CONTEXT: Urothelial carcinoma can exhibit a wide range of variant morphologies. Many variants present diagnostic challenges and carry clinical implications that inform prognosis and treatment decisions. OBJECTIVE: To provide an overview of the diagnostic, therapeutic, and prognostic significance of histological variants of urothelial carcinoma. EVIDENCE ACQUISITION: A PubMed/MEDLINE-based literature search was conducted using the key terms "urothelial carcinoma", "variant histology", "nested", "micropapillary", "microcystic", "sarcomatoid", "squamous differentiation", "glandular differentiation", "clear cell", "plasmacytoid", "lymphoepithelioma-like carcinoma", "squamous cell carcinoma", "small cell carcinoma", "adenocarcinoma", "radiotherapy", "neoadjuvant chemotherapy", and "adjuvant chemotherapy". EVIDENCE SYNTHESIS: The incidence of variant histology is increasing due to improved recognition. Nonetheless, diagnosis can pose challenges due to sampling limitations and interobserver variability. Although associated with advanced disease at presentation, survival outcomes for most variants do not differ significantly compared with pure urothelial carcinoma of the same stage. Controversy exists regarding optimal management due to the low quality of available evidence. For most cases, radical cystectomy with pelvic lymph node dissection (with neoadjuvant chemotherapy when appropriate) represents the standard of care. Small cell carcinoma and lymphoepithelioma-like carcinoma appear to be particularly chemosensitive. CONCLUSIONS: Accurate identification of variant histological subtypes is an important part of risk stratification, as these variants exhibit aggressive biological behaviour. Variant histology tumours are associated with advanced disease at presentation, which must be considered when counselling patients regarding survival outcomes. Optimal management remains to be defined but in most cases; neoadjuvant chemotherapy and radical cystectomy with pelvic lymph node dissection remains the mainstay of treatment. PATIENT SUMMARY: It is important to recognise histological variants of urothelial carcinoma as they indicate aggressive disease. When compared with patients with pure urothelial carcinoma of the same disease stage, survival does not appear to be significantly worse. In most cases, patients with invasive variant histology should be treated with neoadjuvant chemotherapy and radical cystectomy. Take Home Messages Accurate identification of variant histology is important as it exhibits aggressive biological behaviour and affects treatment. Although associated with advanced disease at presentation, with appropriate treatment, survival outcomes are not significantly different compared with pure urothelial carcinoma of the same stage.

Department of Pathology University of Texas MD Anderson Cancer Center Houston TX USA

Department of Surgery McGill University Health Center Montreal Canada

Department of Urology Clínica Alemana de Santiago Chile; Faculty of Medicine Clínica Alemana Universidad del Desarrollo Santiago Chile

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria; Department of Urology Weill Cornell Medical College New York NY USA; Department of Urology University of Texas Southwestern Dallas TX USA; Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic; Institute for Urology and Reproductive Health 1 M Sechenov 1st Moscow State Medical University Moscow Russia

Department of Urology Frimley Health NHS Foundation Trust Frimley Camberley UK

Department of Urology University of Kansas Medical Centre Kansas City KS USA

Division of Cancer Medicine Department of Genitourinary Medical Oncology University of Texas MD Anderson Cancer Center Houston TX USA

Division of Surgery Department of Urology University of Texas MD Anderson Cancer Center Houston TX USA

Division of Urology The University of Texas Medical Branch Galveston TX USA

GRC n°5 ONCOTYPE URO Sorbonne Université AP HP Paris France; Department of Urology Hôpital Pitié Salpêtrière Paris France

Manchester Cancer Research Centre Division of Cancer Science School of Medical Sciences University of Manchester Manchester Academic Health Sciences Centre Manchester UK; Department of Clinical Oncology The Christie NHS Foundation Trust Manchester Academic Health Science Centre Manchester UK

Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York NY USA

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