Abstract
Purpose
Parameters predicting intravesical bacillus Calmette–Guerin (BCG) treatment response in non-muscle-invasive bladder cancer (NMIBC) are limited. This study investigated the effectiveness of tumor invasion patterns in predicting intravesical BCG treatment response, which are known to have prognostic value for NMIBC.
Materials and Methods
Data of 167 primary, stage T1 high-grade NMIBC patients evaluated retrospectively. All transurethral resection samples were re-evaluated for confirmation of pathological variables and determination of invasion patterns. Binary logistic regression analysis applied to obtain determinants of BCG response. Kaplan–Meier curves and log-rank test used to assess relationship between variables and time to recurrence and time to progression.
Results
Tumor invasion pattern was nodular in 83 (49.7%), trabecular in 20 (12.0%) and infiltrative in 64 patients (38.3%). Multivariate analysis revealed multifocality (p=0.001), trabecular invasion (p=0.001) and infiltrative invasion (p=0.001) were independent predictors of poor BCG response. Log-rank test determined infiltrative invasion has higher impact on time to recurrence (p<0.001) and nodular invasion has significantly lower risk for time to progression (p=0.013), during the median follow-up period of 15 months.
Conclusions
Invasion patterns are significantly correlated with BCG response. Assessment of this easily applicable parameter can differ patients who may benefit from BCG treatment and can be used as a prognostic indicator.
Keywords: Intravesical BCG, Invasion patterns, Non-muscle invasive bladder neoplasms
Graphical Abstract
INTRODUCTION
Urothelial bladder cancers are 75% non-muscle-invasive at the primary diagnosis [1]. Among non-muscle-invasive tumors T1 subgroup, characterized with lamina propria invasion, comprise divergent clinicopathological features. Particularly T1 high-grade (HG) tumors have worse oncological outcomes with higher recurrence and progression rates [2]. All T1 HG tumors are included in high and very high-risk groups according to European Association of Urology (EAU) risk classification [3]. Second transurethral resection (TUR) in 2–6 weeks following primary TUR and further intravesical bacillus Calmette–Guérin (BCG) instillations are gold standard treatment except for tumors included in very high-risk group and referred for radical cystectomy.
BCG response is the major determinant for treatment selection between to continue with conservative approach or radical surgery. Early cystectomy has favorable prognosis compared to referral to surgery after BCG failure [4]. Even if it is oncologically superior, radical cystectomy has high morbidity with detrimental effects on quality of life. In this context, several clinicopathological parameters evaluated as determinants of BCG response showing limited value.
Invasion patterns, as nodular, trabecular and infiltrative, have been reported to be a significant prognostic factor both in non-muscle-invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC). Denzinger et al. [5] analyzed data of 205 primary T1 G3 NMIBC and revealed infiltrative invasion showed a statistically significant worse prognosis with a cancer-specific survival of only 59.3% (p<0.001). Correlatively, Krüger et al. [6] reported invasion patterns are independent predictors of disease related survival in a multivariate analysis (p=0.029) regarding data of 153 MIBC. However, there is no study investigating significance of lamina propria invasion patterns on BCG response and relation with other tumor characteristics.
The aim of the present study was to investigate correlation between BCG response, clinicopathological predictors and lamina propria invasion patterns in primary TUR specimen among T1 HG tumors treated with systematic second TUR and further intravesical BCG instillations, retrospectively.
MATERIALS AND METHODS
1. Patient characteristics
After approval by the Institutional Review Board of Bagcilar Training and Research Hospital (approval number: 2023/11/06/072), tissue samples and clinical data of 235 primary T1 HG (WHO 2004/2022 classification) patients diagnosed in the Department of Urology of Bagcilar Training and Research Hospital between March 2018 and March 2023 collected. The written informed consent was waived due to the study’s retrospective design.
All patients underwent second TUR in 2–6 weeks following primary TUR and after second TUR patients received BCG induction as six-weekly instillations and maintenance at 3, 6, 12, 18, 24, 30, and 36 months as three-weekly instillations. BCG unresponsive disease defined as HG recurrences during or after BCG therapy, while at least one year maintenance instillation is required to be considered BCG responsive [7]. Follow-up was carried out in concordance with EAU guidelines as routine cystoscopy and cytology for every 3 months for 2 years and then every 6 months up to 5 years, accompanied by computed tomography imaging annually. Exclusion criteria depicted in Fig. 1.
Fig. 1. Study flowchart. HG, high-grade; TUR, transurethral resection; BCG, bacillus Calmette–Guerin; UTUC, upper urinary tract urothelial cell carcinoma.
2. Histopathological assessment
All samples were re-evaluated by two experienced uropathologists (Ş.Ö. and S.C.) for validation of stage, grade, concomitant carcinoma in situ (CIS) and variant histology. Pattern of lamina propria invasion is reported by consensus of both pathologists for each patient.
Invasion patterns redefined for lamina propria invasion of T1 tumors based on description of Jimenez et al. [8] for muscle invasion. Nodular invasion pattern is consisted of well-formed, rounded nests of tumor cells at invasion front. Trabecular invasion pattern is composed of infiltrating trabeculae with several cell layers, which anastomosed with each other. Infiltrative invasion pattern is defined as infiltrating narrow cords or single cells at invasion front (Fig. 2).
Fig. 2. Demonstration of invasion patterns. (A) Nodular, well-formed, rounded nests of tumor cells (H&E, ×200). (B) Trabecular, anastomosing infiltrative trabeculae with several cell layers (H&E, ×200). (C) Infiltrative, infiltrating narrow cords or single cells (H&E, ×200).
3. Evaluated variables
The primary objective was to establish significance of invasion patterns on BCG response. Other clinicopathological variables evaluated in each case were age, tumor diameter, multifocality, concomitant CIS and variant histology. Correlation between invasion patterns and these clinicopathological features also assessed.
Afterwards relation between time to recurrence and invasion patterns analyzed in addition to time to progression and invasion patterns. Progression defined as detection of muscle invasive tumor where recurrence defined as detection of any bladder tumor during follow-up.
4. Statistical analysis
Statistical analysis was conducted with IBM SPSS version 29.0 software (IBM Corp.). Correlation among the categorical variables was analyzed using chi-square test. Binary logistic regression analysis was used to assess value of invasion patterns and other variables for BCG response. Time to recurrence and time to progression curves were obtained using Kaplan–Meier method and compared by the log-rank test for each invasion pattern. A p-value <0.05 was considered statistically significant.
RESULTS
1. Clinicopathological characteristics
The median age of the patients was 66 years (range, 40–94 years). Of 167 patients, 152 (91.0%) were male. The lamina propria invasion pattern was nodular in 83 (49.7%), trabecular in 20 (12.0%), and infiltrative in 64 patients (38.3%).
We determined the association of invasion patterns with various clinicopathological parameters. Nodular invasion was significantly associated with age ≤70 years (p=0.033). Concomitant CIS and variant histology were significantly associated with invasion patterns. Infiltrative invasion was correlated with high concomitant CIS presence whereas nodular invasion was associated with decreased concomitant CIS (p=0.024). Both nodular and infiltrative invasion were associated with decreased variant histology (p=0.047) (Table 1).
Table 1. Association of invasion patterns with clinicopathological features.
| Invasion pattern | p-value | ||||
|---|---|---|---|---|---|
| Nodular | Trabecular | Infiltrative | |||
| Age | 0.033 | ||||
| ≤70 y | 57 (68.7) | 10 (50.0) | 33 (51.6) | ||
| >70 y | 26 (31.3) | 10 (50.0) | 31 (48.4) | ||
| Tumor diameter | 0.556 | ||||
| ≤3 cm | 16 (19.3) | 4 (20.0) | 17 (26.6) | ||
| >3 cm | 67 (80.7) | 16 (80.0) | 47 (73.4) | ||
| Multifocality | 0.058 | ||||
| No | 35 (42.2) | 11 (55.0) | 18 (28.1) | ||
| Yes | 48 (57.8) | 9 (45.0) | 46 (71.9) | ||
| Concomitant CIS | 0.024 | ||||
| No | 53 (63.9) | 9 (45.0) | 27 (42.2) | ||
| Yes | 30 (36.1) | 11 (55.0) | 37 (57.8) | ||
| Variant histology | 0.047 | ||||
| No | 66 (79.5) | 14 (70.0) | 39 (60.9) | ||
| Yes | 17 (20.5) | 6 (30.0) | 25 (39.1) | ||
Values are presented as number (%).
CIS, carcinoma in situ.
2. Predictors of BCG response
Among 167 patients, 82 patients (49.1%) were BCG responsive with 57 (69.5%) nodular, 10 (12.2%) trabecular, and 15 (18.3%) infiltrative invasion patterns. Univariate and multivariate analyses were performed to determine the predictors of BCG response. Univariate analysis revealed concomitant CIS (odds ratio [OR] 0.40, 95% confidence interval [CI] 0.21–0.75, p=0.004), multifocality (OR 0.26, 95% CI 0.13–0.51, p<0.001), variant histology (OR 0.40, 95% CI 0.19–0.80, p=0.011), infiltrative invasion (OR 0.14, 95% CI 0.06–0.29, p<0.001) and trabecular invasion (OR 0.45, 95% CI 0.16–1.23, p<0.001) were significantly associated with poorer BCG response.
Multivariate analysis of significant parameters in univariate analysis detects multifocality (OR 0.27, 95% CI 0.12–0.57, p=0.001), trabecular invasion (OR 0.49, 95% CI 0.13–1.21, p=0.001) and infiltrative invasion (OR 0.16, 95% CI 0.07–0.37, p=0.001) were statistically significant and independent features for BCG unresponsive disease (Table 2).
Table 2. Univariate and multivariate analyses for BCG response.
| n (%) | BCG response | |||||
|---|---|---|---|---|---|---|
| Univariate | Multivariate | |||||
| OR (95% CI) | p-value | OR (95% CI) | p-value | |||
| Age | ||||||
| ≤70 y | 100 (59.9) | 1 | - | - | - | |
| >70 y | 67 (40.1) | 0.61 (0.32–1.14) | 0.123 | - | - | |
| Tumor diameter | ||||||
| ≤3 cm | 37 (22.2) | 1 | - | - | - | |
| >3 cm | 130 (77.8) | 1.18 (0.56–2.44) | 0.664 | - | - | |
| Multifocality | ||||||
| No | 64 (38.3) | 1 | - | 1 | - | |
| Yes | 103 (61.7) | 0.26 (0.13–0.51) | <0.001 | 0.27 (0.12–0.57) | 0.001 | |
| Concomitant CIS | ||||||
| No | 89 (53.3) | 1 | - | 1 | - | |
| Yes | 78 (46.7) | 0.40 (0.21–0.75) | 0.004 | 0.50 (0.24–1.03) | 0.590 | |
| Variant histology | ||||||
| No | 119 (71.3) | 1 | - | 1 | - | |
| Yes | 48 (28.7) | 0.40 (0.19–0.80) | 0.011 | 0.52 (0.23–1.17) | 0.114 | |
| Invasion pattern | ||||||
| Nodular | 83 (49.7) | 1 | - | 1 | - | |
| Trabecular | 20 (12.0) | 0.45 (0.16–1.23) | <0.001 | 0.49 (0.13–1.21) | 0.001 | |
| Infiltrative | 64 (38.3) | 0.14 (0.06–0.29) | <0.001 | 0.16 (0.07–0.37) | 0.001 | |
BCG, bacillus Calmette–Guerin; OR, odds ratio; CI, confidence interval; CIS, carcinoma in situ.
3. Association of invasion patterns with recurrence and progression
During the median follow-up period of 15 months (range, 3–54 months), 92 patients (55.1%) experienced recurrence, and 31 patients (18.6%) experienced progression to muscle invasive disease.
Recurrence-free survival rates for invasion patterns were nodular 71.1% (95% CI 62.0–81.5) versus trabecular 55% (95% CI 37.0–81.8) versus infiltrative 23.4% (95% CI 15.1–36.5) at 12 months and nodular 66.4% (95% CI 56.6–77.9) versus trabecular 55% (95% CI 37.0–81.8) versus infiltrative 21.9% (95% CI 13.8–34.8) at 36 months, respectively. Additionally, progression-free survival rates for invasion patterns were nodular 88.9% (95% CI 81.9–96.5) versus trabecular 72.9% (95% CI 55.1–96.4) versus infiltrative 65.4% (95% CI 52.7–81.1) at 12 months and nodular 87.4% (95% CI 80.0–95.5) versus trabecular 72.9% (95% CI 55.1–96.4) versus infiltrative 65.4% (95% CI 52.7–81.1) at 36 months, respectively. Kaplan–Meier curves of invasion patterns as predictors of time to recurrence and time to progression shown in Fig. 3. Log-rank test revealed infiltrative invasion has higher impact on time to recurrence (p<0.001) and nodular invasion has significantly lower risk for time to progression (p=0.013).
Fig. 3. Association of invasion patterns with time to recurrence (A) and progression (B).
Multivariate Cox regression analysis showed that multifocality (hazard ratio [HR] 2.01, 95% CI 1.25–3.25, p=0.004), trabecular invasion (HR 1.32, 95% CI 0.64–2.73, p<0.001) and infiltrative invasion (HR 2.43, 95% CI 1.51–3.91, p<0.001) were significant determinants of recurrence, again infiltrative invasion (HR 2.74, 95% CI 1.20–6.25, p=0.017) had a significant influence on tumor progression (Table 3).
Table 3. Univariate and multivariate analyses for tumor recurrence and progression.
| Recurrence | Progression | |||||
|---|---|---|---|---|---|---|
| Univariate p-value | Multivariate HR (95% CI) | Multivariate p-value | Univariate p-value | Multivariate HR (95% CI) | Multivariate p-value | |
| Age | 0.604 | 0.240 | ||||
| Tumor diameter | 0.712 | 0.236 | ||||
| Multifocality | <0.001 | 2.01 (1.25–3.25) | 0.004 | 0.123 | ||
| Concomitant CIS | 0.010 | 1.41 (0.92–2.57) | 0.107 | 0.576 | ||
| Variant histology | 0.017 | 1.44 (0.94–2.21) | 0.093 | 0.019 | 2.03 (0.99–4.16) | 0.052 |
| Invasion pattern (trabecular vs. nodular) | <0.001 | 1.32 (0.64–2.73) | <0.001 | 0.027 | 2.23 (0.74–6.66) | 0.044 |
| Invasion pattern (infiltrative vs. nodular) | <0.001 | 2.43 (1.51–3.91) | <0.001 | 0.080 | 2.74 (1.20–6.25) | 0.017 |
HR, hazard ratio; CI, confidence interval; CIS, carcinoma in situ.
DISCUSSION
As a special subgroup of NMIBC, T1 HG tumors are most challenging sub entity due to several factors as difficulties in histopathological diagnosis and ambiguous prognosis [9]. Shahin et al. [10] concluded T1 G3 NMIBC can be divided into three prognostic groups as patients with never recurring tumors, patients with tumor recurrence and patients with tumor progression requiring radical cystectomy with high risk of metastatic disease. Various classifications and nomograms were designed to predict distribution of T1 HG patients into these prognostic groups [3].
BCG response is the major clinical determinant of prognosis of T1 HG tumors [11,12]. Lack of parameters predicting BCG response, leading controversial disease management, increase necessity for assignment of cost effective and expeditious diagnostic tools. To our knowledge, this the first study evaluating predictive value of invasion patterns on BCG response.
Several studies demonstrated relationship between invasion patterns and recurrence and progression of bladder tumors. Jimenez et al. [8] were first to report infiltrative invasion was associated with survival not reaching a statistical significance (p=0.064), at the final analysis of 93 MIBC patient data. Previously mentioned study of Denzinger et al. [5] included 205 T1 G3 NMIBC patients, invasion patterns were similarly distributed to our study, as 90 (43.9%) nodular, 29 (14.1%) trabecular, and 86 (42.0%) infiltrative patterns. In the mean follow-up period of 6.7 years, there was no statistically significant difference between recurrence-free survival rates in invasion patterns (p=0.176) whereas infiltrative invasion was statistically significant for cancer-specific survival in multivariate analysis (p<0.001). Miyake et al. [13] reported infiltrative invasion was predictive for tumor progression (p=0.005), in the subgroup analysis of 26 T1 NMIBC.
When more recent studies are evaluated, Miyake et al. [14] showed infiltrative invasion was significantly correlated with disease progression (p=0.033) in 106 T1 HG NMIBC. In the multivariate analyses of 226 T1 NMIBC, Otto et al. [15] revealed infiltrative invasion pattern was independent prognostic factor for progression-free survival (p=0.024) and cancer-specific survival (p=0.001). Another study of Otto et al. [16] included 322 T1 HG NMIBC composed of 205 (63.7%) nodular, 47 (14.6%) trabecular, and 70 (21.7%) infiltrative invasion patterns with median follow-up of 42 months. Subgroup analysis of 139 BCG-naive patients concluded infiltrative invasion was independent predictor for progression-free survival (p=0.046) and cancer-specific survival (p=0.042).
In our study as a primary endpoint, we concluded invasion patterns are significantly correlated with BCG response. Especially this relation becomes evident for infiltrative invasion and BCG unresponsive disease (p=0.001). Also, multifocality is another independent predictor of BCG unresponsiveness (p=0.001) among other clinicopathological features.
As a secondary endpoint we evaluated predictive role of invasion patterns on recurrence and progression. These analyses also reflect relationship between clinicopathological determinants and success of BCG treatment. Nodular invasion demonstrated the highest recurrence-free survival and progression-free survival rates (71.1% and 88.9%) at 12 months and (66.4% and 87.4%) at 36 months, indicating a more favorable disease course. In contrast, infiltrative invasion showed markedly lower recurrence-free survival and progression-free survival rates (23.4% and 65.4%) at 12 months and (21.9% and 65.4%) at 36 months, suggesting worse prognosis. Again, infiltrative invasion becomes more prominent parameter as it significantly predicts both recurrence (p<0.001) and progression (p=0.017) while having high impact on time to recurrence (p<0.001).
Our study has several limitations including retrospective design and short follow-up period. Lack of evaluation of gender and smoking status impact on BCG response and prognosis is another remarkable limitation [17,18]. Multicentric and high numbered studies with long follow-up time may improve findings obtained from the present study.
CONCLUSIONS
We revealed invasion patterns are significantly correlated with BCG response. Despite short follow-up period they are also decisive for recurrence and progression. From the perspective of cost and time effectivity, assessment of invasion patterns is simply practicable and can be easily applied in routine pathology report. If these findings are confirmed in large-scale and prospective studies, they can be used to determine which patients may benefit from BCG treatment in this special group of T1 HG NMIBC.
Footnotes
CONFLICTS OF INTEREST: The authors have nothing to disclose.
FUNDING: None.
- Research conception and design: Ismail Ulus, Şule Özsoy, and Atilla Semercioz.
- Data acquisition: Ismail Ulus, Selçuk Cin, and İbrahim Oğulcan Canitez.
- Statistical analysis: Mehmet Yilmaz.
- Data analysis and interpretation: Şule Özsoy, Mehmet Yilmaz, and Gokhan Cil.
- Drafting of the manuscript: Ismail Ulus, Şule Özsoy, Selçuk Cin, and İbrahim Oğulcan Canitez.
- Critical revision of the manuscript: Ismail Ulus, Mehmet Yilmaz, Gokhan Cil, and Atilla Semercioz.
- Supervision: Atilla Semercioz.
- Approval of the final manuscript: all authors.
References
- 1.Babjuk M, Burger M, Capoun O, Cohen D, Compérat EM, Dominguez Escrig JL, et al. European Association of Urology guidelines on non-muscle-invasive bladder cancer (Ta, T1, and carcinoma in situ) Eur Urol. 2022;81:75–94. doi: 10.1016/j.eururo.2021.08.010. [DOI] [PubMed] [Google Scholar]
- 2.Ślusarczyk A, Zapała P, Olszewska-Ślusarczyk Z, Radziszewski P. The prediction of cancer-specific mortality in T1 non-muscle-invasive bladder cancer: comparison of logistic regression and artificial neural network: a SEER population-based study. Int Urol Nephrol. 2023;55:2205–2213. doi: 10.1007/s11255-023-03655-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Sylvester RJ, Rodríguez O, Hernández V, Turturica D, Bauerová L, Bruins HM, et al. European Association of Urology (EAU) prognostic factor risk groups for non-muscle-invasive bladder cancer (NMIBC) incorporating the WHO 2004/2016 and WHO 1973 classification systems for grade: an update from the EAU NMIBC guidelines panel. Eur Urol. 2021;79:480–488. doi: 10.1016/j.eururo.2020.12.033. [DOI] [PubMed] [Google Scholar]
- 4.Jäger W, Thomas C, Haag S, Hampel C, Salzer A, Thüroff JW, et al. Early vs delayed radical cystectomy for 'high-risk' carcinoma not invading bladder muscle: delay of cystectomy reduces cancer-specific survival. BJU Int. 2011;108(8 Pt 2):E284–E288. doi: 10.1111/j.1464-410X.2010.09980.x. [DOI] [PubMed] [Google Scholar]
- 5.Denzinger S, Burger M, Fritsche HM, Bertz S, Hofstädter F, Wieland WF, et al. Prognostic value of histopathological tumour growth patterns at the invasion front of T1G3 urothelial carcinoma of the bladder. Scand J Urol Nephrol. 2009;43:282–287. doi: 10.1080/00365590902854354. [DOI] [PubMed] [Google Scholar]
- 6.Krüger S, Noack F, Böhle A, Feller AC. Histologic tumor growth pattern is significantly associated with disease-related survival in muscle-invasive transitional cell carcinoma of the urinary bladder. Oncol Rep. 2004;12:609–613. [PubMed] [Google Scholar]
- 7.Kamat AM, Sylvester RJ, Böhle A, Palou J, Lamm DL, Brausi M, et al. Definitions, end points, and clinical trial designs for non-muscle-invasive bladder cancer: recommendations from the international bladder cancer group. J Clin Oncol. 2016;34:1935–1944. doi: 10.1200/JCO.2015.64.4070. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Jimenez RE, Gheiler E, Oskanian P, Tiguert R, Sakr W, Wood DP, Jr, et al. Grading the invasive component of urothelial carcinoma of the bladder and its relationship with progression-free survival. Am J Surg Pathol. 2000;24:980–987. doi: 10.1097/00000478-200007000-00009. [DOI] [PubMed] [Google Scholar]
- 9.Lopez-Beltran A, Cheng L. Stage T1 bladder cancer: diagnostic criteria and pitfalls. Pathology. 2021;53:67–85. doi: 10.1016/j.pathol.2020.09.014. [DOI] [PubMed] [Google Scholar]
- 10.Shahin O, Thalmann GN, Rentsch C, Mazzucchelli L, Studer UE. A retrospective analysis of 153 patients treated with or without intravesical bacillus Calmette-Guerin for primary stage T1 grade 3 bladder cancer: recurrence, progression and survival. J Urol. 2003;169:96–100. doi: 10.1016/S0022-5347(05)64044-X. discussion 100. [DOI] [PubMed] [Google Scholar]
- 11.Lerner SP, Tangen CM, Sucharew H, Wood D, Crawford ED. Failure to achieve a complete response to induction BCG therapy is associated with increased risk of disease worsening and death in patients with high risk non-muscle invasive bladder cancer. Urol Oncol. 2009;27:155–159. doi: 10.1016/j.urolonc.2007.11.033. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Jeong SH, Ku JH. Treatment strategies for the Bacillus Calmette-Guérin-unresponsive non-muscle invasive bladder cancer. Investig Clin Urol. 2023;64:103–106. doi: 10.4111/icu.20230042. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Miyake M, Hirao S, Mibu H, Tanaka M, Takashima K, Shimada K, et al. Clinical significance of subepithelial growth patterns in non-muscle invasive bladder cancer. BMC Urol. 2011;11:17. doi: 10.1186/1471-2490-11-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Miyake M, Gotoh D, Shimada K, Tatsumi Y, Nakai Y, Anai S, et al. Exploration of risk factors predicting outcomes for primary T1 high-grade bladder cancer and validation of the Spanish Urological Club for Oncological Treatment scoring model: long-term follow-up experience at a single institute. Int J Urol. 2015;22:541–547. doi: 10.1111/iju.12749. [DOI] [PubMed] [Google Scholar]
- 15.Otto W, Breyer J, Herdegen S, Eder F, Bertz S, May M, et al. WHO 1973 grade 3 and infiltrative growth pattern proved, aberrant E-cadherin expression tends to be of predictive value for progression in a series of stage T1 high-grade bladder cancer after organ-sparing approach. Int Urol Nephrol. 2017;49:431–437. doi: 10.1007/s11255-016-1491-9. [DOI] [PubMed] [Google Scholar]
- 16.Otto W, van Rhijn BW, Breyer J, Bertz S, Eckstein M, Mayr R, et al. Infiltrative lamina propria invasion pattern as an independent predictor for cancer-specific and overall survival of instillation treatment-naïve stage T1 high-grade urothelial bladder cancer. Int J Urol. 2018;25:442–449. doi: 10.1111/iju.13532. [DOI] [PubMed] [Google Scholar]
- 17.Bree KK, Hensley PJ, Brooks N, Matulay J, Nogueras-Gonzalez GM, Navai N, et al. Impact of sex on response to BCG in non-muscle invasive bladder cancer patients: a contemporary review from a tertiary care center. World J Urol. 2021;39:4143–4149. doi: 10.1007/s00345-021-03755-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Sfakianos JP, Shariat SF, Favaretto RL, Rioja J, Herr HW. Impact of smoking on outcomes after intravesical bacillus Calmette-Guérin therapy for urothelial carcinoma not invading muscle of the bladder. BJU Int. 2011;108:526–530. doi: 10.1111/j.1464-410X.2010.09874.x. [DOI] [PubMed] [Google Scholar]