What Is the Significance of Variant Histology in Urothelial Carcinoma?

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.