Review on gender differences in non-muscle invasive bladder cancer
Review Article

Review on gender differences in non-muscle invasive bladder cancer

Konrad Bilski, Łukasz Zapała, Michał A. Skrzypczyk, Maciej Oszczudłowski, Jakub Dobruch; on behalf of the EAU Young Academic Urologists—Urothelial Cancer Working party

Department of Urology, Centre of Postgraduate Medical Education, Independent Public Hospital of Professor W. Orlowski, Warsaw, Poland

Contributions: (I) Conception and design: K Bilski, J Dobruch; (II) Administrative support: K Bilski, J Dobruch; (III) Provision of study material or patients: K Bilski, J Dobruch; (IV) Collection and assembly of data: K Bilski, J Dobruch; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Konrad Bilski. Czerniakowska 231, 00-416 Warsaw, Poland. Email: konradbilski@gmail.com.

Abstract: Differences in the epidemiology, diagnosis and outcomes according to gender in patients diagnosed with non-muscle invasive bladder cancer (NMIBC) has been widely reported. In this article we present gender-specific differences in NMIBC in terms of epidemiology, risk factors, first clinical presentation, management and clinical outcomes based on systematically review evidence of existing literature. A literature search of English-language publications that included an analysis of the association of gender differences in patients with NMIBC was performed using PubMed. Sixty-four studies were selected for analysis with consensus of all authors. The incidence and mortality for urothelial bladder cancer (UBC) are higher in men, whereas cancer specific mortality to incidence ratio is significantly lower for men than for women. This phenomenon could be partially explained by differences in exposure to bladder cancer carcinogens. However female gender is associated with higher stage at presentation. Thirteen studies with a total of 11,069 patients diagnosed with NMIBC were included for analysis according to outcomes. In studies that found statistically significant differences in outcomes between sexes, female gender was reported as risk factor for disease recurrence, progression or cancer specific mortality. None of included studies found worse outcomes in men when compared to women with NMIBC. Results of our review suggest that female gender in patients diagnosed with NMIBC is associated—though inconsistently—with higher stage at presentation and poorer outcomes. Numerous factors may influence gender gap in incidence rate, clinical management and reported outcomes. Consensus on comparable data collection in routine practice and prospective trials including clinical outcomes are required to identify gender-specific differences in patients diagnosed with NMIBC.

Keywords: Bladder cancer; gender; non-muscle invasive bladder cancer (NMIBC)


Submitted Aug 28, 2018. Accepted for publication Oct 22, 2018.

doi: 10.21037/tau.2018.11.06


Introduction

Sex-specific discrepancies in epidemiology, diagnosis, and clinical outcomes of most of non-gender specific cancers have been reported (1,2). The most common malignancy of the urinary tract is urothelial bladder cancer (UBC). In 2016 alone, UBC was diagnosed in 437,000 cases and 186,000 patients succumbed to the disease (3). It remains the 9th commonest diagnosed cancer and the 13th most common cause of death globally. A sex-related differences are observed in the epidemiology of UBC, with about 3-fold higher incidence in men compared to women (4). However, the ratio of cancer-specific mortality (CSM) to incidence in UBC is significantly lower among men than women, indicating that female gender is associated with higher risk of CSM in UBC (4). Moreover, women are more often diagnosed with locally advanced disease and possess greater proportion of nonurothelial cell types at presentation when compared to their male counterparts (5). Furthermore, in the retrospective analysis by Horstmann et al. UBC was diagnosed at a significantly younger age in men than in women (mean age: 62 vs. 67 years) (6). Regardless of the stage, female gender has been shown in number of studies to be dismal prognostic factor among patients diagnosed with UBC (7-9). According to WHO, bladder cancer specific mortality is greater in women when compared with men in the majority of analyzed countries, with only two exceptions of worse outcomes in males. Higher UBC specific morality in men compared with women in Eastern Europe and Russia could be presumably caused by regional differences in exposures to carcinogens, especially tobacco smoking, between gender, contributing to differences in the incidence of aggressive form of UBC (10). Overall, female gender is associated with loosing greater proportion of life expectancy years due to UBC (11).

At presentation, about 75% of UBC is confined to the mucosa [non-muscle invasive bladder cancer (NMIBC)], while in the remaining 25%, cancer infiltrates muscle layer of the bladder wall [muscle invasive bladder cancer (MIBC)] or already formed metastases (12). Age-specific incidence of NMIBC cancer increased from 5.52 to 9.09 per 100,000 from 1998 to 2006, as reported in population-based study on US population (13). Interestingly, the incidence rise of UBC in this population was 25% faster among men compared to women (14). NMIBC is a heterogeneous disease and high-grade lesions invading subepithelial tissue (T1HG) and/or carcinoma in situ (CIS) are known risk factors of progression. Therefore, subgroups of NMIBC were recognized including low, intermediate and high-risk lesions. High-risk NMIBC remains potentially lethal disease with the risk of death ranging from 5% to even 38% (15). In several studies that included patients diagnosed with NMIBC female gender was related with higher risk of disease recurrence and progression, but data is inconsistent (16). Numerous explanations for the observed gender discrepancies have been introduced, including delayed diagnosis, disparate quality of medical care and diverse response to conservative therapy.

The aim of this systematic review is to present gender-related differences in epidemiology, clinical management and outcomes in patients diagnosed with NMIBC.


Evidence acquisition

Systematic search through PubMed database to identify articles devoted to gender diversities in bladder cancer published from 1980 to 2018 in English language was performed. The review was carried out according to the Preferred Reported Items for Systematic Reviews and Meta-analysis guidelines (PRISMA, www.prisma-statement.org) (Figure 1). The following phrases were used during the search: urothelial cancer or bladder cancer, sex, gender, males and females, men and women combined with several groups of keywords relevant to the discussed sections. These included: biology, etiology, management and outcomes with specific attention to non-muscle invasive disease. Clinical series, review articles and editorials were identified and all abstracts were reviewed but only the most significant papers were completely analyzed and used as the references. Eligible studies were approved by every co-author. Additional unique records were identified through the discussions with the supervising, senior author (J Dobruch). In order to store publications and remove duplicates Mendeley Desktop version 1.17.9 (© 2008-2016 Mendeley Ltd.) was used.

Figure 1 Flow chart of the study inclusion process according to PRISMA.

Evidence synthesis

Although gender is widely known risk factor used as a covariate in numerous studies, number of investigators have searched the explanations to unravel gender diversities in bladder cancer. The phenomenon should be presented in the focus of variety of elements including differences in exposures to risk factors and potential gender related mechanisms of chemical compounds metabolism, delayed diagnosis and uneven management of corresponding stages and grades of the disease and diverse biology of the cancer itself as well.


Results

Gender differences and risk factors

Potential risk factors of UBC have been widely investigated. The most common and well established one is cigarette smoking. People, who have ever smoked tobacco are at 2.5-fold greater risk of developing UBC compared to nonsmokers (17-21). According to several observational studies, cigarette smoking was reported as a cause of 50% of all UBC new cases and 40% of all UBC deaths (22-24). Since 1980s, large decrease in the spread of tobacco smoking was noticed for both genders, but on the other hand the quantity of people who smoke increased due to population growth. From 1980 to 2012 significant decrease of cigarette smoking prevalence was observed in the male and female population (41.2% to 31.1% and 10.6% to 6.2%, respectively) (25). Despite significant male predominance in smoking prevalence, data extracted from The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) and National Lung Screening Trial (NLST) to stratify risk of UBC according to sex, age, smoking status showed that gender gap in epidemiology of UBC cannot be fully explained according to differences in daily smoking prevalence between genders (26). The gender-related disparity in incidence of UBC in men and women with similar exposures to tobacco was also reported in previous studies (17,27). Environmental exposure to aromatic amines, polycyclic aromatic hydrocarbons, chlorinated hydrocarbons, arsenic at drinking water is another significant causative agent for UBC (28-30). Several studies report that that hairdressers and barbers may have increased risk of developing UBC due to occupational exposure, but the data are conflicting (31,32). Interestingly, among women using permanent hair dyes compared to never users of dye, who had NAT2 (N-acetyltransferase 2) slow acetylation phenotype, higher risk of UBC was found, on the other hand further analyses did not find correlation between hair dye exposure and increased risk of UBC (31,32). The metabolism of UBC carcinogens and the impact of sex hormone are disputed, emphasizing the theory that observed sex related UBC risk could be consequence of sex hormones cooperation with the hepatic biotransformation of carcinogens, with androgens and estrogens exerting opposing effects (33). In particular, at the molecular level, gender-specific expression patterns of UGTs (uridine 50-diphosphoglucuronosyl transferase), which participate in aromatic liver biotransformation was observed (34). GSTM1 (glutathione-S-transferase M1), another liver enzyme that participate in metabolism of bladder carcinogens by ligating glutathione, could partially explain gender gap in UBC incidence. Indeed, greater risk of UBC related with GSTM1 null genotype was found in women (OR 1.7; 95% CI: 1.0–3.0), but not in male group (OR 0.9; 95% CI: 0.7–1.3). Interestingly, women with the GSTM1 null genotype, increased risk of UBC was observed only among smokers (OR 2.3; 95% CI: 1.1–4.5 in smokers versus OR 0.9; 95% CI: 0.3–2.5 in non-smokers) (35).

Gender gap in diagnosis

Female gender is associated with more advanced disease at the time of diagnosis with UBC. According to Surveillance, Epidemiology and End Results (SEER) database, women are more often diagnosed with MIBC at presentation (22% vs. 25% in Caucasian and 30% vs. 43% in African-American respectively, P<0.001) (9). Data from more than 20,000 patients from the Netherlands Cancer Registry revealed statistically significant sex-related differences in stage distribution (Ta vs. T1) at presentation for NMIBC, with women presenting more often with T1 disease (9). Gender gap in stage at presentation and outcomes could be due to biologic differences as well as diagnostic delay in women. Indeed, there is data reporting no differences in clinical symptoms between sexes, while primary diagnostic approach as shown in numerous studies differ. It was reported that gender gap in evaluation of hematuria exist. Female gender was associated with higher risk of receiving symptomatic treatment for hematuria, without further evaluation (36). The retrospective data of 926 patients revealed 65% greater likelihood of specialized investigation of first or recurrent episode of hematuria (37). Interestingly, the analysis of data from 343 patients with confirmed UBC found among women time-delay from clinical symptoms suggestive for UBC to definitive diagnosis (38). Delay in UBC diagnosis might be responsible for higher stage at presentation and worse outcomes in women compared to men.


Outcomes

Patients treated with organ-preserving therapy

Abundant number of studies revealed female gender as a risk factor for disease recurrence or progression in patients treated with transurethral resection of the bladder tumor (TURBT) with adjuvant intravesical immunotherapy with however controversial conclusions. Seven studies with a total of 5,904 patients were included for analysis in this respect. In one single-institution retrospective study of 146 patients with T1HG UBC treated with BCG, the variable “CIS in the prostatic urethra or female gender” was associated on multivariate analysis with significantly increased risks of recurrence [hazard ratio (HR) 2.53; P=0.0003], progression (HR 3.59; P=0.001), and death from bladder cancer (HR 3.53; P=0.004) (7). It is worth to emphasize that patients did not undergo repeat transurethral resection (reTUR) nor maintenance bacillus Calmette-Guérin (BCG) was adopted, so conclusions are still uncertain. Similarly, Noon et al. using a population-based cancer registry, also detected a significantly increased CSM among women vs. men with NMIBC (39), while Alanee and colleagues noted in the SEER database that female gender was independently associated with higher risk of CSM among patients diagnosed with CIS (HR 1.69) (40). On the other hand, in retrospective analysis of data from 916 patients diagnosed with T1 UBC, women were in significantly greater risk of disease recurrence in the overall cohort. Interestingly in this series, among patients treated additionally with BCG authors did not reveal correlation between gender and risk of disease recurrence (41). Furthermore, in another study with 1,021 patients (756 men and 265 women) who received induction BCG for NMIBC, Boorjian et al. did not report an association between sexes and disease recurrence or progression (42). However, restaging TUR was performed in every case in the latter series, whereas in the former one restaging TUR was not uniformly implemented. At the same time, a meta-analysis of 15,215 patient diagnosed with high-grade T1 NMIBC determined female sex as risk factor for disease progression, but not for recurrence or CSM (43). In conclusion, we found that in one study female gender was associated with increased risk of disease progression as well as recurrence, in two studies, authors reported increased risk for disease recurrence, but not for disease progression. In four analyzed studies, authors did not report correlation between gender and risk of disease progression, recurrence or disease-specific mortality (Table 1).

Table 1
Table 1 Gender-specific outcomes in patients diagnosed with NMIBC treated with organ-preserving therapy
Full table

Patients treated with RC

When diagnosed with MIBC, radical cystectomy (RC) is the standard of care, whereas in patients diagnosed with NMIBC RC could be an option in selected subgroups of high-risk disease. Six studies with a total of 16,389 patients including 5,165 patients with ≤ pT1 were considered for analysis. In a few series of patients treated with RC for NMIBC, gender was the independent risk factor for CSM as well as for early complications (47-49). In a group of patients with CIS resistant to TURBT complemented with intravesical BCG therapy treated with RC, female sex was an independent risk factor for increased CSM (P=0.029) (50). Similar conclusions have been revealed in cohorts treated with RC, which had no evidence of disease (pT0N0) following RC (51). On the other hand the data published by Soave et al. and Mitra et al. showed no difference in survival among gender treated with RC for NMIBC (52,53). It is worth to emphasize that cohort of patients were heterogenous according to administration of neoadjuvant chemotherapy and no detailed information on its usage can be provided. To sum up in four included studies, authors found that female gender was associated with increased risk of cancer specific morality. In two analyzed studies correlation between gender and cancer specific mortality was not statistically significant (Table 2). Potential explanations of these divergent outcomes in females and males diagnosed with NMIBC cancer include that: female gender is associated with worse response to BCG immunotherapy (22), female bladders may be worse staged at primary TURBT (female bladders are typically thinner and so more prone to understaging MIBC) (55) or there is delay in the time to diagnosis for female patients (as irritative bladder symptoms or hematuria in female patients are initially treated as infections or detrusor overactivity, before complete evaluation) (37).

Table 2
Table 2 Gender-specific outcomes in patients diagnosed with NMIBC treated with RC
Full table

Molecular profiles of male and female bladder cancer

According to The Cancer Genome Atlas (TCGA) majority of NMIBC have FGFR3 (fibroblast growth factor receptor 3) mutations, Ras activation, and wild-type TP53 (56,57). There are number of UBC biomarkers implemented to clinical practice. Genetic sex related discrepancies according to UBC may lead to different disease biology among women and remains to be confirmed in well-designed prospective studies (58). Recently, published studies found possible correlation with BCG failure and ARID1A (AT-rich interactive domain 1A) (59). The progression of high-risk NMIBC at molecular level has not been fully understood. Some evidence revealed that p16/P53/RB1 signaling axis promotes progression of high-risk NMIBC (60), but there is lack of investigations showing possible differences at molecular level according to gender, that could explain clinical observed gender gap.

Androgen axis dependence in UBC induction and progression could partially explain the gender discrepancy in epidemiology and outcomes (61). Empirical studies show that estrogens may protect against UBC development, but afterwards support UBC progression (62,63). On the other hand, androgens, may initiate and promote progression of bladder cancer with its receptor playing a principal role (64). It could be assumed that, in females, due to the altered androgen levels, hormone-dependent mechanisms in progression of bladder cancer may impact inferior survival compared to males.


Conclusions

Gender differences in epidemiology, diagnosis, management and outcomes among patients diagnosed with NMIBC are pronounced. Both genetic and environmental factors are believed to play roles in gender differences in bladder cancer. Number of authors reported gender-related differences, when evaluating hematuria. By understanding sex-related discrepancies in NMIBC, gender-specific strategies for diagnosing and treatment, could be adopted to improve outcomes and reduce CSM. The present review does not find clear conclusions according to gender gap in NMIBC. Continued, especially prospective trials are thus required.


Acknowledgements

None.


Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.


References

  1. Edgren G, Liang L, Adami HO, et al. Enigmatic sex disparities in cancer incidence. Eur J Epidemiol 2012;27:187-96. [Crossref] [PubMed]
  2. Najari BB, Rink M, Li PS, et al. Sex disparities in cancer mortality: the risks of being a man in the United States. J Urol 2013;189:1470-4. [Crossref] [PubMed]
  3. Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Akinyemiju TF, et al. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2016: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncol 2018;4:1553-68. [Crossref] [PubMed]
  4. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-86. [Crossref] [PubMed]
  5. Scosyrev E, Noyes K, Feng C, et al. Sex and racial differences in bladder cancer presentation and mortality in the US. Cancer 2009;115:68-74. [Crossref] [PubMed]
  6. Horstmann M, Witthuhn R, Falk M, et al. Gender-specific differences in bladder cancer: a retrospective analysis. Gend Med 2008;5:385-94. [Crossref] [PubMed]
  7. Palou J, Sylvester RJ, Faba OR, et al. Female gender and carcinoma in situ in the prostatic urethra are prognostic factors for recurrence, progression, and disease-specific mortality in T1G3 bladder cancer patients treated with bacillus Calmette-Guérin. Eur Urol 2012;62:118-25. [Crossref] [PubMed]
  8. Fernandez-Gomez J, Solsona E, Unda M, et al. Prognostic factors in patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin: multivariate analysis of data from four randomized CUETO trials. Eur Urol 2008;53:992-1001. [Crossref] [PubMed]
  9. Mungan NA, Kiemeney LA, van Dijck JA, et al. Gender differences in stage distribution of bladder cancer. Urology 2000;55:368-71. [Crossref] [PubMed]
  10. Donsky H, Coyle S, Scosyrev E, et al. Sex differences in incidence and mortality of bladder and kidney cancers: national estimates from 49 countries. Urol Oncol 2014;32:40.e23-31. [Crossref] [PubMed]
  11. Scosyrev E, Golijanin D, Wu G, et al. The burden of bladder cancer in men and women: analysis of the years of life lost. BJU Int 2012;109:57-62. [Crossref] [PubMed]
  12. Burger M, Catto JW, Dalbagni G, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol 2013;63:234-41. [Crossref] [PubMed]
  13. Nielsen ME, Smith AB, Meyer AM, et al. Trends in stage-specific incidence rates for urothelial carcinoma of the bladder in the United States: 1988 to 2006. Cancer 2014;120:86-95. [Crossref] [PubMed]
  14. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58:71-96. [Crossref] [PubMed]
  15. van den Bosch S, Alfred Witjes J. Long-term cancer-specific survival in patients with high-risk, non-muscle-invasive bladder cancer and tumour progression: a systematic review. Eur Urol 2011;60:493-500. [Crossref] [PubMed]
  16. Dobruch J, Daneshmand S, Fisch M, et al. Gender and Bladder Cancer: A Collaborative Review of Etiology, Biology, and Outcomes. Eur Urol 2016;69:300-10. [Crossref] [PubMed]
  17. Freedman ND, Silverman DT, Hollenbeck AR, et al. Association between smoking and risk of bladder cancer among men and women. JAMA 2011;306:737-45. [Crossref] [PubMed]
  18. Kuper H, Boffetta P, Adami HO. Tobacco use and cancer causation: association by tumour type. J Intern Med 2002;252:206-24. [Crossref] [PubMed]
  19. Volanis D, Kadiyska T, Galanis A, et al. Environmental factors and genetic susceptibility promote urinary bladder cancer. Toxicol Lett 2010;193:131-7. [Crossref] [PubMed]
  20. Stewart SL, Cardinez CJ, Richardson LC, et al. Surveillance for cancers associated with tobacco use--United States, 1999-2004. Morbidity and mortality weekly report. MMWR Surveill Summ 2008;57:1-33. [PubMed]
  21. Strope SA, Montie JE. The causal role of cigarette smoking in bladder cancer initiation and progression, and the role of urologists in smoking cessation. J Urol 2008;180:31-7; discussion 37. [Crossref] [PubMed]
  22. Park S, Jee SH, Shin HR, et al. Attributable fraction of tobacco smoking on cancer using population-based nationwide cancer incidence and mortality data in Korea. BMC cancer 2014;14:406. [Crossref] [PubMed]
  23. Agudo A, Bonet C, Travier N, et al. Impact of cigarette smoking on cancer risk in the European prospective investigation into cancer and nutrition study. J Clin Oncol 2012;30:4550-7. [Crossref] [PubMed]
  24. Moolgavkar SH, Stevens RG. Smoking and cancers of bladder and pancreas: risks and temporal trends. J Natl Cancer Inst 1981;67:15-23. [PubMed]
  25. Ng M, Freeman MK, Fleming TD, et al. Smoking prevalence and cigarette consumption in 187 countries, 1980-2012. JAMA 2014;311:183-92. [Crossref] [PubMed]
  26. Krabbe LM, Svatek RS, Shariat SF, et al. Bladder cancer risk: Use of the PLCO and NLST to identify a suitable screening cohort. Urol Oncol 2015;33:65.e19-25. [Crossref] [PubMed]
  27. Hartge P, Harvey EB, Linehan WM, et al. Unexplained excess risk of bladder cancer in men. J Natl Cancer Inst 1990;82:1636-40. [Crossref] [PubMed]
  28. Brown T, Slack R, Rushton L. Occupational cancer in Britain. Urinary tract cancers: bladder and kidney. Br J Cancer 2012;107 Suppl 1:S76-84. [Crossref] [PubMed]
  29. Reulen RC, Kellen E, Buntinx F, et al. A meta-analysis on the association between bladder cancer and occupation. Scand J Urol Nephrol Suppl 2008.64-78. [Crossref] [PubMed]
  30. Samanic CM, Kogevinas M, Silverman DT, et al. Occupation and bladder cancer in a hospital-based case-control study in Spain. Occup Environ Med 2008;65:347-53. [Crossref] [PubMed]
  31. Koutros S, Silverman DT, Baris D, et al. Hair dye use and risk of bladder cancer in the New England bladder cancer study. Int J Cancer 2011;129:2894-904. [Crossref] [PubMed]
  32. Ros MM, Gago-Dominguez M, Aben KK, et al. Personal hair dye use and the risk of bladder cancer: a case-control study from The Netherlands. Cancer Causes Control 2012;23:1139-48. [Crossref] [PubMed]
  33. Zhang Y. Understanding the gender disparity in bladder cancer risk: the impact of sex hormones and liver on bladder susceptibility to carcinogens. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 2013;31:287-304. [Crossref] [PubMed]
  34. Buckley DB, Klaassen CD. Tissue- and gender-specific mRNA expression of UDP-glucuronosyltransferases (UGTs) in mice. Drug Metab Dispos 2007;35:121-7. [Crossref] [PubMed]
  35. Karagas MR, Park S, Warren A, et al. Gender, smoking, glutathione-S-transferase variants and bladder cancer incidence: a population-based study. Cancer Lett 2005;219:63-9. [Crossref] [PubMed]
  36. Santos F, Dragomir A, Kassouf W, et al. Urologist referral delay and its impact on survival after radical cystectomy for bladder cancer. Curr Oncol 2015;22:e20-6. [Crossref] [PubMed]
  37. Johnson EK, Daignault S, Zhang Y, et al. Patterns of hematuria referral to urologists: does a gender disparity exist? Urology 2008;72:498-502; discussion 502-3. [Crossref] [PubMed]
  38. Månsson A, Anderson H, Colleen S. Time lag to diagnosis of bladder cancer--influence of psychosocial parameters and level of health-care provision. Scand J Urol Nephrol 1993;27:363-69. [Crossref] [PubMed]
  39. Noon AP, Albertsen PC, Thomas F, et al. Competing mortality in patients diagnosed with bladder cancer: evidence of undertreatment in the elderly and female patients. Br J Cancer 2013;108:1534-40. [Crossref] [PubMed]
  40. Alanee S, Bauman J, Dynda D, et al. Conservative management and female gender are associated with increased cancer-specific death in patients with isolated primary urothelial carcinoma in situ. Eur J Cancer Care (Engl) 2015;24:444-49. [Crossref] [PubMed]
  41. Kluth LA, Fajkovic H, Xylinas E, et al. Female gender is associated with higher risk of disease recurrence in patients with primary T1 high-grade urothelial carcinoma of the bladder. World J Urol 2013;31:1029-36. [Crossref] [PubMed]
  42. Boorjian SA, Zhu F, Herr HW. The effect of gender on response to bacillus Calmette-Guérin therapy for patients with non-muscle-invasive urothelial carcinoma of the bladder. BJU Int 2010;106:357-61. [Crossref] [PubMed]
  43. Martin-Doyle W, Leow JJ, Orsola A, et al. Improving selection criteria for early cystectomy in high-grade t1 bladder cancer: a meta-analysis of 15,215 patients. J Clin Oncol 2015;33:643-50. [Crossref] [PubMed]
  44. Gontero P, Sylvester R, Pisano F, et al. Prognostic factors and risk groups in T1G3 non-muscle-invasive bladder cancer patients initially treated with bacillus Calmette-Guérin: results of a retrospective multicenter study of 2451 patients. Eur Urol 2015;67:74-82. [Crossref] [PubMed]
  45. Takenaka A, Yamada Y, Miyake H, et al. Clinical outcomes of bacillus Calmette-Guérin instillation therapy for carcinoma in situ of urinary bladder. Int J Urol 2008;15:309-13. [Crossref] [PubMed]
  46. Holz S, Albisinni S, Gilsoul J, et al. Risk factor assessment in high-risk, bacillus Calmette-Guérin-treated, non-muscle-invasive bladder cancer. Res Rep Urol 2017;9:195-202. [Crossref] [PubMed]
  47. Kluth LA, Rieken M, Xylinas E, et al. Gender-specific differences in clinicopathologic outcomes following radical cystectomy: an international multi-institutional study of more than 8000 patients. Eur Urol 2014;66:913-9. [Crossref] [PubMed]
  48. Messer JC, Shariat SF, Dinney CP, et al. Female gender is associated with a worse survival after radical cystectomy for urothelial carcinoma of the bladder: a competing risk analysis. Urology 2014;83:863-7. [Crossref] [PubMed]
  49. May M, Bastian PJ, Brookman-May S, et al. Gender-specific differences in cancer-specific survival after radical cystectomy for patients with urothelial carcinoma of the urinary bladder in pathologic tumor stage T4a. Urol Oncol 2013;31:1141-7. [Crossref] [PubMed]
  50. Tilki D, Reich O, Svatek RS, et al. Characteristics and outcomes of patients with clinical carcinoma in situ only treated with radical cystectomy: an international study of 243 patients. J Urol 2010;183:1757-63. [Crossref] [PubMed]
  51. Sandhu GS, Aprikian A, Chin J, et al. Outcomes of pT0N0 at radical cystectomy: The Canadian Bladder Cancer Network experience. Can Urol Assoc J 2012;6:E116-20. [Crossref] [PubMed]
  52. Soave A, Dahlem R, Hansen J, et al. Gender-specific outcomes of bladder cancer patients: a stage-specific analysis in a contemporary, homogenous radical cystectomy cohort. Eur J Surg Oncol 2015;41:368-77. [Crossref] [PubMed]
  53. Mitra AP, Skinner EC, Schuckman AK, et al. Effect of gender on outcomes following radical cystectomy for urothelial carcinoma of the bladder: a critical analysis of 1,994 patients. Urol Oncol 2014;32:52.e1-9. [Crossref] [PubMed]
  54. Otto W, May M, Fritsche HM, et al. Analysis of sex differences in cancer-specific survival and perioperative mortality following radical cystectomy: results of a large German multicenter study of nearly 2500 patients with urothelial carcinoma of the bladder. Gend Med 2012;9:481-9. [Crossref] [PubMed]
  55. Herkommer K, Hofer C, Gschwend JE, et al. Gender and body mass index as risk factors for bladder perforation during primary transurethral resection of bladder tumors. J Urol 2012;187:1566-70. [Crossref] [PubMed]
  56. Yoshino H, Seki N, Itesako T, et al. Aberrant expression of microRNAs in bladder cancer. Nature reviews. Urology 2013;10:396-404. [Crossref] [PubMed]
  57. Knowles MA, Hurst CD. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nature reviews. Cancer 2015;15:25-41. [Crossref] [PubMed]
  58. Esrig D, Elmajian D, Groshen S, et al. Accumulation of nuclear p53 and tumor progression in bladder cancer. N Engl J Med 1994;331:1259-64. [Crossref] [PubMed]
  59. Bitler BG, Aird KM, Garipov A, et al. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat Med 2015;21:231-8. [Crossref] [PubMed]
  60. Du J, Wang SH, Yang Q, et al. p53 status correlates with the risk of progression in stage T1 bladder cancer: a meta-analysis. World J Surg Oncol 2016;14:137. [Crossref] [PubMed]
  61. Rahmani AH, Alzohairy M, Babiker AY, et al. Implication of androgen receptor in urinary bladder cancer: a critical mini review. Int J Mol Epidemiol Genet 2013;4:150-5. [PubMed]
  62. Lucca I, Fajkovic H, Klatte T. Sex steroids and gender differences in nonmuscle invasive bladder cancer. Curr Opin Urol 2014;24:500-5. [Crossref] [PubMed]
  63. McGrath M, Michaud DS, De Vivo I. Hormonal and reproductive factors and the risk of bladder cancer in women. Am J Epidemiol 2006;163:236-44. [Crossref] [PubMed]
  64. Miyamoto H, Yao JL, Chaux A, et al. Expression of androgen and oestrogen receptors and its prognostic significance in urothelial neoplasm of the urinary bladder. BJU Int 2012;109:1716-26. [Crossref] [PubMed]
Cite this article as: Bilski K, Zapała Ł, Skrzypczyk MA, Oszczudłowski M, Dobruch J; on behalf of the EAU Young Academic Urologists—Urothelial Cancer Working party. Review on gender differences in non-muscle invasive bladder cancer. Transl Androl Urol 2019;8(1):12-20. doi: 10.21037/tau.2018.11.06