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Year : 2015  |  Volume : 31  |  Issue : 4  |  Page : 349-353

Is frozen section analysis of the urethra at the time of radical cystectomy and orthotopic neobladder urinary diversion mandatory?

Department of Urology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

Date of Web Publication1-Oct-2015

Correspondence Address:
Anil Mandhani
Department of Urology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0970-1591.163309

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Introduction: This study was aimed at analyzing the need for routine use of frozen section analysis (FSA) before performing orthotopic neobladder (ONB) after radical cystectomy for carcinoma urinary bladder.
Materials and Methods: A total of 233 patients underwent radical cystectomy from January 2000 to June 2013. Of these, 151 (65.6%) patients were planned for ONB. In the initial 109 (72%) patients, FSA of urethral margin was performed, but, in the subsequent 42 (28%) patients, frozen section of urethral margin was not sent. Impact of hydroureteronephrosis, tumor size and location of tumor in relation to the bladder neck on the status of the urethral margin was analyzed.
Results: Only three of the 109 (2.7%) patients had a positive urethral margin. Two of them had ileal conduit and one, after negative re-resection, had ONB. Although none of the factors was found to be significant, all three patients with a positive urethral margin had growth at the bladder neck and died of cancer at a mean follow up of 29.33 ± 18.3 months, without urethral recurrence. Among the negative FSA (106), two patients had recurrence in the penile urethra. The mean follow-up was 46.3 ± 25.1 months. None of the patients without FSA (42) had urethral recurrence at the mean follow-up of 36 ± 9.3 months. Of the 28 patients who had their growth located at the bladder neck, three had positive FSA, while none with growth away from the bladder neck had positive FSA.
Conclusion: Routine FSA of the urethra before performing ONB can be avoided in those patients where the tumor does not reach the bladder neck.

Keywords: Cystectomy, frozen section, orthotopic neobladder

How to cite this article:
Sureka SK, Yadav A, Arora S, Kapoor R, Mandhani A. Is frozen section analysis of the urethra at the time of radical cystectomy and orthotopic neobladder urinary diversion mandatory?. Indian J Urol 2015;31:349-53

How to cite this URL:
Sureka SK, Yadav A, Arora S, Kapoor R, Mandhani A. Is frozen section analysis of the urethra at the time of radical cystectomy and orthotopic neobladder urinary diversion mandatory?. Indian J Urol [serial online] 2015 [cited 2023 Feb 5];31:349-53. Available from:

   Introduction Top

The standard management for muscle-invasive transitional cell carcinoma (TCC) and non-muscle-invasive TCC of bladder with a high risk of progression is radical cystectomy with pelvic lymph node dissection.[1],[2] Orthotopic neobladder (ONB) substitution is an accepted form of urinary diversion after radical cystectomy with a better quality of life as compared with cutaneous urinary diversion.[2],[3],[4],[5],[6]

There is a possibility of urethral recurrence after ONB substitution, compromising its functional integrity. The reported recurrence rate of urethra after radical cystectomy has a wide variation and ranges from 0.5% to 18%.[7],[8],[9],[10] In initial studies, prostatic involvement was considered as a significant prognosticator for urethral recurrence, but later on it was shown that despite a positive endoscopic biopsy from the prostatic urethra, if the resected margin of the urethra on frozen section analysis (FSA) was negative, then the urethral recurrence is unlikely even after 10 years of follow-up.[8],[11]

There is paucity of data on the robustness of intra-operative FSA, influencing the decision of urinary diversion. more often than not, the yield of FSA is lower than expected, and, in a majority of cases, it seems to be an unnecessary step. It is interesting to see that even a positive urethral margin on FSA does not predict the recurrence of TCC at the urethral stump.[12] This raises an important issue of performing a step as a routine when it may not be necessary. We analyzed our data to assess the need for FSA in patients of radical cystectomy planned for ONB.

   Materials and Methods Top

For this institutional ethics board approved study, data on radical cystectomy performed between January 2000 and June 2013 were retrieved from the hospital information system and internal data management source of our center. A total of 233 radical cystectomies were performed during the study period. Of these, 151 (64.80%) were planned for ONB. Till 2010, FSA was performed for presence or absence of malignancy at the urethra on the patient side. Based on the low yield of FSA, after 2010, this step was not performed as a routine and only those patients who had visible growth at the bladder neck had FSA. For statistical analyses, patients were grouped into three groups, i.e. patients with FSA and positive margin, patients with FSA but negative margin and those in whom FSA was not performed. Pathological characteristics of these groups were compared for local staging and presence or absence of carcinoma in situ.

A contrast-enhanced computed tomography (CECT) scan was performed for local staging. Imaging parameters like hydroureteronephrosis, tumor size at the time of presentation and site of the bladder tumor in relation to the bladder neck were assessed. Location of the tumor in relation to the bladder neck and trigone on CECT was matched with the findings on the cut-open specimen. Final histopathology was correlated with FSA and involvement of the prostate was documented. Patients were followed-up every 4 months with ultrasonography, serum creatinine, lower urinary tract symptoms, uroflowmetry, post-void residue and venous blood gas analysis.

Statistical analysis

Recurrence-free interval and overall survival were calculated using the Kaplan Meir curve. Survival curves for patients whose FSA was negative and patients who did not have FSA were compared with the log rank test. Binary logistic regression analysis was performed to analyze the effect of imaging parameters on the status of the urethral margin. All the statistical analyses were performed using SPSS 16 (Chicago, IL, USA).

   Results Top

The mean age of 151 patients who were planned for ONB was 56.3 ± 10.7 years. The male to female ratio was 14:1. The mean tumor size was 4.25 ± 1.6 cm. Pathological characteristics of patients in three groups are summarized in [Table 1]. Overall, 109 patients had FSA and 42 did not. The outcome and follow-up status are given in [Table 2]. Of those 109 patients, only three (2.7%) patients had a positive urethral margin. Two of them had ileal conduit diversion and one patient, after having a negative biopsy on the second FSA, had ONB. Although none of the factors, i.e. hydroureteronephrosis, tumor size and site, were found to be significant for predicting urethral margin status, all three patients with a positive urethral margin had tumor encroaching the bladder neck [Figure 1]. All the patients with a positive urethral margin died of cancer at a mean follow up of 29.33 ± 18.3 months, but none had urethral recurrence till the time of death. Patients who died of cancer had pelvic and/or distant metastasis.
Table 1: Pathological characteristics of the patients according to the urethral margin status

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Table 2: Outcome of the patients according to the frozen section analysis (FSA) of the urethral margin

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Figure 1: One of the patients with a positive urethral margin who had tumor involving the bladder neck (blue solid arrow)

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Overall, 34/151 (22.5%) patients had growth at the bladder neck on CECT. Of these, six tumors were actually found to be away from the bladder neck on the cut-open specimen. [Figure 2], [Table 3] The false-positive report of bladder neck involvement on CECT was 18%, (six of 34 cases). Therefore, only 28/138 (21.5%) patients had growth at the bladder neck [Table 3]. Of these 28 patients, three (10.7%) had a positive urethral margin and all these three patients had tumor involving the bladder neck.
Figure 2: Tumor involving the bladder neck on the contrast.enhanced computed tomography scan was found to be away from the bladder neck in the cut-opened specimen (white solid arrow)

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Table 3: Comparative results of bladder neck involvement found on CECT and during naked eye examination in the surgical specimen

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Regarding association of the urethral margin with the involvement of the prostate, it was found that of 141 male patients, 10 (7%) had their prostate involved but none had a positive urethral margin [Table 4]. Similarly, two male patients who had a positive urethral margin had no prostatic involvement. Location of the tumor at the bladder neck did not correlate with the involvement of the prostate (P = 0.983) [Table 4].
Table 4: Relationship between location of the tumor and the involvement of the prostate gland (n=128)

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The 1- and 5-year overall survival of patients with negative FSA were 91.5% (95% CI, 85–93.5) and 79% (95% CI, 72–84%), and of those in whom FSA was not performed were 93% (95% CI, 86–95%) and 82% (95% CI, 74–89%). This difference in survival was not significant (P = 0.726). [Figure 3] The mean follow-up times were 46.3 ± 25.1 months and 36 ± 9.3 months for the frozen section negative and not sent groups, respectively. None of the patients without FSA (42) had urethral recurrence at a mean follow-up of 36 ± 9.3 months.
Figure 3: Kaplan–Meir survival curve with log rank test comparing survival in patients with negative urethral margin and in patients in whom frozen was not sent

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Only two patients had recurrence in the penile urethra: One patient after 6 years and the other patient 2 years following ONB. In both the cases, the urethral biopsy was positive for malignancy but the neo bladder urethral junction was normal. Moreover, in both those men, FSA was negative.

   Discussion Top

The gold standard treatment for muscle-invasive or recurrent transitional carcinoma of the urinary bladder is radical cystectomy with urinary diversion.[1],[2] Among the various kinds of urinary diversions, ONB substitution provides the most natural way to void, with a relatively better quality of life.[13],[14]

The whole purpose of using an external sphincter as a continent mechanism for ONB would be defeated if there is recurrence in the urethra. Therefore, it is a standard practice to send the urethral margin for FSA before performing ONB to ensure that the urethral margin is negative. The reported rate of urethral recurrence after radical cystectomy has a wide variation, ranging from 0.5% to 18%.[7],[8],[9],[10] Involvement of the urethra can be due to synchronous or metachronous disease. As recurrence at the urethral stump is known even after having a negative margin, it seems likely that the reason for recurrence is not the status of margin assessed by the available means.

According to early reports, the most consistent risk factor in men for predicting urethral recurrence was the involvement of the prostate.[10],[15],[16] Although urethral recurrence was not common in patients with prostatic urethral involvement, prostatic ductal and stromal involvement were associated with the urethral recurrence, ranging from 10% to 67%.[15],[17],[18] Similarly, women with tumors located at the bladder neck or involving the anterior vaginal wall are at a higher risk for urethral recurrence.[19],[20],[21]

Later on, ONB substitution was perfromed even in patients who had involvement of the prostatic urethra (confirmed on endoscopic biopsy), provided the FSA showed a negative urethral margin.[11] After a minimum follow-up of 10 years, none of the patients had urethral recurrence. In another study of a similar kind, the positive and negative predictive values of the prostatic urethral biopsy prior to cystectomy were 12% and 99.9%, respectively.[14] They concluded that presence of tumor in the prostatic urethra prior to cystectomy would not preclude orthotopic neobladder substitution if the urethral frozen section is negative. Following these studies, intraoperative frozen section biopsy of the urethral margin became the pre-requisite for an ONB, disregarding the status of prostatic involvement.

Interestingly, that the rate of urethral recurrence in patient undergoing ONB has been found to be low. Although these studies are retrospective in nature, where bias of choosing a case with better tumor characteristics could be the reason, the inexplicable protective effect of ONB against recurrence at the urethral margin is quite evident.[8],[22] Freeman et al. published their series and concluded that patients with ONB have a lower risk of urethral recurrence than those who had cutaneous urinary diversion for TCC urinary bladder.[8] This protective effect of ONB for urethral recurrence was also demonstrated by Stein et al., by comparing urethral recurrence in 397 ONBs and 371 cutaneous urinary diversions.[22]

Although one would argue against not performing FSA, one needs to assess the overall impact of FSA in terms of decision making for or against the ONB. Urethral recurrences have also been reported with the negative urethral margin, the incidence of which has been described to range from 0.9% to 2.8%.[12],[14],[23] In one series, two of 13 patients with positive FSA had urethra recurrence as opposed to 13 recurrences in 222 patients who had negative FSA.[12] Therefore, the urethral margin status failed to accurately predict recurrence at the urethral stump. In the present study too, we had a very low yield of frozen section biopsy, wherein we had only 2.7% of positive FSA. All three patients died of their disease, but none had urethral recurrence at the time of death. Among the survivors also, we had only two urethral recurrences at the mid penile urethra, and both the patients had negative FSA as well.

Looking at the recurrence rate of less than 3% at the urethral stump and low positive predictive value of the frozen section, should we be performing FSA in all the patients? Moreover, an overall survival in patients where frozen was not sent was not different from those in whom frozen was sent and had a negative urethral margin.

Interestingly, in our study, although the location and size of the tumor and hydroureteronephrosis did not predict the status of the urethral margin, three patients who did have a positive urethral margin had tumors located at the bladder neck. In our experience, carcinoma in situ (CIS) changes are not found as frequently as reported in the literature; moreover, normal-looking mucosa on cystoscopy is unlikely to have CIS changes. Therefore, the concern of missing CIS is not real. None of the patients who had tumor away from the bladder neck showed a positive margin, and about 77.5% of our patients had growth away from the bladder neck. The cut-section of the specimen immediately after the cystectomy is a useful way to determine the location of the growth at the neck, as six of 34 (18%) cases had a false-positive report on CECT scan.

Involvement of the prostate in the radical cystectomy specimen in the present study was just 7%, as against 17% in one of the largest series on radical cystectomy.[22] None of the patients with prostatic involvement in the present series had a positive urethral margin, which contradicts the theory of synchronous involvement of the urethra. Visual impression of the specimen to determine the encroachment of tumor to the bladder neck, similar to the one we apply during partial nephrectomy, could be helpful in deciding against sending a routine frozen section.

Limitations of the study are relatively less number of patients with positive urethral margin and relatively short follow-up of those in whom we did not send the frozen section.

   Conclusions Top

This study questions the ubiquity of performing a step that is unlikely to help in decision making. In the majority of cases, FSA seems to be an unnecessary step and mere visual impression of the tumor and urethra could be helpful in deciding about sending the urethral margin for FSA. Only patients who have growth located at the bladder neck on the cut-open specimen should have FSA. This would save time and resources.

Financial support and sponsorship


Conflicts of interest

None declared.

   References Top

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Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S, et al. Radical cystectomy in the treatment of invasive bladder cancer: Long term results in 1,054 patients. J Clin Oncol 2001;19:666-75.  Back to cited text no. 2
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Freeman JA, Tarter TA, Esrig D, Stein JP, Elmajian DA, Chen SC, et al. Urethral recurrence in patients with orthotopic ileal neobladders. J Urol 1996;156:1615-9.  Back to cited text no. 8
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Levinson AK, Johnson DE, Wishnow KI. Indications for urethrectomy in an era of continent urinary diversion. J Urol 1990;144:73-5.  Back to cited text no. 10
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Donat M, Wei DC, McGuire S, Herr HW, et al. The efficacy of transurethral biopsy for predicting the long-term clinical impact of prostatic invasive bladder cancer. J Urol 2001;165:1580-4.  Back to cited text no. 12
Dutta SC, Chang SC, Coffey CS, Smith JA Jr, Jack G, Cookson MS. Health related quality of life assessment after radical cystectomy: Comparison of ileal conduit with continent orthotopic neobladder. J Urol 2002;168:164-7.  Back to cited text no. 13
Kassouf, Spiess PE, Brown GA, Liu P, Grossman HB, Dinney CP, et al. Prostatic urethral biopsy has limited usefulness in counseling patients regarding final urethral margin status during orthotopic neobladder reconstruction. J Urol 2008;180:164-7.  Back to cited text no. 14
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Tobisu KI, Tanaka Y, Mizutani T, Kakizoe T. Transitional cell carcinoma of the urethra in men following cystectomy for bladder cancer: Multivariate analysis for risk factors. J Urol 1991;146:1551-3.  Back to cited text no. 16
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Stein JP, Cote RJ, Freeman JA, Esrig D, Elmajian DA, Groshen S, et al. Indications for lower urinary tract reconstruction in women after cystectomy for bladder cancer: Pathological review of female cystectomy specimens. J Urol 1995;154:1329-33.  Back to cited text no. 19
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Stein JP, Esrig D, Freeman JA, Grossfeld GD, Ginsberg DA, Cote RJ, et al. Prospective pathologic analysis of female cystectomy specimens: Risk factors for orthotopic diversion in women. Urology 1998;51:951-5.  Back to cited text no. 21
Stein JP, Clark P, Miranda G, Cai J, Groshen S, Skinner DG, et al. Urethral tumor recurrence following cystectomy and urinary diversion: Clinical and pathological characteristics in 768 male patients. J Urol 2005;173:1163-8.  Back to cited text no. 22
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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3], [Table 4]

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