Neuroendocrine Neoplasms of the Urinary Bladder: Integrating Molecular Advances into a Refined Classification System

Neuroendocrine neoplasms (NENs) of the urinary bladder are rare but highly aggressive tumors that account for under 1% of bladder malignancies. The 2022 WHO classification recognizes small cell neuroendocrine carcinoma (SCNEC), large cell neuroendocrine carcinoma (LCNEC), mixed neuroendocrine neoplasms (MiNEN), well-differentiated neuroendocrine tumor (NET), and paraganglioma; however, this framework is largely extrapolated from other organ systems and does not fully capture the biological complexity of bladder NENs. Most cases represent poorly differentiated neuroendocrine carcinomas, frequently admixed with urothelial carcinoma and characterized by recurrent TP53 and RB1 inactivation, TERT promoter mutations, and epigenetic dysregulation. Emerging transcriptomic data further identify lineage-defined subgroups within SCNEC and LCNEC based on ASCL1, NEUROD1, and POU2F3 expression, with potential prognostic and therapeutic relevance. This review integrates histopathologic, immunophenotypic, and molecular data to highlight diagnostic challenges, biologic heterogeneity, and limitations of current classification schemes. We propose a refined, bladder-specific framework that incorporates proliferative indices, molecular alterations, and recognition of mixed neuroendocrine-non-neuroendocrine neoplasms, with the goal of improving diagnostic reproducibility and informing future biomarker-driven therapeutic strategies.