Int J Clin Oncol (2013) 18:75 80 DOI 10.1007/s10147-011-0346-8 ORIGINAL ARTICLE Transurethral prostate biopsy before radical cystectomy remains clinically relevant for decision-making on urethrectomy in patients with bladder cancer Koji Ichihara Hiroshi Kitamura Naoya Masumori Fumimasa Fukuta Taiji Tsukamoto Received: 5 August 2011 / Accepted: 24 October 2011 / Published online: 8 November 2011 Ó Japan Society of Clinical Oncology 2011 Abstract Background This study retrospectively evaluated the clinical relevance of transurethral prostate biopsy (TUPB) before radical cystectomy by comparing the pathology of prostatic urethra biopsy specimens with that of cystectomy specimens. Methods Of 294 patients who underwent cystectomy and urinary diversion, 101 men with preoperative TUPB were included in this study. For these patients, if the result of TUPB was positive for urothelial carcinoma, we performed urethrectomy as a rule. If it was negative, we presented the option of urethral preservation and decided the final type of urinary reconstruction. The sensitivity, specificity, and positive and negative predictive values (PPV and NPV) of TUPB were assessed, and we investigated the number of final urethral recurrences. We also tried to identify which clinical and pathological findings by TUPB most accurately predicted the remaining in the prostate of cystectomy specimens. Results Of the 25 patients with positive TUPB, 18 had in the prostatic urethra or stroma of cystectomy specimens. There were 3 patients with negative TUPB but with involvement of the prostate in cystectomy specimens. Thus, TUPB achieved 86% sensitivity, 91% specificity, 72% PPV, and 96% NPV. Two patients (1.9%) had urethral recurrence in this period. Among the findings for TUPB, non-papillary tumors most accurately predicted the in the prostate of cystectomy specimens. K. Ichihara (&) H. Kitamura N. Masumori F. Fukuta T. Tsukamoto Department of Urology, Sapporo Medical University School of Medicine, S1, W16, Chuo-ku, Sapporo, 060-8543, Japan e-mail: kichi@sapmed.ac.jp Conclusions TUPB achieved a high NPV and the urethral recurrence rate was acceptable. If TUPB was negative, patients could have chance urethral preservation. Thus, our clinical decision for urethrectomy based on the result of TUPB is still useful. Keywords Bladder neoplasms Prostatic urethra Biopsy Cystectomy Patient selection Introduction Radical cystectomy with pelvic lymph node dissection and urinary diversion is the standard treatment for muscleinvasive and high-risk non-muscle-invasive bladder carcinoma. Previous reports have suggested that 0.5 18% of male patients will develop urethral recurrence after radical cystectomy [1 5]. Risk factors for recurrence include tumors located at the bladder neck, multifocal tumors, concomitant diffuse carcinoma in situ (CIS), a positive urethral margin, tumor in the prostatic urethra or prostatic stromal invasion, and non-orthotopic urinary diversion [6, 7]. In particular, diffuse bladder CIS extending to the prostatic urethra is a sign of high risk for synchronous involvement of cancer in the anterior urethra [8]. During the last 15 years, we have done simultaneous transurethral prostate biopsy (TUPB) together with standard transurethral resection of bladder tumors (TURBT) before cystectomy to determine the indication for urethrectomy in male patients. However, the clinical significance of this biopsy before radical cystectomy is controversial. Several studies have indicated that intraoperative frozen section pathology of the urethral margin during cystectomy is more reliable for determining the indication for urethrectomy [9, 10].
76 Int J Clin Oncol (2013) 18:75 80 Here we retrospectively compared the pathological results of radical cystectomy specimens with those of TUPB, and investigated the final urethral recurrence. Moreover, we reassessed the clinical relevance of TUPB. Our study confirmed that the procedure is still clinically useful for the selection of appropriate patients for urethrectomy. Patients and methods We had 294 male and female patients who received radical cystectomy with urinary diversion for bladder carcinoma from January 1990 to December 2006. Of the 234 male patients, 101 were included in this study after exclusion of 10 with cystectomy for the purpose of maintaining quality of life, 62 with neoadjuvant chemotherapy, 17 with a previous history of or simultaneous association with urothelial carcinoma (UC) in the upper urinary tract, 11 with UC in the prostate that directly invaded from the bladder, 31 without TUPB, and 2 with incomplete medical records. Among the 62 male patients with neoadjuvant chemotherapy, 39 with TUPB were separately evaluated. Institutional review board approval was obtained for the study. All patients had preoperative standard evaluations for extension and the clinical state was determined according to their results. The stage of the bladder cancer was determined using the 2002 revision of the TNM [11]. Radical cystectomy was indicated for patients with highgrade non-muscle-invasive UC or those with muscleinvasive UC who had no apparent pelvic lymph node involvement or distant metastasis. At our hospital, we performed TUPB together with TURBT to assess whether the urethra could be preserved. In the case of positive shown by TUPB, we basically performed urethrectomy together with cystectomy to avoid urethral recurrence. On the other hand, if the result of TUPB was negative, the urethra was preserved. The technique for the prostate biopsy is to resect the prostatic urethra transurethrally at the 5 and 7 o clock positions from the bladder neck to the verumontanum. We confirmed sufficient resection of the prostatic stromal tissue as well as the mucosa of the urethra. We determined the sensitivity and specificity, positive predictive value (PPV), and negative predictive value (NPV) of TUPB based on the final pathology of cystectomy specimens. UC in the prostatic urethra was defined as in the mucosa or stroma of the prostate that was separately present from the bladder lesion. This is because urethrectomy is usually done together with cystectomy, based on the fact that extending directly to the urethra from the bladder is a high-risk condition for urethral recurrence when the urethra is preserved. In this study, 11 patients were excluded from the final examination for this reason. As indicated above, 39 patients with neoadjuvant chemotherapy were evaluated separately because chemotherapy may have influenced the final pathology results. MVAC therapy, consisting of methotrexate, vinblastine, doxorubicin and cisplatin, was given with a median of 2 courses. We also evaluated the clinicopathological variables of TUPB, which might be useful in predicting remaining UC involving the prostate or prostatic urethra in cystectomy specimens. These variables were the configuration of the dominant tumor (papillary or non-papillary), tumor grade (grade 3 or \3 grade), tumor located at the bladder neck (yes or no) and prostatic urethra (yes or no), tumor extension to the prostatic stroma in TUPB (yes or no), concomitant CIS (yes or no), and previous recurrence (yes or no). After surgery, patients were followed up with routine blood tests, computed tomography from the lung to pelvis and a bone scan (if indicated) to assess recurrence of the. Surveillance of urethral recurrence was performed via history and physical examination. If patients had bleeding from the preserved urethra, washing cytology with endoscopic examination was indicated. If patients with a neobladder had hematuria, endoscopic examination of the lower urinary tract was indicated. Image diagnosis of the upper urinary tract was also indicated if necessary. Statistical analysis was done using the chi-squared test and Fisher s exact test. Differences were considered significant at P \ 0.05. Results Patients characteristics The characteristics of patients are summarized in Table 1. The median follow-up period was 44 months, ranging from 1.4 to 175 months. A total of 25 of the 101 patients (24.7%) were identified as having UC in the prostatic urethra before cystectomy, whereas the final pathological examination of cystectomy specimens revealed that the remained in the urethra in 21 patients (20.7%). Results of TUPB and the status of the urethral margin in cystectomy specimens Among the 25 patients positive for UC in the prostatic urethra or stroma by TUPB, 18 (17.8%) had that remained in the same area of cystectomy specimens (Table 2). There were 3 patients (2.9%) with negative TUPB but with involvement of the prostate in cystectomy
Int J Clin Oncol (2013) 18:75 80 77 Table 1 Patients characteristics Age (years), median, (range) 68 (44 83) Clinical stage, n (%) BT1 10 (10) T2 33 (33) T3 33 (33) T4 25 (25) Concomitant carcinoma in situ 7 (7) Tumor grade, n (%) Grade 1 0 Grade 2 24 (24) Grade 3 75 (75) Unclear 2 (2) Pathological stage, n (%) BT1 34 (34) T2 12 (12) T3 20 (20) T4 17 (17) N(?) 18 (18) Type of urinary diversion, n (%) Ileal conduit 68 (67) Ileal neobladder 29 (29) Others 4 (4) Table 2 Disease status in the prostate specimens obtained by TUPB and radical cystectomy Prostate specimens from TUPB with positive with negative Total no. of patients Prostate specimens from radical cystectomy with positive TUPB transurethral prostatic biopsy with negative 18 7 25 3 73 76 21 80 101 Total no. of patients specimens. Thus, the sensitivity of TUPB for the was 86%, specificity 91%, PPV 72%, and NPV 96%. No patients were diagnosed as having a positive urethral margin in cystectomy specimens. Among the 3 patients with negative UC in the prostate by TUPB but positive in cystectomy specimens, one died of cancer-related peritonitis 1 month after cystectomy. The other two patients had no recurrence of the during the follow-up period (62 and 74 months, respectively). Table 3 Predictive factors for UC remaining in the prostatic urethra and stroma of cystectomy specimens in 25 patients with positive TUPB Variables identified by TUPB UC-positive in Cx specimen (18 patients), n (%) UC-negative in Cx specimen (7 patients), n (%) Variables for prediction of UC that remained in the prostatic urethra and stroma of cystectomy specimens in patients with positive TUPB Table 3 shows the results of statistical analysis. In the clinicopathological findings of TUPB before cystectomy, the configuration of the main tumor most accurately predicted whether the remained in the prostatic urethra or stroma of cystectomy specimens (P = 0.03). Concomitant CIS and a history of recurrence were found only in patients with positive UC in cystectomy specimens. Impact of neoadjuvant chemotherapy on the final pathology P value a Tumor grade Grade 3 14 (78) 5 (71) [0.99 \Grade 3 4 (22) 2 (29) Configuration of tumor Non-pap. 12 (67) 1 (14) 0.03 Pap. 6 (33) 6 (86) Tumor at bladder neck Yes 14 (78) 6 (86) [0.99 No 4 (22) 1 (14) Tumor extension to prostatic stroma Yes 7 (39) 2 (29) [0.99 No 11 (61) 5 (71) Visible tumor at prostatic urethra Yes 11 (61) 3 (43) 0.66 No 6 (39) 4 (57) Concomitant CIS Yes 5 (28) 0 0.27 No 13 (72) 7 (100) History of recurrence Yes 7 (39) 0 0.13 No 11 (61) 7 (100) UC urothelial carcinoma. TUPB transurethral prostatic biopsy, nonpap. non-papillary, pap. papillary, Cx radical cystectomy, CIS carcinoma in situ a Fisher s exact test A total 39 patients with TUPB received neoadjuvant chemotherapy before cystectomy. Of the 8 patients who were positive for UC in the prostatic urethra or stroma by TUPB, only 1 had that remained in the same area of cystectomy specimens. There were 4 patients with negative
78 Int J Clin Oncol (2013) 18:75 80 TUPB but with involvement of the prostate in cystectomy specimens. The sensitivity and PPV decreased to 20 and 12.5%, respectively, but the specificity and NPV remained at 79 and 87%, respectively. Final urethral recurrence Of the 101 patients, 2 (1.9%) had urethral recurrence after cystectomy. One patient was positive for the by TUPB, and received urethrectomy with cystectomy, and pathological examination showed that no remained in the specimen. However, UC recurred in the meatus of the glans at 7 months after surgery. The other patient was negative for the by TUPB and no was detected in cystectomy specimens of the prostate. However, UC recurred in the preserved urethra at 24 months after cystectomy and ileal conduit. These 2 patients received resection of the urethral remnant or urethrectomy after diagnosis, but died of the at 41 months and 48 months after urethrectomy, respectively. Discussion UC in the prostatic urethra and stroma is one of risk factors for postoperative urethral recurrence and it is important to evaluate this area before cystectomy. UC in the prostatic urethra or stroma is clearly associated with the clinical courses of patients [12 16]. However, because not all patients develop urethral recurrence, we need to identify appropriate candidates to avoid unnecessary urethrectomy. We performed TUPB for evaluation of the prostatic urethra and stroma when the standard TURBT was done. If the patient was positive for UC according to the results of TUPB, we performed urethrectomy together with cystectomy. In this study, the prostate biopsy achieved 72% PPV and 96% NPV. These results suggested that TUPB was a relevant examination for identifying that remained in the prostate of cystectomy specimens. Thus, when TUPB is negative, preservation of the urethra is highly possible without compromising the patient. This situation allows us to safely recommend orthotopic urinary diversion for patients, because the final pathology of the prostatic urethra and stroma of the cystectomy specimen will be negative for the. It is said that orthotopic urinary diversion may have favorable aspects from the point of view of body image and almost normal voiding condition [17]. In addition, patients and urologists as well are more comfortable when they know whether the urethra can be preserved and can determine the type of urinary diversion before cystectomy. On the other hand, previous reports suggested a low efficacy of TUPB, and supported the relevance of examining intraoperative frozen sections of the urethral margin [9, 10]. Lebret et al. [10] reported that they performed TUPB and also obtained frozen sections from 118 patients, and 9 patients had positive TUPB but negative frozen sections. Based on these results, these 9 patients did not receive urethrectomy. However, none of them had urethral recurrence for 10 years after surgery, and none of the patients with negative frozen sections were positive for TUPB. Kassouf et al. [9] reported that, in 22 of 177 (among 252) neobladder patients who received TUPB, tumors were detected at the prostatic urethra, but only one patient had a tumor at the urethral margin of a radical cystectomy specimen (non-prostatic region). Donat et al. [18] reported that TUPB could not evaluate tumor invasion of the prostate precisely because it had a low PPV (about 21.7 52.8% in their report) and did not reflect urethral recurrence. However, our results support the clinical relevance of TUPB for decision-making on urethral preservation. As described above, we found two patients with urethral recurrence. It is said that the TUPB result does not reflect urethral recurrence precisely. The rate of recurrence in the current study was not significantly different from those of previous studies. Thus, the clinical decision for urethral preservation based on the TUPB result does not generate a clinical disadvantage for patients who receive radical cystectomy. Moreover, 72% PPV does not necessarily imply low clinical relevance for TUPB. That is, if TUPB produces a positive result, there will be a nearly 30% chance for patients to have no in cystectomy specimens. The incidence of the in the prostate according to the cystectomy specimen may depend on the examination method. When a whole mount pathology section is used for this purpose, the incidence increases to 40% [19, 20], although routine pathology yields 20% [21 23]. Therefore, we emphasize the significance of NPV rather than PPV. If the result of TUPB was negative, UC in the prostatic urethra of the cystectomy specimen was negative with high probability. In addition, if the urethra was preserved based on the negative TUPB result, recurrence in the preserved urethra was also highly unlikely. Whatever the procedure is, all we need to do is to identify patients who are very unlikely to have urethral recurrence, which provides patients with more opportunities for urethral preservation and thus for orthotopic urinary reconstruction. At present, our clinical practice may recommend preservation of the urethra and orthotopic urinary reconstruction when TUPB is negative. When TUPB is positive, urethrectomy is basically proposed for patients. However, in this situation, intraoperative frozen sections of the urethral margin may be a practical way to make a final decision if patients strongly desire urethral preservation and orthotopic urinary reconstruction. In this study, we also investigated PPV and NPV in patients who received neoadjuvant chemotherapy. PPV
Int J Clin Oncol (2013) 18:75 80 79 was low (12.5%), but NPV was comparatively high (87%). The chemotherapy may have induced downstaging of the in these patients. In fact, of 8 patients with positive TUPB, 7 were negative for UC of the prostatic urethra in the final pathology and 5 had pt0 or pt1 in the final specimen. However, in patients with neoadjuvant chemotherapy, there were 4 patients who were negative in TUPB but positive in cystectomy specimens. Thus, we need further study to determine the impact of chemotherapy on in the prostatic urethra. Finally, we tried to identify specific clinical features of patients who were revealed to have UC in the prostatic urethra of cystectomy specimens among those who had a positive TUPB. Mazzucchelli et al. [24] reported that tumor diameter ([5 cm), a tumor located at the bladder neck and a history of recurrence were risk factors for positive UC in the prostatic urethra of cystectomy specimens. In our study, a non-papillary tumor was such a factor. If we establish risk factors more concretely, these together with the result of TUPB will select more appropriate patients who really need urethrectomy. The limitations of our study include the small number of patients and its retrospective nature. In addition, patients without TUPB were excluded from the study. These may have contributed to a potential selection bias of the study. Thus, a prospective study with a larger number of patients will be needed to reach a final conclusion. Conclusions We evaluated the clinical relevance of TUPB before cystectomy in this study. TUPB achieved a high NPV and the number of final urethral recurrences was acceptable. Thus, a clinical decision on urethrectomy based on the result of TUPB is still useful. Our clinical practice may recommend preservation of the urethra when TUPB is negative. 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