Transitional Cell Carcinoma of the Bladder in Patients with Renal Pelvic and Ureteral Cancer

0022-534 7/80/1241-0017$02.00/0 THE JOURNAL OF UROLOGY

Vol. 124, July

Cop)'l;ight © 1980 by The Williams & Wilkins Co.

Printed in U.S.A.

TRANSITIONAL CELL CARCINOMA OF THE BLADDER IN PATIENTS WITH RENAL PELVIC AND URETERAL CANCER T ADAO KAKIZOE, * JUN FUJITA, TATSURO MURASE, KEIi CHI MATSUMOTO

AND

KIYOZO KISHI

From the Urology Division and Pathology Division, National Cancer Center Hospital, Tokyo, Japan

ABSTRACT

We reviewed 41 cases of transitional cell carcinoma of the renal pelvis and ureter with special reference to the coexistence or subsequent development of bladder cancer. Bladder cancer was associated with an upper urinary tract neoplasm in 20 of the 41 cases (48 per cent). Most of these patients (15 of 20) were treated by radical total cystectomy or I-stage nephroureterocystectomy. The incidence of ureteral stump cancer after nephrectomy alone or incomplete nephroureterectomy was 64 per cent (7 of 11 patients). Twelve surgically removed specimens of the renal pelvis, ureter and/or bladder were examined extensively for the histological association of pre-neoplastic disease, such as atypical hyperplasia and carcinoma in situ. Every specimen had these changes of the urothelium adjacent to and remote from obvious tumors. Various lines of pathological and clinical evidence indicate that bladder cancer is a gross manifestation of generalized neoplastic change of the urothelium. Atypia and carcinoma in situ frequently can be found in areas of apparently normal urothelium in specimens obtained by cystectomy1• 2 or biopsy3 • 4 from patients with bladder cancer. The incidence of tumors in the ureteral stump after incomplete nephroureterectomy for renal pelvic or ureteral cancer is reported to be 20 to 58 per cent.5- 7 There are reports that the incidence of bladder cancer after complete nephroureterectomy also is 15 to 50 per cent, 5• 8-IO and that the occurrence of transitional cell carcinoma of the bladder at sites or in areas other than that of the original tumor after transurethral resection is as high as 80 per cent. 11• 12 Moreover, the incidence of transitional cell carcinoma of the urethra in men after cystectomy for bladder cancer is reported to be 4 to 12 per cent. 13• 14 We herein describe findings in 41 patients with renal pelvic and ureteral cancer, with special reference to the concomitant or subsequent development of bladder cancer. The association of pre-neoplastic lesions in relation to obvious tumors also was examined in 12 surgically removed specimens.

was possible for the 12 specimens because they were serially sectioned into blocks approximately 0.5 to 1.0 cm. wide. The definition by Koss and associates was used for urothelial lesions, that is normal urothelium, epithelial hyperplasia, atypical hyperplasia and non-papillary carcinoma in situ. 2 RESULTS

The incidence of concurrent or subsequent tumor of the bladder was 28 per cent in cases of renal pelvic cancer, 55 per cent in cases of ureteral cancer and 75 per cent in cases of renal pelvic and ureteral cancer (table 1). The over-all rate of appearance of bladder tumor was 48 per cent (20 of 41 patients). In 90 per cent of the patients with bladder cancer the tumor occurred at the same time as another tumor or within 3 years after the initial operation (table 2). Of 20 patients who had concurrent or subsequent bladder cancer 15 underwent radical total cystectomy or I-stage nephroureterocystectomy. The grade and stage of bladder cancer in these patients and the subsequent histories are shown in table 3. The other 5 patients were treated with radiation and/or chemotherapy because they had advanced local lesions or metastases outside the urinary tract. Of the patients with bladder cancer 80 per cent had multiple lesions on the same side of the bladder as that of the upper urinary tract involved and 20 per cent had cancer almost everywhere in the bladder. Of 7 patients who had concomitant tumors in the renal pelvis, ureter and bladder 2 had transitional cell carcinoma in the anterior urethra after 1-stage nephroureterocystectomy. Urethrectomy was done in these patients. Of all patients treated by incomplete nephroureterectomy 7 (64 per cent) had tumor in the ureteral stump. The 9 patients who initially had metastases outside the urinary tract all died within 1 year, irrespective of the treatment such as radiation and/or chemotherapy with or without nephroureterectomy. Seventy per cent of these patients had metastases to the lungs and the liver. Figures 1 to 3 are schematic diagrams to show the distribution of the lesions in the renal pelvis, ureter and/or bladder. Every specimen had atypical hyperplasia and/or non-papillary carcinoma in situ at adjacent sites or in areas other than that of the original tumors.

MATERIALS AND METHODS

Between 1962 and 1978, 4 7 patients with renal pelvic or ureteral cancer were seen at this hospital. Of these 4 7 patients 6 had squamous cell carcinoma. The other 41 patients had transitional cell carcinoma and are analyzed in our study. Of the 41 patients 19 had been treated initially at other hospitals. Most of the patients underwent nephrectomy only or nephroureterectomy. The records of previous therapy and histological studies were reviewed. The 28 men and 13 women ranged in age from 15 to 83 years, with an average of 60 years. The tumor was on the right side in 21 patients and on the left side in 20. Eighteen patients had renal pelvic cancer, 11 had ureteral cancer and 12 had renal pelvic and ureteral cancer. No patient had renal pelvic or ureteral stones or contralateral urothelial carcinoma. Mapping of neoplastic and pre-neoplastic lesions was conducted for 12 surgically removed specimens; 6 obtained from nephroureterectomy, 4 from cystectomy and 2 from 1-stage nephroureterocystectomy. Sufficient histological examination

DISCUSSION

Accepted for publication August 17, 1979. * Requests for reprints: Urology Division, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104, Japan.

In our series transitional cell carcinoma in the ureteral stump after nephrectomy alone or after incomplete nephroureterec17

18

KAKIZOE AND ASSOCIATES TABLE

1. Coexistent or subsequent bladder cancer

Site of Original Tumor

No. Pts.

Bladder Tumor No. Pts. (%)

18 11 12

5 (28) 6 (55) 9 (75)

Renal pelvis Ureter Renal pelvis and ureter

TABLE 2.

Time of appearance of bladder cancer No. Pts. With Tumor

Followup (mos.) 0 (coexistent) 0-6 6-12 12-24 24-36 >36

TABLE

Grade

Pelvis

Ureter

Pelvis and Ureter

1

2

2

1

7 1 1

1 1

2 1

tomy occurred in 64 per cent (7 of 11) of the patients. This figure is higher than reported values of 20 to 58 per cent, probably because most of our patients (6 of 7) who had ureteral stump cancer underwent nephrectomy alone. The incidence of tumor in the ureteral remnant appears to be proportional to the length of the remaining ureteral stump. 7 Simultaneous or subsequent bladder cancer occurred in 48 per cent (20 of 41) of the patients. This value is similar to those reported by Grabstald and associates,9 and Williams and Mitchell. 10 The high risk period for development of a bladder neoplasm was 3

3. Results of cystectomy for bladder cancer

Stage

II III III II II II III II III III

T2 Tl Tl T2 T3 Tl T3 T2 T3 T2

III II II II III

Tl Tl T2 T2 T3

Followup

Subsequent History

Cystectomy 18mos. Alive 36mos. Alive 72mos. Alive 111 mos. Alive 8mos. Alive 20days Died, intracranial bleeding 58mos. Died,Ca 59mos. Died,Ca Died,Ca 6mos. 17mos. Died, pancreatic Ca Nephroureterocystectomy 55mos. Alive 97mos. Alive 69mos. Alive 48mos. Alive 9mos. Died,Ca

Fm. 2. Mapping of neoplastic and pre-neoplastic lesions in 2, I-stage nephroureterocystectomy specimens. •, obvious carcinoma. llJjl, carcinoma in situ. rn, atypical hyperplasia.

~

223759

193922

203483

201451

219157

Fm. 1. Mapping of neoplastic and pre-neoplastic lesions in 6 nephroureterectomy specimens. •, obvious carcinoma. l:i!il, carcinoma in situ. El, atypical hyperplasia.

ASSOCIATION OF BLADDER CARCINOMA WITH UPPER TRACT NEOPLASM

----~

A 112131

B

131321

.~ \ 1,1!_/

198754

,.'i ~--

C

211090

FIG. 3. Mapping of neoplastic and pre-neoplastic lesions in 4 cystectomy specimens.•, obvious carcinoma. ll!ll, carcinoma in situ. 0, atypical hyperplasia. A, right ureteral carcinoma, nephroureterectomy 9 months previously. B, left renal pelvic carcinoma, incomplete nephroureterectomy 53 months previously. C, left ureteral carcinoma, nephroureterectomy 39 months previously. D, left renal pelvic carcinoma, incomplete nephroureterectomy 15 months previously and remaining ureterectomy 5 months previously.

years in our series but the tumor appeared in the bladder 39 and 53 months, respectively, after the initial operation in 2 patients. Williams and Mitchell noted a 15-month delay in the appearance of bladder cancer postoperatively in patients with renal pelvic carcinoma, 10 and Grabstald and associates observed a 21-month delay. 9 Simultaneous development of bladder tumor occurred in 50 per cent (10 of 20) of the patients and most of these patients had multiple, concomitant tumors in the renal pelvis and ureter. Patients with concurrent or subsequent bladder cancer were treated mainly by radical total cystectomy or 1-stage nephroureterocystectomy. Of the patients 2 were treated initially by repeated transurethral resection or partial cystectomy but finally underwent total cystectomy. We believe that total cystectomy is the best method available for the treatment of concurrent or subsequent bladder carcinoma in association with upper urinary tract urothelial carcinoma because the multifocal tumor occurrence has been well documented in the entire urothelium.1-4 Koss and associates examined 10 surgically removed bladders by mapping cancerous and pre-cancerous urothelial changes and found an extensive neoplastic process ranging from hyperplasia to invasive carcinoma in 8 cases, and involvement of the distal ureter in 7 cases. 2 Cases in our series showed the widespread neoplastic and pre-neoplastic lesion of the epithelium in the renal pelvis, ureter and/or bladder (figs. 2 and 3). However, we found no pre-cancerous lesions in 5 specimens in the epithelium of the ureter resected for renal pelvic carcinoma that possessed pre-cancerous lesions in the renal pelvis (fig. 1). These findings were rather unexpected. The followup periods after nephroureterectomy for these 5 cases were 4, 8, 11, 15 and 42 months, respectively, and no bladder recurrence has been demonstrated to date. It is of interest to follow bladder recurrences in these cases.

19

We use the term recurrence but from our own observations we agree with the comments by Melicow, 1 Koss and associates2 and Schade and Swinney3 that did not justify the concept of recurrent bladder cancer. Most likely, the disturbed epithelium is capable of producing new tumors in adjacent or distant areas of the bladder rather than a recurrence. 2 Presently, we do not know of effective methods for controlling the appearance of multifocal tumors or reversing the pre-neoplastic status of the urothelium. Theoretically, the safest treatment of urothelial carcinoma would be to remove the whole urothelium but since this is not practical careful followup is mandatory. At the same time, important approaches to the prophylaxis or prevention of urothelial carcinoma appear to be to identify urinary carcinogens 15 and to determine the biological characteristics of the urothelium. REFERENCES

1. Melicow, M. M.: Histological study of vesical urothelium intervening between gross neoplasms in total cystectomy. J. Urol., 68: 261, 1952. 2. Koss, L. G., Tiamson, E. M. and Robbins, M.A.: Mapping cancerous and precancerous bladder changes. J.A.M.A., 227: 281, 1974. 3. Schade, R. 0. K. and Swinney, J.: The association of urothelial atypism with neoplasia: its importance in treatment and prognosis. J. Urol., 109: 619, 1973. 4. Heney, N. M., Daly, J., Prout, G. R., Jr., Nieh, P. T., Heaney, J. A. and Trebeck, N. E.: Biopsy of apparently normal urothelium in patients with bladder carcinoma. J. Urol., 120: 559, 1978. 5. Kimball, F. N. and Ferris, H. W.: Papillomatous tumor of the renal pelvis associated with similar tumors of the ureter and bladder. J. Urol., 31:257, 1934. 6. Bloom, N. A., Vidone, R. A. and Lytton, B.: Primary carcinoma of the ureter: a report of 102 new cases. J. Urol., 103: 590, 1970. 7. Strong, D. W., Pearse, H. D., Tank, E. S., Jr. and Hodges, C. V.: The ureteral stump after nephroureterectomy. J. Urol., 115: 654, 1976. 8. Newman, D. M., Allen, L. E., Wishard, W. N., Jr., Nourse, M. H. and Mertz, J. H. 0.: Transitional cell carcinoma of the upper urinary tract. J. Urol., 98: 322, 1967. 9. Grabstald, H., Whitmore, W. F., Jr. and Melamed, M. R.: Renal pelvic tumors. J.A.M.A., 218: 845, 1971. 10. Williams, C. B. and Mitchell, J.P.: Carcinoma of the renal pelvis: a review of 43 cases. Brit. J. Urol., 45: 370, 1973. 11. Green, L. F., Hanash, K. A. and Farrow, G. M.: Benign papilloma or papillary carcinoma of the bladder? J. Urol., 110: 205, 1973. 12. Althausen, A. F., Prout, G. R., Jr. and Daly, J. J.: Non-invasive papillary carcinoma of the bladder associated with carcinoma in situ. J. Urol., 116: 575, 1976. 13. Cordonnier, J. J. and Spjut, H.J.: Urethral occurrence of bladder carcinoma following cystectomy. J. Urol., 87: 398, 1962. 14. Schellhammer, P. F. and Whitmore, W. F., Jr.: Transitional cell carcinoma of the urethra in men having cystectomy for bladder cancer. J. Urol., 115: 56, 1976. 15. Kakizoe, T., Wang, T.-T., Eng, V. W. S., Furrer, R., Dion, P. and Bruce, W. R.: Volatile N-nitrosamines in the urine of normal donors and of bladder cancer patients. Cancer Res., 39: 829, 1979.

EDITORIAL COMMENT This interesting work clearly demonstrates the multifocal nature of urothelial changes in the presence of gross neoplasm. The authors emphasize the need for careful followup in the evaluation of patients with upper tract as well as multiple lower tract neoplasms. They also suggest the need for wide margin excision of an upper tract lesion if attempts are being made to preserve a portion of the renal substance when a transitional cell tumor of the renal pelvis is present. Although the study cannot resolve the controversy as to whether nephroureterectomy should be done in patients with upper tract neoplasia it does suggest that those patients who may be candidates for a less radical excision must, indeed, be selected carefully and followed closely. Michael J. Droller Brady Urological Institute The Johns Hopkins Hospital Baltimore, Maryland