Squamous Cell Carcinoma of the Bladder: A Study of Heterotopic Epidermization, with a Review of the Literature and Report of Cases

Squamous Cell Carcinoma of the Bladder: A Study of Heterotopic Epidermization, with a Review of the Literature and Report of Cases

SQUAMOUS CELL CARCIKOMA OF THE BLADDER A STUDY OF HETEROTOPIC EPIDERMIZATION, WITH A REVIEW OF THE LITERATURE AND REPORT OF GASES FRANK HINMAN AKD T...

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SQUAMOUS CELL CARCIKOMA OF THE BLADDER A STUDY OF HETEROTOPIC EPIDERMIZATION, WITH A REVIEW OF THE LITERATURE AND REPORT OF GASES FRANK HINMAN

AKD

THOMAS E. GIBSON

Department of Urology of the University of Cal'ifornia, San Francisco, California

The writing of this paper was prompted by the occurrence in our series of bladder tumors of three singularly interesting cases of squamous cell carcinoma-interesting not only because of the relative rarity of this type of vesical malignancy, but particularly because of their eitology and pathological significance; two of the tumors being typical cornifying epitheliomata, similar to those seen on cutaneous surfaces. We have endeavored to collect and analyze, as far as possible all the cases reported in the literature. The difficulties connected with such an undertaking are at once apparent. The literature is fragmentary and without correlation, either the pathological aspect or the clinical having been emphasized at the expense of the other, according to the special predilection of the author. This article, therefore, is contributed in the hope of clarifying and stimulating interest in a subject which has been so inadequately treated in the literature. The following three cases occurred in our series: Case I. Private case no. 1628, referred by Dr. Cross, Fresno, California. C. J. Male. Age sixty-eight. White. Rancher. Complaint: Hematuria. Family history: Irrelevant. Past history: Pneumonia and typhoid 1896; N eisser age twenty-five. Syphilis denied. Present illness: Ten years ago the patient first had cloudy urine, and experienced some difficulty in starting the stream. There was a diminution in force but not in size. He consulted a physician who informed him that he had a stricture. Patient says that he was not dilated with 1 THE JOURNAL OF UROLOGY, VOL. VI, NO.

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sounds, but ovei; a period of two months was catheterized and irrigated with "silver" solutions. Between that time and two months ago the patient had no urinary trouble of any sort. Then, out of a clear sky, a quantity of bright red blood was passed per urethram. Since that time the patient has frequently noticed blood in the urine. No other symptoms. Physical examination: Active, thin, bright man, appearing about stated age. Not cachectic looking. Physical examination essentially negative. Blood pressure 200/ 158. Phenolsulphonephth alein test of renal function: One hour, 20 per cent, two hours , 20 per cent, total, 40 per cent. Urine: R. B. C. 100 per H. D . W. B. C. 15-18 per H. D. No casts. Many squamous epithelial cells. Culture: Staphylococcus albus. Cystoscopy: Large, sessile, ulcerating t umor covering and extending above left ureteral orifice. Appearance characteristic of malignancy. On June 1 and 3 the growth was fulgurated . Operation July 5, 1920: Through a suprapubic incision t he portion of the bladder wall involved was resected, including a 1 cm. margin of normal appearing mucosa." The lower portion of the left ureter was involved in the carcinomatous area and considerably dilated above. It was. divided about 2 cm. from the bladder wall and transplanted to the mid-vesical area. 15.3 mgm. of radium were inserted at t he operative site and removed twenty-four hours later. The patient made an uneventful recovery and was allowed to go home about one month after operation. P a-thological report (no. S. 20.1015): Gross pathology : The specimen (fig. 1) consists of a portion of the bladder wall, measuring 7 by 5 by 7 cm. in dimensions. One sees a margin of normal appearing mucosa, in the center of which is a large ragged, crater-like ulcer measuring 3 by 4 cm. The specimen \ncludes about 2 cm. of the left ureter (fig.l ), which opens into the base of the ulcerated area. The ureter is hypertrophied to over twice its normal size, denoting obstrirction. The base of t he ulcer is inelastic, gray, and necrotic looking, with some hemorrhagic extravasation on the surface . The edges are everted, friable, and shiny, just as one sees in cutaneous epitheliomata. Sections for microscopic examination were taken from representative areas. Microscopic pathology: Microscopic examination (see figs. 2, 3, 4, 5, and 6) shows the base of the ulcer, described in the gross, to be covered superficially with hemorrhagic, necrotic material, and inflam·matory exudate. Beneath this one sees solid masses of epit helial cells,

Fm. 1. Typical cancroidal ulceration, or cornifying epithelioma measuring 7 by 5 cm. Its extreme malignancy is indicated by the fact that it is primarily a deeply and rapidly infiltration type of growth. The opening of the left ureter in the base of the ulcer near one edge is indicated by a match inserted in its lumen. It is free from malignant invasion.

Fm. 2. Microphotograph (low power) from area indicated by rectangle in figure 1, showing widespread infiltration with solid columns of squamous cells and tendency to whorl formations. In some areas lymphocytic reaction about the advancing cell masses is very marked. 3

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Fm. 3. Higher magnification of areas indicat ed by square in figure 2, illustrating epithelial pearl formation.

Fm. 4. Microphotograph (low power) from a rea indicated by rectangle in figure 1, illust rating ,t he m anner of growth and a reas of cornification. This p icture simulat es closely t hat seen in cutaneous epit heliom at a. 4

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FIG. 5. Higher magnification microphotograph of area indicated by square in figure 4, which illustrates beautifully cornification.

FIG. 6. Microphotograph (high power) of another portion of this growth showing cornified area with pearl-like structure, and lymphocytic invasion of stroma.

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all of the squamous type, wit h hyperchromatic nuclei and many mitotic figures. The manner of growth is that of cutaneous epidermoid carcinomata, namely, widely infilt rating, irregularly nodular or lobular, with a tendency to whorl formations, and without regard for limiting basement membrane. There is a tremendous lymphocytic i·eaction about the neoplastic cells. The mucosal cells at t he margin of the ulcer appear hyperplastic. In the centers of some of t he nodular growths definite pearls are seen. In some areas the cells approach the basal type, but in others they are typically squamous and intercellular bridges are seen. Eosinophilia and cornification are evident in many places. The underlying musculature is apparently not invaded. (This fact, however, is not always a criterion for favorable prognosis, as we know that metastases may occur in remote areas before such invasion occurs.) The ureter cannot be found in microscopic sections of the base of t he ulcer. Further out, however, it appears in sections. It is markedly hypertrophied, but free from malignancy. Diagnosis: Cornifying epithelioma of the bladder. Subsequent course: Ten months after operation the patient reports in a personal letter that he has never enjoyed better health. Cystoscopic examination on April 14, 1921, by Dr. Cross revealed no sign of recurrence. Bladder capacity 225 cc. No residual. Case II: Private case no. 623. Referred by Dr. Sobey, Paso Robles, California, H. T. Male. Age sixty-three. White. Rancher. Complaint: Hematuria and dysuria. Family history: Negative. Diseases: Measles, pert ussis, varicella, typhoid at age of eleven; pneumonia, age forty, fifty-three, fifty-six. Venereal : Neisser at age of t hirty. Cleared up in two mont hs. N o complications. Syphilis denied. Habits: H eavy smoker. Chews ten-cent plug of tobacco in two days. · Whiskey ii per day up to five years ago. in urine. blood noticed first Present illness : One year ago patient in small pain Occasional Slight burning on urination since that time. This urine. in blood noticed again of back. Three weeks ago patient urination, during penis of has continued since. Also has pain at end never at other times. Pollakiuria for the last year, most marked while working. Nycturia i. Never passed gravel or pieces of tissue. Passes small clot occasionally. Physical examination: Patient well dressed and nourished. Appears healthy and younger t han stated age. Left pupil larger t han

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right and does not react to light. Right reacts sluggishly. Left epiclidymis enlarged and inclurated. Physical examination otherwise essentially negative except for bladder findings. Cystoscopy: Large papillomatous growth at fundus slightly to the right of the midline. Operation January 22, 1918: Suprapubic extraperitoneal omy. The tumor was thoroughly cauterized with a thermo-cautery before excision, so as to avoid the possibility of implantation metastases. Radical excision including a fair margin of normal appearing; mucosa was performed. Implantation of 50 mgm. of radium was done. Removed twenty-four hours later. Uneventful recovery. Pathological rnport (no. 2978): Gross not recorded. Microscopic examination (figs. 7 and 8) shows diffuse infiltration of squamous cells, with a moderate amount of connective tissue cells of young fibrous type. There are areas of somewhat aclenomatous arrangement but the cells are all of the squamous type. No definite cornification or pearl formations are 1nacle out. Diagnosis: Squamous cell carcinoma of the bladder. Subsequent course: This patient is living and well without sign of local recurrence three years and three months after operation. copy, however, has not been done for two years. Dr. Sobey writes, April 5, 1921, that the patient has never enjoyed better health. Case III. S. F. H. No. 51523. E. G. JVIale. Age, sixty-two. White. CarpenteL Complaint: Hematuria, frequency, and burning on urination. Family history: Irrelevant. Past history: Residence and occupation: Patient has always worked as laborer and bridge carpenter in northern states of United States, last twenty years in California. Diseases: Pertussis at age of three, measles at age of fourteen, tonsillitis at age of thirty, penumonia at age of thirty-seven. Venereal: N eisser at age of twenty-two and forty-three. No complications. Chancre and buboes at age of forty-three. No history of secondaries. Habits: Tobacco, ten-cent plug every two days;smokes ten pipefuls per clay. Alcohol: At least 2 quarts of beer daily up to prohibition, occasional whiskey. Bowels constipated. Nycturia and diuria every half hour. Weight: Lost 50 pounds in last eight months. Operation: Incision of inguinal bubo at age of forty-three. Accidents: Very severe burn left leg.

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Fm. 7. M icrophotograph (low power) of non-cornifying type of squamous cell carcinoma of bladder, showing diffusely infiltrat ing type of growth with suggestion here and there of alveolar arrangement. In th e gross the growth was of ·the'villous type.

Fm. 8. Microphotograph (high power) of a rea indicated by squ a re in figure 7, showing diffuse growth of squamous cells approaching b asal type without evidence of cornification.

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Present illness: Patient felt perfectly well until six months ago when on arising in the morning he passed some bloody urine. This has continued ever since with the exception of two weeks in November. The blood sometimes appears at the beginning of micturition, but generally toward the end of the act. At the same time he has had burning pain with and for a while after, urination, beginning at the end of the penis and ascending to the bladder. At the same time there was a burning pain over the whole hypogastrium which the patient likened to boiling water being poured on the skin. Between the acts of micturition there has been a constant dull pain in the hypogastrium. The pains have been more severe the last three months. With the onset of his hematuria there occurred also a greatly increased frequency; diuria and nycturia every hour and finally every half hour. Previous to the onset of his present illness he had nycturia i-ii for about ten years. Although very robust until six months ago he rapidly lost weight (50 pounds) and became very weak. The patient 1attributes his affliction to the fact that with the beginning of probihition he was forced to drink from the alkali water supply of the village where he resided. Physical examination: Poorly dressed and nourished male, appearing rather anemic and older than stated age. The physical findings are negative except for the following positive findings: The skin shows marked telangiectases over the nose and zygomata. Eyes: Traumatic cataract right. Teeth: Dental caries and pyorrhea. Arterial walls: Moderately thickened. Abdomen: Smooth liver edge felt at costal margin. Genitalia: Scar on frenum, and scar of old bubo. Rectal: Prostate enlarged, soft, very tender with surrounding adhesions. Median groove can be made out. Seminal vesicles not palpable. Prostatic secretion shows about 30 per cent pus. Sphincter ani tone good. Phthalein: One hour 25 per cent, two hours 25 per cent. Total 50 per cent. Urine analysis: Smoky, specific gravity, 1.014; reaction alkaline, albumin trace, sugar 0. Microscopic: Erythrocytes very numerous, leucocytes 10-20 every H. D., and abundant triple and amorphous phosphates. Cystoscopy: Residual 30 cc. Capacity 175 cc. Vesical neck very hyperemic, otherwise negative. Trigone somewhat injected. The right ureteral orifice is reddened and gaping and surrounded by moderate edema. The left orifice is negative. In the third bladder zone in the region of the fundus is seen a large ulcerated mass, the center of which is very dark and depressed. The border of

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the mass is greyish white. Necrosis is apparently going on. · The picture is one of advancing malignancy. The posterior urethra is very hyperemic. Operation ·March 30, 1921. At City and County Hospital, by Drs. Hinman and C. P. Mathe. The bladder was distended with air. Through a rriidline suprapubic incision the peritoneum was stripped from the bladder to the region of the fundus, where it was found very adherent over the tumor and could not be stripped. Traction sutures were then placed in the bladder about the t umor and the peritoneum over the growth resected and t he peritoneal cavity closed. The bladder wall including the growth and a fair margin of normal appearing mucosa were resected en bloc. The bleeding was stopped with a continuous row of lock sutures, and the bladder closed with a double row of similar sutures. The prevesical space was packed with gauze and rubber t ubing placed in the lower angle of the wound. Abdominal muscle and fascia closed with no . 2 chromic gut, skin closed with horsehair. Stay sutures of silkworm gut inserted. The patient received 700 cc. saline by hypodermoclysis. The bladder was drained by a Pezzer catheter in the urethra. On the following day the packing and the suprapubic drain were removed. One month after operation the wound shows no drainage and is well healed, and the patient is in good condition. In this case no p1;eliminary fulgutation was clone, no thermocautery was used at the time of operation, nor was radium therapy used. Pathological report (no. S. 770): Gross pat hology: The specimen consists of a section of the bladder wall preserved in 10 per cent formalin (figs. 9 and 10). Thewallisgreatlythickened, and on its mucosal surface is seen a deep crater-like ulcer m easuring 4 by 5 cm. (fig. 9). The base of the ulcer is indurated and covered with necrotic tissue and granular debris. The edges of the ulcer are everted, shiny, thickened, very friable, .almost brittle, chipping easily with a bite of the forceps. In one ·a rea extending from the normal appearing mucosa down toward the base of the ulcer is seen a sheet of whitish skin-like tissue resembling a leukoplakic patch (fig. 9, section I). The growth appears to involve the whole thickness of the bladder wall. In the mucosa beyond the margin of the ulcer are seen numerous small polypoid m asses, and ot her small, whitish, vernicous growths which are apparently neoplastic nodules. On the posterior surface of the specimen is seen an adherent sheet of peritoneum (fig. 10). Section I taken from area resembling leukoplakia. Section II taken from margin of ulcer in another area.

FIG. 9. Photograph of gross specimen. Cancroidal ulceration is present as in case I (see fig. 1) the crater-like ulcer being 5 cm. in its greatest diameter. Block I (fig. 9) is taken from the white pavement-like extension beyond the edge of the ulcer. This area resembles leukoplakia. It differs histologically from block II, taken through the edge of the ulcer only by showing slightly more differentiation and cornification. (Compare figs. 11 and 12, block I, with figs. 13 and 14, block II.)

FIG. 10. Photograph (posterior view) of gross specimen shown in figure 9. The bladder wall is greatly thickened and so infiltrated by the growth as to result in an adherent peritonitis necessitating resection of a portion of the peritoneum at operation. 11

FIG. 11. Microphotograph (low power) of block I, figure 9, which in the gross resembles leukoplakia. This area shows a solid mass of carcinomatous cells of squamous type with evidence of cornification, but no definite pearl formations are seen.

FIG. 12. Microphotograph (high power) of area indicated by square in figure 11, exhibiting cornification. The surface of the growth is covered superficially by inflammatory exudate. 12

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Fm. 13. Microphotogr aph (low power) from block II, figure 9. Solid mass of squamous cells showing little differentiation . Two areas of necrosis are present.

Frn.14. Microphotogr aph (high power) of area indicated by square in figure 13.

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Microscopic examination (figs. 11, 12, 13, and 14): Shows the base of the ulcer to be covered superficially with necrotic tissue and acute inflammatory exudate consisting for the most part of polymorphonuclear neutrophiles. Beneath this layer is seen a solid mass of very malignant cells extending in solid columns far clown into the underlying musculature, in some areas through the whole thickness of the bladder wall. Capillary and lymphatic spaces about the cell masses are seen distended with these cells. · The cells vary in type from basal to typically squamous, with evidence here and there of cornification. No very definite pearls are seen, but there is a very marked tendency to whorl formation and eosinophilia. Intercellular bridges are readily made out in many areas. There is marked lymphocytic reaction about the neoplastic cells. Many of the cells appear to contain two nuclei. The nuclei are very hyperchromatic and typical and atypical mitoses are numerous. Two nuclei are evident in niany cells. In some areas vacuolization is a marked feature. In the centers of some of the cell ;masses necrosis is evident. Hyalin degeneration is a prominent feature in many portions of the growth. The mucosa beyond the margin of the growth appears normal. Section I (figs. 11 and 12) differs from section II (figs. 13 and 14) only in showing slightly more differentiation and evidence of cornification. Diagnosis: Cornifying epithelioma of the bladder. Subsequent course: Patient l~ving and well three months after operation. TERMINOLOGY

The terminology of bladder tumors today is still as confusing as in the days of Fen~, who said: The history of cancer of the bladder is one of the most obscure points in the pathology of the urinary tract, not only because their clinical study has received such little attention, but also because of the deplorable confusion of terms with which these very diverse anatomical lesions have been afflicted.

Geraghty divides malignant tumors of epithelial origin into malignant papilloma, and papillary, scirrhus, adeno, and squamous cell carcinoma. The French terminology of squamous cell neoplasms as expressed by Clado is as follows: Squamous cell carcinoma is

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designated as "epithelioma pavimenteux," which presents two forms: (1). La forme tubulee, (2). La forme lobulee (perle ou come du Albarran). He states that the first is the more common type. 1 In the British literature the term epithelioma is used rather loosely. It designates tumors which may or may not be squamous celled. Many reports of epitheliomata were found in which from the microscopic description it is evident that they were not of the squamous cell type. In the German literature fibro-epithelioma designates what we ordinarily understand by the term papiiloma. Squamous cell carcinomata are commonly designated as "cancroid," "plattenepithelkar zinom," and "pflasterepithelca rcinom." In the Italian, Swedish, and Russian literature the common appelation is "cancroid." ETIOLOGY

It appears very peculiar that neoplasms whose structure corresponds so perfectly to that found in cutaneous neoplasms should occasionally originate in the bladder, an organ which being a derivative of the allantois, is covered with epithelium derived from the entodermic germ layer. To explain the origin of these tumors many hypotheses have been applied which were formerly formulated to explain the origin of other epidermoid cancers which arise occasionally from mucosas covered with cylindrical epithelium (e.g., trachea, bronchi, pancreas, stomach, gall bladder, prostate, uterus, caecum, etc.). The 1 Clado can recall having seen only three instances of the second type. epithelioma pagimenteux tubulee consists of a papillary growth of squamous type of cells which do not exhibit cornification or pearl formations, as exemplified in our second case. There is a tendency to tubular or alveolar formations. Albarran defines "Tubulee" as meaning a growth where the connective tissue framework tends to be at the center of the outgrowth (papilla), and "lobulee" as a growth in which the connective tissue is at the periphery of the lobule (cell masses), the cells growing in more or less solid masses infiitrating the bladder wall. The latter type of growth is the typical cornifying epithelioma with which we are familiar on the lip and other cutaneous surfaces, and is exemplified by our cases Nos. I and III. This type of growth is identical with the so-calle,d cancroid, a term which appears in the medical literature of practically ever_y language. Epithelioma is the term used in the French literature for bladder tumors in general that are malignai:it.

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The origin of epidermoid cancer of the bladder has therefore been attributed to: 1. An ascending epidermization (Marchand). 2. To an ectodermal embryonal inclusion in the vesical wall (Albarran). 3. To a carcinomatous degeneration of a previous leukoplakia (Halle). 4. To a vesical leukoplakia malignant in character from the beginning. 1. The first hypothesis was applied by Marchand to a case of total leukoplakia with relative neoplastic degeneration (in the diaphragm there was found a neoplastic nodule) of the epithelium of the urinary apparatus of a boy aged fourteen, described in a dissertation by Liebenow, in whom there existed a fistula, the walls of which were completely epidermized and which communicated with the perineal region and the urethra membranosa. This hypothesis cannot be generalized, but can only be applied to those cases in which an epidermal invasion is possible through fistulous tracts, etc. But not even in this case can one be sure that the growth has not originated from vesical epithelium irritated because of the abnormal communication with the exterior, rather than from epithelium of the exterior. Fuetterer, citing this case, states that Marchand later changed his opinion concerning ascending epidermization on seeing cases with such epidermoid changes but occurring without fistula. 2. The embryonal origin of squamous cell carcinoma of the bladder was sustained by Albarran, who accordingly placed them among ectopic tumors in a class with dermoid cysts, rhabdomyomata, etc. In his vast experience he saw only four cases of squamous cell carcinoma of the bladder. Only one of these was a true cornifying epithelioma. The latter he believes are always heterotopic, although he does not deny a different. etiology for the less well differentiated types. 3 and 4. Leukoplakia: Any discussion of squamous cell carcinoma of the bladder would be incomplete without giving due consideration to leukoplakia, or, as it has been variously called,.

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pachydermia vesicm, xerosis, cholesteatoma, epidermal plaques, leucoplasia, leukokeratosis, cystitis en plaques (Landsteiner and Stoerck). These names represent one and the same process of squamous cell proliferation and keratinization of the vesical mucosa. Rokitansky was the first to call attention to this rare condition in 1861. His description is worth quoting: In the inflamed bladder there occurs occasionally an epidermoid production, at times circumscribed, at other times occupying the whole mucosa of the urinary apparatus; it produces an abundant desquamation of thick scales, stratified, white, shiny, in the form of cellular epidermoid plates; the adjacent mucosa is chronically inflamed and villcius. Lowenson in 1862 described a case. The most notable papers since then are those of Halle, Rafin, Bolaffi, English, and Kretschmer. English presented a complete review of the subject in 1907, collecting twenty-seven casbs from the literature. Kretschmer brought the subject up to date in 1920, and was able to collect forty-four classic cases of this condition. Halle, in a series of cases, showed that severe chronic cystitis was' apparently the main etiological factor in most cases, and that leukoplakia was an intermediate step to carcinoma. 2 We know that leukoplakia in the mouth often (if not always in the course of time) becomes malignant. Halle describes leukoplakic transformation so complete as to resemble exactly normal epidermis, reproducing in detail the respective layers of the skin. Ikeda has shown the presence of glycogen in the leukoplakic cells, just as occurs in the basal cell layers of the skin. Posadas believes 2 Kuhn's cases (see tables) were cited by the author as illust rating the change from benign to malignant. Civiale first advanced the view that a benign papilloma of the bladder, called at that period fungus, might take on a cancerous change. This view is shared by K uster, Von Antal, Ziegler, Albarran, Zuckerkandl, Legueu, and most American urologists. (See Buerger's excellent article.) On the other hand, Rauschenbusch and Lubarsch hold that this t ransition is not proved, and Nitze and Casper in their vast experience, have never observed a case in which a tumor of the bladder removed at a second operation, showed a different structure than the original. However, the balance of evidence undoubtedy leans toward the tenet t h at a benign papilloma is potentially malignant.

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that leukoplakia arises on a syphilitic basis in most instances. Lecene does not believe that inflammation can account for this condition but believes it to be a congenital heterotopia. That the developmental factor plays a part is supported by Leber's case of a four months old infant with leukoplakia of eye and kidney. Luys, on the other hand, having observed leukoplakia of the urethra associated with chronic urethritis and stricture, believes it to be due to nutritional disturbances of the cells on the basis of severe chronic inflammation. Whether such factors may produce leukoplakia experimentally is not known. 3 Lichtenstern, Legueu, and Desnos and Minet accept Halle's work as demonstrating the origin of leukoplakia on the basis of long standing inflammation and irritation in the majority of cases, and its subsequent malignant degeneration into squamous cell carcinoma. Indeed, it would seem hard to dispute such evidence as is presented in the cases of Cabot, Marion, and others. (See case reports.) M etaplasia. The leukoplakic transformation of vesical mucosa has been considered by Halle as metaplasia, the change of entoderm into ectoderm. Metaplasia is a term generally used rather loosely, but strictly means, as defined by Orth, the transformation of one well characterized tissue into another equally well characterized, but morphologically and functionally different. Formerly (MacCallum) such processes were thought to be very widespread, but now different explanations are available for most of the puzzling conditions in which a tissue is found in a situation totally abnormal for it, and replacing the type that should normally occupy that place. Metaplasia is not meant to include such 3 We know, for example, that if the parotid duct is tied off the epithelial cells become squamous in the course of two or three months. Fuetterer was able to bring about squamous epithelial changes in the stomach of dog by excision of a section of gastric mucosa followed by reduction of hemoglobin by intravenous injections of pyrogallic acid. Eichholz has published an interesting study of experimental epithelial metaplasia. He concludes that epidermis cannot be changed to epithelium of other types experimentally, but that certain types of epithelium can become so like epidermis that it is impossible to differentiate it. He further concludes that epidermoid changes in transitional epithelium (e.g., bladder) cannot with certainty be said to be a metaplasia, but are probably due either to an embryonic cell rest or to an ascending epidermization.

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conditions as embryonic cell rests, or the growth of one tissue in such a way as to_push back the normal and replace it (such as may have occurred in Marchan d's case of ascending epidermization), or . the morphological changes produced by mechanical means, such as keratiniz ation of the mucosa of a prolapsed vagina. Metaplas ia should not, ·therefore, be applied to such a process as leukoplakia, which appears in most instances to be a keratiniz ation of the vesical mucosa in response to irritation . Discussion of probable causation of leukoplakia. We know that cornification is a protectiv e :mechanism, a means of defense util~zed uniformly througho ut the animal kingdom. It is a process occurring normally in the skin because the skin is an epithelium exposed to extrinsic influences, extremes of weather, etc., and occurring abnormal ly where the extrinsic influences are more severe, as in callouses on the hu.nds, and corns of the feet. Hence it has occurred to us to explain leukoplak ia on a similar basis, that is, as a protectiv e mechanism reacting to irritation , and that all epithelium has more or less inherent in its protoplas m 'this protectiv e power of squamous cell differentiation and possibly cornification, which it exercises under conditions with which we are not entirely familiar. Therefore we cannot consider leukoplakia a metaplas ia in that it is a purposeful change of entoderm into ectoderm, but that it is merely the result of a protectiv e or adaptive mechanis m called into play, and character istic of epithelium in general. We must recognize it as the expression of a dual potential ity inherent in the protoplas m, in greater or less degree-n ot only of differentiating and exercising their normal functions according to their location, but also of bringing their protectiv e mechanis ~ into play in a uniform way und€r certain conditions of irritation . This dual potential ity of epithelium is exemplified in the embryo in the ducts of Mueller which are capable of forming indifferently either cylindrical or stratified squamou s epithelium in any part of their courses. Hitschma nn brings out this fact to explain the appearan ce of squamou s epithelium in the uterus under certain pathological conditions. Of course we must exclude from this generalization leukoplak ia arising on the basis of embryoni c cell rests of misTHE JOURNAL OF UROLOGY, VOL . V I , NO.

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placed epithelium or an ascending epidermization, but these conditions, if they really do occur, must be rather in the minority. Why this condition becomes cancerous we do not know any more than we know why cancer develops in any other situation. Cancer is a life process which as yet we are no more capable of defining than we are of definirtg life itself. All we can do is to discover further certain laws governing its nature and growth. So far we have much evidence to show that certain types of cancer have as their main etiological factor or contribut ory stimulus prolonged irritation or trauma of some sort. Without jeopardizing. our theory it is possible that leukoplak ia . may be malignan t f;rom the beginning in accordance with theory no. IV, although it is impossible at present to prove this contentio n. THE OCCURREN CE IN OTHER REGIONS OF "HETEROT OPIC EPIDERMI ZATION''

Cases have come to our attention during the last few years,. and numerous reports occur in the literature , of squamou s cell growths occurring elsewhere in the genito-ur inary tract. Such growths are reported by Kretschm er in the ureter. Berg thinks that in his case the tumor was primary in the pros.;. tate, and that the prostate should have been removed together with the bladder tumor. He believes that squamou s and papillary carcinomata are practicall y the only cancers that are primary in the bladder and quotes Mandelb aum in support of this belief. Squamou s cell carcinoma of the prostate is far less frequent in occurrence than of the bladder and it seems more logical to suppose that in Berg's case the cancer was primary in the bladder. That squamou s epithelioma or acanthom a of the prostate does occur is attested in the cases reported by Beyer and Buchal, Schmidt, and Krebs and Marchan d. In Schmidt' s case, a man aged fifty-three, there · was a chronic suppurati ve prostatiti s associated with extensive squamou s cell metaplas ia and beginning acanthom a. A similar case has come to the attention of the · junior member from our senes of prostates . · In this

CARCINOMA OF THE BLADDER

21

specimen a few small alveoli exhibit an entire replacement of their epithelial lining by heaped up squamous cells encompassing corpora amylacere in the centers of the alveoli. Another alveolus exhibits what might be termed by some a beautiful example of metaplasia. The alveolus is lined by normal columnar epithelium which in one area shows a heaping up of cells into a papilla, the cells varying from high columnar' at the base to . typical squamous at the tip of the papilla. The condition might be termed a benign acanthosis. 4 Wassermann has made a very extensive study of epitheliomata of the urethra. The fact that they were nearly all squamous cell tumors, and that they were preceded in nearly every case by chronic urethritis or stricture, is suggestive. Primrose has recently reported a case of squamous cell car~inoma of the kidney primary in the renal pelvis, and includes other cases from the literature. One has recently occurred on our service. Dr. Rusk of the Department of Pathology has shown us a case of squamous cell carcinoma of the hypophysis. He has also demonstrated squamous cell changes in the uterus. Adler tabulates approximately forty-two cases of squamous cell carcinoma of the lung which he was able to collect. Herxheimer has made an excellent study of "heterologous cancroids" and reports cornifying epitheliomata of the gall bladder assoc:ated with stones and chronic inflammation, and of the stomach, cecum, pancreas, uterine cavity, and parotid gland. Fuetterer reviews the literature of such growths reported as occurring in the eyes, nose, ear; larynx, trachea, bronchi, lungs, stomach, intestine, gall bladder, renal pelvis, bladder, urethra, uterus, . breast and testicle. · 4 Some light is thrown on this astonishing condition by the studies of Aschoff and Schlachta. Schlacta states that t he glandular epithelium of the prostate and utriculus becomes physiologically transformed into squamous epithelium during the fetal period. This changes can be observed in the glands at the beginning of the eighth month. This squamous epithelium desquamates and vanishes completely in the first two months of extra-uterine life. He thinks it a differentiation, not a metaplasia. Prostatic acanthosis might be considered a reversion of epithelium to a fetal type, or perhaps it is a stage in the process of "protective cornification."

------

22

--

FRANK HINMAN AND THOMAS E. GIBSON SUMMARY OF ETIOLOGY

1. Four theories have been advanced to explain the origin of squamous cell carcinoma of the bladder. Definite proof in support of these theories is lacking except in those few cases where the neoplasm appears to be the result of the malignant degeneration of pre-existing leukoplakia. 2. Leukoplakia is a rare condition characterized as a keratinization of the mucosa of the urinary tract as a result in most cases, apparently, of long continued severe inflammation or irritation. 3. Leukoplakia is not a metaplasia, but represents a stage in the process of protective cornification, or keratinization in response to irritation, a characteristic, it would seem, of epithelium in general. 4. Squamous cell growth, or "heterotopic epidermization" so-called, has been reported in practically every region of the body where epithelium occurs. PATHOLOGY

Many of the cases reported are not sufficiently detailed to permit analysis, but certain conclusions may be drawn. Squamous cell carcinoma of the bladder is distinct pathologically from other malignant tumors of the bladder. Indeed the true cancroid is so characteristic that the diagnosis can usually be made through the cystoscope. Whereas other carcinomata of the bladder are grossly papillary, villous, or sessile, the true cancroid is characterized as an indurated infiltration of the bladder wall, generally superficially ulcerated so as to merit the name cancroidal ulceration. It is the same process as occurs in the epitheliomata of cutaneous surfaces-the malignant ulcer with ragged base and hard, friable, everted, pearly, advancing borders. The less well differentiated squamous cell carcinoma of the bladder which might be labelled non-cornifying epithelioma (epithelioma pavimenteux tubulee) is not so characteristic and usually one cannot differentiate them grossly from other types of carcinoma arising in the bladder on the basis of papilloma, as occurred in our second case.

---~~---------------'------

CARCINOMA OF THE BLADDER

23

In our own cases the two cornifying epitheliomata are typical cancroidal ulcerations (cases I and III), the non-cornif ying growth (case II) a papillomatous growth. Histologically the difference between them appears to be one· of degree rather than kind, as case II shows no cornification, case III shows cornification without definite pearl formation, and case I shows both cornification and pearl formation. · In the 90 cases collected 17 are definitely stated to exhibit cornification. Undoubtedly many more were cornified, since in many instances the diagnosis given is simply "cancroid," "squamous call carcinoma," etc., without definite reference to cornification. In 30 cases where the gross picture of the growth is stated, a definite ulcerating type of growth is described in 13 instances. Four of the growths are stated to have begun on a leukoplakic pasis; these showed cornification. The other types of growth are discribed as villous, fungus, nodular, lobulated, cauliflower, etc. Some of these are described as showing cornification. METASTASES

The extreme rarity with which metastases are mentioned suggests either that very few autopsies were done, or that metastasis is not a characteristic feature of this disease. Careful analysis of the literature shows that post-mortem findings are reported in only nine instances (Symonds, Albarran- case no. 3, Bolaffi, Rona, Clarke, Fagge-case no. 26, Godlee, Cabot, Henschen). In Clarke's case the left kidney was found studded with metastatic nodules. Symonds case showed nodules in the lungs, and Godlee found metastases in the left lung. Bolaffi reports the inguinal and hypogastric glands enlarged and softened in his two cases. Fagge (case no. 26) reports involvement of the glands at the bifurcation of the aorta. In Cabot's case, as described by Davis, the retroperitoneal lymph nodes, the kidneys, and the anterior abdominal wall were involved. It would seem on the whole, therefore, that metastasis is not a prominent feature of the disease. However, a most striking feature of the disease, in those cases where the cause of death has been stated, is the uniformity with which the terminal stage

24

FRANK HINMAN AND THOMAS E . GIBSON

of the disease has been characterized by one or more of the following conditions- infection, hydronephrosis, and cachexia. It appears therefore that in general the cause of death in this rapidly progressive type of malignancy is not due to metastases, but to the other factors enumerated. FREQUENCY

A review _of the literature shows that eighty-seven cases have been reported, which with our cases brings the number up to ninety. Of this number ten were reported by American authors: Berg (1 case), Cabot (1 case), Geraghty (1 case), Lilienthal (1 case), Gardner (1 Gase), Buerger (5 cases). It is possible that more cases have been reported, but a careful search of the literature has failed to reveal them. As to their relative frequency, in Buerger's series of 138 bladder tumors, 52 were carcinomata, of which 5 were squamous cell, giving a proportion of 10.4 per cent. In Frisch's series of 300 bladder tumors, 107 were papillomata showing cancerous degeneration on serial section; 65 were papillary carcinomata and 28 squamous cell carcinomata. Thus 7.1 per cent of his carcinomata were squamous cell in type. Haake reports 1 squamous cell carcinoma in a. series of 22 cases, or 4.5 per cent. TABLE 1 .A.GE

20 to 29 30 to 39 40 to 49 50 to 59 60 to 69 70 to 79

NUMBER OF CASES

2 2 16 6 11 1

PERCENTAGE

5.2 5.2 41.6 16 .2 28.6 2 .6

AGE

In only 38 cases is the age stated; rather too small a number on which to base statistics. The youngest was aged twenty-eight, the oldest seventy-eight. Nearly one half the cases occurred in the decade between forty and fifty. Only two cases occurred under the age of thirty (see table 1).

CARCINOM A OF THE BLADDER

25

SEX

In 38 cases in which the sex is stated, 29 were males and 9 females. This incidence corresponds closely to the . statistics given by Kretschm er for leukoplak ia (34 males and 8 females), and also to the sex incidence of other types of vesical carcinom ata. INITIAL SYMPTOM S AND DURATION

Symptom s are not characteristic. The duration of symptom s likewise varies; in some ca,ses there were no prodroma l symptoms except hematuri a of short duration which caused the patient to consult a physician;· in other cases, but due to other causes, the onset of symptom s dates back many years, as in the case reported by Rafin of a man aged sixty-nine who had a traumatic rupture. of the urethra in infancy followed by stricture necessitating three internal urethroto mies. In this case symptoms covered practicall y a whole lifetime. Cabot's case (described by Davis) had sev!c)re chronic cystitis and calcuria of twenty-fo ur years duration. TREATME NT AND RESULTS

That the treatmen t of bladder tumors has made tremendo us strides forward in recent years is evident when we compare modern methods of ·treatmen t to those of 1850 as expressed by Lankeste r: "Maligna nt disease of the bladder is only relievable by opiates; the less done the better for the patient." Even as late as 1896 Geraghty found that no case of tumor of the bladder was admitted to the Johns Hopkins Hospital during the preceding decade in which a diagnosis was made sufficiently early to warrant anything more than suprapubic drainage. 5 Of the The almost uniformly bad results reported in t he past can be explained by the following facts: 1. Cases were generally seen late, the disease often not suspected until operation revealed its true nature, and then operation was often merely palliative. 2. Most of the cases reported occurred previous to the developmen t of cystoscopic methods. Since 1900 only about 14 cases of statistical value have been reported. (See chronologic al t able.) 3. The especially malignant nature of the type of neoplasm under consideration (Clado, Legueu, Buerger, Geraghty) has very probably been a factor in contributin g to the poor results of treatment, 6

26

FRANK HINMAN AND THOMAS E. GIBSON

cases collected, the treatment is stated in 32 cases. In 11 the treatment was palliative, in 21 operative (see table 2). TABLE 2

Treatment and results TYPE

NATURE OF OPERATION

-1

NUMBER OF CASES

RESULTS

Cures

Deaths, Post-operative

3 years-1 (Albarran) 2 years-1 (Pauchet) months-1 3 (Hinman and Gibson) Time not stated

2 years-I (Berg) 4-5 months(Busse) 3 months-1 (Marion) 20 days-1 (Pauchet) Shortly post-operation-1 (Cabot)

--Simple knife

excision

with

11

-1

Results not stated-2

-2

Nature of operation not stated but probably simple excision with knife

-3

5

--Extirpation with vano-cautery

-5

-6 --

7

6 months-1 (Thompson) Post-operatio n 1 (Marchand)

Results not stated-1

gal-

2

4 months-1 (Guyon) Time not stated -1 (Pousson)

Preliminary fulguration, resection with knife, radium to operative site

1

10 months-1 (Hinman and Gibson)

Preliminary cauterization, resection with knife, radium to operative site

1

3 years-1 (Hinman and Gibson)

Thermo-caute rization of operative site after excision with scissors

1

8.5 years-1 (Lilienthal)

-4

5. years-1 (Buerger) 1 month-1 (Lampe)

---

Palliative /non-operative . 8 -Treatment/ operative, 3

Death-11

CARCINOMA OF THE BLADDER

27

As shown in table 2 only one 8.5-year cure, one 5-year cure, two 3-year cures, and one 2-year cure are reported. CONCLUSION

1. Three personal cases of squamous cell carcinoma of the bladder are reported. Radical resection of the cancer has been performed in all. One patient is living and well three years after operation, another ten months and the third three months. 2. Squamous cell carcinoma of the bladder is a relatively rare disease, only ninety cases (including our own cases) having been collected. 3. The etiology of these neoplasms has been variously ascribed to (1) an ascending epidermization, (2) an ectodermal embryona1 inclusion in the vesical wall, (3) a carcinomatous degeneration of pre-existing leukoplakia, and (4) leukoplakia malignant in character from the beginning. It seems that no single theory will explain the etiology of these neoplasms in every case. Definite proof in support of these theories appears to be lacking except in those few cases where the growth appears to be the result of malignant degeneration of preexisting leukoplakia. 4. Leukoplakia is a rare condition characterized as a keratinization of the mucosa of the urinary tract as a result, in most cases, apparently, of long continued severe inflammation or irritation. 5. Leukoplakia is not a metaplasia, but represents, according to our explanation, the effort on the part of epithelium to exercise its inherent power of adaptation to environment in the form of protective cornification, a characteristic, it would seem of epithelium in general. 6. "Heterotopic epidermization '.' so-called, both benign and malignant in nature, has been reported in practically every region of the body where epithelium occurs. 7.- Squamous cell carcinoma appears to be the most malignant form of vesical carcinoma. It is rapidly infiltrating and characterized by early lymphatic involvement. 8. There· are two types of squamous cell carcinoma of the bladder; the tubular type (epithelioma pavimenteux tubulee) or

28

FRANK HINMAN AND THOMAS E. GIBSON

noncornifying epithelioma, and the lobular type (epithelioma pavimenteux lobulee ou come) or cornifying epithelioma. The former is said to be the more common type. The latter is generally a malignant ulcer resembling those seen on cutaneous surfaces. 9. The difference between the two types of neoplasm is apparently one of degree rather than kind. The true cornifying epithelioma is not necessarily heterotopic as held by Albarran. 10. Metastases are uncommon, having been reported in only three cases. The cause of death in most cases is attributed to one or more of the following factors: infection, hydronephrosis, and cachexia. 11. The greatest age incidence is between forty and fifty. Approximately three-fourths of the cases were males.· 12. Symptoms are not characteristic. The most common prodromal symptom is hematuria. 13. Treatment has been palliative in many cases, and the reports of the operative treatment are too incomplete to determine with certainty the results. Two three-year cures, one five-year cure, and one eight-and-a-half-year cure have been reported after resection. CASE REPORTS

Albarran Case I (cited by Rafin 1905). Male. Age thirty-eight. Previous history not stated. Suprapubic extirpation of cancroidal ulcerative growth arising on leukoplakic basis. Patient living and well three years later. Case II (Guyon collection). Female. Age sixty-two. Dysuria first symptom. Duration not stated. Patient died from renal infection. Tumor proved to be pavement cell epithelioma with epidermoid pearls. No eleidin granules seen. The specimen illustrated in Albarran's Treatise shows a very large mass involving both ureteral orifices, infiltrating the bladder wall and extending posteriorly toward the iliac vessels. Case III (Horteloup's service). Female Age fifty-five. First symptom hematuria. Autopsy revealed ulcerating cancroid located near left ureteral orifice. This was the only true cancroid that Albarran ob-

29

CARCINOMA OF THE BLADDE R

served, as it was the only one that showed eleidin granules, filaments of Ranvier, and pearl formations. He accordingly calls it a dermoid and classes it with heterotopic tumors. Chronological table AUTHOR

CASE NUMBER

YEAR

Clarke . . ............. ... ... . . ... .. ... .. .. .. . . .. .. . .. . Sanders ... . .. .... . . .. .. . . . ... . . . ...... . .. . .. . ..... . . . Heilborn . .. . .. .. . .............. ............ .... . .. .. . Marchand .. . . .. . . .. ... . .... . ..... ... . . . .... .... . . . .. . Fagge . . . . . . . . . ... . .... ... . ... .... .. . .. .. . . . .... ..... . Godlee . .. ... . ..... .. . .. . . . . .... .. . .. . . .. .... . .. ... .. . Thompson .. . ..... . .. . .. ..... .. .. ........... . .. .. ... . Winckel. . . .. . . ..... . ...... . .. .. . .. . .. . .. . . ... . .. ... . . Roesen .. ........ . .. ..... .. . .. .. . .. . ..... ......... . . . . Antal. . . ........ . . .. .. . .. ... . ... ... . ...... . . .. . . . . . . . Cabot ..... . .. .. . ... . .. . . .. .. . .... . ... . . .... . .. . . . . . . . Albarran . . . .. . . .. . . . . .. ..... . . ... . ·......... ...... ... . Shapiro . ......... ....... ..... .. .. . . . ...... . .... ... . . . Symonds . .. .. ..... . . .... .. . .. . ...... . .. .. . ....... .. . . Clado . . .. ....... . . ... .. . .. . . ... . .... .... . .... . . ..... . Haake . . . .... . . .. .. .... .. ..... . .. .. .. ........ ...... . . Bourcy . . .... . ... .. . . .... ..... . . . . . . . .. ...... ... . . . . . Berry . .. . ... . . ; . . . .. . . .. .. .... .. .... . ... . .. .. . . . .. .. . Veliaminoff .. .. .... .... . . ...... . . . . . . .... . .. . .. .. .. . .

18 82 6o-61 73 25- 26 57 85 90 80

1860 1864 1869 1873 1877 1884 1884 1885 1886 1888 1891 1892 1893 1894 1895 1895 1895 1896 1896

Wendel. . . ... . . . .... ... . . .. . .... .. . ...... . .. . ... .... . Busse ...... . .... .. . ......... .... .. . . . ..... . .. . . . . . . . . Rona ..... . .. . ... . ...... .... . .. . . ... . . .. ... . . . .. . . .. . Keller .... ·............. .. . .. . .. ... ......... ....... .. . Frisch .. . .. .. . .. . . . .. .. .. .. .. .. . .. . .. .. . .... ... .. ... . Berg . .. .... . .. ... . .. .. .. . .. . . . . ..... .... .... . .. ..... . Cassanello . ... ... .. . .. . .. . ... .. . . . . .. .. . ... . . ... . .. . . Wagner .. .. ... . .. ..... . . . .. . .. . . .... .. . .. . .... .. . . .. . Herxheimer .... . . . .. . . .... .. .. .. . .. . .. . . .... . . ... ... . Bolaffi ... .. . . .. .. ... . .. . .. .. . .. . . ..... .. . . . . ... .... . . Cornil and Ranvier . .. . . . .... . . . . .. ... . .. . . .. .. .. .. . . Kuhn . . . ... . .. .. ... . . ........ .. . .. . . .... .. . .. .. .. ... . Buerger ..... ........ ....... .. .. . .. .. . . .... . . ... .. . .. . Gardner . . .. . .. .... . . . . . ... . . . . . . .. . . . . ... ..... ... .. . Lilienthal. ... .. .. .. ... . .. .. . . . ...... . .. . . . ... .. . .. . . . Marion .. . .. . . .. .. . . . .. .... . . . . .... .... . . .... ... ... . . Hinman and Gibson . . . ... ..... .. .... . .. . . . . .... .. . .. .

88- 89 15 81 68 27- 54

4

16 2

83 84 17 59 9 6

86

5 19- 20 87 62 7- 8 21- 24 69- 70 10-14

55 72 74 64-66

1900 1901 1901 1906 1907 1908 1909 1910 1911 1912 1912 1913 1915 1915 1917 1920 1921

Total number of cases since 1900, 58 (of these 58, because of the paucity of data reported, only about 14 cases are of much statistical value).

30

F'RANK HINMAN AND THOMAS E. GIBSON

Antal

Female. Age forty. Severe chronic cystitis many years duration, accompanied by foul, purulent, ammoniacal urine and hematuria. Induration of the vesical wall could be felt on bimanual palpation. Operation by vaginal route. Extirpation of growth found impossible. Neoplasm was true cancroidal ulceration. Later course not stated. Berg

Male. Age not stated. Before operation nodule size of hazelnut noted in prostate. Not thought malignant. Neoplasm in bladder size of silver half dollar removed with terminal one half inch of left ureter. Ureter re-implanted in vertex of bladder. Wounds all healed in four weeks. Patient had good bladder function and was well until fourte'en months after operation. He then showed evidence of prostatic enlargement. Examinatio n showed the nodule in the prostate previously noted to be much larger. Patient succumbed to prostatic cancer two years after the operation for the bladder neoplasm. Berg thinks bladder tumor was secondary to the prostatic tumor, and that the prostate should have been removed together with the bladder tumor. Berry

Male. Age fifty-five._ Pollakiuria and dysuria two years duration. Hematuria six months duration. At operation a hard sessile mass was found on the posterior wall. Diagnosis-s quamous epithelioma. Death fourteen days after operation. Only a part of the growth was removed at operation. Bolaffi (two cases)

Both cases were essentially the same. The bladders containing the tumors were obtained from two old men at autopsy, age not stated. Bolaffi describes the growths 1n minute detail both grossly andhistologically. They were typical cornifying epithelioma ta containing keratohyalinized cells and epider moid pearls. The interior of the bladder of each showed numerous verrucous vegetations and ulceration. The ureters were not involved, although the growths were far advanbed. The muscularis of the bladder was deeply invaded. Some of the neoplastic cells assume the form of normal vesical epithelium. Prostates normal in each case. The author describes in detail the morphological characters of the cells.

CARCINOMA OF THE BLADDER

31

Bourcy

Case reported as kankroid. Further data not obtainable. Buerger

Buerger, in a very valuable contribution covering a series of 113 cases at the Mt. Sinai Hospital and flome 25 other cases of bladder tumors, describes 5 primary squamous cell carcinomata. In a personal communication of recent date he reports a female age sixty-three living and well five years after operation. Busse

Male. Age fifty. Seven years previously had severe pain in left kidney region associated with hematuria. At operation a tumor was excised together with a left hydronephrotic kidney. An encrusted, ulcerating mass was found infiltrating the bladder wall, associated with a papilloma in the left ureter. The bladder growth was a squamous cell carcinoma· resembling those seen on cutaneous surfaces. Patient died four and a half months after operation. Cabot Male. Age forty. Cut for stone in 1870. . In 1884 sharp attack of cystitis. Five years later fragments of stone passed. In 1889 patient entered hospital. Bladder searched and washed out with Bigelow. evacuator. Suprapubic cystotomy. A thick flat sheet of tissue was · peeled off from the mucous membrane of the bladder; pachydermi a vesicre or leukoplakia. Good recovery. Patient discharged as cured. In the bladder washings were many pavement cells, and the sheet peeled off was epidermoidal in type. A subsequent paper by Davis includes thls interesting case with the later course of events. In 1892 the patient was suffering from pain and pollakiuria. In 1894 he. re-entered the hospital with a discharging fistula above the pubis. The fistulous opening was enlarged by Dr. Cabot and the intei;ior of the bladder explored. It was found invaded by new growth. A small portion which was removed proved to be epidermoid carcinoma. The patient died shortly after, and at autopsy the bladder, kidneys, muscles of the abdominal wall and retroperitoneal lymph glands were found involved in the disease.

NUM--

BER

., AUTHOR

~

-"

1

Albarran cited by Rafin

2

Albarran

,a

0

M

.,

I NITIAL SYMPTOM

4

Antal cited 1888 40F Hematuria by Rafin cystitis, pyuria

5

Berg

7

Bolaffi

ANAT OMY

Suprapubic ex- Ulceration tirpation

55F Hematuria

1908

Many years Palliative

M

1896 55 M Pollakiuria, dysuria, hematuria

1912

HISTOLOGY

RESULTS

Leukoplakic basis

Patient well 3 years after

Pavement cell epithelioma, no pearls or eleidin granules

Death from renal infection

Ulceration

True cancroid

Death

Ulceration

Cancroid

1892 62F Dysuria

Albarran

Berry

TREATMENT

i:,,, 1:-,:)

38 M

3

6

DURATION

- < "'

2½ years

I ~

....::i::

z~

i

Suprapubic ex- Tumor size of tirpation silver half left ureter, doliar transplant ed to vertex

Squamous cell carcinoma

Operation, incomplete removal

Hard mass sessile posterior wall

Squamous epithelioma

Death 14 days post-operation from uremia

Aut opsy

Numerous ver: rucous vegetations, ureters free

Squamous cell carcinoma

Death

Death 2 years post-operation, carcinoma of prostate

~

0

~

Ul

~

s to

r/1

0

z

.I

8

Bolaffi

9

Bourcy

10-14 Buerger (1)

15

16

17

Busse

Cabot

Clado

1912

Autopsy

Same

Same

Death

Cancroid Squamous cell carcinoma

Well 5 years after operation

Extirpation Encrusted inand left hyfiltrating uldronephrotic cer sac removed

Squamous cell carcinoma, bladder papilloma in ureter

Death 4 to 5 months postoperation

Operations for Leukoplakic stone and sheets pachydermia vesicae

Squamous cell Death carcinoma, pearls, Ieukoplakic basis

1915 63

1901 50 M Pain left kidney and hematuria 7 years before

7years before

1891 40 M Calcuria and chronic cystitis

24 years

1895

C

~

C H

~

~ 0

>.,:j

~

ttj

!:Ii

E

Kankroid

1::1 ttj

18

Clarke

1860 59F Hematuria

Multiple nodules and viilous vegetations

Squamous cell epithelioma with epitheIial globes

19--20 Cassanello

1909

Kankroid

21- 24 Cornil and Ranvier

1912

Kankroids

Death

~

~ ~

NUM-

BER

..,. .. -01

AUTHOR

--

A

01 "'

-

M 01

"'

INITIAJ;. SYMPTOM

DURATION

TREATMENT

ANATOMY

HISTOLOGY

RESULTS

c,:i

25

Fagge

1877 69 M Stricture and cystitis

26

Fagge

1877 48 M Stricture, 27 years Palliative Calcuria hema- Toward end turia

30 years

Palliative

Ulceration posterior wall

Squamous epithelioma

Death

Sloughing mass at fundus in:filtrating all coats

Squamous epithelioma

Death

.

~

;J z>l:>'I

27- 54 Frisch

1907

Squamous cell carcinoma

55

Gardner

1915

Squamous cell carcinoma

56

Geraghty

1918

Squamous cell carcinoma

57 Godlee

1884 78M Dysuria

Long time

Palliative

Fungus growth Squamous epi1 inch diamthelioma eter perforhorni:fied ating bladpearls der

ES

~ ~

~

§ Death

is:

g; !:'.I !;)

....l;d

Ul

58

Guyon cited by Ra:fin

45M Hematuria

.

Suprapubic ex- Multiple tutirpation mors inwith galfected segvano-caument of tery bladder

0

Pedunculated lobulated epithelioma pavement cell no :filaof ments union, no corni:fication

P atient well after 4 months

z

59

Haake

6()-{il Heilborn Herxheim er

1911

63

Henschen

1882 49 M Hematuri a

65

66

Hinman and 1920 68 M Stricture and cystitis Gibson Hematuri a

Hinman and 1918 63 M Hematuri a, pollakiuri a Gibson slight pain with urination

Pavement cell carcinoma

Death

Kankroid s

1869

62

64

Apple-size sessile tumor posterior wall

1895 60 M

4 years

years before 2 months

10

1 year

6 months Hinman and 1921 62M Hematuri a pollakiuri a Gibson burning with urination

Extensive malignant ulceration

Krankoid

Villous growth

Squamous cell carcinoma , large pearls and prickle cells

Death 4 years after appearance of first symptoms

Sectio alta ex- Large malig- Cornifyin g epitheliom a tirpation nant ulcer left ureter about left transplant ed, ureter orifice radium insert

Patient living and well 10 months after operation

Medicinal

·o

~

Q H

~

~ 0

'":I

~

t;1

t:d

Sectio alta thermo-ca uterization radical extirpation with knife

Papillary cauliflower growth on right posterior wall

Squamous cell carcinoma , no cornification

Patient living and well 3 years after operation

alta Sectio radical resection

Large malignant ulcer at fundus

Cornifyin g epitheliom a

Good post-opreerative covery. Living-well 3 after mos. operation.

~ tj

t,,J !;ti

~

C,t

N UM-

BER

AUTHOR

68

69

70

E<

A

-67

...,

Horteloup cited by Rafin Keller

Kuhn

Kuhn

"'"'

---<

.

M

INITIAL SYMPTOM

DUR ATION

TREATMENT

ANATOMY

H IST OL OGY

RESULTS

00

62M St rict ure Hematur ia

Many years 1 month

1906 48M

1913 49 M

1913 49 M Dysuria and hematuria

11 years

2 years

Sectio alta incomplete re.moval

Tumor

Myo-epithe liDeath follow~ oma, pseudoing day cornified

Operation

Cauliflower growth, hard edges, in exst rophy of bladder

Pavement cell epithelioma , showing malign ant degeneration

Infiltrating mass on right near vert ex

i:cj

::0

~

....J:I1

~

1897 papilloma Squamous cell removed. epit helioma 1904 recurrence of pap illoma removed . 1908 recurrence of malignant papilloma. Operation First operation papilloma removed ; second operation for malign ant recurrence

Patient followed 6 months, result?

~

0:,

'

~

~ ~

0

ls::

>

Ul

ttj

Pavement cell carcinoma

e td

Ul

0

z

in

Several months

M Hematuria and burning on urination

2 months

71

Lampe

1905 48 M Changes bladder

72

Lilienthal

1917

73

Marchand

1873 40 M Stricture and chronic cysti tis

Ulcerated exstrophied bladder

Cancroid

Well 1 month after

Suprapubic ex- Cauliflower growth2 cm. tirpation in diameter with Pacqueabout right lin cautery ureter orifice

Squamous cell carcinoma

Patient alive and well 8½ years after

Operation

Kankroid with pearls

Operation

C

Death after operation

~ C .... ~

~

0

74

Marion

1920

M Severe chronic cystitis

Long duration

alta Sectio radically resected

2 malignant ul- Kankroid on leukoplakic cers on leubasis koplakic basis

Suprapubic ex- Large sessile tumor t irpation

Kankroid

Death 2 months after operation

~ t'.l

t,:j

well Patient after 2 years

Pauchet cited by Rafin

28 M Hematuria

76

Pauchet cited by Rafin

28F Hematuria and pain

Suprapubic ex- Sessile tumor tirpation

Kankroid

Death 20 days post-operation

77

Pousson cited by Rafin

51M

Suprapubic extirpation with thermo-cautery

Pavement cell carcinoma

Cure

75

l,;j

~ ~

t'.l

p;j

C..:>

-.:i

NUM-

BER

AUTHOR

--

"1 E<

< A

fil

~

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INITIA L SYMPTOM

78

Pousson cited by Rafin

51 M

79

Rafin

60 M Traumatic rupture urethra in infancy, 3 internal urethrotomies, pyuria

80

81

82

Roesen

Rona·

Sanders

DURATION

Nearly whole life

.T REAT MENT

Curettage palliative

1864 43 M Pieces of tissue discharged in urine

Diffuse vegetat ions, infilt ration, suppuration

H ISTOLOGY

RESULTS

Pavement cell carcinoma

Death in 4 months

Pavement cell carcinoma

Fistula, death 3 months from eachexia and infection

~

00

i el

1886 33 M Stones, chronic 2 years cystitis, pain on urination 1901 46 M

ANATOMY

Infiltrating perforating growth Autopsy

~

Pavement cell carcinoma with pearls

§

Malignant ul- Cancroid cerat ion bladder. Xerosis right kidney. Purulent pyelonephritis, diphtheritic cystitis

Death

Cancer involv- Squamous cell ing nearly epithelioma whole bladwith pearls der wall

Death

~

rf).

!:'.I 0

....b:!

rf).

0

z

83

Shapiro

1893 42F Pain on urination

3 weeks

Palliativ e

84

Symonds

1893 48 M Hematur ia, pollakiu ria, pain

6 months

Operatio n, incomplete removal

85

86

87

Thompso n

Wagner

88-89 Wendel 90 Winckel

1910 49 M Incontin ence 1900

1885 62F

Large fungous mass around left ureter

Operatio n

1884 67 M

1896 49F Hematur ia Veliaminoff and dysuria by cited Rafin

' Tumor size of Squamou s papillary car-goose egg cinoma

18 months

2 years

Suprapu bic reof section tumor

Palliativ e

Tumor 3-4 by 10 cm.

Exstroph ie vesicae

Death

Squamou s epithelioma

Death 3 weeks post-ope ration

Squamou s epithelioma with cell " nests"

Death 6 months post-ope raation

Cancer with epithelia l pearls and alveo1ar structure s

Cure with fistula

Cancroid

C

~

~ ~ 0

>,j

~t_,j b:l

~

Death

t_,j ~

Cancroid s Cancroid ~ ~

40

FRANK HINMAN AND THOMAS E. GIBSON

Clado

Clado describes a personal case in his treatise 1895, and notes the fact that he has seen only about three such cases. Clarke

Female. Age fifty-nine. Complaint: Hematuria . There were pieces of tissue expelled in the urine showing tesselated epithelium. At autopsy the left kidney was found involved in new growth metastatic from the bladder neoplasm. Histologically the cells were chiefly of the squamous type. There were villous outgrowths about the left ureter. These showed squamous cells and epithelial pearls. Other parts of the mucous membrane were studded with nodules of the same type of cells. The ureters appeared normal grossly. Cassanello

Cassanello in a discussion of epidermoid changes in the bladder mentions two cases of squamous cell carcinomata of the bladder under the appellation "Kankroi d." Cornil and Ranvier

These authors, in their text on pathology, report having studied four cases of vesical cancroids. Their conclusions agree in the main with those of Halle. Fagge Case I. Male. Age sixty-nine. Thirty years before the patient was in the hospital for stricture. At that time he had a perinea! section performed, and he ever afterward passed his urine in comfort through the fistulous opening then made. He was in the habit of introducin g a catheter into the bladder through the fistulous opening from time to time. The urine was thick and ammoniacal and contained albumin. The immediate cause of death seemed to be suppurativ e inflammation of the kidneys. The bladder was contracted and the mucous membrane deeply inflamed. There was an o'pen ulcer on the posterior wall the size of a five-shilling piece, with irregular sloughy surface, thick, raised, everted edges, and with floor and margins alike infiltrated with thick, opaque, white, soft growth obviously of a m?,lignant nature. Microscopically it was a typical squamous epithelioma, with numerous "bird nest" aggregatipns. Fagge says: "It will be observed that the

CARCINOMA OF THE BLADDER

41

seat of the ulcer was not at the trigone, but behind it, corresponding exactly with the spot at which the point of a catheter would impinge upon the bladder wall." The author believes the catheter the chief contributory factor in the development of this tumor. Case II. Case similar to first, the only difference being that the patient did not have instruments passed very frequently to the bladder (see table). Frisch

Frisch reports 300 bladder tumors, 28 of which were apparently squamous cell carcinomata : "knotige plattenepithel und teils knollige, teils infiltrierte medullarkarzinome.'' Gardner

Gardner has reviewed 1702 bladder tumors. His tables include two squamous cell tumors, one a papilloma, the other a carcinoma. There are probably more than this, but the histology is not reported in every case. Godlee

Male. Age seventy-eight. Complaint: Dribbling of urine and difficulty in emptying the bladder for some time. At autopsy a large tumor three inches in circumference was found surrounding the right ureter. The edges overlapped the surrounding mucous membrane. The surface of the tumor was ragged with fungous-like projections. The bladder was perforated by the growth with resulting peritonitis. The ureter seemed to pass into the tumor, but the urine was not putrefied in the pelvis of either kidney. There were metastases in the lungs. The tumor was a typical cornifying epithelioma. Guyon (cited by Rafin 189/i, also by Albarran 1891)

Male. Age forty-five. H ematuria almost to point of complete exsanguination. Suprapubic operation by Guyon. Extirpation of multiple tumors inferior segment of bladder by galvanic cautery. The tumor proved to be a pedunculated lobulated epithelioma of pavement cell type without filaments of Ranvier, and without cornification, located about the ureteral orifices. Patient made good recovery and was well four months lat er.

42

FRANK HINMAN AND THOMAS E. GIBSON

Haake

In a series of twenty-two bladder tumors one squamous cell carcinoma. Man. Age ' sixty. Apple size tumor posterior bladder wall. Bladder contracted on tumor. Surface smooth, covered with grey exudate. Broad base. Openings of both ureters normal. Prostate not enlarged and not invaded. Masses of squamous cells through all coats of bladder. Heilborn Heilborn in his treatise mentions two cases of kankroids. Herxheimer

Herxheimer demonstrated a specimen showing very extensive cancroidal ulceration of the bladder. No further data available. Henschen

Male. Age forty. Active life as business man. Acquired severe form of lues. Treated. Married many years. Healthy children. First symptoms of cancer hematuria, later pieces of tissue expelled, occasional clots. Treatment medicinal only. At autopsy a small villous growth was found which had infiltrated the wall of the bladder very extensively. There was moderate unilateral hydronephrosis probaably due to pressure on ureteral aperture by the growth. Diagnosis: Pavement cell carcinoma showing prickle cells and many large pearls. Horteloup (cited by Rafin 1905, also by Albarran 1891)

Male. Age sixty-two. Treated for stricture for years. Hematuria and purulent urine one month duration. Bimanual palpation reveals hard tumor extending up within one finger breadth of umbilicus. Operation by suprapubic route. Adherent peritonitis found. Tumor curetted and incompletely removed. Myo-epitheliomatou s pseudocornified growth containing psorosperms, and situated at the fundus. Death on following day. Keller

Male. Age forty-eight. Cornifying epithelioma in exstrophied bladder. Exstrophied bladder covered with pavement epithelium showing malignant degeneration. Thinks it metaplasia. It was a cauliflower-like growth with hard edges. Case followed for six months. No further data.

CARCINOMA OF THE BLADDER

43

Kuhn Case I. Man. Age forty-nine. 1897 papilloma removed. 1904 small apple-sized tumor recurrence removed. Free from symptoms until 1908 when he suffered pain on urination and terminal hematuria. Patient again operated. The interior of the bladder was found filled with tumor mass histologically squamous cell carcinoma (cited by Blum). · Case II. Man. Age forty-nine . 1906 papilloma removed. 1907 burning on urination and hematuria (terminal). Cystoscopy showed bleeding papilloma size of hazel nut. 1908 sectio alta by Blum. Tumor histologically squamous cell carcinoma. Lampe Male. Age forty-eight. Extopia vesicre. Noticed changes in his bladder for several. months and finally bleeding. He was very anemic. Fixed tumor, precipitous borders rising 5 to 6 cm. above level of abdominal wall. In its right half numerous papillary structures. In the left half a necrotic crater-like ulcer. Left ureter meatus projects from base of this ulcer. The right is covered by papillary structures. Per rectum the bladder feels like a hard plate, somewhat nodular in its middle portion. Patient operated four weeks before by Sonnenburg's method for extopia vesicre. Patient made good recovery. Diagnosis: Cancroid. Lilienthal Middle aged male. Complaint: Slight burning on urination and general uneasi:r;iess in region of genitals. Occasionally difficulty in starting stream. Two months later hematuria. Cystoscopy revealed cauliflower-like tumor in region of right ureter about 2 cm. in diameter. It appeared to surround the ureteral orifice. The entire mass was removed with the scissors and a good margin of healthy tissue left. After removal the wound was cauterized with the Paquelin cautery. 1.5 cm. of the ureter was removed with the tumor. On t he eleventh day after operation the patient's temperature mounted to 104° F. A von Dittell perinea! incision was made and a large amount of pus drained. The cavity was packed with gauze. The sepsis still persisted. Right pyonephrosis and pyoureter were discovered. Operation for same. Three and a half years later operated on prostate transvesically and found soft cicatrix in place of cancer~ No sign of recurrence. No trace of malignancy in prostate. . Patient reported living and well eight

44

FRANK HINMAN AND THOMAS E. GIBSON

and one half years after operation for carcinoma of bladder. communication of recent date.)

(Personal

Marchand

Male. Age forty. Urethrotomy for impermeable stricture. Severe chronic _cystitis. Autopsy revealed perforation of bladder with pericy°stic abscess, and abscess in kidneys. Ulcerating tumor in pars prostatica of bladder. Many _epidermoid pearls. Diagnosis: True cancroid. Marion Male. Severe chronic cystitis of several years duration which did not yield to treatment. No hematuria noted. Pain region of right kidney. Cystoscopic examination revealed numerous white leukoplakic patches in bladder with two malignant looking ulcers about the · size of a franc near the right ureteral orifice. Function of the right kidney much impaired. At operation a right hydro-ureter and infected hydronephrosis found. The ureter was sectioned and radical excision of ulcers performed. Owing to an accident, it was impossible to reimplant the ureter. After the operation the patient developed a high fever in which it was evident that the right kidney was the cause. Seven weeks after operation the right kidney was drained, a large amount of pus escaping. One week later the kidney was removed altogether with about 500 cc. of pus. Six days later the patient died of progressive infection and cachexia. The ulcerated areas proved microscopically to be a true "epithelioma corne" with many cornifying pearls, developing on a leukoplakic basis. Mandelbaum

Mandelbaum, in a study of bladder tumors, cites two cases of squamous cell carcinomata. His cases are from the Mt. Sinai Hospital and are probably already included in Buerger's report. He believes that vesical. cancers other than the squamous or papillary forms are as a rule secondary in the bladder. Pauchet (cited by Rafin) Case I. Male. Age twenty-eight. Complaint: Hematuria. Operation by suprapubic route. Large sessile c(!,ncroid removed. Patient made good recovery and was living and well two years later.

CARCINOMA OF THE BLADDER

45

Case II. Female. Age twenty-eigh t. Complaint: Hematuria and pain on urination. Sectio alta. Tumor removed which was partly sessile, partly pedunculate d. It proved to be a true cancroid. Death occurred twenty days after operation from thrombo-phl ebitis and embolism. Pousson (cited by Rafin) Case I. Male. Age fifty-three. Squamous cell growth extirpated with thermo-caut ery, resulting in cure. No further data. Case II. Male. Age fifty-one. Growth similartoabo ve extirpated, resulting in cure. No further data. Rafin Male. Age sixty. Had traumatic rupture of urethra in infancy, following which three internal urethrotomi es were performed. Urine very turbid. Capacity ·of bladder very small. Trifling improvemen t with instillations which permitted cystoscopic examination. Condition thought to be a vegetative cystitis. Palliative operation done. Curettage of bladder through suprapubic incision, and diffuse, infiltrating, suppurating vegetations removed. Microscopic examination revealed squamous cell carcinoma. Death three months later from infection and cachexia. Roesen Male. Age thirty-three. Dysuria and purulent cystitis two years duration. Numerous oxalate stones in bladder. An infiltrating and perforating·g rowth was found about a stone inbedded in the vesical wall near the prostate. Microscopically it was a cornifying epithelioma with widespread pearl formation. Rona Male. Age forty-six, laborer. Clinical diagnosis: Pulmonary and genito-urina ry tuberculosis. Anatomical diagnosis: Purulent pyelonephritic, diphtheritic cystitis extending down to the muscularis; ureteral dilatation with chronic ureteritis; xerosis right renal pelvis. No xerosis of ureters. True kankroid in bladder showing many pearls. Many neoplastic nodules between the muscle bundles. Growths began ap· parently on leukoplakic basis.

46

FRANK HINMAN AND THOMAS E. GIBSON

Sanders

Male. Age forty-three. The patient had no hematuria at any time. Fragments of tissue were passed frequently per urethra. Also passed concentric globular bodies size of starch globules to three or four times that size. The cancer involved nearly the whole interior of the bladder and obstructed completely the left ureter. Examination of the cancer post-mortem showed structures resembling the "laminated epithelial capsules" of Paget, or the "globes epidermiques" of Lebert; Shapiro .

Female. Age forty-two, extremely anemic and cachectic. Complaint: Pain on urination first noticed three weeks before. A catheter was readily passed through the urethra, and about two teaspoonfuls of dark, turbid urine was obtained in which were suspended dirty red and yellow shreds. The patient died shortly thereafter, and at autopsy a tumor situated on the trigone was found, about the size of a mediumsized apple. From the invasiveness of the tumor and the cell types the author concludes that it is a papillary squamous cell carcinoma. No metastases found . Symonds

Male. Age forty-eight. Complaint: Hematuria six months duration. Frequent and painful micturition last six weeks. Operation by perineal route. Large fungating mass found near orifice of left ureter. Death three weeks after operation. At autopsy metastases were found in the lungs. The new growth involved the entire urethra. Diagnosis: Squamous epithelioma. Thompson

Male. Age sixty-seven. Operation followed by death six months later. No further data. Veliaminoff

Female. Age forty-nine. Hematuria and dysuria eighteen months duration. Hard tumor felt on bimanual examination. Sectio alta with subtotal resection of bladder. Tumor measuring 3 to 4 by 10 cm. proved to be true cornifying epithelioma with epithelial pearls.

-

-----

CARCINOMA OF THE BLADDER

47

Symonds

In some areas the growth showed an alveolar structure. The patient recovered but had a permanent urinary fistula. not stated. Wagner

Later course of events

Male. Age forty-nine. Laborer. Had ectopia vesicre. Since 1905 inguinal hernia, left sided rib fracture, and impairment of bladder function. Since this time felt weak and could not work. Last two years could no longer control his urine and it dribbled continually. The last six months his bladder became ragged, and greatly annoyed him. Pale sick-looking man. Hemoglobin 62 per cent Sahli. Left saphenous veins varicose. Scrotal hernia. Bladder exposed over an area measuring 8 by 8 cm. In the middle of the bladder was a projecting mass about 5 cm. high, of reddish color, bleeding easily and covered by thin mucoid material. Photograph showing ureters opening o_n either side of tumor. Urine negative. Total epispadias. Case not operated. Piece removed for diagnosis- cancroid. Also adenoma in gland mclusion of bladder wall. Wendel The author mentions two cases of cancroidal growths in the bladder in his treatise on bladder tumors. Winckel

Winckel in his treatise describes a cancroid, encrusted with urinary salts, occurring in a female at the age of sixty-two. Cases not included in table

Barling reports 74 cancers of the bladder, of which he states that 47 are of the true squamous cell type. He divides carcinomata of the bladder into two classes: (1) Squamous cell carcinoma; (2) Alveolar carcinoma. He states that squamous cell growths are approximate ly twice as frequent as the other. Such a statement is at variance with facts reported by other competent observers who, as a whole, are practically unanimous in regarding squamous cell carcinoma, and particularly the cornifying type, as a rarity. Consequently we cannot accept this report without further qualification, and have omitted his cases from our table of ninety cases. Dell'Aqua reports a case of typical cornifying epithelioma occurring in a mare of twelve years.

48

FRANK HINMAN AND THOMAS E. GIBSON

REFERENCES ADLER: Tumors of the Lung, 1912. ALBARRAN: Tumeurs de la Vessie, 1892, p. 130. Sur un Cas de Leucoplasie Vesicale. Revue Practique des Mal. des Org. G.-Urin., 1907. AscHOFF: Ein Beitrag zur normalen und Pathologischen Anatomie der Schleimhaut der Harnwege und ihren Drusigen Anhange. Virchow's Arch., cxxxviii, 119 and 195, 1894. BARLING: Epithelioma of the bladder. Birmingham Med. Rev., p. 129, 1890. BERG: The radical treatment of carcinoma of the bladder. Ann. Surg., xlviii, 355, 1908. BERRY: Notes of a case of epithelioma of the bladder. Scalpel, Lond., vi, 208, 1896. BEYER: I. D., Greifswald 1896. BLuM: Zeitschrift. f. Urologie, iii, 1909. BoLAFFr: Sul Significato della Evoluzione Epidermoidale in Alcuni Cancri della Vesica. Lo Sperimentale, Arch di Biol., Firenze, xvii, 643, 1912. BUERGER, LEO: The pathological diagnosis of tumors of the bladder with particular reference to papilloma and carcinoma. Surg. Gyn., and Obs., 179,·1915; N. Y. Med. Jour., clxxxxiv, 841, 1916. BussE : Geschwiilstbildung in den Grossen Harnwegen. Virch. Arch f. Path .. Anat., clxiv, 119, 1908. CABOT: (A. T.) A case of epithelial cancer of the bladder and kidney. Med. · Times and Gaz., London, ii, 154, 1860. CASSANELLo: Contributo Allo Studio dell Epithelioma Epidermoidale della vescica. Folia Urologia, iii, no. 5, p. 509, 1909. CASPER: Berlin Klin. Woch., xlv, 303, 1908. CrvrALE: Traite Pratique sur Jes Maladies des Organes Genito-urinaires, 1842. CLADo: Tumeurs de la Vessie, 1895, p. 105. CoRNIL AND RANVIER: Manuel d'Histologie Pathologique, 1912, v. 4, pt. 2, p. 1591. CLARKE: A case of epithelial cancer of the bladder and kidney. Med. Times and Gaz., London, ii, 154, 1860. DAvrs: Primary tumors of the urinary bladder. A study of 41 cases at the Massachusetts General Hospital, Ann. Surg., xliii, 566, 1906. DELL 'AQUA: Epithelioma Pavimentosa della Vesica. La Clin. Vet., Milano, xxix, 7-11, 1906. DEsNos ET MINET: Traite des Maladies des Voies Urinaires. Paris, 1909, p. 598. ENGLISH: Ueber Leukoplasie und Malakoplasie. Zeitschr. f. Urol. Bd. 1. H ., viii, 641, 1907. FAGGE: A case of epithelioma of the posterior wall of the bladder, secondary to perinea! fistula of thirty years standing, and probably due to irritation from catheterism. Trans. Path. Soc., London, xxviii, 167, 1877. FirnE:_Du Cancer de la Vessie. Paris, 1883. · FRISCH: Bericht uber 300 operierte Blasentumoren. Wien. Klin. Wchnschr., xx, 1205, 1907. FUTTERER: Ueber Epithelmetaplasie.-Er gebnisse der Alig. Path. 9, abt. 2, 1903, p. 706.



CARCIN OMA OF THE BLADDE R

49

various GARDNER: Clinical results in operation s on tumors of the bladder by operator s for the last fifteen years : A review of 1702 cases. Trans. Amer. Urol. Ass., ix, 226, 1915. Y GERAGHT : Cabot's Modern Urology, ii, p. 208. only GoDLEE: Squamou s epithelio ma of the bladder, with secondar y growths xxxii. 188, xxx, Lond., Soc. Path. Trans. lung. left in the , 1895. HAAKE: U eber den Primaren Krebs der Harnblas e. Thesis, Freiburg Mal des des Ann. Urinaire. il L'appare de es Candroid et sies HALLE: Leucopla ' Org. Gen .-Urin., xiv, 481, 1896. 302, HANSEMANN: Ueber Malakop lakia der Harnblas e. Virch. Arch., clxxiii, 1903. HEILBORN : Ueber den Krebs der Harnblas e, 1869. xvii, HENSCHEN: Primar Villos Kankroi d i Blasan. Upsala Lakaref Forh., 75---97, 1882. ge CanHERXHEIMER: Berliner Klin. Wchnsch r., 1911, p. 1867. Ueber Heterolo croid. Beitr. z. Path. Anat. u. Allg. Path. Bd. 41, S. 348-411, 1907. HERTZLER: A Treatise on Tumors, 1912. f. gyn., HITSCHMANN : Ein Beitrag zur Keimtnis s des Corpusca rcinoms . . Arch. lxix, 629-680, 1903. eIKEDA : Beitrage zur Lehre der Epiderm oidalen Umwand lung des Harnblas 1907. 369, v., ., H I. Bd. Urol., f. nepithels . Zeitschr. HarnKELLER: Ueber Einen Fall von Plattene pithel Krebs einer Exstroph ierten 1906. Leipzig, Thesis, ng. Behandlu e Operativ blase, und seine KuHN : Zur Kasuisti k der Harnblas entumor en. Thesis, Berlin, 1913. g KUSTER : U eber Harnblas engeschw iilste und deren Behandl ung. Sammlun Klin. Vortrage , Volkman n, . p . 267, 1884. gen KrMLA: V. Hansema nn's Malakop lakia Vesicae Urinaria e und Ihre Beziehun zur Plaquefo rmigen Tuberku lose der Harnblas se. Virch. Arch., 1866. and Osb., KRETSCHMER: Leukopl akia of the bladder: and ureter. Surg. Gyn. xxxi, 325, 1920. LANDSTEINER AND STOERCK: Zieglers Beitrag., 1904. , January LANKESTER: Maligna nt disease of the bladder. Lond. Jour. Med., June, 1850, p. 298. LEGUEU, ALBARRAN, AND SEBILEAu: Voies Urinaire s, 1900, p. 195. Grafe's LEBER : Die Xerosis der Conjunc tiva und Cornea Kleiner Kinder. Arch. f. Ophthalm ol., 1883, xxix, 1 Abth., 328. LECENE : J . d'Urol., 1913, iii, 129--137. LEWISOHN : Zeitschr . f. Krebsfor schung, iii, 9 , 1905. LEGUEU: Traite Chirurgi cal d'urologi e, pp . 864 and 451, 1910. e. LIEBENOW: Ausgede hnte Epiderm isbekleid ung d. Schleimh aut d. Harnweg 1891. , Marburg Thesis, on. LILIENTHAL: Cancer of the bladder- patient well five years after extirapti 1917. 386, cv, Jour., N. Y. Med. Ectopia LAMPE: Demons tration eines Praparat s von Carcinom der Harnblas e bei 1905. 229, xxxiv, Chir., f. . Gesellsch . Deutsche l. Verhand Vesicae. Wein. LrcHTENSTERN : Ein Beitrag zur Metaplas ie des Harnblas enepithe ls. ·13_ no. xvii, 1904, r., Wchnsch Klin: Luys: Text Book on Gonorrho ea, 1917, p. 167.

I

50

FRANK HINMAN AND THOMAS E. GIBSON

LoWENSON: Ueber einen besonder n Folgezus tand der Epiderm oidalen Unwand lung des Harnblas enepithe ls. St. Petersbu rg Med. Zeitschr. , ii, 225, 1862. LuBARSCH: Ergibnis se der Allgemeinen Patholog ischen Morphol ogie und Physiologie die Mensche n und Thiere, 1895. MARCHAND: Beitrag zur Kasuisti k der Blasentu moren. Thesis, Marburg , 1887. Arch. f. Klin. Chir., xxii, 676, 1878: MENDELBAUM: The patholog y of new growths of the bladder. Surg. Gyn. and Obs., v, 1907, p . 315. MARION: Un cas de Leucopla sie tres etundue de la vessie, avec degenere scence epithelio mateuse d'une partie de la leucoplasie. J. d'Urol. Med. et Chir., 1920, ix, 257. MACCALLUM: Textboo k of Patholog y, 1918, p. 184. NITZE u. SONNENBURG: Handbuc h der Praktisc hen Chirurgi e, von Bergman , von Bruns, von Mickulicz, Bd. iii, S. 822. PRIMROSE: Squamou s cell carcinom a of the kidney. J . A. M.A., July 3, 1920, p. 12. PosADAs: Argentin a Medica,· 1905, January 21; abstracte d in Ann. des Mal. d. voies Gen.-Uri n., 1906, xxiv, 58. PoussoN : Precis des Maladies des Voies Urinaire s, Collectio n Testut. (Tumeurs de la Vessie), p. 652. RoESEN: Ueber Steine und Krebs der Harnblas e. Munch.- Med. Wchnsch r., xxxiii, 424, 1886. RAFIN: Indicatio ns et Resultat s du Traitem ent Chirurgi cal des Tumeurs de la Vessie. Ass. Fr. d'urologi e, 1905, p. 1. RoNA: Epithelv erhornun g der Schleimh aut der oberen Harnweg e. Monatsc hr. ·f. Urol., vi, 705, 1901. RoKITANSKY: Lehrbuc h der Pathol. Anat., Wien, 1861. SANDERS: Epithelio ma of the bladder. Edinb. Med. Jour., x, 273, 1864. SHAPIRO: Carcinom a Corneum Papillom atodes Ves. Urinaria e. Objazat. Pat.Anat. Izlied. Stud.-Me d. Imp. Charkov. Univ., ii, 126-131, 1898. ScHRIDDE: Die Entwickl ungsgesc hichte des Menschl ichen Speisero hrenepithels. Wiesbad en, 1907. SCHMIDT : Ueber Epiderm isbildung in der Prostata . Ziegler's Beitrag. z. Path. Anat., xl, 120, 1906--07. ScHLACHTA: Beitrage zur Mikrosk opischen Anatomi e der Prostata und Mamma des Neugebo renen. Arch. Mik. Anat., lxiv, 405-480, 1904. SYMONDS: Squamou s epithelio ma of the bladder involvin g entire urethra. Trans. Path. Soc. Lond., i, 1011, 1894. THOMPSON: Tumors of the bladder, 1884 (plate VI). WAGNER: Kankroi d der Exstroph ierten Harnblas e. Deutsch e Zeitschr. f. Chir., civ, 329, 1910. WENDEL: Beitrage zur Lehre von den Blasengeschwiilsten, Bd. VI, 1900. WASSERMANN: Epithelio ma Primitif de L'urethr e. Paris Thesis, 1895, pp. 1-157. WrncKEL: Deutsche Chirurgi e 1885, Lief. 62. ZucKERKANDL: Die Localen Erkranku ngen der Harnblas e. Weiri, 1899. 0