Japanese Journal of Clinical Oncology

INTRODUCTION

Multifocal tumor development in the entire urinary tract in time and space is a well-known biological phenomenon of transitional cell carcinoma (TCC), particularly in the bladder (1). Ureteral and urethral involvement of TCC needs serious consideration when cystectomy is necessary and reconstruction of the urinary tract is indicated. Synchronous and asynchronous urethral TCC in relation to bladder cancer in male and female patients is the subject of the present mini-review.

URETHRAL INVOLVEMENT IN MALE PATIENTS

In male patients, it has been reported that 4-18% of patients will develop recurrent urethral TCC in the remnant urethra after cystectomy (2-4). The reported incidence of urethral cancer varies in part because the method of analysis is different and sample size differs from report to report. Gowing (5) autopsied patients who died of bladder cancer and found carcinoma in situ (CIS) in the urethra in six of 33 autopsies (18%). Stockleet al. (6) observed urethral recurrences after radical cystoprostatectomy and found urethral recurrences in 23 of 251 patients (9.2%). Based on these findings, they recommended performing primary prophylactic urethrectomy. Cordonnier and Spjut (7) reported a series of 174 patients treated with cystectomy, of whom seven (4%) developed urethral cancer after 2-33 months. Their conclusion was again that urethrectomy should regularly accompany cystectomy. Ashworth (8) reported on 1307 patients with bladder cancer regarding concomitant urethral cancers. Fifty of 914 men (5.4%) with benign papillomatous lesions or cancer had urethral tumors that were preferably treated by fulguration. Recently, Erckertet al. (3) reported urethral tumor involvement in 910 patients treated for bladder cancer at a single institution over a period of 25 years. The overall incidence of urethral cancer in 2052 primary and recurrent bladder tumor events was 6.1%. Alken (9) reviewed the literature of similar problems and reported 18% of urethral recurrences with an average interval of three years after cystectomy. Thus, depending on the different standpoints of observation, the incidence of urethral cancer occurrence differs.

However, the following clinicopathological findings of bladder cancer in male patients have been reported as a kind of consensus to correlate with an increased risk of urethral recurrence (2-4,10-14): multifocal cancers in the bladder, concurrent upper urinary tract cancers, diffuse carcinoma in situ, involvement by cancer of the bladder neck or trigone, involvement of the prostatic urethra or prostatic ducts or prostatic tissue, and positive urethral margin on intraoperative frozen section. Prophylactic urethrectomy has been recommended in the presence of these findings in male patients. However, new discussion (15,16) regarding urethrectomy in relation to indications for neobladder replacement at the time of cystectomy has emerged.

URETHRAL INVOLVEMENT IN FEMALE PATIENTS

In female patients with bladder cancer, radical cystourethrectomy has been the standard procedure. This is because simultaneous urethrectomy with cystectomy is an easy and safe procedure from the standpoints of anatomy and radicality of cancer surgery. We (17) conducted a step-section analysis in female cystourethrectomy specimens and found involvement of the urethra in three (6.3%) of the 47 patients; all three patients with urethral involvement had bladder cancer involving the bladder neck. These findings indicated that female patients at high risk for involvement of the urethra should be excluded prior to orthotopic neobladder construction.

The incidence and characteristics of urethral involvement in female patients with bladder cancer have not been discussed in depth. Ashworth (8) reported a 1.4% incidence of urethral involvement during follow-up cystoscopy in 293 female patients. De Paepeet al. (18) examined 22 cystourethrectomy specimens from female bladder cancer patients and determined the frequency and extent of urethral involvement in 36% of the patients. A difference in incidence between our series (17) and De Paepe's series (18) is partly due to the difference in pathological stages of bladder cancer. Some investigators also reported cases of recurrence in the retained urethra after cystectomy in female patients (19). Stenzlet al. (20) observed that seven of 356 patients (2%) had urethral involvement during follow-up cystoscopies. Since the characteristics of the background of bladder cancer are different, presentation of the absolute incidence value alone has no meaning and that figure should be clearly related to the population studied. The low 1.4-2.0% incidence of urethral involvement reported by Ashworth (8) and Stenzlet al. (20) probably represents that of a general population of female bladder cancer patients, and the high 37% incidence (18) is a reflection of a highly selected population of deeply invasive bladder cancer.

Very recently, the risk of recurrence in the retained urethra after cystectomy in female patients was reported by Chenet al. (21). Of 115 patients who underwent radical cystectomy for TCC of the bladder, nine (8%) also had secondary TCC of the urethra, including two with concomitant involvement of the vagina or cervix. By logistic regression analysis, the sole significant risk factor for urethral involvement was bladder neck involvement. However, the important point of this report is that secondary urethral cancer without apparent bladder neck involvement was observed in two of nine patients.

MOLECULAR EVIDENCE INDICATING CLONAL ORIGIN OF MULTIPLE UROTHELIAL CARCINOMAS

Multifocal tumor development in the urinary tract has been hotly debated for a long time, whether it is due to multicentricity or implantation of cancers. Recently, several molecular studies strongly indicated that multifocal urothelial cancers are of single-cell origin, indicating implantation or seeding of cancer cells in the urinary tract. Sidranskyet al. (22) examined the pattern of X chromosome inactivation in four cystectomized female bladder cancer patients. In a total 10 cancers from three patients, it was found that the same X chromosome was inactivated in all the cancers from each patient, suggesting that each cancer arose from a single clone of cells. Habuchiet al. (23) also reported the monoclonality of multiple cancers in the renal pelvis, ureter and bladder using comparison of the mutation pattern of the p53 tumor suppressor gene. They observed identical p53 gene mutations, both in codon and base change, in heterotopic metachronous urothelial cancers, indicating that multifocal urothelial cancers are derived from a single progenitor cell. Similar reports (22,22) supporting monoclonality of multifocal cancers in the urinary tract indicate the possible seeding or implantation of bladder cancer cells to the retained urethra.

URETHRAL CANCER DEVELOPMENT WHEN URINE FLOW IN THE URETHRA IS PRESERVED

Our previous analysis (26) of 169 male patients who underwent radical cystectomy revealed that 18 (10.6%) experienced subsequent urethral cancer development within five years. Risk factors for urethral cancer by multivariate analysis were: (1) papillary cancers, (2) multiple cancers and (3) cancers arising in the bladder neck, prostatic urethra and prostatic tissue. Conversely, during the same period, we conducted 19 simultaneous urethrectomies with radical cystoprostatectomies in patients at higher risk for urethral recurrence. However, no remarkable histological changes were found in these patients' urethras when examined by step-sectioning. The variety of cancerous changes observed in the 18 patients with urethral recurrence is in sharp contrast to the simultaneously resected urethras of 19 patients with almost no cancerous changes. However, in our previous series of patients, the risk of diffuse CIS could not be evaluated because, before 1986, our patients with diffuse CIS in the bladder underwent prophylactic urethrectomy at the time of cystectomy. Consequently, we (27) re-analyzed the correlation of diffuse CIS and multifocal bladder cancers with synchronous urethral TCC.

Between 1980 and 1996, 52 male patients with bladder cancer underwent radical cystoprostatectomy with simultaneous en bloc urethrectomy at the National Cancer Center Hospital. All patients had one or more of the risk factors for urethral recurrence described above. Patients were 37-79 (mean 61) years old. For clarification of the clinical importance of diffuse CIS extending to the prostatic urethra, the 52 patients were divided into two categories: 19 with diffuse CIS in the bladder with tumor extension to both the internal urethral orifice and prostatic urethra, and 33 without these histological findings. Of these, four (21%) of 19 patients with diffuse CIS in the bladder extending to the internal urethral orifice and prostatic urethra had synchronous cancers in the anterior urethra at the time of cystectomy. On the other hand, none of the 33 patients without diffuse CIS extension to the prostatic urethra had anterior urethral TCC.

Freemanet al. (28) reported the urethral recurrence rate of 174 men with a Kock ileal neobladder and 262 with a cutaneous urinary diversion. Patients with a Kock ileal neobladder had a lower risk of urethral recurrence (2.9%) than those with cutaneous urinary diversion (11.1%), even when associated with a high-risk pathological condition predicting increased risk of urethral recurrence. They also pointed out that prostatic urethral involvement by cancer, particularly stromal invasion, significantly increased the probability of recurrence. Hautmannet al. (29) reported a 2% urethral recurrence rate in 211 patients, and Studeret al. (30) described a 6% rate in 100 patients who underwent radical cystectomy and ileal neobladder construction. We observed urethral recurrence in none of 217 patients who underwent multiple repeated transurethral resection (TUR) for superficial papillary bladder cancers (unpublished).

Findings by our own and other groups suggest that continuous spread and/or cancer cell implantation on the distal urethra, rather than multifocal tumorigenesis, is the likely mechanism of tumor extension. One possibility is that mucus covering the surface of the distal urethra may keep the cancer cells spilled in the urethra during the cystectomy procedure. When cutaneous diversion is performed, viable cancer cells may be kept and harvested in the retained urethra after cystectomy. Conversely, if the urethra is used for voiding, these cancer cells may be shed out by the flow of urine. Only cancer cells already implanted into the mucosal layer or invading into the deeper layer will survive and progress to overt urethral cancer thereafter. This is a hypothesis explaining the difference in the rate of urethral cancer between the defunctioned urethra without urine flow and the functioning urethra with urine flow.

HOW TO HANDLE THE URETHRA IN MEN AND WOMEN HAVING BLADDER CANCER IN AN ERA OF NEOBLADDER

It is necessary to carefully rule out male and female patients at high risk for urethral involvement or urethral recurrence. In male patients, prostatic urethral involvement and stromal invasion mainly due to CIS extension seem to be the most important risk factors. In female patients, bladder neck involvement by cancer seems most important. By excluding male and female bladder cancer patients having these characteristics for simultaneous urethrectomy, other patients are good candidates for reconstruction of the urinary tract by an orthotopic neobladder which will offer a good quality of life to bladder cancer patients after cystectomy.