Bacillus Calmette-Guérin may have clinical benefit for glandular or squamous differentiation in non-muscle invasive bladder cancer patients: retrospective multicenter study

Bacillus Calmette-Guérin may have clinical benefit for glandular or squamous differentiation in... Abstract Objectives To clarify the efficacy of intravesical Bacillus Calmette-Guérin (BCG) instillation for non-muscle invasive bladder (NMIBC) cancer with variant histology, especially glandular differentiation or squamous differentiation. Materials and methods From May 1991 through June 2016, 53 patients were diagnosed retrospectively as having NMIBC with variant histology. Among these patients, 47 NMIBC patients with squamous differentiation or glandular differentiation were analyzed for this study. The median follow-up interval from diagnosis of NMIBC with variant histology was 28.9 months (1.5–168.8). Results Of these patients, 38 (80.9%) and 9 (19.1%) were diagnosed as having glandular differentiation and squamous differentiation, respectively. Radical cystectomy was conducted for six (12.8%) immediately after the diagnosis of NMIBC with variant histology. Of the 41 patients with bladder preservation, 20 (48.8%), 3 (7.3%), 3 (7.3%) and 15 (36.6%) underwent BCG, THP, MMC and no additional treatment, respectively. There were significant differences between BCG and other treatments or no additional treatment for recurrence (P = 0.034), progression (P = 0.004) and cancer-specific survival (P = 0.014). Conclusion Overall, our results show that intravesical BCG instillation for variant histology in NMIBC leads to a better prognosis with regard to progression and cause-specific survival than other intravesical treatments or no additional treatment. BCG treatment may also have a clinical benefit for variant histology in non-muscle invasive bladder cancer patients. Bacillus Calmette-Guérin, non-muscle invasive bladder cancer, variant histology, glandular differentiation, squamous differentiation Introduction Urothelial carcinoma (UC) is the most common histologic subtype of urinary bladder cancer. A number of histologic variants of UC have been recognized in recent years (1). Previous studies have showed that 5–40% of cases consist of UC with variant histology or non-UC (2–11). Variant histology is more aggressive than conventional UC. UCs with variant histology are associated with a higher grade and stage compared with conventional UC. Some reports showed that at the time of the initial diagnosis of UC with VH, 70% or more of patients had muscle invasive bladder cancer and 15–30% NMIBC (3,5,7,12–14). A pathological re-review of cystectomy specimens indicated that variant histology was associated with a high rate of locally advanced disease, which might impact the rate of survival (11). Furthermore, NMIBC with variant histology often has a poor prognosis with an increased risk for progression. NMIBC with variant histology is considered to be a high risk condition and is recommended for early cystectomy or restaging transurethral resection of the bladder tumor (TURBT) (15). On the other hand, the efficacy of intravesical Bacillus Calmette-Guérin (BCG) instillation for NMIBC cancer with variant histology is unclear. There are few reports or case studies of the efficacy of BCG treatment for NMIBC patients with variant histology (16,17). Since the most common histological variants are squamous differentiation (SC) and glandular differentiation (GD) (3,14), the aim of this study was to clarify the clinical efficacy of BCG treatment for NMIBC patients with these variant histologies. Patients and methods Patients’ characteristics (Table 1) Data from 53 consecutive patients who were diagnosed as having NMIBC with variant histology from May 1991 through June 2016 were retrospectively obtained from two institutes (Sapporo Medical University and NTT East Japan Sapporo Hospital). Among these patients, 47 NMIBC patients with GD or SC differentiation were analyzed in this study. Patients who had a history of muscle-invasive bladder cancer (MIBC) or NMIBC with different variant histology from GD and SC were excluded from this study. The pathology slides, except for those of 21 patients for whom archived slides were not available, were reviewed by two urological pathologists to examine the variant rate. The pathological grades were classed as Grade 1 (G1), Grade 2 (G2) or Grade 3 (G3) according to the 1973 WHO system. The mean follow-up interval from TURBT followed by diagnosis of NMIBC with GD or SC differentiation was 28.9 months (1.5–168.8). For all patients, pathological staging was performed according to the TNM system. Progression was defined as muscular invasion and remote and lymph node metastasis during the follow-up period. The immunotherapy protocol included an induction course of at least four or more weekly intravesical instillations of BCG. Maintenance therapy included three instillations at 3, 6 and 12 months for 1 year followed by every 6 months for an additional 2 years. Maintenance therapy and second transurethral resection of the bladder tumor (second TUR) were offered depending on the clinical doctor’s selection. Table 1. Patients’ characteristics. Characteristic Overall (n = 47) Sex  Male 37 (78.7%)  Female 10 (21.3%) Median age (range) 72 (41–93) Variant histology  Glandular 38 (80.9%)  Squamous 9 (19.1%) Recurrent tumor  Yes 9 (19.1%)  No 38 (80.9%) Multiplicity  Unifocal 27 (57.4%)  Multifocal 20 (42.6%) Tumor size (cm)  Less than 3 39 (83.0%)  3 or Greater 8 (17.0%) Tumor morphology  Papillary 29 (61.7%)  Non-papillary 18 (38.3%) T stage  Tis 2 (4.3%)  Ta 5 (10.6%)  T1 40 (85.1%) Grade  Grade 1 0  Grade 2 7 (14.9%)  Grade 3 40 (85.1%) Variant rate (%)  Less than 50 9 (19.1%)  More or 50 17 (36.2%)  Unknown 21 (44.7%) Concomitant CIS  Yes 9 (19.1%)  No 38 (80.9%) Second TUR  Yes 23 (49.0%)  No 24 (51.1%) Characteristic Overall (n = 47) Sex  Male 37 (78.7%)  Female 10 (21.3%) Median age (range) 72 (41–93) Variant histology  Glandular 38 (80.9%)  Squamous 9 (19.1%) Recurrent tumor  Yes 9 (19.1%)  No 38 (80.9%) Multiplicity  Unifocal 27 (57.4%)  Multifocal 20 (42.6%) Tumor size (cm)  Less than 3 39 (83.0%)  3 or Greater 8 (17.0%) Tumor morphology  Papillary 29 (61.7%)  Non-papillary 18 (38.3%) T stage  Tis 2 (4.3%)  Ta 5 (10.6%)  T1 40 (85.1%) Grade  Grade 1 0  Grade 2 7 (14.9%)  Grade 3 40 (85.1%) Variant rate (%)  Less than 50 9 (19.1%)  More or 50 17 (36.2%)  Unknown 21 (44.7%) Concomitant CIS  Yes 9 (19.1%)  No 38 (80.9%) Second TUR  Yes 23 (49.0%)  No 24 (51.1%) CIS, carcinoma in situ; TUR: transurethral resection. Table 1. Patients’ characteristics. Characteristic Overall (n = 47) Sex  Male 37 (78.7%)  Female 10 (21.3%) Median age (range) 72 (41–93) Variant histology  Glandular 38 (80.9%)  Squamous 9 (19.1%) Recurrent tumor  Yes 9 (19.1%)  No 38 (80.9%) Multiplicity  Unifocal 27 (57.4%)  Multifocal 20 (42.6%) Tumor size (cm)  Less than 3 39 (83.0%)  3 or Greater 8 (17.0%) Tumor morphology  Papillary 29 (61.7%)  Non-papillary 18 (38.3%) T stage  Tis 2 (4.3%)  Ta 5 (10.6%)  T1 40 (85.1%) Grade  Grade 1 0  Grade 2 7 (14.9%)  Grade 3 40 (85.1%) Variant rate (%)  Less than 50 9 (19.1%)  More or 50 17 (36.2%)  Unknown 21 (44.7%) Concomitant CIS  Yes 9 (19.1%)  No 38 (80.9%) Second TUR  Yes 23 (49.0%)  No 24 (51.1%) Characteristic Overall (n = 47) Sex  Male 37 (78.7%)  Female 10 (21.3%) Median age (range) 72 (41–93) Variant histology  Glandular 38 (80.9%)  Squamous 9 (19.1%) Recurrent tumor  Yes 9 (19.1%)  No 38 (80.9%) Multiplicity  Unifocal 27 (57.4%)  Multifocal 20 (42.6%) Tumor size (cm)  Less than 3 39 (83.0%)  3 or Greater 8 (17.0%) Tumor morphology  Papillary 29 (61.7%)  Non-papillary 18 (38.3%) T stage  Tis 2 (4.3%)  Ta 5 (10.6%)  T1 40 (85.1%) Grade  Grade 1 0  Grade 2 7 (14.9%)  Grade 3 40 (85.1%) Variant rate (%)  Less than 50 9 (19.1%)  More or 50 17 (36.2%)  Unknown 21 (44.7%) Concomitant CIS  Yes 9 (19.1%)  No 38 (80.9%) Second TUR  Yes 23 (49.0%)  No 24 (51.1%) CIS, carcinoma in situ; TUR: transurethral resection. Follow-up schedule The follow-up protocol consisted of cystoscopy and urine cytology every 3 months in the first 3 years and subsequently every 6 months. In this follow-up period, if bladder cancer recurrence was suspected based on urine cytology or cystoscopy, TUR was performed to determine whether the patient was disease free. Upper urinary tract monitoring was performed with either computed tomography or an intravenous urogram. The endpoints in this study were recurrence-free survival (RFS), progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). The secondary endpoint in this study was cystectomy-free survival (CFS). The study was approved by the ethics committee in our university. Statistics Kaplan–Meier curves were calculated for RFS, PFS, CSS, OS and CFS. RFS, PFS, CSS, OS and CFS in univariate analysis were compared between the groups using the log-rank test. Age distribution was compared using the Mann–Whitney U test. The variables sex, variant histology, recurrent tumors, tumor size and concomitant carcinoma in situ (CIS) were compared using Fischer’s exact test. Multiplicity, tumor morphology and second TUR were compared using the chi-squared test. T stage, grade and the variant histology rate were compared using the Kruskal–Wallis test. Statistical tests were performed with EZR version 1.35 (EZR, Saitama Medical Center, Jichi Medical University, Saitama, Japan). Differences were considered significant if P < 0.05. Results The patients’ characteristics are shown in Table 1. Thirty-eight (80.9%) of the patients had GD and nine (19.1%) had SC (Fig. 1). Forty-one patients selected bladder preservation therapy and six selected early radical cystectomy. During the follow-up period, 1 of the 6 (16.7%) patients who underwent early radical cystectomy died of bladder cancer. Of the 41 patients with bladder preservation therapy, 20 received intravesical instillation of BCG. Nineteen patients received BCG at a dose of 80 mg and one received it at a dose of 40 mg. Three (15%) patients received BCG maintenance therapy. Of the 21 patients without BCG treatment, 3, 3 and 15 underwent intravesical instillation of THP, MMC and no adjuvant treatment after TURBT, respectively (Fig. 2). Figure 1. View largeDownload slide Representative (a) histology of squamous differentiation (SC), (b) mixed histology in urothelial carcinoma (UC) and SC, (c) histology of glandular differentiation (GD) and (d) mixed histology in UC and GD (H-E, ×200). Figure 1. View largeDownload slide Representative (a) histology of squamous differentiation (SC), (b) mixed histology in urothelial carcinoma (UC) and SC, (c) histology of glandular differentiation (GD) and (d) mixed histology in UC and GD (H-E, ×200). Figure 2. View largeDownload slide The study cohort. Figure 2. View largeDownload slide The study cohort. Table 2 shows predictive factors for patients with and without BCG treatment after TURBT for the 41 patients with bladder preservation therapy. The only significant difference was the proportion of those with second TUR before BCG treatment (P = 0.042). Table 2. Characteristics of patients with bladder preservation therapy (n = 41) Characteristic BCG (n = 20) Non-BCG (n = 21) P value Sex  Male 16 (80.0%) 16 (76.2%) 1.000*  Female 4 (20.0%) 5 (23.8%) Median age (range) 73 (41–88) 75 (42–93) 0.754† Variant histology  Glandular 16 (80.0%) 18 (85.7%) 0.697*  Squamous 4 (20.0%) 3 (14.3%) Recurrent tumor  Yes 1 (5.0%) 4 (19.0%) 0.343*  No 19 (95.0%) 17 (81.0%) Multiplicity  Unifocal 11 (55.0%) 14 (66.7%) 0.656**  Multifocal 9 (45.0%) 7 (33.3%) Tumor size (cm)  Less than 3 17 (85.0%) 18 (85.7%) 1.000*  3 or Greater 3 (15.0%) 3 (14.3%) Tumor morphology  Papillary 14 (70.0%) 12 (57.1%) 0.596**  Non-papillary 6 (30.0%) 9 (42.9%) T stage  Tis 1 (5.0%) 0 0.798‡  Ta 2 (10.0%) 2 (9.5%)  T1 17 (85.0%) 19 (90.5%) Grade  Grade 1 0 0 0.631‡  Grade 2 4 (20.0%) 3 (14.3%)  Grade 3 16 (80.0%) 18 (85.7%) Variant histology rate (%)  Less than 50 5 (25.0%) 4 (19.0%) 0.368‡  More or 50 10 (50.0%) 5 (23.8%)  Unknown 5 (25.0%) 12 (57.1%) Concomitant CIS  Yes 5 (25.0%) 1 (4.8%) 0.093*  No 15 (75.0%) 20 (95.2%) secondTUR  Yes 14 (70.0%) 7 (33.3%) 0.042**  No 6 (30.0%) 14 (66.7%) Characteristic BCG (n = 20) Non-BCG (n = 21) P value Sex  Male 16 (80.0%) 16 (76.2%) 1.000*  Female 4 (20.0%) 5 (23.8%) Median age (range) 73 (41–88) 75 (42–93) 0.754† Variant histology  Glandular 16 (80.0%) 18 (85.7%) 0.697*  Squamous 4 (20.0%) 3 (14.3%) Recurrent tumor  Yes 1 (5.0%) 4 (19.0%) 0.343*  No 19 (95.0%) 17 (81.0%) Multiplicity  Unifocal 11 (55.0%) 14 (66.7%) 0.656**  Multifocal 9 (45.0%) 7 (33.3%) Tumor size (cm)  Less than 3 17 (85.0%) 18 (85.7%) 1.000*  3 or Greater 3 (15.0%) 3 (14.3%) Tumor morphology  Papillary 14 (70.0%) 12 (57.1%) 0.596**  Non-papillary 6 (30.0%) 9 (42.9%) T stage  Tis 1 (5.0%) 0 0.798‡  Ta 2 (10.0%) 2 (9.5%)  T1 17 (85.0%) 19 (90.5%) Grade  Grade 1 0 0 0.631‡  Grade 2 4 (20.0%) 3 (14.3%)  Grade 3 16 (80.0%) 18 (85.7%) Variant histology rate (%)  Less than 50 5 (25.0%) 4 (19.0%) 0.368‡  More or 50 10 (50.0%) 5 (23.8%)  Unknown 5 (25.0%) 12 (57.1%) Concomitant CIS  Yes 5 (25.0%) 1 (4.8%) 0.093*  No 15 (75.0%) 20 (95.2%) secondTUR  Yes 14 (70.0%) 7 (33.3%) 0.042**  No 6 (30.0%) 14 (66.7%) CIS, carcinoma in situ; TUR, transurethral resection. *Fischer’s exact test, †Mann–Whitney U test, **Chi-squared test, ‡Kruskal–Wallis test. Table 2. Characteristics of patients with bladder preservation therapy (n = 41) Characteristic BCG (n = 20) Non-BCG (n = 21) P value Sex  Male 16 (80.0%) 16 (76.2%) 1.000*  Female 4 (20.0%) 5 (23.8%) Median age (range) 73 (41–88) 75 (42–93) 0.754† Variant histology  Glandular 16 (80.0%) 18 (85.7%) 0.697*  Squamous 4 (20.0%) 3 (14.3%) Recurrent tumor  Yes 1 (5.0%) 4 (19.0%) 0.343*  No 19 (95.0%) 17 (81.0%) Multiplicity  Unifocal 11 (55.0%) 14 (66.7%) 0.656**  Multifocal 9 (45.0%) 7 (33.3%) Tumor size (cm)  Less than 3 17 (85.0%) 18 (85.7%) 1.000*  3 or Greater 3 (15.0%) 3 (14.3%) Tumor morphology  Papillary 14 (70.0%) 12 (57.1%) 0.596**  Non-papillary 6 (30.0%) 9 (42.9%) T stage  Tis 1 (5.0%) 0 0.798‡  Ta 2 (10.0%) 2 (9.5%)  T1 17 (85.0%) 19 (90.5%) Grade  Grade 1 0 0 0.631‡  Grade 2 4 (20.0%) 3 (14.3%)  Grade 3 16 (80.0%) 18 (85.7%) Variant histology rate (%)  Less than 50 5 (25.0%) 4 (19.0%) 0.368‡  More or 50 10 (50.0%) 5 (23.8%)  Unknown 5 (25.0%) 12 (57.1%) Concomitant CIS  Yes 5 (25.0%) 1 (4.8%) 0.093*  No 15 (75.0%) 20 (95.2%) secondTUR  Yes 14 (70.0%) 7 (33.3%) 0.042**  No 6 (30.0%) 14 (66.7%) Characteristic BCG (n = 20) Non-BCG (n = 21) P value Sex  Male 16 (80.0%) 16 (76.2%) 1.000*  Female 4 (20.0%) 5 (23.8%) Median age (range) 73 (41–88) 75 (42–93) 0.754† Variant histology  Glandular 16 (80.0%) 18 (85.7%) 0.697*  Squamous 4 (20.0%) 3 (14.3%) Recurrent tumor  Yes 1 (5.0%) 4 (19.0%) 0.343*  No 19 (95.0%) 17 (81.0%) Multiplicity  Unifocal 11 (55.0%) 14 (66.7%) 0.656**  Multifocal 9 (45.0%) 7 (33.3%) Tumor size (cm)  Less than 3 17 (85.0%) 18 (85.7%) 1.000*  3 or Greater 3 (15.0%) 3 (14.3%) Tumor morphology  Papillary 14 (70.0%) 12 (57.1%) 0.596**  Non-papillary 6 (30.0%) 9 (42.9%) T stage  Tis 1 (5.0%) 0 0.798‡  Ta 2 (10.0%) 2 (9.5%)  T1 17 (85.0%) 19 (90.5%) Grade  Grade 1 0 0 0.631‡  Grade 2 4 (20.0%) 3 (14.3%)  Grade 3 16 (80.0%) 18 (85.7%) Variant histology rate (%)  Less than 50 5 (25.0%) 4 (19.0%) 0.368‡  More or 50 10 (50.0%) 5 (23.8%)  Unknown 5 (25.0%) 12 (57.1%) Concomitant CIS  Yes 5 (25.0%) 1 (4.8%) 0.093*  No 15 (75.0%) 20 (95.2%) secondTUR  Yes 14 (70.0%) 7 (33.3%) 0.042**  No 6 (30.0%) 14 (66.7%) CIS, carcinoma in situ; TUR, transurethral resection. *Fischer’s exact test, †Mann–Whitney U test, **Chi-squared test, ‡Kruskal–Wallis test. The RFS, PFS, CSS and OS of patients with and without BCG treatment are shown in Fig. 3. There were significant differences between BCG and other treatments or no additional treatment for recurrence (P = 0.034), progression (P = 0.004), and cancer-specific survival (P = 0.014). However, there was no significant difference in OS between the two groups (P = 0.160). We analyzed the RFS and PFS for the six patients with intravesical BCG therapy without second TUR and seven patients without intravesical BCG with second TUR. Although there was no significant difference in RFS between the two groups (P = 0.92), there was a significant difference between the patients with BCG without second TUR and without BCG with second TUR for progression (P = 0.023). The patients with intravesical BCG without second TUR had a lower incidence of progression than patients without intravesical BCG with second TUR (Supplement 1a-b). Among the 41 patients with bladder preservation therapy, three patients with BCG treatment and three without it underwent cystectomy during the follow-up period. There was no significant difference in CFS between the two groups (P = 0.604) (Supplement 1c). Their median times to recurrence were 54.2 and 14.4 months, respectively. None of the patients with bladder preservation therapy died of bladder cancer after BCG treatment. Four of the patients without BCG treatment died of bladder cancer during the follow-up period. Figure 3. View largeDownload slide Kaplan–Meier curves for (a) recurrence-free survival (RFS), (b) progression-free survival (PFS), (c) cancer-specific survival (CSS) and (d) overall survival (OS) for patients with SC and/or GD in NMIBC from TURBT according to treatment with intravesical BCG (n = 20) and without intravesical BCG or other treatments (n = 21). The RFSs of patients with and without BCG treatment were 76.6% and 36.7% at 3 years and 30.6% and 36.7% at 5 years (P = 0.034), respectively (a). The PFSs of patients with and without BCG treatment, were 100% and 67.5% at 3 years and 75.0% and 33.7% at 5 years (P = 0.004), respectively (b). The CSSs of patients with and without BCG treatment were 100% and 80.0% at 3 years and 100% and 30.0% at 5 years (P = 0.014), respectively (c). The OSs of patients with and without BCG treatment were 90.9% and 75.3% at 3 years and 90.9% and 28.2% at 5 years (P = 0.160), respectively (d). Figure 3. View largeDownload slide Kaplan–Meier curves for (a) recurrence-free survival (RFS), (b) progression-free survival (PFS), (c) cancer-specific survival (CSS) and (d) overall survival (OS) for patients with SC and/or GD in NMIBC from TURBT according to treatment with intravesical BCG (n = 20) and without intravesical BCG or other treatments (n = 21). The RFSs of patients with and without BCG treatment were 76.6% and 36.7% at 3 years and 30.6% and 36.7% at 5 years (P = 0.034), respectively (a). The PFSs of patients with and without BCG treatment, were 100% and 67.5% at 3 years and 75.0% and 33.7% at 5 years (P = 0.004), respectively (b). The CSSs of patients with and without BCG treatment were 100% and 80.0% at 3 years and 100% and 30.0% at 5 years (P = 0.014), respectively (c). The OSs of patients with and without BCG treatment were 90.9% and 75.3% at 3 years and 90.9% and 28.2% at 5 years (P = 0.160), respectively (d). We analyzed the correlation between the variant histology rate and prognosis for the 24 patients whose slides were available. There were no significant difference in RFS (P = 0.257), PFS (P = 1.00), CSS (P = 1.00) or OS (P = 0.173) between patients with less than 50% and those with 50% or more rates of variant histology. Discussion It is well known that UCs have a variety of variant histology. From 5% to 40% consist of UC with variant histology or non-urothelial cancer (2–11). In bladder cancer with variant histology, SC and GD are the most frequent variants and they are observed in from 25% to 60% and 9% to 18% of cases, respectively (1,3,7,9). Some reports noted that 70% of patients treated with cystectomy for SC and GD were diagnosed with pT3-T4 tumors and 20% of these patients had pN+ (14,18). Although UC with SC, GD or both types of differentiation has higher frequencies of advanced stage disease, some patients with SC or GD are diagnosed as having primary NMIBC at TURBT. Shah et al. showed that, on initial TURBT, 31% of patients with variant histology presented with clinical T1 disease, 44% with SC and 23% with GD (3). Other reports showed that the distribution according to stage was 25% for the patients with SC and/or GD for stage pT1 (5). The method of management for patients with NMIBC with SC and/or GD is unclear. Wasco et al. reported that the presence of mixed histologic features at TURBT was an independent predictor of extravesical disease in a multivariate logistic regression model (7). Therefore they suggested that patients with mixed histologic features at TURBT might benefit from early cystectomy. However, radical cystectomy, despite advances in urinary diversion techniques, has disadvantages such as a high complication rate (19). Furthermore, there are few reports on the efficacy of intravesical BCG treatment for patients with NMIBC with variant histology. We found that intravesical BCG instillation for SC and/or GD histology in NMIBC led to a better prognosis with regard to PFS and CSS than other treatments. Shapur et al. compared the responses to intravesical BCG treatment of 22 patients with variant NMIBC to those of 144 patients with conventional high grade UC (16). The 2- and 5-year PFS were 92% and 84% for patients with conventional UC compared to 81% and 63%, respectively, for patients with variant histology (P = 0.02). However there was no significant difference in CSS between the two groups. They concluded that patients with SC and/or GD histology in NMIBC could be managed with BCG treatment if the tumor was not bulky (>4 cm). Gofrit et al. compared a group of 41 patients with variant histology in NMIBC to a group of 140 patients with conventional UC treated with BCG (17). Patients with variant histology in NMIBC treated with BCG had a 27% chance of dying from this disease within 5 years compared to a 7.5% chance for patients with conventional UC. Compared with these two reports, our results showed a better outcome and prognosis in patients with SC and/or GD histology in NMIBC treated with BCG. This might have been because our patients only had SC and/or GD histology in NMIBC and not any other variant histology. Bladder cancer with variant histology is heterogeneous with different prognoses. NMIBC with the micropapillary variant is particularly aggressive with a poor prognosis compared to other types of variant histology. Of patients with the micropapillary variant in NMIBC treated with BCG, 67% developed disease progression, including 22% who developed metastatic disease (20). In our study, the patients only had only SC and/or GD histology and our results showed that intravesical BCG treatment could be effective for SC and/or GD histology in NMIBC. There are some limitations in this study. First, this was a retrospective study. The most important limitation is the small number of patients with SC and/or GD histology after BCG treatment. Not all of the patients underwent maintenance BCG instillation or second TUR. Despite these limitations, we believe that our results are clinically informative and will be useful for the management of patients SC and/or GD histology in NMIBC. However, to determine the best strategy for NMIBC with variant histology, a prospective study using a larger cohort is still needed. Conclusions Our results show that intravesical BCG instillation for SC and/or GD histology in NMIBC leads to a better prognosis with regard to PFS and CSS than other treatments. BCG treatment may also have a clinical benefit for variant histology in NMIBC patients. However, this was a retrospective study with a small patient population and a prospective study using a larger cohort is still needed. Supplementary data Supplementary data are available at Japanese Journal of Clinical Oncology online. Conflict of interest statement None declared. Funding The study was supported in part by the National Cancer Center Research and Development Fund (29-A-3). Abbreviations UC, urothelial carcinoma; BCG, Bacillus Calmette-Guérin; NMIBC, non-muscle invasive bladder cancer; TURBT, transurethral resection of bladder tumor; SC, squamous differentiation; GD, glandular differentiation; MIBC, muscle invasive bladder cancer; RFS, recurrence-free survival; PFS, progression-free survival; CSS, cancer-specific survival; CFS, cystectomy free survival; OS, overall survival; CIS, carcinoma in situ; second TUR, second transurethral resection of bladder tumor. References 1 Lopez-Beltran A , Cheng L . Histologic variants of urothelial carcinoma: differential diagnosis and clinical implications . Hum Pathol 2006 ; 37 : 1371 – 88 . Google Scholar CrossRef Search ADS PubMed 2 Kantor AF , Hartge P , Hoover RN , et al. . Epidemiological characteristics of squamous cell carcinoma and adenocarcinoma of the bladder . Cancer Res 1988 ; 48 : 3853 – 5 . Google Scholar PubMed 3 Shah RB , Montgomery JS , Montie JE , et al. . 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For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Japanese Journal of Clinical Oncology Oxford University Press

Bacillus Calmette-Guérin may have clinical benefit for glandular or squamous differentiation in non-muscle invasive bladder cancer patients: retrospective multicenter study

Japanese Journal of Clinical Oncology , Volume Advance Article (7) – May 4, 2018

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Abstract

Abstract Objectives To clarify the efficacy of intravesical Bacillus Calmette-Guérin (BCG) instillation for non-muscle invasive bladder (NMIBC) cancer with variant histology, especially glandular differentiation or squamous differentiation. Materials and methods From May 1991 through June 2016, 53 patients were diagnosed retrospectively as having NMIBC with variant histology. Among these patients, 47 NMIBC patients with squamous differentiation or glandular differentiation were analyzed for this study. The median follow-up interval from diagnosis of NMIBC with variant histology was 28.9 months (1.5–168.8). Results Of these patients, 38 (80.9%) and 9 (19.1%) were diagnosed as having glandular differentiation and squamous differentiation, respectively. Radical cystectomy was conducted for six (12.8%) immediately after the diagnosis of NMIBC with variant histology. Of the 41 patients with bladder preservation, 20 (48.8%), 3 (7.3%), 3 (7.3%) and 15 (36.6%) underwent BCG, THP, MMC and no additional treatment, respectively. There were significant differences between BCG and other treatments or no additional treatment for recurrence (P = 0.034), progression (P = 0.004) and cancer-specific survival (P = 0.014). Conclusion Overall, our results show that intravesical BCG instillation for variant histology in NMIBC leads to a better prognosis with regard to progression and cause-specific survival than other intravesical treatments or no additional treatment. BCG treatment may also have a clinical benefit for variant histology in non-muscle invasive bladder cancer patients. Bacillus Calmette-Guérin, non-muscle invasive bladder cancer, variant histology, glandular differentiation, squamous differentiation Introduction Urothelial carcinoma (UC) is the most common histologic subtype of urinary bladder cancer. A number of histologic variants of UC have been recognized in recent years (1). Previous studies have showed that 5–40% of cases consist of UC with variant histology or non-UC (2–11). Variant histology is more aggressive than conventional UC. UCs with variant histology are associated with a higher grade and stage compared with conventional UC. Some reports showed that at the time of the initial diagnosis of UC with VH, 70% or more of patients had muscle invasive bladder cancer and 15–30% NMIBC (3,5,7,12–14). A pathological re-review of cystectomy specimens indicated that variant histology was associated with a high rate of locally advanced disease, which might impact the rate of survival (11). Furthermore, NMIBC with variant histology often has a poor prognosis with an increased risk for progression. NMIBC with variant histology is considered to be a high risk condition and is recommended for early cystectomy or restaging transurethral resection of the bladder tumor (TURBT) (15). On the other hand, the efficacy of intravesical Bacillus Calmette-Guérin (BCG) instillation for NMIBC cancer with variant histology is unclear. There are few reports or case studies of the efficacy of BCG treatment for NMIBC patients with variant histology (16,17). Since the most common histological variants are squamous differentiation (SC) and glandular differentiation (GD) (3,14), the aim of this study was to clarify the clinical efficacy of BCG treatment for NMIBC patients with these variant histologies. Patients and methods Patients’ characteristics (Table 1) Data from 53 consecutive patients who were diagnosed as having NMIBC with variant histology from May 1991 through June 2016 were retrospectively obtained from two institutes (Sapporo Medical University and NTT East Japan Sapporo Hospital). Among these patients, 47 NMIBC patients with GD or SC differentiation were analyzed in this study. Patients who had a history of muscle-invasive bladder cancer (MIBC) or NMIBC with different variant histology from GD and SC were excluded from this study. The pathology slides, except for those of 21 patients for whom archived slides were not available, were reviewed by two urological pathologists to examine the variant rate. The pathological grades were classed as Grade 1 (G1), Grade 2 (G2) or Grade 3 (G3) according to the 1973 WHO system. The mean follow-up interval from TURBT followed by diagnosis of NMIBC with GD or SC differentiation was 28.9 months (1.5–168.8). For all patients, pathological staging was performed according to the TNM system. Progression was defined as muscular invasion and remote and lymph node metastasis during the follow-up period. The immunotherapy protocol included an induction course of at least four or more weekly intravesical instillations of BCG. Maintenance therapy included three instillations at 3, 6 and 12 months for 1 year followed by every 6 months for an additional 2 years. Maintenance therapy and second transurethral resection of the bladder tumor (second TUR) were offered depending on the clinical doctor’s selection. Table 1. Patients’ characteristics. Characteristic Overall (n = 47) Sex  Male 37 (78.7%)  Female 10 (21.3%) Median age (range) 72 (41–93) Variant histology  Glandular 38 (80.9%)  Squamous 9 (19.1%) Recurrent tumor  Yes 9 (19.1%)  No 38 (80.9%) Multiplicity  Unifocal 27 (57.4%)  Multifocal 20 (42.6%) Tumor size (cm)  Less than 3 39 (83.0%)  3 or Greater 8 (17.0%) Tumor morphology  Papillary 29 (61.7%)  Non-papillary 18 (38.3%) T stage  Tis 2 (4.3%)  Ta 5 (10.6%)  T1 40 (85.1%) Grade  Grade 1 0  Grade 2 7 (14.9%)  Grade 3 40 (85.1%) Variant rate (%)  Less than 50 9 (19.1%)  More or 50 17 (36.2%)  Unknown 21 (44.7%) Concomitant CIS  Yes 9 (19.1%)  No 38 (80.9%) Second TUR  Yes 23 (49.0%)  No 24 (51.1%) Characteristic Overall (n = 47) Sex  Male 37 (78.7%)  Female 10 (21.3%) Median age (range) 72 (41–93) Variant histology  Glandular 38 (80.9%)  Squamous 9 (19.1%) Recurrent tumor  Yes 9 (19.1%)  No 38 (80.9%) Multiplicity  Unifocal 27 (57.4%)  Multifocal 20 (42.6%) Tumor size (cm)  Less than 3 39 (83.0%)  3 or Greater 8 (17.0%) Tumor morphology  Papillary 29 (61.7%)  Non-papillary 18 (38.3%) T stage  Tis 2 (4.3%)  Ta 5 (10.6%)  T1 40 (85.1%) Grade  Grade 1 0  Grade 2 7 (14.9%)  Grade 3 40 (85.1%) Variant rate (%)  Less than 50 9 (19.1%)  More or 50 17 (36.2%)  Unknown 21 (44.7%) Concomitant CIS  Yes 9 (19.1%)  No 38 (80.9%) Second TUR  Yes 23 (49.0%)  No 24 (51.1%) CIS, carcinoma in situ; TUR: transurethral resection. Table 1. Patients’ characteristics. Characteristic Overall (n = 47) Sex  Male 37 (78.7%)  Female 10 (21.3%) Median age (range) 72 (41–93) Variant histology  Glandular 38 (80.9%)  Squamous 9 (19.1%) Recurrent tumor  Yes 9 (19.1%)  No 38 (80.9%) Multiplicity  Unifocal 27 (57.4%)  Multifocal 20 (42.6%) Tumor size (cm)  Less than 3 39 (83.0%)  3 or Greater 8 (17.0%) Tumor morphology  Papillary 29 (61.7%)  Non-papillary 18 (38.3%) T stage  Tis 2 (4.3%)  Ta 5 (10.6%)  T1 40 (85.1%) Grade  Grade 1 0  Grade 2 7 (14.9%)  Grade 3 40 (85.1%) Variant rate (%)  Less than 50 9 (19.1%)  More or 50 17 (36.2%)  Unknown 21 (44.7%) Concomitant CIS  Yes 9 (19.1%)  No 38 (80.9%) Second TUR  Yes 23 (49.0%)  No 24 (51.1%) Characteristic Overall (n = 47) Sex  Male 37 (78.7%)  Female 10 (21.3%) Median age (range) 72 (41–93) Variant histology  Glandular 38 (80.9%)  Squamous 9 (19.1%) Recurrent tumor  Yes 9 (19.1%)  No 38 (80.9%) Multiplicity  Unifocal 27 (57.4%)  Multifocal 20 (42.6%) Tumor size (cm)  Less than 3 39 (83.0%)  3 or Greater 8 (17.0%) Tumor morphology  Papillary 29 (61.7%)  Non-papillary 18 (38.3%) T stage  Tis 2 (4.3%)  Ta 5 (10.6%)  T1 40 (85.1%) Grade  Grade 1 0  Grade 2 7 (14.9%)  Grade 3 40 (85.1%) Variant rate (%)  Less than 50 9 (19.1%)  More or 50 17 (36.2%)  Unknown 21 (44.7%) Concomitant CIS  Yes 9 (19.1%)  No 38 (80.9%) Second TUR  Yes 23 (49.0%)  No 24 (51.1%) CIS, carcinoma in situ; TUR: transurethral resection. Follow-up schedule The follow-up protocol consisted of cystoscopy and urine cytology every 3 months in the first 3 years and subsequently every 6 months. In this follow-up period, if bladder cancer recurrence was suspected based on urine cytology or cystoscopy, TUR was performed to determine whether the patient was disease free. Upper urinary tract monitoring was performed with either computed tomography or an intravenous urogram. The endpoints in this study were recurrence-free survival (RFS), progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). The secondary endpoint in this study was cystectomy-free survival (CFS). The study was approved by the ethics committee in our university. Statistics Kaplan–Meier curves were calculated for RFS, PFS, CSS, OS and CFS. RFS, PFS, CSS, OS and CFS in univariate analysis were compared between the groups using the log-rank test. Age distribution was compared using the Mann–Whitney U test. The variables sex, variant histology, recurrent tumors, tumor size and concomitant carcinoma in situ (CIS) were compared using Fischer’s exact test. Multiplicity, tumor morphology and second TUR were compared using the chi-squared test. T stage, grade and the variant histology rate were compared using the Kruskal–Wallis test. Statistical tests were performed with EZR version 1.35 (EZR, Saitama Medical Center, Jichi Medical University, Saitama, Japan). Differences were considered significant if P < 0.05. Results The patients’ characteristics are shown in Table 1. Thirty-eight (80.9%) of the patients had GD and nine (19.1%) had SC (Fig. 1). Forty-one patients selected bladder preservation therapy and six selected early radical cystectomy. During the follow-up period, 1 of the 6 (16.7%) patients who underwent early radical cystectomy died of bladder cancer. Of the 41 patients with bladder preservation therapy, 20 received intravesical instillation of BCG. Nineteen patients received BCG at a dose of 80 mg and one received it at a dose of 40 mg. Three (15%) patients received BCG maintenance therapy. Of the 21 patients without BCG treatment, 3, 3 and 15 underwent intravesical instillation of THP, MMC and no adjuvant treatment after TURBT, respectively (Fig. 2). Figure 1. View largeDownload slide Representative (a) histology of squamous differentiation (SC), (b) mixed histology in urothelial carcinoma (UC) and SC, (c) histology of glandular differentiation (GD) and (d) mixed histology in UC and GD (H-E, ×200). Figure 1. View largeDownload slide Representative (a) histology of squamous differentiation (SC), (b) mixed histology in urothelial carcinoma (UC) and SC, (c) histology of glandular differentiation (GD) and (d) mixed histology in UC and GD (H-E, ×200). Figure 2. View largeDownload slide The study cohort. Figure 2. View largeDownload slide The study cohort. Table 2 shows predictive factors for patients with and without BCG treatment after TURBT for the 41 patients with bladder preservation therapy. The only significant difference was the proportion of those with second TUR before BCG treatment (P = 0.042). Table 2. Characteristics of patients with bladder preservation therapy (n = 41) Characteristic BCG (n = 20) Non-BCG (n = 21) P value Sex  Male 16 (80.0%) 16 (76.2%) 1.000*  Female 4 (20.0%) 5 (23.8%) Median age (range) 73 (41–88) 75 (42–93) 0.754† Variant histology  Glandular 16 (80.0%) 18 (85.7%) 0.697*  Squamous 4 (20.0%) 3 (14.3%) Recurrent tumor  Yes 1 (5.0%) 4 (19.0%) 0.343*  No 19 (95.0%) 17 (81.0%) Multiplicity  Unifocal 11 (55.0%) 14 (66.7%) 0.656**  Multifocal 9 (45.0%) 7 (33.3%) Tumor size (cm)  Less than 3 17 (85.0%) 18 (85.7%) 1.000*  3 or Greater 3 (15.0%) 3 (14.3%) Tumor morphology  Papillary 14 (70.0%) 12 (57.1%) 0.596**  Non-papillary 6 (30.0%) 9 (42.9%) T stage  Tis 1 (5.0%) 0 0.798‡  Ta 2 (10.0%) 2 (9.5%)  T1 17 (85.0%) 19 (90.5%) Grade  Grade 1 0 0 0.631‡  Grade 2 4 (20.0%) 3 (14.3%)  Grade 3 16 (80.0%) 18 (85.7%) Variant histology rate (%)  Less than 50 5 (25.0%) 4 (19.0%) 0.368‡  More or 50 10 (50.0%) 5 (23.8%)  Unknown 5 (25.0%) 12 (57.1%) Concomitant CIS  Yes 5 (25.0%) 1 (4.8%) 0.093*  No 15 (75.0%) 20 (95.2%) secondTUR  Yes 14 (70.0%) 7 (33.3%) 0.042**  No 6 (30.0%) 14 (66.7%) Characteristic BCG (n = 20) Non-BCG (n = 21) P value Sex  Male 16 (80.0%) 16 (76.2%) 1.000*  Female 4 (20.0%) 5 (23.8%) Median age (range) 73 (41–88) 75 (42–93) 0.754† Variant histology  Glandular 16 (80.0%) 18 (85.7%) 0.697*  Squamous 4 (20.0%) 3 (14.3%) Recurrent tumor  Yes 1 (5.0%) 4 (19.0%) 0.343*  No 19 (95.0%) 17 (81.0%) Multiplicity  Unifocal 11 (55.0%) 14 (66.7%) 0.656**  Multifocal 9 (45.0%) 7 (33.3%) Tumor size (cm)  Less than 3 17 (85.0%) 18 (85.7%) 1.000*  3 or Greater 3 (15.0%) 3 (14.3%) Tumor morphology  Papillary 14 (70.0%) 12 (57.1%) 0.596**  Non-papillary 6 (30.0%) 9 (42.9%) T stage  Tis 1 (5.0%) 0 0.798‡  Ta 2 (10.0%) 2 (9.5%)  T1 17 (85.0%) 19 (90.5%) Grade  Grade 1 0 0 0.631‡  Grade 2 4 (20.0%) 3 (14.3%)  Grade 3 16 (80.0%) 18 (85.7%) Variant histology rate (%)  Less than 50 5 (25.0%) 4 (19.0%) 0.368‡  More or 50 10 (50.0%) 5 (23.8%)  Unknown 5 (25.0%) 12 (57.1%) Concomitant CIS  Yes 5 (25.0%) 1 (4.8%) 0.093*  No 15 (75.0%) 20 (95.2%) secondTUR  Yes 14 (70.0%) 7 (33.3%) 0.042**  No 6 (30.0%) 14 (66.7%) CIS, carcinoma in situ; TUR, transurethral resection. *Fischer’s exact test, †Mann–Whitney U test, **Chi-squared test, ‡Kruskal–Wallis test. Table 2. Characteristics of patients with bladder preservation therapy (n = 41) Characteristic BCG (n = 20) Non-BCG (n = 21) P value Sex  Male 16 (80.0%) 16 (76.2%) 1.000*  Female 4 (20.0%) 5 (23.8%) Median age (range) 73 (41–88) 75 (42–93) 0.754† Variant histology  Glandular 16 (80.0%) 18 (85.7%) 0.697*  Squamous 4 (20.0%) 3 (14.3%) Recurrent tumor  Yes 1 (5.0%) 4 (19.0%) 0.343*  No 19 (95.0%) 17 (81.0%) Multiplicity  Unifocal 11 (55.0%) 14 (66.7%) 0.656**  Multifocal 9 (45.0%) 7 (33.3%) Tumor size (cm)  Less than 3 17 (85.0%) 18 (85.7%) 1.000*  3 or Greater 3 (15.0%) 3 (14.3%) Tumor morphology  Papillary 14 (70.0%) 12 (57.1%) 0.596**  Non-papillary 6 (30.0%) 9 (42.9%) T stage  Tis 1 (5.0%) 0 0.798‡  Ta 2 (10.0%) 2 (9.5%)  T1 17 (85.0%) 19 (90.5%) Grade  Grade 1 0 0 0.631‡  Grade 2 4 (20.0%) 3 (14.3%)  Grade 3 16 (80.0%) 18 (85.7%) Variant histology rate (%)  Less than 50 5 (25.0%) 4 (19.0%) 0.368‡  More or 50 10 (50.0%) 5 (23.8%)  Unknown 5 (25.0%) 12 (57.1%) Concomitant CIS  Yes 5 (25.0%) 1 (4.8%) 0.093*  No 15 (75.0%) 20 (95.2%) secondTUR  Yes 14 (70.0%) 7 (33.3%) 0.042**  No 6 (30.0%) 14 (66.7%) Characteristic BCG (n = 20) Non-BCG (n = 21) P value Sex  Male 16 (80.0%) 16 (76.2%) 1.000*  Female 4 (20.0%) 5 (23.8%) Median age (range) 73 (41–88) 75 (42–93) 0.754† Variant histology  Glandular 16 (80.0%) 18 (85.7%) 0.697*  Squamous 4 (20.0%) 3 (14.3%) Recurrent tumor  Yes 1 (5.0%) 4 (19.0%) 0.343*  No 19 (95.0%) 17 (81.0%) Multiplicity  Unifocal 11 (55.0%) 14 (66.7%) 0.656**  Multifocal 9 (45.0%) 7 (33.3%) Tumor size (cm)  Less than 3 17 (85.0%) 18 (85.7%) 1.000*  3 or Greater 3 (15.0%) 3 (14.3%) Tumor morphology  Papillary 14 (70.0%) 12 (57.1%) 0.596**  Non-papillary 6 (30.0%) 9 (42.9%) T stage  Tis 1 (5.0%) 0 0.798‡  Ta 2 (10.0%) 2 (9.5%)  T1 17 (85.0%) 19 (90.5%) Grade  Grade 1 0 0 0.631‡  Grade 2 4 (20.0%) 3 (14.3%)  Grade 3 16 (80.0%) 18 (85.7%) Variant histology rate (%)  Less than 50 5 (25.0%) 4 (19.0%) 0.368‡  More or 50 10 (50.0%) 5 (23.8%)  Unknown 5 (25.0%) 12 (57.1%) Concomitant CIS  Yes 5 (25.0%) 1 (4.8%) 0.093*  No 15 (75.0%) 20 (95.2%) secondTUR  Yes 14 (70.0%) 7 (33.3%) 0.042**  No 6 (30.0%) 14 (66.7%) CIS, carcinoma in situ; TUR, transurethral resection. *Fischer’s exact test, †Mann–Whitney U test, **Chi-squared test, ‡Kruskal–Wallis test. The RFS, PFS, CSS and OS of patients with and without BCG treatment are shown in Fig. 3. There were significant differences between BCG and other treatments or no additional treatment for recurrence (P = 0.034), progression (P = 0.004), and cancer-specific survival (P = 0.014). However, there was no significant difference in OS between the two groups (P = 0.160). We analyzed the RFS and PFS for the six patients with intravesical BCG therapy without second TUR and seven patients without intravesical BCG with second TUR. Although there was no significant difference in RFS between the two groups (P = 0.92), there was a significant difference between the patients with BCG without second TUR and without BCG with second TUR for progression (P = 0.023). The patients with intravesical BCG without second TUR had a lower incidence of progression than patients without intravesical BCG with second TUR (Supplement 1a-b). Among the 41 patients with bladder preservation therapy, three patients with BCG treatment and three without it underwent cystectomy during the follow-up period. There was no significant difference in CFS between the two groups (P = 0.604) (Supplement 1c). Their median times to recurrence were 54.2 and 14.4 months, respectively. None of the patients with bladder preservation therapy died of bladder cancer after BCG treatment. Four of the patients without BCG treatment died of bladder cancer during the follow-up period. Figure 3. View largeDownload slide Kaplan–Meier curves for (a) recurrence-free survival (RFS), (b) progression-free survival (PFS), (c) cancer-specific survival (CSS) and (d) overall survival (OS) for patients with SC and/or GD in NMIBC from TURBT according to treatment with intravesical BCG (n = 20) and without intravesical BCG or other treatments (n = 21). The RFSs of patients with and without BCG treatment were 76.6% and 36.7% at 3 years and 30.6% and 36.7% at 5 years (P = 0.034), respectively (a). The PFSs of patients with and without BCG treatment, were 100% and 67.5% at 3 years and 75.0% and 33.7% at 5 years (P = 0.004), respectively (b). The CSSs of patients with and without BCG treatment were 100% and 80.0% at 3 years and 100% and 30.0% at 5 years (P = 0.014), respectively (c). The OSs of patients with and without BCG treatment were 90.9% and 75.3% at 3 years and 90.9% and 28.2% at 5 years (P = 0.160), respectively (d). Figure 3. View largeDownload slide Kaplan–Meier curves for (a) recurrence-free survival (RFS), (b) progression-free survival (PFS), (c) cancer-specific survival (CSS) and (d) overall survival (OS) for patients with SC and/or GD in NMIBC from TURBT according to treatment with intravesical BCG (n = 20) and without intravesical BCG or other treatments (n = 21). The RFSs of patients with and without BCG treatment were 76.6% and 36.7% at 3 years and 30.6% and 36.7% at 5 years (P = 0.034), respectively (a). The PFSs of patients with and without BCG treatment, were 100% and 67.5% at 3 years and 75.0% and 33.7% at 5 years (P = 0.004), respectively (b). The CSSs of patients with and without BCG treatment were 100% and 80.0% at 3 years and 100% and 30.0% at 5 years (P = 0.014), respectively (c). The OSs of patients with and without BCG treatment were 90.9% and 75.3% at 3 years and 90.9% and 28.2% at 5 years (P = 0.160), respectively (d). We analyzed the correlation between the variant histology rate and prognosis for the 24 patients whose slides were available. There were no significant difference in RFS (P = 0.257), PFS (P = 1.00), CSS (P = 1.00) or OS (P = 0.173) between patients with less than 50% and those with 50% or more rates of variant histology. Discussion It is well known that UCs have a variety of variant histology. From 5% to 40% consist of UC with variant histology or non-urothelial cancer (2–11). In bladder cancer with variant histology, SC and GD are the most frequent variants and they are observed in from 25% to 60% and 9% to 18% of cases, respectively (1,3,7,9). Some reports noted that 70% of patients treated with cystectomy for SC and GD were diagnosed with pT3-T4 tumors and 20% of these patients had pN+ (14,18). Although UC with SC, GD or both types of differentiation has higher frequencies of advanced stage disease, some patients with SC or GD are diagnosed as having primary NMIBC at TURBT. Shah et al. showed that, on initial TURBT, 31% of patients with variant histology presented with clinical T1 disease, 44% with SC and 23% with GD (3). Other reports showed that the distribution according to stage was 25% for the patients with SC and/or GD for stage pT1 (5). The method of management for patients with NMIBC with SC and/or GD is unclear. Wasco et al. reported that the presence of mixed histologic features at TURBT was an independent predictor of extravesical disease in a multivariate logistic regression model (7). Therefore they suggested that patients with mixed histologic features at TURBT might benefit from early cystectomy. However, radical cystectomy, despite advances in urinary diversion techniques, has disadvantages such as a high complication rate (19). Furthermore, there are few reports on the efficacy of intravesical BCG treatment for patients with NMIBC with variant histology. We found that intravesical BCG instillation for SC and/or GD histology in NMIBC led to a better prognosis with regard to PFS and CSS than other treatments. Shapur et al. compared the responses to intravesical BCG treatment of 22 patients with variant NMIBC to those of 144 patients with conventional high grade UC (16). The 2- and 5-year PFS were 92% and 84% for patients with conventional UC compared to 81% and 63%, respectively, for patients with variant histology (P = 0.02). However there was no significant difference in CSS between the two groups. They concluded that patients with SC and/or GD histology in NMIBC could be managed with BCG treatment if the tumor was not bulky (>4 cm). Gofrit et al. compared a group of 41 patients with variant histology in NMIBC to a group of 140 patients with conventional UC treated with BCG (17). Patients with variant histology in NMIBC treated with BCG had a 27% chance of dying from this disease within 5 years compared to a 7.5% chance for patients with conventional UC. Compared with these two reports, our results showed a better outcome and prognosis in patients with SC and/or GD histology in NMIBC treated with BCG. This might have been because our patients only had SC and/or GD histology in NMIBC and not any other variant histology. Bladder cancer with variant histology is heterogeneous with different prognoses. NMIBC with the micropapillary variant is particularly aggressive with a poor prognosis compared to other types of variant histology. Of patients with the micropapillary variant in NMIBC treated with BCG, 67% developed disease progression, including 22% who developed metastatic disease (20). In our study, the patients only had only SC and/or GD histology and our results showed that intravesical BCG treatment could be effective for SC and/or GD histology in NMIBC. There are some limitations in this study. First, this was a retrospective study. The most important limitation is the small number of patients with SC and/or GD histology after BCG treatment. Not all of the patients underwent maintenance BCG instillation or second TUR. Despite these limitations, we believe that our results are clinically informative and will be useful for the management of patients SC and/or GD histology in NMIBC. However, to determine the best strategy for NMIBC with variant histology, a prospective study using a larger cohort is still needed. Conclusions Our results show that intravesical BCG instillation for SC and/or GD histology in NMIBC leads to a better prognosis with regard to PFS and CSS than other treatments. BCG treatment may also have a clinical benefit for variant histology in NMIBC patients. However, this was a retrospective study with a small patient population and a prospective study using a larger cohort is still needed. Supplementary data Supplementary data are available at Japanese Journal of Clinical Oncology online. Conflict of interest statement None declared. Funding The study was supported in part by the National Cancer Center Research and Development Fund (29-A-3). Abbreviations UC, urothelial carcinoma; BCG, Bacillus Calmette-Guérin; NMIBC, non-muscle invasive bladder cancer; TURBT, transurethral resection of bladder tumor; SC, squamous differentiation; GD, glandular differentiation; MIBC, muscle invasive bladder cancer; RFS, recurrence-free survival; PFS, progression-free survival; CSS, cancer-specific survival; CFS, cystectomy free survival; OS, overall survival; CIS, carcinoma in situ; second TUR, second transurethral resection of bladder tumor. References 1 Lopez-Beltran A , Cheng L . Histologic variants of urothelial carcinoma: differential diagnosis and clinical implications . Hum Pathol 2006 ; 37 : 1371 – 88 . Google Scholar CrossRef Search ADS PubMed 2 Kantor AF , Hartge P , Hoover RN , et al. . Epidemiological characteristics of squamous cell carcinoma and adenocarcinoma of the bladder . Cancer Res 1988 ; 48 : 3853 – 5 . Google Scholar PubMed 3 Shah RB , Montgomery JS , Montie JE , et al. . Variant (divergent) histologic differentiation in urothelial carcinoma is under-recognized in community practice: impact of mandatory central pathology review at a large referral hospital . Urol Oncol 2013 ; 31 : 1650 – 5 . Google Scholar CrossRef Search ADS PubMed 4 Abdollah F , Sun M , Jeldres C , et al. . Survival after radical cystectomy of non-bilharzial squamous cell carcinoma vs urothelial carcinoma: a competing-risks analysis . BJU Int 2012 ; 109 : 564 – 9 . Google Scholar CrossRef Search ADS PubMed 5 Billis A , Schenka AA , Ramos CC , et al. . Squamous and/or glandular differentiation in urothelial carcinoma: prevalence and significance in transurethral resections of the bladder . Int Urol Nephrol 2001 ; 33 : 631 – 3 . Google Scholar CrossRef Search ADS PubMed 6 Zaghloul MS , Nouh A , Nazmy M , et al. . Long-term results of primary adenocarcinoma of the urinary bladder: a report on 192 patients . Urol Oncol 2006 ; 24 : 13 – 20 . Google Scholar CrossRef Search ADS PubMed 7 Wasco MJ , Daignault S , Zhang Y , et al. . Urothelial carcinoma with divergent histologic differentiation (mixed histologic features) predicts the presence of locally advanced bladder cancer when detected at transurethral resection . Urology 2007 ; 70 : 69 – 74 . Google Scholar CrossRef Search ADS PubMed 8 Xylinas E , Rink M , Robinson BD , et al. . Impact of histological variants on oncological outcomes of patients with urothelial carcinoma of the bladder treated with radical cystectomy . Eur J Cancer 2013 ; 49 : 1889 – 97 . Google Scholar CrossRef Search ADS PubMed 9 Amin MB . Histological variants of urothelial carcinoma: diagnostic, therapeutic and prognostic implications . Mod Pathol 2009 ; 22 : S96 – 118 . Google Scholar CrossRef Search ADS PubMed 10 Monn MF , Kaimakliotis HZ , Pedrosa JA , et al. . Contemporary bladder cancer: variant histology may be a significant driver of disease . Urol Oncol 2015 ; 33 : 18.e15 – 18.e20 . Google Scholar CrossRef Search ADS 11 Linder BJ , Boorjian SA , Cheville JC , et al. . The impact of histological reclassification during pathology re-review – evidence of a Will Rogers effect in bladder cancer? J Urol 2013 ; 190 : 1692 – 6 . Google Scholar CrossRef Search ADS PubMed 12 Rogers CG , Palapattu GS , Shariat SF , et al. . Clinical outcomes following radical cystectomy for primary nontransitional cell carcinoma of the bladder compared to transitional cell carcinoma of the bladder . J Urol 2006 ; 175 : 2048 – 53 . Google Scholar CrossRef Search ADS PubMed 13 Mitra AP , Bartsch CC , Bartsch G Jr , et al. . Does presence of squamous and glandular differentiation in urothelial carcinoma of the bladder at cystectomy portend poor prognosis? An intensive case-control analysis . Urol Oncol 2014 ; 32 : 117 – 27 . Google Scholar CrossRef Search ADS PubMed 14 Black PC , Brown GA , Dinney CPN . The impact of variant histology on the outcome of bladder cancer treated with curative intent . Urol Oncol 2009 ; 27 : 3 – 7 . Google Scholar CrossRef Search ADS PubMed 15 Seisen T , Compérat E , Léon P , et al. . Impact of histological variants on the outcomes of nonmuscle invasive bladder cancer after transurethral resection . Curr Opin Urol 2014 ; 24 : 524 – 31 . Google Scholar CrossRef Search ADS PubMed 16 Shapur NK , Katz R , Pode D , et al. . Is radical cystectomy mandatory in every patient with variant histology of bladder cancer? Rare Tumors 2011 ; 3 : e22: 67 – 70 . Google Scholar CrossRef Search ADS 17 Gofrit ON , Yutkin V , Shapiro A , et al. . The response of variant histology bladder cancer to intravesical immunotherapy compared to conventional cancer . Front Oncol 2016 ; 6 : 43 . Google Scholar CrossRef Search ADS PubMed 18 Kim SP , Frank I , Cheville JC , et al. . The impact of squamous and glandular differentiation on survival after radical cystectomy for urothelial carcinoma . J Urol 2012 ; 188 : 405 – 9 . Google Scholar CrossRef Search ADS PubMed 19 Soloway MS , Sofer M , Vaidya A . Contemporary management of stage T1 transitional cell carcinoma of the bladder . J Urol 2002 ; 167 : 1573 – 83 . Google Scholar CrossRef Search ADS PubMed 20 Kamat AM , Dinney CP , Gee JR , et al. . Micropapillary bladder cancer: a review of the University of Texas M. D. Anderson Cancer Center experience with 100 consecutive patients . Cancer 2007 ; 110 : 62 – 7 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Japanese Journal of Clinical OncologyOxford University Press

Published: May 4, 2018

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