Genetic investigation in patients with histological variants of bladder cancer: clinical implications

Understanding histological variants is crucial for accurate diagnosis and management of bladder cancer (BC). Most BCs are urothelial carcinomas (UC), which can evolve into aggressive histological variants (HVs) such as micropapillary, plasmacytoid, small-cell carcinoma, and sarcomatoid subtypes. This review will focus on the clinicopathologic characteristics of the most common non-urothelial and other rare variants (signet-ring cell variant, decoy cells, osteoclastic giant cell variant) BCs, to be distinguished from BC variant histology containing a UC component. In addition, we reviewed the effects of understanding HVs in developing therapeutic and diagnostic methods for BC. Our analysis combines evidence from searches in PubMed/NCBI, Google Scholar, ClinicalTrials.gov, and key conference proceedings from 2011 to 2025. Recognizing and differentiating between various variant histology (VH) subtypes is crucial for tailoring treatment strategies and improving patient outcomes. Discovering and uniform reporting of variant histology in UC is essential. Clinical trials focusing specifically on patients with HVs are needed to evaluate the impact of new treatment modalities and optimize management strategies. More clinical studies with specific guidelines and goals, along with research, patient records, databases, and tissue banks, are needed to improve treatment plans and identify markers for patients with urinary tract cancer.