extramedullary, 194, 800, 
831 
from endothelial cells, 192 
in liver in congenital syphilis, 746 
Blood-forming organs, 800 
diseases of, 830 
classification, 832 
effects of injuries upon, 799 
of benzol on, 804 
of x-rays on, 389 
of different species, precipitation test 
for, 165 
Blood-platelets, 7 
in thrombi, 8 
Blood-pressure, maintenance of, 561 
Blood-vessels, 460 
calcification of, 108 
effect of adrenaline on, 898 
elastic tissue in, 333 
endothelioma of, 1002 
hyaline degeneration of, 97, 98 
occlusion of, 69 
regeneration of, 202 
syphilis of, 726 
thrombi in, 223 
Boils, 532 
Bone, actinomycosis of, 632 
atrophy of, in leprosy, 628, 628 
erosion of, by aneurysm, 68, 70, 360 
formation in muscles after injury, 952 
relation of internal secretions to, 917 
retardation of, in myxoedema, 876 
fracture of, 370 
repair of, 202 
healing, 201 
growth of, disturbances in, 915 
effect of calcium deficiency on, 915 1128 
INDEX 
Bone, growth of, normal, 917 
in infantile scurvy, 927, 927, 928 
in osteomalacia, 924 
in Paget's disease, 929, 930 
in rickets, 919 
regeneration of, 200 
osteoblasts in, 201 
syphilis of, 720, 722 
congenital, 748, 748, 749, 750, 751 
references to literature, 726 
transplantation of, 209, 210 
tuberculosis of, 222, 686, 685, 687, 775 
references to literature, 687 
tumors of, carcinoma, metastatic, 1058, 
1066 
chondroma, 949, 949, 950 
osteoma, 952, 952 
osteosarcoma, 983, 985, 986 
sarcoma, 987 
giant-cell, 983, 984 
Bone-marrow, 801 
destruction of, by metastatic tumors, 
821 
effect of rr-rays on, 389 
focal necrosis of, in typhoid fever, 610 
hyperplasia of, in anaemia, 206 
in leucocytosis, 827, 828 
in acute lymphoid leukaemia, 839 
in benzol poisoning, 802, 803, 804, 805 
in chronic lymphoid leukaemia, 834, 834 
in chronic myeloid leukaemia, 850, 851 
in pernicious anaemia, 815, 815, 816 
in secondary anaemia, 812, 813 
in smallpox, 767 
in typhoid fever, 610, 829 
of normal adult, 800 
infant, 801 
references to literature, 824 
regeneration of, 204 
after benzol poisoning, 803, 804, 804, 
805 
types of cells in, 802 
Bothriocephalus latus, 785 
as cause of pernicious anaemia, 81 
Botulism, 579 
references to literature, 580 
Bradycardia, 497 
Brain, abscesses in, 540 
in otitis media, 517 
character of repair in, 207 
compression of, from subdural haemor- 
rhage, 372 
cysts of, 967 
glioma of, 964, 965, 966, 967 
Brain, gumma of, 710, 731 
haemorrhage in, 364, 364 
indementia paralytica, 741, 741 
in lead poisoning, 401 
in malaria, 779, 781 
infarction of, 28, 35, 36, 37 
oedema of, 383 
phagocytes in, 36 
senile atrophy of, 64 
syphilis of, 710, 730, 731 
tuberculosis of, 683 
tumor of, experimental inoculation in 
animals, 1115 
ventricles of, 502 
Branchial cysts, 1089 
Breast,^adenocarcinoma of, 1070 
adenofibroma of, 1016, 1017, 1018 
adenoma of, 1016, 1019, 1020 
carcinoma of, 1064, 1065, 1068, 1069, 
1070 
colloid, 1065, 1071, 1072 
medullary, 1067 
mode of spread, 1065 
references to literature, 1077 
scirrhus, 1070, 1071 
types of, 1064 
cystic mastitis, 1070 
cysts of, 1018 
intracanalicular adenofibroma, 1019, 
1020 
mixed tumors of, 1093 
sarcoma of, 983 
Brill's disease, 689 
Bronchi, amyloid deposits in, 103 
carcinoma of, 1032 
chondroma of, 950 
diphtheria of, 575 
obstruction of, 430, 432 
syphilis of, 721 
Bronchiectasis, 360, 431, 432, 434 
aetiology of, 434 
references to literature, 435 
types of, 433 
Bronchiolitis, obliterative, in measles, 759 
Bronchitis, catarrhal, 228, 228 
tuberculous, 656 
Bronchopneumonia, 252, 255, 256 514, 
515, 596. See also Pneumonia, lobular. 
degeneration rectus abdominis in, 516 
emphysema in, 516 
gangrene of lung in, 257 
in measles, 513 
interstitial, 516 
mode of infection in, 255 INDEX 
1129 
Bronchopneumonia, relation to anaphy- 
lactic sensitization, 516 
septicaemia in, 516 
Brown atrophy of heart, 63, 64, 464 
induration of lung, 485 
Bruise, 369 
Buboes, 705 
scarlatinal, 761 
Bubonic plague, 585 
Bubonuli, 705 
Burns, 381 
from electricity, 391 
haemoglobinuria in, 381 
shock in, 381 
thrombosis of vessels in, 381 
Cachexia in cancer, 65 
Caisson disease, 369 
Calcification, chemistry of, 110 
experimental, 110, 193 
in normal bone formation, 918 
of blood-vessels, 108 
of cartilages in senility, 108 
of dead tissue, 109, 194 
of elastic tissue, 114 
of heart valves, 251 
of kidney, experimental, 109, 194 
of lymph-glands, 41 
of necrotic renal epithelium, 109 
of osteosarcoma, 986 
of psammonata, 108 
of thrombi, 249 
of thyroid, 880 
of trichinae in muscles, 108 
of tubercles, 648 
references to literature, 112 
relation of fats to, 110 
of iron to, 114 
role of soaps in, 110, 340 
Calcified tissue, ossification of, 111 
Calcium deficiency, effect on bone growth, 
106, 915 
on excitability of nerves, 107 
in osteomalacia, 106 
in osteoporosis, 106 
in rickets, 106 
in tetany, 107 
deposits, experimental, 111 
excess of, 108 
in blood, 110 
importance of, in bone growth, 916 
metabolism in rickets, 923 
disturbances of, 106 
references to literature, 112 
Calcium metabolism, relation of parathy- 
roids to, 890 
salts, metastasis of, 111 
Calculi in bladder, 444 
in gall-bladder, 408. See also Chole- 
lithiasis. 
in kidney, 452, 452 
in pancreas, 413 
laminated vesical, 445 
oxalate, 446, 446 
and urate, 448 
phosphatic, 447, 448 
uric acid, 445, 446, 447 
urinary, 444 
aetiology of, 445 
composition of, 445 
references to literature, 449 
Cancer, 1026. See also Tumors, Carci- 
noma, and Sarcoma. 
immunity to, in lower animals, 1114 
references to literature, 1121 
theories as to etiology of, 1115 
Capillaries, paralysis of, in shock, 143 
of heart valves, 245, 246 
Carbohydrate metabolism, 73, 103, 869 
disturbances of, 105 
in diabetes mellitus, 864, 869 
in myxoedema, 878 
influence of adrenals on, 871, 898 
of pancreas on, 870 
of thyroid on, 871 
references to literature, 105 
relation of sympathetic nervous sys- 
tem to, 871 
Carbolic acid poisoning, 398 
lesions of stomach in, 398 
Carbon monoxide poisoning, 397 
lesions of lenticular nuclei in, 397 
tetrachloride, poisoning from, 400 
Carbuncle, 261 
in anthrax, 590 
Carcinoma, 1025 
differentiation of, from adenoma, 1068 
from alveolar sarcoma, 981 
general characteristics, 1025 
infiltrative growth of, 1030 
metastasis of, 1030 
of bile-ducts, 1054 
of bladder, 1033 
of breasts, 1064, 1065, 1068, 1069, 1070 
of bronchi, 1032 
of gall-bladder, 1033, 1054, 1055 
of intestine, 1056, 1057 
of liver, primary, 1074, 1076 1130 
INDEX 
Carcinoma of lung, 1032 
of oesophagus, 1032 
of ovary, 1061, 1062, 1071 
of pancreas, 1056 
of prostate, 1057, 1059 
of rectum, 4^6, 1058, 1057 
of stomach, 1042, 1043, 1044, 1045, 1046, 
1048 
of thyroid, 1073 
of ureter, 1035 
types of, basal cell, 1016, 1026 
references to literature, 1041 
colloid, of breast, 1065, 1071, 1072 
of ovary, 1062 
of stomach, 1052, 1053, 1053, 1054 
cylindrical-cell, 1026 
flat or squamous-cell, 1026 
gland-cell, 1064 
medullary, 1064, 1067 
scirrhus, of breast, 1064, 1070, 1071 
of stomach, 1047, 1047 
Cardiac failure in shock, 379 
Cartilage, calcification of, in senility, 108 
in chondrodystrophia fcetalis, 925 
pigmentation of, 87 
regeneration of, 200 
urate deposits in, 90 
Casts, hyaline, 273 
Caustic alkalies, poisoning by, 398 
Cell division, amitotic, in regenerating 
epithelium, 196 
pathological, 196 
Cells, adventitial, 150 
clasmatocyte, 150 
death of, 58 
degeneration of, 60 
differentiation of, in embryo, 190 
embryonic, resemblance to cells of 
pathological new growths, 188 
endothelial, 192 
as phagocytes, 192 
in blood formation, 192 
lymphocyte, 148 
mast, 150 
membranes of, 50, 78 
mesenchymal, 190 
metabolism of, 48 
disturbances in, 60 
motile, 53 
necrosis of, 55 
specialization of, 191 
structure of, 48 
references to literature, 59 
variations in appearance of, 54 
Cells, wandering, 146 
mononuclear, 150, 153 
Centrioles, 49 
Centrosomes, 49 
Cephalin, 7 
Cerebellopontine tumors, 963 
Cerebral hemorrhage, artery of, 365 
Cerebrosides, 73, 74, 85 
function of, 79 
Cerebrospinal meningitis, epidemic, 554 
Cestode infections, 784 
references to literature, 788 
Cestodes, 784 
Chalicosis, 129 
Chancre, 702 
histology of, 703 
of Eustachian tube, 721 
of lip, 713 
of penis, 701, 702 
of tongue, 713 
of tonsil, 713 
production of, in animals, 703 
Chancroid, 704, 705 
Charcot artery, rupture of, 364 
"Charcot's joints;" 738, 739 
Chemotaxis, 144 
importance of, in inflammation, 145 
Chicken-pox, aetiology of, 757 
Chilblains, 18, 384 
Chloasma in pregnancy, 118 
in tuberculosis, 118 
Chlorine poisoning, 399 
Chloroform poisoning, 400 
liver in, 311, 313 
Chloroleucosarcoma, 840 
Chloroma, 840 
lymphoid, 840 
myeloid, 856 
references to literature, 863 
Chloromyelosarcoma, 856 
Chlorosis, 114 
defective absorption of iron in, 114 
syphilitic, 713 
Choked disc, 964 
Cholangitis, suppurative, 41®, 412 
Cholecystitis, 408 
acute and chronic, with gall-stones, 410 
phlegmonous, 408 
after typhoid fever, 611 
chronic, 411 
recurring, 409 
subacute and chronic, with gall-stones, 
407 
Cholelithiasis, 406 INDEX 
1131 
Cholelithiasis, references to literature, 413, 
427 
Cholera, Asiatic, 581 
blood changes in, 582 
bone-marrow in, 584 
intestinal contents in, 583 
lesions of organs in, 582 
oligaemia in, 3 
references to literature, 585 
rigor mortis in, 581 
sicca, 583 
nostras, 615 
Cholesteatoma, 1089 
Cholesterine, 73, 74 
esters, 75 
in arteriosclerosis, 338 
in kidney, 301 
in blood, increase during pregnancy, 80 
in gall-stones, 406 
metabolism, 76, 80 
Chondrioconts, 50 
Chondrodystrophia foetalis, 876, 925 
aetiology of, 925 
changes in cartilages, 925, 926 
hydrocephalus in, 926 
pelvis in, 926 
references to literature, 926 
Chondroma, 949, 951 
common sites of, 949 
of phalanx, 949, 950 
references to literature, 951 
Chondrosarcoma, 976 
Chordoma, 1094 
Chorionic epithelioma, 1077, 1078 
of testicle, 1081 
references to literature, 1080 
relation to hydatidiform, 1081 
Choroid, melanoma of, 992 
pigment of, 118 
Chromaffin system in status lymphaticus, 
848 
tissue in adrenals, 896 
tumors, 963 
Chromate poisoning, necrosis of kidney 
epithelium in, 223 
Chromatophores, 118 
origin of, 119 
relation to naevus cells, 990 
Chyle, fat in, 77 
Chylous ascites, 797 
Chyluria, 797 
Circulation, collateral, after obstruction of 
vena cava superior, 24 
disturbances of, in arteriosclerosis, 463 
Circulation, disturbances of, references to 
literature, 472 
mechanism of, 459 
obstruction of, in cardiac valvular dis- 
ease, 473 
mechanism of, 473 
terminal, diagram of, 26 
Cirrhosis of liver, 319. See also Liver, 
cirrhosis of. 
Clasmatocyte, 150 
Claudication, intermittent, 19 
Clonorchis sinensis, 790 
Clostridium botulinum, 580 
Clot, postmortem, 5, 5, 6 
Clotting of blood, 3, 6, 7 
appearance under ultramicroscope, 7 
Howell's theory, 7 
mechanism of, 4 
references to literature, 14 
Cloudy swelling, 92 
references to literature, 94 
Coagulation of blood, 3, 6, 7 
appearance under ultramicroscope, 7 
in haemophilia, 8 
in icterus, 8 
in pneumonia, 8 
in purpura, 8 
Coal pigment in lungs, 129 
Cod-liver oil in rickets, 106 
Cohnheim's theory of the origin of tumors, 
1118 
Cold, injuries from, 383 
gangrene produced by, 384 
mechanism of injury produced by, 
384 
reaction of tissues to, in vitro, 383 
references to literature, 385 
Colds, 384 
Colitis, amoebic, 771, 171, 772, 773 
diphtheritic, in mercury poisoning, 402 
ulcerative, in dysentery, 619 
Colles' law, 699 
Colloid carcinoma of breast, 1071, 1072 
of ovary, 1062 
of stomach, 1053 
droplets in kidney epithelium, 95, 278 
Comedones, 1010 
Compensation of heart, 480 
Complement, 169 
Concussion of brain, 370 
Conduction system of heart, 493 
Condyloma, 706, 1009 
relation to papilloma, 1008 
Congestion, chronic passive, 484 1132 
INDEX 
Congestion, chronic passive, of kidney, 
491 
of liver, 485, 486, 487 
of lungs, 484, 484 
of spleen, 490, 490 
Conjunctivitis in measles, 759 
Connective-tissue cells, division of, 198 
degeneration granules in, 51 
specialization of, 191 
growth of, in vitro, 51, 178, 179, 180 
metaplasia of, 193 
miotchondria in, 59 
Contrecoup, mechanism of, 370 
Coronary arteries, arteriosclerosis of, 466 
occlusion of, 31, 248 
experimental, 466 
Corpora amylacea in lung, 97 
in prostate, 97 
Corpus luteum, endogenous pigments of, 
125 
Coryza in congenital syphilis, 744 
Courvoisier's law, 127 
Cowper's glands, gonococcus infections of, 
559 
Cretinism, 878 
aetiology of, 879 
Cretins, 878 
Cyanide poisoning, 399 
Cylindroma, 1000, 1001 
of salivary glands, 1010 
Cystadenoma, 1006 
of ovary, 1009, 1020, 1021, 1022 
Cysticercus cellulosae, 784 
Cystinuria, 87 
Cystitis, 449 
diphtheritic, 560 
gonococcus, 560 
in typhoid fever, 613 
types of, 449 
Cystoma, 1006 
Cystosine, 88 
Cysts, atheromatous, 1089 
branchial, 1089 
dermoid, 1088, 1088, 1089, 1090 
references to literature, 1095 
echinococcus, 785, 785, 786, 787 
of breast, 1018 
of kidney, congenital, 1093 
in chronic nephritis, 290 
reference to literature, 1095 
of ovary, 1020 
teratomatous, 1087, 1089, 1090 
of parovarium, 1024 
relation of, to adenomata, 1010 
Cysts, traumatic epidermal, 193 
Cytolysins, 164 
Cytoplasm, 50 
Cytoryctes variola), 757, 764 
Death of body, 58 
of cells, 58 
tissue changes after, 59 
Debridement, 375 
Deciduoma, experimental, 1079 
malignant, 1078. See also Chorionic 
epithelioma. 
Decompensation, cardiac, 480, 482 
Defensive mechanism of body against 
infection, 160 
Degeneration, 61 
amyloid, 61 
fatty, 84 
hyaline, 61, 95 
of cells, 60 
parenchymatous, 51, 92, 92, 93 
Delirium tremens, 400 
Dementia paralytica, 739 
lesions of brain in, 741, 741 
of meninges in, 741, 742 
of spinal cord in, 743 
references to literature, 743 
trophic disturbances in, 740 
Dercum's disease, relation of hypophysis 
to, 910 
Dermatitis, gonococcus, 566 
Dermoid cyst, 1087, 1088 
of ovary, 1087, 1087 
references to literature, 1095 
Diabetes, gangrene in, 40, 40 
glycogen in, 105 
islands of Langerhans in, 869 
insipudus, relation of hypophysis to, 913 
lipaemia in, 872 
mellitus, 864 
acetone bodies in, 873 
acidosis in, 873 
action of insulin in, 873 
arteriosclerosis of peripheral vessels 
in, 343 
cause of death in, 865 
disturbance of carbohydrate metabo- 
lism in, 869 
of fat metabolism in, 81, 872 
of protein metabolism in, 872 
metabolism in, 105 
pancreas in, 865 
pathological anatomy of, 865 
references to literature, 105, 875 INDEX 
1133 
Diabetes, references, resume of, 874 
Digestive organs, tuberculosis of, 672 
Dilatation of heart, 480 
Diphtheria, 465, 573 
acute interstitial nephritis in, 285 
focal necrosis of liver in, 315 
heart-failure in, 465, 576 
nephritis in, 576 
obstruction of larynx in, 429 
of bronchus, 575 
of trachea, 574 
paralysis in, 577 
references to literature, 577 
sequela) of, 576 
Diplococcus intracellularis meningitidis, 
554 
Diseases, mental, metabolism in, 65 
Dispar, 797 
Ducrey's bacillus, 705 
Ductless glands, diseases of, 864 
tuberculosis of, 684 
Ductus arteriosus, closure of, 351 
Duke's fourth disease, aetiology of, 757 
Duodenum, ulcer of, 420 
Dust diseases, 129 
Dysentery, amoebic, 771, 771, 772, 773 
intestinal lesions in, 771 
mode of infection in, 771 
references to literature, 776 
antitoxin for, 620 
bacillary, 616 
agglutination tests in, 620 
arthritis in, 619 
intestinal lesions in, 617, 617, 618, 618, 
619 
lesions of nervous system in, 620 
mode of infection in, 616 
references to literature, 620 
Dyspnoea, cardiac, 483 
renal, 483 
Eburnation, 539 
Echinococcus cysts, 785, 785, 786, 787 
infection, 785 
serum diagnosis of, 788 
Eek's fistula, 32 
Eclampsia, 314 
changes in liver in, 223, 314, 314, 315 
necrosis of kidney epithelium in, 280 
Ehrlich's side-chain theory, 168 
Elastic tissue, calcification of, 109, 114 
of blood-vessels, 333 
in arteriosclerosis, 337 
iron incrustations of, 114 
Elastic tissue, regeneration of, 200 
Electricity, burns from, 391 
death from, 391 
injuries caused by, 390 
references to literature, 391 
Electrocardiographic tracings, 495, 496 
Elephantiasis, 797, 797 
Emboli, 19 
air, 21 
bacterial, 22, 249, 263 
cell, 22 
fat, 22, 375 
infected, 39 
lodgment of, 20 
parasitic, 22 
softening of, 39 
Embolism, 19 
references to literature, 42 
Embryo, development of, 1084 
differentiation of cells in, 190 
Emphysema, pulmonary, 435 
aetiology of, 436 
chronic substantive, 436 
circulatory disturbances in, 462 
hypertrophy of heart in, 437 
in bronchopneumonia, 516 
vicarious, 436 
references to literature, 438 
Empyema, 233, 234 
pneumococcus, 552 
Encephalitis, epidemic, 693 
experimental production, 694 
lesions of, 694 
mode of transmission, 694 
lethargica, 693 
syphilitic, 730 
End-arteries, 25 
Endarteritis, obliterative, 351, 354 
in senile ovary, 352 
uterus, 352, 352 
in tuberculosis, 664 
references to literature, 355 
Endocarditis, 243 
acute vegetative, 244, 247 
embolic nephritis in, 524 
bacteriology of, 245 
chronic, 250 
gonococcus, 247, 566 
character and localization of vege- 
tations, 521 
healing of, 249 
influenzal, 597 
meningococcus, 558 
mode of infection in, 245 INDEX 
1134 
Endocarditis, pneumococcus, 552 
character of vegetations, 521 
rheumatic, 243, 246, 246, 568, 570, 569 
Aschoff bodies in, 571, 570 
character and localization of vegeta- 
tions, 521 
staphylococcus, 536 
character and localization of vegeta- 
tions, 521 
streptococcus, 521 
character and localization of vegeta- 
tions, 246 
haemolyticus, 521, 522 
viridans, 249, 523, 524, 571 
character and localization of vege- 
tations, 521, 523, 525 
syphilitic, 727 
types of, 243, 247, 521 
typhoid, 613 
ulcerative, 247 
verrucous, 246, 247 
Endometritis, diphtheritic, 259 
puerperal, 257, 520 
complications of, 259 
Endostitis fibrosa in rickets, 923 
Endothelial cells in typhoid fever, 604 
Endothelioma. 998 
from blood-vessel endothelium, 1002 
from lymphatic endothelium, 1000 
of meninges, 1001, 1003 
of peritoneum, 1000 
of pleura, 1000 
references to literature, 1004 
Endothelium, covering of thrombi by, 223 
in blood formation, 192 
specificity of, 192 
Endotoxins, 161, 509 
Enostoses, 952 
Entamoeba coli, 770 
histolytica, 770, 771 
tetragena, 771 
Enteritis, diphtheritic, 263, 264, ^55 
in chronic nephritis, 305 
in dysentery, 617, 617 
Enteroptosis, 461 
Eosinophile leucocytes, 149 
Eosinophiles in lesions of Hodgkin's dis- 
ease, 859 
regeneration of, 205 
Eosinophilia, changes in blood-forming 
organs, 830 
diseases associated with, 827 
Ependymitis granularis in dementia para- 
lytica, 742 
Epidemic encephalitis, 693 
Epididymis, tuberculosis of, 670, 682, 681 
Epididymitis, gonococcus, 561 
Epithelioid cells in tubercles, 644 
origin of, 646 
Epithelioma, 1026. See also Carcinoma, 
squamous-cell. 
adamantine, 1015, 1015 
basal-cell, 1037, 1038, 1039 
references to literature, 1041 
resemblance of naevi to, 1039 
chorionic, 1077, 1079 
references to literature, 1080 
of larynx, 1032 
of lip, 1027 
of mouth, 1031 
of mucosae, 1031 
of oesophagus, 1032 
of penis, 1038, 1029 
of skin, 1027, 1030 
of tongue, 1031, 1031 
of tonsils, 1032 
of trachea, 1032 
of uterus, 1035, 1035, 1036 
references to literature, 1016 
relation of stroma to epithelium, 1005 
Epithelium, growth of, in vitro, 178, 180 
metaplasia of, 193 
regeneration of, in healing of wounds 
and ulcers, 195, 195, 196, 220 
Epulis, 984, 984 
Equilibrium among tissues, 179 
functional, 178 
Ergot poisoning, 42 
Erysipelas, 519 
Erythema infectiosum, aetiology of, 757 
Erythraemia, 810 
Eustachian tube, chancre of, 721 
mechanism of, 517 
Exanthem in leprosy, 629 
Exanthematic diseases, 757 
Exophthalmic goitre, 886 
Exostoses, 952, 953 
references to literature, 888 
Extra-systoles, experimental, 501 
origin of, 499 
tachycardia from, 500 
Extremities, gangrene of, 40, 354 
oedema of, 43 
Eye, glioma of, 968 
Eyelids, xanthoma of, 954 
Fallopian tubes, tuberculosis of, 682 
Fasting, effects of, 63 INDEX 
1135 
Fat-metabolism, 72 
action of insulin on, 874 
in diabetes, 872 
references to literature, 875 
Fat-necrosis, 416, 416 
Fat-phanerosis, 83 
Fat-tissue, abscess in, 221 
atrophy of, serous, 64 
embryonic, 76, 77 
regeneration of, 200 
Fats, 73 
absorption of, 76 
anisotropic, 85 
in kidney, 290 
distribution of, in body, 76 
emboli of, 22, 375 
in blood, 77 
in chyle, 77 
in lymph, 77 
in parenchymatous organs, in obesity, 
80 
"masked," 78 
in renal epithelium, 52 
of Bacillus tuberculosis, 80 
references to literature, 86 
relation of calcification to, 110 
source of, 75 
Fatty acids as ferment inhibitors, 79, 154 
degeneration, 84 
infiltration, 82, 85 
experimental, 85 
of arteries, 84 
of heart, 83, 464 
of kidney, 84 
of liver, 68, 80, 83 
of necrotic tissue, 85 
references to literature, 86 
Ferments, oxidizing, 118 
proteolytic in leucocytes, 154 
inhibition of, 79 
Fever, 133, 156 
in anaphylactic shock, 159 
in inflammation, 142 
in leprosy, 629 
mechanism of, 159 
metabolism in, 65, 157 
references to literature, 159 
relation to hypothalamus, 159 
to immunity, 158 
Fibrillation of heart, 447 
Fibrinogen, 7 
Fibroblasts, 178 
Fibroma, 943 
common sites of, 944 
Fibroma molluscum, 945 
oedematous, 943 
of kidney, 947 
of ovary, 947 
of skin, 945 
references to literature, 948 
types of, 943, 944 
Fibromyoma of uterus, 954, 955 
Fibrosarcoma, 979 
Filaria Bancroft!, 797 
references to literature, 798 
Fistulae, 223 
Fluids of body, disturbances of, 1 
relation to tissues, 1 
Fluorescent substances, 385 
toxic action of, 387 
Foreign body giant-cells, 150, 187 
bodies, reaction of tissues to, 214, 216 
Fracture of bones, 370 
comminuted, 370 
compound, 370 
greenstick, 370 
healed, 371 
Fragilitas ossium, 376 
Fragmentation of myocardium, 471, 4^1, 
472 
Frambcesia, 753 
Freezing, death from, 383 
gangrene produced by, 384 
of tissues, effects of, 384 
Friedlander bacillus, 541 
Frohlich's syndrome, 910, 910 
Functional equilibrium, 178, 181 
Furunculosis, 262, 532 
in typhoid fever, 614 
Gall-bladder, carcinoma of, 1033, 1054, 
1055 
references to literature, 1063 
relation to gall-stones, 1054 
inflammation of, 408. See also Chole- 
cystitis. 
obstruction of, 329 
by gall-stones, 126 
oedema of, 44 
Gall-stones, 406 (Fig. 201, facing p. 408) 
bacteria in, 408, 612 
cholesterine, 407 (Fig. 201, facing p. 410) 
mixed cholesterine and pigment (Fig. 
201, facing p. 410) 
obstruction of gall-ducts by, 126, 329, 
330, 409 
references to literature, 413, 427 1136 
INDEX 
Gall-stones, relation to carcinoma of gall- 
bladder, 1054 
varieties of, 406 (Fig. 201, facing p. 410) 
Ganglion-cells, endogenous pigmentation 
of, 125 
Ganglioneuroma, 963 
Gangrene, 40 
dry, 40, 41 
moist, 40 
of extremities, 40, 41, 354 
from exposure to cold, 384 
in diabetes, 41 
in ergot poisoning, 42 
of lungs, 257 
in lobar pneumonia, 552 
Garget, 513 
Gas bacillus infection of endometrium, 258 
Gastric ulcer, 419, 420 
Gastritis, phlegmonous, streptococcal, 518 
Gaucher's splenomegaly, 824 
General paresis, 739 
Genital organs, effect of x-rays on, 390 
syphilis of, 727 
references to literature, 729 
Genito-urinary tract, tuberculosis of, 679 
mode of infection in, 679 
references to literature, 683 
German measles, aetiology of, 757 
Giant-cells, foreign body, 150, 187 
origin of, 153 
in gummata, 709, 711 
in lesions of Hodgkin's disease, 859 
in pneumonic exudates, 256 
in tubercles, 644, 644, 648 
in tumors, 983 
Gigantism, 185, 905, 907, 908. See also 
Acromegaly. 
relation of hypophysis to, 905 
Glanders, 587 
of lung, 588, 588 
of nose, 587 
of skin, 588 
references to literature, 589 
Glioma, 964 
cyst formation in, 967 
ependymal, 968 
of brain, 964, 965, 966, 967 
with hemorrhage, 965 
of eye, 968 
references to literature, 968 
Gliosarcoma, 976 
Glossinae, transmission of trypanosomiasis 
by, 783 
Glottis, foreign bodies in, 429 
Glottis, oedema of, 439 
Glycogen, action of insulin on, 874 
in disturbances of carbohydrate metabo- 
lism, 869 
in liver cells, 53 
in tissues, 104 
in diabetes mellitus, 105, 865 
in tumors, 105 
staining of, 105 
Glycolysis, 869 
Glycosuria, 870. See also Diabetes mellitus. 
adrenaline, 898 
experimental, 865 
following pancreas extirpation, 870 
stimulation of sympathetic, 871 
piqure, 871 
in drug poisoning, 872 
in narcosis, 872 
in phloridzin poisoning, 872 
references to literature, 875 
Goitre, 879 
adenomatous, 880, 881, 881 
colloid, 879 
exophthalmic, 65, 883, 883, 884 
aetiology of, 886 
eye changes in, 884 
functional disturbances in, 883 
metabolism in, 884 
thymus in, 894 
thyroid in, 884, 885 
mechanical effects of, 882 
obstruction of trachea in, 429 
references to literature, 888 
Golgi's reticular apparatus, 50 
Gonococcus infection, 559 
of bladder, 560, 561 
of conjunctiva, 565 
of Cowper's glands, 559 
of endocardium, 247, 566 
character and localization of vege- 
tations, 521 
of epididymis, 561 
of Fallopian tubes, 561, 564 
sequelae of, 561 
of joints, 565 
of kidneys, 561 
of Littre's glands, 559 
of meninges, 566 
of myocardium, 566 
of pericardium, 566 
of peritoneum, 235 
of prostate, 561 
of seminal vesicles, 561 
of skin, 566 INDEX 
1137 
Gonococcus infection of ureters, 561 
of urethra, 559 
sequelae of, 561 
of vagina, 561 
in children, 561, 567 
references to literature, 567 
Gonorrhea, urethral stricture following, 
439, 560 
Gout, aetiology of, 89 
association of, with lead poisoning, 89 
metabolism in, 87 
nephritis in, 89 
references to literature, 91 
tophi in, 90, 91 
urate deposits in, 90, 90 
uric acid of blood in, 90 
Granulation tissue, 199, 214, 215, 219, 219, 
220, 222 
about foreign bodies, 216 
syphilitic, 711 
tuberculous, 649, 649 
Graves' disease, 883. See also Goitre, 
exophthalmic. 
Grawitz tumors, 994. See also Hyper- 
nephroma. 
Growth, abnormal, in tumors, 1099 
causes of, 175 
influence of internal secretions on, 184 
of nervous system on, 176 
mechanical influences in, 176 
of normal tissues, 1098 
stimulation of, 184, 184 
Guanine, 88 
Gumma, 697, 708, See also Syphilis, 
tertiary stage. 
differentiation, from tubercle, 709 
giant-cells in, 709, 711 
of brain, 710, 730, 731 
of heart, 727 
of kidney, 719 
of liver, 710, 715, 716, 717 
miliary, 709, 709, 710 
of lung, 721 
of lymph-glands, 712 
of meninges, 72, 732 
of pancreas, 718 
relation to diabetes, 719 
of periosteum, 710 
of pharynx, 714 
of salivary glands, 718 
of testicle, 708, 728, 728 
of tonsils, 714 
spirochete in, 709 
Gunshot wounds, 373 
Haemangioma, 969 
common sites of, 969 
of heart valves, 972, 973 
of intestine, 970, 971 
of liver, 971, 972 
of muscles, 970 
of skin, 969, 970 
plexiform, 969 
references to literature, 974 
telangiectatic, 969 
Hsematin, decomposition of, 112 
Haematoidin, 121 
Haematomyelia, 372 
Haematopoietic organs, 800. See also 
Blood-forming organs. 
Haematoporphyrin, 116 
in sulphonal poisoning, 121 
Haemochromatosis, 115, 116, 819 
iron pigments in, 116 
references to literature, 116 
Haemofuscin in haemochromatosis, 124 
Haemoglobin, composition of, 112 
excretion of, 121 
pigments derived from, 121 
Haemoglobinuria in burns, 381 
in malaria, 120 
Haemoglobinuric fever, 782 
Haemolymph nodes, 809 
references to literature, 825 
Haemolysins, 164 
Haemolysis, bacterial, 121 
due to streptococcus, 511 
poisons causing, 811 
postmortem, 121 
relation of lipoids to, 81 
Haemopericardium, 373 
Haemophilia, blood-clotting in, 8 
haemorrhage in, 376 
Haemorrhages in brain, 364, 364 
in chronic myeloid leukaemia, 849 
in scurvy, 928 
of lung, 34 
of meninges, 370 
petechial, 526 
subdural, with compression of brain, 372 
Haemorrhoids, 491 
Haemosiderin, 121 
in liver cells, 124 
in phagocytic cells, 122 
Haldane-Smith method of estimating 
quantity of blood in body, 2 
Halisteresis in rickets, 922 
Halteridium, 777 
Hamartomata, 972 INDEX 
1138 
Harrison's groove, 428 
Heart, abscesses in, 465 
Aschoff bodies in, 465, 466, 568 
brown atrophy of, 63, 64, 464 
compensation of, 480 
conduction bundle, diseases of, 497 
system of, diagram of, 494 
interruption of, 497 
pathology of, 493 
references to literature, 501 
decompensation of, 482 
dilatation of, 480, 483 
failure in shock, 379 
of compensation of, 482 
fatty infiltration of, 83, 83, 84, 464 
fibrillation of, 499 
gumma of, 727 
association with heart block, 727 
hypertrophy of, 250, 467, 480 
aetiology of, 481 
in chronic nephritis, 300 
in emphysema, 437 
in pulmonary obstruction, 462 
references to literature, 492 
in myeloid leukaemia, 855 
in smallpox, 767 
infarction of, 28, 29, 30, 466, 467 
injection of vessels of, 246 
mechanism of action of, 459 
syphilis of, 726 
references to literature, 727 
thrombi in, 10, 12, 467 
tumors of, myxoma, 987 
rhabdomyoma, 959 
valvular diseases of, 473, 493 
effects of, 473 
references to literature, 492 
Heart-beat, irregularity of, 497 
Heart-block, electrocardiographic tracing, 
499, 499 
"Heart-failure" cells, 123, 123, 484, 495 
Heart-muscle, 463 
endogenous pigments of, 125 
Heart-valves, calcification of, 251 
haemangioma of, 972, 973 
insufficiency and stenosis of, 250, 252, 
475, 477, 478, 479 
senile thickening of, 244 
types of vegetations on, caused by vari- 
ous organisms, 521 
vascular supply of, 246 
Heat, injuries from, 380 
references to literature, 383 
prostration, 382 
Heat stroke, 382 
Heine-Medin's disease, 690 
Heparin, 7 
Hepatization, 543 
Hepatolysins, 165 
Heredity, relation of, to tumors, 1112 
Hernia, 16, 37, 423 
femoral, 423 
incarcerated, 424 
inguinal, 423 
internal, 423 
strangulated, 17, 424 
umbilical, 423 
Heterotope impulses, 497 
arrhythmia from, 498 
His bundle, 493 
Histamine, 143, 167. See Beta-imidazol- 
ethylamine. 
in intestinal obstruction, 422 
production of, in tissues, 143, 144 
Hodgkin's disease, 857 
aetiology of, 862 
cause of death in, 858 
characteristics of lesions, 858, 858, 860 
differentiation of, from pseudoleu- 
kaemia, 843 
early stage, 859 
evidence as to infectious nature of, 862 
references to literature, 863 
relation of, to tumors, 1101 
Hookworm disease, 793, 795 
Howell's theory of blood-clotting, 7 
Hunger, 63 
Hutchinson's teeth, 752 
Hyaline casts, 303 
connective tissue, 97 
degeneration, 61 
of blood-vessels, 97, 98 
of muscle, 96, 516 
droplets in kidney epithelium, 95, 97, 278 
epithelial, 96 
thrombi, 98 
Hydatidiform mole, 1077 
Hydrocephalus, 502 
communicating, 505 
following meningitis, 503, 504, 558 
obstruction of aqueduct of Sylvius, 
505 
in chondrodystrophia fcetalis, 926 
in tuberculous meningitis, 683 
mechanism of retention of fluid in, 504 
obstructive, 505 
pneumoventriculography in, 503 
references to literature, 505 INDEX 
1139 
Hydrocephalus, syphilitic, 751 
Hydrochloric acid poisoning, 398 
Hydrogen-ion concentration, of blood, 170 
Hydronephrosis, 67, 451, 451, 454 
references to literature, 458 
Hydropericardium, 43 
Hydrosalpinx, 565, 564 
Hydrothorax, 43 
Hygromata, cystic, 974 
Hyperaemia, 16 
active, 16 
chronic passive, 16, 17, 484. See also 
Congestion, chronic passive. 
Hyperglycaemia following pancreas extir- 
pation, 870 
in diabetes mellitus, 865 
Hypernephroma, 994, 995, 996 
metastasis of, 995 
origin of cells in, 997 
references to literature, 997 
sites of origin, 994 
Hyperostosis, 952 
Hyperplasia, 70, 180 
relation of injury to, 182 
Hypertension, 304 
experimental production of, 305 
Hyperthyroidism, experimental, 887 
Hypertrophy, 70, 180 
of bladder, 443, 450 
of heart, 480 
of prostate, 441, 443, 443 
relation of injury to, 182 
Hypophyseal duct, tumors of, 1016 
Hypophysis, adenoma of, 1015 
cholesteatoma of, 1089 
disturbances in secretion of, relation to 
obesity, 81 
effect of tumors of, 913 
effects of extirpation, 904, 907 
hyperactivity, 905 
hypoactivity, 905, 910 
in pregnancy, 913 
influence of, on bone development, 904 
on sexual development, 905, 907, 911 
insufficiency, effect of, 911 
properties of extracts, 903 
relation of, to acromegaly, 905 
to adiposis dolorosa, 910, 912 
to bone formation, 917 
to diabetes insipidus, 913 
to lipomatosis, 910, 912 
secretion of, 903 
structure of, 903 
references to literature, 914 
Hypostasis, 17 
Hypoxanthine, 88 
Ichthyosis syphilitica, 747 
Icterus, 125. See also Jaundice. 
haemolytic, 820 
Ileus, paralytic, 425. See also Intestinal 
obstruction. 
Illuminating gas poisoning, 397 
Immunity, antitoxic, 167 
artificial, 163 
methods of producing, 164 
as response to injury, 133 
influence of temperature changes on, 162 
of lower animals to transplantable tu- 
mors, 1114 
passive, 164 
production of, 133 
racial, 162 
references to literature, 169 
relation of fever to, 158 
of lipoids to, 80 
to chemical poisons, 162 
Impetigo contagiosa, 532 
Implantation of tumors, 1105 
Inactivity, 66 
Infantile paralysis, 690 
Infarct, anaemic, 28, 29 
haemorrhagic, 29, 33, 39 
healing of, 40 
of brain, 28, 36, 35, 37 
of heart, 29, 31, 466, 467 
of intestine, 36, 38, 425 
of kidney, 28, 29, 30, 57 
of liver, 29, 32 
septic, 523 
of lung, 32 
with acute pleurisy, 231 
of spleen, 29, 31, 31 
type of necrosis of, 58 
uric acid, of kidney, 446 
Infarction, 27 
references to literature, 42 
Infection, amoebic, 770 
bacterial, 507, 510 
lowered resistance to, 508 
natural resistance to, 509, 509 
references to literature, 510 
diphtheritic, 573 
dysentery, 616 
gonococcus, 559 
influenza, 592 
meningococcus, 554 
mixed, 161 INDEX 
1140 
Infection, paratyphoid, 615 
pneumococcus, 541 
secondary, 509 
spirochaetal, 753 
staphylococcus, 531 
streptococcus, 511 
terminal, 509 
tetanus, 577 
typhoid, 599 
typhus, 688 
Inflammation, 134 
acute, 136 
axone reflex in, 143 
catarrhal, 227 
chronic, 142 
croupous, 227 
diphtheritic, 227, 263, 264, ^65, 574 
emigration of leucocytes in, 139 
experimental, 136, 650 
fever in, 142, 156 
fibrino-purulent, 229 
gangrenous, 227 
new growth of tissue in, 174 
pain in, 155 
phagocytosis in, 144, 153 
phlegmonous, 227 
protective, 175 
references to literature, 155 
role of nervous system in, 143 
serofibrinous, 229 
slowing of blood stream in, 144 
temperature changes in, 144 
tuberculous, acute, 650 
formation of tubercle nodules and. 
relation, 651 
vascular changes in, 136, 136, 143 
wandering cells in, 146 
Influenza, 592 
antrum infection in, 598 
bronchiectasis in, 434 
endocarditis in, 597 
immunity to, 593 
leukopenia in, 592 
meningitis in, 597 
pneumonia in, 594, 596, 597 
portal of entry in, 593 
references to literature, 598 
relation to tuberculosis, 598 
of Bacillus influenzae to, 593 
secondary infection in, 593 
sequelae, 594 
similarity to exanthemata, 592 
transmission of, 593 
types of pneumonia following, 594 
Influenza types produced by Friedlander 
bacillus, 596 
by Pfeiffer bacillus, 569 
by pneumococcus, 595 
by staphylococcus, 596 
by Streptococcus haemolyticus, 596 
Injuries as cause of tumors, 1109 
bacterial, 507. See also Infection and 
Inflammation. 
chemical, 160, 392 
references to literature, 404 
defensive mechanisms against, 133 
from cold, 383 
references to literature, 385 
from electricity, 385 
references to literature, 391 
from heat, 380 
references to literature, 383 
from light, 385 
references to literature, 391 
lowered resistance to, 375 
mechanical, 160, 367 
references to literature, 376 
reactions to, 132 
Insolation, 382 
Insulin in diabetes, 105, 873 
action of, 873 
on fat metabolism, glycogen, 874 
mechanism of action of, 874 
overdose of, effects, 873 
Internal secretions, derangements of, 65 
influence on growth, 185, 1112 
organs of, transplantation of, 210 
Interstitial pneumonia, 514, 515, 596, 597 
Intestinal obstruction, 421 
histamine in, 422 
mechanism of, 421 
post-operative, 425 
reference to literature, 427 
Intestine, abscess of, 263, 534 
actinomycosis of, 632 
amyloid infiltration of, 100 
infarction of, 28, 29, 36, 38, 425 
in amoebic dysentery, 771, 771, 772, 774 
in anthrax, 590 
in bacillary dysentery, 617, 617, 618, 619 
in status lymphaticus, 846 
in typhoid fever, 600, 600, 601, 602, 607 
intussusception of, 38, 38, 424 
oedema of, 44 
parasites in, 784 
perforation of, 375 
stenosis of, 426 
strangulation of, 17 INDEX 
1141 
Intestine, stricture of, 426 
syphilis of, 714 
tuberculosis of, 672, 673, 673, 674, 675, 
676 
tumors of, adenoma of, 1011, 1011, 1012 
carcinoma of, 1056, 1057 
haemangioma of, 970 
lymphosarcoma of, 844, 845 
papilloma of, 1008 
Intussusception, 38, 38, 424 
Involucrum in osteomyelitis, 538, 539 
Iodides, action of, in syphilis, 716 
Iodine in thyroid, 882 
poisoning, tubular nephritis in, 284 
Iron, absorption of, 112 
deficiency of, 113 
distribution in body, 112 
disturbances in metabolism of, 112 
in haemochromatosis, 116 
references to literature, 116 
excretion of, 112 
function of, in body, 113 
pigments, 116 
in haemochromatosis, 115, 116 
in pernicious anaemia, 815 
reaction for, in tissues, 485 
quantity of, in blood, 112 
relation to calcification, 114 
Irritation as cause of tumors, 1109, 1116 
Islands of Langerhans, lesions of, in dia- 
betes, 866, 867 
Jaundice, 125 
bile pigments in, 125, 128 
causes of, 126 
delayed blood clotting in, 7, 126 
experimental, 127 
haemolytic, 127, 820 
references to literature, 825 
in acute yellow atrophy, 127 
in cirrhosis of liver, 127, 314, 331 
in phosphorus poisoning, 402 
in pneumonia, 127 
obstructive, 126, 329, 409 
necrosis of liver in, 411 
of liver, 125, 128 
of newborn, 127 
Jaw, actinomycosis of, 631 
adamantine epithelioma of, 1015 
sarcoma of, 984, 984 
Joints, free bodies in, 939 
in acute rheumatism, 568, 569 
in arthritis deformans, 933 
staphylococcus infections of, 534 
Joints, syphilis of, 722 
tuberculosis of, 686 
references to literature, 687 
types of infections of, 932 
Kalkfanger, 110 
Karyolysis, 54, 56 
Karyorrhexis, 56, 57 
Keith's node, 493 
Keloids, 946 
Kephaline, 74 
Kerasin, 74 
Kidney, abscess of, 260, 261, 455 
amyloid infiltration of, 99, 101, 296, 2971 
298, 299 
anisotropic fats in, 290 
arteriosclerotic, 296 
atrophy of, 19, 70 
ascending infection of, 455, 535 
atrophy of, from obstruction of ureter, 
183 
calcification of, experimental, 193 
of necrotic epithelium in mercury 
poisoning, 108, 283 
calculi in, 444, 452, 45# 
changes in, in congenital syphilis, 748 
chromate poisoning of, 223 
chronic passive congestion of, 491 
cloudy swelling of, 93 
colloid droplets in epithelium of, 95, 
277, 278 
compensatory hypertrophy in, 291 
congenital cystic, 1092, 1093 
references to literature, 1095 
epithelium, regeneration of, 198 
specificity of function, 302 
fatty infiltration of, 53, 84 
functional insufficiency of, 302 
gummata of, 719 
haematogenous infection of, 535 
hyaline degeneration of, 294, 295 
droplets in epithelium of, 97 
hydronephrosis, 451, 451, 454 
infarction of, 28, 28, 29, 30, 56 
uric acid, 446 
inflammation of, 267. See also Neph- 
ritis. 
in congenital syphilis, 748 
in eclampsia, 280 
in mercury poisoning, 403 
in pernicious anaemia, 124 
in smallpox, 767 
in typhoid fever, 612 
obsolete scars in, 269 1142 
INDEX 
Kidney, parenchymatous degeneration of, 
92 
primary contracted (arteriosclerotic), 
287 
secondary contracted, 279, 280, 281 
syphilis of, 719 
congenital, 748 
transplantation of, 210 
tuberculosis of, 670, 682, 682 
tumors of, adenoma, 1012, 1013 
fibroma, 947 
hypernephroma, 995 
lipoma, 948 
lymphosarcoma, 843, 844 
mixed tumors, 1092 
references to literature, 1095 
uranium poisoning of, 223 
Koplik's spots in measles, 759 
Krukenberg tumor of ovary, 1073 
Kupffer cells, elaboration of bile pigments 
by, 127 
Langhans' cells of chorion, 1077 
Laryngismus stridulus, 428 
Laryngitis in leprosy, 626 
in typhoid fever, 613 
Larynx, epithelioma of, 1032 
obstruction of, 428 
oedema of, 428 
references to literature, 435 
syphilis of, 721 
tuberculosis of, 655, 670 
Lateral sinus, thrombosis of, 517 
Lead poisoning, 401 
anaemia in, 401 
brain in, 401 
chronic nephritis in, 401 
peripheral neuritis in, 81, 401 
Lecithin, 74 
as activator of cobra venom, 80 
Leiomyoma, 954, 958 
common sites of, 954 
malignant changes in, 957 
Lenticular nuclei, degeneration of, in illu- 
minating gas poisoning, 397 
Lenticulo-optic artery, 395 
Lenticulo-striate artery, 395 
Leontiasis ossea, 929 
Lepra cells, 625, 627 
Leprosy, 621 
anaesthetic, 621, 624 
atrophy of bones in, 628, 628 
bacillus, 625 
bronchitis in, 626 
Leprosy, exanthem in, 629 
febrile attacks in, 629 
granulation tissue in, 625 
laryngitis in, 626 
lesions of lungs, 626 
of organs in, 628 
neuritis in, 525, 628 
nodular, 621, 622, 623 
pharyngitis in, 626 
references to literature, 629 
skin lesions in, 623 
transmission of, 621 
tubercular, 623 
Leptospira icteroides, 755 
Leucine in urine, 87 
Leucocidins, 162 
Leucocytes, emigration of, in inflamma- 
tion, 139 
eosinophile, 149 
neutrophile, 149 
polymorphonuclear, regeneration of, 205 
Leucocytosis, 146, 205, 826 
blood-forming organs in, 827, 828 
conditions associated with, 827 
eosinophilic, 827 
in infections, 526 
lymphatic, 827 
neutrophilic, 827 
Leucoderma, 131 
syphilitic, 706, 720 
Leucopenia, 826 
in influenza, 592 
Leucoprotease, 154 
Leucosarcoma, 840, 841 
references to literature, 848 
relation to other sarcomata, 997 
Leukaemia, classification of, 832 
lymphoid, acute, 836, 837 
chronic, 833, 834, 835, 837, 838 
myeloblastic, 855 
myeloid, acute, 855 
chronic, 849, 850, 851, 852, 853, 854 
references to literature, 848 
Lichen scrophulosorum, 685 
Light, injuries from, 385 
references to literature, 391 
rays, nature of, 385 
Lip, chancre of, 713 
epithelioma of, 714 
Lipaemia in diabetes, 872 
Lipochromes, 64, 73, 75 
staining of, 125 
Lipoids, 73 
antitoxic action of, 79 INDEX 
1143 
Lipoids, function of, 78 
in adrenals, 897 
in cell membranes, 78 
in hypernephromata, 997 
in Wassermann reaction, 79 
in xanthomata, 954 
relation to haemolysis, 81 
to immunity, 80 
toxic action of, 80 
Lipoma, 948 
arborescens in joints, 939 
common sites of, 948 
multiple, 948 
of kidney, 948 
references to literature, 949 
Lipomatosis, relation of hypophysis to, 
910, 912 
Littre's glands, gonococcus infection of, 
559 
Liver, abscess of, 262, 263, 412 
amoebic, 773, 774, 775 
actinomycosis of, 632, 633 
action of insulin on, 874 
acute yellow atrophy of, 313 
jaundice in, 127 
amyloid infiltration of, 99, 102 
atrophy of, 63, 64 
autolysis of, 58 
blood formation of, in congenital syph- 
ilis, 746 
in osteosclerotic anaemia, 821, 822 
chronic passive congestion of, 485, 486, 
487 
types of, 489 
cirrhosis of, 225, 319 
alcoholic, 319 
atrophic, 319 
biliary, 319, 328, 330, 331 
circulatory disturbances in, 327, 328, 
329 
experimental, 319 
Hanot's, 320, 331 
hypertrophic biliary, 320, 331 
m Banti's disease, 822, 823 
jaundice in, 314 
Laennec's, 320 
nodular, 318, 319, 320, 320, 321, 322, 
323, 324, 325 
•obstructive biliary, 319, 328 
portal, 319 
references to literature, 332 
regeneration of, 198, 315, 322, 325 
syphilitic, 320 
tuberculous, 320 
Liver, cloudy swelling of, 93 
compression of, 68 
echinococcus cyst of, 787 
fatty infiltration of, 83 
from pressure, 68 
in obesity, 80 
focal necrosis of, 312 
in diphtheria, 315 
in eclampsia, 315, 316 
in paratyphoid, 615 
in typhoid fever, 312, 315, 610, 611, 
612 
glycogen in, 53 
gumma of, 709, 710, 715, 716, 717 
haemochromatosis of, 115, 116 
haemosiderin in, 124 
in acute yellow atrophy, 313, 318 
in chloroform poisoning, 313 
in chronic lymphoid leukemia, 834 
in eclampsia, 314, 314, 315 
in leprosy, 628 
in malaria, 120, 780, 781 
in myeloid leukaemia, 850, 853, 854 
in pernicious anaemia, 124, 819 
in smallpox, 767 
in typhoid fever, 312, 610 
infarction of, 29, 32 
septic, 523 
injury and repair of, 310, 315 
references to literature, 332 
jaundice of, 125, 127 
necrosis of, in acute yellow atrophy, 
in chronic passive congestion, 311, 
311, 311, 486, 487 
in chloroform poisoning, 311 
in eclampsia, 314, 315 
in obstructive jaundice, 412 
in phosphorus poisoning, 399 
in streptococcus peritonitis, 310 
mid-zonal, 224 
"nutmeg," 486 
rupture of, 369 
sarcoma of, in rats, 1111 
structure of, 308, 309 
syphilis of, 709, 710, 715, 716, 717, 718, 
719 
congenital, 745, 746 
tuberculosis of, miliary, 655, 673 
experimental production of, 647 
tumors of, adenoma, 1012 
carcinoma, primary, 1056, 1074, 1075 
references to literature, 1077 
secondary, 1049, 1050, 1051 
haemangioma, 971, 972 1144 
INDEX 
Liver, tumors of, melanoma, 118, 119, 993, 
994 
sarcoma, metastatic, 979 
Liver-cells, regeneration of, 326 
from bile-ducts, 197, 316, 317, 323 
Livor mortis, 15 
Lockjaw, 577. See also Tetanus. 
Locomotor ataxia, 733 
references to literature, 739 
Lordosis in chondrodystrophia foetalis, 926 
Ludwig's angina, 428, 513 
Luetin reaction, 699 
relation of anaphylaxis to, 167 
Lung, abscess of, 257, 263, 534, 536 
amoebic, 776 
actinomycosis of, 632 
anthracosis of, 129 
anthrax, 590 
atelectasis of, 430 
autolysis of, 58 
"brown induration" of, 485 
chronic passive congestion of, 123, 123, 
484, 484 
corpora amylacea in, 97 
emphysema of, 435 
circulatory disturbances in, 462 
gangrene of, 42, 257 
gummata in, 721 
haemorrhage in, 34 
in bubonic plague, 586, 587 
infarction of, 32, 33 
inflammation of, 542. See also Pneu- 
monia. 
oedema of, 45, 46 
from adrenaline, 46 
of children, tuberculosis in, 670, 671, 671 
pigmentation in, 129 
syphilis of, 721 
congenital, 744 
tuberculosis, of, 655 
acute, 643, 652, 660, 659,660, 661, 662, 
663 
chronic, 658, 663, 666 
healing, 657, 667 
in children, 670, 671, 671 
secondary infection in, 669 
tumors of, carcinoma, 1032 
metastatic, 1051, 1052, 1055 
sarcoma, metastatic, 979 
Lupus vulgaris, effect of light rays on, 
387 
Lycopodium spores as foreign body irri- 
tants, 186, 187 
Lymph, 1, 43 
Lymph, clotting of, 4 
fat in, 77 
Lymphangioma, 972 
common sites of, 972 
cystic, 973 
of tongue, 972 
references to literature, 974 
Lymphatic vessels, 1, 43 
endothelioma of, 1000 
obstruction of, 44 
in filariasis, 797 
regeneration of, 203 
Lymph-glands, amyloid infiltration of, 100 
anthracosis of, 129, 129 
calcification of, 41, 108 
carcinoma of, metastatic, 1062, 1073 
effects of x-rays on, 389 
gummata in, 712 
in acute poliomyelitis, 693 
in anthrax, 590 
in bubonic plague, 586 
in Hodgkin's disease, 858, 860 
in lymphoid leukaemia, acute, 836 
chronic, 833 
in myeloid leukaemia, 851 
in scarlet fever, 762 
in smallpox, 767 
in trypanosomiasis, 783 
in typhoid fever, 604, 605, 607, 608 
lymphosarcoma of, 843 
regeneration of, 204 
sarcoma of, 980 
syphilis of, 712 
tuberculosis of, 657, 678, 679, 678 
Lymphocytes, 148 
formation of, 149 
Lymphocytosis, 827 
changes in blood-forming organs in, 
830 
in syphilis, 713 
references to literature, 824 
Lymphogranulomatosis, 857. See also 
Hodgkin's disease. 
Lymphoid tissue, 809 
hyperplasia in exophthalmic goitre, 
886 
in status lymphaticus, 847, 847 
Lymphosarcoma, 843, 844, 
differentiation of, from related affections, 
845, 977 
references to literature, 848 
types of, 843 
Lymphosarcomatosis, 843 
Lysol poisoning, 398 INDEX 
1145 
Macroglossia, 972 
Macrophages in typhoid fever, 607 
Malaria, 777 
anaemia, in, 812 
haemoglobinuria in, 120, 782 
lesions of organs in, 120, 779, 780, 780, 
781 
parasites of, 777 
references to literature, 782 
Malformations, 1112 
Mammitis, infectious, 513 
in measles, 513 
relation to infected milk, 513 
Mast cells, 150 
in nasal polyps, 943, 946 
staining, 150 
Mastitis,cystic, 1070 
relation of, to carcinoma, 1067, 1069 
in typhoid fever, 614 
Measles, 757 
aetiology of, 758 
epidemics of, 513 
immunity to, 757 
Koplik spots in, 759 
lesions of organs in, 759 
lobular pneumonia in, 513, 759 
mammitis in, 513 
obliterative bronchiolitis in, 759 
otitis media in, 759 
racial susceptibility to, 162 
references to literature, 759 
skin lesions in, 759 
streptococcus infection in, 513, 758 
susceptibility to tuberuclosis in, 758 
Megaloblasts, 804 
Megalokaryocytes, 803 
in pneumonic lung, 548 
regeneration of, 804, 806 
Melanins, 117 
Melanoblasts, 118 
Melanoma, 991 
metastasis of, 993, 993 
origin of cells in, 992 
references to literature, 994 
sites of origin, 992 
Melanosarcoma, 993. See also Melanoma. 
Meninges, cholesteatoma of, 1089 
endothelioma of, 1001, 1003 
haemorrhage of, 370 
in dementia paralytica, 741 
Meningitis, epidemic cerebrospinal, 554, 
556, 557 
hydrocephalus in, 558, 503, 504 
exudate in, 557 
Meningitis, gonococcus, 566 
haemorrhagic, in anthrax, 591 
influenzal, 597 
lesions in organs, 558 
paratyphoid, 615 
pneumococcus, 553 
staphylococcus, 541 
syphilitic, 351, 730, 730, 733 
tuberculous, 684, 683 
typhoid, 614 
Meningococcus as cause of endocarditis, 
558 
carriers, 555 
infections with, 554 
references to literature, 559 
portals of entry, 555 
types of, 554 
Mercury poisoning, 402 
colitis and enteritis in, 263, 403 
necrosis of kidney epithelium in, 108, 
109, 403 
Metabolism in cells, 48 
disturbances of, 60 
in diabetes mellitus, 81, 105, 864, 869 
in disturbances of internal secretion, 65 
in fever, 65, 157 
in gout, 87 
in mental diseases, 65 
in tumors, 65 
of calcium, 106 
of carbohydrates, 103, 869 
disturbances of, 104, 869 
of cholesterine, 76, 80 
of fat, action of insulin on, 874 
disturbances of, 72 
of iron, 112 
of pigments, 117 
of proteins, disturbances of, 87 
of purines, disturbances of, 87 
Metaplasia, connective tissue, 193, 198 
epithelial, 193 
in bladder, 193 
in bronchus, 193 
in gall-bladder, 193 
myeloid, 831 
references to literature, 824 
Metastasis of calcium salts, 111 
of tumors, 1030, 1105 
Metathrombin, 7 
Micrococci, pyogenic, 510 
neof ormans, 1111 
Middle cerebral artery, 395 
ear, infections of, 517 
complications of, 517 1146 
INDEX 
Middle ear, infections of, mechanism of, 
517 
organisms concerned in, 517 
Milk leg, 45 
Mitochondria, 49, 50 
in connective tissue, 51 
in parenchymatous degeneration, 94 
references to literature, 59 
relation to fat metabolism, 78 
Mitosis, atypical, in tumors, 975 
Mitral insufficiency, 477, 478 
stenosis, 250, 479, 479 
Mixed tumors, 1090 
of breast, 1093 
of kidney, 1092 
of salivary glands, 1090, 1091 
of testicle, 1093 
references to literature, 1095 
Moles, pigmented, 989. See also Naevi. 
papillary, 1008 
Moller-Barlow's disease, 927 
Monckeberg type of arteriosclerosis, 343 
Monoblast, 150 
Monocyte, 148, 150 
Mononuclear wandering cells, 148, 153 
Morphine, increased tolerance of, 162 
poisoning, oedema in, 45 
Mouth, epithelioma of, 1031 
lesions of, in smallpox, 766 
Mucosae, epitheliomata of, 1031 
healing of lesions in, 223 
Mucous patches, 706 
Muscles, abscesses of, 533 
atrophy of, 63, 66, 67 
disuse, 63 
senile, 63 
bone formation in, after injury, 952 
haemangioma of, 970 
hyaline changes in, 96 
regeneration of, 202 
trichinae in, 791, 791, 792 
tuberculosis of, 655 
Zenker degeneration of, in typhoid 
fever, 613 
Myasthenia gravis, 894 
thymus enlargement in, 894 
Myeline bodies, 85 
Myelins, 36 
Myelitis, compression, 372 
Myeloblasts, 149 
Myelocytes, 140 
Myeloid transformation of tissues, 147 
Myeloma, albumosuria in, 841 
lymphoid, 841, 84® 
Myeloma, myeloid, 856, 857 
plasma cell, 841 
references to literature, 848, 863 
relation to sarcoma, 997 
types of, 841 
Myocarditis, 464 
chronic fibrous, 465, 469, 470 
experimental, 470 
Myocardium, abscesses in, 465 
Aschoff bodies in, 568, 571 
fragmentation of, 471, 471, 47® 
inflammation of, 464. See also Myo- 
carditis. 
scars in, 468, 470 
toxic injuries of, 464 
Myoma, 954 
leio-, 957 
malignant, 958 
of bladder, 957 
of intestine, 957 
of skin, 957 
of stomach, 957 
of uterus, 954 
of vagina, 957 
references to literature, 958, 960 
rhabdo-, 959, 959 
Myosarcoma, 976 
Myositis, acute, 141 
ossificans, metaplasia in, 194 
progressive, 952 
Myxochondroma, 987 
Myxcedema, 185, 876 
disturbances of development in, 876 
metabolism in, 877 
Myxoma, 987 
references to literature, 988 
sites of origin, 987 
Myxo-osteoma, 987 
N®vr, 989, 1032 
non-pigmented, 991, 991 
origin of cells in, 989, 992 
pigmented, 991 
references to literature, 994 
resemblance to basal-cell epithelioma, 
1040 
vascular, 969. See also Haemangioma. 
Narcosis, glycosuria in, 871 
Overton's theory of, 78 
Nasal septum, infection of, in leprosy, 624 
Necator Americanus, 793 
Necrobiosis, 55 
Necrosis, 55 
coagulative, 28 INDEX 
1147 
Necrosis, focal, of bone-marrow, 610 
of liver, 312, 610, 611, 612, 616 
of fat, 417 
Necrotic tissue, fatty infiltration of, 
85 
Nematode infections, 796 
references to literature, 798 
Nephritis, 267 
aetiology of, 267 
amyloid in, 298 
blood-pressure in, 304 
classification of, 270 
enteritis in, 305 
experimental, 267 
hypertrophy of heart in, 300, 305 
in diphtheria, 576 
in gout, 89 
in lead-poisoning, 401 
in pregnancy, 280 
in scarlet fever, 762 
in typhoid fever, 612 
literature on, recent, 306 
oedema in, 304 
pericarditis in, 305 
references to literature, 305 
relation of anatomical changes to func- 
tional disturbances, 268 
trench, 307 
types of, 269 
acute diffuse, 279, 279 
glomerulo-, 272, 272 
interstitial, 271, 284, 285, 286 
suppurative, 286, 455, 534, 535 
mode of infection in, 417, 535 
tubular, 280, 282 
.chronic arteriosclerotic, 269, 286, 
287, 288, 290, 291, 292, 293, 294, 
296 
■ diffuse, 281 
glomerulo-, 272 
interstitial, 226, 271, 284 
parenchymatous, 271 
primary contracted kidney, 287 
secondary contracted kidney, 279, 
280, 281 
tubular, 280 
• combined inflammatory and arterio- 
sclerotic, 296 
■ embolic, 249 
in acute endocarditis, 524 
glomerulo-, 272 
acute, 272, 272 
chronic, 272 
diffuse, 280 
Nephritis, types of, glomerulo-, intracapil- 
lary, 273, 273 
subacute, interstitial, 284, 284 
types of, tuberculous, 280, 282 
Nephrolithiasis, 452 
Nephrolysins, 165 
Nephrosis, 306 
Nerves, degeneration of, 82 
in alcohol poisoning, 81 
in arsenic poisoning, 81 
in lead poisoning, 81 
effect of section of, 67 
excitability of, in calcium deficiency, 107 
injuries of, 373 
transplantation of, 210 
tumors of, 962 
Nervous system, embryological relations 
of elements of, 961 
influence on growth, 176 
in acute poliomyelitis, 691 
syphilis of, 730 
congenital, 752 
references to literature, 733 
tuberculosis of, 683 
tumors arising in, 961 
references to literature, 968 
tissue, regeneration of, 206 
Neurinoma, 963 
Neuritis in beri-beri, 81 
in lead poisoning, 401 
in leprosy, 627, 628 
in typhoid fever, 614 
Neuroblastoma, 962 
Neurocytoma, 962 
Neuro-epithelioma, 968 
Neurofibroma, 962 
Neurofibromatosis, multiple, 946, 947 
Neuroma, amputation, 962 
Neutrality of solutions, preservation of, 170 
Neutrophile leucocytes, 149 
Nitric acid poisoning, oedema of lungs in, 
398 
Noma, 42 
Nomotope impulses, 497 
Normoblasts, 804 
Nose, glanders of, 587, 588 
obstruction of, 428 
by adenoids, 428 
by tumors, 428 
polyps of, 943, 946 
syphilis of, 720 
congenital, 751 
Nucleic acid, 88 
Nucleus, 49 INDEX 
1148 
"Nutmeg" liver, 486, 486. See also Liver, 
chronic passive congestion. 
Nutrition of cells, disturbances of, 60 
Obesity, 80 
Obliterative endarteritis, 354 
Obstruction of alimentary tract, 421 
references to literature, 427 
of circulatory system, 473 
references to literature, 492 
of respiratory tract, 428 
references to literature, 438 
of urinary tract, 444, 450 
references to literature, 444 
Ochronosis, 120 
(Edema, 43 
from alterations in nervous activity, 45 
from cardiac failure, 478 
from lymphatic obstruction, 44 
from renal disease, 46, 304 
from venous obstruction, 44 
in cachexias, 45 
inflammatory, 140, 519 
of extremities, 43 
of gall-bladder, 44 
of glottis, 429 
of intestine, 44 
of lungs, 44, 45, 46 
caused by adrenaline, 46 
nitric acid fumes, 399 
references to literature, 47 
salt retention in, 46, 47 
theories of, 44 
(Esophagus, carcinoma of, 1032 
diverticulum of, 418 
epithelioma of, 1032 
obstruction of, 63, 418 
syphilis of, 714 
tuberculosis of, 672 
varices of, 329 
Oligaemia, 2, 3 
from haemorrhage, 3 
from loss of fluid, 3 
Ophthalmia, gonococcus, 565 
neonatorum, 565 
Opisthorchis felineus, 790 
sinensis, 790 
Opisthotonos in tetanus, 577 
Opsonins, 164 
Orchitis in typhoid fever, 614 
syphilitic, 728, 728 
Organization of inflammatory exudates, 
217, 217 
of thrombi, 218, 225 
Organs, interrelation of, 180 
parenchymatous, injuries of, 223 
transplantation of, 209 
Ornithin, oxidation of, 118 
Ossification, effect of calcium deficiency 
on, 106 
normal, 106, 107 
of calcified tissue, 111 
Osteitis deformans, 929 
Osteoarthropathy, pulmonary, 185, 185 r 
913 
Osteoblasts in bone repair, 201 
Osteochondritis, syphilitic, 748, 748, 749r 
750, 751 
Osteochondrosarcoma, 985 
Osteoclasts, 69 
function of, 106, 107 
Osteogenesis imperfecta, 929 
references to literature, 929 
Osteoid tissue in rickets, 921 
Osteoma, 951, 952, 953 
references to literature, 954 
Osteomalacia, 924 
deficiency of calcium in, 106 
deformities of bones in, 924 
references to literature, 925 
Osteomyelitis in typhoid fever, 613 
involucrum in, 538 
sequestrum in, 538 
staphylococcus, 537 
variolosa, 767 
Osteoperiostitis, syphilitic, 726 
Osteophytes, 539 
in syphilis, 724, 725 
Osteoporosis from calcium deficiency, 106 
senile, 63, 107, 916 
Osteopsathyrosis, 376 
Osteosarcoma, 976, 976, 985, 985, 986 
calcification of, 109 
Otitis media, complications of, 517 
in measles, 759 
mechanism of occurrence, 517 
organisms producing, 517 
pneumococcus, 553 
streptococcus, 517 
Ovary, cysts of, 1020 
dermoid, 1087, 1087 
effects of z-rays on, 390 
extirpation of, 65 
tuberculosis of, 682 
tumors of, carcinoma, 1062, 1062, 1071 
cystadenoma, 1020, 1021, 1022, 1023 
fibroma, 947 
Krukenberg tumor, 1073 INDEX 
1149 
Ovary, papilloma of, 1005, 1009, 1023 
references to literature, 1077 
tumors of, sarcoma, 977 
teratoma, 1083, 1089, 1090 
Overton's theory of anaesthesia, 50, 78 
Oxalate calculi, 446 
Oxydase reaction, 806 
references to literature, 824 
Oxyuris vermicularis, 796 
Pachymeningitis, chronic haemorrhagic, 
122 
in chronic alcoholism, 122 
in syphilis, 122, 741, 741 
staphylococcus, 540 
Paget's disease of bones, 929 
aetiology of, 930 
bone changes in, 929, 930 
references to literature, 931 
of nipple, 1064 
Palsy, shaking, 694 
Panaritium, 532 
Pancreas, abscesses in, 417 
atrophy of, following duct ligation, 867, 
867, 868 
calculi in ducts of, 413 
carcinoma of, 1056 
references to literature, 1063 
disturbances of internal secretion of, 864 
effect of extirpation of, 865, 870 
extract of, 105 
ferment produced by enabling muscles 
to consume sugar, 870 
gumma of, 718 
haemorrhage in, 417 
in diabetes mellitus, 865 
inflammation of, 415. See also Pan- 
creatitis. 
islands of Langerhans, granules in cells 
of, 51 
syphilis of, 718 
congenital, 747, 747 
tuberculosis of, 673 
Pancreatic ducts, obstruction of, 67, 413 
Pancreatitis, acute, 415 
haemorrhagic, 409, 415 
aetiology of, 394 
experimental, 414 
references to literature, 417 
chronic, 414 
Papilloma, 1006 
common sites of, 1007 
of bladder, 1009, 1033, 1034 
of intestine, 1008 
Papilloma of ovary, 1005, 1009, 1023 
of skin, 1007, 1007 
of stomach, 1008 
Paraganglioma, 963 
Paragonimus Westermanni, 789 
Paralysis in acute poliomyelitis, 691 
in diphtheria, 577 
Parasites, animal, adaptation of, 769 
as emboli, 22 
diseases caused by, 768 
intestinal, 784 
relation to host, 768 
types of injury produced by, 160 
Parasitic theory as to origin of tumors, 
1116 
Parasyphilitic diseases, 697, 730, 733 
Parathyroid glands, disturbances of func- 
tion of, 889 
effect of extirpation of, 889, 917 
physiology of, 889 
references to literature, 891 
relation to bone formation, 917 
to calcium metabolism, 890 
to tetany, 107 
transplantation of, 210 
Paratyphoid infections, 615 
focal necrosis of liver in, 616 
intestional lesions in, 616 
meningitis, 615 
references to literature, 616 
Parenchymatous degeneration, 93 
mitochondria in, 94 
of organs in infections, 526 
Paronychia, 532 
Parotid gland, mixed tumors of, 1090, 
1091 
Parotitis in typhoid fever, 614 
Parovarium, cysts of, 1024 
Pediculus vestimentorum in transmission 
of typhus fever, 689 
Penis, chancre of, 700, 701, 702 
epithelioma of, 1028, 1029 
papilloma of, 1007, 1007 
Peptone poisoning, relation to anaphylaxis, 
166 
Pericardial effusion, 230, 461 
Pericarditis, 229 
acute fibrinous, 230, 230, 232 
in chronic nephritis, 229 
chronic adhesive, 224, 224, 346 
in rheumatism, 570 
fibrino-purulent, 230 
gonococcus, 566 
rheumatic, 570 1150 
INDEX 
Pericarditis, sero-fibrinous, 230 
Pericardium, abscesses of, 533 
inflammation of, 229. See also Peri- 
carditis. 
synechia in, 223 
Perihepatitis, aetiology of, 677 
Periosteum, gumma of, 710 
sarcoma of, 984 
Periostitis, chronic, 538, 539 
syphilitic, 722, 724 
excessive bone formation in, 953 
Perisplenitis, aetiology of, 677 
Perithelioma, 1004 
Peritoneum, endothelioma of, 1000 
pseudomyxoma of, 1024 
Peritonitis, gonococcus, 235 
haematogenous, 235 
mode of infection, 234 
pneumococcus, 235, 553 
tuberculous, 674, 677 
Perl's reaction for iron pigment, 485 
Phagocytes, 53, 122 
endothelial, 192 
in removal of dead tissue, 58 
Phagocytosis, 144, 164 
as defensive mechanism, 163 
effect of fever on, 158 
importance in inflammation, .45, 153 
in typhoid fever, 604, 609, 609 
Pharyngitis in leprosy, 626 
in scarlet fever, 761 
in typhoid fever, 613 
streptococcal, 520 
Pharynx, gumma of, 714 
Phimosis, 439 
Phlebolith, 109 
Phlegmasia alba dolens in typhoid fever, 
613 
Phlegmons, 263 
Phloridzin poisoning, glycosuria in, 872 
Phosphatic calculi, 448 
Phosphatides, 73, 74, 85 
function of, 79 
Phosphorus poisoning, 402 
acute, 402 
chronic, 402 
relation to rickets, 923 
Phrenosins, 74 
as neutralizer of tetanus toxin, 79 
Phthisis florida, 662 
Pigeon breast, 428 
Pigment metabolism, 117 
Pigmentation of cartilage, 87 
of lung in chronic passive congestion, 123 
Pigmentation of melanotic tumors, 119 
of organs in malaria, 120, 780 
of skin, 117 
from sunlight, 386 
in Addison's disease, 119, 900 
Pigments, bile, in jaundice, 125 
coal, 129 
elaboration of, by Kupffer cells, 127 
endogenous, 117, 125 
exogenous, 117, 129 
haematogenous, 120 
iron-containing, 116 
lipochrome, 64 
normal, deficiency of, 130 
of adrenals, 125 
of choroid, 118 
of corpus luteum, 125 
of heart muscle, 125 
of malarial parasites, 125 
of retina, 118 
of testicle, 125 
references to literature, 131 
Piqure, 871 
Placenta in typhoid fever, 614 
syphilis of, 743 
Placentoma, experimental, 1080 
Plague, bubonic, 585 
lymph-glands in, 586 
pneumonic, 587 
lungs in, 586, 587 
references to literature, 587 
Plasma cells, 153, 697 
Plasmodium falciparum, 777 
malaria), 777 
vivax, 777 
Plasmosomes, 51 
Plethora, 2 
Pleura, endothelioma of, 1000 
inflammation of, 231. See also Pleurisy. 
lymphatics of, 229 
Pleural effusion, compression of lung by, 232 
Pleurisy, 231 
acute, in pneumonia, 231 
with infarction of lung, 33 
fibrino-purulent, 233, 234 
organization of, 217 
Pneumococcus, importance of capsule 
formation, 162 
infections, 541 
types of, 541 
empyema, 552 
endocarditis, 552 
character and organization of 
vegetations, 521 INDEX 
1151 
Pneumococcus infections, types of, men- 
ingitis, 553 
otitis media, 553 
peritonitis, 235, 5S3 
portals of entry in, 553 
references to literature, 553 
septicaemia, 552 
Pneumonia alba in congenital syphilis, 
744, 745 
aspiration, 254 
caseous, 659 
in lungs of children, 671 
complications of, 552 
crisis in, 547 
ether, 543 
experimental production of, 543 
following influenza, 594 
gelatinous, 659 
indurative, in chronic pulmonary tuber- 
culosis, 663 
in influenza, 593 
hypostatic, 17 
influenzal, 593, 596 
in measles, 514 
interstitial, 514, 515, 516, 596, 597 
jaundice in, 127 
lobar, 542, 544, 545, 546, 548 
abscesses in, 549 
gangrene in, 552 
organization in, 550, 550, 551 
pneumococcal, in influenza, 595 
references to literature, 553 
resolution in, 548 
stages of, 543, 544, 545, 546, 548 
lobular, 252, 254, 514, 515, 594 
bacteriology of, 253 
complication of, 257 
degeneration rectus abdominis in, 516 
emphysema in, 516 
giant-cells in, 256 
in glanders, 588 
in measles, 759, 514 
in scarlet fever, 761 
references to literature, 257 
resolution of, 256 
rapid clotting of blood in, 7 
retention of chlorides in, 157 
septicaemia in, 516 
staphylococcus, 537 
streptococcal, 594 
tuberculous, 660, 660, 661, 662, 663 
fatty cells in, 659 
Pneumonokoniosis, 129 
Pneumoventriculography, 503 
Poikilocytosis, 814 
Poisoning, alcohol, 81, 400 
ammonia, 399 
arsenic, 81 
benzol, anaemia in, 206, 804 
bone-marrow changes, 802, 803, 804, 804, 
805 
carbolic acid, 398 
carbon monoxide, 398 
tetrachloride, 400 
caustic alkalis, 398 
chlorine, 399 
chloroform, 400 
liver in, 313 
chromate, necrosis of kidney epithelium 
in, 223 
cobra venom, 80 
cyanide, 399 
oxidation in, 161 
ergot, 42 
hydrochloric acid, 398 
illuminating gas, 398 
lesions in lenticular nuclei, 397, 397 
lead, 81, 401 
anaemia in, 401 
association with gout, 89 
lysol, 398 
mercury, 402 
calcification of kidneys in, 108, 109, 
283, 403 
colitis in, 264, 403 
morphine, oedema in, 45 
nitric acid, 398 
phloridzin, glycosuria in, 872 
phosphorus, 402 
prussic acid, 399 
silver, 130 
sulphonal, blood changes in, 121 
haematoporphyrin in, 121 
sulphuric acid, 398 
uranium, necrosis of kidney epithelium 
in, 223 
Poisons, absorption of, 395 
antagonistic action of, 394 
corrosive, 397 
elimination of, 393 
general effects of, 395 
haemolytic, 811 
immunity to, 394 
increased tolerance of, 393 
lipoid activation of, 80 
mechanism of resistance to, 394 
nature of, 392 
putrefactive, 395 1152 
INDEX 
Poisons, selective action of, 396 
varying effects of, 392 
Polioencephalitis, 693 
Poliomyelitis, acute, 690, 692 
aetiology of, 690 
atrophy of muscles in, 691 
experimental, 691 
lesions of nervous system in, 691 
lesions in organs, 693 
organism of, 690 
paralysis in, 691 
portals of entry in, 691 
references to literature, 693 
relation of streptococcus to, 690 
to epidemic encephalitis, 694 
transmission of, 691 
Polyarthritis, chronic progressive, 906. 
See also Arthritis deformans. 
Polyblasts, 150 
Polycythaemia from loss of fluid, 809 
references to literature, 824 
rubra, 810 
Polydipsia in diabetes, 864 
Polyphagia in diabetes, 864 
Polyps, adenomatous, of intestine, 1012, 
1012 
of nose, 943, 946 
Pores of Cohn, 547 
Portal vein, occlusion of, 32 
Portals of entry for bacteria, 160, 508 
Postmortem changes, 15 
haemolysis, 121 
redistribution of blood, 15 
Precipitation of tricalcium phosphate, 111 
Precipitins, 165, 169 
Pregnancy, changes in hypophysis in, 913 
acute nephritis in, 280 
chloasma in, 118 
Pressure, effects of, 68 
on skin, 68 
on tissues, 368 
Pro-antithrombin, 7 
Profeta's law, 699 
Progressive paralysis of insane, 739 
Prostate, carcinoma of, 1057, 1059 
corpora amylacea in, 97, 442 
hypertrophy of, 441, 442, 443 
aetiology, 443 
obstruction of urethra from enlarge- 
ment of, 440 
references to literature, 444 
tuberculosis of, 682 
Prostatitis, gonococcus, 561 
Protein metabolism, disturbances of, 87 
Protein metabolism in diabetes, 872 
in exophthalmic goitre, 884 
Proteosoma, 777 
Prothrombin, 7 
Protozoa, pathogenic, classification of, 
770 
Prussic acid poisoning, 399 
Psammoma, calcification in, 108 
Pseudoleukaemia, 843 
references to literature, 848 
Pseudomelanosis, postmortem, 125 
Pseudomyxoma peritonei, 1024 
Puerperal endometritis, 257, 258, 520 
infections, 257 
Pulmonary valve, insufficiency of, 480 
stenosis of, 480 
Pulse tracings, 495 
Pulsus bigeminus, tracing of, 499, 500 
irregularis perpetuus, 499 
Purine bodies, chemistry of, 87 
metabolism, disturbances of, 87 
Purpura, prolonged bleeding time in, 8 
Pyaemia, 260, 510 
complicating puerperal infection, 260 
Pyelitis, 455 
Pyelonephritis, 455, 456, 457, 535 
gonococcus, 561 
references to literature, 458 
Pyknosis, 55, 56 
Pylephlebitis, suppurative, 242, 243 
Pyogenic micrococci, 510 
Pyorrhoea alveolaris, relation of amoebae 
to, 776 
Pyosalpinx, gonococcus, 564, 564 
Rachitis, 918 
Radium, effects of, on tissues, 388 
Ranula, 1010 
Rat-bite fever, 755 
Raynaud's disease, 18 
Rectum, carcinoma of, 426, 1057, 1058 
references to literature, 1063 
syphilis of, 714, 715 
Rectus abdominis muscle, hyaline de- 
generation of, 516 
Recurrence of tumors, 1109 
Reflex, axone, in vascular widening in in- 
flammation, 143 
Regeneration, 174, 194 
of blood, 204 
after haemorrhage, 205 
in anaemia, 206 
of blood-vessels, 203 
of bone, 200 INDEX 
1153 
Regeneration of bone-marrow, 204 
of cartilage, 200 
of eosinophiles, 205 
of fat tissue, 200 
of heart muscle, 202 
of kidney epithelium, 198 
of liver cells from bile-ducts, 197, 316, 
317 
of lymphocytes, 204 
of lymphoid tissue, 204 
of lymph-vessels, 203 
of muscle, non-striated, 202 
striated, 202 
of nervous tissue, 206 
of polymorphonuclear leucocytes, 204 
Relapsing fever, 755 
Repair, 133, 174, 189 
character of, in brain, 207 
excessive, following injuries by Bacillus 
tuberculosis, 186 
by Spirochaeta pallida, 186 
general phenomena of, 189 
of bone fractures, 202 
Respiratory quotient, 869 
tract, bacteriology of, 253 
obstruction of, 428 
references to literature, 438 
syphilis of, 719 
tuberculosis of, 655 
Reticulo-endothelial apparatus, 76, 152 
Retina, pigment of, 118 
Retinitis, albuminuric, 305 
Retroperitoneal region, myxoma of, 987, 
988 
sarcoma of, 980 
Rhabdomyoma, 959, 959 
common sites of, 959 
of bladder, 959 
of heart, 959 
of vagina, 958, 959 
references to literature, 960 
Rhagades in congenital syphilis, 744 
Rheumatism, acute, 567 
aetiology of, 568 
arthritis in, 568 
endocarditis in, 571, 569 
pericarditis in, 570 
references to literature, 571 
tonsillitis in, 568 
muscular, from exposure to cold, 385 
Ribbert's theory as to origin of tumors, 
1119 
Ricin poisoning, changes in bone-marrow 
in, 804 
Rickets, 918 
aetiology of, 924 
calcium deficiency in, 106, 923 
cod-liver oil in, 106 
disturbance of ossification, 920, 920, 921, 
922 
endostitis fibrosa in, 923 
enlargement of spleen in, 923 
exostoses in, 923 
experimental production, 923 
halisteresis in, 922 
phosphorus deficiency in, 923 
references to literature, 924 
sunlight in, 106 
ultraviolet rays in, 388 
Rickettsia prowazeki, relation of, to ty- 
phus fever, 689 
Rigg's disease, relation of amoebae to, 776 
Rodent ulcers, 1037, 1038 
Roentgen rays, 385 
effects of, on tissues, 388 
Rose spots, 614 
Rupia, 706 
SADDLE-nose in congenital syphilis, 720, 
751 
Sago spleen, 99 
Salivary glands, cylindroma of, 1000, 1010 
mixed tumors of, 1090 
references to literature, 1095 
obstruction of ducts of, 406 
syphilis of, 718 
transplantation of, 210 
Salpingitis, gonococcus, 561, 561, 562, 564 
pseudofollicular, 563 
Sarcoma, 974 
atypical mitosis in, 975 
of fowl (Rous), filterable virus of, 1112 
of liver, in rats, 1111 
of lymph-glands, 980 
of ovary, 977, 980 
of testicle, 981, 1093, 1094 
of thyroid, 977 
references to literature, 987 
stroma of, 975 
types of, 976 
alveolar, 976, 981 
differentiation from carcinoma, 981 
giant-cell, 983, 983, 984 
of bone, 984 
melanotic, 890 
pigment of, 118 
references to literature, 994 
mixed cell, 976, 977, 980 1154 
INDEX 
Sarcoma, types of, osteo-, 985, 986 
round cell, 977, 980 
differentiation from lymphosarco- 
ma, 845 
spindle cell, 976, 977, 978, 978 
Scar formation, 134, 221. See also Re- 
pair. 
Scarlet fever, 760 
aetiology of, 760 
cause of death in, 761 
enlargement of lymph-glands in, 762 
experimental, 760 
immunity in, 760 
nephritis following, 762 
pharyngitis, 761 
pneumonia in, 761 
references to literature, 763 
skin lesions in, 760 
tonsillitis in, 761 
Scars, 213, 221 
Scharlach R, stimulation of growth by, 184 
Schick reaction, 168 
Schistosomum haematobium, 788 
mansoni, 788 
japonicum, 788 
Scurvy, 927 
bone changes in, 927, 927, 928 
experimental, 928 
haemorrhages in, 928 
references to literature, 929 
Sebaceous glands in dermoid cysts, 1087, 
tumors of, 1010 
Secretion, mechanism of, 68 
Seminal vesicles, pigments of, 125 
tuberculosis of, 682 
Senility, 63 
atrophy of organs and tissues in, 63 
calcification of cartilage in, 108 
rarefaction of bones in, 63 
relation of, to tumors, 1112 
thickening of heart valves in, 244 
Septicaemia, 510 
in bronchopneumonia, 516 
pneumococcus, 552 
staphylococcus, 532, 533, 534 
streptococcus, 525 
Sequestrum in osteomyelitis, 538, 539 
Serosae, structure of, 229 
Sexual characters, secondary, in status 
lymphaticus, 847 
development, influence of adrenals on, 
899 
influence of hypophysis on, 905, 907, 
911 
Shaking palsy, 694 
Shock, 376 
adrenals in, 370 
anaphylactic, 166 
capillaries, paralysis of, in, 143, 380 
cardiac failure in, 379 
conditions simulating, 166 
histamine in, 143, 380, 422 
in burns, 381 
primary, 379 
secondary, 379 
surgical, 376 
lowered blood-pressure in, 377 
references to literature, 380 
symptoms of, 376 
theories regarding nature of, 377 
theories regarding production of, 378 
Side-chain theory, 169 
Siderosis, 129 
Silver poisoning, 130 
Sinus formation in actinomycosis, 222 
in tuberculosis, 222 
Skin, abscess of, 261 
atrophy of, senile, 63 
effects of cold on, 383 
of electricity on, 391 
of heat on, 380 
of pressure on, 68 
of radium on, 388 
of x-rays on, 388 
glanders, lesions in, 588 
haemorrhages in, 526 
keloids in, 946 
lesions in measles, 759 
in scarlet fever, 760 
in smallpox, 764, 765, 766 
in typhoid fever, 614 
pigmentation of, 117 
from sunlight, 387 
in Addison's disease, 900 
in argyria, 130 
rodent ulcers of, 1037, 1038 
staphylococcus infections of, 531 
streptococcus infection of, 519 
syphilis of, 704, 705, 706, 707 
congenital, 744 
transplantation of, 209 
tuberculosis of, 655, 684 
tumors of, adenoma, 1010 
epithelioma, 1026, 1037, 1038, 1039 
fibroma, 945, 945, 946 
haemangioma, 969, 970 
myoma, 957 
naevus, 989, 990 INDEX 
1155 
Skin, tumors of, papilloma, 1007, 1007 
xanthoma, 954 
Skull, fracture of, 370 
syphilitic erosion of, 725 
Smallpox, 763 
aetiology of, 764 
cytorrhyctes in skin in, 757 
enlargement of lymph-glands in, 767 
of spleen in, 767 
immunity to, 163 
lesions of organs in, 766 
of skin and mucosae in, 764, 765, 766 
references to literature, 767 
relation to vaccinia, 763 
streptococci in, 764 
Soaps, role in calcification, 110, 340 
Sore throat, streptococcal, 512 
Sphaeroliths, 446 
Spina ventosa, 687 
Spinal cord, anatomy of, 736 
in dementia paralytic, 743 
in locomotor ataxia, 734, 735, 735, 736 
in pernicious anaemia, 819 
injuries of, 370 
syphilis-of, 733. See also Tabes dorsalis. 
tuberculosis of, 683 
Spirochaeta pallida, excessive repair fol- 
lowing injuries by, 186 
in brain in dementia paralytica, 742 
in cerebrospinal fluid in syphilis of 
nervous system, 733 
in gummata, 709 
in organs in congenital syphilis, 743 
in primary and secondary syphilitic 
lesions, 697 
Spirochaetal infections, 753 
icterohemorrhagica, 754 
pertenue, 753 
Spirochaetosis icterohemorrhagica, 754 
Spleen, actinomycosis of, 633 
acute splenic tumor, 527, 527, 528, 609 
gray type, 530 
red type, 530 
amyloid infiltration of, 99, 99, 101 
Banti's disease of, 822, 822, 823 
chronic passive congestion of, 490, 808 
effect of z-rays on, 389 
enlargement of, in cirrhosis of liver, 330 
in rickets, 923 
in smallpox, 767 
function of, 808 
in iron metabolism, 113 
in acute lymphatic leukaemia, 836, 837, 
838, 838 
Spleen in chronic lymphoid leukemia, 834, 
835 
in chronic myeloid leukaemia, 850, 850, 
852, 852 
in Hodgkin's disease, 860, 861 
in leprosy, 624 
in leucocytosis, 828 
in malaria, 780, 781 
in pernicious anaemia, 817, 818 
in typhoid fever, 609 
infraction of, 29, 31, 31 
pigmentation of, in malaria, 120 
in pernicious anaemia, 124 
sago, 99 
structure of, 151, 806, 806, 807 
references to literature, 824 
tuberculosis of, 648, 679 
Splenic anaemia, 822 
Splenomegaly, Gaucher type, 824 
primary (Banti's disease), 822, 822, 823 
references to literature, 825 
Spondylitis deformans, 940, 941 
St. Anthony's fire, 42 
Staphylococcus infections, 531 
arthritis, 534 
endocarditis, 536 
furunculosis, 531 
meningitis, 540 
osteomyelitis, 537 
pneumonia, 537 
references to literature, 540 
septicaemia, 532, 533, 534 
synovitis, 534 
Starvation, atrophy from, 62 
Status lymphaticus, 847 
constitutional abnormalities in, 847, 
895 
hyperplasia of lymphoid tissue in, 
846, 847 
references to literature, 848 
thymus in, 848 
Stokes-Adams' disease, 498 
Stomach in carbolic acid poisoning, 398 
in lysol poisoning, 398, 399 
in poisoning by corrosive substances, 397 
obstruction of, 418 
by tumors, 1042 
perforation of, 375 
syphilis of, 714 
tuberculosis of, 672 
tumors of, adenoma, 1011 
carcinoma, 1042, 1043, 1045, 1046, 
1048 
adeno-, 1043 1156 
INDEX 
Stomach, tumors of, carcinoma, colloid, 
1052, 1053, 1053, 1054 
references to literature, 1063 
scirrhus, 1047, 1047 
solid, 1043 
myoma, 957 
papilloma, 1008 
ulcer of, 419, 420, 421 
origin of carcinoma in, 1046 
Stomatitis, ulcerative, in acute myeloid 
leukaemia, 855 
Streptococci in scarlet fever, 760 
in smallpox, 764 
Streptococcus haemolyticus, endocarditis 
due to, 522 
character and localization of vegeta- 
tions, 521 
types of haemolysis due to, 511 
infections, 511 
of blood (septicaemia), 525 
of endocardium, 247, 521 
of intestines, 518 
of lung (pneumonia), 520 
of middle ear, 517 
of pharynx, 520 
of respiratory tract, 512 
of skin, 519 
of stomach, 518 
of throat, 512 
of tonsil, 512 
of uterus (puerperal), 257, 520 
of wounds, 518 
references to literature, 530 
sore throat due to, 512 
mucosus, 521 
endocarditis, character and localiza- 
tion of vegetations, 521, 525 
viridans (mitior), 521, 571 
endocarditis, 245, 249, 523, 524 
character and localization of vege- 
tations, 521 
Streptothrix, 630 
Stricture of urethra, 439 
gonorrheal, 439, 440, 560 
Struma, 879. See also Goitre. 
carcinomatous, 1074 
Sudan III as stain for fats, 75 
stain for lipochrome pigments, 64, 125 
stimulation of growth by, 184 
Sulphonal poisoning, blood changes in, 121 
haematoporphyrin in, 121 
Sulphuric acid poisoning, 398 
Sunlight in rickets, 106 
pigmentation of skin from, 387 
Sunstroke, 382 
Sweat glands in temperature regulation, 
156 
tumors of, 1010 
Sympathetic nervous system, influence of, 
on thyroid growth, 887 
tumors of, 962 
Sympathoblastoma, 962 
Syncytiolysin, 1079 
Synechiae of pericardium, 223 
Synovitis, staphylococcus, 534 
Syphilide, follicular, 707 
macular, 702, 705 
papular, 704, 705 
papulopustular, 706 
pustular, 705, 706 
Syphilis, acquired, primary stage, 700, 701, 
702, 703 
secondary stage, 702, 705, 706, 707 
tertiary stage, 708. See also Gum- 
mata, 723, 724, 725. 
action of iodides on, 716 
aetiology of, 696 
alopecia in, 706 
blood changes in, 713 
anemia in, 713 
bone-marrow in, 749 
chancre in, 700, 713 
chlorosis in, 713 
congenital, 698, 720, 743 
changes in kidney in, 748 
hydrocephalus in, 751 
late forms of, 744, 750 
lesions in nervous system, 752 
references to literature, 752 
retardation of development in, 751, 
752 
Spirochaeta pallida in organs, 743 
stigmata of, 751 
dementia paralytica in, 739 
endocarditis in, 727 
gummata in, 697, 708, 723 
immunity in, 698, 699 
lesions of, 697 
leucoderma in, 706 
locomotor ataxia in, 733 
luetin reaction in, 699 
lymphocytosis in, 713 
lymphoid cells in, 697 
mucous patches in, 706 
of alimentary tract, 713 
of aorta, 348, 349, 350 
of blood-vessels, 348, 726 
references to literature, 727 INDEX 
1157 
Syphilis of bone, 720, 722, 748 
congenital, 720, 748, 748, 749, 750. 751 
references to literature, 626 
of brain, 730 
of bronchi, 721 
of genital organs, 727 
references to literature, 629 
of heart, 726 
of intestine, 714 
of joints, 722 
of kidneys, congenital, 748 
of larynx, 721 
of liver, 715, 717 
congenital, 745, 746 
of lungs, 721 
congenital, 744 
of lymph-glands, 712 
of meninges, 351, 730, 733 
of nervous system, 697, 730 
congenital, 752 
references to literature, 733 
of nose, 720 
congenital, 720, 751 
of oesophagus, 714 
of pancreas, 747 
congenital, 747 
of periosteum, 722 
excessive bone formation on, 953 
of placenta, 743 
of rectum, 714, 715 
of respiratory tract, 719 
references to literature, 722 
of salivary glands, 718 
of skin, congenital, 744 
of stomach, 714 
of teeth, congenital, 752 
of testicle, 708, 727, 728, 729 
congenital, 748 
of tongue, 714 
of trachea, 721 
plasma cells in, 697 
references to literature, 700, 722 
rupia in, 706 
Spirochaeta pallida in lesions of, 697 
tardive, 751 
transmission to animals, 696, 703 
Wassermann reaction in, 699 
Syringomyelia, 967 
Tabardillo, 689 
Tabes dorsalis, 733 
Charcot's joints in, 739 
lesions of spinal cord in, 734, 735, 736 
pathogenesis of, 738 
Tabes dorsalis, references to literature, 739 
trophic disturbances in, 739 
Tachycardia, 497 
Taenia echinococcus, 784, 785 
saginata, 784 
solium, 784 
Tapeworms, life cycle of, 768. See also 
Toenia. 
Teeth, deformities of, in congenital syph- 
ilis, 752 
Telangiectasis, multiple, 969 
Temperature of body, influence on pha- 
gocytosis, 158 
influence on experimental infections, 
158 
regulation of, 156 
Teratoma, 1081 
aetiology of, 1083, 1086 
common sites of origin, 1083 
of ovary, 1083 
of testicle, 1082, 1084, 1083, 1093, 1094 
origin of malignant tumors in, 1112 
references to literature, 1095 
Terminal circulation, 25 
Testicle, chorionic epithelioma of, 1081 
references to literature, 1095 
effect of extirpation, 65 
of x-rays on, 390 
endogenous pigments of, 125 
gumma of, 708, 727, 728 
mixed tumors of, 1093 
references to literature, 1095 
sarcoma of, round-cell, 981, 1093, 1094 
syphilis of, 708, 727, 728 
congenital, 748 
teratoma of, 1082, 1083, 1084, 1093, 1094 
Tetanus infection, 577 
lesions of nervous system in, 578 
references to literature, 579 
spread of toxin in, 577 
toxin, neutralization of, by phrenosin, 
79 
Tetany following extirpation of parathy- 
roids, 889 
calcium deficiency in, 107 
salts in treatment of, 890 
hyperexcitability of nerves in, 890 
in human beings, 891 
types of, 891 
references to literature, 891 
ultraviolet rays in, 388 
Throat, diphtheritic infection of, 573 
streptococcus infection of, 512 
Thrombi, 8, 20, 243 INDEX 
1158 
Thrombi agglutination, 13 
calcification of, 249 
canalization of, 225, 353, 353, 354 
formation of, 13 
hyaline, 98, 270 
in aorta, 12 
in arteries, 11 
in heart, 10, 12, 467 
in veins, 11, 12 
method of formation, 9 
organization of, 20, 178, 218, 223, 225 
precipitation, 13 
propagated, 12 
septic, 259 
structure of, 7 
Thrombin in blood coagulation, 6, 7 
Thrombo-angiitis obliterans, 351, 353 
references to literature, 355 
Thrombo-endocarditis, 243. See also En- 
docarditis. 
Thrombokinase in blood coagulation, 7, 
13, 56 
Thromboplastin in blood coagulation, 7 
Thrombosis, 8 
as protective mechanism, 12, 353 
causes of, 13 
references to literature, 14 
Thyinene, 88 
Thymus, abnormal persistence of, 893 
diseases due to disturbed function of, 
892 
effects of x-rays on, 389 
evolution of, normal, 893 
extirpation of, 893 
hyperplasia of, 893 
in exophthalmic goitre, 886, 894 
in status lymphaticus, 858, 894 
involution of, accidental, 895 
normal, 893 
references to literature, 895 
relation of, to bone formation, 917 
types of cells in, 892 
weight of, 893 
Thyroid, active principle of, 882 
effect of extirpation of, 65, 876 
enlargement of, 882. See also Goitre. 
function of, 875 
insufficiency of, in adenomatous 
goitre, 881 
functional disturbances of, 875 
relation of, to obesity, 81 
hyperplasia of, relation of iodine to, 
882 
in colloid goitre, 879 
Thyroid in cretinism, 878 
in exophthalmic goitre. 885, 885 
in inyxcedema, 876 
influence of, on carbohydrate metabo- 
lism, 871 
on experimental glycosuria, 867 
iodine content of, 882 
references to literature, 888 
stimulation of function, by nerve anas- 
tomosis, 887 
transplantation of, 210 
tuberculosis of, 655 
tumors of, adenoma, 880, 880, 881, 101^, 
1014 
carcinoma, 1077 
sarcoma, 977 
Tissue changes after death, 58 
cultivation of, in vitro, 176, 179, 180, 
181, 217 
equilibrium, 179 
new growth of, 174 
causes of, 175, 179 
new growth of, in inflammation, 174 
repair of, 189 
references to literature, 208 
specificity of, 190 
transplantation of, 209 
references to literature, 211 
Toluylendiamine poisoning, jaundice in, 
127 
Tongue, chancre of, 713 
epithelioma of, 1031, 1031 
syphilis of, 1027 
Tonsil, chancre of, 1026 
epithelioma of, 1032 
gumma of, 1027 
Tonsillitis in acute rheumatism, 568 
in scarlet fever, 761 
streptococcus, 512 
Tophi in gout, 90, 91 
Toxin, diphtheria, 161 
tetanus, 161 
Trachea, chondroma of, 950 
diphtheria of, 574 
epithelioma of, 1032 
obstruction of, 429 
syphilis of, 721 
tuberculosis of, 655, 670 
Transplantation, autoplastic, 210 
factors determining success of, 210 
heteroplastic, 210 
homoplastic, 210 
in lower animals, 209 
of bone, 209 INDEX 
1159 
Transplantation of kidney, 210 
of limbs, 210 
of nerves, 210 
of organs, 209 
of internal secretion, 210 
of parathyroid, 210 
of salivary glands, 210 
of skin, 209 
of thyroid, 210 
of tissues, 209 
of tumors, 1102 
references to literature, 211 
Trauma, effects of, 369 
Trematode infections, 788 
references to literature, 790 
Trench nephritis, 307 
Tricalcium phosphate, precipitation of, 11 
Trichinae in muscles, 790, 791, 792 
calcification of, 108 
Trichinella spiralis, 790 
in tissues, 791 
Trichiniasis, 790 
references to literature, 793 
Trichocephalus trichiuris, 797 
Tricuspid regurgitation, 480 
stenosis, 479, 480 
Trophic disturbances in dementia para- 
lytica, 740 
in tabes dorsalis, 739 
Trypanolysins, 165 
Trypanosomes, immune sera for, 165 
resistance to arsenic compounds, 162 
Trypanosomiasis, 783 
enlargement of lymph-glands in, 783 
references to literature, 783 
Tsetse fly disease, 783 
Tubercle bacillus, distribution in body, 652 
reaction of tissues to, 642 
references to literature, 672 
calcification of, 108, 648 
conglomerate, 646 
differentiation of, from gumma, 709 
healing of, 619 
miliary, 643 
structure of, 644, 644, 645 
necrosis of, 645, 647 
nodules, formation of, relation to acute 
tuberculous inflammation, 651 
solitary, 648, 648 
in brain, 683 
Tuberculin tests, relation of anaphylaxis 
to, 167 
Tuberculosis, 634 
acute, 650 
Tuberculosis, acute, miliary, 643, 654 
aetiology of, 634 
bacillus of, 634 
types of, 634 
distribution and transportation of, 
635 
chloasma in, 118 
congenital, 637 
experimental, 639, 650 
fat accumulation in organs, 669 
giant-cells, formation of, 648 
references to literature, 649 
granulation tissue in, 649, 649 
historical sketch of, 634 
hypersensitization to, 639 
immunity to, 639, 641 
in lungs of children, 670, 671, 671 
metabolic changes in, 669 
disturbances in, 669 
mode of infection, 636 
references to literature, 642 
obliterating endarteritis in, 664 
of adrenals in Addison's disease, 900 
of alimentary tract, 639 
of animals, 635 
of bones, 685, 686, 687 
references to literature, 687 
of brain, 683 
of bronchi, 656 
of digestive organs, 672 
of ductless glands, 684 
of epididymis, 670, 681, 682 
of Fallopian tubes, 682 
of genital tract, 679 
mode of infection in, 679 
references to literature, 683 
of intestines, 672, 673, 673, 674, 675, 676 
of joints, 686 
references to literature. 687 
of kidney, 670, 680, 682 
of larynx, 655, 670 
of liver, 655, 673 
of lungs, 655 
acute exudative, 659, 660, 660, 661, 
662, 663. See also Pneumonia, 
tuberculous. 
miliary, 654 
chronic, 657, 658, 667, 668, 669 
cavity formation in, 663, 666, 667,. 
668, 669 
healed, 657 
healing of, 667 
references to literature, 672 
secondary infection in, 669 INDEX 
1160 
Tuberculosis of lungs, spread of, 665 
of lymph-glands, 657, 678, 678, 679 
of meninges, 683, 684 
of nervous system, 683 
of oesophagus, 672 
of ovary, 682 
of pancreas, 673 
of peritoneum, 674 
of respiratory tract, 655 
of seminal vesicles, 682 
of skin, 655, 684 
of spinal cord, 683 
of spleen, 648, 679 
of stomach, 672 
of trachea, 655, 670 
of ureter, 682 
of urinary tract, 679 
references to literature, 683 
of uterus, 683 
of vertebrae, psoas abscess in, 222 
placental transmission of, 637 
portals of entry, 636, 637 
relation of anaphylaxis to, 640 
relation of trauma to, 375 
spread of, in body, 662, 670 
susceptibility to, 636 
tuberculin test for, 636 
■Tuberculous peritonitis, 674, 677 
'Tumors, 942 
aetiology of, 1109, 1115 
classification of, 942, 1096 
connective-tissue, 943 
.epithelial, 1005 
benign, 1006. See also Papilloma and 
Adenoma. 
malignant, 1025. See also Carcinoma 
and Epithelioma. 
general character of, 942, 1098 
glycogen in, 105 
immunity reaction, histological char- 
acter of, 1114 
immunity to, 1114 
implantation of, 1105 
malignant, cachexia in, 65 
invasive growth of, 1105 
metastasis of, 23, 1030, 1105 
recurrences of, 1109 
metabolism in, 65 
mixed, 978, 1090 
nutrition of, 1103 
parasites in, 1111 
pigmented, 989 
references to literature. 1121 
relation of heredity to, 1112 
Tumors, relation of internal secretion to, 
1112 
of irritation to, 1109 
of senility to, 1112 
theory of cell fertilization, 1120 
chronic irritation, 1116 
Cohnheim's, 1118 
displacement of embryonic cells, 
1118 
parasitic, 1116 
Hibbert's, 1119 
transplantation of, 1102 
Typhoid fever, agglutination in, 165 
and typhoid infections, 599 
arthritis in, 614 
blood changes in, 610 
bone-marrow changes in, 610, 829 
carriers, 612 
cholecystitis following, 611 
cystitis in, 613 
endocarditis in, 613 
endothelial cells in, 604 
experimental, 599 
focal necrosis of liver in, 312, 315, 
610, 611, 612 
furunculosis in, 614 
haemorrhage in, from intestines, 603 
heart in, 613 
intestinal lesions in, 600, 600, 601, 
602, 606, 607 
kidney lesions in, 612 
laryngitis in, 613 
leptomeningitis in, 614 
liver lesions in, 312, 315, 610, 611, 612 
lymphoid tissues and lymph-glands 
in, 603, 604, 605, 608, 608 
macrophages in, 607 
mastitis in, 614 
muscles in, Zenker degeneration of, 
96, 613 
neuritis in, 614 
orchitis in, 614 
osteomyelitis in, 613 
parotitis in, 614 
peritonitis in, 236 
phagocytosis in, 609 
pharyngitis in, 613 
phlegmasia alba dolens in, 613 
placental transmission of, 614 
pneumonia in, 613 
portal of entry in, 599 
references to literature, 614 
skin lesions in, 614 
spleen in, 609, 609 INDEX 
1161 
'Typhoid fever, thrombosis in, 613 
vaccination for, 600 
wandering cells in, 607 
Typhus fever, 688. See also Brill's disease. 
aetiology of, 689 
experimental, 689 
lesions of organs in, 688 
references to literature, 690 
Tyrosinase, 901 
Tyrosine in urine, 87 
oxidation of, 118 
^Ulcers, decubitus, 368 
healing, 195, 219, 221 
of duodenum, 420 
of intestine, 264 
dysenteric, 618 
tuberculous, 673 
typhoid, 601, 602 
of stomach, 410, 420 
Ultraviolet rays, effects of, 387 
in rickets, 388 
in tetany, 388 
Uncinaria duodenale, 793 
Uncinariasis, 793, 795 
references to literature, 796 
Uraemia, 304 
Uranium poisoning, necrosis of kidney epi- 
thelium in, 223 
Urate deposits in gout, 90, 90 
Ureter, carcinoma of, 1035 
obstruction of, 183, 453 
tuberculosis of, 682 
Ureteritis, gonococcus, 559 
Urethra, obstruction of, 439 
references to literature, 444 
stricture of, 439, 440, 560, 561 
structure of, 559 
Urethritis, gonococcus, 559 
Uric acid calculi, 445, 447 
deaminization of, 88 
infarct of kidney, 446 
in gout, 90 
Urinary tract, obstruction of, 439, 444, 450 
references to literature, 444, 458 
Urticaria in echinococcus infection, 788 
lUterus, calcification of vessels of, 352 
effect of adrenaline on, 898 
obliterative endarteritis of, 352, 352 
streptococcus infection of, 520 
tuberculosis of, 683 
tumors, adenoma, 1024 
carcinoma, 1035 
adeno-, 1035, 1060, 1060 
Uterus, tumors, carcinoma, referertces to 
literature, 1063 
squamous cell, 1035, 1035, 1036 
epithelioma, 1035, 1035, 1036 
chorionic, 1078 
fibromyoma, 954, 955 
leucosarcoma, 840, 841 
Vaccinia, 763 
Vagina, myoma of, 957 
rhabdo-, 959 
Vaginitis, gonococcus, 561 
Variola, 764 
Vas deferens, tuberculosis of, 682 
Vasomotor apparatus in temperature 
regulation, 156 
Veins, obstruction of, 25, 44 
thrombi in, 12 
Vena cava, obstruction of, 177 
thrombus in, 11 
collateral circulation after, 24 
Ventricles of brain, diagram of, 502 
Vertebra;, erosion of, by aneurysm, 70 
tuberculosis of, 222, 686, 687 
Vesiculitis, gonococcus, 561 
Viruses, filterable, diseases caused by, 
757 
Vitamines, 182 
Vitiligo, 131 
Volvulus, 36, 425 
von Recklinghausen's disease, 946, 947 
Vulvovaginitis, gonococcus, 561 567 
Wandering cells, 146 
function of, 156 
in embryonic tissues, 147 
mononuclear phagocytic, 150 
origin and relation of, 149 
references to literature, 155 
types of, 151, 152 
Wart, 1007. See also Papilloma and 
Naevus. 
Wassermann reaction, 699 
lipoids in, 79 
Weigert stain for myelin sheaths, 735 
Weil's disease, 754 
aetiology of, 755 
transmission of, 754 
Wool-sorters' disease, 589 
Worms, pathogenic classification of, 770 
Wounds, 373 
effects of, immediate, 373 
secondary, 374 
gun-shot, 373 INDEX 
1162 
Wounds, healing of, 182, 211, 212, 213 
factors preventing, 211 
relation of diet to, 184, 221 
incised, 373 
infection of, 374 
streptococcus, 518 
Xanthine, 88 
Xanthoma, 954 
lipoids in, 954 
Xeroderma pigmentosum, 387 
X-rays, 385 
cancer following irritation by, 1117 
effects of, on blood-forming organs, 389 
bone-marrow, 389 
on genital organs, 390 
on lymph-glands, 389 
X-rays, effects of, on pathological tissues,. 
390 
on skin, 388 
on spleen, 389 
on thymus, 389 
Yaws, 753 
lesions in, 753 
reaction of, to salvarsan, 754 
skin lesions in, 753, 753, 754 
transmission of, 753 
Yellow fever, 755 
{etiology of, 755 
references to literature, 755 
relation of leptospira icteroides to, 
755 
Zenker's degeneration, 516