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Local Urethral Recurrence After Radical Cystectomy and Orthotopic Bladder Substitution in Women:: A Prospective Study
0022-5347/04/1711-0275/0 THE JOURNAL OF UROLOGY® Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 171, 275–278, January 2004 Printed in U.S.A.
DOI: 10.1097/01.ju.0000101184.50051.6f
LOCAL URETHRAL RECURRENCE AFTER RADICAL CYSTECTOMY AND ORTHOTOPIC BLADDER SUBSTITUTION IN WOMEN: A PROSPECTIVE STUDY BEDEIR ALI-EL-DEIN,* MOHAMED ABDEL-LATIF, ALBAIR ASHAMALLAH, MONA ABDEL-RAHIM AND MOHAMED A. GHONEIM From the Urology and Pathology (MA-R) Departments, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
ABSTRACT
Purpose: We prospectively studied the pathological outcome and incidence of urethral recurrence after radical cystectomy and orthotopic bladder substitution in women. Materials and Methods: Between January 1995 and December 2001, 145 women with a mean age of 50 ⫾ 8.5 years underwent standard radical cystectomy and orthotopic substitution for bladder cancer. Histopathological examination of the cystectomy specimens was assessed by a single pathologist. Clinically evident pelvic lymphadenopathy, bladder neck and/or vaginal wall involvement, or positive intraoperative frozen section from the urethra were considered contraindications. Results: One patient died postoperatively of a massive pulmonary embolism. Followup was 12 to 97 months (mean 36, median 55.8). Pathological stage was P1, P2 (superficial muscle invasion), P3a (deep muscle invasion), P3b (perivesical fat infiltration) and P4a in 12, 29, 56, 44 and 4 patients, respectively. Grade was G1 in 61 patients, G2 in 62 and G3 in 22. Lymph nodes were positive in 28 cases and negative in 117. Histopathology of the trigone revealed carcinoma in situ in 11 cases and squamous metaplasia in 7, while results were free of disease in the remainder. At followup isolated urethral recurrence developed in 2 patients (1.4%), in whom definitive pathological findings showed P3a N1 (positive iliac lymph nodes) M0, grade 2 squamous cell carcinoma in 1 and P3b N0M0 tumor associated with trigonal carcinoma in situ in 1. Local pelvic recurrence developed in 18 patients, distant metastasis developed in 6 and the 2 conditions developed in 10. Oncological failure positively correlated with high stage, high grade and positive lymph nodes. Conclusions: The rate of urethral recurrence after radical cystectomy and orthotopic bladder substitution in women is low and acceptable and, thus, it justifies the continued performance of this type of diversion. Proper selection of cases is mandatory. Close followup for oncological failure in this group of patients after cystectomy is necessary. KEY WORDS: cystectomy, bladder, urinary diversion, urethra, neoplasm metastasis
Orthotopic bladder substitution after radical cystectomy in women has become an established mode of diversion. The oncological outcome of this relatively new approach, especially tumor recurrence in the retained urethra, has not yet been determined because of the relatively short followup and limited number of patients in most series. We report in a prospective way the incidence of oncological failure and tumor recurrence in the urethra after radical cystectomy and orthotopic bladder substitution in women. PATIENTS AND METHODS
Between January 1995 and December 2001, 239 women underwent cystectomy and different types of urinary diversion. Of these women 145 underwent orthotopic bladder substitution and 94 underwent another type of diversion. In the orthotopic substitution group patient age was 23 to 73 years (mean ⫾ SD 50 ⫾ 8.5). Clinically evident pelvic lymphadenopathy, bladder neck involvement, vaginal wall involvement or positive intraoperative frozen urethral section were considered contraindications. Evaluation for tumor staging and grading included abdominal ultrasound, chest x-ray, computerized tomography (CT) or magnetic resonance imag-
ing (MRI) of the abdomen and pelvis, bone scintigraphy, bimanual examination using anesthesia, cystoscopy, and multiple biopsies of the tumor, trigone and bladder neck. Vaginal involvement was ruled out by vaginal examination and by transvaginal ultrasonography using a 7 mHz probe. Standard radical cystectomy without any attempt at autonomic nerve preservation was performed using a previously described technique.1 Histopathological examination of the radical cystectomy specimens was done by a single pathologist. Postoperatively the patients were oncologically evaluated every 3 months during year 1 and every 6 months thereafter. This evaluation included physical examination of the vaginal stump and remaining urethra, and abdominal and transvaginal ultrasound. If there was suspicious finding on physical examination or ultrasound, further evaluation was done by CT or MRI. Urine samples for urinary cytology were taken yearly. Further evaluation by panendoscopy was performed if there were suspicious findings on urinary cytology, bleeding via the urethra or hematuria. Upper tract imaging by excretory urography or magnetic resonance urography was done annually unless otherwise indicated. Survival was estimated using Kaplan-Meier curves.
Accepted for publication August 29, 2003. RESULTS * Correspondence: Urology Department, Urology and Nephrology CenThe causes of exclusion from orthotopic substitution in the ter, Mansoura University, Mansoura, Egypt (telephone: 20-50-2262222-6; 94 women who underwent other types of diversion were a FAX: 20-50-2263717; e-mail: [email protected]). 275
276
LOCAL URETHRAL RECURRENCE AFTER CYSTECTOMY TABLE 1. Definitive cystectomy specimen histopathology Parameter
Histological type: Squamous cell Ca Transitional cell Ca Adenoca Undifferentiated Ca Mixed tumor Leiomyosarcoma Pathological stage: P1 P2 P3a P3b P4 Grade: G1 G2 G3 Lymph nodes: Neg Pos Trigone: Disease-free CIS Squamous metaplasia
No. Whole Series (%)
No. Oncological Failure (%)
88 (60.7) 31 (21.4) 17 (11.7) 1 (0.7) 7 (4.8) 1 (0.7)
23 (26.1) 4 (12.9) 6 (35.3) 1 (100) 1 (14.3) 1 (100)
12 (8.3) 29 (20) 56 (38.6) 44 (30.3) 4 (2.8)
1 3 10 20 2
61 (42) 62 (43) 22 (15)
11 (18) 15 (24.2) 10 (45.5)
117 (80.7) 28 (19.3)
24 (20.5) 12 (42.9)
127 (87.6) 11 (7.6) 7 (4.8)
31 (24.4) 4 (36.4) 1 (14.3)
(8.3) (10.3) (17.9) (45.5) (50)
tumor at or close to the bladder neck in 50, vaginal involvement in 3, clinically evident metastatic lymphadenopathy and/or locally advanced tumor in 21, high serum creatinine and/or poor creatinine clearance in 11, inadequate urethral closure function in 5, intraoperative positive frozen section of the urethral margin in 3 and a short mesentery in 1. In the 145 women who underwent orthotopic substitution there was no intraoperative mortality. One patient died postoperatively of a massive pulmonary embolism. Table 1 shows definitive histopathological findings in the radical cystectomy specimens. In cystectomy specimens the histological type of cancer was squamous cell carcinoma in 88 patients, transitional cell carcinoma in 31, adenocarcinoma in 17, undifferentiated carcinoma in 1, mixed tumor in 7 and leiomyosarcoma in 1. Pathological stage was most frequently P3a (56 patients) with infiltration of the deep muscle layer or p3b (44 patients) and infiltration of the perivesical fat. Histological grade was grade 1 in 61 patients, grade 2 in 62 and grade 3 in 22. Positive lymph node disease was detected in 28 patients. Histopathological evaluation of the trigone revealed carcinoma in situ (CIS) in 11 patients (7.6%) and squamous metaplasia in 7 (4.8%), while it was disease-free in the remainder. Oncological failure in the form of local recurrence and/or distant metastasis developed in 36 patients (24.8%) at a mean followup ⫾ SD of 17.4 ⫾ 15 months (range 4 to 77.5). Table 1 shows definitive histopathological findings in cystectomy specimens in these patients. Table 2 lists the incidence of different types of oncological failure. Isolated local urethral recurrence developed in 2 patients. Table 2 shows the original histopathological findings in the cystectomy specimens of these patients. These 2 patients complained of bleeding via the urethra and the tumors were seen by transvaginal ultrasound (fig. 1). The diagnosis was confirmed by cystoscopic biopsy. CT or MRI excluded disease at other sites. One of
FIG. 1. Transvaginal ultrasound in woman with local urethral recurrence after cystectomy shows tumor in urethra (arrow) extending into pouch.
these patients who was treated with urethrectomy and conversion to a continent cutaneous ileal reservoir died 8 months later, while the other patient was not a candidate for surgery. Oncological failure positively correlated with pathological stage, histological grade and lymph node status at cystectomy (table 3). Another 8 patients (5.5%) died of unrelated diseases. Therefore, at a mean followup of 55 ⫾ 26 months (range 12 to 97, median 55.8) overall disease-free survival was 69.7% and actuarial 5-year disease-free survival was 68.2% (fig. 2). DISCUSSION
The incidence and risk factors for urethral recurrence in men with transitional cell carcinoma of the bladder have been well documented.2–7 On the other hand, the incidence and characteristics of urethral involvement in women with bladder cancer have not been well studied until recently. The reasons were the relative rarity of bladder cancer in women in relation to men and routine urethral removal at cystectomy. Therefore, it did not receive any significant interest before the era of orthotopic bladder replacement. In the era of orthotopic bladder substitution in women a detailed knowledge of urethral involvement as a primary or recurrent tumor in association with bladder cancer is of a paramount importance. Lack of this knowledge may jeopardize the success of radical surgery, resulting in unacceptable rates of local urethral or pelvic recurrences. It is because the urethra in women is much shorter than in men and urethral surgical safety margins would be in closer proximity to the bladder. Few retrospective studies have been performed to define the incidence and characteristics of urethral involvement in female patients undergoing cystectomy for bladder cancer.2, 4, 5, 8 –11 In 1990 De Paepe et al investigated urethral involvement in cystourethrectomy specimens from female patients with bladder cancer and reported malignant involvement of the urethra in 8 of the 22 studied specimens (36%).8 Three of the
TABLE 2. Sites of failure and pathological characteristics of cystectomy specimens in patients with oncological failure Parameter No. pts Site Pathological characteristics at cystectomy
Isolated Local Urethral Recurrence 2 Urethra with or without extension to pouch P3a N1 (pos external iliac lymph nodes) M0, G2 squamous cell Ca (1 pt), P3b N0M0 G3 transitional cell Ca associated with trigonal CIS (1)
Local Pelvic Recurrence 18 In pelvis outside of pouch Variable
Metastasis 6 Bone (3 pts), lung (1), multiple (2) Variable
Recurrence ⫹ Metastasis 10 Variable Variable
LOCAL URETHRAL RECURRENCE AFTER CYSTECTOMY TABLE 3. Local recurrence and/or distant metastasis in relation to tumor stage, grade and lymph node status at cystectomy Parameter Stage: P1 P2 P3a P3b P4a Grade: G1 G2 G3 Lymph nodes: Neg Pos
No. Oncological Failure/ Total No. (%)
p Value (log rank test) ⬍0.001
2/12 5/29 12/56 22/44 3/4
(16.7) (17.2) (21.4) (50) (75) 0.01
14/61 (23) 18/62 (29) 12/22 (54.6) 0.01 30/117 (25.6) 14/28 (50)
8 specimens with urethral involvement showed carcinoma in situ, 2 showed noninvasive papillary cancer and 3 showed invasive papillary or nonpapillary cancer. De Paepe et al suggested that these findings justified the continued performance of urethrectomy in conjunction with cystectomy in women with invasive bladder cancer. They were criticized that they did not provide any details regarding the localization of primary tumors in the bladder or secondary tumors in the urethra.9, 10 Coloby et al reviewed 47 consecutive step-section cystourethrectomy specimens of bladder cancer in female patients to determine the incidence and characteristics of urethral involvement.11 Urethral involvement was observed in only 3 of the 43 patients (7%) with transitional cell carcinoma. In all of these cases the bladder neck was involved. In addition, high stage (P3 or greater), high grade (grade 3), associated CIS in the adjacent bladder mucosa, and/or lymphatic and vascular invasion were detected in the cystectomy specimens of these women. Therefore, Coloby et al advocated the necessity of prophylactic urethrectomy in cases of papillary or papillarynodular tumors encroaching on the bladder neck and trigone. In other situations the urethra can be preserved in preparation for orthotopic bladder reconstruction. Stenzl et al found primary urethral tumor involvement in 2% of their study group of 356 female patients and in only 1% of patients with localized (T2-T3b N0M0) invasive cancer amenable to radical cystectomy.10 They correlated the incidence of primary urethral tumors with the various tumor locations in the bladder. The only significant and consistent risk factor for concomitant urethral involvement was simultaneous primary tumor involving the bladder neck
277
(p ⬍0.001). Tumors involving the trigone correlated only marginally with urethral tumor involvement. They concluded that a large caudal segment of the urethra could safely be spared in select female patients undergoing cystectomy and orthotopic urinary reconstruction to the remnant urethra. It is true provided that neither preoperative biopsies of the bladder neck nor intraoperative frozen sections of the urethra at the level of transection show any tumor or CIS. There was an apparently lower incidence of secondary urethral tumors in women than in men.6, 7 The investigators explained this observation by the fact that transitional cell mucosa in women covers a much smaller urethral segment with the remainder being normal or metaplastic squamous cell mucosa. Furthermore, the area covered with transitional epithelium decreases with advancing age since the line of demarcation between the transitional and squamous epithelium moves craniad during menopause. In the sixth and seventh decades of life the whole urethra, bladder neck and a portion of the trigone may be covered with metaplastic squamous cell mucosa.12 Stein et al performed a pathological review of the cystectomy specimens of 67 consecutive women undergoing radical cystectomy for transitional cell carcinoma of the bladder.9 Histological evidence of tumor (CIS in situ or overt carcinoma) involving the urethra was present in 9 patients (13%) and the bladder neck was involved in 17 (25%). All patients with urethral tumors had concomitant evidence of carcinoma involving the bladder neck. In this study patients with an uninvolved bladder neck also had an uninvolved urethra. In addition, tumor involving the bladder neck and urethra tended to be more commonly associated with high grade and stage, and node positive disease. Stein et al concluded that approximately 75% of women undergoing cystectomy for transitional cell carcinoma of the bladder may be appropriate candidates for orthotopic bladder substitution after excluding those in whom tumor involved the bladder neck. To our knowledge we report the first prospective study of the incidence of local urethral recurrence after radical cystectomy and orthotopic bladder reconstruction in women with the possible exception of a single case report.13 The 1.4% rate of urethral recurrence in the current study is low and comparable to that recently reported in men after radical cystectomy and neobladder reconstruction.14 In addition, the rate of local recurrence and/or distant metastasis in this study are comparable to those reported recently after radical cystectomy for bladder cancer.14, 15 The positive correlation of oncological failure in this study with pathological stage, tumor grade and lymph node status
FIG. 2. Disease-free survival after cystectomy in study group
278
LOCAL URETHRAL RECURRENCE AFTER CYSTECTOMY
at cystectomy is well known and has been studied before.16 Although CIS was detected at the trigone in the cystectomy specimens in 1 of the patients with urethral recurrence, it was not detected in the other patient. Furthermore, trigonal CIS in the cystectomy specimens in our cases was not associated with a significantly higher local recurrence rate at followup compared with cases without trigonal CIS. High grade and involved lymph nodes at cystectomy in the second case may explain the development of metachronous urethral recurrence because a centripetal lymphatic tumor cell spread may occur caudal beside the urethra. However, because of the small number of patients who had local urethral recurrence and the relatively short followup we cannot draw solid conclusions concerning risk factors for urethral recurrence in this subset of patients. CONCLUSIONS
The incidence of local urethral recurrence after radical cystectomy and orthotopic bladder substitution in women is low and acceptable and, thus, it justifies the continued performance of this type of diversion. Proper selection of patients for this mode of diversion is mandatory. Close followup for oncological failure in this group is necessary after cystectomy. However, because of the small number of patients with urethral recurrence and the relatively short followup we cannot draw solid conclusions concerning risk factors for urethral recurrence. REFERENCES
1. Ali-El-Dein, B., El-Sobky, E., Hohenfellner, M. and Ghoneim, M. A.: Orthotopic bladder substitution in women: functional evaluation. J Urol, 161: 1875, 1999 2. Cordonnier, J. J. and Spjut, H. J.: Urethral occurrence of bladder carcinoma following cystectomy. J Urol, 87: 398, 1962 3. 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 4. Richie, J. P. and Skinner, D. G.: Carcinoma in situ of the urethra associated with bladder carcinoma: the role of urethrectomy.
J Urol, 119: 80, 1978 5. Coutts, A. G., Grigor, K. M. and Fowler, J. W.: Urethral dysplasia and bladder cancer in cystectomy specimens. Br J Urol, 57: 535, 1985 6. Hardeman, S. W. and Soloway, M. S.: Urethral recurrence following radical cystectomy. J Urol, 144: 666, 1990 7. Sto¨ ckle, M., Go¨ kcebay, E., Riedmiller, H. and Hohenfellner, R.: Urethral tumor recurrences after radical cystoprostatectomy: the case for primary cystoprostatourethrectomy? J Urol, 143: 41, 1990 8. De Paepe, M. E., Andre, R. and Mahadevia, P.: Urethral involvement in female patients with bladder cancer. A study of 22 cystectomy specimens. Cancer, 65: 1237, 1990 9. Stein, J. P., Cote, R. J., Freeman, J. A., Esrig, D., Elmajian, D. A., Groshen, S. et al: Indications for lower urinary tract reconstruction in women after cystectomy for bladder cancer: a pathological review of female cystectomy specimens. J Urol, 154: 1329, 1995 10. Stenzl, A., Draxl, H., Posch, B., Colleselli, K., Falk, M. and Bartsch, G.: The risk of urethral tumors in female bladder cancer: can the urethra be used for orthotopic reconstruction of the lower urinary tract? J Urol, 153: 950, 1995 11. Coloby, P. J., Kakizoe, T., Tobisu, K.-I. and Sakamoto, M.-I.: Urethral involvement in female bladder cancer patients: mapping of 47 consecutive cysto-urethrectomy specimens. J Urol, 152: 1438, 1994 12. Packham, D.: The epithelial lining of the female trigone and urethra. Br J Urol, 43: 201, 1971 13. Jones, J., Melchior, S. W., Gillitzer, R., Fichtner, J., El-Mekresh, M. and Thu¨ roff, J. W.: Urethral recurrence of transitional cell carcinoma in a female patient after cystectomy and orthotopic ileal neobladder. J Urol, 164: 1646, 2000 14. Yossepowitch, O., Dalbagni, G., Golijanin, D., Donat, S. M., Bochner, B. H., Herr, H. W. et al: Orthotopic urinary diversion after cystectomy for bladder cancer: implications for cancer control and patterns of disease recurrence. J Urol, 169: 177, 2003 15. Hautmann, R. E.: 15 Years experience with the ileal neobladder. What have we learned? Urologe A, 40: 360, 2001 16. Ghoneim, M. A., El-Mekresh, M. M., El-Baz, M. A., El-Attar, I. A. and Ashamallah, A.: Radical cystectomy for carcinoma of the bladder: critical evaluation of the results in 1,026 cases. J Urol, 158: 393, 1997
Vol. 171, 275–278, January 2004 Printed in U.S.A.
DOI: 10.1097/01.ju.0000101184.50051.6f
LOCAL URETHRAL RECURRENCE AFTER RADICAL CYSTECTOMY AND ORTHOTOPIC BLADDER SUBSTITUTION IN WOMEN: A PROSPECTIVE STUDY BEDEIR ALI-EL-DEIN,* MOHAMED ABDEL-LATIF, ALBAIR ASHAMALLAH, MONA ABDEL-RAHIM AND MOHAMED A. GHONEIM From the Urology and Pathology (MA-R) Departments, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
ABSTRACT
Purpose: We prospectively studied the pathological outcome and incidence of urethral recurrence after radical cystectomy and orthotopic bladder substitution in women. Materials and Methods: Between January 1995 and December 2001, 145 women with a mean age of 50 ⫾ 8.5 years underwent standard radical cystectomy and orthotopic substitution for bladder cancer. Histopathological examination of the cystectomy specimens was assessed by a single pathologist. Clinically evident pelvic lymphadenopathy, bladder neck and/or vaginal wall involvement, or positive intraoperative frozen section from the urethra were considered contraindications. Results: One patient died postoperatively of a massive pulmonary embolism. Followup was 12 to 97 months (mean 36, median 55.8). Pathological stage was P1, P2 (superficial muscle invasion), P3a (deep muscle invasion), P3b (perivesical fat infiltration) and P4a in 12, 29, 56, 44 and 4 patients, respectively. Grade was G1 in 61 patients, G2 in 62 and G3 in 22. Lymph nodes were positive in 28 cases and negative in 117. Histopathology of the trigone revealed carcinoma in situ in 11 cases and squamous metaplasia in 7, while results were free of disease in the remainder. At followup isolated urethral recurrence developed in 2 patients (1.4%), in whom definitive pathological findings showed P3a N1 (positive iliac lymph nodes) M0, grade 2 squamous cell carcinoma in 1 and P3b N0M0 tumor associated with trigonal carcinoma in situ in 1. Local pelvic recurrence developed in 18 patients, distant metastasis developed in 6 and the 2 conditions developed in 10. Oncological failure positively correlated with high stage, high grade and positive lymph nodes. Conclusions: The rate of urethral recurrence after radical cystectomy and orthotopic bladder substitution in women is low and acceptable and, thus, it justifies the continued performance of this type of diversion. Proper selection of cases is mandatory. Close followup for oncological failure in this group of patients after cystectomy is necessary. KEY WORDS: cystectomy, bladder, urinary diversion, urethra, neoplasm metastasis
Orthotopic bladder substitution after radical cystectomy in women has become an established mode of diversion. The oncological outcome of this relatively new approach, especially tumor recurrence in the retained urethra, has not yet been determined because of the relatively short followup and limited number of patients in most series. We report in a prospective way the incidence of oncological failure and tumor recurrence in the urethra after radical cystectomy and orthotopic bladder substitution in women. PATIENTS AND METHODS
Between January 1995 and December 2001, 239 women underwent cystectomy and different types of urinary diversion. Of these women 145 underwent orthotopic bladder substitution and 94 underwent another type of diversion. In the orthotopic substitution group patient age was 23 to 73 years (mean ⫾ SD 50 ⫾ 8.5). Clinically evident pelvic lymphadenopathy, bladder neck involvement, vaginal wall involvement or positive intraoperative frozen urethral section were considered contraindications. Evaluation for tumor staging and grading included abdominal ultrasound, chest x-ray, computerized tomography (CT) or magnetic resonance imag-
ing (MRI) of the abdomen and pelvis, bone scintigraphy, bimanual examination using anesthesia, cystoscopy, and multiple biopsies of the tumor, trigone and bladder neck. Vaginal involvement was ruled out by vaginal examination and by transvaginal ultrasonography using a 7 mHz probe. Standard radical cystectomy without any attempt at autonomic nerve preservation was performed using a previously described technique.1 Histopathological examination of the radical cystectomy specimens was done by a single pathologist. Postoperatively the patients were oncologically evaluated every 3 months during year 1 and every 6 months thereafter. This evaluation included physical examination of the vaginal stump and remaining urethra, and abdominal and transvaginal ultrasound. If there was suspicious finding on physical examination or ultrasound, further evaluation was done by CT or MRI. Urine samples for urinary cytology were taken yearly. Further evaluation by panendoscopy was performed if there were suspicious findings on urinary cytology, bleeding via the urethra or hematuria. Upper tract imaging by excretory urography or magnetic resonance urography was done annually unless otherwise indicated. Survival was estimated using Kaplan-Meier curves.
Accepted for publication August 29, 2003. RESULTS * Correspondence: Urology Department, Urology and Nephrology CenThe causes of exclusion from orthotopic substitution in the ter, Mansoura University, Mansoura, Egypt (telephone: 20-50-2262222-6; 94 women who underwent other types of diversion were a FAX: 20-50-2263717; e-mail: [email protected]). 275
276
LOCAL URETHRAL RECURRENCE AFTER CYSTECTOMY TABLE 1. Definitive cystectomy specimen histopathology Parameter
Histological type: Squamous cell Ca Transitional cell Ca Adenoca Undifferentiated Ca Mixed tumor Leiomyosarcoma Pathological stage: P1 P2 P3a P3b P4 Grade: G1 G2 G3 Lymph nodes: Neg Pos Trigone: Disease-free CIS Squamous metaplasia
No. Whole Series (%)
No. Oncological Failure (%)
88 (60.7) 31 (21.4) 17 (11.7) 1 (0.7) 7 (4.8) 1 (0.7)
23 (26.1) 4 (12.9) 6 (35.3) 1 (100) 1 (14.3) 1 (100)
12 (8.3) 29 (20) 56 (38.6) 44 (30.3) 4 (2.8)
1 3 10 20 2
61 (42) 62 (43) 22 (15)
11 (18) 15 (24.2) 10 (45.5)
117 (80.7) 28 (19.3)
24 (20.5) 12 (42.9)
127 (87.6) 11 (7.6) 7 (4.8)
31 (24.4) 4 (36.4) 1 (14.3)
(8.3) (10.3) (17.9) (45.5) (50)
tumor at or close to the bladder neck in 50, vaginal involvement in 3, clinically evident metastatic lymphadenopathy and/or locally advanced tumor in 21, high serum creatinine and/or poor creatinine clearance in 11, inadequate urethral closure function in 5, intraoperative positive frozen section of the urethral margin in 3 and a short mesentery in 1. In the 145 women who underwent orthotopic substitution there was no intraoperative mortality. One patient died postoperatively of a massive pulmonary embolism. Table 1 shows definitive histopathological findings in the radical cystectomy specimens. In cystectomy specimens the histological type of cancer was squamous cell carcinoma in 88 patients, transitional cell carcinoma in 31, adenocarcinoma in 17, undifferentiated carcinoma in 1, mixed tumor in 7 and leiomyosarcoma in 1. Pathological stage was most frequently P3a (56 patients) with infiltration of the deep muscle layer or p3b (44 patients) and infiltration of the perivesical fat. Histological grade was grade 1 in 61 patients, grade 2 in 62 and grade 3 in 22. Positive lymph node disease was detected in 28 patients. Histopathological evaluation of the trigone revealed carcinoma in situ (CIS) in 11 patients (7.6%) and squamous metaplasia in 7 (4.8%), while it was disease-free in the remainder. Oncological failure in the form of local recurrence and/or distant metastasis developed in 36 patients (24.8%) at a mean followup ⫾ SD of 17.4 ⫾ 15 months (range 4 to 77.5). Table 1 shows definitive histopathological findings in cystectomy specimens in these patients. Table 2 lists the incidence of different types of oncological failure. Isolated local urethral recurrence developed in 2 patients. Table 2 shows the original histopathological findings in the cystectomy specimens of these patients. These 2 patients complained of bleeding via the urethra and the tumors were seen by transvaginal ultrasound (fig. 1). The diagnosis was confirmed by cystoscopic biopsy. CT or MRI excluded disease at other sites. One of
FIG. 1. Transvaginal ultrasound in woman with local urethral recurrence after cystectomy shows tumor in urethra (arrow) extending into pouch.
these patients who was treated with urethrectomy and conversion to a continent cutaneous ileal reservoir died 8 months later, while the other patient was not a candidate for surgery. Oncological failure positively correlated with pathological stage, histological grade and lymph node status at cystectomy (table 3). Another 8 patients (5.5%) died of unrelated diseases. Therefore, at a mean followup of 55 ⫾ 26 months (range 12 to 97, median 55.8) overall disease-free survival was 69.7% and actuarial 5-year disease-free survival was 68.2% (fig. 2). DISCUSSION
The incidence and risk factors for urethral recurrence in men with transitional cell carcinoma of the bladder have been well documented.2–7 On the other hand, the incidence and characteristics of urethral involvement in women with bladder cancer have not been well studied until recently. The reasons were the relative rarity of bladder cancer in women in relation to men and routine urethral removal at cystectomy. Therefore, it did not receive any significant interest before the era of orthotopic bladder replacement. In the era of orthotopic bladder substitution in women a detailed knowledge of urethral involvement as a primary or recurrent tumor in association with bladder cancer is of a paramount importance. Lack of this knowledge may jeopardize the success of radical surgery, resulting in unacceptable rates of local urethral or pelvic recurrences. It is because the urethra in women is much shorter than in men and urethral surgical safety margins would be in closer proximity to the bladder. Few retrospective studies have been performed to define the incidence and characteristics of urethral involvement in female patients undergoing cystectomy for bladder cancer.2, 4, 5, 8 –11 In 1990 De Paepe et al investigated urethral involvement in cystourethrectomy specimens from female patients with bladder cancer and reported malignant involvement of the urethra in 8 of the 22 studied specimens (36%).8 Three of the
TABLE 2. Sites of failure and pathological characteristics of cystectomy specimens in patients with oncological failure Parameter No. pts Site Pathological characteristics at cystectomy
Isolated Local Urethral Recurrence 2 Urethra with or without extension to pouch P3a N1 (pos external iliac lymph nodes) M0, G2 squamous cell Ca (1 pt), P3b N0M0 G3 transitional cell Ca associated with trigonal CIS (1)
Local Pelvic Recurrence 18 In pelvis outside of pouch Variable
Metastasis 6 Bone (3 pts), lung (1), multiple (2) Variable
Recurrence ⫹ Metastasis 10 Variable Variable
LOCAL URETHRAL RECURRENCE AFTER CYSTECTOMY TABLE 3. Local recurrence and/or distant metastasis in relation to tumor stage, grade and lymph node status at cystectomy Parameter Stage: P1 P2 P3a P3b P4a Grade: G1 G2 G3 Lymph nodes: Neg Pos
No. Oncological Failure/ Total No. (%)
p Value (log rank test) ⬍0.001
2/12 5/29 12/56 22/44 3/4
(16.7) (17.2) (21.4) (50) (75) 0.01
14/61 (23) 18/62 (29) 12/22 (54.6) 0.01 30/117 (25.6) 14/28 (50)
8 specimens with urethral involvement showed carcinoma in situ, 2 showed noninvasive papillary cancer and 3 showed invasive papillary or nonpapillary cancer. De Paepe et al suggested that these findings justified the continued performance of urethrectomy in conjunction with cystectomy in women with invasive bladder cancer. They were criticized that they did not provide any details regarding the localization of primary tumors in the bladder or secondary tumors in the urethra.9, 10 Coloby et al reviewed 47 consecutive step-section cystourethrectomy specimens of bladder cancer in female patients to determine the incidence and characteristics of urethral involvement.11 Urethral involvement was observed in only 3 of the 43 patients (7%) with transitional cell carcinoma. In all of these cases the bladder neck was involved. In addition, high stage (P3 or greater), high grade (grade 3), associated CIS in the adjacent bladder mucosa, and/or lymphatic and vascular invasion were detected in the cystectomy specimens of these women. Therefore, Coloby et al advocated the necessity of prophylactic urethrectomy in cases of papillary or papillarynodular tumors encroaching on the bladder neck and trigone. In other situations the urethra can be preserved in preparation for orthotopic bladder reconstruction. Stenzl et al found primary urethral tumor involvement in 2% of their study group of 356 female patients and in only 1% of patients with localized (T2-T3b N0M0) invasive cancer amenable to radical cystectomy.10 They correlated the incidence of primary urethral tumors with the various tumor locations in the bladder. The only significant and consistent risk factor for concomitant urethral involvement was simultaneous primary tumor involving the bladder neck
277
(p ⬍0.001). Tumors involving the trigone correlated only marginally with urethral tumor involvement. They concluded that a large caudal segment of the urethra could safely be spared in select female patients undergoing cystectomy and orthotopic urinary reconstruction to the remnant urethra. It is true provided that neither preoperative biopsies of the bladder neck nor intraoperative frozen sections of the urethra at the level of transection show any tumor or CIS. There was an apparently lower incidence of secondary urethral tumors in women than in men.6, 7 The investigators explained this observation by the fact that transitional cell mucosa in women covers a much smaller urethral segment with the remainder being normal or metaplastic squamous cell mucosa. Furthermore, the area covered with transitional epithelium decreases with advancing age since the line of demarcation between the transitional and squamous epithelium moves craniad during menopause. In the sixth and seventh decades of life the whole urethra, bladder neck and a portion of the trigone may be covered with metaplastic squamous cell mucosa.12 Stein et al performed a pathological review of the cystectomy specimens of 67 consecutive women undergoing radical cystectomy for transitional cell carcinoma of the bladder.9 Histological evidence of tumor (CIS in situ or overt carcinoma) involving the urethra was present in 9 patients (13%) and the bladder neck was involved in 17 (25%). All patients with urethral tumors had concomitant evidence of carcinoma involving the bladder neck. In this study patients with an uninvolved bladder neck also had an uninvolved urethra. In addition, tumor involving the bladder neck and urethra tended to be more commonly associated with high grade and stage, and node positive disease. Stein et al concluded that approximately 75% of women undergoing cystectomy for transitional cell carcinoma of the bladder may be appropriate candidates for orthotopic bladder substitution after excluding those in whom tumor involved the bladder neck. To our knowledge we report the first prospective study of the incidence of local urethral recurrence after radical cystectomy and orthotopic bladder reconstruction in women with the possible exception of a single case report.13 The 1.4% rate of urethral recurrence in the current study is low and comparable to that recently reported in men after radical cystectomy and neobladder reconstruction.14 In addition, the rate of local recurrence and/or distant metastasis in this study are comparable to those reported recently after radical cystectomy for bladder cancer.14, 15 The positive correlation of oncological failure in this study with pathological stage, tumor grade and lymph node status
FIG. 2. Disease-free survival after cystectomy in study group
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LOCAL URETHRAL RECURRENCE AFTER CYSTECTOMY
at cystectomy is well known and has been studied before.16 Although CIS was detected at the trigone in the cystectomy specimens in 1 of the patients with urethral recurrence, it was not detected in the other patient. Furthermore, trigonal CIS in the cystectomy specimens in our cases was not associated with a significantly higher local recurrence rate at followup compared with cases without trigonal CIS. High grade and involved lymph nodes at cystectomy in the second case may explain the development of metachronous urethral recurrence because a centripetal lymphatic tumor cell spread may occur caudal beside the urethra. However, because of the small number of patients who had local urethral recurrence and the relatively short followup we cannot draw solid conclusions concerning risk factors for urethral recurrence in this subset of patients. CONCLUSIONS
The incidence of local urethral recurrence after radical cystectomy and orthotopic bladder substitution in women is low and acceptable and, thus, it justifies the continued performance of this type of diversion. Proper selection of patients for this mode of diversion is mandatory. Close followup for oncological failure in this group is necessary after cystectomy. However, because of the small number of patients with urethral recurrence and the relatively short followup we cannot draw solid conclusions concerning risk factors for urethral recurrence. REFERENCES
1. Ali-El-Dein, B., El-Sobky, E., Hohenfellner, M. and Ghoneim, M. A.: Orthotopic bladder substitution in women: functional evaluation. J Urol, 161: 1875, 1999 2. Cordonnier, J. J. and Spjut, H. J.: Urethral occurrence of bladder carcinoma following cystectomy. J Urol, 87: 398, 1962 3. 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 4. Richie, J. P. and Skinner, D. G.: Carcinoma in situ of the urethra associated with bladder carcinoma: the role of urethrectomy.
J Urol, 119: 80, 1978 5. Coutts, A. G., Grigor, K. M. and Fowler, J. W.: Urethral dysplasia and bladder cancer in cystectomy specimens. Br J Urol, 57: 535, 1985 6. Hardeman, S. W. and Soloway, M. S.: Urethral recurrence following radical cystectomy. J Urol, 144: 666, 1990 7. Sto¨ ckle, M., Go¨ kcebay, E., Riedmiller, H. and Hohenfellner, R.: Urethral tumor recurrences after radical cystoprostatectomy: the case for primary cystoprostatourethrectomy? J Urol, 143: 41, 1990 8. De Paepe, M. E., Andre, R. and Mahadevia, P.: Urethral involvement in female patients with bladder cancer. A study of 22 cystectomy specimens. Cancer, 65: 1237, 1990 9. Stein, J. P., Cote, R. J., Freeman, J. A., Esrig, D., Elmajian, D. A., Groshen, S. et al: Indications for lower urinary tract reconstruction in women after cystectomy for bladder cancer: a pathological review of female cystectomy specimens. J Urol, 154: 1329, 1995 10. Stenzl, A., Draxl, H., Posch, B., Colleselli, K., Falk, M. and Bartsch, G.: The risk of urethral tumors in female bladder cancer: can the urethra be used for orthotopic reconstruction of the lower urinary tract? J Urol, 153: 950, 1995 11. Coloby, P. J., Kakizoe, T., Tobisu, K.-I. and Sakamoto, M.-I.: Urethral involvement in female bladder cancer patients: mapping of 47 consecutive cysto-urethrectomy specimens. J Urol, 152: 1438, 1994 12. Packham, D.: The epithelial lining of the female trigone and urethra. Br J Urol, 43: 201, 1971 13. Jones, J., Melchior, S. W., Gillitzer, R., Fichtner, J., El-Mekresh, M. and Thu¨ roff, J. W.: Urethral recurrence of transitional cell carcinoma in a female patient after cystectomy and orthotopic ileal neobladder. J Urol, 164: 1646, 2000 14. Yossepowitch, O., Dalbagni, G., Golijanin, D., Donat, S. M., Bochner, B. H., Herr, H. W. et al: Orthotopic urinary diversion after cystectomy for bladder cancer: implications for cancer control and patterns of disease recurrence. J Urol, 169: 177, 2003 15. Hautmann, R. E.: 15 Years experience with the ileal neobladder. What have we learned? Urologe A, 40: 360, 2001 16. Ghoneim, M. A., El-Mekresh, M. M., El-Baz, M. A., El-Attar, I. A. and Ashamallah, A.: Radical cystectomy for carcinoma of the bladder: critical evaluation of the results in 1,026 cases. J Urol, 158: 393, 1997