BACKGROUND: Female sex in patients treated by radical cystectomy (RC) is associated with more advanced stage and worse survival. However, studies supporting these findings mostly or exclusively relied on urothelial carcinoma of the urinary bladder (UCUB) and did not address non-urothelial variant-histology bladder cancer (VH BCa). We hypothesized that female sex is associated with a more advanced stage and worse survival in VH BCa, similarly to that of UCUB. MATERIALS AND METHODS: Within the SEER database (2004-2016), we identified patients aged ≥18 years, with histologically confirmed VH BCa, and treated with comprehensive RC. Logistic regression addressing the non-organ-confined (NOC) stage, as well as cumulative incidence plots and competing risks regression addressing CSM for females vs. males, were fitted. All analyses were repeated in stage-specific and VH-specific subgroups. RESULTS: Overall, 1623 VH BCa patients treated with RC were identified. Of those, 38% were female. Adenocarcinoma (n = 331, 33%), neuroendocrine tumor (n = 304, 18%), and other VH (n = 317, 37%) were less frequent in females but not squamous cell carcinoma (n = 671, 51%). Across all VH subgroups, female patients had higher NOC rates than males did (68 vs. 58%, p < 0.001), and female sex was an independent predictor of NOC VH BCa (OR = 1.55, p = 0.0001). Overall, five-year cancer-specific mortality (CSM) were 43% for females vs. 34% for males (HR = 1.25, p = 0.02). CONCLUSION: In VH BC patients treated with comprehensive RC, female sex is associated with a more advanced stage. Independently of stage, female sex also predisposes to higher CSM.

Cancer Prognostics and Health Outcomes Unit Division of Urology University of Montréal Health Center Montréal QC H4A 3J1 Canada

Department of Maternal Child and Urological Sciences Policlinico Umberto 1 Hospital Sapienza University of Rome 00161 Rome Italy

Department of Medical Biotechnology University of Siena 53100 Siena Italy

Department of Surgical and Diagnostic Integrated Sciences University of Genova 16146 Genova Italy

Department of Urology 2nd Faculty of Medicine Charles University 128 08 Prague Czech Republic

Department of Urology Comprehensive Cancer Center Medical University of Vienna 1090 Vienna Austria

Department of Urology Regina Elena National Cancer Institute 00144 Rome Italy

Department of Urology University Hospital Frankfurt Goethe University Frankfurt am Main 60596 Frankfurt am Main Germany

Department of Urology University of Texas Southwestern Dallas TX 75390 USA

Department of Urology Weill Cornell Medical College New York NY 10065 USA

Division of Experimental Oncology Unit of Urology URI Urological Research Institute IRCCS San Raffaele Scientific Institute 20132 Milan Italy

Hourani Center for Applied Scientific Research Al Ahliyya Amman University Amman 11942 Jordan

Institute for Urology and Reproductive Health 1 M Sechenov 1st Moscow State Medical University 119991 Moscow Russia

Martini Klinik Prostate Cancer Center University Hospital Hamburg Eppendorf 20251 Hamburg Germany

Sbarro Institute for Cancer Research and Molecular Medicine Center for Biotechnology Department of Biology College of Science and Technology Temple University Philadelphia PA 19122 USA

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