Urethral recurrence after cystectomy: current preventative measures, diagnosis and management

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1 Urethral recurrence after cystectomy: current preventative measures, diagnosis and management Yvonne Chan*, Patrick Fisher*, Derya Tilki* and Christopher P.Evans* *Department of Urology, Medical Center, University of California, Davis, Sacramento, CA, USA Y.C. and P.F. contributed equally to this work. To summarise the current literature on the diagnosis and management of urethral recurrence (UR) after radical cystectomy (RC), as UR after RC is rare but associated with high mortality. With the recently increased use of orthotopic bladder substitution and the questionable benefit of prophylactic urethrectomy, identification of patients at high risk of UR, management of the remnant urethra, and treatment of UR become critical questions. A review of the PubMed database from 1980 to 2014 was performed to identify studies evaluating recurrent urothelial cancer of the urethra after RC. The search terms used included urethral recurrence, cystectomy or cystoprostatectomy. Selected studies provided information on the type of urinary diversion performed, the incidence of UR, and the time to UR. Incidence of UR after RC ranges from 1% to 8% with most recurrences occurring within the first 2 years after surgery. Increased risk of UR is associated with involvement of the prostate, tumour multifocality, bladder neck involvement, and cutaneous diversion. The median overall survival after UR ranges from 6 to 54 months and the 5-year disease-specific survival after UR is reported to be between zero and 83%. UR remains a relatively rare event. Current literature suggests that urethral wash cytology may be useful in patients with intermediate- to high-risk of recurrence to enable early detection of non-invasive disease, which may be amenable to conservative therapy before urethrectomy. Keywords urethral recurrence, review, urothelial carcinoma and urethrectomy Introduction When radical cystectomies (RCs) were first performed in the 1950s to treat bladder tumours, prophylactic urethrectomy was a common practice in men with risk factors for urethral recurrence (UR) including the presence of multiple tumours, diffuse carcinoma in situ (CIS), and upper tract disease [1]. En bloc urethrectomy and anterior pelvic exenteration were also performed routinely in women until the 1990s due to concerns for urethral tumour involvement given the female urethra s short length and its proximity to the bladder neck [2]. This practice was in part based on the presumed lack of function of the residual urethra and poor survival of patients with UR [3]. However, the advent and increased use of orthotopic bladder substitutions (OBS) combined with the questionable survival benefit of prophylactic urethrectomy have made this practice more selective in recent years. This change has led to the questions of who is at risk for UR and when prophylactic urethrectomy should be performed. Furthermore, the decrease in prophylactic urethrectomy has yielded a population of patients at risk of UR. How these patients should be followed and how they should be managed should UR be detected become critical questions. Given its rarity, recurrent urothelial cancer of the urethra after RC poses diagnostic and therapeutic challenges. To date, no definitive treatment guidelines exist for the surveillance of the urethra after RC or the management of UR after diagnosis. Here we offer a review of current preventative measures and diagnostic and management practices for UR. Patients and Methods A review of the PubMed database from 1980 to 2014 was performed to identify studies in the English language evaluating recurrent urothelial cancer of the urethra after RC (Fig. 1). The search terms used included urethral recurrence, cystectomy or cystoprostatectomy. The search yielded 427 articles. The available abstracts of these articles were screened for relevance and 363 articles were discarded. In all, 64 full text articles were reviewed. The 17 selected studies provided information on the type of urinary diversion performed, the incidence of UR, and the time to UR. BJU International 2015 BJU International doi: /bju BJU Int 2016; 117: Published by John Wiley & Sons Ltd. wileyonlinelibrary.com

2 Fig. 1 Preferred Reporting Items for Systematic s and Meta-analysis (PRISMA) flowchart. Records identified through Pubmed database search (n=469) Records after duplicates removed (n=427) Records screened for relevance (n=427) Full text articles assessed for eligibility(n=64) Studies included (n=17) Results Records excluded (n=363) Full text articles excluded (n=47): Duplicated dataset (n=2) articles (n=18) Did not meet criteria (n=27) The Incidence of and Risk Factors for UR The average incidence of UR after RC as reported in contemporary RC series is between 1% and 8% [4 18]. Incidence in women is lower than in men, with studies reporting incidences of UR to be 2 4% in women vs 2 6% in men [4,5,7,10,14,17,19]. The lower incidence in women may be explained by the fact that squamous cell mucosa is more predominant in the female urethra [20]. Most URs occur within the first 2 years after surgery, with median times to UR in large series ranging from 8 to 28 months [4 6,13,16 19]. However, a few earlier series reported slightly higher rates of UR up to 11 13% [19,21], and an earlier metaanalysis in 2002 reported an average rate of 8.1% [20]. Table 1 summarises RC series reporting on UR [4 6,8 19,21]. The factors associated with increased risk of UR include type of bladder substitution, involvement of the prostate in men, tumour multifocality [22], bladder neck involvement, and anterior vaginal wall invasion in women [23]. Type of Bladder Substitution Most authors who have compared the risk of UR in patients treated with OBS vs cutaneous diversion have noted that OBS is associated with decreased risk of UR [4 6,10,11,19]. The series reported by Huguet et al. [5] of 729 men, identified 34 URs and a higher rate of UR with cutaneous diversion (5.6%) than with OBS (2.2%), which tended toward but did not reach statistical significance (P = 0.073). In this case, the authors could not exclude patient selection as a cause because the cutaneous diversion arm had more cases with prostate involvement and prior history of non-muscle-invasive bladder cancer (NMIBC), which are independent risk factors for UR. Indeed, the selection of healthier patients with less advanced disease for OBS could have explained these findings. However, when Stein et al. [6] evaluated a series of 768 men and 45 cases of UR, there were significantly more URs in those who had cutaneous diversion (8%) compared with those who had OBS (4%), even after controlling for pathological characteristics such as CIS, multifocality, tumour grade, pathological stage, and prostatic involvement. In one of the largest series to date reporting specifically on UR, Boorjian et al. [4] reviewed the cases of 1506 men and women who underwent RC (16% OBS and 83% cutaneous diversion) and identified 85 URs. They also noted a significantly higher risk of UR in patients who underwent cutaneous diversion (6.4%) compared with OBS (2.1%) after controlling for date of operation, smoking history, tumour stage, CIS, multifocality, and prostatic tumour involvement. There is no proven mechanism to explain this difference, although some have postulated that having urine in contact with remnant urothelium may be protective, while others have attributed it to selection bias, because patients with more favourable disease tend to receive orthotopic diversion. Another postulation was the juxtaposition to ileum, which may prevent UR [19]. Prostatic Involvement and Tumour Multifocality Prostatic involvement and tumour multifocality may also predict UR [1,24]. Huguet et al. [5] showed that previous history of NMIBC, NMIBC subgroup (ptis, pta, pt1), or any prostate tumour involvement were significant independent predictors of UR, with odds ratios (ORs) of 4.47, 3.3, and 5.6, respectively. In particular, non-invasive prostate involvement (ptis, ducts, papillary) was highly predictive of UR (OR 9.9). Of 54 patients in the series with non-invasive prostate involvement, 24% developed UR. Although Stein et al. [6] observed that the presence of CIS and tumour multifocality tended to be associated with increased risk of UR (risk ratio 1.77, P = 0.07; and 1.89, P = 0.06, respectively), this finding did not reach significance. They found an estimated 5-year likelihood of UR of 5% without prostate involvement and 12% and 18% with non-invasive and invasive prostate involvement, respectively. Finally, Boorjian et al. [4] identified prostatic urethral involvement at RC (hazard ratio [HR] 4.89) and bladder tumour multifocality (HR 2.34) as being independently associated with UR. Importantly, none of the aforementioned studies 564 BJU International 2015 BJU International

3 Urethral recurrence after cystectomy Table 1 Summary of studies reporting UR after RC for bladder cancer. References Year Total N Number of women Number of patients with orthotopic diversion Orthotopic UR, n (%) Number of patients with cutaneous diversion Cutaneous UR, n (%) Median (range) months to UR Median follow-up, months Freeman et al. [19] (2.9) (11.1) 19 (NR) 72 Yossepowitch et al. [8] (1.4) 0 NA NR 32 Yamashita et al. [21] (13.7) 0 NA 22 (NR) 60 Varol et al. [9] NR (4) 0 NA 14 (3 70) NR Hassan et al. [10] (0.5) (2.1) 66 (NR) 30 Nieder et al. [11] (0.9) (6.4) 12.8 (3 38) 34 Stein et al. [6] (4) (8) 25 (6 115) 156 Yoshida et al. [12] (5) 0 NA 28 (6 45) 60 Studer et al. [13] (5) 0 NA 14 (3 158) 32 Huguet et al. [5] (2.2) (5.6) 14 (NR) 38 Cho et al. [15] NA (4.4) 17 (6 63) 54 Taylor et al. [14] (2.3) 0 NA 29 (9 36) 144 Boorjian et al. [4] (2.7) (6.4) 13.3 (IQR 6 23) 152 Perlis et al. [16] (3.8) (2.7) 28 (8 96) 45 Hrbacek et al. [17] (2.6) 0 NA 8 (4 55) 64 Mitra et al. [18] NR** NR NR NR 36 (1.8) 25 (22 28) 144 NR, not reported; IQR, interquartile range. **55 total recurrences reported in this study, six in women but the distribution of OBS vs cutaneous diversions in the cohort is not reported. have found an association between tumour grade or pathological stage and UR. The finding that prostatic involvement might predict UR prompted investigation of pre- RC prostate biopsy as a means for predicting UR [25 30]. If pre-rc prostate biopsy results predicted UR, then biopsy might help guide surgical management of the urethra. In the only prospective study of this subject, 118 men systematically underwent transurethral biopsies of the lateromontanal prostate (4 and 8 o clock positions from the bladder neck to the verumontanum) 2 weeks preoperatively and frozen urethral sectioning at the time of RC. In 12 patients, carcinoma was found on both preoperative biopsy and frozen section, and urethrectomy was performed; however, of the remaining patients with negative frozen sections, nine had positive preoperative biopsies. The authors concluded that only a positive frozen section should indicate a prophylactic urethrectomy [26]. Retrospective investigations have led to similar conclusions [28 31]. Ichihara et al. [28] reported in a series of 101 men with a pre-rc transurethral prostate biopsy that biopsy achieved 85% sensitivity, 91% specificity, a 72% positive predictive value and 96% negative predictive value (NPV). Kassouf et al. [29] studied 245 cases with available pre-rc biopsies and found a similarly high NPV of prostate biopsy (99%) but noted that the NPV of frozen section was 100%. Finally, Gaya et al. [30] recently evaluated 234 men who underwent pre-rc prostate biopsy with either cold cup (49%) or transurethral (41%) biopsies. Although a negative biopsy did predict a negative urethral margin, an alarming 29% of patients who underwent urethrectomy at the time of RC based on a positive prostate biopsy ended up having a negative prostatic urethra on final pathology. No differences were found between the biopsy techniques in their predictive values, sensitivity or specificity. Therefore, although prostatic biopsy is highly predictive of negative final pathology, it is probably not better than frozen section and carries the significant risk of false positive results, which may be used to plan concurrent radical urethrectomy at the time of RC. Risk Factors for UR in Women UR is less well understood in women as en bloc urethrectomy during RC had been a common practice until relatively recently. Now, an improved understanding of the functional anatomy of the female urethra and the advent of the nervesparing dissection technique have improved urinary continence and sexual function after OBS, making it a viable and more common procedure. This evolution has prompted further investigation of risk factors for UR in women [2]. In women, bladder neck and anterior vaginal wall involvement have been associated with increased risk for urethral tumour [32]. Stein et al. [33] examined 67 women who underwent RCs for TCC of the bladder. Involvement of the anterior vaginal wall was associated with tumour at the bladder neck, and presence of tumour in the bladder neck was highly associated with urethral involvement (P < 0.001). About 50% of these cases had urethral involvement. Association between bladder neck involvement and urethral involvement was further demonstrated by Chen et al. [23] who retrospectively reviewed 115 cases of women who underwent RC for TCC of the bladder. Nine patients (8%) had urethral tumour involvement. Bladder neck involvement was found to be the sole risk factor for urethral involvement (P < 0.001). Interestingly, two patients with urethral involvement did not have bladder neck involvement, supporting the need for BJU International 2015 BJU International 565

4 intraoperative frozen section analysis of the proximal urethral margin. Urethrectomy The rate of urethrectomy for prophylaxis, positive intraoperative margins, or metachronous recurrence is 8.1% [34]. Nelles et al. [34] reviewed data for 2401 men who underwent radical cystoprostatectomy between 1991 and In all, 195 underwent urethrectomy, of which 103 cases were performed simultaneously with RC or staged. The study did not differentiate whether these were for positive margins or prophylactic for high-risk disease. In all, 92 cases were delayed (>6 weeks after RC) and occurred at a median of 9 months after RC. They were presumed to be salvage urethrectomies. The study found that stage of disease was the only significant predictor of urethrectomy (P < 0.001). Not surprisingly, there was a high proportion of Stage IV disease in the immediate urethrectomy group (33% of the group), but there was also a high incidence of Stage I disease in the delayed urethrectomy group, which the authors presumed was due to multifocal disease or CIS. The incidence of concurrent urethrectomies was lower at teaching hospitals (OR 2.60, 95% CI ), which may have been due to increasing cases of OBS at these locations compared with community hospitals [34]. The decision of immediate vs staged urethrectomy is based largely on surgeon preference, with consideration of patient co-morbidities and indication. Spiess et al. [35] demonstrated that immediate urethrectomies were usually performed for prostatic involvement during staging transurethral resection (TUR), whereas staged urethrectomies were for positive urethral margins or prostatic stromal involvement. It is important to note that patients with confirmed UR or clinical suspicion for recurrence were excluded from this study. Currently, the only absolute indication for urethrectomy is a positive urethral surgical margin at the time of RC. Figure 2 details this process. Intraoperative frozen section is widely used to determine the need for either immediate or delayed urethrectomy; a positive frozen section usually precludes OBS and indicates urethrectomy if a cutaneous diversion is planned [36 38]. In a series with pathological examination of the urethral margin, the incidence of a positive margin ranged between 1.2% and 5% [39]. Many authors agree that using intraoperative frozen section of the urethra, as a determinate of whether or not to do OBS, is reliable and does not increase the risk of UR [6,19]. Early Diagnosis of UR Via Cytology and Survival Benefit Surveillance of the urethra after RC remains an issue of debate, and to our knowledge, there are no established guidelines. The median time to the diagnosis of UR is 1 2 years and most URs are evident within the first 3 years [1,6], although UR has been reported up to 20 years after RC [40]. UR can present either symptomatically or with positive wash cytology in an asymptomatic patient. Symptoms associated with UR include urethral bleeding or discharge (80%) and pain (32%) [4]; less commonly, a penile mass or changes in urinary habits in patients with OBS are observed [1]. Urethral wash cytology has been recommended for monitoring of recurrence after RC. This process involves saline urethral barbotage to obtain cells for diagnosis. Varol et al. [9] have described this procedure and advocate screening by this method biannually for the first 2 years postoperatively and annually thereafter. Giannarini et al. [41] have also found this protocol effective in detecting UR. Cytology is relatively well tolerated, easy, and safe [9,11]. In addition, it has been shown to detect recurrence before patients become symptomatic. Varol et al. [9] studied a series of 371 cases with 15 URs, all of which were in men and 14 of which were detected by cytology at a median time of 14 months. Of the 85 URs studied by Boorjian et al. [4], 55% were detected by cytology rather than symptom driven examinations. However, the critical question is whether early diagnosis of UR by cytology confers any advantage to clinical outcomes to justify its routine use in follow-up. Huguet et al. [5] Fig. 2 Obtaining urethral margin for frozen section by using a knife to cut on both sides of the specimen distal to the apex of the prostate. 566 BJU International 2015 BJU International

5 Urethral recurrence after cystectomy showed that most invasive URs were actually diagnosed during evaluation of symptomatic patients, whereas patients diagnosed via cytology had non-invasive UR. Patients with non-invasive UR (CIS, pta) did not have significantly better overall survival than those with invasive UR (pt1 pt4; median survival 53 vs 45 months, P = 0.195). Lin et al. [42] compared survival of patients with UR diagnosed by cytology vs symptoms and found no difference. Knapik and Murphy [43] similarly demonstrated no difference in rate of disease progression between patients monitored by urethral wash cytology vs those who were not. In that study, the authors evaluated 176 patients with UR at their institution of which 48 individuals were monitored with urethral wash cytology within 10 months of surgery. Disease progression was seen in 25% of patients monitored with cytology and in 33% of patients not monitored with cytology (P < 0.42). In contrast, Giannarini et al. [41] have found that urethral washing enables early diagnosis and conservative therapy. The authors followed 479 patients who underwent RC for TCC. Among those found to have a UR, it was detected by cytology in 21 of 24 patients (88%). Of these patients 13 had CIS and 12 were managed effectively with endourethral BCG. Six of these patients (46%) were disease free after a mean follow up of 6.2 years from surgery. As most studies show no definitive survival benefit in monitoring with urethral cytology, Sherwood and Sagalowsky [22] argue against routine urethral wash cytology for all patients. Instead, they propose that symptomatic patients be pursued aggressively. They argue that the rate of recurrence is too low to justify routine invasive examination and that urine cytology has unconfirmed reliability and a high false positive rate. In their proposed algorithm they advocate no routine surveillance for low-risk patients (those without prostatic involvement) and surveillance with urine analysis, cytology and urethroscopy for intermediate- or high-risk patients (those with prostatic involvement), as sensitivity and specificity in these populations are significantly higher. Management of UR Currently, there is no standard practice for management of UR after RC. However, in patients with cutaneous diversion, urethrectomy, including removal of the navicular fossa, is the desired treatment. For patients with a functional OBS, transition to cutaneous diversion is less desirable. As such, more conservative approaches, including TUR, intraurethral instillations of 5-fluorouracil (5-FU), and BCG treatment have been used as first-line therapy for low-grade, non-invasive tumour to maintain the neobladder. Clark et al. [44] reported on the treatment of three patients with OBS and low-stage disease with intraurethral instillations of 5-FU. One patient with a small Ta tumour remained disease-free with 7 years of follow-up. Two patients developed local UR within 1 year and eventually died of metastatic disease. Huguet et al. [45] described five patients with UR and their management. Two of these patients had non-invasive disease and were managed with TUR. One died of metastatic disease. One patient had CIS and underwent successful BCG treatment. Urethrectomy was performed in two patients for multifocality and urethral infiltration. In the latter cases, the isoperistaltic proximal ileal limb of the Studer OBS was successfully converted to the ileal conduit. Varol et al. [9] noted UR in 15 of 371 patients who underwent RC and OBS; 10 of these patients were treated with two cycles of intraurethral BCG. Six of these patients had denuding urethritis with positive cytology or CIS. Five of these six patients were responsive to therapy, resulting in a response rate of 83%. However, four patients with evidence of papillary or invasive UR on biopsy were unresponsive to therapy and required urethrectomy or no further treatment due to metastatic disease. The absence of response may be due to the biology of the tumour or that the BCG did not activate the immune response of the urethral epithelium [9]. Yoshida et al. [12] managed four patients with UR in their study with initial TUR. Of these, three eventually required salvage urethrectomy for recurrent disease. However, one patient showed no evidence of recurrence at 45 months from initial TUR. Yossepowitch et al. [8] also documented managing two patients with non-invasive recurrence with TUR. These patients were disease free at the last follow-up, although this time frame was not specified. Although the numbers of patients were limited in these studies, they nevertheless suggest that conservative therapy may be considered for non-invasive recurrence prior to urethrectomy. Specifically, Varol et al. [9,22] suggest that BCG therapy may be considered before urethrectomy for patients with CIS, whereas patients with high-grade or invasive disease should probably proceed with urethrectomy and conversion to cutaneous diversion. Survival After UR Given the relatively few URs reported in the literature and variable durations of follow-up between series, there is significant variability in reported survival after UR. The median overall survival after UR ranges from 6 to 54 months and 5-year disease-specific survival after UR is reported to be between zero and 83% [4,5,14,15,18,21]. In addition, studies may have reported survival after local recurrence or urothelial recurrence but did not specifically address UR [18,46]. Huguet et al. [5] estimated the median overall survival after diagnosis BJU International 2015 BJU International 567

6 of UR to be 53.9 months with a 5-year actuarial survival of 43%. In that study, neither bladder nor urethral pathology showed any superiority as a predictor of overall survival, probably because upper tract disease was present in a third of the cases. However, it is noteworthy that the estimated 5-year survival rates are 50% and 27% in patients with non-invasive vs invasive prostate involvement, respectively, the difference of which was statistically significant. In the larger series, Boorjian et al. [4] estimated the 3- and 5-year cancer-specific survival to be 74% and 63%, respectively. In one of the largest series to report on UR, Mitra et al. [18] studied 2029 patients who underwent RC and 55 instances of UR. With a median follow-up after UR of 38 months, they reported disease-specific survival at 2, 3 and 5 years to be 85%, 65% and 55%, respectively. In this series the type of urinary diversion was not significantly associated with survival. Additionally, most URs occurred within the first 2 years after RC, and UR in this time period was associated with worse prognosis. Patients with symptomatic presentations of recurrence had poorer disease-specific survival but did not have different overall survival. Interestingly, Mitra et al. [18] found comparable rates of UR and upper tract recurrence (1.7% and 2.7%, respectively), and comparable post-recurrence courses. They also found that although urethrectomy may improve survival, time to surgery and whether or not salvage chemotherapy was given did not predict survival. Conclusions UR is a relatively rare event after RC in both men and women. Most URs occur within the first 2 years of surgery, and recurrence during this period carries a poorer prognosis compared with late recurrence. Since the advent and popularisation of OBS, contemporary strategies for urethral management have evolved. Risk factors for UR include type of diversion, prostatic urethral involvement, and tumour focality (but not stage and grade). Studies of pre-rc biopsy show its inferiority to frozen section in determining the need for urethrectomy and frozen section has been widely adopted. Surveillance for UR and subsequent management remain challenging topics. of the current literature suggests that cytology may be useful in patients with intermediate- to high-risk of recurrence, to enable early detection of noninvasive disease. This may be more amenable to local resection and/or BCG treatment, giving patients the chance to preserve their neobladder. More advanced disease does not appear amenable to this therapy, which may give patients few options but to proceed with urethrectomy and conversion to cutaneous diversion. Given the relative low incidences of UR, further studies will be needed to elucidate the most effective treatment algorithm and duration of surveillance. 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Eur Urol 2003;43: Neuzillet Y, Soulie M, Larre S et al. Positive surgical margins and their locations in specimens are adverse prognosis features after radical cystectomy in non-metastatic carcinoma invading bladder muscle: results from a nationwide case-control study. BJU Int 2013; 111: Correspondence: Christopher P. Evans, Department of Urology, Urologic Surgical Oncology, University of California, Davis, School of Medicine, 4860 Y St., Suite 3500, Sacramento, California 95817, USA. christopher.evans@ucdmc.ucdavis.edu Abbreviations: CIS, carcinoma in situ; 5-FU, 5-fluorouracil; HR, hazard ratio; NMIBC, non-muscle-invasive bladder cancer; NPV, negative predictive value; OBS, orthotopic bladder substitutions; OR, odds ratio; RC, radical cystectomy; TUR, transurethral resection; UR, urethral recurrence. BJU International 2015 BJU International 569