Molecular Characteristics, Heterogeneity, Plasticity, and Cell of Origin of Neuroendocrine Bladder Cancer

Neuroendocrine bladder cancer (NEBC) is a rare but highly aggressive cancer, representing approximately 1% of urinary bladder cancer. The most common NEBC is small cell bladder cancer (SCBC), characterized by high rates of recurrence, chemotherapy resistance, and early mortality. SCBC is histologically identical to small cell lung cancer (SCLC) but remains significantly understudied. Advances in next-generation sequencing techniques have partially elucidated the molecular characteristics of NEBC and identified druggable targets. This review compiles recent studies on human NEBC samples, summarizing key findings on their genomic alterations and molecular subtyping. Notably, it highlights specific mutations in the TERT promoter and epigenetic modifiers in NEBC, as well as molecular subtyping based on lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. Furthermore, this review explores the significant tumor heterogeneity and cellular plasticity observed in NEBC and discusses its cell of origin and potential therapeutic targets (MET inhibitor or DLL3) identified by preclinical NEBC models. Emerging evidence suggests that NEBC may share a common origin with urothelial carcinoma (UC), arising from a UC precursor. Advancing our understanding of NEBC tumorigenesis and identifying druggable targets will enhance treatment outcomes for patients with NEBC.