Urologic Oncology: Seminars and Original Investigations 33 (2015) 204.e17–204.e23
Original article
Urethral recurrence in women with orthotopic bladder substitutes: A multi-institutional study Georgios Gakis, M.D.a,*, Bedeir Ali-El-Dein, M.D.b, Marko Babjuk, M.D.c, Jan Hrbacek, M.D.c, Petr Macek, M.D.d, Fiona C. Burkhard, M.D.e, George N. Thalmann, M.D.e, Atallah-Abdel Shaaban, M.D.b, Arnulf Stenzl, M.D.a a
Department of Urology, University Hospital Tübingen, Tübingen, Germany Urology and Nephrology Center, Mansoura University, Mansoura, Egypt c 2nd Faculty of Medicine, Charles University, Prague, Czech Republic d 1st Faculty of Medicine, Charles University, Prague, Czech Republic e Department of Urology, University of Bern, Bern, Switzerland
b
Received 23 October 2014; received in revised form 26 December 2014; accepted 26 January 2015
Abstract Objectives: To evaluate risk factors for urethral recurrence (UR) in women with neobladder. Material and methods: From 1994 to 2011, 297 women (median age ¼ 54 y; interquartile range: 47–57) underwent radical cystectomy with ileal neobladder for bladder cancer in 4 centers. None of the patients had bladder neck involvement at preoperative assessment. Univariable and multivariable analyses were used to estimate recurrence-free survival and overall survival. The median follow-up was 64 months (interquartile range: 25–116). Results: Of the 297 patients, 81 developed recurrence (27%). The 10- and 15-year recurrence-free survival rates were 66% and 66%, respectively. The 10- and 15-year overall survival rates were 57% and 55%, respectively. UR occurred in 2 patients (0.6%) with solitary urethral, 4 (1.2%) with concomitant urethral and distant recurrence, and 1 with concomitant urethral and local recurrence (0.3%). Bladder tumors were located at the trigone in 27 patients (9.1%). None of these patients developed UR. Lymph node tumor involvement was present in 60 patients (20.2%). On univariable and multivariable analyses, pathologic tumor and nodal stage were independent predictors for the overall risk of recurrence. UR was associated with a positive final urethral margin status (P o 0.001) whereas no significant associations were found for carcinoma in situ, pathologic tumor and nodal stage, and bladder trigone involvement. Conclusions: In this series, only 0.6% of women developed solitary UR. A positive final urethral margin was associated with an increased risk of UR. Women with involvement of the bladder trigone were not at higher risk of UR. r 2015 Elsevier Inc. All rights reserved.
Keywords: Female; Neobladder; Radical cystectomy; Recurrence; Urethral
1. Introduction Radical cystectomy (RC) is the mainstay of treatment for women with muscle-invasive bladder cancer (BC) [1]. Orthotopic bladder substitutes (OBSs) have been shown to provide an oncologically safe option in women with invasive BC. According to single-center series, the rates of urethral recurrence (UR) in women with ileal neobladder range between 0% * Corresponding author. Tel.: þ49-707-1298-5092; fax: þ49-707-1295092. E-mail address: [email protected] (G. Gakis).
http://dx.doi.org/10.1016/j.urolonc.2015.01.020 1078-1439/r 2015 Elsevier Inc. All rights reserved.
and 1% [2–4]. Various risk factors for UR have been reported in these studies. These include a positive urethral margin at RC, primary tumor involvement of the bladder neck and lymph node–positive disease [5]. In addition, it has been questioned whether women with a primary tumor at the bladder trigone should be considered for an OBS [6]. Owing to the low incidence of UR in women with neobladder and the low number of included patients in prior series [2–4], none of these risk factors have been evaluated in depth thus far. Indeed, there is still uncertainty as to the clinical decision making for an OBS in women [7]. This is related to the issue of (i) whether it is necessary to perform
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an intraoperative frozen-section analysis (FSA) of the distal urethral margin when preoperative cystoscopic assessment excludes the presence of a tumor at the bladder neck [8], (ii) whether an orthotopic approach should be avoided in women with lymph node–positive disease at RC [7], and (iii) whether a primary tumor location at the bladder trigone is also associated with an increased risk of UR [6]. In a recent study we already reported on treatment and outcomes of urethral recurrence in our collective [9]. To adequately address these pertinent issues, we analyzed the outcomes of women who underwent RC with orthotopic bladder substitution in a multicenter setting.
2. Material and methods 2.1. Patient selection This is a retrospective observational analysis of data from 4 international academic centers. Before initiation of data analysis, institutional review board approval and data sharing agreements were obtained at each study site. A computerized database was then generated to combine all data sets. Reports were generated to identify data inconsistencies, and through regular communication with all sites, all identified anomalies were resolved before analysis. Of our database containing 456 patients we collected complete data on the 297 cases who underwent RC with ileal neobladder reconstruction for BC between 1994 and 2011. All patients were staged cM0 preoperatively. Patient medical records and physician records were reviewed to investigate the following clinical and pathologic parameters: age at RC, pathologic tumor stage at RC, lymph node tumor involvement at RC, underlying histology, number of retrieved lymph nodes, carcinoma in situ (CIS), primary tumor location, and final urethral margin status. Any patient lacking any of these parameters was excluded from analysis. A prerequisite of this study was that all participating centers followed the same oncologic criteria. In all centers, the oncologic exclusion criteria for OBS were tumors staged cT4b at preoperative imaging, bladder neck involvement, bulky lymph node metastatic disease (cN3, not cN1–2), and a positive urethral margin at intraoperative FSA. By contrast, women with tumors located at the bladder trigone, but not at the bladder neck, were considered eligible for an OBS. Diffuse or multifocal CIS and multifocal tumors were considered contraindications for ileal neobladder. Evaluations for tumor staging and grading included abdominal ultrasound; excretory urography (intravenous pyelogram); chest x-ray; computerized tomography of the abdomen, pelvis, and chest; bone scintigraphy; bimanual examination with anesthesia; and multiple cold cup biopsies from the tumor, the trigone, and bladder neck if there was a suspicious finding on imaging or cystoscopy. In case of positive intraoperative frozen section of the urethral margin or positive preoperative biopsy of the bladder neck, women were excluded from orthotopic diversion.
The functional exclusion criteria included a preoperative glomerular filtration rate less than 60 ml/min, severe hepatic insufficiency, and stress urinary incontinence. Women with severe physical or mental disorders that would preclude them from the ability to perform clean intermittent catheterization in case of urinary retention were also considered ineligible for an OBS. 2.2. Operative technique RC was performed open according to standardized techniques, including the removal of the tumor-bearing bladder, uterus, adnexes, and anterior vaginal wall [1]. Bilateral pelvic lymphadenectomy was performed in all centers. Nervesparing techniques for preservation of the lateral vaginal walls were performed whenever it was deemed oncologically feasible [1]. Different center-specific types of OBSs were constructed, as has been outlined in prior studies [11–13]. Intraoperative FSA of the distal urethral margin was routinely performed except for one center. In this center, a biopsy of the bladder neck was preoperatively performed to assess a patient's eligibility for an OBS; nonetheless, the presence of malignancy at the distal margin was routinely assessed at final histopathologic analysis. 2.3. Histologic assessment All cystectomy specimens were processed according to standardized pathologic procedures at each institution. Dedicated genitourinary pathologists confirmed histology. All specimens were finally processed on formalin-fixed, paraffinembedded sections. The histopathologic evaluation was based on the TNM classification of 2002 approved by the American Joint Committee on Cancer [14]. Tumors were graded according to the World Health Organisation 1973 classification [15]. Malignancy at the distal urethral margin was defined as either CIS or high-grade noninvasive or invasive carcinoma [15]. 2.4. Follow-up Patient medical records and physician records were also reviewed to determine clinical outcome. Patients generally were seen postoperatively at least every 3 to 4 months for the first year, semiannually for the second and third years, and annually thereafter. Follow-up examinations included radiologic imaging with cross-sectional imaging. In addition to physical examination with laboratory testing, intravenous pyelography, urethropouchoscopy, urine cytology, urethral washings, and bone scintigraphy were carried out at each institution. Disease recurrence was defined as local when located in the surgical bed and as distant when located at distant organs. Urethral or upper tract recurrence was defined as an endoscopically confirmed tumor in the urethra or upper urinary tract, respectively. Clinical outcomes were measured from the date of cystectomy to the date of first documented recurrence, the date of death, or the date of
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last follow-up when the patient had not experienced disease recurrence. The median follow-up was 64 months (3–196). 2.5. Statistical analysis Univariable and multivariable Cox regression models were constructed to evaluate the potential risk factors for recurrence. Kaplan-Meier plots with log-rank testing were used to estimate recurrence-free survival and overall survival (OS). P values were 2-sided and P o 0.05 was considered as the level of significant difference. Statistical analysis was performed with JMP 10.0. The values are given as mean ⫾ S.E.M. for all continuous variables or as median (range) for noncontinuous variables.
3. Results The primary patient characteristics are listed in Table 1. The median age at RC was 54 years (range: 23–75). Pure urothelial carcinoma (UC), squamous cell carcinoma (SCC), Table 1 Patients characteristics in the 297 women with ileal neobladder Variable
No. of patients (%)
Median age at radical cystectomy (range)
54 years (23–75)
Tumor stage at RC rpT2b (organ confined) ZpT3a (locally advanced)
120 (40.4) 177 (59.6)
Bladder trigone involvement Present Not present
27 (9.1) 270 (90.9)
Lymph node tumor involvement pN0 pNþ pNX
235 (79.1) 60 (20.2) 2 (0.7)
Histologic findingsa Pure UC Pure SCC Pure AC Mixed UC/SCC Mixed UC/AC Mixed UC/sarcomatoid
151 126 13 5 1 1
Number of retrieved lymph nodes at radical cystectomy Median (range)
(50.8) (42.4) (4.4) (1.8) (0.3) (0.3)
19 (0–36)
b
Final urethral margin status Negative Positive
Carcinoma in situ at radical cystectomy Solitary Concomitant
290 (97.6) 7 (2.4) 5 (1.7) 9 (3.0)
AC ¼ adenocarcinoma. Definitive histopathologic analysis (a positive finding on frozen-section analysis had been an exclusion criterion). a
b
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and adenocarcinoma were present in 50.8%, 42.4%, and 4.4% of cases, respectively, while mixed histology was found in 2.4%. A total of 177 patients had locally advanced (ZpT3a) tumor stage (59.6%) at RC. The median number of removed lymph nodes was 19. Pathologic analysis demonstrated lymph node tumor involvement in 60 of 297 patients (20.2%). Locally advanced disease (ZpT3a or pNþ) was present in 196 patients (66.0%). Bladder tumors were located at the trigone in 27 (9.1%) patients. Solitary and concomitant CIS were present in 5 and 9 patients, respectively. None of the patients displayed bladder neck involvement at final analysis. Of the 297 patients, 7 had a positive final urethral margin status, although (as dictated by our protocol) intraoperative FSA had been negative in all. Only 1 of the 7 patients developed UR subsequently (14.3%). Overall recurrence was noted in 81 patients (27%). The 5-, 10-, and 15-year recurrence-free survival rates (for local, distant, ureteral, and UR) were 70%, 66%, and 66%, respectively (Fig.). Likewise, the 5-, 10-, and 15-year OS rates were 66%, 57%, and 55%, respectively (Fig.). Of these 81 patients with recurrence, 32 (10.8%) had solitary local, 28 (9.4%) solitary distant, 13 (4.4%) concomitant local and distant, 4 (1.2%) concomitant urethral and distant, 2 (0.6%) solitary urethral, 1 concomitant urethral and local (0.3%), and 1 (0.3%) solitary ureteral recurrence (Table 2). The median time to UR was 30 months (range: 8–64). In 1 of the 7 patients with UR (14.3%), the final urethral margin status was positive while negative on frozen-section analysis (Table 2). Only 1 of these 7 patients had locally advanced tumor stage (pT3aN0) at RC, whereas all the others exhibited organ-confined disease (rpT2bN0). None of the 27 women with involvement of the bladder trigone developed UR. UR occurred in 5 women with pure urothelial carcinoma, in 1 woman with pure squamous cell carcinoma, and in 1 with mixed squamous cell and urothelial carcinoma. The location of recurrence within the urethra is listed in Table 3. The 3-year OS was 25.0% for patients with any urethral (either solitary or concomitant local or distant or a combination of both) recurrence, 22.6% for those with solitary distant recurrence, 16.9% and for those with solitary local recurrence (P ¼ 0.27). The patient with upper tract recurrence died 3 months postoperatively. In univariable and multivariable analyses, pathologic lymph node tumor involvement (hazard ratio ¼ 2.3, 1.3–3.5, P ¼ 0.006) and pathologic tumor stage (hazard ratio ¼ 2.1, 1.3– 3.7, P ¼ 0.007) were independent risk factors for overall recurrence (Table 4). In univariable analysis, subanalyzed for patients with solitary or concomitant UR (n ¼ 7), final urethral margin status (P o 0.001) was associated with an increased risk of UR. No significant associations were found for pathologic tumor stage, lymph node tumor CIS at RC (P ¼ 0.21), and involvement of the bladder trigone (Table 5). Subanalyzed for patients with pure urothelial carcinoma (n ¼ 151), only a positive final urethral margin status (P ¼ 0.005) was associated with increased risk of UR. Furthermore, in this subgroup, bladder trigone involvement
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Fig. Recurrence-free and overall survival in the 297 patients. At 5, 10, and 15 years, recurrence-free survival rates were 70%, 66%, and 66%, respectively and overall survival rates were 66%, 57%, and 55%, respectively.
(P ¼ 0.56), CIS at RC (P ¼ 0.52), or pathologic tumor (P ¼ 0.43) and nodal stage (P ¼ 0.58) were not associated with increased risk of UR. Subanalyzed for patients with nonpure urothelial carcinoma (n ¼ 146), no significant associations were found for final urethral margin status (P ¼ 0.08), pathologic tumor (P ¼ 0.38) and nodal (P ¼ 0.18) stage, bladder trigone involvement (P ¼ 0.46), and CIS at RC (P ¼ 0.28). 4. Discussion In this long-term study, representing the largest series yet to evaluate outcomes in women after RC and ileal neobladder, the median age at RC was relatively low (54 y) and approximately two-thirds of women had locally advanced disease. Moreover, 49% of the patients had nonpure urothelial carcinoma pathology, which is often associated with severely impaired prognosis after RC [1,11,16]. Despite this, after 15 years of follow-up, recurrence-free survival was relatively high (66%). These data support the soundness of our preoperative clinical decision making and the long-term oncologic efficacy of ileal neobladder in women. In multivariable analysis, tumor stage and nodal involvement were found to be independently associated with overall recurrence. Both parameters represent risk factors for recurrence that have been reported in numerous studies [11,17–21]. One of the aims of this study was to investigate whether preoperative cystoscopic exclusion of a tumor at the bladder Table 2 Location of recurrence in the 297 female patients with ileal neobladder Location of recurrence
Patients, number (%)
Solitary local Solitary distant Concomitant local and distant Solitary urethral Concomitant urethral and local Concomitant urethral and distant Solitary ureteral
32 28 13 2 1 4 1
(10.8) (9.4) (4.4) (0.6) (0.3) (1.2) (0.3)
neck reliably predicts a negative final urethral margin at RC, thus possibly obviating the need for routine frozen-section analysis. This issue is pertinent, as previous studies have demonstrated that concomitant urethral malignancy is present in up to 40% of women with tumors at the bladder neck [22]. In contrast to the low rate (approximately 2%) of concomitant urethral malignancy in women with primary BC [23], a higher rate of urethral malignancy at RC (up to 7%) has been reported previously [1]. By contrast, in the present series, only 2.4% of the women displayed a malignant urethral margin at final analysis. This is because of the common practice in all participating centers to consider only patients for an orthotopic approach when preoperative cystoscopic assessment reveals no evidence of malignancy at the bladder neck. However, although the bladder neck was preoperatively and postoperatively considered tumor free in all patients, 7 patients had a malignant distal urethral margin at final analysis (2.4%). It should be noted that all of these patients had a negative result on FSA of the distal urethral margin and only 1 had bladder CIS. With regard to the inaccuracy of intraoperative FSA to reliably detect malignant margins, these data suggest that a carefully obtained preoperative biopsy of the bladder neck may be oncologically equivalent when compared with frozen-section analysis of the distal urethral margin for appropriate selection of patients for an OBS. The aim of this study was not to statistically validate existing observations or strategies, as recommendations on the role of FSA of the urethral margin at RC in women are based on smaller singlecenter series [1]. The rationale for excluding women with involvement of bladder neck is based on prior studies. In these studies, the risk of tumor involvement of the distal urethra at RC was found to be significantly higher in patients with bladder neck involvement and preoperatively enlarged inguinal lymph nodes, as up to 40% with bladder neck tumors exhibited concomitant urethral malignancy [22,24,25]. A detailed histopathologic study of 67 cystectomy specimens obtained from women showed that concomitant urethral cancers were located exclusively in the proximal or middle urethra, whereas the distal third was tumor free. This study also confirmed that
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Table 3 Tumor stage, condition at the bladder trigone/neck, final urethral margin status, presence of CIS histology, and site of urethral recurrence in the 7 patients with urethral recurrence Patient
Stage
Trigone
Neck
Final urethral margin
Bladder CIS at RC
Histology
Site of urethral recurrence
1 2 3 4 5 6 7
pT3aN0 pT2bN0 pTaN0 pT2aN0 pTaN0 pTisN0 pT2aN0
NED NED NED NED NED NED NED
NED NED NED NED NED NED NED
NED NED NED NED EDa NED NED
NED NED NED NED NED EDa NED
UC UC/SCC UC UC UC UC SCC
Neobladder outlet Proximal Distal Proximal Proximal Proximal Proximal
a CIS ¼ carcinoma in situ; ED ¼ evidence of disease; NED ¼ no evidence of disease; Rec ¼ recurrence; SCC ¼ squamous cell carcinoma; UC ¼ urothelial carcinoma.
localization of the primary tumor at the bladder neck correlated strongly with concomitant urethral malignancy. These tumors were of a higher grade and stage and harbored a higher risk of node-positive disease [24]. Stein et al. [22] also prospectively evaluated cystectomy specimens in 71 women and reported tumor localization at the bladder neck and in the urethra in 19% and 7% of the cases, respectively. Bladder neck involvement correlated significantly with the highest risk of concomitant urethral malignancy. In the present study, urethral margins were positive in 7 patients at definitive histopathologic analysis, whereas UR was seen only in one. Altogether, UR was seen in 7 of the 297 patients (2.4%). These data are in line with previous smaller series reporting the risk of UR to range between 1% and 4% [4,16,26,27]. Strikingly, none of our patients with UR had a positive distal urethral margin on FSA. By contrast, a positive final distal urethral margin was present in only 1 of the 7 patients (14.3%), which was associated with a significantly increased risk of UR. However, these results have to be interpreted carefully owing to the relatively low number of included cases. We also aimed to assess the effect of lymph node tumor involvement on the risk of UR in the context of an adequately performed lymph node dissection (in the present series a median of 19 removed lymph nodes). Positive lymph nodes were found in 20% of the patients. Lymph node tumor involvement was significantly associated with overall recurrence, but not with UR. Moreover, 6 of the 7 women with UR had organ-confined disease at RC (rpT2bN0). We
also investigated the effect of tumor location at the bladder trigone as a risk factor for subsequent UR [6] but did not find any significant association. As recurrence was observed in 5 women with pure UC and only in 1 woman with mixed SCC and UC as well as 1 woman with pure SCC, these data suggest that the risk of UR in women derives mainly from urothelial carcinoma histology. Altogether, these data support the assumption that women with limited lymph node–positive disease (pN1-2) or primary tumor at the bladder trigone, or both, can safely undergo an orthotopic bladder substitution if preoperative assessment excludes the presence of bulky lymph node disease and involvement of the bladder neck. This study has limitations inherent to any retrospective and multicenter analysis, such as lack of data on prior treatment, possible delay between diagnosis and treatment, and exclusion of women with bladder neck involvement or a positive urethral margin at FSA. Despite our efforts to set up this multicenter study, the relatively low number of UR cases precluded the performance of a multivariable analysis. As the number of patients with involvement of the bladder trigone and UR is relatively low, results have to be interpreted carefully. Another limitation is the (possible) pathologic interobserver variability, absence of central pathologic review and the high rate of nonurothelial carcinoma pathology. We could also not adjust for the number of surgeons, their surgical preferences and experiences, and different neobladder techniques. However, all women were treated in centers dedicated to the treatment of muscle-invasive BC and orthotopic neobladder reconstruction. As our study excluded
Table 4 Univariable and multivariable analyses of risk factors for overall recurrence Variable
Univariable a
ZpT3a vs. rpT2b pNþ vs. pN0 Positive vs. negative Final urethral margin Bladder trigone involvement (present vs. not present) Carcinoma in situ at RC a
HR ¼ hazard ratio.
Multivariable
HR (95% CI)
P value
HR (95% CI)
P value
1.9 (1.1–3.3) 2.3 (1.4–3.7) 2.5 (0.6–6.8)
0.013 0.001 0.16
1.9 (1.1–3.5) 2.1 (1.2–3.5) 3.6 (0.8–11.0)
0.015 0.007 0.09
1.0 (0.3–2.1)
0.93
0.6 (0.2–1.6)
0.35
0.7 (0.1–2.2)
0.58
0.6 (0.1–2.3)
0.47
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5. Conclusions
Table 5 Univariable analysis for urethral recurrence Variable
Univariable, P value
ZpT3a vs. rpT2b pNþ vs. pN0 Positive vs. negative Final urethral margin Bladder trigone involvement (present vs. not present) Carcinoma in situ at RC
0.32 0.88 o0.001 0.45 0.21
patients from OBS in case of a positive finding on FSA, we cannot retrospectively assess the accuracy of FSA to detect malignant urethral margins at RC. In previous studies, FSA of the distal urethral margin showed a 100% sensitivity and specificity for detection of a positive final urethral margin [22]. As in our series, only 1 patient who subsequently experienced UR demonstrated a positive final urethral margin status, one must be mindful of a possible submucosal extension of the primary bladder tumor into the urethra with the urothelial layer remaining unaffected at FSA [25]. In this study, as UR often occurred in the proximal urethra despite negative urethral margins on FSA and tumor-free bladder necks, these data highlight the importance of an adequate fullthickness biopsy of the urethral margin for FSA [8]. Therefore, based on the present data, we must acknowledge that the pathogenesis of UR in women after RC is still poorly understood. For UR, SCC may have a different tumor biology compared with UC. Strikingly, UR occurred only in 1 woman with pure SCC although 43% of our patients had pure SCC. The question that derives from this observation is why women with UC are at higher risk for UR compared with those with SCC, although the risk for developing local or distant recurrence does not seem to differ between both histologic entities. As preoperative assessment was conducted similarly between centers, it seems unlikely that this finding may be related to different preoperative workup strategies. Another possible explanation may be that the invasive urothelial tumors may have developed because of a cancerfield defect of the urothelium (including the remnant urothelium) whereas the reason for developing SCC is linked to chronic cystitis with Schistosoma haematobium. As highlighted in Table 2, most women with UR exhibit organ-confined disease, but the rate of recurrence is very low. Thus, we think that even if we performed adjusted matched-pairs analysis, we would not obtain statistically robust results. Therefore, from a clinical perspective, we need to identify UR at the earliest possible stage as UR in early stages is associated with improved survival [1]. As the pathogenesis of UR in women after RC is still poorly understood, we think that performance of a whole-genome analysis would be helpful in identifying genetic risk factors in these 7 cases. This may be used to prospectively advocate the use of OBS in women and intensify followup investigations in those at highest risk of UR.
In this long-term, multi-institutional series of women undergoing RC with ileal neobladder, 15-year recurrence-free and OS rates were 66% and 55%, respectively. Although approximately two-thirds of the women presented with locally advanced disease at RC, only 0.6% of them developed solitary UR. A positive final urethral margin was associated with UR. Women with involvement of the bladder trigone and positive nodes were not at increased risk of UR. These data provide further evidence for the oncologic safety of OBSs in women with invasive BC. References [1] Gakis G, Efstathiou JA, Lerner SP, Cookson MS, Keegan KA, Guru KA, et al. ICUD-EAU International Consultation on Bladder Cancer 2012: radical cystectomy and bladder preservation for muscle-invasive urothelial carcinoma of the bladder. Eur Urol 2013;63:45–57. [2] Stenzl A, Jarolim L, Coloby P, Golia S, Bartsch G, Babjuk M, et al. Urethra-sparing cystectomy and orthotopic urinary diversion in women with malignant pelvic tumors. Cancer 2001;92:1864–71. [3] Jentzmik F, Schrader AJ, de Petriconi R, Hefty R, Mueller J, Doetterl J, et al. The ileal neobladder in female patients with bladder cancer: long-term clinical, functional, and oncological outcome. World J Urol 2012;30:733–9. [4] Stein JP, Penson D, Lee C, Cai J, Miranda G, Skinner DG. Long-term oncological outcomes in women undergoing radical cystectomy and orthotopic diversion for bladder cancer. J Urol 2009;181:2052–8. [5] Chen ME, Pisters LL, Malpica A, Pettaway CA, Dinney CP. Risk of urethral, vaginal and cervical involvement in patients undergoing radical cystectomy for bladder cancer: results of a contemporary cystectomy series from M. D. Anderson Cancer Center. J Urol 1997;157:2120–3. [6] Kochakarn W, Chaimuangraj S, Leenanupunth C, Muangman V. Risk factors of urethral involvement of bladder cancer after radical cystectomy with orthotopic neobladder in females. J Med Assoc Thai 2001;84:889–92. [7] Gakis G, Jentzmik F, Schrader M, Stenzl A, Sievert KD. Benefits and risks of orthotopic neobladder reconstruction in female patients. Aktuelle Urol 2011;42:109–14. [8] Stein JP, Penson D, Wu SD, Skinner DG. Pathological guidelines for orthotopic urinary diversion in women with bladder cancer: a review of the literature. J Urol 2007;178:756–60. [9] Hrbacek J, Macek P, Ali-El-Dein B, Thalmann GN, Stenzl A, Babjuk M, et al. Treatment and outcomes of urethral recurrence of urinary bladder cancer in women after radical cystectomy and orthotopic neobladder: a series of 12 cases. Urol Int 2015;94(1):45–9. [10] Witjes JA, Comperat E, Cowan NC, De Santis M, Gakis G, Lebret T, et al. EAU guidelines on muscle-invasive and metastatic bladder cancer. Eur Urol 2014;65:778–92. [11] Ghoneim MA, Abdel-Latif M, el-Mekresh M, Abol-Enein H, Mosbah A, Ashamallah A, et al. Radical cystectomy for carcinoma of the bladder: 2,720 consecutive cases 5 years later. J Urol 2008;180:121–7. [12] Hautmann RE, de Petriconi R, Gottfried HW, Kleinschmidt K, Mattes R, Paiss T. The ileal neobladder: complications and functional results in 363 patients after 11 years of followup. J Urol 1999;161:422–7. [13] Hautmann RE, de Petriconi R, Volkmer BG. Lessons learned from 1,000 neobladders: the 90-day complication rate. J Urol 2010;184: 990–4. [14] Sobin DH, Wittekind C. TNM classification of malignant tumours, 6th ed. New York: Wiley-Liss; 2002. [15] Epstein JI, Amin MB, Reuter VR, Mostofi FK. The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary
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[22] 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. [23] Stenzl A, Draxl H, Posch B, Colleselli K, Falk M, Bartsch G. The risk of urethral tumors in female bladder cancer: can the urethra be used for orthotopic reconstruction of the lower urinary tract? J Urol 1995;153:950–5. [24] Stein JP, Cote RJ, Freeman JA. Indications for lower urinary tract reconstruction in women after cystectomy for bladder cancer: a pathological review of female cystectomy specimens. J Urol 1995;154: 1329–33. [25] Maralani S, Wood DP Jr, Grignon D, Banerjee M, Sakr W, Pontes JE. Incidence of urethral involvement in female bladder cancer: an anatomic pathologic study. Urology 1997;50:537–41. [26] Akkad T, Gozzi C, Deibl M, Müller T, Pelzer AE, Pinggera GM, et al. Tumor recurrence in the remnant urothelium of females undergoing radical cystectomy for transitional cell carcinoma of the bladder: long-term results from a single center. J Urol 2006;175: 1268–71. [27] Ali-el-Dein B, Abdel-Latif M, Ashamallah A, Abdel-Rahim M, Ghoneim M. Local urethral recurrence after radical cystectomy and orthotopic bladder substitution in women: a prospective study. J Urol 2004;171:275–8.
Original article
Urethral recurrence in women with orthotopic bladder substitutes: A multi-institutional study Georgios Gakis, M.D.a,*, Bedeir Ali-El-Dein, M.D.b, Marko Babjuk, M.D.c, Jan Hrbacek, M.D.c, Petr Macek, M.D.d, Fiona C. Burkhard, M.D.e, George N. Thalmann, M.D.e, Atallah-Abdel Shaaban, M.D.b, Arnulf Stenzl, M.D.a a
Department of Urology, University Hospital Tübingen, Tübingen, Germany Urology and Nephrology Center, Mansoura University, Mansoura, Egypt c 2nd Faculty of Medicine, Charles University, Prague, Czech Republic d 1st Faculty of Medicine, Charles University, Prague, Czech Republic e Department of Urology, University of Bern, Bern, Switzerland
b
Received 23 October 2014; received in revised form 26 December 2014; accepted 26 January 2015
Abstract Objectives: To evaluate risk factors for urethral recurrence (UR) in women with neobladder. Material and methods: From 1994 to 2011, 297 women (median age ¼ 54 y; interquartile range: 47–57) underwent radical cystectomy with ileal neobladder for bladder cancer in 4 centers. None of the patients had bladder neck involvement at preoperative assessment. Univariable and multivariable analyses were used to estimate recurrence-free survival and overall survival. The median follow-up was 64 months (interquartile range: 25–116). Results: Of the 297 patients, 81 developed recurrence (27%). The 10- and 15-year recurrence-free survival rates were 66% and 66%, respectively. The 10- and 15-year overall survival rates were 57% and 55%, respectively. UR occurred in 2 patients (0.6%) with solitary urethral, 4 (1.2%) with concomitant urethral and distant recurrence, and 1 with concomitant urethral and local recurrence (0.3%). Bladder tumors were located at the trigone in 27 patients (9.1%). None of these patients developed UR. Lymph node tumor involvement was present in 60 patients (20.2%). On univariable and multivariable analyses, pathologic tumor and nodal stage were independent predictors for the overall risk of recurrence. UR was associated with a positive final urethral margin status (P o 0.001) whereas no significant associations were found for carcinoma in situ, pathologic tumor and nodal stage, and bladder trigone involvement. Conclusions: In this series, only 0.6% of women developed solitary UR. A positive final urethral margin was associated with an increased risk of UR. Women with involvement of the bladder trigone were not at higher risk of UR. r 2015 Elsevier Inc. All rights reserved.
Keywords: Female; Neobladder; Radical cystectomy; Recurrence; Urethral
1. Introduction Radical cystectomy (RC) is the mainstay of treatment for women with muscle-invasive bladder cancer (BC) [1]. Orthotopic bladder substitutes (OBSs) have been shown to provide an oncologically safe option in women with invasive BC. According to single-center series, the rates of urethral recurrence (UR) in women with ileal neobladder range between 0% * Corresponding author. Tel.: þ49-707-1298-5092; fax: þ49-707-1295092. E-mail address: [email protected] (G. Gakis).
http://dx.doi.org/10.1016/j.urolonc.2015.01.020 1078-1439/r 2015 Elsevier Inc. All rights reserved.
and 1% [2–4]. Various risk factors for UR have been reported in these studies. These include a positive urethral margin at RC, primary tumor involvement of the bladder neck and lymph node–positive disease [5]. In addition, it has been questioned whether women with a primary tumor at the bladder trigone should be considered for an OBS [6]. Owing to the low incidence of UR in women with neobladder and the low number of included patients in prior series [2–4], none of these risk factors have been evaluated in depth thus far. Indeed, there is still uncertainty as to the clinical decision making for an OBS in women [7]. This is related to the issue of (i) whether it is necessary to perform
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an intraoperative frozen-section analysis (FSA) of the distal urethral margin when preoperative cystoscopic assessment excludes the presence of a tumor at the bladder neck [8], (ii) whether an orthotopic approach should be avoided in women with lymph node–positive disease at RC [7], and (iii) whether a primary tumor location at the bladder trigone is also associated with an increased risk of UR [6]. In a recent study we already reported on treatment and outcomes of urethral recurrence in our collective [9]. To adequately address these pertinent issues, we analyzed the outcomes of women who underwent RC with orthotopic bladder substitution in a multicenter setting.
2. Material and methods 2.1. Patient selection This is a retrospective observational analysis of data from 4 international academic centers. Before initiation of data analysis, institutional review board approval and data sharing agreements were obtained at each study site. A computerized database was then generated to combine all data sets. Reports were generated to identify data inconsistencies, and through regular communication with all sites, all identified anomalies were resolved before analysis. Of our database containing 456 patients we collected complete data on the 297 cases who underwent RC with ileal neobladder reconstruction for BC between 1994 and 2011. All patients were staged cM0 preoperatively. Patient medical records and physician records were reviewed to investigate the following clinical and pathologic parameters: age at RC, pathologic tumor stage at RC, lymph node tumor involvement at RC, underlying histology, number of retrieved lymph nodes, carcinoma in situ (CIS), primary tumor location, and final urethral margin status. Any patient lacking any of these parameters was excluded from analysis. A prerequisite of this study was that all participating centers followed the same oncologic criteria. In all centers, the oncologic exclusion criteria for OBS were tumors staged cT4b at preoperative imaging, bladder neck involvement, bulky lymph node metastatic disease (cN3, not cN1–2), and a positive urethral margin at intraoperative FSA. By contrast, women with tumors located at the bladder trigone, but not at the bladder neck, were considered eligible for an OBS. Diffuse or multifocal CIS and multifocal tumors were considered contraindications for ileal neobladder. Evaluations for tumor staging and grading included abdominal ultrasound; excretory urography (intravenous pyelogram); chest x-ray; computerized tomography of the abdomen, pelvis, and chest; bone scintigraphy; bimanual examination with anesthesia; and multiple cold cup biopsies from the tumor, the trigone, and bladder neck if there was a suspicious finding on imaging or cystoscopy. In case of positive intraoperative frozen section of the urethral margin or positive preoperative biopsy of the bladder neck, women were excluded from orthotopic diversion.
The functional exclusion criteria included a preoperative glomerular filtration rate less than 60 ml/min, severe hepatic insufficiency, and stress urinary incontinence. Women with severe physical or mental disorders that would preclude them from the ability to perform clean intermittent catheterization in case of urinary retention were also considered ineligible for an OBS. 2.2. Operative technique RC was performed open according to standardized techniques, including the removal of the tumor-bearing bladder, uterus, adnexes, and anterior vaginal wall [1]. Bilateral pelvic lymphadenectomy was performed in all centers. Nervesparing techniques for preservation of the lateral vaginal walls were performed whenever it was deemed oncologically feasible [1]. Different center-specific types of OBSs were constructed, as has been outlined in prior studies [11–13]. Intraoperative FSA of the distal urethral margin was routinely performed except for one center. In this center, a biopsy of the bladder neck was preoperatively performed to assess a patient's eligibility for an OBS; nonetheless, the presence of malignancy at the distal margin was routinely assessed at final histopathologic analysis. 2.3. Histologic assessment All cystectomy specimens were processed according to standardized pathologic procedures at each institution. Dedicated genitourinary pathologists confirmed histology. All specimens were finally processed on formalin-fixed, paraffinembedded sections. The histopathologic evaluation was based on the TNM classification of 2002 approved by the American Joint Committee on Cancer [14]. Tumors were graded according to the World Health Organisation 1973 classification [15]. Malignancy at the distal urethral margin was defined as either CIS or high-grade noninvasive or invasive carcinoma [15]. 2.4. Follow-up Patient medical records and physician records were also reviewed to determine clinical outcome. Patients generally were seen postoperatively at least every 3 to 4 months for the first year, semiannually for the second and third years, and annually thereafter. Follow-up examinations included radiologic imaging with cross-sectional imaging. In addition to physical examination with laboratory testing, intravenous pyelography, urethropouchoscopy, urine cytology, urethral washings, and bone scintigraphy were carried out at each institution. Disease recurrence was defined as local when located in the surgical bed and as distant when located at distant organs. Urethral or upper tract recurrence was defined as an endoscopically confirmed tumor in the urethra or upper urinary tract, respectively. Clinical outcomes were measured from the date of cystectomy to the date of first documented recurrence, the date of death, or the date of
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last follow-up when the patient had not experienced disease recurrence. The median follow-up was 64 months (3–196). 2.5. Statistical analysis Univariable and multivariable Cox regression models were constructed to evaluate the potential risk factors for recurrence. Kaplan-Meier plots with log-rank testing were used to estimate recurrence-free survival and overall survival (OS). P values were 2-sided and P o 0.05 was considered as the level of significant difference. Statistical analysis was performed with JMP 10.0. The values are given as mean ⫾ S.E.M. for all continuous variables or as median (range) for noncontinuous variables.
3. Results The primary patient characteristics are listed in Table 1. The median age at RC was 54 years (range: 23–75). Pure urothelial carcinoma (UC), squamous cell carcinoma (SCC), Table 1 Patients characteristics in the 297 women with ileal neobladder Variable
No. of patients (%)
Median age at radical cystectomy (range)
54 years (23–75)
Tumor stage at RC rpT2b (organ confined) ZpT3a (locally advanced)
120 (40.4) 177 (59.6)
Bladder trigone involvement Present Not present
27 (9.1) 270 (90.9)
Lymph node tumor involvement pN0 pNþ pNX
235 (79.1) 60 (20.2) 2 (0.7)
Histologic findingsa Pure UC Pure SCC Pure AC Mixed UC/SCC Mixed UC/AC Mixed UC/sarcomatoid
151 126 13 5 1 1
Number of retrieved lymph nodes at radical cystectomy Median (range)
(50.8) (42.4) (4.4) (1.8) (0.3) (0.3)
19 (0–36)
b
Final urethral margin status Negative Positive
Carcinoma in situ at radical cystectomy Solitary Concomitant
290 (97.6) 7 (2.4) 5 (1.7) 9 (3.0)
AC ¼ adenocarcinoma. Definitive histopathologic analysis (a positive finding on frozen-section analysis had been an exclusion criterion). a
b
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and adenocarcinoma were present in 50.8%, 42.4%, and 4.4% of cases, respectively, while mixed histology was found in 2.4%. A total of 177 patients had locally advanced (ZpT3a) tumor stage (59.6%) at RC. The median number of removed lymph nodes was 19. Pathologic analysis demonstrated lymph node tumor involvement in 60 of 297 patients (20.2%). Locally advanced disease (ZpT3a or pNþ) was present in 196 patients (66.0%). Bladder tumors were located at the trigone in 27 (9.1%) patients. Solitary and concomitant CIS were present in 5 and 9 patients, respectively. None of the patients displayed bladder neck involvement at final analysis. Of the 297 patients, 7 had a positive final urethral margin status, although (as dictated by our protocol) intraoperative FSA had been negative in all. Only 1 of the 7 patients developed UR subsequently (14.3%). Overall recurrence was noted in 81 patients (27%). The 5-, 10-, and 15-year recurrence-free survival rates (for local, distant, ureteral, and UR) were 70%, 66%, and 66%, respectively (Fig.). Likewise, the 5-, 10-, and 15-year OS rates were 66%, 57%, and 55%, respectively (Fig.). Of these 81 patients with recurrence, 32 (10.8%) had solitary local, 28 (9.4%) solitary distant, 13 (4.4%) concomitant local and distant, 4 (1.2%) concomitant urethral and distant, 2 (0.6%) solitary urethral, 1 concomitant urethral and local (0.3%), and 1 (0.3%) solitary ureteral recurrence (Table 2). The median time to UR was 30 months (range: 8–64). In 1 of the 7 patients with UR (14.3%), the final urethral margin status was positive while negative on frozen-section analysis (Table 2). Only 1 of these 7 patients had locally advanced tumor stage (pT3aN0) at RC, whereas all the others exhibited organ-confined disease (rpT2bN0). None of the 27 women with involvement of the bladder trigone developed UR. UR occurred in 5 women with pure urothelial carcinoma, in 1 woman with pure squamous cell carcinoma, and in 1 with mixed squamous cell and urothelial carcinoma. The location of recurrence within the urethra is listed in Table 3. The 3-year OS was 25.0% for patients with any urethral (either solitary or concomitant local or distant or a combination of both) recurrence, 22.6% for those with solitary distant recurrence, 16.9% and for those with solitary local recurrence (P ¼ 0.27). The patient with upper tract recurrence died 3 months postoperatively. In univariable and multivariable analyses, pathologic lymph node tumor involvement (hazard ratio ¼ 2.3, 1.3–3.5, P ¼ 0.006) and pathologic tumor stage (hazard ratio ¼ 2.1, 1.3– 3.7, P ¼ 0.007) were independent risk factors for overall recurrence (Table 4). In univariable analysis, subanalyzed for patients with solitary or concomitant UR (n ¼ 7), final urethral margin status (P o 0.001) was associated with an increased risk of UR. No significant associations were found for pathologic tumor stage, lymph node tumor CIS at RC (P ¼ 0.21), and involvement of the bladder trigone (Table 5). Subanalyzed for patients with pure urothelial carcinoma (n ¼ 151), only a positive final urethral margin status (P ¼ 0.005) was associated with increased risk of UR. Furthermore, in this subgroup, bladder trigone involvement
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Fig. Recurrence-free and overall survival in the 297 patients. At 5, 10, and 15 years, recurrence-free survival rates were 70%, 66%, and 66%, respectively and overall survival rates were 66%, 57%, and 55%, respectively.
(P ¼ 0.56), CIS at RC (P ¼ 0.52), or pathologic tumor (P ¼ 0.43) and nodal stage (P ¼ 0.58) were not associated with increased risk of UR. Subanalyzed for patients with nonpure urothelial carcinoma (n ¼ 146), no significant associations were found for final urethral margin status (P ¼ 0.08), pathologic tumor (P ¼ 0.38) and nodal (P ¼ 0.18) stage, bladder trigone involvement (P ¼ 0.46), and CIS at RC (P ¼ 0.28). 4. Discussion In this long-term study, representing the largest series yet to evaluate outcomes in women after RC and ileal neobladder, the median age at RC was relatively low (54 y) and approximately two-thirds of women had locally advanced disease. Moreover, 49% of the patients had nonpure urothelial carcinoma pathology, which is often associated with severely impaired prognosis after RC [1,11,16]. Despite this, after 15 years of follow-up, recurrence-free survival was relatively high (66%). These data support the soundness of our preoperative clinical decision making and the long-term oncologic efficacy of ileal neobladder in women. In multivariable analysis, tumor stage and nodal involvement were found to be independently associated with overall recurrence. Both parameters represent risk factors for recurrence that have been reported in numerous studies [11,17–21]. One of the aims of this study was to investigate whether preoperative cystoscopic exclusion of a tumor at the bladder Table 2 Location of recurrence in the 297 female patients with ileal neobladder Location of recurrence
Patients, number (%)
Solitary local Solitary distant Concomitant local and distant Solitary urethral Concomitant urethral and local Concomitant urethral and distant Solitary ureteral
32 28 13 2 1 4 1
(10.8) (9.4) (4.4) (0.6) (0.3) (1.2) (0.3)
neck reliably predicts a negative final urethral margin at RC, thus possibly obviating the need for routine frozen-section analysis. This issue is pertinent, as previous studies have demonstrated that concomitant urethral malignancy is present in up to 40% of women with tumors at the bladder neck [22]. In contrast to the low rate (approximately 2%) of concomitant urethral malignancy in women with primary BC [23], a higher rate of urethral malignancy at RC (up to 7%) has been reported previously [1]. By contrast, in the present series, only 2.4% of the women displayed a malignant urethral margin at final analysis. This is because of the common practice in all participating centers to consider only patients for an orthotopic approach when preoperative cystoscopic assessment reveals no evidence of malignancy at the bladder neck. However, although the bladder neck was preoperatively and postoperatively considered tumor free in all patients, 7 patients had a malignant distal urethral margin at final analysis (2.4%). It should be noted that all of these patients had a negative result on FSA of the distal urethral margin and only 1 had bladder CIS. With regard to the inaccuracy of intraoperative FSA to reliably detect malignant margins, these data suggest that a carefully obtained preoperative biopsy of the bladder neck may be oncologically equivalent when compared with frozen-section analysis of the distal urethral margin for appropriate selection of patients for an OBS. The aim of this study was not to statistically validate existing observations or strategies, as recommendations on the role of FSA of the urethral margin at RC in women are based on smaller singlecenter series [1]. The rationale for excluding women with involvement of bladder neck is based on prior studies. In these studies, the risk of tumor involvement of the distal urethra at RC was found to be significantly higher in patients with bladder neck involvement and preoperatively enlarged inguinal lymph nodes, as up to 40% with bladder neck tumors exhibited concomitant urethral malignancy [22,24,25]. A detailed histopathologic study of 67 cystectomy specimens obtained from women showed that concomitant urethral cancers were located exclusively in the proximal or middle urethra, whereas the distal third was tumor free. This study also confirmed that
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Table 3 Tumor stage, condition at the bladder trigone/neck, final urethral margin status, presence of CIS histology, and site of urethral recurrence in the 7 patients with urethral recurrence Patient
Stage
Trigone
Neck
Final urethral margin
Bladder CIS at RC
Histology
Site of urethral recurrence
1 2 3 4 5 6 7
pT3aN0 pT2bN0 pTaN0 pT2aN0 pTaN0 pTisN0 pT2aN0
NED NED NED NED NED NED NED
NED NED NED NED NED NED NED
NED NED NED NED EDa NED NED
NED NED NED NED NED EDa NED
UC UC/SCC UC UC UC UC SCC
Neobladder outlet Proximal Distal Proximal Proximal Proximal Proximal
a CIS ¼ carcinoma in situ; ED ¼ evidence of disease; NED ¼ no evidence of disease; Rec ¼ recurrence; SCC ¼ squamous cell carcinoma; UC ¼ urothelial carcinoma.
localization of the primary tumor at the bladder neck correlated strongly with concomitant urethral malignancy. These tumors were of a higher grade and stage and harbored a higher risk of node-positive disease [24]. Stein et al. [22] also prospectively evaluated cystectomy specimens in 71 women and reported tumor localization at the bladder neck and in the urethra in 19% and 7% of the cases, respectively. Bladder neck involvement correlated significantly with the highest risk of concomitant urethral malignancy. In the present study, urethral margins were positive in 7 patients at definitive histopathologic analysis, whereas UR was seen only in one. Altogether, UR was seen in 7 of the 297 patients (2.4%). These data are in line with previous smaller series reporting the risk of UR to range between 1% and 4% [4,16,26,27]. Strikingly, none of our patients with UR had a positive distal urethral margin on FSA. By contrast, a positive final distal urethral margin was present in only 1 of the 7 patients (14.3%), which was associated with a significantly increased risk of UR. However, these results have to be interpreted carefully owing to the relatively low number of included cases. We also aimed to assess the effect of lymph node tumor involvement on the risk of UR in the context of an adequately performed lymph node dissection (in the present series a median of 19 removed lymph nodes). Positive lymph nodes were found in 20% of the patients. Lymph node tumor involvement was significantly associated with overall recurrence, but not with UR. Moreover, 6 of the 7 women with UR had organ-confined disease at RC (rpT2bN0). We
also investigated the effect of tumor location at the bladder trigone as a risk factor for subsequent UR [6] but did not find any significant association. As recurrence was observed in 5 women with pure UC and only in 1 woman with mixed SCC and UC as well as 1 woman with pure SCC, these data suggest that the risk of UR in women derives mainly from urothelial carcinoma histology. Altogether, these data support the assumption that women with limited lymph node–positive disease (pN1-2) or primary tumor at the bladder trigone, or both, can safely undergo an orthotopic bladder substitution if preoperative assessment excludes the presence of bulky lymph node disease and involvement of the bladder neck. This study has limitations inherent to any retrospective and multicenter analysis, such as lack of data on prior treatment, possible delay between diagnosis and treatment, and exclusion of women with bladder neck involvement or a positive urethral margin at FSA. Despite our efforts to set up this multicenter study, the relatively low number of UR cases precluded the performance of a multivariable analysis. As the number of patients with involvement of the bladder trigone and UR is relatively low, results have to be interpreted carefully. Another limitation is the (possible) pathologic interobserver variability, absence of central pathologic review and the high rate of nonurothelial carcinoma pathology. We could also not adjust for the number of surgeons, their surgical preferences and experiences, and different neobladder techniques. However, all women were treated in centers dedicated to the treatment of muscle-invasive BC and orthotopic neobladder reconstruction. As our study excluded
Table 4 Univariable and multivariable analyses of risk factors for overall recurrence Variable
Univariable a
ZpT3a vs. rpT2b pNþ vs. pN0 Positive vs. negative Final urethral margin Bladder trigone involvement (present vs. not present) Carcinoma in situ at RC a
HR ¼ hazard ratio.
Multivariable
HR (95% CI)
P value
HR (95% CI)
P value
1.9 (1.1–3.3) 2.3 (1.4–3.7) 2.5 (0.6–6.8)
0.013 0.001 0.16
1.9 (1.1–3.5) 2.1 (1.2–3.5) 3.6 (0.8–11.0)
0.015 0.007 0.09
1.0 (0.3–2.1)
0.93
0.6 (0.2–1.6)
0.35
0.7 (0.1–2.2)
0.58
0.6 (0.1–2.3)
0.47
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5. Conclusions
Table 5 Univariable analysis for urethral recurrence Variable
Univariable, P value
ZpT3a vs. rpT2b pNþ vs. pN0 Positive vs. negative Final urethral margin Bladder trigone involvement (present vs. not present) Carcinoma in situ at RC
0.32 0.88 o0.001 0.45 0.21
patients from OBS in case of a positive finding on FSA, we cannot retrospectively assess the accuracy of FSA to detect malignant urethral margins at RC. In previous studies, FSA of the distal urethral margin showed a 100% sensitivity and specificity for detection of a positive final urethral margin [22]. As in our series, only 1 patient who subsequently experienced UR demonstrated a positive final urethral margin status, one must be mindful of a possible submucosal extension of the primary bladder tumor into the urethra with the urothelial layer remaining unaffected at FSA [25]. In this study, as UR often occurred in the proximal urethra despite negative urethral margins on FSA and tumor-free bladder necks, these data highlight the importance of an adequate fullthickness biopsy of the urethral margin for FSA [8]. Therefore, based on the present data, we must acknowledge that the pathogenesis of UR in women after RC is still poorly understood. For UR, SCC may have a different tumor biology compared with UC. Strikingly, UR occurred only in 1 woman with pure SCC although 43% of our patients had pure SCC. The question that derives from this observation is why women with UC are at higher risk for UR compared with those with SCC, although the risk for developing local or distant recurrence does not seem to differ between both histologic entities. As preoperative assessment was conducted similarly between centers, it seems unlikely that this finding may be related to different preoperative workup strategies. Another possible explanation may be that the invasive urothelial tumors may have developed because of a cancerfield defect of the urothelium (including the remnant urothelium) whereas the reason for developing SCC is linked to chronic cystitis with Schistosoma haematobium. As highlighted in Table 2, most women with UR exhibit organ-confined disease, but the rate of recurrence is very low. Thus, we think that even if we performed adjusted matched-pairs analysis, we would not obtain statistically robust results. Therefore, from a clinical perspective, we need to identify UR at the earliest possible stage as UR in early stages is associated with improved survival [1]. As the pathogenesis of UR in women after RC is still poorly understood, we think that performance of a whole-genome analysis would be helpful in identifying genetic risk factors in these 7 cases. This may be used to prospectively advocate the use of OBS in women and intensify followup investigations in those at highest risk of UR.
In this long-term, multi-institutional series of women undergoing RC with ileal neobladder, 15-year recurrence-free and OS rates were 66% and 55%, respectively. Although approximately two-thirds of the women presented with locally advanced disease at RC, only 0.6% of them developed solitary UR. A positive final urethral margin was associated with UR. Women with involvement of the bladder trigone and positive nodes were not at increased risk of UR. These data provide further evidence for the oncologic safety of OBSs in women with invasive BC. References [1] Gakis G, Efstathiou JA, Lerner SP, Cookson MS, Keegan KA, Guru KA, et al. ICUD-EAU International Consultation on Bladder Cancer 2012: radical cystectomy and bladder preservation for muscle-invasive urothelial carcinoma of the bladder. Eur Urol 2013;63:45–57. [2] Stenzl A, Jarolim L, Coloby P, Golia S, Bartsch G, Babjuk M, et al. Urethra-sparing cystectomy and orthotopic urinary diversion in women with malignant pelvic tumors. Cancer 2001;92:1864–71. [3] Jentzmik F, Schrader AJ, de Petriconi R, Hefty R, Mueller J, Doetterl J, et al. The ileal neobladder in female patients with bladder cancer: long-term clinical, functional, and oncological outcome. World J Urol 2012;30:733–9. [4] Stein JP, Penson D, Lee C, Cai J, Miranda G, Skinner DG. Long-term oncological outcomes in women undergoing radical cystectomy and orthotopic diversion for bladder cancer. J Urol 2009;181:2052–8. [5] Chen ME, Pisters LL, Malpica A, Pettaway CA, Dinney CP. Risk of urethral, vaginal and cervical involvement in patients undergoing radical cystectomy for bladder cancer: results of a contemporary cystectomy series from M. D. Anderson Cancer Center. J Urol 1997;157:2120–3. [6] Kochakarn W, Chaimuangraj S, Leenanupunth C, Muangman V. Risk factors of urethral involvement of bladder cancer after radical cystectomy with orthotopic neobladder in females. J Med Assoc Thai 2001;84:889–92. [7] Gakis G, Jentzmik F, Schrader M, Stenzl A, Sievert KD. Benefits and risks of orthotopic neobladder reconstruction in female patients. Aktuelle Urol 2011;42:109–14. [8] Stein JP, Penson D, Wu SD, Skinner DG. Pathological guidelines for orthotopic urinary diversion in women with bladder cancer: a review of the literature. J Urol 2007;178:756–60. [9] Hrbacek J, Macek P, Ali-El-Dein B, Thalmann GN, Stenzl A, Babjuk M, et al. Treatment and outcomes of urethral recurrence of urinary bladder cancer in women after radical cystectomy and orthotopic neobladder: a series of 12 cases. Urol Int 2015;94(1):45–9. [10] Witjes JA, Comperat E, Cowan NC, De Santis M, Gakis G, Lebret T, et al. EAU guidelines on muscle-invasive and metastatic bladder cancer. Eur Urol 2014;65:778–92. [11] Ghoneim MA, Abdel-Latif M, el-Mekresh M, Abol-Enein H, Mosbah A, Ashamallah A, et al. Radical cystectomy for carcinoma of the bladder: 2,720 consecutive cases 5 years later. J Urol 2008;180:121–7. [12] Hautmann RE, de Petriconi R, Gottfried HW, Kleinschmidt K, Mattes R, Paiss T. The ileal neobladder: complications and functional results in 363 patients after 11 years of followup. J Urol 1999;161:422–7. [13] Hautmann RE, de Petriconi R, Volkmer BG. Lessons learned from 1,000 neobladders: the 90-day complication rate. J Urol 2010;184: 990–4. [14] Sobin DH, Wittekind C. TNM classification of malignant tumours, 6th ed. New York: Wiley-Liss; 2002. [15] Epstein JI, Amin MB, Reuter VR, Mostofi FK. The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary
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