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Significance of Bladder Neck Involvement in Risk Substratification of Intermediate-Risk Non–muscle-invasive Bladder Cancer
EUF-863; No. of Pages 7 E U RO P E A N U R O L O GY F O C U S X X X ( 2 019 ) X X X– X X X
available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus
Significance of Bladder Neck Involvement in Risk Substratification of Intermediate-Risk Non–muscle-invasive Bladder Cancer Hiroshi Fukushima, Shingo Moriyama, Yuma Waseda, Shohei Fukuda, Sho Uehara, Hajime Tanaka, Toshiki Kijima, Soichiro Yoshida, Minato Yokoyama, Junichiro Ishioka, Yoh Matsuoka, Kazutaka Saito, Yasuhisa Fujii * Department of Urology, Tokyo Medical and Dental University, Tokyo, Japan
Article info Associate Editor: Richard Lee
Keywords: Bladder neck involvement Non–muscle-invasive bladder cancer Progression Risk substratification
Abstract Background: Intermediate-risk non–muscle-invasive bladder cancer (NMIBC) involves heterogeneous patients, resulting in uncertainty regarding its prognosis and the indication of adjuvant therapy. Previous studies suggested a correlation between tumor location, especially bladder neck involvement (BNI), and patient prognosis of NMIBC. Objective: We investigated the role of BNI in risk substratification of intermediate-risk NMIBC patients. Design, setting, and participants: This single-institutional study included 436 primary or recurrent intermediate-risk NMIBC patients based on risk stratification in the European Association of Urology guidelines. Intervention: All patients underwent transurethral resection of the bladder tumor. Outcome measurements and statistical analysis: The primary and secondary endpoints were progression and recurrence, respectively. The associations of BNI with the endpoints were examined using the Kaplan-Meier method and the Cox proportional hazards model. Results and limitations: Overall, 205 (47%) patients had multiple tumors and 276 (63%) underwent intravesical therapy. BNI was observed in 53 (12%) patients. During the median follow-up of 42 mo,12 (3%) and 211 (48%) patients experienced progression and recurrence, respectively. Multivariate analysis showed that BNI was an independent predictor for both progression (hazard ratio 10.98, p < 0.001) and recurrence (hazard ratio 2.12, p < 0.001). The progression rate was significantly higher in patients with BNI compared with those without BNI (13% vs 1% at 3 yr and 20% vs 1% at 6 yr; p < 0.001). Analogous findings were observed for recurrence. The progression rate was more remarkably stratified by BNI in 103 recurrent cases (17% vs 3% at 3 yr and 34% vs 3% at 6 yr in patients with vs without BNI; p < 0.001). A limitation of this study was its retrospective nature. Conclusions: BNI substratified intermediate-risk NMIBC patients well regarding their risks of progression and recurrence, which could help determine follow-up and therapeutic strategies for these patients. Patient summary: The associations of bladder neck involvement with progression and recurrence were evaluated in patients with intermediate-risk non–muscle-invasive bladder cancer. We found that bladder neck involvement was a good factor for substratifying patients based on their risks of progression and recurrence. Bladder neck involvement can be useful in determining follow-up and therapeutic strategies for intermediate-risk non–muscle-invasive bladder cancer. © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Corresponding author. Department of Urology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. Tel. +81-3-5803-5295; Fax: +81-3-5803-5295. E-mail address: [email protected] (Y. Fujii).
https://doi.org/10.1016/j.euf.2020.01.006 2405-4569/© 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Fukushima H, et al. Significance of Bladder Neck Involvement in Risk Substratification of Intermediate-Risk Non–muscle-invasive Bladder Cancer. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.01.006
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1.
Introduction
Bladder cancer is the sixth most common malignancy in males worldwide, with approximately 429 800 new cases and 165 100 deaths from bladder cancer in 2012 [1]. It is classified into the following two groups based on the stage: non–muscle-invasive bladder cancer (NMIBC) and muscleinvasive bladder cancer (MIBC). MIBC is a lethal disease and the gold standard treatment is radical cystectomy. The prognosis for patients with NMIBC is relatively favorable and it is generally treated with bladder-preservation therapy including transurethral resection of the bladder (TURB) tumor. However, about a half of NMIBC patients experience recurrence, and 10–15% eventually progress to MIBC [2,3]. To predict recurrence and progression in NMIBC patients, the risk groups were stratified into low-, intermediate-, and high-risk groups, based on the European Association of Urology (EAU) and International Bladder Cancer Group (IBCG) guidelines that have been used widely in contemporary clinical practice [4,5]. These guidelines clearly classified low- and high-risk groups. However, the intermediate-risk group has traditionally included very heterogeneous patients who do not fit into the low- or high-risk group, resulting in uncertainty regarding its prognosis and the indication of adjuvant intravesical therapy [6]. Thus, risk substratification of the intermediate-risk group can be helpful in determining the follow-up and therapeutic strategies. However, there are few established prognostic factors or models for this group [6,7]. Previous studies including ours reported that tumor location was related to the prognosis in NMIBC patients [2,8–12]. We revealed that bladder neck involvement (BNI) was a significant and independent predictor of recurrence and progression in NMIBC patients [2,8–10]. Similarly, Kurth et al [11] reported BNI as one of the predictors of progression in their univariate analysis. Moreover, Vukomanovic et al [12] showed that bladder neck tumors had a significantly higher recurrence rate following intravesical bacillus Calmette-Guérin (BCG) therapy in high-grade NMIBC patients. Thus, clinical information regarding tumor location, especially BNI, may contribute to risk substratification of intermediate-risk NMIBC patients. In the present study, we investigated the prognostic value of BNI in intermediate-risk NMIBC patients and its role in their risk substratification.
2.
Patients and methods
2.1.
Patients
We retrospectively reviewed 747 NMIBC patients who underwent TURB at Tokyo Medical and Dental University Hospital from January 2000 to April 2018. All the tumors were pathologically diagnosed as urothelial carcinoma, which was graded according to the 1973 World Health Organization grading system [13] and staged according to the 2002 American Joint Committee on Cancer TNM classification [14]. Risk group stratification was according to the
EAU guidelines: (1) low risk: primary, solitary, TaG1, <3 cm, and no carcinoma in situ; (2) intermediate risk: all tumors between the categories of low and high risk; and (3) high risk: any of the following: T1 tumor, G3 tumor, carcinoma in situ, or multiple, recurrent, and large (>3 cm) Ta G1/2 tumors [4]. The presence of carcinoma in situ was determined based on pathological reports. Our review identified 451 primary or recurrent intermediate-risk NMIBC patients. Thirteen patients with missing data and two male patients who had tumors in the prostatic urethra were excluded, and the remaining 436 patients were included in the analysis. The institutional review board approved the present study. We basically plan a second TURB in case of pT1 tumors, incomplete initial TURB, and doubt about complete resection at initial TURB. In the present study, no intermediaterisk NMIBC patients underwent a second TURB because tumors were thought to be completely resected at initial TURB. Patients were routinely followed up with cystoscopy and voided urine cytology every 3 mo for the first 2 yr, every 6 mo for the next 3 yr, and yearly thereafter. Ultrasonography, computed tomography, and/or magnetic resonance imaging were conducted as appropriate to evaluate the upper urinary tract. Patients routinely received single-dose intravesical chemotherapy with doxorubicin immediately after TURB. Six to eight weekly instillations of BCG or chemotherapy with doxorubicin or mitomycin were administered approximately 4 wk after TURB. Basically, intravesical BCG therapy was indicated for recurrent tumors, and repeated chemotherapy instillations were conducted in patients with multiple or recurrent tumors in whom BCG therapy was avoided. Intravesical chemotherapy agents were determined at the discretion of urologists. 2.2.
Variables
The following variables were analyzed: age at TURB, sex, tumor size, tumor architecture, tumor multiplicity, BNI, voided urine cytology, tumor grade, any intravesical therapy, and European Organization Research Treatment of Cancer (EORTC) score [3]. Urologists who conducted TURB determined tumor location including BNI. The definition of BNI was a tumor located adjacent to the bladder neck, within approximately 1 cm of the internal urethral orifice, but not in the urethra [8–10]. Voided urine cytology was preoperatively evaluated without any interventions in the urinary tract. Reports of preoperative voided urine cytology of class IIIb were considered to be positive urine cytology results because class IIIb was defined as cytological findings that were suspicious of, but not conclusive for, malignancy with advanced dysplasia [15]. The “IBCG model,” which was proposed by the IBCG to stratify the intermediate-risk NMIBC, was an algorithm that included the following parameters: multiple tumors, tumor size >3 cm, early recurrence (<1 yr), and frequent recurrence (>1/yr) [6,7]. 2.3.
Endpoint
The primary endpoint in the present study was progression, which was defined as the development of pathologically
Please cite this article in press as: Fukushima H, et al. Significance of Bladder Neck Involvement in Risk Substratification of Intermediate-Risk Non–muscle-invasive Bladder Cancer. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.01.006
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confirmed muscle invasion or metastatic disease that was detected by imaging studies. The secondary endpoint was recurrence. Recurrence was defined as the occurrence of new bladder tumors that were pathologically confirmed. The time to recurrence and progression was calculated from the date of TURB. 2.4.
3.
Results
3.1.
Patient characteristics
Table 1 shows the overall patient characteristics. The median (interquartile range) age was 68 (60–76) yr, and 339 (78%) and 97 (22%) of patients were male and female, respectively. A total of 333 (76%) and 103 (24%) patients had primary and recurrent tumors, respectively, and 205 (47%) had multiple tumors. Among the 436 patients, 276 (63%) had the following intravesical instillations during their follow-up examinations: doxorubicin or mitomycin (n = 198), BCG (n = 52), and BCG and doxorubicin or mitomycin (n = 26). BNI was observed in 53 (12%) patients. BNI was significantly associated with a higher prior recurrence rate (p = 0.024), multiple tumors (p = 0.003), anterior (p = 0.016) and posterior (p = 0.024) wall tumors, positive urine cytology (p < 0.001), intravesical BCG therapy (p = 0.004), and a higher EORTC score for recurrence (p < 0.001) and progression (p < 0.001).
Statistical analysis
Categorical and continuous variables were compared using the chi-square test and the Mann-Whitney U test, respectively. The probabilities of recurrence and progression were estimated using the Kaplan-Meier method, and the statistical significance of the difference between curves was assessed using the log-rank test. Factors predicting recurrence and progression were examined using the Cox proportional hazards model. Variables with p <0.10 in the univariate analysis were entered into the multivariate analysis. Reduced multivariate models were constructed using the stepwise backward method. The predictive ability of prognostic models for progression was assessed using Harrell’s c-index, which is analogous to the area under the receiver operating characteristic curve for censored data. One thousand bootstrap resamples were used for internal validation of the accuracy estimates. JMP 9.0.2 (SAS Institute Inc., Cary, NC, USA) and R version 3.3.3 (R Foundation for Statistical Computing, Vienna, Austria) were used for all statistical analyses. Two-tailed p <0.05 was defined as statistically significant.
3.2.
Factors associated with progression
The median (interquartile range) follow-up was 42 (17–84) mo. Progression occurred in 12 (3%) patients (seven patients with BNI and five without BNI) during the follow-up period. The overall progression probability at both 3 and 6 yr was
Table 1 – Patient characteristics. Variables
No. of patients Age, median (IQR) Sex Prior recurrence rate
Tumor size (cm) Tumor architecture Multiplicity Tumor location
Voided urine cytology Tumor grade Intravesical therapy
EORTC score, median (IQR)
– Male Female Primary 1/yr >1/yr <3 3 Papillary Nonpapillary Solitary Multiple Anterior wall Posterior wall Dome Left lateral wall Right lateral wall Trigone Positive Negative G1 G2 No Adriamycin or mitomycin BCG Recurrence Progression
Total cohort
BNI
p value
n (%)
Yes, n (%)
No, n (%)
436 68 (60–76) 339 (78) 97 (22) 333 (76) 50 (11) 53 (12) 401 (92) 35 (8) 421 (97) 15 (3) 231 (53) 205 (47) 31 (7) 131 (30) 27 (6) 139 (32) 137 (31) 86 (20) 70 (16) 366 (84) 28 (6) 408 (94) 160 (37) 224 (51) 78 (18) 3.0 (1.0–4.0) 2.0 (0–3.0)
53 (12) 66 (57–73) 43 (81) 10 (19) 35 (66) 12 (23) 6 (11) 46 (87) 7 (13) 50 (94) 3 (6) 18 (34) 35 (66) 8 (15) 23 (43) 5 (9) 14 (26) 18 (34) 13 (25) 17 (32) 36 (68) 2 (4) 51 (96) 18 (34) 23 (43) 17 (32) 4.0 (3.5–7.0) 3.0 (2.0–5.0)
383 (88) 68 (60–76) 296 (77) 87 (23) 298 (78) 38 (10) 47 (12) 355 (93) 28 (7) 371 (97) 12 (3) 213 (56) 170 (44) 23 (6) 108 (28) 22 (6) 125 (33) 119 (31) 73 (19) 53 (14) 330 (86) 26 (7) 357 (93) 142 (37) 201 (52) 61 (16) 3.0 (1.0–4.0) 2.0 (0–3.0)
0.084 0.53 0.024
0.14 0.34 0.003 0.016 0.024 0.30 0.36 0.67 0.35 <0.001 0.40
0.21 0.004 <0.001 <0.001
BCG = bacillus Calmette-Guérin; BNI = bladder neck involvement; EORTC = European Organization Research Treatment of Cancer; IQR = interquartile range.
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3%. Univariate analysis showed that a higher prior recurrence rate (p = 0.009) and BNI (p < 0.001) were significantly associated with progression (Table 2). On multivariate analysis, BNI was a significant and independent predictor of progression (hazard ratio 10.98, p < 0.001) along with a higher prior recurrence rate (p = 0.041). 3.3.
Factors associated with recurrence
Recurrence occurred in 211 (48%) patients (36 patients with BNI and 175 patients without BNI) during the follow-up period. The overall recurrence probabilities at 3 and 6 yr were 51% and 63%, respectively. The variables that were significantly associated with recurrence on univariate analysis were as follows: a higher prior recurrence rate, multiple tumors, BNI, and intravesical therapy (all p < 0.001; Supplementary Table 1). On multivariate analysis, BNI was a significant and independent predictor of recurrence (hazard ratio 2.12, p < 0.001) along with multiple tumors (p = 0.029) and intravesical therapy (p < 0.001). BNI was independently associated with recurrence (hazard ratio 2.06, p < 0.001) when intravesical therapy was excluded from the multivariate analysis (detailed data not shown). 3.4.
Risk substratification by BNI
Based on the result of our multivariate analyses, we substratified the intermediate-risk NMIBC patients into two groups using BNI. The probability of progression at 3 and 6 yr was significantly higher in patients with BNI than in those without BNI (13%/20% vs 1%/1%, p < 0.001; Fig. 1A). Similarly, the probability of recurrence at 3 and 6 yr was significantly higher in patients with BNI than in those without BNI (82%/86% vs 47%/60%, p < 0.001; Fig. 1B).
We further conducted risk substratification in the subgroups of the primary and recurrent patients. In the subgroup of 333 primary intermediate-risk NMIBC patients, the probability of progression at 3 and 6 yr was 12% in patients with BNI and 1% in those without BNI (p = 0.004; Fig. 2A). In the subgroup of 103 recurrent cases, the probabilities of progression at 3 and 6 yr were, respectively, 17% and 34% in patients with BNI, and the probability was 3% at both 3 and 6 yr in those without BNI (p < 0.001; Fig. 2B). Finally, we evaluated the predictive ability of BNI for progression by Harrell’s c-index. The c-index of BNI to predict progression was 0.725. The c-index of the IBCG model, which includes multiple tumors, tumor size >3 cm, early recurrence (<1 yr), and frequent recurrence (>1/ yr) [6,7], was 0.649. When BNI was added to the IBCG model, the c-index improved to 0.746.
4.
Discussion
We demonstrated that BNI was a significant and independent predictor of progression of intermediate-risk NMIBC patients in the present study. BNI was also an independent predictor for recurrence. Progression probability curves were clearly separated by BNI; the probabilities of progression at 3 and 6 yr in patients with BNI were 13% and 20%, respectively, which were significantly worse compared with the probabilities in those without BNI (both 1%). In the subgroup of recurrent cases, the probabilities of progression at 3 and 6 yr were 17% and 34%, respectively, in patients with BNI. Thus, BNI is a good factor for substratifying intermediate-risk NMIBC patients. Given the very low risk of progression in the intermediate-risk patients without BNI, they may safely avoid adjuvant intravesical therapy
Table 2 – Cox proportional hazards analysis for progression. Variables
Age Sex Prior recurrence rate
Tumor size (cm) Tumor architecture Tumor multiplicity BNI Positive urine cytology Tumor grade Intravesical therapy
Continuous Female Male Primary 1/yr >1/yr <3 3 Papillary Nonpapillary Solitary Multiple No Yes No Yes G1 G2 No Yes
Univariate
Multivariate
p value
HR
95% CI
Ref. 4.88 3.34
1.36–19.49 0.46–17.60
Ref. 10.98
3.29–39.72
p value
0.23 0.72 0.009
0.041
0.77 0.52 0.48 <0.001
<0.001
0.12 0.80 0.30
BNI = bladder neck involvement; CI = confidence interval; HR = hazard ratio; Ref. = reference.
Please cite this article in press as: Fukushima H, et al. Significance of Bladder Neck Involvement in Risk Substratification of Intermediate-Risk Non–muscle-invasive Bladder Cancer. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.01.006
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Fig. 1 – (A) Progression and (B) recurrence probability curves based on bladder neck involvement in intermediate-risk non–muscle-invasive bladder cancer patients. BNI = bladder neck involvement.
and intensive follow-up by cystoscopy. Owing to high recurrence and progression rates in patients with BNI, adjuvant intravesical BCG therapy with maintenance or, especially in recurrent cases, radical cystectomy can be a treatment option for these patients. In the present study, BNI was not associated with a higher tumor grade. However, the prognostic significance of BNI can be explained by the biological aggressiveness of bladder neck tumors because BNI was significantly associated with positive urine cytology. Positive urine cytology represents the presence of atypical cells and the fragility of cancer cells’ intercellular adhesion [16]. Thus, bladder neck tumors may have a higher invasive potential because the loss of intercellular adhesion is a critical biological process by which cancer cells invade into the surrounding tissues. Recently, Weiner et al [17] showed that trigone and bladder neck tumors were associated with higher rates of nodal involvement in bladder cancer patients who were treated with radical cystectomy, suggesting their higher invasive and metastatic potential. Although the mechanism that facilitates biological aggressiveness of bladder neck tumors is unclear, cancer stem cell theory might be related to their
5
Fig. 2 – Progression probability curves based on bladder neck involvement in the subgroups of the (A) primary and (B) recurrent intermediate-risk non–muscle-invasive bladder cancer patients. BNI = bladder neck involvement.
high malignant potential [18]. As a previous study using the rat bladder indicated that urothelial stem cells are mostly located at the trigone and bladder neck, cancer stem cells may be highly distributed in these areas of the bladder [19]. Moreover, the significance of BNI for predicting progression and recurrence may have an anatomical explanation. Transurethral resection of bladder neck tumors can be technically difficult, resulting in incomplete resection of the tumors. However, because intermediate-risk tumors are basically of low grade and low stage, it is unreasonable for residual tumors to develop MIBC after TURB. Several previous studies reported the risk substratification of intermediate-risk NMIBC. Matsumoto et al [20] showed that patients with a low-grade tumor that recurred after a high-risk tumor had higher recurrence rates than those with a low-grade tumor that recurred after a low-risk tumor and those with initial multiple low-grade tumors; however, progression rates were not significantly different among the three groups. IBCG recommended substratification of intermediate-risk NMIBC using an algorithm including multiple tumors, tumor size >3 cm, early recurrences
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(<1 yr), and frequent recurrences (>1/yr) [6,7]. However, the predictive ability of the IBCG model for progression was lower compared with BNI in the present study. Moreover, because the IBCG model includes four factors, our risk substratification by BNI is simple and easy to use in clinical practice. The present study has several limitations. First, the present study is a retrospective single-institutional study. Our findings should be validated using a prospective multi-institutional cohort. BNI was independently associated with progression in high-risk NMIBC patients of our cohort (Supplementary Table 2), which supports the prognostic significance of BNI. Second, no patients underwent a second TURB in the present study. However, tumor characteristics and prognoses in the present study are similar to those in a previous study reported by Sylvester et al [3], suggesting adequate resection during our initial TURB. Third, smoking status was not available in all patients of our cohort and excluded from analysis. Fourth, the rate of intravesical BCG therapy is relatively low in our cohort. Thus, we could not evaluate the impact of BNI on the therapeutic response of intravesical BCG therapy in intermediate-risk NMIBC patients. Finally, we did not evaluate the role of BNI in the development of prostatic stromal invasion. This should be elucidated in future studies because silent prostatic stromal invasion can occur through the bladder neck directly into the prostatic stroma [21].
Funding/Support and role of the sponsor: This research was supported by JSPS KAKENHI Grant Number JP26462403. The funder did not play any role in the study design, collection, analysis, or interpretation of data, or in the drafting of this paper.
Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10. 1016/j.euf.2020.01.006.
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We demonstrated that BNI was able to substratify intermediate-risk NMIBC patients well regarding their risks of progression and recurrence. Although our preliminary findings should be confirmed by prospective multi-institutional studies, the present study indicates the clinical relevance of BNI in managing intermediate-risk NMIBC patients.
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Author contributions: Yasuhisa Fujii had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Fukushima, Fujii. Acquisition of data: Fukushima, Moriyama, Waseda, Yokoyama. Analysis and interpretation of data: Fukushima, Tanaka. Drafting of the manuscript: Fukushima. Critical revision of the manuscript for important intellectual content: Fukuda, Uehara, Tanaka, Kijima, Yoshida, Yokoyama, Ishioka, Matsuoka, Saito, Fujii. Statistical analysis: Fukushima, Waseda. Obtaining funding: Fujii. Administrative, technical, or material support: None. Supervision: Fujii. Other: None.
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Financial disclosures: Yasuhisa Fujii certifies that all conflicts of interest, including specific financial interests and relationships and affiliations
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available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus
Significance of Bladder Neck Involvement in Risk Substratification of Intermediate-Risk Non–muscle-invasive Bladder Cancer Hiroshi Fukushima, Shingo Moriyama, Yuma Waseda, Shohei Fukuda, Sho Uehara, Hajime Tanaka, Toshiki Kijima, Soichiro Yoshida, Minato Yokoyama, Junichiro Ishioka, Yoh Matsuoka, Kazutaka Saito, Yasuhisa Fujii * Department of Urology, Tokyo Medical and Dental University, Tokyo, Japan
Article info Associate Editor: Richard Lee
Keywords: Bladder neck involvement Non–muscle-invasive bladder cancer Progression Risk substratification
Abstract Background: Intermediate-risk non–muscle-invasive bladder cancer (NMIBC) involves heterogeneous patients, resulting in uncertainty regarding its prognosis and the indication of adjuvant therapy. Previous studies suggested a correlation between tumor location, especially bladder neck involvement (BNI), and patient prognosis of NMIBC. Objective: We investigated the role of BNI in risk substratification of intermediate-risk NMIBC patients. Design, setting, and participants: This single-institutional study included 436 primary or recurrent intermediate-risk NMIBC patients based on risk stratification in the European Association of Urology guidelines. Intervention: All patients underwent transurethral resection of the bladder tumor. Outcome measurements and statistical analysis: The primary and secondary endpoints were progression and recurrence, respectively. The associations of BNI with the endpoints were examined using the Kaplan-Meier method and the Cox proportional hazards model. Results and limitations: Overall, 205 (47%) patients had multiple tumors and 276 (63%) underwent intravesical therapy. BNI was observed in 53 (12%) patients. During the median follow-up of 42 mo,12 (3%) and 211 (48%) patients experienced progression and recurrence, respectively. Multivariate analysis showed that BNI was an independent predictor for both progression (hazard ratio 10.98, p < 0.001) and recurrence (hazard ratio 2.12, p < 0.001). The progression rate was significantly higher in patients with BNI compared with those without BNI (13% vs 1% at 3 yr and 20% vs 1% at 6 yr; p < 0.001). Analogous findings were observed for recurrence. The progression rate was more remarkably stratified by BNI in 103 recurrent cases (17% vs 3% at 3 yr and 34% vs 3% at 6 yr in patients with vs without BNI; p < 0.001). A limitation of this study was its retrospective nature. Conclusions: BNI substratified intermediate-risk NMIBC patients well regarding their risks of progression and recurrence, which could help determine follow-up and therapeutic strategies for these patients. Patient summary: The associations of bladder neck involvement with progression and recurrence were evaluated in patients with intermediate-risk non–muscle-invasive bladder cancer. We found that bladder neck involvement was a good factor for substratifying patients based on their risks of progression and recurrence. Bladder neck involvement can be useful in determining follow-up and therapeutic strategies for intermediate-risk non–muscle-invasive bladder cancer. © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Corresponding author. Department of Urology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. Tel. +81-3-5803-5295; Fax: +81-3-5803-5295. E-mail address: [email protected] (Y. Fujii).
https://doi.org/10.1016/j.euf.2020.01.006 2405-4569/© 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Fukushima H, et al. Significance of Bladder Neck Involvement in Risk Substratification of Intermediate-Risk Non–muscle-invasive Bladder Cancer. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.01.006
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1.
Introduction
Bladder cancer is the sixth most common malignancy in males worldwide, with approximately 429 800 new cases and 165 100 deaths from bladder cancer in 2012 [1]. It is classified into the following two groups based on the stage: non–muscle-invasive bladder cancer (NMIBC) and muscleinvasive bladder cancer (MIBC). MIBC is a lethal disease and the gold standard treatment is radical cystectomy. The prognosis for patients with NMIBC is relatively favorable and it is generally treated with bladder-preservation therapy including transurethral resection of the bladder (TURB) tumor. However, about a half of NMIBC patients experience recurrence, and 10–15% eventually progress to MIBC [2,3]. To predict recurrence and progression in NMIBC patients, the risk groups were stratified into low-, intermediate-, and high-risk groups, based on the European Association of Urology (EAU) and International Bladder Cancer Group (IBCG) guidelines that have been used widely in contemporary clinical practice [4,5]. These guidelines clearly classified low- and high-risk groups. However, the intermediate-risk group has traditionally included very heterogeneous patients who do not fit into the low- or high-risk group, resulting in uncertainty regarding its prognosis and the indication of adjuvant intravesical therapy [6]. Thus, risk substratification of the intermediate-risk group can be helpful in determining the follow-up and therapeutic strategies. However, there are few established prognostic factors or models for this group [6,7]. Previous studies including ours reported that tumor location was related to the prognosis in NMIBC patients [2,8–12]. We revealed that bladder neck involvement (BNI) was a significant and independent predictor of recurrence and progression in NMIBC patients [2,8–10]. Similarly, Kurth et al [11] reported BNI as one of the predictors of progression in their univariate analysis. Moreover, Vukomanovic et al [12] showed that bladder neck tumors had a significantly higher recurrence rate following intravesical bacillus Calmette-Guérin (BCG) therapy in high-grade NMIBC patients. Thus, clinical information regarding tumor location, especially BNI, may contribute to risk substratification of intermediate-risk NMIBC patients. In the present study, we investigated the prognostic value of BNI in intermediate-risk NMIBC patients and its role in their risk substratification.
2.
Patients and methods
2.1.
Patients
We retrospectively reviewed 747 NMIBC patients who underwent TURB at Tokyo Medical and Dental University Hospital from January 2000 to April 2018. All the tumors were pathologically diagnosed as urothelial carcinoma, which was graded according to the 1973 World Health Organization grading system [13] and staged according to the 2002 American Joint Committee on Cancer TNM classification [14]. Risk group stratification was according to the
EAU guidelines: (1) low risk: primary, solitary, TaG1, <3 cm, and no carcinoma in situ; (2) intermediate risk: all tumors between the categories of low and high risk; and (3) high risk: any of the following: T1 tumor, G3 tumor, carcinoma in situ, or multiple, recurrent, and large (>3 cm) Ta G1/2 tumors [4]. The presence of carcinoma in situ was determined based on pathological reports. Our review identified 451 primary or recurrent intermediate-risk NMIBC patients. Thirteen patients with missing data and two male patients who had tumors in the prostatic urethra were excluded, and the remaining 436 patients were included in the analysis. The institutional review board approved the present study. We basically plan a second TURB in case of pT1 tumors, incomplete initial TURB, and doubt about complete resection at initial TURB. In the present study, no intermediaterisk NMIBC patients underwent a second TURB because tumors were thought to be completely resected at initial TURB. Patients were routinely followed up with cystoscopy and voided urine cytology every 3 mo for the first 2 yr, every 6 mo for the next 3 yr, and yearly thereafter. Ultrasonography, computed tomography, and/or magnetic resonance imaging were conducted as appropriate to evaluate the upper urinary tract. Patients routinely received single-dose intravesical chemotherapy with doxorubicin immediately after TURB. Six to eight weekly instillations of BCG or chemotherapy with doxorubicin or mitomycin were administered approximately 4 wk after TURB. Basically, intravesical BCG therapy was indicated for recurrent tumors, and repeated chemotherapy instillations were conducted in patients with multiple or recurrent tumors in whom BCG therapy was avoided. Intravesical chemotherapy agents were determined at the discretion of urologists. 2.2.
Variables
The following variables were analyzed: age at TURB, sex, tumor size, tumor architecture, tumor multiplicity, BNI, voided urine cytology, tumor grade, any intravesical therapy, and European Organization Research Treatment of Cancer (EORTC) score [3]. Urologists who conducted TURB determined tumor location including BNI. The definition of BNI was a tumor located adjacent to the bladder neck, within approximately 1 cm of the internal urethral orifice, but not in the urethra [8–10]. Voided urine cytology was preoperatively evaluated without any interventions in the urinary tract. Reports of preoperative voided urine cytology of class IIIb were considered to be positive urine cytology results because class IIIb was defined as cytological findings that were suspicious of, but not conclusive for, malignancy with advanced dysplasia [15]. The “IBCG model,” which was proposed by the IBCG to stratify the intermediate-risk NMIBC, was an algorithm that included the following parameters: multiple tumors, tumor size >3 cm, early recurrence (<1 yr), and frequent recurrence (>1/yr) [6,7]. 2.3.
Endpoint
The primary endpoint in the present study was progression, which was defined as the development of pathologically
Please cite this article in press as: Fukushima H, et al. Significance of Bladder Neck Involvement in Risk Substratification of Intermediate-Risk Non–muscle-invasive Bladder Cancer. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.01.006
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confirmed muscle invasion or metastatic disease that was detected by imaging studies. The secondary endpoint was recurrence. Recurrence was defined as the occurrence of new bladder tumors that were pathologically confirmed. The time to recurrence and progression was calculated from the date of TURB. 2.4.
3.
Results
3.1.
Patient characteristics
Table 1 shows the overall patient characteristics. The median (interquartile range) age was 68 (60–76) yr, and 339 (78%) and 97 (22%) of patients were male and female, respectively. A total of 333 (76%) and 103 (24%) patients had primary and recurrent tumors, respectively, and 205 (47%) had multiple tumors. Among the 436 patients, 276 (63%) had the following intravesical instillations during their follow-up examinations: doxorubicin or mitomycin (n = 198), BCG (n = 52), and BCG and doxorubicin or mitomycin (n = 26). BNI was observed in 53 (12%) patients. BNI was significantly associated with a higher prior recurrence rate (p = 0.024), multiple tumors (p = 0.003), anterior (p = 0.016) and posterior (p = 0.024) wall tumors, positive urine cytology (p < 0.001), intravesical BCG therapy (p = 0.004), and a higher EORTC score for recurrence (p < 0.001) and progression (p < 0.001).
Statistical analysis
Categorical and continuous variables were compared using the chi-square test and the Mann-Whitney U test, respectively. The probabilities of recurrence and progression were estimated using the Kaplan-Meier method, and the statistical significance of the difference between curves was assessed using the log-rank test. Factors predicting recurrence and progression were examined using the Cox proportional hazards model. Variables with p <0.10 in the univariate analysis were entered into the multivariate analysis. Reduced multivariate models were constructed using the stepwise backward method. The predictive ability of prognostic models for progression was assessed using Harrell’s c-index, which is analogous to the area under the receiver operating characteristic curve for censored data. One thousand bootstrap resamples were used for internal validation of the accuracy estimates. JMP 9.0.2 (SAS Institute Inc., Cary, NC, USA) and R version 3.3.3 (R Foundation for Statistical Computing, Vienna, Austria) were used for all statistical analyses. Two-tailed p <0.05 was defined as statistically significant.
3.2.
Factors associated with progression
The median (interquartile range) follow-up was 42 (17–84) mo. Progression occurred in 12 (3%) patients (seven patients with BNI and five without BNI) during the follow-up period. The overall progression probability at both 3 and 6 yr was
Table 1 – Patient characteristics. Variables
No. of patients Age, median (IQR) Sex Prior recurrence rate
Tumor size (cm) Tumor architecture Multiplicity Tumor location
Voided urine cytology Tumor grade Intravesical therapy
EORTC score, median (IQR)
– Male Female Primary 1/yr >1/yr <3 3 Papillary Nonpapillary Solitary Multiple Anterior wall Posterior wall Dome Left lateral wall Right lateral wall Trigone Positive Negative G1 G2 No Adriamycin or mitomycin BCG Recurrence Progression
Total cohort
BNI
p value
n (%)
Yes, n (%)
No, n (%)
436 68 (60–76) 339 (78) 97 (22) 333 (76) 50 (11) 53 (12) 401 (92) 35 (8) 421 (97) 15 (3) 231 (53) 205 (47) 31 (7) 131 (30) 27 (6) 139 (32) 137 (31) 86 (20) 70 (16) 366 (84) 28 (6) 408 (94) 160 (37) 224 (51) 78 (18) 3.0 (1.0–4.0) 2.0 (0–3.0)
53 (12) 66 (57–73) 43 (81) 10 (19) 35 (66) 12 (23) 6 (11) 46 (87) 7 (13) 50 (94) 3 (6) 18 (34) 35 (66) 8 (15) 23 (43) 5 (9) 14 (26) 18 (34) 13 (25) 17 (32) 36 (68) 2 (4) 51 (96) 18 (34) 23 (43) 17 (32) 4.0 (3.5–7.0) 3.0 (2.0–5.0)
383 (88) 68 (60–76) 296 (77) 87 (23) 298 (78) 38 (10) 47 (12) 355 (93) 28 (7) 371 (97) 12 (3) 213 (56) 170 (44) 23 (6) 108 (28) 22 (6) 125 (33) 119 (31) 73 (19) 53 (14) 330 (86) 26 (7) 357 (93) 142 (37) 201 (52) 61 (16) 3.0 (1.0–4.0) 2.0 (0–3.0)
0.084 0.53 0.024
0.14 0.34 0.003 0.016 0.024 0.30 0.36 0.67 0.35 <0.001 0.40
0.21 0.004 <0.001 <0.001
BCG = bacillus Calmette-Guérin; BNI = bladder neck involvement; EORTC = European Organization Research Treatment of Cancer; IQR = interquartile range.
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3%. Univariate analysis showed that a higher prior recurrence rate (p = 0.009) and BNI (p < 0.001) were significantly associated with progression (Table 2). On multivariate analysis, BNI was a significant and independent predictor of progression (hazard ratio 10.98, p < 0.001) along with a higher prior recurrence rate (p = 0.041). 3.3.
Factors associated with recurrence
Recurrence occurred in 211 (48%) patients (36 patients with BNI and 175 patients without BNI) during the follow-up period. The overall recurrence probabilities at 3 and 6 yr were 51% and 63%, respectively. The variables that were significantly associated with recurrence on univariate analysis were as follows: a higher prior recurrence rate, multiple tumors, BNI, and intravesical therapy (all p < 0.001; Supplementary Table 1). On multivariate analysis, BNI was a significant and independent predictor of recurrence (hazard ratio 2.12, p < 0.001) along with multiple tumors (p = 0.029) and intravesical therapy (p < 0.001). BNI was independently associated with recurrence (hazard ratio 2.06, p < 0.001) when intravesical therapy was excluded from the multivariate analysis (detailed data not shown). 3.4.
Risk substratification by BNI
Based on the result of our multivariate analyses, we substratified the intermediate-risk NMIBC patients into two groups using BNI. The probability of progression at 3 and 6 yr was significantly higher in patients with BNI than in those without BNI (13%/20% vs 1%/1%, p < 0.001; Fig. 1A). Similarly, the probability of recurrence at 3 and 6 yr was significantly higher in patients with BNI than in those without BNI (82%/86% vs 47%/60%, p < 0.001; Fig. 1B).
We further conducted risk substratification in the subgroups of the primary and recurrent patients. In the subgroup of 333 primary intermediate-risk NMIBC patients, the probability of progression at 3 and 6 yr was 12% in patients with BNI and 1% in those without BNI (p = 0.004; Fig. 2A). In the subgroup of 103 recurrent cases, the probabilities of progression at 3 and 6 yr were, respectively, 17% and 34% in patients with BNI, and the probability was 3% at both 3 and 6 yr in those without BNI (p < 0.001; Fig. 2B). Finally, we evaluated the predictive ability of BNI for progression by Harrell’s c-index. The c-index of BNI to predict progression was 0.725. The c-index of the IBCG model, which includes multiple tumors, tumor size >3 cm, early recurrence (<1 yr), and frequent recurrence (>1/ yr) [6,7], was 0.649. When BNI was added to the IBCG model, the c-index improved to 0.746.
4.
Discussion
We demonstrated that BNI was a significant and independent predictor of progression of intermediate-risk NMIBC patients in the present study. BNI was also an independent predictor for recurrence. Progression probability curves were clearly separated by BNI; the probabilities of progression at 3 and 6 yr in patients with BNI were 13% and 20%, respectively, which were significantly worse compared with the probabilities in those without BNI (both 1%). In the subgroup of recurrent cases, the probabilities of progression at 3 and 6 yr were 17% and 34%, respectively, in patients with BNI. Thus, BNI is a good factor for substratifying intermediate-risk NMIBC patients. Given the very low risk of progression in the intermediate-risk patients without BNI, they may safely avoid adjuvant intravesical therapy
Table 2 – Cox proportional hazards analysis for progression. Variables
Age Sex Prior recurrence rate
Tumor size (cm) Tumor architecture Tumor multiplicity BNI Positive urine cytology Tumor grade Intravesical therapy
Continuous Female Male Primary 1/yr >1/yr <3 3 Papillary Nonpapillary Solitary Multiple No Yes No Yes G1 G2 No Yes
Univariate
Multivariate
p value
HR
95% CI
Ref. 4.88 3.34
1.36–19.49 0.46–17.60
Ref. 10.98
3.29–39.72
p value
0.23 0.72 0.009
0.041
0.77 0.52 0.48 <0.001
<0.001
0.12 0.80 0.30
BNI = bladder neck involvement; CI = confidence interval; HR = hazard ratio; Ref. = reference.
Please cite this article in press as: Fukushima H, et al. Significance of Bladder Neck Involvement in Risk Substratification of Intermediate-Risk Non–muscle-invasive Bladder Cancer. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.01.006
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Fig. 1 – (A) Progression and (B) recurrence probability curves based on bladder neck involvement in intermediate-risk non–muscle-invasive bladder cancer patients. BNI = bladder neck involvement.
and intensive follow-up by cystoscopy. Owing to high recurrence and progression rates in patients with BNI, adjuvant intravesical BCG therapy with maintenance or, especially in recurrent cases, radical cystectomy can be a treatment option for these patients. In the present study, BNI was not associated with a higher tumor grade. However, the prognostic significance of BNI can be explained by the biological aggressiveness of bladder neck tumors because BNI was significantly associated with positive urine cytology. Positive urine cytology represents the presence of atypical cells and the fragility of cancer cells’ intercellular adhesion [16]. Thus, bladder neck tumors may have a higher invasive potential because the loss of intercellular adhesion is a critical biological process by which cancer cells invade into the surrounding tissues. Recently, Weiner et al [17] showed that trigone and bladder neck tumors were associated with higher rates of nodal involvement in bladder cancer patients who were treated with radical cystectomy, suggesting their higher invasive and metastatic potential. Although the mechanism that facilitates biological aggressiveness of bladder neck tumors is unclear, cancer stem cell theory might be related to their
5
Fig. 2 – Progression probability curves based on bladder neck involvement in the subgroups of the (A) primary and (B) recurrent intermediate-risk non–muscle-invasive bladder cancer patients. BNI = bladder neck involvement.
high malignant potential [18]. As a previous study using the rat bladder indicated that urothelial stem cells are mostly located at the trigone and bladder neck, cancer stem cells may be highly distributed in these areas of the bladder [19]. Moreover, the significance of BNI for predicting progression and recurrence may have an anatomical explanation. Transurethral resection of bladder neck tumors can be technically difficult, resulting in incomplete resection of the tumors. However, because intermediate-risk tumors are basically of low grade and low stage, it is unreasonable for residual tumors to develop MIBC after TURB. Several previous studies reported the risk substratification of intermediate-risk NMIBC. Matsumoto et al [20] showed that patients with a low-grade tumor that recurred after a high-risk tumor had higher recurrence rates than those with a low-grade tumor that recurred after a low-risk tumor and those with initial multiple low-grade tumors; however, progression rates were not significantly different among the three groups. IBCG recommended substratification of intermediate-risk NMIBC using an algorithm including multiple tumors, tumor size >3 cm, early recurrences
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(<1 yr), and frequent recurrences (>1/yr) [6,7]. However, the predictive ability of the IBCG model for progression was lower compared with BNI in the present study. Moreover, because the IBCG model includes four factors, our risk substratification by BNI is simple and easy to use in clinical practice. The present study has several limitations. First, the present study is a retrospective single-institutional study. Our findings should be validated using a prospective multi-institutional cohort. BNI was independently associated with progression in high-risk NMIBC patients of our cohort (Supplementary Table 2), which supports the prognostic significance of BNI. Second, no patients underwent a second TURB in the present study. However, tumor characteristics and prognoses in the present study are similar to those in a previous study reported by Sylvester et al [3], suggesting adequate resection during our initial TURB. Third, smoking status was not available in all patients of our cohort and excluded from analysis. Fourth, the rate of intravesical BCG therapy is relatively low in our cohort. Thus, we could not evaluate the impact of BNI on the therapeutic response of intravesical BCG therapy in intermediate-risk NMIBC patients. Finally, we did not evaluate the role of BNI in the development of prostatic stromal invasion. This should be elucidated in future studies because silent prostatic stromal invasion can occur through the bladder neck directly into the prostatic stroma [21].
Funding/Support and role of the sponsor: This research was supported by JSPS KAKENHI Grant Number JP26462403. The funder did not play any role in the study design, collection, analysis, or interpretation of data, or in the drafting of this paper.
Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10. 1016/j.euf.2020.01.006.
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We demonstrated that BNI was able to substratify intermediate-risk NMIBC patients well regarding their risks of progression and recurrence. Although our preliminary findings should be confirmed by prospective multi-institutional studies, the present study indicates the clinical relevance of BNI in managing intermediate-risk NMIBC patients.
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Author contributions: Yasuhisa Fujii had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Fukushima, Fujii. Acquisition of data: Fukushima, Moriyama, Waseda, Yokoyama. Analysis and interpretation of data: Fukushima, Tanaka. Drafting of the manuscript: Fukushima. Critical revision of the manuscript for important intellectual content: Fukuda, Uehara, Tanaka, Kijima, Yoshida, Yokoyama, Ishioka, Matsuoka, Saito, Fujii. Statistical analysis: Fukushima, Waseda. Obtaining funding: Fujii. Administrative, technical, or material support: None. Supervision: Fujii. Other: None.
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Financial disclosures: Yasuhisa Fujii certifies that all conflicts of interest, including specific financial interests and relationships and affiliations
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