UROTHELIAL TUMORS OF UPPER TRACT FOLLOWING TREATMENT OF PRIMARY BLADDER TRANSITIONAL CELL CARCINOMA CURTIS B. SCHWARTZ, M.D. HUSEYIN BEKIROV, M.D. ARNOLD MELMAN, M.D.
From the Department of Urology, Montefiore Medical Center/ The Albert Einstein School of Medicine, Bronx, New York ABSTRACT- We studied, retrospectively, the incidence of upper tract urothehal tumors following the treatment of primary transitional cel1 carcinoma of the bladder in 638 patients. Subsequent tumor development was found in 20 patients (3.1%) with a mean latency interval between initial treatment of the bladder cancer and diagnosis of the upper urinary tract tumor of eighty months. We did not find a significant differente among treatment modalities on the incidence of upper tract occurrences. Other than carcinoma in situ, tumor stage was not an independent predictive variable.
There are more than 30,000 new cases of transitional cel1 carcinoma of the urinary bladder reported annually in the United States. In contrast, urothelial tumors of the kidney and ureter constitute only 5 percent of al1 transitional cel1 tumors.’ Local resection of bladder tumors is followed by a high recurrence rate. It is accepted that patients who present with upper tract urothelial tumors have a high incidence of subsequent bladder tumors. 3 However, the incidence of upper tract transitional cel1 carcinoma following the diagnosis and treatment of primary bladder tumors is not wel1 known and data concerning this issue have been sparse. Our study was designed to define the incidence of secondary transitional cel1 carcinoma of the upper urinary tract; how this is related to the antecedent bladder tumor; and how various treatment modalities used for the bladder tumor may affect this incidence. Material and Methods Between 1972 and 1982, 638 patients having undergone treatment for various stages of transitional cel1 carcinoma of the bladder were studied retrospectively. Of these patients, 100 had undergone radical cystectomy, 68 were
UROLOGY
/ DECEMBER1992
/ VOLUME40,NUMBERô
treated with partial cystectomy, and 470 had undergone transurethral resection andlor fulguration with or without intravesical chemotherapy. Al1 patients were followed for five years or more. Follow-up tests included intravenous urography (IVP), cytologie examination of the urine, and in later years, sonography and computerized tomography (CT) scan if indicated. Al1 patients were followed with urine cytologie+ most at regular intervals. In addition, al1 patients had at least one follow-up IVP while many had yearly interval IVPs. The Jewett-Strong-Marshall method of staging was applied to the removed specimens. None of these patients had prior occupational exposure to known carcinogenic dyes. Diagnosis of upper urinary tract transitional cel1 tumors made by the aforementioned studies were confirmed by an operation. The incidence of these upper tract urothelial tumors was compared with both treatment modality as wel1 as stage of the bladder tumor. In those patients having undergone multiple transurethral resections of recurrent bladder tumors, the stage recorded represents the highest stage of the bladder tumor prior to diagnosis of upper tract tumor.
509
TABLE 1.
Incìdence of upper tract cancer following radical cystectomy
Stage CIS O+A c D TOTALS
No. of Pts. (%) 15 0 55 12 18
(15) (0) (55) (12) (18)
100 (100)
Subsequent Upper fiact -mors No. of Pts. (%) 2 0 1 0 1
(13.3) (0) (1.9) (0) (5.5)
4
(4)
Results Tables 1 to 111 detail the incidence of subsequent upper tract transitional cel1 carcinoma with comparison of stage of bladder tumor and modality of treatment. Stage B disease is a combination of both superficial (Bl) as wel1 as deep muscle-invasive tumors (B2).
In 100 patients having undergone radical cystectomy 4 percent had subsequent upper tract occurrence (Table 1); 50 percent of recurrences within this group had carcinoma in situ (CIS). Upper tract urothelial tumors developed in 4.4 percent of the 68 patients included in our series having been treated with partial cystectomy, with an even distribution among Stages 0, A, and B (Table 11). Of the 470 patients having undergone transurethral resection and/or fulguration with or without intravesical chemotherapy, future upper tract tumors developed in 2.8 percent. Of the 40 patients with CIS within this treatment category, subsequent upper tract tumors developed in 5 (13 % ) (Table 111). The mean time between the date of first diagnosis and subsequent upper tract tumor development was eighty months. Of interest, al1 patients with upper tract occurrence in our study had a prior history of heavy cigarette smoking (2 1 pack per day) which continued up to the time of diagnosis. Comment
Our study reports on the incidence of subsequent upper tract transitional cel1 carcinoma following the diagnosis and treatment of urothelial transitional tumor of the bladder. The proper form of treatment of bladder carcinema is stil1 highly controversial. We did not find a sienificant differente among treatment modaliti& on the incidence of upper tract occurrences. In addition, other than CIS, the stage of the bladder tumor did not play an im510
TABLE 11.
Incidence of upper tract cancer following partial cystectomy
Stage
No. of Pts. (%)
CIS
0 (0)
O+A : D TOTALS
Subsequent Upper Tract Tumors No. of Pts.(%)
0 (0)
22 (32.4) 46 (67.6) 0 (0) 0
1 2 0 0
68 (100)
(4.5) (4.4) (0) (0)
3 (4.4)
TABLE 111. Incidence
of upper tract cancer following transurethral resection and/or fulguration with or without intrauekal chemotherapy
Stage
No. of Pts. (%)
Subsequent Upper Tract mmors No. of Pts. (%)
CIS OtA B C D
40 (8.5) 278 (59.1) 70 (14.9) 82 (17.4) 0 (0)
5 (13) 2 (0.6) 2 (2.4) 4 (4.9) 0 (0)
TOTALS
470 (100)
13 (2.8)
portant role in the prediction of future upper tract involvement. CIS was also found to be a significant predictor of the subsequent development of carcinoma of the renal pelvis or ureter in a recent study of an unselected group of 657 patients by Oldbring, Glifberg, and Hellsten.4 Their reported overall incidence of subsequent upper tract tumor development was 1.7 percent. However, their group also found that radical cystectomy for widespread CIS or for multifocal recurrent bladder tumors was a significant independent risk factor with an incidence of 3-6 percent4 which compares favor-
ably with our incidence of 4 percent in this treatment group. We observed that the frequency of subsequent upper tract tumors increases with time and that on the average such tumors took a considerably longer time to develop (average of 80 months). This trend is consistent with previous reports. 5*6 Cases in which upper tract tumors developed after twenty years or more have been reported.e It may be that the development of subsequent upper tract tumors is related to a time factor, and that long-term follow-up of patients with treated bladder tumors allows one to
UROLOGY
/
DECEMBER1992
/
VOLUME40,NUMBER6
stantially greater. Consequently, the increased risk of secondary upper tract tumors in patients with VUR, as cited previously, may actually be a function of a longer exposure time of that urothelium to the carcinogen. l” Regardless of treatment, regular urine cytology is indicated in the follow-up of patients with treated bladder carcinoma for the early detection of upper tract tumors. In addition, interval intravenous urography is recommended for patients at higher risk for the development of these tumors, namely to those who had features of CIS.‘O
evaluate the natural history of urothelial tumors.’ Regarding the possible etiology of upper urinary tract tumor secondary to bladder cancer, there have been two theories: one concerns the implantation of tumor cells into normal mucosa, and the other theory relates to a biochemical urinary carcinogen.5 A good basis on which to support the theory of cel1 implantation is the presence of vesicoureteral reflux (VUR). Amar and Das6 report that patients with bladder carcinoma and associated VUR have an approximately fifteen-fold greater risk of subsequent upper tract cancer developing compared with those patients without reflux. DeTorres Mateos et aL9 reported on a twenty-two-fold greater risk for those patients with reflux. These recommended a post-transurethral authorP resection voiding cystogram to evaluate the existence of VUR and the consideration of an antireflux technique in selected patients with multiple bladder tumors or multiple recurrences. In our patients, voiding cystography was not performed. We found, however, that the incidence of future upper tract recurrence was independent of the treatment used. We have found that patients with CIS may be particularly prone to the development of subsequent upper tract tumors. This finding is consistent with the concept of multifocal tumors arising from an unstable urothelium. The current consensus on the etiology of multiple synchronous and metachronous urothelial tumors is that biochemical carcinogenesis is the final common pathway to urothelial carcinoma leading to a field defect and an unstable urothelium.‘O Since biochemical carcinogens have a longer contact time with the bladder urothelium than with the upper tracts, the incidence of the carcinoma arising in the bladder is sub-
UROLOGY
/
DECEMBER
1992
/
VOLUME
40,
NUMBER
Bronx, New York 10467 (DR.
SCHWARTZ)
References 1. Walzer Y, and Soloway MS: Should the follow-up of patients with bladder cancer include routine excretory urography?, J Urol 130: 672 (1983). 2. Williams JL, Hammonds JC, and Saunders N: Tl bladder tumours, Br J Urol 49: 663 (1977). 3. Kakixoe T, Fujita J, Murase T, and Matsumoto Kishi K: Transitional cel1 carcinoma of the bladder in patients with renal pelvic and ureteral cancer, J Urol 124: 17 (1980). 4. Oldbring J, Glifberg 1, and Hellsten M: Carcinoma of the renal pelvis and ureter following bladder carcinoma: frequency, risk factors, and clinicopathological findings, J Urol 140: 745 (1980). 5. Shinka T, et al: Occurrence of uroepithelial tumors of the upper urinary tract after the initial diagnosis of bladder carcinema, J Urol 140: 745 (1980). 6. Smart JG: Renal and ureteric tumours in association with bladder tumours, Br J Urol 36: 380 (1964). 7. Sherwood T: Upper urinary tract tumours following on bladder carcinoma: natural history of urothelial neoplastic discase, Br J Radio1 44: 137 (1971). 8. Amar AD, and Das S: Upper urinary tract transitional cel1 carcinoma in patients with bladder carcinoma and associated vesicoureteral reflw, J Urol 133: 468 (1985). 9. DeTorres Mateos JA, Banus Gassol JM, Palou Redorta J, and Morote Robles J: Vesicorenal reflux and upper urinary tract transitional cel1 carcinoma after transurethr&resection of recurrent suoerficial bladder carcinoma. 1 Urol 138: 49 (1987). 10. Zincke H, Gasbeff PJ, aard Beashrs JR: UPper urinary tract transitional cell cancer after radical cystectomy for bladder cancer, J Urol 131: 50 (1984).
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511
From the Department of Urology, Montefiore Medical Center/ The Albert Einstein School of Medicine, Bronx, New York ABSTRACT- We studied, retrospectively, the incidence of upper tract urothehal tumors following the treatment of primary transitional cel1 carcinoma of the bladder in 638 patients. Subsequent tumor development was found in 20 patients (3.1%) with a mean latency interval between initial treatment of the bladder cancer and diagnosis of the upper urinary tract tumor of eighty months. We did not find a significant differente among treatment modalities on the incidence of upper tract occurrences. Other than carcinoma in situ, tumor stage was not an independent predictive variable.
There are more than 30,000 new cases of transitional cel1 carcinoma of the urinary bladder reported annually in the United States. In contrast, urothelial tumors of the kidney and ureter constitute only 5 percent of al1 transitional cel1 tumors.’ Local resection of bladder tumors is followed by a high recurrence rate. It is accepted that patients who present with upper tract urothelial tumors have a high incidence of subsequent bladder tumors. 3 However, the incidence of upper tract transitional cel1 carcinoma following the diagnosis and treatment of primary bladder tumors is not wel1 known and data concerning this issue have been sparse. Our study was designed to define the incidence of secondary transitional cel1 carcinoma of the upper urinary tract; how this is related to the antecedent bladder tumor; and how various treatment modalities used for the bladder tumor may affect this incidence. Material and Methods Between 1972 and 1982, 638 patients having undergone treatment for various stages of transitional cel1 carcinoma of the bladder were studied retrospectively. Of these patients, 100 had undergone radical cystectomy, 68 were
UROLOGY
/ DECEMBER1992
/ VOLUME40,NUMBERô
treated with partial cystectomy, and 470 had undergone transurethral resection andlor fulguration with or without intravesical chemotherapy. Al1 patients were followed for five years or more. Follow-up tests included intravenous urography (IVP), cytologie examination of the urine, and in later years, sonography and computerized tomography (CT) scan if indicated. Al1 patients were followed with urine cytologie+ most at regular intervals. In addition, al1 patients had at least one follow-up IVP while many had yearly interval IVPs. The Jewett-Strong-Marshall method of staging was applied to the removed specimens. None of these patients had prior occupational exposure to known carcinogenic dyes. Diagnosis of upper urinary tract transitional cel1 tumors made by the aforementioned studies were confirmed by an operation. The incidence of these upper tract urothelial tumors was compared with both treatment modality as wel1 as stage of the bladder tumor. In those patients having undergone multiple transurethral resections of recurrent bladder tumors, the stage recorded represents the highest stage of the bladder tumor prior to diagnosis of upper tract tumor.
509
TABLE 1.
Incìdence of upper tract cancer following radical cystectomy
Stage CIS O+A c D TOTALS
No. of Pts. (%) 15 0 55 12 18
(15) (0) (55) (12) (18)
100 (100)
Subsequent Upper fiact -mors No. of Pts. (%) 2 0 1 0 1
(13.3) (0) (1.9) (0) (5.5)
4
(4)
Results Tables 1 to 111 detail the incidence of subsequent upper tract transitional cel1 carcinoma with comparison of stage of bladder tumor and modality of treatment. Stage B disease is a combination of both superficial (Bl) as wel1 as deep muscle-invasive tumors (B2).
In 100 patients having undergone radical cystectomy 4 percent had subsequent upper tract occurrence (Table 1); 50 percent of recurrences within this group had carcinoma in situ (CIS). Upper tract urothelial tumors developed in 4.4 percent of the 68 patients included in our series having been treated with partial cystectomy, with an even distribution among Stages 0, A, and B (Table 11). Of the 470 patients having undergone transurethral resection and/or fulguration with or without intravesical chemotherapy, future upper tract tumors developed in 2.8 percent. Of the 40 patients with CIS within this treatment category, subsequent upper tract tumors developed in 5 (13 % ) (Table 111). The mean time between the date of first diagnosis and subsequent upper tract tumor development was eighty months. Of interest, al1 patients with upper tract occurrence in our study had a prior history of heavy cigarette smoking (2 1 pack per day) which continued up to the time of diagnosis. Comment
Our study reports on the incidence of subsequent upper tract transitional cel1 carcinoma following the diagnosis and treatment of urothelial transitional tumor of the bladder. The proper form of treatment of bladder carcinema is stil1 highly controversial. We did not find a sienificant differente among treatment modaliti& on the incidence of upper tract occurrences. In addition, other than CIS, the stage of the bladder tumor did not play an im510
TABLE 11.
Incidence of upper tract cancer following partial cystectomy
Stage
No. of Pts. (%)
CIS
0 (0)
O+A : D TOTALS
Subsequent Upper Tract Tumors No. of Pts.(%)
0 (0)
22 (32.4) 46 (67.6) 0 (0) 0
1 2 0 0
68 (100)
(4.5) (4.4) (0) (0)
3 (4.4)
TABLE 111. Incidence
of upper tract cancer following transurethral resection and/or fulguration with or without intrauekal chemotherapy
Stage
No. of Pts. (%)
Subsequent Upper Tract mmors No. of Pts. (%)
CIS OtA B C D
40 (8.5) 278 (59.1) 70 (14.9) 82 (17.4) 0 (0)
5 (13) 2 (0.6) 2 (2.4) 4 (4.9) 0 (0)
TOTALS
470 (100)
13 (2.8)
portant role in the prediction of future upper tract involvement. CIS was also found to be a significant predictor of the subsequent development of carcinoma of the renal pelvis or ureter in a recent study of an unselected group of 657 patients by Oldbring, Glifberg, and Hellsten.4 Their reported overall incidence of subsequent upper tract tumor development was 1.7 percent. However, their group also found that radical cystectomy for widespread CIS or for multifocal recurrent bladder tumors was a significant independent risk factor with an incidence of 3-6 percent4 which compares favor-
ably with our incidence of 4 percent in this treatment group. We observed that the frequency of subsequent upper tract tumors increases with time and that on the average such tumors took a considerably longer time to develop (average of 80 months). This trend is consistent with previous reports. 5*6 Cases in which upper tract tumors developed after twenty years or more have been reported.e It may be that the development of subsequent upper tract tumors is related to a time factor, and that long-term follow-up of patients with treated bladder tumors allows one to
UROLOGY
/
DECEMBER1992
/
VOLUME40,NUMBER6
stantially greater. Consequently, the increased risk of secondary upper tract tumors in patients with VUR, as cited previously, may actually be a function of a longer exposure time of that urothelium to the carcinogen. l” Regardless of treatment, regular urine cytology is indicated in the follow-up of patients with treated bladder carcinoma for the early detection of upper tract tumors. In addition, interval intravenous urography is recommended for patients at higher risk for the development of these tumors, namely to those who had features of CIS.‘O
evaluate the natural history of urothelial tumors.’ Regarding the possible etiology of upper urinary tract tumor secondary to bladder cancer, there have been two theories: one concerns the implantation of tumor cells into normal mucosa, and the other theory relates to a biochemical urinary carcinogen.5 A good basis on which to support the theory of cel1 implantation is the presence of vesicoureteral reflux (VUR). Amar and Das6 report that patients with bladder carcinoma and associated VUR have an approximately fifteen-fold greater risk of subsequent upper tract cancer developing compared with those patients without reflux. DeTorres Mateos et aL9 reported on a twenty-two-fold greater risk for those patients with reflux. These recommended a post-transurethral authorP resection voiding cystogram to evaluate the existence of VUR and the consideration of an antireflux technique in selected patients with multiple bladder tumors or multiple recurrences. In our patients, voiding cystography was not performed. We found, however, that the incidence of future upper tract recurrence was independent of the treatment used. We have found that patients with CIS may be particularly prone to the development of subsequent upper tract tumors. This finding is consistent with the concept of multifocal tumors arising from an unstable urothelium. The current consensus on the etiology of multiple synchronous and metachronous urothelial tumors is that biochemical carcinogenesis is the final common pathway to urothelial carcinoma leading to a field defect and an unstable urothelium.‘O Since biochemical carcinogens have a longer contact time with the bladder urothelium than with the upper tracts, the incidence of the carcinoma arising in the bladder is sub-
UROLOGY
/
DECEMBER
1992
/
VOLUME
40,
NUMBER
Bronx, New York 10467 (DR.
SCHWARTZ)
References 1. Walzer Y, and Soloway MS: Should the follow-up of patients with bladder cancer include routine excretory urography?, J Urol 130: 672 (1983). 2. Williams JL, Hammonds JC, and Saunders N: Tl bladder tumours, Br J Urol 49: 663 (1977). 3. Kakixoe T, Fujita J, Murase T, and Matsumoto Kishi K: Transitional cel1 carcinoma of the bladder in patients with renal pelvic and ureteral cancer, J Urol 124: 17 (1980). 4. Oldbring J, Glifberg 1, and Hellsten M: Carcinoma of the renal pelvis and ureter following bladder carcinoma: frequency, risk factors, and clinicopathological findings, J Urol 140: 745 (1980). 5. Shinka T, et al: Occurrence of uroepithelial tumors of the upper urinary tract after the initial diagnosis of bladder carcinema, J Urol 140: 745 (1980). 6. Smart JG: Renal and ureteric tumours in association with bladder tumours, Br J Urol 36: 380 (1964). 7. Sherwood T: Upper urinary tract tumours following on bladder carcinoma: natural history of urothelial neoplastic discase, Br J Radio1 44: 137 (1971). 8. Amar AD, and Das S: Upper urinary tract transitional cel1 carcinoma in patients with bladder carcinoma and associated vesicoureteral reflw, J Urol 133: 468 (1985). 9. DeTorres Mateos JA, Banus Gassol JM, Palou Redorta J, and Morote Robles J: Vesicorenal reflux and upper urinary tract transitional cel1 carcinoma after transurethr&resection of recurrent suoerficial bladder carcinoma. 1 Urol 138: 49 (1987). 10. Zincke H, Gasbeff PJ, aard Beashrs JR: UPper urinary tract transitional cell cancer after radical cystectomy for bladder cancer, J Urol 131: 50 (1984).
6
511
