Squamous cell carcinoma of the bladder: Current evidence, therapeutic challenges, and research perspectives from the French AVENTUR group

Squamous cell carcinoma (SCC) of the bladder is a rare subtype accounting for 2-5% of bladder cancers in Western countries. Its epidemiology, biological drivers, and clinical behavior differ substantially from urothelial carcinoma (UC), yet most management strategies remain extrapolated from UC due to the absence of dedicated evidence. Robust data are limited, and therapeutic decision-making is challenged by the rarity of this aggressive variant. Bladder SCC is strongly associated with chronic inflammatory conditions, including schistosomiasis, long-term catheterization, and recurrent urinary infections. Most patients present with muscle-invasive disease, characterized by marked local aggressiveness and a lower incidence of early nodal or distant metastases compared with UC. Molecular profiling indicates a predominant basal/squamous phenotype with frequent EGFR pathway activation and TP53/RB1 alterations, highlighting potential therapeutic vulnerabilities. However, the efficacy of perioperative chemotherapy, immunotherapy, or antibody-drug conjugates remains uncertain, as SCC patients are consistently underrepresented in clinical trials and outcomes are rarely reported separately. Emerging targeted strategies, such as Nectin-4 and Trop-2-directed agents, show promise but require prospective, SCC-specific evaluation. Bladder SCC remains an orphan malignancy with significant unmet clinical needs. Dedicated multicenter efforts are crucial to refine diagnostic pathways, integrate molecular characterization, and develop tailored therapeutic approaches. The French AVENTUR Group aims to address these gaps by coordinating national collaboration across institutions and promoting prospective clinical and translational research to improve outcomes in this rare and aggressive bladder cancer subtype.