A UNIQUE COINCIDENCE OF MULTIPLE SUBCU- TANEOUS HAEMANGIO-ENDOTHELIOMA, MULTI- PLE LYMPHANGIO-ENDOTHELIOMA OF THE INTESTINAL TRACT AND MULTIPLE POLYPI OF THE STOMACH UNDERGOING MALIGNANT CHANGES; ASSOCIATED WITH GENERALIZED VASCULAR SCLEROSIS AND CIRRHOSIS OF THE LIVER. By M. C. Winternitz, M. D., Associate in Pathology in the Johns Hopkins University, Assistant Resident Pathologist, Johns Hopkins Hospital, AND Thomas R. Boggs, M. D., Associate in Medicine in the Johns Hopkins University, Resident Physician, the Johns Hopkins Hospital. (From the Medical Service and Pathological Laboratory of the Johns Hopkins Hospital.) [From The Johns Hopkins Hospital Bulletin, Vol. XXI, No. 232, July, U.910.] I A UNIQUE COINCIDENCE OF MULTIPLE SUBCU- TANEOUS HAEMANGIO-ENDOTHELIOMA, MULTI- PLE LYMPHANGIO-ENDOTHELIOMA OF THE INTESTINAL TRACT AND MULTIPLE POLYPI OF THE STOMACH UNDERGOING MALIGNANT CHANGES; ASSOCIATED WITH GENERALIZED VASCULAR SCLEROSIS AND CIRRHOSIS OF THE LIVER. By M. C. Winternitz, M. D., Associate in Pathology in the Johns Hopkins University, Assistant Resident Pathologist, Johns Hopkins Hospital, , AND Thomas R. Boggs, M. D., Associate in Medicine in the Johns Hopkins University, Resident Physician, the Johns Hopkins Hospital. (From the Medical Service and Pathological Laboratory of the Johns Hopkins Hospital.) Introduction. The basis for the following histological studies with the [203| theoretical deductions appended is found in a case which has been under clinical observation for the past three years. This showed such unusual features during life that we undertook an exhaustive investigation of the tissues at autopsy. The material will be presented in the following order: 1. Description of the case. 2. Protocol of the autopsy. 3. Histological studies. 4. Summary and theoretical deductions. (1) Clinical History. [308] T. H., male, mulatto, 65 years old. Ship's cook. Born in Hindustan. Was admitted to the Johns Hopkins Hospital, November 17, 1906. Medical number 20,395. Complaint: " Swelling of stomach." Family History: Unimportant. Personal History: Patient had measles as a child, small- pox at 9. He does not recall having had any other diseases in childhood. Has never had typhoid fever, pneumonia, or pleurisy. No cardiac or respiratory symptoms. Gastro-Intestinal: Patient has always had a good appetite. His bowels have moved once a day regularly. He has never had any colic or pain in the abdomen. About 20 months ago, after quitting drink, he began to have occasional attacks of vomiting in the morning. The vomitus was yellow and tasted very bitter. He has had similar attacks (one every 2 to 3 weeks) up to the present. Has not noticed blood in his stools. Urinary: Patient has slight nycturia, but never has had any burning or pain on micturition. Patient denies having [204] had syphilis and gives no definite history of a hard or soft chancre. No history of secondaries. Gonorrhoea at 17. Skin: Patient has never been jaundiced. He has never had any skin eruption, or itching. Extremities: No ulcers on legs. No pain in joints or bones. Habits: Patient's work has always been light-cooking on shipboard, and serving in army and navy. Alcohol: Up to two years ago patient was a steady drinker. When on shore he drank 3 to 4 glasses of beer a day and half a pint to a pint of whiskey. He got no liquor while at sea, but went on a spree whenever in port. Two years ago he quit drinking entirely, and has not used alcohol since. Tobacco: Practically none. Present Illness: About 3| months ago, while working in a store, he noticed swelling of the feet. At this time he had to walk a great deal. The swelling got worse during the day, but subsided at night. Gradually his " stomach " became swollen, and the oedema of the legs remained constant. About (2) months ago he quit work for a week or so, rested, and took [204] large doses of Epsom salt. He states that his stools were of clear, watery fluid. The ascites subsided, and he went back to work, at which he continued till 10 days before admission. His only symptom has been abdominal swelling. His bowels have moved once a day. A few times he has vomited a little bitter yellow fluid in the morning. This contained no blood. He has not noticed any blood in his stools. His appetite has been good. His micturition has been as usual. He has had no palpitation or shortness of breath till recently, when he has had dyspnoea on exertion. He has had no cough. Has not lost weight. Physical Examination: The patient is a light mulatto, sparely nourished. There is no exophthalmos. Pupillary reactions are normal. Gums and mucous membranes show slight cyanosis. Thyroid isthmus is slightly enlarged; the lobes are barely palpable. Lymphatics of the neck seem normal. Respirations are shallow and costal in character; expansion is limited on both sides. Percussion note is hyper- resonant over the upper lobes in front with dulness low in the axillae and in both backs. The breath sounds are harsh and clear over the upper lobes, diminishing over the impaired area and accompanied by numerous fine moist rales on forced inspiration. No evidence of fluid in the pleura. Heart: Displaced upward. Point of maximum impulse in 4th left interspace 10.5 cm. from mid line. Dulness reaches 13.5 cm. to left in 4th interspace and above to 1st interspace, 2.5 cm. to right in 3d interspace. The heart sounds are clear and regular and of normal intensity. The pulse is 80, regular in force and rhythm, of moderate tension, with very marked sclerosis of the peripheral arteries. Abdomen: The abdomen is very tense and swollen; its skin is shiny. The superficial veins are enlarged, especially those along the lateral margins. There is no caput medusae. Epi- gastric veins are not prominent. Umbilicus is protruding. Fluctuation wave is definite. Liver not palpable. Spleen not felt. There is movable dulness on percussion. The liver dulness begins at the 3d rib and extends to point 3.5 cm. (3) [204] above the costal border in the right mammillary line. The girth of the abdomen at umbilicus is 106 cm. Genitalia: Normal except for an atrophic undescended left testicle. Extremities: There is marked clubbing of the fingers and toes. There is oedema of the thighs and legs. The knee kicks are normal. Plantar response is normal. Nov. 19: Abdomen tapped and 7.5 litres of straw-colored fluid removed from the abdominal cavity. Nothing remarkable about the appearance on microscopic examination of this material. The cellular elements were few. Specific gravity, 1011; albumin, 6.6 grams per litre. Blood: Showed secondary anaemia. R. B. C., 4,492,000; W. B. C., 5400; Hb., 82 per cent. Differential Count: Showed slight reduction of the poly- morphonuclears and small mononuclears. Slight increase in large mononuclears and transitionals. Patient was much relieved by the removal of the ascitic fluid. The edge of the liver could not be made out definitely. Spleen was not palpable. Patient was tapped again on Nov. 30 and 5.5 litres removed. From this time he gradually improved and was discharged Dec. 17, 1906. 2d admission, March 23, 1907: Patient was readmitted in much the same condition as before. In the three months since he left the hospital he had been unable to work and has had some occasional morning vomiting and gradually in- creasing ascites, anasarca, and dyspnoea. Physical Examination: Is practically as on first admission, except that on admission it was noted the peripheral arteries, generally, and the veins, as well, were very greatly thickened. The anaemia had somewhat increased, haemoglobin being 62 per cent, 5000 white cells, and 4,000,000 red cells. The great distension and dyspnoea were relieved by tapping and removal of 10 litres of ascitic fluid. After repeated tappings, patient's condition gradually im- proved. The edge of the liver is noted as palpable on June 10, small, smooth and hard. Patient was discharged on June 15, somewhat improved. (4) 3d admission, Sept. 16, 1907: Patient was confined to [204] his bed much of the time between his discharge from the hospital and readmission with the same symptoms as before; marked ascites, swelling of the legs, dyspnoea, occasional nausea and vomiting. No blood in the vomitus or stools. Physical Examination: Practically as on previous notes, except for some increase in cyanosis. The girth was 112 cm. on admission; 86 cm. after tapping and removal of 11 litres of straw-colored fluid. Character of the fluid practically the same as previously noted. Dr. Emerson, Nov. 14: A few small nodules along the right forearm which suggest phleboliths; not attached to any vein. The edge of liver is distinctly palpable after tapping. The liver seems very small. The lateral abdominal veins are large with a distinct upward current in them. There is a slight enlargement of both parotid glands. Dec. 19 it is noted that the skin on the lower arms shows marked wrinkled lines suggesting ichthyosis. A small I305! firm subcutaneous nodule is found above the left scapula. Patient discharged at his own request, slightly improved, Dec. 19, 1907. 4th admission, Feb. 3, 1908: Patient spent the intervening time in bed. Has been very comfortable. The increase in ascites and shortness of breath forced him to return to the hospital. Physical Examination: Practically as in previous ad- missions. Dr. Thayer: Increase in the clubbing of the fingers, palpable small liver and enlarged spleen. Parotid enlargement increased. Moderate dilatation of the superficial veins of the abdomen and thorax. No caput medusce. Patient improved under treatment after repeated tappings and was discharged on April 21, 1908. Diagnosis: Cirrhosis of the liver (atrophic). 5th admission, June 16, 1909: In four weeks, since his discharge, patient has gradually become cedematous and the ascites is very marked. Some dyspnoea and morning vomiting. Physical Examination, Dr. Clough, June 18, 1908: Ema- (5) [205] dated. Skin dry, scaly, of a peculiar chocolate color. Scleras distinctly jaundiced. Marked arcus senilis. Mucous mem- brane of mouth distinctly pale. Lymph glands are somewhat enlarged, firm and shotty throughout. Both epitrochlears felt. Chest flaring. Movements rather shallow and restricted. Lungs clear throughout on percussion. Breath sounds vesi- cular throughout. Numerous crackles at bases and lower axillae. Heart: Displaced upward. Sounds clear throughout, normal in character. Pulse regular, fair in volume, tension not increased. Brach- ial and radial arteries markedly tortuous, visible; diffusely sclerotic. Abdomen: Much distended, bulging in flanks. Veins are distended. On palpation very tense-nothing can be felt. No tenderness. Marked fluctuation wave. On percussion, tympany in epigastrium and upper abdomen. Movable dulness in the flanks. Legs are moderately cedematous. Oct. 27, 1908: R. B. C., 4,270,000; W. B. C., 8600; Hb., 53 per cent. Dr. Boggs, Nov. 3, 1908: Scattered along the inner aspect of right upper arm and forearm, and somewhat on ulnar side of forearm, are several subcutaneous nodules, of fairly uniform size, averaging about 5 mm. in diameter. They are quite firm in consistency, the skin moves freely over them, and they are more or less adherent to the fascia, though some of them can be picked up in fingers and moved freely. No pain on pressure over them. On stretching the skin tightly over them, they are seen, in good light, to have a faint blue color, similar to that of the veins. There are a very few similar nodules on the left forearm, mostly on its ulnar aspect; none on the upper arm. There are a few, also, scattered about the back, at the right scapular angle and along the spine. No nodules felt in skin of lower legs. Dr. Boggs, Nov. 18, 1908: The larger subcutaneous nodules noted in the arms, apparently have pulsation on picking them up. The subcutaneous tissue in lower leg is somewhat cede- (6) matous and no nodules can be made out. About the popliteal r205l space on both sides are a few small nodules, corresponding in size and texture to those noted in the arms. No nodules made out in the back, which is (edematous. On costal border are two small angiomata symmetrically placed, just above costo-chondra] articulation of 6th rib on each side. Dr. Boggs, Dec. 24, 1908: The subcutaneous angiomata have increased in size especially on right forearm. Under local anaesthesia an attempt was made to excise one of the subcutaneous nodules at junction of mid and lower third of right arm. On exposure it seemed to have a deep purple color and lay parallel and in close relation to a small cutaneous artery. On attempting to free it from surrounding tissues, the capsule was punctured and the small tumor collapsed, leaving an actively pulsating arterial lesion. This wound was closed, as the tumor could no longer be recognized, and a second node on inner side of elbow was excised with artery lying parallel to and supplying it. It was placed in Zenker's fluid for microscopic examination. This mass, when exposed, seemed to be a direct offshoot of a very sclerotic artery. Dr. Boggs, Feb. 3, 1909: The small angioma, which col- lapsed on attempted excision Dec. 24, has filled up and pre- sents the same picture as before. The number of nodules somewhat increased, especially along extensor surface of fore- arm on both sides. Dr. Boggs, April 21, 1909: Patient continues to fill up rapidly after tapping. General condition otherwise much the same. The clubbing of fingers is perhaps more marked than on admission. Wassermann reaction, negative. Dr. Boggs, June 5, 1909: The subcutaneous angiomata are increasing in size and number on both arms. A new one, in the right hand at middle of the ulnar margin, shows some redness in skin over it. Another, not previously noted, at base of first finger and near it a marked ecchymosis. Patient's general condition is very much as in last note. Parotid glands are rather more swollen, have a soft induration, and are not tender. Dr. Brotherhood, June 10, 1909: 33d tapping. 9 litres (7) [2051 of straw-colored fluid removed, slightly cloudy. Reaction neutral. Specific gravity 1012. Albumin-Esbach, 3| grams per litre. Microscopically-contains few endothelial cells, few mononuclear leucocytes. Dr. Boggs, June 21, 1909: Few scattered subcutaneous nodules on the legs similar, on palpation, to those noted on the arms, but smaller. One or two small ones felt about popliteal spaces on both sides. Dr. Bladen, Aug. 5, 1909: To-day there are two fairly good-sized nodules just over right zygoma, not previously noted. Two new ones on right wrist, and over arms and face are many small red macules from which the blood is easilv expressed, which suggest new formed angiomata. Dr. Fulcher, Sept. 10, 1909: Patient has not been so well for the past few days. The bowels, which have been rather [206] loose throughout, have been more so in the past three days, as many as ten stools a day. Forearms, particularly over the ulnar aspect, present numerous subcutaneous visible and pal- pable nodules, ranging from 0.5 to 1.5 cm. There are prob- ably 20 to 30 on each arm. Skin is movable over them and they are movable on subjacent structures. They appear to be situated chiefly along the course of subcutaneous veins, often being observed at junction of two veins. They are fairly firm -do not diminish materially in size on pressure. Dr. Boggs, Sept. 13, 1909: Emaciation has progressively increased. The angiomatous nodules under skin of arms have increased in size and number, and color shows through skin. Many of them have a reddish-purple tint. Fore- arms are quite thickly studded with these nodules. A few are found on wrists and dorsa of the hands-none on the fingers. There has been no appreciable increase in number of the nodules about the shoulder girdle. None are found on the back. A few small ones are found about the iliac crests and over the sacrum, which were not noticeable eight weeks ago. There are a few of these similar nodules, quite small, but palpable, on the inner side of the thigh along the course of superficial veins. There is a group of nodules, not larger than wheat grains, just below the popliteal space and a few along the course of the long saphenous vein on the right side. (8) On the left leg the nodules in the thigh are slightly more [206] numerous than on the right, and larger. Distribution on the left leg is quite similar to that on right. None made out on dorsum of foot. Dr. Boggs, Oct. G, 1909: The number of the subcutaneous nodules is increasing, the skin over some of the larger is becoming more atrophied, and color shows through quite dis- tinctly, either reddish or purplish. The small nodules on legs are also increasing in number and size. General condition otherwise much as before. Oct. 16, 1909: Abdominal tapping No. 43. 8150 cc. of pale yellow, turbid fluid removed. Specific gravity 1008. Reaction neutral. Albumin 6 grams per litre. Endothelial cells, with eccentric nuclei and granular cytoplasm. Blood Examination, Oct. 22, 1909: R. B. C., 3,940,000; W. B. C., 11,800; Hb., 50 per cent. Dr. Boggs, Dec. 12, 1909 : Patient has gradually sunk into coma with respirations taking on a true air-hunger type. The ascites has disappeared. The skin is wrinkled and loose over the abdomen. There is oedema of the hands and depend- ent portions of the body, moderate in grade, with numerous subcutaneous haemorrhages into deeper layers of the skin, varying from petechiae of small size to several centimeters in diameter. Breath has rather a fruity odor. The dessicated condition of the skin has brought into prominence some small nodules not previously noted, having the same character as those described on the arms. There are several masses on the face above the zygoma, above the tragus, a third just below the right malar; none made out on left side of face. Some impairment of respiration movements in both bases behind and deep inspiratory movements are accompanied by showers of rather dry rales. Nowhere is any tubular breathing made out. Along the left border of the heart there are showers of dry crackling rales at the end of inspiration. Heart sounds are distinct and feeble. Liver dulness begins at rib vi, extends only about 4 cm. in mammillary line. Neither liver nor spleen is felt. Small subcutaneous nodules, noted in legs, have increased in size, apparently involving the skin, and differ from others in show- (9) [206] ing fine radiating vessels about margin, of bright red color. They are very hard and shotty. There is slight oedema of thighs and also of lower leg. The ichthyosis is very marked. Dec. 15, 1909 : The coma persisted and the patient became gradually weaker and died at 9.10 a. m. During this last admission 432 litres of fluid were drawn from abdomen in 47 tappings. This represented a protein loss of 260 grams. Diagnosis: Atrophic cirrhosis of liver; multiple subcu- taneous haemangiomata; ichthyosis simplex. Chronic gastritis and colitis. Autopsy. T. H., aet. 67 years. Ward M. Died 9.10 a. m., Dec. 15, 1909. Autopsy (No. 3310) 9.30 a. m., Dec. 15, 1909. Dr. Winternitz. Anatomical Diagnosis: Cirrhosis of liver; ascites; chronic proliferative peritonitis; collateral circulation established through the diaphragm to the lungs and through the omentum to the parietal peritoneum; arterio-sclerosis with diffuse dila- tation of the aorta and thrombus formation; sclerosis of the peripheral arteries and veins with multiple subcutaneous and visceral haemangiomata undergoing malignant change (endo- thelioma) ; multiple lymph-angiomata of the intestine and stomach undergoing similar change; chronic gastritis with multiple polypi undergoing carcinomatous degeneration; chronic fibrous myocarditis; pulmonary emphysema; chronic fibrous pleurisy; chronic interstitial and peri-splenitis; chronic diffuse nephritis. Only those portions of the protocol which have a bearing upon the subsequent investigations will be given in detail. Body: Is that of a somewhat emaciated mulatto man, 173 cm. in length. Rigor mortis has not y«t set in, and there is no lividity even in the dependent parts. The face is somewhat emaciated and both temporal fossae are conspicuous and the orbits are somewhat depressed. The conjunctivae are slightly pigmented about the periphery of the corneae. The pupils are equal and measure about 4 mm. in diameter. There is a slight arcus senilis. The thorax is barrel-shaped. The ab- (10) domen is scaphoid. The veins over the abdomen are rather [206] more prominent than normal. In the median line beneath the umbilicus is a non-pigmented scar-like area. Perhaps the most noteworthy thing on external examination is the presence of numerous small, subcutaneous nodules (Fig. 1) ; these have been described in detail in the history. The nature of these nodules in general is as follows: They are elevated and vary somewhat in their consistence, some being extremely firm and shot-like; others not quite so firm, and a few can be decreased markedly in size on pressure. They are all of them freely movable on the underlying tissue. In a [207] few the skin is slightly adherent. These tumors vary in size; the largest ones measuring about 1 x .75 x .75 cm., while small ones occur which are almost miliary in size. Their distribu- tion is somewhat as follows: On the right side of the head just above the zygoma; in the region of the temporal veins above the orbit; beneath the malar process; and a small one just anterior to the tragus. The left side of the face seems to be free from tumors, and none are to be made out in the neck. On the trunk the tumors are scanty and irregular. There are none on the anterior wall and axillae with the exception of a single node in the middle of the left upper abdominal quad- rant. On the back there are a few nodules about the right scapula and some large ones in the sacral and gluteal regions. Scattered over the arms and legs, in general parallel to the course of the subcutaneous vessels, are many nodules, the larger being confined to the upper extremities, while those in the legs are somewhat smaller and softer. The relation of these tumors to the vessels can be much more distinctly seen on subcutaneous examination. On reflecting the skin there is found an extreme diffuse thickening of the subcutaneous veins. Over the outer half of the elbow and the upper third of the forearm a number of small, nodular masses are found lying in the superficial fascia. These masses correspond in general appearance to those previously excised and described during life and vary in size from about 6x4x3 mm. to scarcely more than a pin-head. The larger ones are dark red in color and firm in consistence, having a well-defined capsule. The smaller are rather translucent, very much paler in color and firmer (11) [207] in consistence. Although these are very superficial in position they have nowhere invaded the skin proper, and in some places the injection 1 of small capillaries in the skin over the tumors involves the capsule of the tumor, but not the tumor itself. In position these masses have a striking relation to the small branches of the superficial veins. In general they lie parallel to the larger veins and small branches diverge toward them from these trunks. At one point, where the deep layer of fascia has been cut, a small tumor nodule is found lying in the fascia between the muscles, but not invading the muscle. Abdomen: Contains an excess of clear yellowish fluid. The omentum is rolled up, thickened, and extensively adherent to the parietal peritoneum, especially in the left upper quad- rant, and the adhesions are almost entirely composed of vessels averaging 2 to 3 mm. in diameter. Numerous haemor- rhagic areas are scattered through the omental fat. The dome of the right lobe of the liver is adherent to the diaphragm by strong fibrous bands in which are a number of large vessels. These latter penetrate the diaphragm and anastomose with vessels in a mass of pleural adhesions. The spleen is firmly adherent to the diaphragm and to the stomach. These ad- hesions are dense and in some places calcified. The stomach is small, extending only a short distance below the costal margin. The parietal peritoneum is considerably thickened and shows numerous dilated vessels. Otherwise the abdomen and pelvic viscera are normally disposed. Thorax: The ribs are brittle, with thin walls, large spaces and little marrow. The pleural cavities are almost obliter- ated by rather old fibrous adhesions which are easily separated. There is no excess of fluid. The pericardial sac is normal. Heart: Weight 270 gms. Presents nothing of note. Lungs: In addition to the pleuritic adhesions above noted, the principal point of interest is the marked sclerosis of the 1 In order to study the relation of the nodules to the blood- vessels, an injection of Berlin-Blue was begun within twenty minutes after death. Fluid was forced into the left brachial artery under 200 mm. Hg. pressure, the excess being allowed to drain from the cephalic vein. The injection continued for two hours. (12) pulmonary vessels which involves not only the large trunks, [207] but even the smaller vessels which stand out conspicuously on section. Spleen: Shows a thickening of the fibrous trabeculae and marked general sclerosis of the vessels. Stomach: Is contracted: the pylorus is thickened and re- sembles the external os of the uterus. On opening the stomach along the greater curvature a remarkable condition is dis- closed (Fig. 2). The surface is covered with a blood-stained mucous exudate and is everywhere studded with polypus-like masses of varying size. The mucosa, as a whole, is of a deep red color except along the upper portion of the lesser curva- ture. The discoloration is intensified in the mucosa covering the polypi. These polypi vary greatly in appearance, showing every gradation from small sessile masses 0.5 cm. in diameter to those having a definite stalk and a cauliflower-like ex- tremity, some of which have a diameter of 2 to 3 cm. Some of the largest nodules show no pedicle. Such a group is found in a circular arrangement near the cardiac orifice. The periph- ery of this circle is composed of several nodules which are in intimate contact. In the center is a crater-like depression which is covered by an unbroken mucosa. The -extreme diameter of the mass is about 6 cm., height 2 cm., and the diameter of the crater about 3 cm. Section through the polypus-like masses shows them to be for the most part quite superficial, only involving the mucosa and submucosa. The cut surface of these is reddish, mottled by small translucent cysts and grayish white, more opaque areas. In several no- dules, especially those above described in the region of the cardia, this grayish-white tissue composes the entire polyp. In two of these the underlying muscularis is thickened and firmer in consistence, with translucent or colloid strands in- vading and separating the muscle bundles; this involvement of the muscularis extends only about 2.5 cm. beyond the bases of these polypi. Intestines: The peritoneal surface of the intestine is not uniform, but thickened here and there by small milky patches. Many small nodules may be felt in the wall of the gut. On opening the intestine along the mesenteric border the mucosa (13) L207I is everywhere covered with blood-stained exudate. The rugae are prominent and somewhat oedematous. The entire intes- tinal wall is beaded with nodules. Some project slightly and are covered by a darker red mucosa. On transillumination it is seen that these nodules are innumerable and occasionally [208] arranged in chains following the long axis of the bowel. In many places they are confluent. They are seen to lie at differ- ent levels in the intestinal wall, some, as above described, just beneath the mucosa, others near the peritoneal coat, showing through as pale brownish spots. About these latter small vessels radiate in the peritoneum. The individual nodules vary from 2 to 6 cm. in diameter. On section these nodules are sharply defined, rather firm in consistence, and have a pinkish-brown color. It is of interest to note the presence of these nodules in the oesophagus, duodenum, throughout the small and large intestine, and as subsequently shown on histological examination, also in the stomach. There were no gross abnormalities in the mesentery. Liver: Measures 21 x 15 x 9 cm. and weighs 1070 gms. The surface of the liver is very irregular and nodular. The capsule is delicate except at the point of origin of the vascular adhesions above described. The vessels in these fibrous bands have extremely thick sclerotic walls. The liver is firmer than normal. On section the normal architecture is absolutely obliterated and coarse bands of fibrous tissue divide the liver into false lobules of varying size. Small areas of semi-trans- lucent, brownish liver tissue are seen throughout, while most of the tissue between the fibrous bands is yellow and opaque. Here and there small islands of regenerating liver tissue pro- ject from the cut surface. These are circumscribed, pale brownish in color, and not involved by the fibrous overgrowth. Pancreas, Adrenal, Pelvic Organs: Present nothing note- worthy. Kidneys: The blood-vessels are everywhere prominent as a result of a thickening of their walls. There is also a slight increase in connective tissue. Blood-Vessels: The aorta shows extreme sclerosis, and chronic processes are seen with atheromatous ulcers and calci- (14) fled placques lying side by side. There is a diffuse dilatation [208] of the arch and a large thrombus overlies its descending por- tion. The veins also show an extreme grade of sclerosis. Microscopic Notes. Subcutaneous Nodules: Skin nodule No. 1 removed during life (Dec. 24, 1908). The section includes the skin and sub- cutaneous tissues. Lying beneath the skin is a small nodule which is composed of large cavernous sinuses containing well- preserved red blood. The walls of these sinuses are, for the most part, quite thin, lined on either side by flat endothelial cells, and containing between these a pinkish staining ground substance in which an occasional spindle nucleus is to be made out. Toward the periphery of the nodule the walls become slightly thicker and more cellular, resembling fibrous tissue. Skin nodule No. 2, removed during life (Aug. 15, 1909). This nodule was cut in serial sections to show its relation to the vessels. The sections show an overlying layer of skin which is uninvolved by the tumor mass, and lying in the sub- cutaneous fat is a small nodule which is quite cellular. It is composed of many spindle cells which, on tangential section, have long nuclei with pointed ends. These show an outer nuclear membrane and pale protoplasm, in which numerous darker staining chromatin granules are found. The outline of the cells is, for the most part, made out with difficulty, but where they are seen, they are found to be relatively short; their protoplasm staining pale pink with delicate prolonga- tions. The blood spaces described in Section 1 are very much less conspicuous in this section, although the tumor is quite vascular. The walls of the spaces, however, do not correspond in any way to those described in Section 1; for they are made of spindle cells similar to those described in the body of the tumor. One sees, in studying the series, that, although numer- ous small vessels can be seen to enter the nodule in its course, there is no large vessel connected with the tumor at any part. At no place does the mass seem to be connected with nervous tissue. An occasional nerve is found in the subcutaneous tissue, but none of these are in contact with the tumor, nor can any be seen projecting into the mass. The nodule varies (15) [2081 somewhat in its consistence; for the most part, it is quite firm, composed of the spindle cells, above described, but occasionally small, irregular endothelial lined cavities are to be made out. Skin Nodules at Autopsy: In order to study the nature of these vascular spaces to a greater advantage, the brachial artery was exposed and Berlin-Blue was injected. Several nodules were removed from the injected limb and studied in serial sections. In all, about 25 nodules were examined. Suffice it to say that they are all quite vascular, and in many of them there are hsemangiomatous caverns. In the surround- ing subcutaneous tissue many vessels are to be found, but only small ones seem to be in direct contact with the tumor. The larger ones show an interesting change which will be described below. On detailed examination, the nodules are, in general, quite similar. They vary somewhat in their characteristics, and it will suffice to describe completely one in which a composite picture is found, practically including the variations. One sees a tumor mass (Fig. 3) surrounded partially by a definite membrane which is composed apparently of muscle. The cells are long and spindle-shaped, with long, pale staining nuclei, in which a considerable chromatin network can be seen. The protoplasm of these capsule cells is pale pink and stands out in sharp contrast to the cells of the tumor which have much less protoplasm and more deeply staining nuclei. This capsule surrounds the tumor in part only. In other parts it has greatly thinned out and allows the tumor mass to project into the subcutaneous fat. The tumor varies some- what in its consistence; while in one area it is quite cellular and only a small number of blood-vessels can be made out, in other areas it is composed of blood spaces separated from each other by thin walls lined with endothelium (Figs. 4, 5). The spaces are irregular, gradually becoming smaller as they project into the more cellular tumor. As the spaces grow smaller, their walls become considerably thickened. The walls of the large spaces are, in places, composed of but a single layer of endothelium, or may show a double layer, one lining each adjacent cavity (Fig. 6). Between this layer of (16) endothelial cells there is a small amount of pink, homogeneous [2081 tissue in which an occasional slender, deep blue-staining [209] nucleus occurs. The blood in these spaces is well preserved, normal blood. As above stated, there is a simultaneous in- crease in the thickness of the walls with a decrease in the size of the spaces. The walls increase by fusion and by prolifer- ation, and lose their fibrous character and become cellular. These cells resemble in every respect those lining the cavities. In this manner the angiomatous portion of the tumor merges on all sides into the cellular mass above described. It is to be noted, however, that some of the nodules, even small ones, are composed of cell masses without blood spaces. This was brought out very characteristically in the study of one nodule in serial section, which had an hour-glass shape. This hour-glass had for its center a thick-walled blood-vessel. From the center the wall was distended and thinned toward the poles by the tumor mass, and in places the mass pro- truded through into the surrounding tissue. The lumen of this vessel was filled with cells indistinguishable from the endothelial lining and similar in all respects to those making up the tumor mass (Fig. 7). The appearance of this nodule led to a detailed study of the blood-vessels. The Blood-Vessels: There was evident a marked increase in number of the vessels throughout the connective tissue, and these vessels showed great thickening of their walls, which involved all three coats. The large vessels show several types of thickening and diminution of their lumen. The changes are most marked and varied in the intima and subintimal tissue. From a simple oval slit-like lumen (Fig. 8), lined by one layer of cells and surrounded by a greatly increased subintimal layer, poor in nuclei, it is possible to trace by steps, a grad- ually increasing complexity in the form of the lumen. In some vessels the lumen is encroached upon by nodular pro- jections which give it an irregular outline like that of the Fallopian tube. In still others, bridges of tissue extend across the lumen, dividing it into separate channels (Fig. 9). These strands may be lengthened and folded so as to give the lumen a labyrinthine appearance. The bridges are lined by a single (17) [209] layer of endothelium and made up of the thick subintimal coat. The small vessels are likewise greatly increased in number, many of them showing a marked thickening of their walls. While some of these show an increase in all their coats, the changes are, for the most part, in the endothelial lining. The endothelium may be increased uniformly to several layers, or it may proliferate in a nodular manner, and project into the lumen like a polyp (Fig. 10). In other vessels the masses of endothelium seemed to lie free in the lumen and no connection with the wall could be made out in serial sections. In another group of vessels the endothelium forms nodal thickenings of several layers at different points on the wall. Finger-like columns of cells project into the lumen from these nodes and at times the space between the fingers is bridged by a single cell. In this way the lumen is divided into two or more parts, forming angiomata (Figs. 11, 12, 13, 14). In still other vessels multiple caverns are formed in a different manner. Here the endothelium seems to dip into the wall, or even to push the wall before it into the surrounding tissue, as bays push in from the borders of a lake. The necks of these bays are narrow and may be closed by a mass of endothelium, when we have separate caverns in juxtaposition (Figs. 15, 16). This is a definite new formation of blood-vessels by budding similar to that seen in granulation tissue and in the embryo. In correlating the foregoing detailed studies, we see first, a striking generalized sclerosis of the arteries and veins, cor- responding to that described in the subcutaneous vessels. This thickening may be seen in all the coats, leaving a slit-like lumen, or there may be an irregular proliferation of the intimal tissue in nodes, or strands, which divide the lumen into narrow channels, or obliterate it altogether. Associated with this narrowdng of the larger stream bed, there is a development of many small vessels. But here again many of the small vessels show marked thickening and, in some, the changes are confined to the endothelium alone. This endothelial over-growth is expressed in different modes. (18) The simplest type is found in a loop-like dipping of the [209] endothelium into the surrounding tissue. The loop may then be cut off in its narrow part, leaving a separate cavity. Again, nodal proliferation may take place at several points, on the wall and these nodes may be prolonged to form bridges dividing the vessel into different compartments. Lastly, the nodal proliferation may fill the vessel with a solid mass of cells and even invade the surrounding tissue. In this way we trace the formation of cavernous angiomata and of solid tumors to the same basal process, namely, the vegetative overgrowth of endothelium. In comparing the larger nodules of the subcutaneous tissue, we find a close relation to the changes described in the small vessels, some of these nodules showing cavernous structures in which the endothelium has obliterated the cavities in varying degrees; and in others, solid masses of endothelial cells without any trace of a preceding angioma. The question arises whether these nodules are all primary or in part metastatic. From the observations above described-that isolated masses of endothe- lial cells occur in some of the smaller vessels, and that no root or connection with the neighboring wall could be found in serial section, it seems probable that metastases play some part in the multiple tumor formation. Intestinal Nodules: These all arise in the submucosa. They vary considerably in size; the smaller ones do not invade either the mucosa or the muscularis, but as they grow larger these structures are gradually involved. The tumor mass in some places pushes the mucosa outward and is separated from it by the muscularis. In other areas this line of demarcation is not apparent (Fig. 17), and one sees the tumor invading directly the villi. Such villi no longer show their normal structure; they are dilated and club-shaped, entirely denuded of their surface epithelium, and show only an occasional small atrophic gland in their bodies. The villus, except where it is replaced by tumor cells, is composed of dilated blood-vessels and areas of round cell infiltration. As the tumor invades the [210] muscular coat it follows the course of the vessels in finger-like projections which gradually obliterate the muscle bundles (Fig. 18). (19) [210] The nodules vary considerably in structure. Some are quite solid, others contain numbers of well-formed blood- vessels (Fig. 19), and others again show large irregular cavi- ties lined with endothelium (Fig. 20). These cavities do not contain blood, but only precipitated albuminous material. The nature of the above cavities is best shown in the portion of intestine injected at autopsy. This part of the gut was first injected through the mesenteric artery with carmin-gelatin, and then the lymphatics of the same piece were injected with India ink. The India ink injection was not altogether success- ful, but did enter some of the nodules. On serial section of the injected nodules, their general charactertistics are as described above. The carmin-gelatin has filled all the blood-vessels in the several intestinal coats and in the tumor nodules. Even the finest capillaries are injected. It becomes apparent at once that many of the large vessels and spaces with endothelial lining contain neither blood nor injection mass, but only the albuminous material previously noted (Fig. 20). These cavities lie within the tumor nodules and resemble exactly those described in the subcutaneous tissue, except that they do not contain blood. The cavities are divided into compartments by strands of tissue, varying in thickness. The thinner strands consist of two layers of endothelial cells with a very slight fibrous tissue between. In the thicker ones the walls are made up of numerous layers of endothelial cells similar to those lining the cavities. The endothelial cells are spindle-shaped, with long blue-staining nuclei and scanty pink protoplasm. Here and there the nuclei are more vesicular or show mitoses. Selecting a node which has been injected with India ink, as well as carmin, we find that the cavernous spaces are filled with the black mass (Fig. 21), and on tracing this through a series of sections, it is found that one of the large injected lymph vessels of the submucosa opens directly into the cavity. It is, therefore, certain that the angiomata of the intestine arise from the lymphatic vessels. That they are not haeman- giomata is evident from the fact that they do not contain any of the carmin-gelatin, which fills all the blood-vessels, but only the India ink, which is confined to the lymphatic channels. (20) The cavernous areas merge on all sides into solid tumors, [210| just as the areas described in the haemangiomata from the subcutaneous tissue. Scattered through the more solid parts of the nodules are narrow channels lined by endothelium. These do not contain blood or carmin-gelatin and are evidently not blood-vessels. On tracing them through serial sections, they gradually in- crease in size and merge into cavernous spaces, or into large lymphatic vessels (Fig. 22). These latter show large pro- jections into the lumen from either wall, which are apparently valves. These lymphatic channels are especially numerous about the larger blood-vessels which intersect the tumor nodules. The blood-vessels themselves show a general thickening of their walls. Here and there the endothelium of the lymphatic channels is proliferated to form nodes on the vessel wall, pro- jecting into the lymph spaces. The cells in the nodes have the characteristic perithelial arrangement, with the strands of cells at right angles to the axis of the vessel (Fig. 23). In many instances this nodular growth completely surrounds the blood-vessel. In resume, then, we find that the endothelium of the in- testinal lymphatics has proliferated at many points to form nodular tumors. In these tumors many of the lymphatic vessels are obliterated by the endothelial masses. Other ves- sels are dilated, and here and there the proliferation has resulted in definite cavernous angiomata.1 The structural similarity of the subcutaneous and intestinal tumors suggests a possible analogy in their mode of formation. In the subcutaneous tissue there is a marked obliteration of the larger blood-vessels (generalized sclerosis) and an active production of new blood-vessels has taken place. In these small vessels the endothelium shows marked proliferative growth leading to the formation of angiomatous caverns and to solid endothelial tumors. Similarly, from some cause un- known, there has been an active proliferation of the endo- 1 Tumors of similar structure were found in the oesophagus, stomach, mesentery, and adrenal capsule, as well as in the intestines. (21) [210] thelium in the intestinal lymphatics, leading, again, to the production of cavernous angiomata and solid endothelial tumors. Stomach. A. Mucosa in General: The gastric mucosa (Fig. 24) is thinner than normal and is everywhere covered by an exudate composed of mucus, red blood cells, and desquamated epithelial cells. The mucosa presents a picture of diffuse chronic gastritis with increase of fibrous tissue and round cell infiltra- tion. In many places the villi are denuded of epithelium, but, as the submucosa is approached, the glandular structures become more prominent and show many changes. Some glands are atrophic, with degenerated epithelium. Others are hypertrophied and show as tortuous crypts or as groups of normal gland tissue in cross-section. The glands may become greatly dilated at their bases and be lined either by columnar mucous cells or by a flat epi- thelium. B. Polypi: These are so numerous and show such complex changes that we shall only describe the types of variation observed. The simplest polypi are sessile and show a mass of acini separated by a small amount of fibrous tissue (Fig. 25). Many of the acini are slightly tortuous and all are lined by normal goblet cells (Fig. 26). All the other types of polypi show not only glandular hyper- trophy, but also chronic inflammatory changes. In some of them the inflammatory change predominates and there are [211] large areas where no acini are found, but only masses of fibrous tissue with round cell infiltration. Many cells in these areas show a hyaline, pink-stained protoplasm, and rather flattened dark blue nuclei. Some of these cells show the hyaline portion divided in small round masses about the size of a red blood cell, and the nuclear material as pale blue spots. In others the cell membrane has disappeared and the round particles are scattered in the interstitial tissue (Fig. 27). In the next group of polypi the hypertrophy is modified by the inflammatory process and is varied more from normal structure (Figs. 28, 29). The acini are tortuous or dilated (22) and may show normal mucous cells or flat epithelium (Fig. [211] 30). In other areas the acini show an infolding of the epi- thelium which may form subdivisions of the acinus (Fig. 31). Here the epithelium may change from the normal goblet cell to a still longer cell with large central nucleus and granular protoplasm. Some of these nuclei are dividing (Fig. 32). Still other acini may be prolonged toward the base of the polyp. These show several layers of cells which have lost their secreting character and masses of protoplasm occur which have more than one nucleus (Figs. 33, 34). In still another group of polypi the stalk is more prolonged and narrow, and covered by the inflamed mucosa (Fig. 35). At the cauliflower-like extremity, however, we see some chronic inflammation and simple hypertrophy, but by far the greater number of acini show the marked abnormalities described in single crypts of the foregoing group (Fig. 36). That is, the acini are irregular and tortuous, with large columnar epithelial cells of undifferentiated type. A further abnormal development is seen in the next two types of polypi. These are sessile and composed wholly of convoluted glands. In the first of these there are some crypts with normal mucous cells. But most of the glands have high columnar epithelium with actively dividing nuclei (Fig. 37). At the base of the polyp, where the dilatation and epi- thelial growth are most marked, some strands of epithelial cells have penetrated the basement membrane into the ad- jacent tissue (Fig. 38). In the second type all the crypts are lined by an actively proliferating epithelium. Toward the base of the polypus the acini dilate and the epithelium and basement membrane pro- ject as irregular masses into the lumen which is filled with mucus and cell debris. Where these cavities invade the mus- cularis they are often imperfect and broken on one side (Fig. 39) The nodules of epithelium on the basement membrane may project either toward or away from the lumen (Fig. 40) The epithelium is of a definite vegetative character. The protoplasm stains deep blue, and is divided irregularly, often containing two or more deep black, or vesicular nuclei (Figs. 41, 42). (23) [211] Many other polypi were examined in which the above de- scribed changes occur in varying degree and association. And it is to be noted that there are areas in the mucosa showing can- cerous metamorphosis without polypus formation (Fig. 43). In brief, we find in the stomach extensive chronic gastritis with multiple polypus formation. In these polypi we find asso- ciated with the gastritis, simple hypertrophy, benign and ma- lignant adenoma, and cancer, with extensive invasion from multiple points of origin. This case presents many unique features and is of interest, not only as a remarkable example of multiple heterologous tumor formation, but also as a basis for some generalization on the origin of tumors. After a fairly wide examination of the literature, we were unable to find any like instance of multiple subcutaneous haemangio-endotheliomata. Nor did we discover any record of a similar lymphangio-endothelioma formation throughout the entire intestinal tract. Lastly, also, we were unable to find any instance in which so many diverse types of epithelial tumor formation occurred in one stomach. So that, so far as we know, each of the three groups of tumors, present in this one case, is unique in the extent and character of its occur- rence. And that all three should have occurred in one indi- vidual is truly remarkable. It is inevitable that such an extraordinary coincidence of multiple tumors of different type in one individual should lead to some speculation as to possible common factors in their origin. We shall suggest therefore some hypothetical ex- planation of the facts observed. Turning our attention, first, to the general picture, we find in an old man, with a marked alcoholic history, extreme generalized sclerosis of arteries, veins, and parenchymatous tissues. In the blood-vascular system we find an extreme grade of sclerosis affecting the aorta and larger arteries throughout the body, and a very marked phlebo-sclerosis, as well. In the subcutaneous tissue this sclerosis has resulted in obliteration of much of the stream bed and a compensatory General Summary and Conclusions. (24) formation of new vessels. These new blood-vessels are formed L211] by the proliferation of the endothelium, as in granulation tissue. But in many places the endothelium loses its power of organization with a resultant exuberance of endothelial growth into cavernous angiomata. By a still further loss of this organizing force, the vegetative function of the cell pre- dominates and we have the formation of solid endothelial tumors. The solid tumors may, in turn, give rise to metas- tases. In considering the proliferation of the lymphatic endo- thelium in the intestine, we have no obvious factor, like the generalized sclerosis of the blood-vessels. It may be suggested, however, that the extreme portal obstruction, associated with the cirrhosis of the liver and the proliferative peritonitis and ascites, may play a part somewhat analogous. It may further be suggested that portal obstruction leads to over-loading of the lyrtiph channels and that, in the attempt to compensate for the extra load, proliferation and new formation of lymph vessels may take place. Here again a loss of organization may lead to the development of cavernous angiomata and of solid endothelial tumors. The changes in the gastric mucosa offer some points an- [212] alogous to those considered in the discussion of the formation of the endotheliomata. We may suggest a sequence here somewhat as follows: Cell destruction as a result of chronic alcoholism. Chronic gastritis as a protective effort on the part of the tissue. Regeneration in excess with polypus formation. And lastly, as a result of loss of organization, lawless growth with the pro- duction of adenoma and carcinoma, at many points simul- taneously. While the foregoing studies throw a certain, and we think important, light on the origin and method of tumor formation, it is equally certain that other factors, as yet unknown, play an even more important part in the determination of lawless cell growth. No attempt will be made to give the extensive literature on the occurrence of multiple tumors. This field, in general, has been covered recently by Woolley (Bost. Med. and Surg. (25) [212] J., 1903, cxlviii, 1), while Verse (Arbeiten aus den patho- logischen Institut zu Leipsig, 1908) has discussed exhaustively their occurrence in the stomach. N. B.-In conclusion we wish to thank Professors L. F. Barker and W. S. Thayer for permission to use the case, Professor W. H. Welch for his interest and encouragement, and Dr. H. M. Evans for assistance in the injection of the specimens. (26) THE JOHNS HOPKINS HOSPITAL BULLETIN, JULY, 1910. Fig. 1.-Drawing of right fore-arm showing subcutaneous nodules. Fig. 3.-Subcutaneous nodule of mixed type with angiomatous and solid portions. PLATE XII. Fig. 2.-Photograph of stomach opened along the greater curvature. Fig. 4.-Same as Fig. 3. Higher magnification showing capsule and blood spaces. THE JOHNS HOPKINS HOSPITAL BULLETIN, JULY, 1910. PLATE XIII. Fig. 7.-Center of hour-glass nodule. The lumen of the vessel is completely filled with endothelial cells. Fig. 5.-Same as Fig. 3. Higher magnification showing charac- ter of endothelial cells. Fig. 8.-Sclerotic subcutaneous vessel show- ing slit-like lumen. Fig. 6.-Same as Fig. 3. Higher magnification showing character of angiomatous portion. Fig. 9.-Another vessel showing extreme proliferation of inti- mal and subintimal coats with labyrinthine lumen. THE JOHNS HOPKINS HOSPITAL BULLETIN, JULY, 1910. PLATE XIV. Fig. 10.-Polypus-like outgrowth of endothe- lial lining of a small vessel. Fig. 13.--Subdivision of larger vessel by strands of endothelium. Fig. 11.-Outgrowth of endothelial strands in small vessel forming separate channels. Fig. 14.-Valve-like strands in small vessels. Fig. 12.-Same as Fig. 11. Slightly different focus. Fig. 15.-Formation of separate channels by budding. THE JOHNS HOPKINS HOSPITAL BULLETIN, JULY, 1910 PLATE XV Fig. 16.-Same as Fig. 15. Fig. 18.-Intestinal nodule invading muscularis. Fig. 17.-Intestinal nodule invading villi. Fig. 19.-Intestinal nodule showing larger blood-vessels. THE JOHNS HOPKINS HOSPITAL BULLETIN, JULY, 1910. PLATE XVI. Fig. 20.-Intestinal nodule showing lymphangiomatous caverns. Fig. 22.-Intestinal nodule showing dilated lymphatics with valves. Fig. 21.-Intestinal nodule injected with India ink. White lines crossing the black show injection mass. Dark masses without lines show carmin-gelatin in the blood-vessels. Fig. 23.-Same as Fig. 19. Higher magnification showing endothelial proliferation in the lymph spaces. THE JOHNS HOPKINS HOSPITAL BULLETIN, JULY, 1910. PLATE XVII. Fig. 24.-Chronic gastritis. Fig. 26.-Same as Fig. 25. Higher magnification, Fig. 27.-Chronic gastritis showing " Russell's Bodies.' Fig. 25.-Sessile polypus. THE JOHNS HOPKINS HOSPITAL BULLETIN, JULY, 1910. PLATE XVIII Fig. 28.-Cauliflower polypus Fig. 29.-Cauliflower polypus. Fig. 31.-Same as Fig. 29. Higher magnification of aci- nus, showing papillomatous proliferation of epithelium. Fig. 30.-Same as Fig. 28. High magnification showing tortuous and dilated acini. THE JOHNS HOPKINS HOSPITAL BULLETIN, JULY, 1910 PLATE XIX Fig. 32.-Same as Fig. 31. Higher magnifica tion showing atypical epithelial cells. Fig. 33.-Crypt from Fig. 28 Fig. 34.-Same as Fig. 33. Higher magnification show'ing prolifera- tion of epithelium and multinuclear cells. Fig. 35.-Cauliflower polypus showing adenomatous change. THE JOHNS HOPKINS HOSPITAL BULLETIN, JULY, 1910. PLATE XX Fig. 38.-Acinar epithelium invading basement membrane. Fig. 36.-Same as Fig. 35. Higher magnification Fig. 37-Portion of adenomatous polypus showing normal and undif- ferentiated acinar epithelium. Fig. 39.-Cancerous polypus invading muscularis. THE JOHNS HOPKINS HOSPITAL BULLETIN, JULY, 1910. PLATE XXI Fig. 40.-Same as Fig. 39. Higher magnification of acinus. Fig. 42.-Same as Fig. 41. Fig. 41.-Same as Fig. 40. Higher magnification showing cancerous character of epithelium. Fig. 43.-Cancerous metamorphosis of mucosa uninvolved by polypus.