The Pathogenesis of Bladder Carcinoma

THE JOURNAL OF UROLOGY

Vol. 88, No, 6 December 1962 Copyright © 1962 by The Williams & Wilkins Co. Printed in U.S.A.

THE PATHOGENESIS OF BLADDER CARCINOMA WILLIAM SIMON, JUSTIN J. CORDONNIER

AND

W. T. SNODGRASS

From the Department of Surgery, Section on Urology, Washington University School of Medicine ancl the U. S. Veterans Hospital, St. Louis, Mo.

The spread and development of cancer of the bladder have been attributed to various means, including lymphatic spread and occurrence of precancerous lesions. To study the significance of these various processes, we investigated entire cystectomy specimens by taking microscopic sections from 11 portions of each bladder. From these, we reconstructed representative maps that created a microscopic portrayal of the whole bladder (fig. 1). Thus, not only the tumorous and suspicious areas, but the normal appearing areas as well were examined in this standardized examination. The use of this method enabled us to search the bladder in a regular rather than a random way and also permitted the entire thickness of the bladder wall in each area to be inspected. Our first objective was to search for lymphatic vessel invasion by tumor away from the principal tumor. The studies of distant lymphatic spread far from the tumor as postulated by Baker1 served to stimulate this investigation. The work of Jewett and Eversole 2 on local modes of invasion by carcinoma of the bladder has demonstrated that lymphatics are more frequently involved by tumors that are deep in the bladder wall, and that local lymphatic metastases traveled in a direction more or less perpendicular to the plane of the overlying bladder mucosa. Our investigation disclosed the existence of local lymphatic invasion just beneath the advancing carcinoma. The presence of tumor in lymphatic channels far from the principal tumor was not found. We also studied the epithelial changes of atypical hyperplasia, Brunn's nests, cystitis cystica and carcinoma-in-situ. The occurrence of mucosal lesions in association with bladder

tumors was recently studied by Eisenberg, Roth, and Schweinsberg,3 who found these lesions in the vicinity of approximately 22 per cent of papillary tumors and 30 per cent of the infiltrating tumors in their,investigation of bladder biopsies. Melicow4 studied the grossly normal-appearing mucosa in 10 cystectomy specimens removed for carcinoma; all showed some form of epithelial change. He further postulated that microscopic foci of neoplasia invisible to the naked eye were present in some of the bladders at time of surgery and subsequently, these foci came of age and the patient had additional tumors. Mostofi 5 has stated that transitional tumors may arise: 1) directly from surface epithelium, 2) through polypoid cystitis, 3) through formation of Brunn's nests or from a combination of all three. METHOD

Thirty-eight cystectomy specimens were studied. Immediately after removal, each was distended with and the entire specimen immersed in formalin solution. After several days of fixation, the bladders were opened by a longitudinal incision through the anterior surface and 24 sections were made from each specimen. These represented all portions of the bladder and prostatic urethra, and included all layers of the wall. Hematoxylin and eosin microsections were made in a plane perpendicular to the bladder mucosa. vVe believe that thin microsections are preferable to large, thick celloidin sections for study of lymphatic invasion. The grossly observed lesions were mapped when the bladder was opened, and the map location of each tissue block was recorded. The microscopic sections were then examined by the

Read at annual meeting of the American Urological Association, Inc., Philadelphia, Pa., May 14-17, 1962. 1 Baker, R.: Correlation of circumferential lymphatic spread of vesical cancer with depth of treatment. J. Urol., 73: 681, 1955. 2 Jewett, H.J. and Eversole, S. L., Jr.: Carcinoma of bladder; characteristic modes of local invasion. J. Urol., 83: 383, 1960.

797

a Eisenberg, R. B., Roth, R. B. and Schweinsberg, M. H.: Bladder tumors and associated proliferative mucosal lesions. J. Urol., 84: 544, 1960. 4 Melicow, M. M.: Histological study of vesical urothelium intervening between gross neoplasms in total cystectomy. J. Urol., 68: 261, 1952. 5 Mostofi, F. K.: Potentialities of bladder epithelium. J. Urol., 71: 705, 1954.

798

W. SIMON, J. J. CORDONNIER AND W. T. SNODGRASS

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BLUE II

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ATYPISM (Micro)

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Frn. 1. Bladder map urology department and by Dr. Harlan Spjut* of the surgical pathology department. Microscopic observations were then correlated with the previously observed gross lesion by use of the bladder map. Thirty-four men and 4 women constituted the series. The ages ranged from 34 to 75 with the majority between 50 and 60 years old. Twenty of these carcinomas were grade 4, twelve were grade 3 and six, grade 2. Cystectomy was performed in the grade 2 group because of * The authors wish to express appreciation for the valuable assistance rendered in this study by Harlan Spjut, M.D., associate professor of surgical pathology and pathology, Department of Surgical Pathology, Washington University School of Medicine.

TABLE

1. J ewett's grade Class Total

Grade A

B1

B,

C

0

0 1

0 0 2 2

0 0

1 2

5

3

3

4

4

3 3

4

11

0 6 12 20

rapid or prolonged persistent recurrence, or the presence of muscle invasion on biopsy. In the grade 4 group, two had definite epidermoid components. In accordance with the classi-

PATHOGENESIS OF BLADDEH CAHClSOMA

4

Fw. 2. Tumor thrombi in thin-walled vascular channels, presumably lymphatics, ca.rcinoma is grn,fo transitional cell. Vessels are near primary tumor. X50.

fications of Jrwett, l l carcinomas penetrated into fat were class C, hvo were class B2 , three were class B, , and four \Yem superficial class A (table l). The grade 3 group bad 4 class C, 2, class 132, three class B, and three wern class A. Five of the grade 2 group \Yerr class A. One grade 2 invaded muscle less than 50 prr cent for a classification of

TABLE

2. Lyrnphatir: 1•c.sscl fr,.vasion

(~rade

4 4 4

;3

.Jewett Jewett Je1yett Jewett

C (cpidermoidJ C

B2 C

l

2

B1 Kone of the eases exhibitrd any gross evicknrr of extension to lymph nodes at time of surgiC'al exploration. Periaortic and peh'ic lymph nodes biopsied at time of surgery were negative. LY:VIFF-UTIC SPHEAD

Ver:- careful and repeated study of microsections disclosed tumor in lymphatic vessels in 9 specimens. ln each case, the invasion was in n'ry close proximity to the principal tumor mass. The irffaded lymphatics were found in the

muscle layn and the 1wri\-esical fat just ahead the ad,-ancing tumor. They were close to tlH, tumor but showed no din·ct connection (fig. 2). ,-\11 \Yere in association with Yery irn-asi\'C t11111cm:, eight of which 1Yerc classified as Jcwctt's C :rnd the other one as .Jewctt'8 B2 . ~en'n were 4 and two were grade 3 (table 2). One of tl1e gradr· 4 tumors showed definite squamous changr~ and inYaded numrrous lymphatics just ahead of acl\-ancing tumor (fig. :3). None of the :-l8

800

W. SIMON, J. J. CORDONNIER AND W. T. SNODGRASS

Frn. 3. Focus of carcinoma having appearance of epidermoid carcinoma is present. Intercellular bridges were demonstrable. X150. revealed tumor in lymphatic channels farther than 5 mm. away from the principal tumor mass. There was no evidence of circumferential lymphatic spread. In 2 specimens, tumor was found in a lymph node on microscopic study. The lymph node in the first case (T. A., 60-2328, grade 4, Jewett C) was in the perivesical fat only about 1 mm. from the advancing tumor mass. In the second case (H. C., 60-8666, grade 3, Jewett C) however, the malignant node was far removed from the principal tumor. Microscopic study of the bladder wall intervening between the overt tumor and the malignant node disclosed no lymphatics containing tumor. 6 Although lymphatic channel invasion in close proximity to the main tumor was a frequent finding indicating spread of tumor through the lymphatics, continuous plugging of lymphatic channels from tumor to the involved node was not found. Lymphatic invasion was not found in any a Hinman, F., Jr.: The recurrence of bladder tumors. J. Urol., 83: 294, 1960.

tumor of Jewett's A or B 1 classification, irrespective of grade. PRE-CANCEROUS MUCOSAL CHANGES

The presence of proliferative mucosal change 7 was observed in association with the bladder tumor in all but four of the 38 specimens. The most prevalent change noted was atypical hyperplasia.4 Cystitis cystica (fig. 4, A) and Brunn's nests (fig. 4, B) were also seen frequently. Most of the changes were found within approximately a 4 to 5 cm. radius of the tumor, but in 10 cases the atypism was seen far removed from the overt tumor. No correlation could be made between the presence of proliferative mucosal changes and the grade of carcinoma present or depth of tumor penetration. In 3 cases a definite carcinoma-in-situ was observed far from the principal tumor mass (fig. 5). These were of such small size that they were grossly unobservable. These 3-minute tumors 7 Masina F.: Mucosal changes in relation to bladder tu~ors. Brit. J. Urol., 24: 344, 1952.

PATHOGENESIS OF BLADDER CARCIXOMA

801

·Fm. 4. A, cystitis cystica and sub-epithelial fibrosis ,ue present. X 140. B, surface epithelial h)'perp!asia and Brunn's nests are seen. ::VIoderate chronic inflammation and edenrn are prespnt,, )(80.

802

W. SIMON, J. J. CORDONNIER .\XD W. T. SNODGRASS

Fm. 5. C~·stitis cystic a and a focus of carcinoma-in-situ are illustrated. X 140 were found in association ·with a grade 4, Jewett B1; a grade 4, Jewett A; and a grade 3, Jewett

B2. 8 SUMMARY

The spread of carcinoma of the bladder was investigated by use of multiple microsections to create a map of each cystectomy specimen. Kine of 38 bladders (24 per cent) were found to have invasion to the lymphatic channels, but only in close 11roximity to the principal tumor mass. Three of these nine arc still alive. Two have no evidence of recurrence after 1 }1 years, but the third has just recently shown evidence of recurrence. All of the nine were very malignant, inva8 Melicow, M. M.: Tumors of the urinary bladder; a clinicopathological analysis of over 2500 specimens and biopsies. J. Urol., 74: 498, 1955.

sirn carcinomas, penetrating deep into muscle and in most cases, into fat. There were no lymphatic invasions seen in association with superficial tumors. Proliferative mucosal changes such as atypical hyperplasia, Brunn's nests, and cystitis cystica were observed in 89 per cent of the bladder8 studied. Three bladders were found to contain preYiously unnoticed and grossly undetectable carcinoma-in-situ far removed from the principal tumor mass. Transurethral resection or partial cystectomy ,rnuld not ha \'e removed these minute carcinomas. In the majority of the bladders studied, the proliferative mucosal changes would have still been present following extirpat.ion of only the apparent lesion.