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Bladder Neoplasms Associated with Augmentation Cystoplasty: Report of 2 Cases and Literature Review
0022-534 7/89 /1422-0377$02.00/0 THE JOURNAL OF UROLOGY Copyright© 1989 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Vol. 142, August Printed in U.S.A.
BLADDER NEOPLASMS ASSOCIATED WITH AUGMENTATION CYSTOPLASTY: REPORT OF 2 CASES AND LITERATURE REVIEW JACOB GOLOMB, CARL G. KLUTKE, KLAUS J. LEWIN, WILLARD E. GOODWIN, JEAN B. DEKERNION AND SHLOMO RAZ From the Department of Surgery, Division of Urology and Department of Pathology, Division of Surgical Pathology, UCLA School of Medicine, Los Angeles, California
ABSTRACT
Bladder neoplasms associated with augmentation cystoplasty have been reported to date in 12 patients. We add 2 cases: 1 with invasive transitional cell carcinoma involving the native bladder and bowel segment, and 1 with a poorly differentiated invasive oat cell (small cell) carcinoma confined to the bladder. The predisposing factors and pertinent literature are reviewed. (J. Ural.,
142:377-380, 1989) The use of bowel segments for urinary tract reconstruction is common and usually yields satisfactory results. The main indications are bladder augmentation, ureteral replacement in stone disease or after trauma, bypass of a ureteropelvic or ureterovesical junction, urinary undiversion and total bladder substitution. Bladder augmentation may be indicated in various pathological conditions that cause a functional or organic small bladder capacity (that is tuberculosis, radiation therapy, interstitial cystitis, congenital deformities, neurogenic bladder not responding to conservative measures and so forth). Reconstruction of the urinary tract with bowel segments has many advantages. Besides the supply of abundant tissues that are pliable to different shapes and needs, and protection of the upper urinary tracts, urinary reconstruction has improved the self-esteem and quality of life of the majority of patients. However, an issue that rarely is addressed is the potential longterm implications of establishing a permanent contact between the urinary tract and an isolated segment of the gastrointestinal tract. It is clear that the interaction with urine induces profound histological and functional changes in the bowel segments, including mucosa! flattening, atrophy of the villi and inflammatory infiltrate of the mucosa. At the same time, the adjacent urinary tract is being exposed to bowel secretions, mucus and a variety of unknown stimuli that have not been closely examined to date. The reconstructed bladder also may require intermittent catheterization and this can introduce the effects of recurrent bacterial infections. This combination of factors has been considered safe since 1950, when Couvelaire renewed interest in augmentation cystoplasty. 1 However, review of the literature reveals 12 reported cases of neoplasm formation after bladder augmentation. In our series of more than 400 cases of augmentation enterocystoplasty, performed between 1960 and 1987, 2 cases of late development of bladder carcinoma have occurred. The paucity of tumor cocurrences compared to colonic adenocarcinoma after ureterosigmoidostomy, with approximately 100 cases reported as of 1982, 2 is striking. Therefore, this should not challenge the use of bowel for urinary tract reconstruction but, rather, it should alert us to the need for close and long-term followup of the patients undergoing this procedure. CASE REPORTS
Case 1. A 45-year-old white man presented in 1960 with a history of Cowper's gland abscess and recurrent urethral strictures, resulting in chronic cystitis with a severely contracted Accepted for publication February 21, 1989. Supported in part by The University Urological Research Foundation.
bladder. The history was significant for left nephrectomy and right partial nephrectomy for calculous disease. There was no smoking history. Augmentation sigmoidocystoplasty, combined with 1-stage Johanson urethroplasty was done. A second-stage urethroplasty was performed 4 years later. He did well postoperatively, although he required periodic urethral dilation, as well as repeated antibiotic treatment for recurrent urinary tract infections, especially with Pseudomonas, Proteus and Escherichia coli. In 1984, 24 years after the enlargement cystoplasty, the patient presented with macroscopic hematuria and positive urine cytology results for malignancy. At hospitalization physical examination and laboratory evaluation were normal. Cystoscopy revealed an extensive tumor at the bladder dome involving the anastomotic site. Biopsies were compatible with grade 3 transitional cell carcinoma with invasion into muscle and extensive necrosis. A right retrograde pyelogram was normal. Chest x-rays were negative for metastases. Partial cystectomy, including the colocystoplasty segment, was done along with augmentation ileocystoplasty. The specimen contained a large infiltrating tumor measuring approximately 7 X 3 X 3 cm. involving the anastomotic site. The tumor consisted of poorly differentiated grade 3/4 transitional cell carcinoma of the bladder that extended through the muscularis of the bladder into the perivesical fat and also infiltrated the bowel wall into the pericolic fat (fig. 1). Lymph nodes in the pericolic fat showed no tumor. Convalescence was uneventful and there was no evidence of tumor recurrence at 3 years. Case 2. A 20-year-old woman presented in 1968 with a lifelong history of urinary incontinence secondary to hypospadias and frequent urinary tract infections, mainly with E. coli and Proteus. After multiple failed operations an ileal conduit urinary diversion was done in 1971, and transvaginal urethroplasty and augmentation ileocecocystoplasty were performed in 1979. Subsequently, pyocystis developed due to stenosis of the cecovesical anastomosis, necessitating revision. In 1980 the augmented bladder was of adequate capacity and continent, and the patient underwent undiversion, with the cutaneous urinary diversion being taken down and the ileal conduit anastomosed to the ileal stump of the augmenting ileocecal segment. Postoperatively, the patient did well on self-catheterization for 7 years until in late 1987 she noticed a decrease in bladder capacity with increased urinary frequency and urgency, and frequent urinary tract infections. A cystogram revealed good bladder capacity with no vesicoureteral reflux but, in addition, multiple calculi were seen at the junction of the native bladder with the attached bowel. An excretory urogram showed bilateral blunted calices with good kidney function and drainage, and bladder calculi. Cystoscopy demonstrated multiple free bladder
377
378
GOLOMB AND ASSOCIATES
FIG. 1. Case 1. Transitional cell carcinoma of bladder shows infiltrating tongue of poorly differentiated tumor. H & E, reduced from XlOO.
FIG. 2. Case 2. Poorly differentiated invasive oat cell (small cell) carcinoma of bladder demonstrates irregular nests of darkly staining cells with irregular, hyperchromatic, finely stippled nuclei and scant cytoplasm. H & E, reduced from Xl60.
stones and a yellow-whitish plaque diffusely covering the mucosa of the bladder base and up to the anastomosis. The plaque was resected transurethrally and the initial pathological diagnosis was poorly differentiated invasive carcinoma. Metastatic evaluation was negative. Radical cystectomy and continent urinary diversion were performed. The resected specimen contained an ulcerating tumor in the bladder approximately 5 cm. in diameter invading through the muscularis into the perivesical fat. Histologically, the tumor had features of poorly differentiated oat cell (small cell) carcinoma with solid sheets and nests of mitotic active small cells, and moderately sized angular, finely stippled nuclei exhibiting nuclear moulding (fig. 2). Neither the bowel segment nor the lymph nodes showed any evidence of malignancy. Convalescence was uneventful and she was free of tumor at 6 months. DISCUSSION
Review of the current literature reveals 12 reported cases of neoplasm formation after augmentation cystoplasty, to which we add our 2 (see table). 3 - 12 In 8 patients the original disease was tuberculous involvement of the urinary tract with a resultant contracted bladder. 3 - 5 • 8 •9 • 11 Nine patients had undergone ileocystoplasty and in all except 2 recurrent urinary tract infections and/or poor emptying of the augmented bladder dominated the postoperative period_ 3 - 5 , 7 ,s,n For 3 patients the postoperative result is not reported. The latent period between
bladder augmentation and diagnosis of tumor ranged from 3 to 24 years, with an average of 16 years. In our 2 patients the latent period was 8 and 24 years, respectively. Seven patients had invasive adenocarcinoma, which involved the native bladder and bowel in 3, was confined to the bowel in 2 and consisted of signet ring adenocarcinoma of the ileum in 1; in 1 the histological details were not reported. 3 • 5 • 6 • 8 • 9 • 11 Five patients had transitional cell carcinoma, which was confined to the bladder in 1, 3 while in 1 patient 2 sessile tumors developed from the urothelium, which regenerated over a dura patch used for augmentation cystoplasty, together with infiltrating transitional cell carcinoma in the native bladder. 10 One of our patients had a high grade transitional cell carcinoma that invaded the native bladder and bowel segment. Lamm and Gittes reported on transitional cell carcinoma in a male patient with interstitial cystitis, which they termed inflammatory carcinoma. 12 In the remaining patient the tumor was found in the ileal segment only. The latter case, reported by Smith and Hardy, is intriguing, since the patient had invasive transitional cell carcinoma in the ileal segment without any accompanying tumor in the bladder and without any history of bladder neoplasia. 4 One patient, reported on by Egbert and associates, had an undifferentiated sarcoma of the bowel with a satellite lesion in the bladder, which proved to be an aggressive neoplasm that metastasized widely. 7 One of our patients had a high grade invasive oat cell (small cell) carcinoma confined to the bladder, which was amenable to resection. Interestingly, in a case report and literature survey regarding small cell carcinoma of the bladder Swanson and associates implied that metaplastic changes secondary to chronic cystitits may have a role in the histogenesis of this rare neoplasm. 13 Our patient as well had protracted chronic cystitis for many years that could have contributed to the malignant changes. Our patient who presented with invasive transitional cell carcinoma in the native bladder and bowel after a prolonged history of chronic cystitis and recurrent urinary tract infections is reminiscent of the patient reported on by Lamm and Gittes, who has had irritative urinary symptoms for many years without any evidence of carcinoma in situ. 12 He was diagnosed as having interstitial cystitis, and underwent supratrigonal cystectomy and cecocystoplasty. The symptoms improved thereafter only temporarily and after a latency period of 3 years invasive transitional cell carcinoma developed involving the residual bladder and cecal segment, which the authors have termed inflammatory carcinoma. On the other hand, our patient had a recurrent urethral stricture resulting in persistent urinary tract infections and chronic cystitis. He experienced prolonged relief after bladder augmentation and only after 24 years did the neoplasm develop. It is highly unlikely that carcinoma in situ was present in the bladder during this entire quiescent period only to manifest 24 years later as invasive carcinoma. The issue of late malignant transformation in bowel mucosa exposed to urine flow for a prolonged period is challenging. A review of several series of patients with ureterosigmoidostomy reveals the incidence of either polyps or colonic adenocarcinoma occurring at the anastomotic site to be as high as 5 to 40 per cent, 14 a 500 to 7,000-fold increased incidence compared to the general population in selected decades of life. 14• 15 The incubation period observed between the procedure and finding of a tumor varies between 7 and 49 years, with an average of 20 years. 14 According to Gittes, the carcinogenesis of ureterosigmoidostomy clearly depends on the initial presence of urine, feces, urothelium and colonic epithelium in close apposition at a healing anastomotic suture line. 14 Animal models using 2 rat strains, Sprague-Dawley and Wistar-Furth, also demonstrated that colonic carcinogenesis needs the concomitant action of feces and urine, probably through local activation of fecal carcinogens by urine or urothelium. 14• 16 This theory is challenged by a report of an adenocarcinoma that developed after a latent period of 26 years in a colon conduit in which there had never been a fecal stream. 17 In an editorial comment to
Reported data on neoplasm formation after augmentation cystoplasty Reference Stone and associates3
Sex-Age
Original Disease
Procedure
Tuberculosis
Ileocystoplasty
Good
Adenoca.
M-53
Tuberculosis
Ileocystoplasty
Adenoca.
F-54
Tuberculosis
Ileocystoplasty
Recurrent infections, high residual urine Poor drainage
F-43
Tuberculosis
Ileocystoplasty
Leedham and England'
F-52
Tuberculosis
Ileocystoplasty
F-42
Squamous cell Ca of cervix Neurogenic bladder
Cecocystoplasty Heocystoplasty
Recurrent infections, high residual urine Recurrent infections
Recurrent infections
Recurrent infections, recurrent obstruction
Egbert and associates 7
M-43
Takasaki and associates 8
M-42
Tuberculosis
Ileocystoplasty
Harzmann and associates9
M-44
Tuberculosis
Colocystoplasty Dura patch
Not specified
Ileocystoplasty
Not specified
Selli and associates'° Kamidono and associates"
Tumor Histology
M-42
Smith and Hardy4
Kirby and Lloyd-Davies6
Result
F-57 M-47
Lamm and Gittes 12
M-62
Present series
M-69
F-40
Transitional cell Ca of bladder Tuberculosis Interstitial cystitis Chronic cystitis
Urinary incontinence
Cecocystoplasty Sigmoid colocystoplasty Ileocecocystoplasty
Not specified
Improved Recurrent infections, recurrent obstruction Recurrent infections, multiple surgeries
Transitional cell Ca plus Ca in situ Transitional cell Ca Adenoca., Ca in situ in ileum Adenoca. Sarcoma
Signet ring adenoca. Adenoca. Transitional cell Ca Adenoca. Transitional cell Ca Transitional cell Ca Small cell Ca
Location
Followup
Both
Latent Period (yrs.)
+
24
Dead at 1 yr.
+
22
Dead at 1 yr.
Grade/Stage Bowel* Not specified/not specified Not specified/not specified Not specified/not specified
Bladder
+
5
Free oftumor
0:,, ~ :,,,
t;l t;;J i?,j
:,;J
zM
0
'"'ti
Poorly differentiated/invasive Moderately differentiated/invasive Not specified/not specified Undifferentiated/ invasive
+
High/invasive
+
Not specified/not specified Not specified/invasive Undifferentiated/ invasive High/invasive
Not specified
15
Free of tumor
["-"1
ti->
rt)
+
+
t
rn ,-;
+
8
+
19
20 Not specified
17
+ +
High/invasive
High/invasive
17
+
Free oftumor Dead at 2 mos. Dead at 7 days Not specified
3
Not specified
20
Dead at 2 yrs. Residual tumor Free oftumor
+
3
+
24 8
Free of tumor
>-cc'
'-<
:i, ~
r;'.l
t
t•J
£~
"".l
,
> .
...-, 0
z (~l
,.-,:
(/2
....,
()
',J
I:."'
;l;-,. i)'}
,-']
~(1
* Dura patch in patient 10.
c,.;,
CJ:;
.380
GOLOMB AND ASSOCIATES
this case report Richie suggested that the chronic presence of urinary bacteria in the conduit may have assumed much of the putative function of the fecal bacteria in the pathogenesis of adenocarcinoma after ureterosigmoidostomy. These bacteria can act by reducing urinary nitrates to nitrites with formation of N-nitrosamines, which are known potent carcinogens for colonic mucosa.17 This is a plausible theory, since chronic infection has been a dominant factor in many of the patients who had tumors after augmentation cystoplasty. Stewart and associates also postulated that N-nitrosamines were the etiological agents in carcinogenesis following ureterocolonic anastomosis.18 They noted that dietary nitrates excreted into the colon conduit can be converted to N-nitroso compounds in the presence of mixed bacterial flora. The demonstration of these compounds in the rectal urine is highly significant, since these compounds normally are not found other than in trace amounts either in human urine or feces. Therefore, the detection of these mutagens in the urine may be an indication for their role in carcinogenesis. The etiology of malignant changes in augmentation cystoplasty in our cases as well as the previously reported patients is unclear. Most of the patients had concomitant risk factors, for example a history of tuberculosis with chronic inflammatory changes, radiation therapy, multiple operations, poor drainage of the bladder and recurrent bacterial infections with several organisms. In addition, chronic inflammatory changes secondary to the constant exposure of bowel to urine may increase the risk of malignancy. Indeed, Moorcraft and associates studied the histological changes in the mucosa of colon conduits. 19 They demonstrated chronic inflammation with a dense infiltration of plasma cells and eosinophils. The changes were progressive and correlated with the duration of urinary diversion. The authors assumed that these persistent inflammatory changes may act as a precursor of malignancy. 19 Mansson and Willen studied the mucosa! morphology of urinary cecal reservoirs and also demonstrated interstitial inflammatory cell proliferation with a slight increase in collagen fibers. 20 To the best of our knowledge, similar studies have not been done in augmentation cystoplasty but it can be assumed with relative certainty that the augmenting bowel segment, under constant exposure to urine, undergoes equivalent changes to those found in colon reservoirs and conduits. The occurrence of malignant tumors in ileal and colon conduits also is rare, with only sporadic cases reported. Tomera and associates reported on late development of an adenomatous polyp in an ileal conduit 22 years postoperatively. 21 Histological sections of the mucosa of this conduit had a definite colonic appearance that may be a metaplastic response to the urinary stream and may explain why an adenomatous polyp arose at this site, since adenomatous polyps are rare in the small bowel. Shousha and associates described ileal loop carcinoma developing 20 years after cystectomy for bladder exstrophy with diffuse metastasis and early death. 22 Wilson and Morales reported on early development of adenocarcinoma in a transverse colon conduit 12 months postoperatively, 23 and Marchetti and associates presented a case of adenocarcinoma in a sigmoid conduit occurring 8 years postoperatively. 24 Filmer reviewed the literature regarding malignant tumor formation after bladder augmentation, and ileal and colon conduits, and noted certain similarities with the development of colonic carcinoma following ureterosigmoidostomy, namely latency period, tumor histology and possible carcinogenic effect of chronic bacterial infection. 25 The latent period between bladder augmentation and manifestation of the neoplastic changes, averaging 16 years in our series, is reminiscent of the incubation period for tumor formation in ureterosigmoidostomy and implies that similar carcinogenic environments may have a role in these 2 entities. Chronic inflammatory changes, urine stasis and recurrent infections all can contribute to the occurrence of malignancy. Since primary adenocarcinoma of the ileum is rare, the reports of late development of malignancy of the bowel segment in
bladder augmentation and urinary diversion, which are constructed largely of ileum, are of great significance and should alert us to the need for closer supervision of these patients. In conclusion, with the increasing trend to incorporate bowel segments into the urinary tract for bladder augmentation or substitution, the low but still distinct risk of late 'malignant changes should be considered, and therefore, these patients must have life-long followup. Since the presenting signs of such a tumor can be bizarre, as in case 2, a high index of suspicion should be maintained. REFERENCES
1. Kay, R. and Straffon, R.: Augmentation cystoplasty. Urol. Clin. N. Amer., 13: 295, 1986. 2. Spence, H. M.: Ureterosigmoidostomy: the pros and cons. Dial. Ped. Urol., 5: 3, March 1982. 3. Stone, A. R., Davies, N. and Stephenson, T. P.: Carcinoma associated with augmentation cystoplasty. Brit. J. Urol., 60: 236, 1987. 4. Smith, P. and Hardy, G. J.: Carcinoma occurring as a late complication of ileocystoplasty. Brit. J. Urol., 43: 576, 1971. 5. Leedham, P. W. and England, H. R.: Adenocarcinoma developing in an ileocystoplasty. Brit. J. Surg., 60: 158, 1973. 6. Kirby, R. S. and Lloyd-Davies, R. W.: Adenocarcinoma occurring within a caecocystoplasty. Brit. J. Urol., 57: 357, 1985. 7. Egbert, B. M., Kraft, J. K. and Perkash, I.: Undifferentiated sarcoma arising in an augmented ileocystoplasty patch. J. Urol., 123: 272, 1980. 8. Takasaki, E., Murahashi, I., Toyoda, M., Honda, M. and Waku, S.: Signet ring adenocarcinoma of ileal segment following ileocystoplasty. J. Urol., 130: 562, 1983. 9. Harzmann, R., Kopper, B. and Carl, P.: Karzinominduktion durch Harnab- oder -umleitung iiber Darmabschnitte? Urologe A, 25: 198, 1986. 10. Selli, C., Carcangiu, M. L. and Carini, M.: Bladder carcinoma arising from regenerated urothelium over lyophilized dura patch. Urology, 27: 53, 1986. 11. Kamidono, S., Arakawa, S., Umezu, K., Ishigami, J. and Maeda, S.: A rare case of adenocarcinoma of bladder following augmentation enterocystoplasty. Acta Urol. Jap., 31: 315, 1985. 12. Lamm, D. L. and Gittes, R. F.: Inflammatory carcinoma of the bladder and interstitial cystitis. J. Urol., 117: 49, 1977. 13. Swanson, P. E., Brooks, R., Pearse, H. and Stenzel P.: Small cell carcinoma of urinary bladder. Urology, 32: 558, 1988. 14. Gittes, R. F.: Carcinogenesis in ureterosigmoidostomy. Urol. Clin. N. Amer., 13: 201, 1986. 15. Leadbetter, G. W., Jr., Zickerman, P. and Pierce, E.: Ureterosigmoidostomy and carcinoma of the colon. J. Urol., 121: 732, 1979. 16. Daher, N., Gautier, R., Abourachid, H., Decaens, C. and Bara, J.: Rat colonic carcinogenesis after ureterosigmoidostomy: pathogenesis and immunohistological study. J. Urol., 139: 1331, 1988. 17. Chiang, M. S., Minton, J. P., Clausen, K., Clatworthy, H. W. and Wise, H. A., II: Carcinoma in a colon conduit urinary diversion. J. Urol., 127: 1185, 1982. 18. Stewart, M., Hill, M. J., Pugh, R. C. B. and Williams J.P.: The role of N-nitrosamine in carcinogenesis at the ureterocolic anastomosis. Brit. J. Urol., 53: 115, 1981. 19. Moorcraft, J., DuBoulay, C. E. H., Isaacson, P. and Atwell, J, D.: Changes in the mucosa of colon conduits with particular reference to the risk of malignant change. Brit. J. Urol., 55: 185, 1983. 20. Mansson, W. and Willen, R.: Mucosal morphology and histochemistry of the continent cecal reservoir for urine. J. Urol., 139: 1199, 1988. 21. Tomera, K. M., Unni, K. K. and Utz, D. C.: Adenomatous polyp in ileal conduit. J. Urol., 128: 1025, 1982. 22. Shousha, S., Scott, J. and Polak, J.: Ileal loop carcinoma after cystectomy for bladder exstrophy. Brit. Med. J., 2: 397, 1978. 23. Wilson, J. W. L. and Morales, A.: Development of adenocarcinoma in transverse colon conduit. Urology, 20: 182, 1982. 24. Marchetti, D. L., Piver, M. S. and Tsukada, Y.: Adenocarcinoma in an isolated sigmoid urinary conduit. Obst. Gynec., suppl. 3, 63: 54S, 1984. 25. Filmer, R. B.: Malignant tumors arising in bladder augmentations, and ileal and colon conduits. Soc. Ped. Urol. Newsletter, pp. 3335, December 9, 1986.
Vol. 142, August Printed in U.S.A.
BLADDER NEOPLASMS ASSOCIATED WITH AUGMENTATION CYSTOPLASTY: REPORT OF 2 CASES AND LITERATURE REVIEW JACOB GOLOMB, CARL G. KLUTKE, KLAUS J. LEWIN, WILLARD E. GOODWIN, JEAN B. DEKERNION AND SHLOMO RAZ From the Department of Surgery, Division of Urology and Department of Pathology, Division of Surgical Pathology, UCLA School of Medicine, Los Angeles, California
ABSTRACT
Bladder neoplasms associated with augmentation cystoplasty have been reported to date in 12 patients. We add 2 cases: 1 with invasive transitional cell carcinoma involving the native bladder and bowel segment, and 1 with a poorly differentiated invasive oat cell (small cell) carcinoma confined to the bladder. The predisposing factors and pertinent literature are reviewed. (J. Ural.,
142:377-380, 1989) The use of bowel segments for urinary tract reconstruction is common and usually yields satisfactory results. The main indications are bladder augmentation, ureteral replacement in stone disease or after trauma, bypass of a ureteropelvic or ureterovesical junction, urinary undiversion and total bladder substitution. Bladder augmentation may be indicated in various pathological conditions that cause a functional or organic small bladder capacity (that is tuberculosis, radiation therapy, interstitial cystitis, congenital deformities, neurogenic bladder not responding to conservative measures and so forth). Reconstruction of the urinary tract with bowel segments has many advantages. Besides the supply of abundant tissues that are pliable to different shapes and needs, and protection of the upper urinary tracts, urinary reconstruction has improved the self-esteem and quality of life of the majority of patients. However, an issue that rarely is addressed is the potential longterm implications of establishing a permanent contact between the urinary tract and an isolated segment of the gastrointestinal tract. It is clear that the interaction with urine induces profound histological and functional changes in the bowel segments, including mucosa! flattening, atrophy of the villi and inflammatory infiltrate of the mucosa. At the same time, the adjacent urinary tract is being exposed to bowel secretions, mucus and a variety of unknown stimuli that have not been closely examined to date. The reconstructed bladder also may require intermittent catheterization and this can introduce the effects of recurrent bacterial infections. This combination of factors has been considered safe since 1950, when Couvelaire renewed interest in augmentation cystoplasty. 1 However, review of the literature reveals 12 reported cases of neoplasm formation after bladder augmentation. In our series of more than 400 cases of augmentation enterocystoplasty, performed between 1960 and 1987, 2 cases of late development of bladder carcinoma have occurred. The paucity of tumor cocurrences compared to colonic adenocarcinoma after ureterosigmoidostomy, with approximately 100 cases reported as of 1982, 2 is striking. Therefore, this should not challenge the use of bowel for urinary tract reconstruction but, rather, it should alert us to the need for close and long-term followup of the patients undergoing this procedure. CASE REPORTS
Case 1. A 45-year-old white man presented in 1960 with a history of Cowper's gland abscess and recurrent urethral strictures, resulting in chronic cystitis with a severely contracted Accepted for publication February 21, 1989. Supported in part by The University Urological Research Foundation.
bladder. The history was significant for left nephrectomy and right partial nephrectomy for calculous disease. There was no smoking history. Augmentation sigmoidocystoplasty, combined with 1-stage Johanson urethroplasty was done. A second-stage urethroplasty was performed 4 years later. He did well postoperatively, although he required periodic urethral dilation, as well as repeated antibiotic treatment for recurrent urinary tract infections, especially with Pseudomonas, Proteus and Escherichia coli. In 1984, 24 years after the enlargement cystoplasty, the patient presented with macroscopic hematuria and positive urine cytology results for malignancy. At hospitalization physical examination and laboratory evaluation were normal. Cystoscopy revealed an extensive tumor at the bladder dome involving the anastomotic site. Biopsies were compatible with grade 3 transitional cell carcinoma with invasion into muscle and extensive necrosis. A right retrograde pyelogram was normal. Chest x-rays were negative for metastases. Partial cystectomy, including the colocystoplasty segment, was done along with augmentation ileocystoplasty. The specimen contained a large infiltrating tumor measuring approximately 7 X 3 X 3 cm. involving the anastomotic site. The tumor consisted of poorly differentiated grade 3/4 transitional cell carcinoma of the bladder that extended through the muscularis of the bladder into the perivesical fat and also infiltrated the bowel wall into the pericolic fat (fig. 1). Lymph nodes in the pericolic fat showed no tumor. Convalescence was uneventful and there was no evidence of tumor recurrence at 3 years. Case 2. A 20-year-old woman presented in 1968 with a lifelong history of urinary incontinence secondary to hypospadias and frequent urinary tract infections, mainly with E. coli and Proteus. After multiple failed operations an ileal conduit urinary diversion was done in 1971, and transvaginal urethroplasty and augmentation ileocecocystoplasty were performed in 1979. Subsequently, pyocystis developed due to stenosis of the cecovesical anastomosis, necessitating revision. In 1980 the augmented bladder was of adequate capacity and continent, and the patient underwent undiversion, with the cutaneous urinary diversion being taken down and the ileal conduit anastomosed to the ileal stump of the augmenting ileocecal segment. Postoperatively, the patient did well on self-catheterization for 7 years until in late 1987 she noticed a decrease in bladder capacity with increased urinary frequency and urgency, and frequent urinary tract infections. A cystogram revealed good bladder capacity with no vesicoureteral reflux but, in addition, multiple calculi were seen at the junction of the native bladder with the attached bowel. An excretory urogram showed bilateral blunted calices with good kidney function and drainage, and bladder calculi. Cystoscopy demonstrated multiple free bladder
377
378
GOLOMB AND ASSOCIATES
FIG. 1. Case 1. Transitional cell carcinoma of bladder shows infiltrating tongue of poorly differentiated tumor. H & E, reduced from XlOO.
FIG. 2. Case 2. Poorly differentiated invasive oat cell (small cell) carcinoma of bladder demonstrates irregular nests of darkly staining cells with irregular, hyperchromatic, finely stippled nuclei and scant cytoplasm. H & E, reduced from Xl60.
stones and a yellow-whitish plaque diffusely covering the mucosa of the bladder base and up to the anastomosis. The plaque was resected transurethrally and the initial pathological diagnosis was poorly differentiated invasive carcinoma. Metastatic evaluation was negative. Radical cystectomy and continent urinary diversion were performed. The resected specimen contained an ulcerating tumor in the bladder approximately 5 cm. in diameter invading through the muscularis into the perivesical fat. Histologically, the tumor had features of poorly differentiated oat cell (small cell) carcinoma with solid sheets and nests of mitotic active small cells, and moderately sized angular, finely stippled nuclei exhibiting nuclear moulding (fig. 2). Neither the bowel segment nor the lymph nodes showed any evidence of malignancy. Convalescence was uneventful and she was free of tumor at 6 months. DISCUSSION
Review of the current literature reveals 12 reported cases of neoplasm formation after augmentation cystoplasty, to which we add our 2 (see table). 3 - 12 In 8 patients the original disease was tuberculous involvement of the urinary tract with a resultant contracted bladder. 3 - 5 • 8 •9 • 11 Nine patients had undergone ileocystoplasty and in all except 2 recurrent urinary tract infections and/or poor emptying of the augmented bladder dominated the postoperative period_ 3 - 5 , 7 ,s,n For 3 patients the postoperative result is not reported. The latent period between
bladder augmentation and diagnosis of tumor ranged from 3 to 24 years, with an average of 16 years. In our 2 patients the latent period was 8 and 24 years, respectively. Seven patients had invasive adenocarcinoma, which involved the native bladder and bowel in 3, was confined to the bowel in 2 and consisted of signet ring adenocarcinoma of the ileum in 1; in 1 the histological details were not reported. 3 • 5 • 6 • 8 • 9 • 11 Five patients had transitional cell carcinoma, which was confined to the bladder in 1, 3 while in 1 patient 2 sessile tumors developed from the urothelium, which regenerated over a dura patch used for augmentation cystoplasty, together with infiltrating transitional cell carcinoma in the native bladder. 10 One of our patients had a high grade transitional cell carcinoma that invaded the native bladder and bowel segment. Lamm and Gittes reported on transitional cell carcinoma in a male patient with interstitial cystitis, which they termed inflammatory carcinoma. 12 In the remaining patient the tumor was found in the ileal segment only. The latter case, reported by Smith and Hardy, is intriguing, since the patient had invasive transitional cell carcinoma in the ileal segment without any accompanying tumor in the bladder and without any history of bladder neoplasia. 4 One patient, reported on by Egbert and associates, had an undifferentiated sarcoma of the bowel with a satellite lesion in the bladder, which proved to be an aggressive neoplasm that metastasized widely. 7 One of our patients had a high grade invasive oat cell (small cell) carcinoma confined to the bladder, which was amenable to resection. Interestingly, in a case report and literature survey regarding small cell carcinoma of the bladder Swanson and associates implied that metaplastic changes secondary to chronic cystitits may have a role in the histogenesis of this rare neoplasm. 13 Our patient as well had protracted chronic cystitis for many years that could have contributed to the malignant changes. Our patient who presented with invasive transitional cell carcinoma in the native bladder and bowel after a prolonged history of chronic cystitis and recurrent urinary tract infections is reminiscent of the patient reported on by Lamm and Gittes, who has had irritative urinary symptoms for many years without any evidence of carcinoma in situ. 12 He was diagnosed as having interstitial cystitis, and underwent supratrigonal cystectomy and cecocystoplasty. The symptoms improved thereafter only temporarily and after a latency period of 3 years invasive transitional cell carcinoma developed involving the residual bladder and cecal segment, which the authors have termed inflammatory carcinoma. On the other hand, our patient had a recurrent urethral stricture resulting in persistent urinary tract infections and chronic cystitis. He experienced prolonged relief after bladder augmentation and only after 24 years did the neoplasm develop. It is highly unlikely that carcinoma in situ was present in the bladder during this entire quiescent period only to manifest 24 years later as invasive carcinoma. The issue of late malignant transformation in bowel mucosa exposed to urine flow for a prolonged period is challenging. A review of several series of patients with ureterosigmoidostomy reveals the incidence of either polyps or colonic adenocarcinoma occurring at the anastomotic site to be as high as 5 to 40 per cent, 14 a 500 to 7,000-fold increased incidence compared to the general population in selected decades of life. 14• 15 The incubation period observed between the procedure and finding of a tumor varies between 7 and 49 years, with an average of 20 years. 14 According to Gittes, the carcinogenesis of ureterosigmoidostomy clearly depends on the initial presence of urine, feces, urothelium and colonic epithelium in close apposition at a healing anastomotic suture line. 14 Animal models using 2 rat strains, Sprague-Dawley and Wistar-Furth, also demonstrated that colonic carcinogenesis needs the concomitant action of feces and urine, probably through local activation of fecal carcinogens by urine or urothelium. 14• 16 This theory is challenged by a report of an adenocarcinoma that developed after a latent period of 26 years in a colon conduit in which there had never been a fecal stream. 17 In an editorial comment to
Reported data on neoplasm formation after augmentation cystoplasty Reference Stone and associates3
Sex-Age
Original Disease
Procedure
Tuberculosis
Ileocystoplasty
Good
Adenoca.
M-53
Tuberculosis
Ileocystoplasty
Adenoca.
F-54
Tuberculosis
Ileocystoplasty
Recurrent infections, high residual urine Poor drainage
F-43
Tuberculosis
Ileocystoplasty
Leedham and England'
F-52
Tuberculosis
Ileocystoplasty
F-42
Squamous cell Ca of cervix Neurogenic bladder
Cecocystoplasty Heocystoplasty
Recurrent infections, high residual urine Recurrent infections
Recurrent infections
Recurrent infections, recurrent obstruction
Egbert and associates 7
M-43
Takasaki and associates 8
M-42
Tuberculosis
Ileocystoplasty
Harzmann and associates9
M-44
Tuberculosis
Colocystoplasty Dura patch
Not specified
Ileocystoplasty
Not specified
Selli and associates'° Kamidono and associates"
Tumor Histology
M-42
Smith and Hardy4
Kirby and Lloyd-Davies6
Result
F-57 M-47
Lamm and Gittes 12
M-62
Present series
M-69
F-40
Transitional cell Ca of bladder Tuberculosis Interstitial cystitis Chronic cystitis
Urinary incontinence
Cecocystoplasty Sigmoid colocystoplasty Ileocecocystoplasty
Not specified
Improved Recurrent infections, recurrent obstruction Recurrent infections, multiple surgeries
Transitional cell Ca plus Ca in situ Transitional cell Ca Adenoca., Ca in situ in ileum Adenoca. Sarcoma
Signet ring adenoca. Adenoca. Transitional cell Ca Adenoca. Transitional cell Ca Transitional cell Ca Small cell Ca
Location
Followup
Both
Latent Period (yrs.)
+
24
Dead at 1 yr.
+
22
Dead at 1 yr.
Grade/Stage Bowel* Not specified/not specified Not specified/not specified Not specified/not specified
Bladder
+
5
Free oftumor
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:,;J
zM
0
'"'ti
Poorly differentiated/invasive Moderately differentiated/invasive Not specified/not specified Undifferentiated/ invasive
+
High/invasive
+
Not specified/not specified Not specified/invasive Undifferentiated/ invasive High/invasive
Not specified
15
Free of tumor
["-"1
ti->
rt)
+
+
t
rn ,-;
+
8
+
19
20 Not specified
17
+ +
High/invasive
High/invasive
17
+
Free oftumor Dead at 2 mos. Dead at 7 days Not specified
3
Not specified
20
Dead at 2 yrs. Residual tumor Free oftumor
+
3
+
24 8
Free of tumor
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'-<
:i, ~
r;'.l
t
t•J
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,
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...-, 0
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* Dura patch in patient 10.
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.380
GOLOMB AND ASSOCIATES
this case report Richie suggested that the chronic presence of urinary bacteria in the conduit may have assumed much of the putative function of the fecal bacteria in the pathogenesis of adenocarcinoma after ureterosigmoidostomy. These bacteria can act by reducing urinary nitrates to nitrites with formation of N-nitrosamines, which are known potent carcinogens for colonic mucosa.17 This is a plausible theory, since chronic infection has been a dominant factor in many of the patients who had tumors after augmentation cystoplasty. Stewart and associates also postulated that N-nitrosamines were the etiological agents in carcinogenesis following ureterocolonic anastomosis.18 They noted that dietary nitrates excreted into the colon conduit can be converted to N-nitroso compounds in the presence of mixed bacterial flora. The demonstration of these compounds in the rectal urine is highly significant, since these compounds normally are not found other than in trace amounts either in human urine or feces. Therefore, the detection of these mutagens in the urine may be an indication for their role in carcinogenesis. The etiology of malignant changes in augmentation cystoplasty in our cases as well as the previously reported patients is unclear. Most of the patients had concomitant risk factors, for example a history of tuberculosis with chronic inflammatory changes, radiation therapy, multiple operations, poor drainage of the bladder and recurrent bacterial infections with several organisms. In addition, chronic inflammatory changes secondary to the constant exposure of bowel to urine may increase the risk of malignancy. Indeed, Moorcraft and associates studied the histological changes in the mucosa of colon conduits. 19 They demonstrated chronic inflammation with a dense infiltration of plasma cells and eosinophils. The changes were progressive and correlated with the duration of urinary diversion. The authors assumed that these persistent inflammatory changes may act as a precursor of malignancy. 19 Mansson and Willen studied the mucosa! morphology of urinary cecal reservoirs and also demonstrated interstitial inflammatory cell proliferation with a slight increase in collagen fibers. 20 To the best of our knowledge, similar studies have not been done in augmentation cystoplasty but it can be assumed with relative certainty that the augmenting bowel segment, under constant exposure to urine, undergoes equivalent changes to those found in colon reservoirs and conduits. The occurrence of malignant tumors in ileal and colon conduits also is rare, with only sporadic cases reported. Tomera and associates reported on late development of an adenomatous polyp in an ileal conduit 22 years postoperatively. 21 Histological sections of the mucosa of this conduit had a definite colonic appearance that may be a metaplastic response to the urinary stream and may explain why an adenomatous polyp arose at this site, since adenomatous polyps are rare in the small bowel. Shousha and associates described ileal loop carcinoma developing 20 years after cystectomy for bladder exstrophy with diffuse metastasis and early death. 22 Wilson and Morales reported on early development of adenocarcinoma in a transverse colon conduit 12 months postoperatively, 23 and Marchetti and associates presented a case of adenocarcinoma in a sigmoid conduit occurring 8 years postoperatively. 24 Filmer reviewed the literature regarding malignant tumor formation after bladder augmentation, and ileal and colon conduits, and noted certain similarities with the development of colonic carcinoma following ureterosigmoidostomy, namely latency period, tumor histology and possible carcinogenic effect of chronic bacterial infection. 25 The latent period between bladder augmentation and manifestation of the neoplastic changes, averaging 16 years in our series, is reminiscent of the incubation period for tumor formation in ureterosigmoidostomy and implies that similar carcinogenic environments may have a role in these 2 entities. Chronic inflammatory changes, urine stasis and recurrent infections all can contribute to the occurrence of malignancy. Since primary adenocarcinoma of the ileum is rare, the reports of late development of malignancy of the bowel segment in
bladder augmentation and urinary diversion, which are constructed largely of ileum, are of great significance and should alert us to the need for closer supervision of these patients. In conclusion, with the increasing trend to incorporate bowel segments into the urinary tract for bladder augmentation or substitution, the low but still distinct risk of late 'malignant changes should be considered, and therefore, these patients must have life-long followup. Since the presenting signs of such a tumor can be bizarre, as in case 2, a high index of suspicion should be maintained. REFERENCES
1. Kay, R. and Straffon, R.: Augmentation cystoplasty. Urol. Clin. N. Amer., 13: 295, 1986. 2. Spence, H. M.: Ureterosigmoidostomy: the pros and cons. Dial. Ped. Urol., 5: 3, March 1982. 3. Stone, A. R., Davies, N. and Stephenson, T. P.: Carcinoma associated with augmentation cystoplasty. Brit. J. Urol., 60: 236, 1987. 4. Smith, P. and Hardy, G. J.: Carcinoma occurring as a late complication of ileocystoplasty. Brit. J. Urol., 43: 576, 1971. 5. Leedham, P. W. and England, H. R.: Adenocarcinoma developing in an ileocystoplasty. Brit. J. Surg., 60: 158, 1973. 6. Kirby, R. S. and Lloyd-Davies, R. W.: Adenocarcinoma occurring within a caecocystoplasty. Brit. J. Urol., 57: 357, 1985. 7. Egbert, B. M., Kraft, J. K. and Perkash, I.: Undifferentiated sarcoma arising in an augmented ileocystoplasty patch. J. Urol., 123: 272, 1980. 8. Takasaki, E., Murahashi, I., Toyoda, M., Honda, M. and Waku, S.: Signet ring adenocarcinoma of ileal segment following ileocystoplasty. J. Urol., 130: 562, 1983. 9. Harzmann, R., Kopper, B. and Carl, P.: Karzinominduktion durch Harnab- oder -umleitung iiber Darmabschnitte? Urologe A, 25: 198, 1986. 10. Selli, C., Carcangiu, M. L. and Carini, M.: Bladder carcinoma arising from regenerated urothelium over lyophilized dura patch. Urology, 27: 53, 1986. 11. Kamidono, S., Arakawa, S., Umezu, K., Ishigami, J. and Maeda, S.: A rare case of adenocarcinoma of bladder following augmentation enterocystoplasty. Acta Urol. Jap., 31: 315, 1985. 12. Lamm, D. L. and Gittes, R. F.: Inflammatory carcinoma of the bladder and interstitial cystitis. J. Urol., 117: 49, 1977. 13. Swanson, P. E., Brooks, R., Pearse, H. and Stenzel P.: Small cell carcinoma of urinary bladder. Urology, 32: 558, 1988. 14. Gittes, R. F.: Carcinogenesis in ureterosigmoidostomy. Urol. Clin. N. Amer., 13: 201, 1986. 15. Leadbetter, G. W., Jr., Zickerman, P. and Pierce, E.: Ureterosigmoidostomy and carcinoma of the colon. J. Urol., 121: 732, 1979. 16. Daher, N., Gautier, R., Abourachid, H., Decaens, C. and Bara, J.: Rat colonic carcinogenesis after ureterosigmoidostomy: pathogenesis and immunohistological study. J. Urol., 139: 1331, 1988. 17. Chiang, M. S., Minton, J. P., Clausen, K., Clatworthy, H. W. and Wise, H. A., II: Carcinoma in a colon conduit urinary diversion. J. Urol., 127: 1185, 1982. 18. Stewart, M., Hill, M. J., Pugh, R. C. B. and Williams J.P.: The role of N-nitrosamine in carcinogenesis at the ureterocolic anastomosis. Brit. J. Urol., 53: 115, 1981. 19. Moorcraft, J., DuBoulay, C. E. H., Isaacson, P. and Atwell, J, D.: Changes in the mucosa of colon conduits with particular reference to the risk of malignant change. Brit. J. Urol., 55: 185, 1983. 20. Mansson, W. and Willen, R.: Mucosal morphology and histochemistry of the continent cecal reservoir for urine. J. Urol., 139: 1199, 1988. 21. Tomera, K. M., Unni, K. K. and Utz, D. C.: Adenomatous polyp in ileal conduit. J. Urol., 128: 1025, 1982. 22. Shousha, S., Scott, J. and Polak, J.: Ileal loop carcinoma after cystectomy for bladder exstrophy. Brit. Med. J., 2: 397, 1978. 23. Wilson, J. W. L. and Morales, A.: Development of adenocarcinoma in transverse colon conduit. Urology, 20: 182, 1982. 24. Marchetti, D. L., Piver, M. S. and Tsukada, Y.: Adenocarcinoma in an isolated sigmoid urinary conduit. Obst. Gynec., suppl. 3, 63: 54S, 1984. 25. Filmer, R. B.: Malignant tumors arising in bladder augmentations, and ileal and colon conduits. Soc. Ped. Urol. Newsletter, pp. 3335, December 9, 1986.