| Japanese Journal of Clinical Oncology | Pages |
Introduction
Materials And Methods
Results
Discussion
Acknowledgements
References
Involvement of the Anterior Urethra in Male Patients with Transitional Cell Carcinoma of the Bladder Undergoing Radical Cystectomy with Simultaneous Urethrectomy
Histological tumor extension into the prostate, urethra and ureters was examined in 52 specimens obtained by cystourethrectomy for transitional cell carcinoma of the bladder with one or more risk factors for urethral involvement. In four (21.1%) of 19 patients with diffuse carcinoma in situ in the bladder extending to the internal urethral orifice and prostatic urethra, the anterior urethra was affected by transitional cell carcinoma, including one specimen with invasion into the corpus spongiosum. However, none of 33 patients without these findings had synchronous anterior urethral transitional cell carcinoma involvement. It is recommended that patients with diffuse carcinoma in situ extending into the prostatic urethra undergo careful preoperative assessment of the anterior urethra before cystectomy. In other cases, the anterior urethra can be preserved and used for orthotopic neobladder replacement.
INTRODUCTION
Multifocal tumor development throughout the entire urinary tract is a well known biological characteristic of transitional cell carcinoma (TCC), particularly in the bladder. Recently, synchronous and asynchronous anterior urethral TCC in patients with bladder TCC has been discussed in relation to indications for neobladder replacement at the time of cystectomy (1-4). It has been reported that 4-17% of patients will develop recurrent anterior urethral TCC after cystectomy and the following clinicopathologic features have been associated with an increased risk of urethral recurrence (1,3-13): multifocal cancer, concurrent upper urinary tract tumors, diffuse carcinoma in situ (CIS), involvement of the bladder neck or trigone, involvement of the prostatic urethra or deep prostatic invasion, and positive urethral margins on intraoperative frozen sections. Although prophylactic urethrectomy has been recommended in the presence of these findings, there are discrepancies in the conclusions and recommendations of previous reports.
We have previously reported (12) an anterior urethral recurrence rate of 10.6% (18 out of 169 male cystectomy patients). Our multivariate analysis of risk factors for urethral occurrence revealed criteria similar to those summarized above. However, in our 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.
Using the above criteria, the majority of patients with bladder TCC have one or more risk factors for urethral recurrence and therefore should undergo simultaneous urethrectomy. However, as we showed in our previous report (12), synchronous anterior urethral TCC is seldom found even in the presence of one or more known risk factors for urethral recurrence. This finding suggested to us that strict application of these risk factors was useful only for patients who undergo cutaneous urinary diversion leaving the anterior urethra as a defunctionalized blind duct. In other words, these criteria may be invalid for neobladder replacement patients with preserved urinary flow in the retained urethra. This discrepancy raises the question of the mechanism of urethral extension of TCC and suggests that the criteria for prophylactic urethrectomy need to be reconsidered.
In this report, we analyze the correlation of diffuse CIS and multifocal bladder cancer with synchronous anterior urethral TCC. Through this analysis, we can select more candidates for preservation of the anterior urethra and orthotopic neobladder replacement and at the same time reconsider the mechanism of anterior urethral involvement by bladder TCC.
Between 1980 and 1996, 52 male patients ranging in age from 37 to 79 (mean 61) years with bladder cancer underwent radical cystoprostatectomy and simultaneous en bloc urethrectomy at the National Cancer Center Hospital. All patients had one or more of the risk factors for urethral recurrence mentioned above. Cystoprostatourethrectomy specimens were fixed in 10% buffered formalin. The entire area of the bladder, prostate and lower ureters were cut stepwise sagittally or transversely into sections 5-7 mm wide. The anterior urethra and bilateral distal ureters were also cut into stepwise sections, longitudinally or transversely along their axes. All specimens were stained with hematoxylin and eosin. Tumor extension into the ureter, internal urethral orifice, prostatic urethra, prostatic duct, prostatic stroma, membranous urethra and anterior urethra as well as the pathological characteristics of the bladder lesions were examined. The 52 patients were divided into four categories according to the characteristics of their bladder TCC (Table 1): a) 21 patients with diffuse primary CIS with or without microinvasion in the bladder. Before 1986, primary CIS cases with widespread lesions within the bladder were considered to be candidates for cystourethrectomy (5 cases). Since 1987, Bacillus Calmette-Guerin (BCG) instillation therapy has been our primary therapy for such cases. If the first or second trial of BCG therapy fails, cystourethrectomy is performed (3 cases). Whenever biopsies revealed multiple areas of microscopic submucosal invasion or prostatic urethral and/or lower ureteral involvement, cystourethrectomy was recommended (13 cases); b) 10 patients with nodular and/or papillary tumors with both adjacent and remote diffuse CIS; c) 10 patients with tumor having adjacent CIS and extending to the bladder neck with or without positive biopsies in the prostatic urethra and/or direct invasion of the prostate; d) 11 patients with numerous papillary and/or nodular tumors within the bladder. The correlation of the pathological characteristics of bladder TCC with synchronous anterior urethral involvement was analyzed. In order to clarify the clinical importance of diffuse CIS extending to the prostatic urethra, the 52 cases 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 (Table 2). In both groups of patients, anterior urethral involvement was examined. Tumor extension to the prostate, urethra and ureter according to the pathological characteristics of bladder TCC is shown in Table 1. Of 21 patients with diffuse primary CIS with or without microscopic invasion, four (19.0%) had abnormal findings in the anterior urethra. Of these four, three had CIS in the ureter. Three (14.3%) had CIS in the bulbar urethra extending from the prostatic and membranous urethra (Fig. Table 1
Table 2
Figure 1. Four cases of anterior urethral transitional cell carcinoma demonstrated by mapping of abnormal findings. In Figures 1a, b and c, diffuse spread of CIS with microinvasion in the bladder and involvement of CIS in both of the bilateral lower ureters and bulbar urethra are shown. In Figure 1d, invasive nodular cancer and CIS in the bladder and invasive TCC in the corpus spongiosum urethrae are shown. Solid areas, pT1b or deeper invasion; hatched areas, CIS; dotted areas, dysplasia.
Of 10 patients with nodular invasive tumor with both adjacent and remote diffuse CIS extending to the internal urethral orifice and/or prostatic urethra, one (10.0%) had TCC invasion of the penile urethral corpus spongiosum. This patients also had tumor extension to the internal urethral orifice and prostatic urethra as well as the left distal ureter (Fig. Therefore, four (21.1%) of 19 patients with diffuse CIS in the bladder with tumor extension to both the internal urethral orifice and prostatic urethra had synchronous malignant changes in the anterior urethra at the time of cystectomy (Table 2). Of these four, three had bulbar urethral CIS (Fig. Even when the bladder is sacrificed for cure of TCC, orthotopic neobladder replacement can make possible a natural voiding pattern and good quality of life if the urethra is safely preserved (14-16). However, simultaneous total urethrectomy should be considered for patients with a high risk of synchronous or asynchronous anterior urethral TCC. Assessment of risk factors for synchronous and asynchronous urethral cancer in patients with bladder TCC has been reported to aid appropriate selection of candidates for neobladder replacement (1-4,12-13). Retrospective analysis of cystectomy series revealed a correlation between specific pathological characteristics of bladder TCC and anterior urethral occurrence, including tumor multiplicity, existence of diffuse CIS, involvement of the internal urethral orifice and prostatic urethra, and particularly invasion into the prostatic ducts or stroma. However, this analysis was performed in patients who underwent cutaneous diversion, leaving a defunctionalized anterior urethra. It is doubtful whether these criteria are also valid for patients who will use the urethra for voiding. For example, anterior urethral occurrence was seldom observed in patients with superficial multiple tumors treated conservatively by transurethral resection or vesical instillation therapy, despite having multiple tumors at the internal urethral orifice (data not shown). Moreover, it has been reported that in patients undergoing neobladder replacement, the incidence of anterior urethral occurrence is lower than that in patients with cutaneous diversion (13). A further discrepancy that should be reconsidered is the low incidence of synchronous anterior urethral TCC at the time of cystourethrectomy even in patients having one or more risk factors for urethral involvement (12). A reconsideration of these risk factors is warranted in order to select appropriate candidates for neobladder replacement. First, we must clarify the risk factors for synchronous TCC involvement in the anterior urethra and second, we must reconsider the risk factors for asynchronous TCC recurrence in the anterior urethra when it is used for natural voiding. The former analysis is important in order to select high-risk patients who should undergo simultaneous urethrectomy. In our series of 52 cystourethrectomy specimens, 11 had multiple papillary tumors in the bladder and nine of these (81.8%) had tumor extension to the internal urethral orifice. However, none of the 11 had urethral or prostatic involvement. Of 10 specimens with nodular and/or papillary tumors with adjacent CIS, four showed prostatic stromal invasion and prostatic urethral extension of CIS. Also in this group of patients, none had an anterior urethral lesion. However, of 21 specimens showing diffuse primary CIS with or without microinvasion extending to the prostatic urethra, four (19.0%) had histologically abnormal findings in the anterior urethra, including CIS in three cases and severe dysplasia in the other. As a whole, four (21.1%) of 19 patients with diffuse CIS extending continuously to the prostatic urethra had TCC in the anterior urethra. Even in cases of extensive CIS within the bladder, as long as the distal margin did not extend to the prostatic urethra, the anterior urethra was free of cancer. Thus, if we select only high-risk patients, a substantial incidence of synchronous anterior urethral involvement is observed, although the incidence among all patients undergoing cystourethrectomy will be very low, as reported previously (1,12). These findings suggest the following mechanism of anterior urethral involvement by TCC. Continuous spread and/or tumor cell implantation on the distal urethra rather than multifocal neocarcinogenesis is the likely mechanism of tumor extension (17,18). In the bladder, frequent recurrence of TCC is observed. A recent investigation supports the possibility of a monoclonal origin of recurrent tumor cells (19). According to this hypothesis, asynchronous occurrence of anterior urethral TCC following cystectomy is explained as proliferation of tumor cells that were already present in the retained urethra immediately after cystectomy. Moreover, this hypothesis can explain the low incidence of synchronous urethral TCC even in patients with one or more risk factors, as well as the low incidence of asynchronous anterior urethral TCC in patients with neobladder replacement or bladder preservation treatment for superficial bladder cancer. One possibility is that mucus containing tumor cells covered the anterior urethral mucosa during the cystectomy procedure. In cases of cutaneous diversion, viable cancer cells may be retained and incubated in the urethra after cystectomy. On the other hand, if the urethra is used for voiding, these cancer cells are shed out by the flow of urine. Only cancer cells already implanted into the mucosal layer or invading into deeper layers will survive and progress to overt anterior urethral TCC. From this viewpoint, careful analysis of risk factors for synchronous TCC involvement in the anterior urethra is a crucial procedure for selecting good candidates for neobladder replacement. Indeed, even if risk factors for synchronous TCC in the anterior urethra are analyzed, it does not mean that risk factors for asynchronous TCC occurrence are completely elucidated. However, considering the low incidence of de novo anterior urethral TCC in men without bladder cancer, patients without risk of synchronous anterior urethral TCC will be good candidates for neobladder replacement. In conclusion, we have found that diffuse bladder CIS extending to the prostatic urethra is a sign of high risk for synchronous anterior urethral involvement. Patients having this risk factor should be distinguished from candidates who are suitable for neobladder replacement. Otherwise, preoperative anterior urethral wash cytology or multiple cold punch biopsies can be used to rule out tumor extension to the anterior urethra. This work was supported in part by a Grant-in-Aid from the Ministry of Health and Welfare, Japan, for the Second-term, Comprehensive 10-Year Strategy for Cancer Control.MATERIALS AND METHODS
RESULTS
Category
Internal urethral orifice
Prostatic urethra
Prostate gland
Urethra
Ureter
duct
stroma
bulbar
penile
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Diffuse CIS with or without microinvasion (21 cases)
14 (66.7)
13 (61.9)
9 (42.9)
1 (4.8)
4 (19.0)*
0 (0.0)
10 (47.6)
Nodular and/or papillary tumors with diffuse CIS(10 cases)
9 (90.0)
6 (60.0)
2 (20.0)
1 (10.0)
0 (0.0)
1 (10.0)[dagger]
3 (30.0)
Nodular and/or papillary tumors with adjacent CIS(10 cases)
10 (100)
4 (40.0)
0 (0.0)
4 (40.0)
0 (0.0)
0 (0.0)
0 (0.0)
Multiple papillary tumors in the bladder(11 cases)
9 (81.8)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Characteristics of bladder TCC
Cases
Anterior urethral involvement(%)
TCC
Dysplasia
Total
With diffuse CIS extension intothe prostatic urethra
19
4
0
4 (21.1%)
Without diffuse CIS extension intothe prostatic urethra
33
0
1
1 (3.0%)
DISCUSSION
Acknowledgements
References
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Last modification: 19 May 1998
Copyright© Japanese Journal of Clinical Oncology, 1997.
This page is run by Oxford University Press, Great Clarendon Street, Oxford OX2 6DP, as part of the OUP Journals
Comments and feedback: www-admin{at}oup.co.uk
Last modification: 19 May 1998
Copyright© Japanese Journal of Clinical Oncology, 1998.
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T. Tsukamoto, H. Kitamura, A. Takahashi, and N. Masumori
Treatment of Invasive Bladder Cancer: Lessons from the Past and Perspective for the Future
Jpn. J. Clin. Oncol.,
June 1, 2004;
34(6):
295 - 306.
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