THE ANATOMY AND DEVELOPMENT OF RODENT ULCER. A BOYLSTON MEDICAL PRIZE ESSAY FOR 1872. BY J. COLLINS WARREN, M.D. BOSTON: LITTLE, BROWN, AND COMPANY. 1872. CAMBRIDGE: PRESS OF JOHN WILSON AND SON. NOTE By an order adopted in 1826, the Secretary of the Boyls- ton Medical Committee was directed to publish annually the following votes : Ist. That the Board do not consider themselves as approv- ing the doctrines contained in any of the dissertations to which premiums may he adjudged, 2d. That in case of publication of a successful dissertation, the author be considered as bound to print the above vote in connection therewith. The cases quoted in the text occurred in the services of Dr. Hodges and Dr. White, at the Massachusetts General Hospital. The accompanying plates were drawn upon stone by Dr. H. P. Quincy, artist to the Massachusetts General Hospital, from the drawings of the author. 2 Park St., July, 1872. RODENT ULCER. It is hardly necessary to preface these remarks with the statement that the disease, with which most of ns are familiar under the name of Rodent Ulcer, is still but very imperfectly understood by English and American pathologists. The Surgeon, indeed, struck with its strong clinical peculiarities, is impressed with the idea that there is something “ cancerous ” in its nature, yet looks in vain for a solution of the problem by the Microscopist. In other countries, the name Rodent Ulcer is almost unknown. The disease is not recognized as a peculiar affection standing by itself, but is classi- fied with other diseases, such as cancer of the skin or chronic inflammatory processes, according to the views of the writer. A glance at the nomenclature will serve to show the existing confusion. It has been variously termed, cancroid Ulcer, ulcere rongeant, ulcere chancreux du visage, cancroid de la face (Lebert), Rodent cancer (Moore), flache epithelial Krebs 6 (Billroth and Thiersch), and lastly, the well-known names, Lupus Exedens, and noli me tangere. It will he seen that many believe it to be a form of cancer; others have been induced by the gross appearances to liken it to lupus, or even chancre, while the older writers placed it under chronic inflammations, an opinion shared by a large num- ber of modern pathologists. To the practitioner the disease in question is familiar, in its earlier stages, as a small ulcer situated on the upper part of the face, generally near the nose or eye. Its superficial character, its raised and hardened edges, and extremely slow progress, together with the perfectly healthy appearance of the tissues immediately adjoining, serve to distin- guish it from any other form of ulcer, occurring in this region. The age of the patient is also characteristic, it being rarely seen in an individual under forty. The diagnosis is generally not difficult. The patient usually states that it has been preceded in former years by an annoying pimple, covered fre- quently by a small scab. This may disappear from time to time, but does not remain absent many months. The ulcer, once fairly formed, slowly, but steadily spreads, until, after the lapse it may be of years, the nose, eyelid, or the eye itself is 7 attacked by the disease. The hones of the face, even, are not spared in the later stages, and frightful deformities result, which have earned for it the significant names given above. Curiously enough, the lymphatic glands through all this remain untouched. Similar ulcers have been reported as occurring on the breast, and ex- ternal genital organs, but no very reliable accounts of such cases are to be found. Statistics show that there is very little difference to be observed in regard to sex, though nearly all of the cases which have come under the observation of the writer happen to have been males. In Holmes’ Surgery * the disease is treated of under “ ulcers.” This writer finds many points in which it resembles lupus, yet its difference is proved, he says, among other distinctions, by its occurring as generally in the later half of life, as lupus does in the earlier and by its affinity with cancer, and not with struma. The minute anat- omy is not spoken of. Paget f 'm his article on Rodent Ulcer says : “It has been confounded by many, with different forms of cancer, yet it is distinct from them in structure, as well as in history, and had better be * Holmes’ Surgery, i. 210. t Paget’s Surgical Pathology, edition of 1870. 8 described by some name, which may not add to the yearly increasing confusion that arises from the use of terms expressing likeness to cancer. . . . Yot only is the Rodent Ulcer usually unlike that of cancer in its aspect, rate and mode of progress, but the tissues bounding it, and forming its base and walls, never contain any epithelial, or other cancerous structures : they are infiltrated with only such structures as may be formed in the walls of common chronic ulcers. I have examined, very carefully, six of these ulcers removed by excision, and have never seen, in, or near them, a structure resembling epithelial, or any other form of cancer.” Such is the unqualified opinion of one of the most eminent writers in surgical pathology. We shall see, however, that this opinion is by no means generally accepted, even in England. Yet it is but a confirmation of Hutchinson’s whose reports on Rodent Ulcer are among the most elaborate that we have, and which deserve there- fore more than a passing notice. They are based on the observations of forty-two cases, which are all given in detail. In case fourteen he gives an account of the microscopical examination ; his sec- tions, made with a Valentine’s knife, and torn to pieces with needles, “ showed on examination none * Medical Times and Gazette, 1860. 9 of the elements of epithelial or scirrhus cancer. Its structure consisted of fibroid tissue, in which were imbedded numerous nucleated exudation cells. I may here remark that this sketch may be taken as applying, generally, to all the cases of rodent ulcer, in which I have had an opportunity of using the microscope.” In cases fifteen and sixteen it is doubtful, however, whether he has to deal with epithelial cancer, or true rodent. lie says : “No doubt the boundary line between these affections, perfectly distinct as they are in most instances, is not an abrupt one. Transitional cases now and then occur and baffle all accurate classification. . . . No decisive evidence was offered by the micro- scope. There were also some dimly granular, near- ly circular corpuscles, like the enlarged free nuclei of young cells of epithelial cancer, but these too, were very scanty and doubtful. I could not satisfy myself as to the existence of any true epithelial particles.” He states again, at the conclusion of his report, that sections of these ulcers show cell structures found only in organizing fibrous tissue. He there- fore concludes that although it deserves the name of locally malignant, it should not be called cancer of the skin, as it is liable to be confounded with other forms of cutaneous cancer, epithelial scirrhus, 10 &c.; essentially different from it, and of a far higher degree of malignancy. Antagonistic to these views are those of Mr. Moore,* in whose monograph this disease receives the epithet of Rodent Cancer. The microscopical investigations of this observer, as well as those of Hutchinson, can hardly be said to meet the present demands of science. The method chiefly employed was that of picking small fragments to pieces, with needles, but when not combined with the examina- tion of very thin sections, taken in various direc- tions from the fresh or hardened specimens, it can hardly claim to settle a very doubtful point like this. To this somewhat primitive method of investigation may be ascribed “ the yearly increasing confusion ” which Mr. Paget complains of. Mr. Moore, in giving an account of his micro- scopical examinations, says : “ The microscopic characters of the solid infiltrating substance which constitutes the disease are not precisely those of any natural texture, yet they do not ordinarily so much deviate from the appearances of cutaneous epithelium, and of granules, as to be entitled to the epithet malignant.” Yet he adds, immediately be- low, “ I have found parts of the diseased substance presenting a minute textural composition, precisely * Moore on Rodent Cancer, 1867. 11 answering to that of the epithelial form of cancer.” These latter appearances he finds only occasion- ally; more frequently he says it is made up of such innocent, microscopic corpuscles, that it has been likened to chronic nicer of the leg, or to a perfora- ting nicer of the stomach. He is obliged, there- fore, after all, to fall back on its clinical peculiarities in order to defend his theory of its cancerous na- ture. He endeavors to explain the exemption of the lymphatic glands, by the slowness of its growth, by the innocent nature of its material, and by its relation to the lymphatic vessels. The majority of the French and German writers place it among the Epitheliomas. Lebert * divides epithelial cancer of the face into two varieties, viz.: cancer of the lip, and cancer of the rest of the face, and includes Rodent Ulcer with the latter, Thierschf makes two varieties; the flat, and the deeply infiltrating (tiefgreifende). Ulcers corres- ponding in description to Rodent are described as flat epithelial cancers. He also quotes Schuh, as giving them this name. Forster J finds in Rodent Ulcer, only the elements of an ordinary granulation tissue. Billroth’s § classification of epithelial can- * Lebert, Traite des Maladies Cance'reuses. t Thiersch, Epithelial Krebs, 1865. 1 Porster, Pathologische Anatomic. § Billroth, Surgical Pathology. 12 cer corresponds with that of Thiersch. He takes cancer of the lip as the type of the infiltrating, or more malignant form. This contains both large and small epithelium cells, while the flat epithelial cancer is made up of cylindrical masses of cells which resemble the small round cells of the rete. He formerly described the latter as cicatrizing or contracting epithelial cancer, or scirrhus cutis, to define it more accurately from ordinary epithelial cancer; but now makes no special sub-division of it, and considers it merely as the mildest form of cancer of the skin. He identifies this variety with the Rodent Ulcer of Hutchinson, although his de- scription does not correspond with it fully; for he alludes to cicatrization as one of its peculiarities, and, as we have seen, at one time named it accord- ingly. Moreover, he says, “ There are also cases in which there is no ulceration at all, hut only infiltration of the skin with the formation of epider- mis crusts, and subsequent cicatricial contraction.” Evidently, the flat cancer of the skin is not con- fined by him to Rodent Ulcer alone. These quotations selected only from those writers who have made independent investigations serve to show the prevalent opinions. The majority of English observers, it will be seen, believe in the non-malignant character of the 13 anatomical changes, yet there is a lurking sus- picion in the minds of many that this ulcer is some- thing more than the result of a mere chronic inflammatory process. Those who believe it to be cancer, on the other hand, failing to find the anato- mical structures peculiar to that disease, have been compelled to fall back upon its clinical peculiarities to support their theory. As the microscope alone can settle a disputed point like this, they have simply failed in their demonstration. The elaborate reports and beautiful plates of Thiersch convey a very perfect idea of the minute anatomy of the flat epithelial cancer. In alluding to Rodent Ulcer, however, he does not leave it perfectly clear, whether he considers the two identical. This glance at the literature of the disease ex- plains readily the prevailing uncertainty in this country, in regard to its true nature. The following cases are reported with the hope of throwing light on what, to the medical world at large, may fairly be said to be a somewhat obscure point in pathological anatomy: 14 REPORT OF CASES. Case I. —J. L., set. 66, presented himself for treatment Feb. 7, 1870. First noticed a “ wart ” or “wen” on the left side of the upper lip, eight years ago, which was kept continually irri- tated, by shaving and picking. This was removed by an operation, and in the cicatrix an ulcer formed which has steadily increased in size until a portion of the left ala nasi has been destroyed, and the whole of the upper lip, from the septum nasi, to the angle of the mouth. The disease has also at- tacked the septum, and the alveolar process. The edges of the ulcer are somewhat elevated, ragged, and covered with brown scabs. There are no en- larged glands in the neighborhood. The patient is made miserable by difficulty in eating, and by a constant escape of saliva. On the 10th the patient was etherized, and a greater part of the disease wms removed by the knife, and the whole surface burned with the Oalvano-Cautery. The wound healed readily, leaving considerable deformity, for which two plastic operations afterwards were performed. On October 4th of the same year, there had been no return of the disease. Microscopical examination. The fragments re- moved were taken from the elevated borders of the 15 nicer chiefly, and when examined in the fresh state by scraping the cut surfaces, or by tearing small fragments with needles, nothing resembling an epithelial cell was seen. The specimen was then hardened in a solution of chromic acid (one part of acid to one hundred parts water), remaining in this solution for a few days, and then preserved in alcohol about sixty per cent in strength. Thin sec- tions made in different directions showed the pres- ence of a large amount of fibrous cicatricial tissue, the bundles of fibres interlacing one another in vari- ous directions. There were very few small round cells such as are seen in inflammatory growths. At considerable intervals in this tissue were found small masses of epithelial cells. These cell-masses were narrow and elongated in shape, occasionally sending out small branches, on one side or the other. The cells of which these masses were com- posed were small in size, and resembled the cells of the rete Malpighii more nearly than those of any other epithelial structure. They were, with difficulty, colored in carmine, and contrasted in this respect with the cells of the rete, which imbibed the coloring matter readily. In the centre, or at one end of these cell clumps, the cells were fre- quently packed together in concentric layers, form- ing the well-known epidermic balls. These were, 16 however, small in size, and not always present. The newly-formed epithelial structures were situ- ated some distance from the epidermis, which was quite narrow, resembling that which usually covers a cicatrix. There was none of the adjoining healthy skin in any of the fragments removed. Remarks. The growth appeared, at the first glance, to consist solely of hypertrophied connec- tive tissue, which evidently gave rise to the elevated edges at the border of the nicer. It was only after a somewhat careful search, that the epithelial dis- ease was discovered. Case 11. James 0., set. 65, presented himself for treatment Sept. 16, 1870. Thirty-two years ago he first noticed a pimple on the left temple, near the eye. This was generally covered with a scab; it underwent no considerable change until six months ago, when he fell and scratched it. Since then it has gradually increased in size, until now there is an ulcer three-quarters of an inch in diameter, of an oval shape, and with a raised rim about a quarter of an inch in thickness. The sur- face has a dirty brownish look, and discharges very slightly. The surrounding skin is perfectly healthy. The disease does not seem to penetrate below the cutis vera. The nicer was carefully dissected out 17 with the knife, and the edges of the wound brought together with sutures. The wound healed rapidly, and there has been no return of the disease since. Microscopical examination. An examination in the fresh state, by picking small fragments apart, showed simply a few connective tissue fibres, and small round or oval cells. The specimen being then hardened in the same manner as described in Case 1., a large number of vertical and horizontal sec- tions were made with the razor. These were colored in carmine, and preserved either in Canada balsam or glycerine. A vertical section showed the surface of the ulcer to be made up of irregularly-shaped masses of epi- thelial cells, separated by deep clefts. These cells were mostly broken down, and heaped together without order, their nuclei being in but few in- stances apparent. The base and edges of the ulcer were composed of a fibrous, vascular, alveolar stroma, containing in its meshes masses of cells. These cells, though small in size, were distinctly epithelial in character. Both vertical and horizontal sections showed the cell masses, nests, or cylinders, as they have var- iously been termed, to vary considerably in shape. The most frequent arrangement Avas in elongated, more or less cylindrical-shaped masses, anastomos- 18 ing with other similar masses, and presenting fre- quent constrictions. (See Drawing 6.) At other points, generally near the periphery of the growth, the form was oval. The most marked peculiarity of the cells was their small size, con- trasting greatly with the large pavement epithe- lium cell that is found in cancer of the lower lip. They contained an oval, well defined granular nucleus, which colored readily with carmine, at those points where the structure was not beginning to break down. When the cells were not closely crowded together, their form was either globular, or the borders of the cells were not well defined, the nuclei appearing imbedded in a continuous mass of protoplasm. At certain parts of the edges of these cell structures, the cells resembled cylinder epithelium, reminding one of the shape and ar- rangement of the epithelium immediately sur- rounding the papillae of the skin. Nearly all of the cell-nests contained the epidermic balls, in the immediate neighborhood of which the cells were, of course, more or less flattened out. (Drawing 6.) These balls, however, are by no means as large, nor did they catch the eye as easily as those very striking forms which predominate to such an ex- tent in the large cell epithelial cancers, like cancer of the lip. It may be said of the cells in general, 19 that they resembled the smaller cells of rete muco- sum, more nearly than any other form of epi- thelium. At the periphery of the new growth, particularly in the parts surrounding rather than those underlying the ulcerated surface, the nests of cells did not have the appearance of epithelium. Here the epidermic balls were wanting, nor was there that regularity in the arrangement of the cells which is characteristic of epithelium. The cells were much smaller than those in the central masses and resembled rather the “ indifferent ” or “ wandering ” cells which were seen in numbers in the neighborhood, where they appeared no longer in isolated masses, but infiltrated the tissues. It was interesting to notice that these peripheral cell-nests were penetrated, almost in every case, by a small vessel which generally ran through the centre of the mass. This central vessel was never seen, on the other hand, in any of the epithelial clusters. (See Drawings, 3, d.) The epidermis, as it approached the diseased part, was somewhat thickened, but tapered off to a fine point at the edge of the ulcer. Beneath the rete mucosum of that part of the skin which cov- ered the borders of the ulcer, the small wander- ing cells were quite numerous. These cells were not collected in nests, but infiltrated the cutis, and 20 at many points came in direct contact with the cells of the rete. Here the well-defined border which separates the rete from the papillae, was lost, and the epithelial and connective tissue cells appeared to mingle with one another on the border line. The hair follicles, which were quite numerous on one side of the nicer, being probably those of the eyebrow, appeared to be unaltered except in those parts which were actually invaded by the disease ; here the hair shaft had disappeared, leaving behind a collapsed tube, lined with cylinder epithelium. These tubes became smaller as the edge of the nicer was approached, there being no visible altera- tion in the cell contents, and finally disappeared entirely. The sebaceous and sweat-glands appeared to be unaltered. The examination of this specimen brings out several points of interest. "We find here again epithelial structures, and of the same general char- acter as in Case 1., resembling the small cells of the rete. An appearance worthy of notice, as being frequently met with in certain forms of cancer, is seen here at several points, viz.: the fusion of the protoplasm of neighboring cells so as to form one continuous mass, in which the nuclei are imbedded. This was shown well in the specimen from which 21 Drawing 6 was taken. The epithelial structures are more numerous than in the last case, and the branching and anastomosis of the cell-nests more general. The central cell-nests are fairly repre- sented in Drawing 6. The peripheral nests resem- ble in shape Drawing 3, though here the develop- ment has not reached a sufficiently advanced stage to show many epithelial cells. Here we see the central thread of fibres, dividing the alveolus in its long diameter. A still earlier stage is represented in Drawing 4, at a point situated on the extreme borders of the growth. Here the cells resemble the connective tissue cells, and the axis of the alve- olus is represented by a delicate blood-vessel. The different stages of development observed in this specimen are well shown in the sections from which the above drawings were taken. Case HI. Male, set. 42. Disease began as a pimple on the right ala nasi, eleven years ago. In consequence of scratching it, an ulcer formed which steadily increased in size ; was twice removed by a plaster. Seven years ago it healed, and remained so for nine months, when it reappeared. The dis- ease now occupies the entire ala, and appears as an oval-shaped ulcer, with slightly raised edges. The adjacent skin and tissues are healthy, and 22 there are no enlarged glands to be found any where. It has increased quite rapidly of late. Patient’s general health is excellent. The disease was clean- ly cut out with the knife, a small portion of healthy skin being removed at the same time. Microscopical examination. The little cake thus removed was cut in halves with a sharp knife, and the surfaces exposed were scraped, and the frag- ments obtained examined under the microscope. Beside the elements of ordinary connective tissue, one small clump of small globular epithelium cells closely adherent to one another was found. The specimen was then placed in a one per cent solution of chromic acid, and allowed to remain there two days. Owing to the thinness of the spe- cimen, a too great degree of hardening was obtained. The cells were too much shrunken, in consequence, to show satisfactorily, nor were they clearly brought out by imbibition with carmine ; nevertheless, the examination left no doubt as to the character of the disease. After allowing the specimen to remain in weak alcohol for a few days, oblique, vertical, and hori- zontal sections were made with the razor. Due allowance being made for the imperfect method of hardening, the cells may still be said not to possess so well marked an epithelial character as 23 in the preceding cases. With low powers, the dis- eased structures like ordinary granulation tissue ; with three hundred and fifty diameters, however, it was easy to distinguish between the epithelial cells, and the small round cells, which invaded the surrounding stroma. The former were small sized, with large oval nuclei, and nucleoli. Their borders, for the most part, were not easily distinguishable, the protoplasm appearing like one continuous mass, in which the nuclei were imbed- ded. These cell masses were quite narrow, gener- ally the thickness of two cells, and elongated, and anastomosed freely in all directions with one an- other, so as to give the appearance of a system of vessels, crowded with epithelial cells. (See Draw- ing 5 a.) There was, however, no enclosing wall or central cavity. The arrangement was similar to what is seen in the so-called tubular variety of epithelial cancer. This was more apparent in oblique than in vertical or horizontal sections, where there appeared to be no definite order, the cells at some points being crowded together in large masses, at others in long, narrow lines. The epidermic balls were nowhere seen. The separation of the epithelial structures, from the connective tissue stroma, was always ap- parent in the fully developed portions of the growth. 24 There was no infiltration of the stroma by them, as was the case with the small, round, indifferent cells. The connective tissue stroma which supported the epithelial cells was not abundant: near the periph- ery it was so small in amount, that the adjacent cell cylinders seemed almost to run together into one continuous mass. At this point the cells be- gan to lose their ejnthelial character and arrange- ment, and soon became undistinguishable from the small round cells which infiltrated the surrounding structures. The epidermis was slightly thickened in the raised border of the ulcer, but tapered off to a fine point at its edge. In the border, the por- tions of the rete which lie between the papillm, penetrated the cutis more deeply than usual. They were surrounded by young, round cells, which were quite numerous at this point, and intervened be- tween the old normal epithelium, and that of new formation. (See Drawing 5 &.) At this part of the rete, the boundary line between the epithelium and the connective tissue was not preserved, and the cells of the two structures were intermingled for a short distance. In the papillae of the adjacent healthy skin, it should be said, that the boundary line was well marked. There were no hair follicles, nor sweat-glands, to be seen. One or two large sebaceous glands were 25 found under the adjacent healthy skin. The num- ber of blood-vessels was small. Remarks. —We do not find in this specimen large or well-defined masses of epithelial cells; and yet a careful examination leaves no doubt as to their nature. This is precisely one of those cases which might easily be mistaken for a simple chronic inflammatory process, where proper methods of examination had not been employed. A point of interest in this case was the intermingling of the rawing 3.) This disposition of the cell-clusters is obviously different from what we find in the last three cases. In these, the cells are contained in an anastomosing system of tubes, and form quite an ornamental net- work occupying the full thickness of the skin. The disposition of the spaces reminds one strongly of the now well-known system of plas- matic canals, from which the lymphatic capillaries take their origin. Indeed it is quite possible that the lymphatics, themselves, may have been invaded for a certain distance, though this was a point which could not be demonstrated. There was no epithelial lining to the tubes to be seen, indicating their lymphatic nature. (See Koester. Entwicke- lung der Carcinome.*) In all cases, then, we find the cells forming in spaces in the connective tissue of the cutis. In one set of cases these spaces surround the vessels of 34 the skin, whereas in another set, they appear to be perfectly independent of them. Should it he deemed desirable to base a classifi- cation of these cases, on the anatomical arrange- ment of the cells, we might designate the first class, to which Cases I. and 11. would belong, as alveolar, and the second class as tubular. Another point of difference between these two classes is the almost total absence of any thing resembling an epidermic ball in the tubular variety, while we find them in abundance in the alveolar. This may possibly be due to the want of free communication between the alveoli. The pro- liferating cells, having no opportunity to spread easily, are crowded together and assume these forms. Ao such obstacle to their progress is offered by the freely anastomosing tubes. There is, indeed, a slight concentric arrangement in the large cluster represented in Drawing 5, but this was found nowhere else. The form of the epithe- lial cells is in all cases essentially the same,— slightly oval, except, perhaps, in Case 111., where they are rather globular. The cells immediately bordering on the connective tissue-stroma, how- ever, frequently have a shape and arrangement re- sembling columnar epithelium. The nuclei are round or oval, coarsely granular, frequently con- 35 taming a nucleus, and always sharply defined, con- trasting in both respects with the protoplasm or bodies of the cells, which are finely granular, and frequently run together into an inseparable mass. The most marked peculiarity of these cells, wherein they differ particularly from those forms of epithelial cancer with which we are most familiar, is their small size. Comparing them with the nor- mal epithelial structures of the skin, we find a resemblance between these cells and the younger cells of the rete Malpighii, sufficiently striking to be deemed worthy of notice. The connective tissue-structures varied some- what in quantity in the different cases. It was decidedly less prominent in the tubular forms, than in the alveolar. In Cases IV. and Y., the cellular ele- ments of the stroma were much less numerous than in the other cases ; indeed, much less than we ordinarily find in the neighborhood of any morbid growth, and it was interesting to observe, that in these two cases alone was there any apparent connection of the epithelial structures with those of the skin. (See Drawing 1.) To sum up the result of our analysis of these cases, at this point, we feel justified in arriving at the following conclusions : 36 Ist. All those cases of Rodent Ulcer examined are forms of epithelial cancer. 2d. They differ from those forms of epithelial cancer, of which cancer of the lower lip is the type, in the small size of the epithelial cells. 3d. These ulcers may be divided histologically into two different groups, according to the arrange- ment of the cancer-cells; viz., into tubular and alveolar. Allusion has been made frequently to other forms of cancer of the skin. A word here, there- fore, on the classification of cancers of this region may not be amiss. Paget divides them into superficial, and deep- seated, the former involving the skin itself, the latter forming beneath, and independent of the skin. Some of the French writers, for example, Lebert, bases this division on the special layer in which the disease originates. Others, as Cornil and Ranvier, adopting a microscopical basis for their classifica- tion, although they make no special division of can- cers of the skin, speak of a lobulated and tubular form growing in this part of the body; the former representing cancer of the lip, the latter the tubu- lar form already mentioned. According to Thiersch, Billroth, and others, 37 there are two varieties of skin cancer, the flat or superficial, and the deeply infiltrating (tiefgrei- fende). The flat cancer consists of a shallow layer of epithelial cells, separated from the tissues be- neath by a well-defined outline. The deeply infil- trating does not present any such line of demarca- tion, but penetrates in irregular masses into the deep-seated tissues. This form is rapid in its growth, and infects readily the surrounding struct- ures. The former is, on the contrary, quite slow in growth, and the skin immediately about it ap- pears quite healthy. This variety appears as a flat ulcer with slightly raised edges ; while the deeply infiltrating has an ulcerated surface surrounded by large nodulated masses. There is also a micro- scopical difference. The flat form is composed of a homeomorphous growth, while the infiltrating has, in addition to these cells, the large flat cell of varying shape and size. The cell growth in this case is polymorphous. We have, in this division into two forms, a classification based both upon a well-marked clinical and microscopical difference, and one which can be applied to all forms of can- cer of this region. It would seem to be not onty scientific, but eminently practical. It is easy to recognize in the infiltrating form cancers of the lower lip, penis, vulva, back of hand, &c. This class indeed includes both the forms mentioned by Paget; his deeply-seated form being a most excellent example of the large cell, or poly- morphous cell form. The flat cancers, on the other hand, are evidently intended to include the Rodent Ulcer. "Whether this is the only representative of this class is not definitely stated by German authors. The writer has not found any account of other forms. A certain number of cancers of the cheek have, however, fallen under his observation, which may fairly be placed in this class. Their micro- scopical appearance corresponds to what he has stated above to be the alveolar form of Rodent Ulcer, while their clinical history is not unlike this disease. They are seen generally as a somewhat superficial, nodular infiltration of the skin, accom- panied with little or no ulceration. They are not quite so sharply separated from the surrounding tissues as is Rodent Ulcer, yet their growth is quite slow, and they are only occasionally accompanied by an infection of the neighboring glands. In addition to these points of resemblance, they have another claim to be placed in the same class with Rodent Ulcer, in an occasional occur- rence of the two forms in the same individual. A case of this kind came lately under the writer’s observation. The nodulated epithelial growth oc- 39 cupied the right cheek, while a Rodent Ulcer had attacked and destroyed the left eye, and a portion of the lids. They were both of long duration, and on neither side were the lymphatic glands affected. The character of the epithelial cells, in the two cases, was similar; but their arrangement was tubular in the ulcer, and alveolar in the nodu- lated form. In addition to the forms above enumerated, there are also a certain number of pediculated and warty- like epithelial growths, which frequently remain perfectly superficial, and are composed of the large epithelial cells. Their tendency, however, to change into a more rapidly growing infiltrating form, to- gether with the microscopical character of their cells, would seem to be sufficient ground for classi- fying them with the large-cell variety. Adopting then the form and appearance of the cancer-cell as a basis for classification, we have a simple means of avoiding the difficulties involved in one based on the situation or accidental external appearances of the growth, and we obtain one which corresponds in the main to an important clinical difference ; namely, the degree of malignancy. We have then to recapitulate two forms of can- cer of the skin: Ist. The large-cell variety, or the infiltrating 40 form, for which we may select cancer of the lower iip as a type. We find a greater degree of malig- nancy in this form, both in the more rapid growth and in the liability to an infection of the neighbor- ing lymphatic glands, or of more distant parts. 2d. The small-cell variety, or flat or superficial cancer, the most typical form of which is the Rodent Ulcer. This form is characterized by a slow growth, and is very rarely followed by an infection of distant parts. We now approach a somewhat more difficult part of our subject; namely, the development of the disease. A study of the growth and develop- ment of this new formation gives ns naturally a more accurate knowledge of its character, than we should derive merely from an examination of the anatomical structure when fully matured, the standpoint from which we have thus far considered it. It is obviously quite as necessary to study the disease in its various phases. Moreover, in the earlier stages, the relation between the normal structures and the newly-formed elements is more easily determined. We are consequently enabled to arrive at some conclusions as to the origin of the elements and the route which they take in their further development. Possibly we may find here an explanation of some of the peculiarities of this 41 form of cancer, particularly the very remarkable immunity of the lymphatic glands. It must be confessed however, at the very out- set, that the origin of the cancer-cell, notwithstand- ing innumerable investigations, still remains an open and difficult question. We hope, however, to be able to arrive at some conclusions on this point, from a study of the cases above reported, as some of the specimens obtained proved suitable for this purpose. Before doing this, however, it will be necessary to give a brief sketch of the ques- tion as it now stands. It was for a long time supposed by German ob- servers, that cancer was develoj>ed from glandular structures ; but Virchow’s studies on connective tissue led him to believe that this theory was incor- rect, and that it was the connective tissue cells that became the starting point of the disease. We have therefore, according to him, in cancer, a type of the truly heterologous formation ; namely, a formation of cells in a part where those cells, normally, do not exist. This theory was generally adopted, and remained for some time undisputed. Forster, fol- lowing Virchow’s views, found it necessary to sep- arate from epithelioma those growths which he had hitherto considered as originating from the epi- thelial structures, and called them papilloma, and 42 destructive glandular tumors. Those only were called epithelioma, which were developed in a stro- ma entirely independent from pre-existing epithe- lium. Many other German writers supported this opinion of Virchow, and among them C. O. Weber, Eindfleisch, and others. Observations supporting this view are numerous. C. J. Eberth * describes an epithelioma of the pia mater in which the epithe- lial cells could have no other than an epithelial ori- gin. Yolkman f describes cancer cylinders formed by the proliferation of the nuclei of muscular fibres. Kindfleisch, however, allows a certain participation of the epithelium ; he has observed in the earliest stages of the development of cancer of the skin an inward growth of the depressions of the rete mu- cosum which lie between the papillae; also an activ- ity of the cells of the glandular organs of the skin. In explaining his views, however, he says : “ I dis- tinguish in epithelium, as in cartilage, a primary and a secondary growth. The first consists in the apposition of younger and smaller cells on the border of the epithelium and the connective tissue. The second is an enlargement and proliferation of the epithelial cells themselves. Through the for- mer the onward growth is produced; and by the * Virchow, Archiv., xlix. 51. t Virchow, Archiv., 1. 643. 43 latter the enlargement in tlie transverse diameter of the epithelial masses.” Remack, on the other hand, had always consid- ered that all epithelial formations were developed from epithelial germs only, as is the case in embry- onic development. There we find that the skin, mucous membrane, and the glands, are developed from the horny and intestinal gland membranes only. That which is destined to become connec* tive tissue, the middle germinal membrane, does not mingle with the other two. The process of development goes on separately. He argues that in pathological changes the same separation is maintained, for it is not probable, he says, that pathological processes are governed by other his- togenetic laws, than those which apply to normal processes. The development of epithelial cancer, in parts where there exists normally no epithelium, is explained by the straying of an epithelial germ during embryonic life, which, being misplaced, de- velops its malignancy at a favorable opportunity. Thiersch, one of the most prominent of German writers on epithelial cancer, espoused this theory of Remack, for although, according to Yirchow, there is a sufficient amount of connective tissue everywhere for the development of cancer, the fad is, that we find the disease in glandular organs only. Observations of Kolliker on the teeth sacs, and the formation of the crystalline lens, and the labyrinth, he thinks confirm this view. He cites also the formation of epithelium on open ulcers, considering that it takes its origin from the pre- existing epithelium alone. Thiersch quotes a number of authorities,—Fiihrer, Hannover, Yemeuil, and others,—all of whom are of the same opinion with him in regard to the epithe- lial origin of the cancer-cells. The structures from which he considers epithelial cancer of the skin to originate are chiefly the sebaceous glands. This he endeavors to show in the plates which accom- pany his very admirable work on this subject. In some cases, he thinks the epithelial disease takes its origin from the Malpighian layer of the skin, or from the hair follicles ; in others, from the sudori- parous glands. Billroth, also, adopts the Remack theory exclusively ; that is, he does not allow of any mingling of connective tissue and epithelial cells. He formerly thought that the small-cell in- filtration of the surrounding stroma played an im- portant part in the development of these growths. He believes now, however, that the epithelial struct- ures of the skin are, from the beginning, the points of departure of the disease. The cutis, he says, is covered by an epithelial layer, from which in the foetus ingrowths take place into the subjacent tis- sue; namely,* the hair follicles, sebaceous, and sudo- riparous glands. It has been maintained that all these structures may give rise to epithelial growths. Billroth thinks it mosf easily proved, however, in the case of the rete Malpighii. “ The young cells of the rete,” to use his own words, “ retain at first, during their inward growth, their form and size perfectly. The relation to the cutis, moreover, re- mains the same, for we find that those cells which are adjacent to the connective tissue retain the same cylindrical form which they have in the pa- pillae of the cutis.” (An example of this appear- ance is seen in Drawing 1.) As these cell-masses grow inwards, they find their way into the connec- tive tissue spaces, for the tissue here offers the least resistance; and from here into the lymphatic ves- sels. This activity of the epidermic structures has been maintained lately by Auspitz, in the Archiv fiir Dermatologic und Syphilis, 1870, in which the development of the skin is described at length. He believes that the papillae are not to be looked upon as elevations of the cutis, but are formed by depressions in the cutis produced by the actively proliferating epithelial structures above ; in other words, that the cutis plays a purely passive part in the process, and is simply moulded into shape by 46 the more active parts above. His pathological in- vestigations lead him to conclusions which one would infer from the physiology and development of the skin, so far as one is able to study them. E23ithelioma, he concludes, represents the type of the hypertrophic ingrowth of the epidermis, into the connective tissue stroma. Cornil and Ranvier (Manuel d’ Histologic pa- thologique) are of the opinion that epithelioma has its origin in glandular structures or in embryonic cells in their neighborhood, probably belonging to the connective tissue. The epithelial structures, in the latter case, exert a sort of action de pres- ence. C. and R. have observed in certain cases changes in the sebaceous and in the sweat glands, which lead them to infer a development from these structures. Hebert may be said to derive the cancer-cell from the cells of the epidermis. The investigations of English writers are not of a character to afford us much information on this point. Moore and Bennett have little to say upon the question. Paget agrees with "Virchow in the heterologous character of the epithelial formation. He says, “ even that delusive appearance of homology, which exists when the structures like those of epithelium 47 are formed in the dermal tissues, and therefore near the surface, is lost in nearly all the cases of deep-seated epithelial cancers, and in all the similar affections of the lymphatic glands and in- ternal organs.” f A somewhat novel view has been advanced lately, by Ivoester and Recklinghausen (Entwicke- liing der Carcinome). The latter was the first to ]3oint to a development from the lymphatics, show- ing that the epithelial cylinders might be the swollen ends of lymphatic vessels. Recklinghau- sen supposed the epithelial cancer-cell to originate from th.e connective tissue, and find its way into the lymphatic vessels through the plasmatic canals, or that a mingling of these cells with the lymphatic epithelium took place. A series of investigations by Koester, made for the purpose of clearing up this point, led him to believe that the cancer-cells actually originated from the lymphatic epithelium. As lymphatic epithelium differs from other forms of epithelium, in originating from the middle ger- minal membrane, and not from either of the other two membranes, these views would necessarily be an- tagonistic to those of Thiersch, Billroth, and others already mentioned. They have not, indeed, been very generally received, although it is allowed by many7 that the lymphatics are frequently the seat 48 of the disease in certain stages. A case reported by Pagenstecker,* for the purpose of showing the resemblance between the anastomosing cell cylin- ders and the lymphatics, did not show any ac- tivity of the lymphatic epithelium as described by Koester. A great deal of valuable work bearing upon this point has been done by those who have investi- gated the reproduction of normal epithelium on wounds, ulcers, &c. Rindfleisch observes, that the matrix of epithe- lium is to be found in the subjacent connective tissue, and that the young cells- in the deeper layers are derived from that tissue. This statement is supported by observations of Recklinghausen on the epithelium of the cornea, in which he finds the epithelium developed from the wandering cells. Biesiadecki (Sitzungsberichte of the Vienna Academy) has shown also that the mucous layer of the skin possesses, beside the epithelial cells, others more like the cells of fibrous tissue, and that these cells originating from the corium (wandering cells of Recklinghausen) penetrate the mucous layer. The youngest cells of the rete are developed from a nucleolated protoplasm belonging to the corinm. * Virchow, Archiv., xlv. 490. 49 These views he has confirmed by actual observa- tion on the web of a frog’s foot, where he has seen the escape of white corpuscles from the vessels, their disposition over a surface deprived of its epi- thelium, and their gradual metamorphosis into epithelium cells. An objection may be made to this view, on the ground that in a healing wound epithelium forms only at the edges, and not in the centre, as we should suppose would be the case were the con- nective tissue alone concerned. Eindfleisch over- comes this by the statement, that a connective tissue-cell can only be converted by coming in ac- tual contact with the pre-existing epithelium. We must believe, he says, in a kind of epithelial infec- tion. This participation of the two structures in the development of the new cells has been noticed by other observers. Arnold,* who has made a num- ber of carefully prepared experiments for studying the regeneration of epithelium in wounds, finds that the epithelium cells are formed neither from the connective tissue alone, nor from the epithelium alone, but from the former with the influence of the latter. This view has, however, not been confirmed by Wadsworth and E berth,*)* who find that the re- * Virchow, Archiv., xlvi. 168. t Virchow, Archiv., li. 361. 50 generation in these cases proceeds from the epithe- lium alone. This theory of infection reminds one strongly of the action de presence alluded to by Cornil and Ranvier, and also to a curious theory advanced by Klebs. This is a participation of two individuals in the production of the new cells, in cases of can- cer; the malignant growth being the result of this unlawful intercourse. We will close this sketch with an observation of Classen,* showing the participation of the white- blood corpuscle, or the wandering cell of Reckling- hausen, as it is called when seen in the connective tissue, in the formation of the cancer-cells. The case is one of cancer of the cornea, and the vessels surrounding the cancer-tissue are encompassed by young round cells, which appear to participate in the development of the growth. Similar observa- tions by Hirschfeld are reported in the Jahres- bericht for 1870, page 75. lie thinks, in certain cases, that cancers are of epithelial origin, though he believes that Thiersch carries his views too far. The different germinal membranes, after all, spring from the same source ; namely, the formative cell which has not yet undergone a differentiation ; and it is probable that in the developed organism such * Virchow, Archiv., 1. 56. 51 cells may still exist, which possess the power of becoming either a connective tissue, or an epithe- lial cell; namely, the white-blood corpuscle. It will be seen that this question like many others in this branch of science has suffered many fluctua- tions. The views of Thiersch and others on the epithelial origin of cancer-cells succeeded rapidly to that of Virchow, and gained many adherents, probably on account of their simplicity. They ex- plained satisfactorily the striking resemblance be- tween the new formations and the neighboring epithelial structures. This resemblance it was that gave rise to the terra, tumeurs heteradeniques, used by some French writers. We find, moreover, that not only do cancers almost invariably develop in or near some epithelial structure, but also that there is frequently some communication between the two. The observations of Conheim and Recklinghausen, however, on the cells of connective tissue, throw- ing as they did much light on onr knowledge of this structure, have given a new interest to this question. They were rapidly followed by a host of other investigations, among which those of Biesia- decki, reported above, are most satisfactory, show- ing the regeneration of epithelium from the con- nective tissue, or white-blood corpuscle. If this law is true for normal structures, may we 52 not infer a similar origin for the cancer-cell, par- ticularly when we find that pathological appear- ances are suggestive of such a change ? We will leave here the literature of this interest- ing question, and delay no longer to gather what information we may from some of our own cases selected for this purpose. Cases 11. aud 111. are the most suitable, for in these the whole of the diseased mass, and a portion of the surrounding healthy structures, were ob- tained for observation. In Case 11. we find the diseased tissue, which extends downwards to the subcutaneous cellular tissue, and laterally for a short distance beyond the border of the ulcer, to be made up of masses of cells of new formation, which except at the extreme periphery are enclosed in alveoli of somewhat varying shape, communicating to a certain extent with one another. At the cen- tre of the disease, they have the appearance of epi- thelial cells, and crowd together, frequently forming epidermic balls. Their general character is not to be mistaken. (Drawing 6.) As we approach the periphery, cells of an epithelial character become fewer in number, and those which predominate here resemble the small round cells which are so fre- quently found in all morbid growths. We come finally to alveoli, which are composed 53 solely of these latter cells. (Drawing 4.) The difference between the two kinds is sufficiently well marked to prevent any mistake arising, on a toler- ably careful examination; and yet with only a mod- erately low power, it might be said to be quite difficult to determine at what particular point the boundary line between the two existed. One distinguishing feature of those more peri- pheral alveoli, in which the young indifferent cells exist, was the presence of a vessel running through the centre of the cluster of cells. This at many points was perfectly formed, and contained num- bers of blood corpuscles. (Drawing 4, a.) It could occasionally be traced to some larger trunk, leaving no doubt as to its nature. At others, this central axis, as it were, was simply a band of fibres, with the appearance of a central cavity. (Drawing 3, a.) At still other points, the resemblance to a vessel was less distinct, and yet in all, or very nearly all these alveoli, the central axis appeared to exist in one of these forms. We have already mentioned that in the epithelial clusters this appearance was entirely wanting. We see then, that in the earliest stages of devel- opment of the growth an accumulation of young cells has taken place immediately about some small vessel, and to such an extent as to crowd away the connective tissue-fibres immediately surrounding its walls for some little distance, in such a man- ner as to leave a somewhat elongated oval space through the centre of which the vessel runs. As the disease progresses, we find that these cells no longer maintain their original character, but that here and there, among the mass of cells, cells of an epithelial character are found (Drawing 3, c). These grow more numerous as we approach the older portions of the disease, until indeed we find that the epithelial cell has entirely supplanted the young cell. In the mean time our delicate vessel becomes somewhat indistinct in its contours, later is represented by a few fibres merely, wdiile finally no trace of it is found to remain. The young cells are found however, only in the immediate vicinity of blood-vessels. The cell- clusters give off offshoots, which either commu- nicate with other alveoli, or wedge their way between the fibres of the connective tissue. 4Ye find them also in tolerably large numbers in the tissues surrounding the disease, particularly in the papillae which are in the skin immediately sur- rounding the ulcer. These cells crowd so closely on the epithelium of the rete mucosura immedi- ately above, as to force their way frequently for some little distance beyond the boundary line, and 55 between the cells of the rete, the outline of the papillae at this point becoming somewhat indis- tinct. Any such intermingling of the cancer-cells with the epithelium of the shin is, on the other hand, seen nowhere. There are several interesting points brought to light here, bearing upon the question of develop- ment. The first of these is the accumulation of the youngest elements of the diseased structures about the walls of blood-vessels. These elements differ in no way from the small indifferent cell of certain authors, the wandering cell of Recklinghausen, or, if we choose to go one step farther, the white corpuscles of Conheim. May we not here have to deal with cells which have escaped from the cavity of a blood-vessel ? The situation and arrangement of these cells is eminently suggestive of such an origin, even if we did not find at certain points vessels whose cavity is filled with white corpuscles. Some of these have penetrated the wall of the vessel, while in the immediate vicinity are to be found cells of precisely similar character, mingled with others of somewhat varying shape, suggesting an amoboid movement at the time of the death of the part. (Drawing 2, c.) Secondly. We find that these cells are collected 56 in clusters, and not infiltrated, if we may use the term, in the tissues about. These clusters, at first, have a shape corresponding somewhat to the direc- tion which the vessel takes; later, we find off- shoots from the main mass existing to such an extent that the different clusters communicate more or less with one another. The cells lie evidently in channels in the connec- tive tissue, and are not interspersed between the individual fibres. Thirdly. There is free contact at certain points between these cells and the pre-existing epithelium, and lastly, we find that in these young cell-clusters the first traces of the new epithelial or cancer-cell are discovered. In Case 111. we have a very different arrange- ment of the cancer-cells. Here, they fill very nar- row tubes, which anastomose much more freely with one another, than the alveoli of Case 11. We find the so-called tubular form of epithelial cancer. The cancer-cells are to be found only in the central por- tions of the diseased structure, while at the peri- phery Wi. find again only young indifferent cells. These latter are not arranged in clusters, as in Case 11., but infiltrate the connective tissue. The cori- um and papillae are crowded with them, and they penetrate, as in the former case, between the cells of the rete. As we approach the central parts, a certain arrangement of the cells in rows is discern- ible, while at the same time a gradual change in the appearance of the cells takes place, until we come upon the tubular arrangement and epithelial character, already described. At no point was any communication to be found between the cancer-cells and the normal epithelium of the part, although a careful examination was made with this object in view. It seems justifia- ble, therefore, to conclude from the data afforded by these observations that, in some instances at least, the cancer-cells are in no way connected dur- ing their development with the previously existing epithelial structures, and that we are to seek for their origin rather among the young cells of new formation, which are present in large numbers, and with which the cancer-cells appear to come in inti- mate relation. Indeed, we, are able to observe in both these cases such a gradual change in the character of the cells, from the earliest pathological change to the fully developed diseased structure, as to leave hardly any room for doubt upon this point. The next question which naturally arises, is, the origin of these young cells: are they produced by a proliferation of any of the normal elements of the 58 part, or are they, as we have already suggested, in any way connected with the corpuscles of the blood ? It is not probable that the epithelium takes any part in their formation, for although we have seen an intermingling of these young cells with those of the rete, there is nowhere any appearance which suggests a proliferation of the epithelial cells of this part. On the contrary, we find simply an atrophy, and destruction of the epithelial structures, keeping pace with the advance of the disease. To what ex- tent the so-called fixed cells of the connective tissue of the part were implicated in the process, it was impossible to say, as there was no evidence bearing upon this point afforded by the specimens exam- ined. It was quite evident, however, that the vas- cular system was in some way connected with the early history of the disease. The masses of young cells, which are arranged in clusters around the walls of blood-vessels, and the frequent accumula- tion of white corpuscles within, together with the other data given in Case 11., render it extremely probable that the parent cells of the future cancer are derived in part at least from the white corpus- cles of the blood. We have alluded several times to the accumula- tion of the young cells in the papillae of the skin and their frequent contact with the epithelial cells 59 of the rete. Observations similar to this, as we have seen, have been made by Bi'esiadecki in the study of the process of regeneration of epithelium, and the development of the epithelium of the rete. When, in addition to this, we find the cancer-cells resembling strongly the epithelium of the part, it seems quite possible to believe in a certain influence exerted by the normal epithelium on the new cells; the action cle 'presence of the French writers. Or it may be that the cancer-cell is the result of a sort of infection or impregnation of these young cells, by the same elements. Such a theory would allow, at the most, only of an indirect participation of the epithelium in the formation of the new cancer-cells. That the lymphatic spaces of the connective tis- sue of the skin are the seat of the new formation, is shown quite satisfactorily in Case 11. in the earli- est stages of development, and in the anatomical arrangement of the cancer-cells in all the specimens examined. The so-called perivascular lymph-spaces are distended by the young cells which accumulate about the vessels in the manner already described. Prom this point, the young wandering cells appear to penetrate the lymphatic network of the skin, where, collecting in clusters of varying shape, the eventual development into cancer-cells takes place. The anatomical arrangement of the newly-formed 60 cells, as seen in the different stages of development, speaks strongly for this supposition. By peculiar methods of preparation, Kdster has been able to demonstrate this point in a large number of epithe- lial cancers, both of the large and small cell variety. An actual invasion of the lymphatic vessels by the disease, as observed by Kdster, does not appear to have existed in these cases, except perhaps to a very limited extent. This immunity of the lym- phatic vessels is further shown by the superficial character of the disease, and an entire absence of any infection of the neighboring glands. We have based our conclusions on the mode of development thus far, on Cases 11. and 111. It is necessary, however, to mention that both in Cases IY. and y., a communication with the epithelium of the rete Malpighii was found to exist; a fact which would seem to controvert the opinion that the cancer-cells are derived from the connective tissue elements alone, and accord at least a certain participation to the epithelial structures. As we have said before, these cases were ill suited for an investigation for this purpose, the limits of the disease, and the surrounding healthy parts, not being obtained for examination. It was not possible, therefore, to decide to what extent the connective tissue participated in the development. 61 At certain points, indeed, an accumulation of white corpuscles was seen within the blood-vessels, and occasionally the penetration through the wall, and the accumulation about the vessels, were also ob- served, showing at least a certain activity of these elements. This communication with the epithe- lium of the rete, moreover, was found only at one or two points, although a careful search was made for the purpose (see Drawing 1); nor did there appear to be any proliferation of the cells of this layer, as one would expect to find were an active ingrowth taking place into the parts below. The direct participation then of the epithelium in the formation of the new growth, although suggested by appearances found at certain points, did not seem to admit of satisfactory proof, while, on the other hand, the connective tissue showed in all cases signs of a more or less active participation in the process. In summing up then the result of these observa- tions, we find that in certain cases, 1. The formation of the cancer-cells is preceded by an escape of the white blood corpuscles through the walls of the vessels, and an accumulation of similar cells in the adjoining lymphatic canals. 2. That this is followed by an apparent trans- formation of these cells into cells resembling strongly the epithelium of the rete Malpighii. 62 3. That the epithelium of the parts affected does not appear to take an active part in the pro- cess, but may exert a certain influence on the char- acter of the formation taking place. 4. That the cancer-cells lie in the lymphatic spaces of the connective tissue, and do not invade, to any appreciable extent, the lymphatic vessels. Do these observations afford us an explanation of the very striking peculiarity of the disease, its purely local character, and the immunity both of distant organs and the neighboring glands ? Few of the writers, already quoted, endeavor to account for this. Mr. Moore offers as an explanation, the shrinking of the lymphatic vessels and an obstruc- tion to the lymph stream by a growth of connec- tive tissue about them, so that the elements find no outlet to the lymphatic glands. No such altera- tion of the lymphatics was observed in any of these cases, and the growth of the connective tissue was found to be exceedingly variable: at times the amount seen was quite considerable, as in Case I.; at others it had disappeared almost entirely. On what does the malignant character of any new formation depend? Chiefly, on the quantity and activity of its cellular elements, on the amount of juices, either inter or intra cellular, which it may contain, or on its richness in blood-vessels. In these cases we find that the presence of a large number of blood-vessels was not a prominent feature. There did not seem to be that local in- crease of the vascular supply that one would ex- pect to find in cases of epithelial cancer. The nutrition of the newly formed elements must there- fore suffer accordingly. In fact, the dry character of the ulcerated surface is considered one of the most characteristic clinical features of the disease. The cells can never accumulate in large masses, owing to their low formative power, and the early retrograde changes which they undergo. The latter is due chiefly to the delicate nature of the cells and their imperfect nutrition. They are es- sentially a short-lived race, the retrograde changes following very closely upon the formative. In this peculiarity of the cells, we find an explanation of the ulcerative character of the disease. The cancer-cells, when once formed, appear to possess little power to multiply themselves by further proliferation. The masses of cancer-cells certainly do not show any signs of such activity. We find no evidences of an active cell proliferation, and consequently no active outgrowth into the neighboring tissue. Contrast these conditions with what is found in the large-cell variety of epithelial cancer. There the cells are nourished by a rich net-work of blood-vessels, and when once formed undergo a rapid proliferation, enabling them to penetrate deeply into the tissues about. The retro- grade changes do not appear until a late stage of the disease,’when the excessive growth cuts off the vascular supply to the more central parts, and a consequent degeneration of the cells follows. In Rodent Ulcer, the cells rarely extend a line or two below the surface of the ulcer, and beyond its edges. The lymphatic vessels, as we have seen, are invaded at the most to a very limited extent, while in other forms of cancer the cells penetrate freely into the lymphatic net-work about them, and by repeated multiplication are enabled to continue their progress until conditions are arrived at most favorable for the infection of the adjacent glands. The low formative power of the elements, the absence of power to multiply themselves to any ex- tent, when once formed, and their extremely short- lived character, seem to afford the most satisfactory explanation of the inability of the disease to affect distant parts. These peculiarities combine to make Rodent Ulcer the type of the mildest form of cancer with which we have to deal. 65 EXPLANATION OF DRAWINGS* Drawing 1. Vertical section from ulcer of Case V. a Epithelial cancer-cells. h Connective tissue-stroma. c Papillae containing indifferent cells. d—Epithelium of rete. Drawing 2. Section from a fragment removed from edge of ulcer of Case IV. a Branching mass of cancer-cells. h Large cells, around which there is a concentric ar- rangement of cells. c—Connective tissue-stroma, filled with cells, which have evidently been in active movement. d Vessel filled with white blood corpuscles. One or two red corpuscles are also to be seen. Drawing 3. Clump of young indifferent cells at periphery of same sec- tion. a a Central fibres, showing situation of blood-vessel. h— Indifferent cells. c Cancer-cells, forming among preceding. d—Stroma. * The power used for these drawings was Hartnack’s 9 immersion lens, with 2 eye piece. 1, 2, and 5 have been reduced to one-half the size of the original drawing. 66 Drawing 4. Clump of cells seen at deepest point of the disease, in same case. The central vessel is here still preserved. a a—A blood-vessel, in which the blood corpuscles are distinctly seen. h Young cells. c— Stroma. d Branch from blood-vessel, a. Drawing 5. Vertical section from ulcer described in Case 111. a— Anastomosing tubes of cancer-cells. b—Young cells occupying papillae, and upper part of coriurn. c—Epithelium of rete Malpighii. d Papillae. e Point where the indifferent cells become continuous with cancer-cells. Drawing 6. Clump of cancer-cells in vertical cut, taken from specimens of Case 11. The cells are near the centre of the diseased mass. a Epidermic balls. h Stroma. Warren on Rodent Ulcer □r.H.R Ijimiry Del. Warreit on Rodent Ulcer Dr. H.P.Quincy Del.