Immunohistochemical stratification of bladder small cell carcinoma reveals two major phenotypes with distinct therapeutic biomarker profiles

Aims Small cell carcinoma of the bladder (SmCCB) is a rare and aggressive malignancy that remains poorly defined. Using the transcriptional taxonomy established for small cell lung carcinoma (SCLC), we aimed to stratify SmCCB by dominant transcription factors and assess associations between IHC‐defined phenotype, neuroendocrine differentiation and therapeutic biomarker expression. Methods and results A retrospective multi‐institutional cohort of 88 SmCCBs was assembled. Of these, 79 cases underwent immunohistochemical characterization for ASCL1, NEUROD1, POU2F3, YAP1 and HNF4α, along with classical neuroendocrine markers, therapeutic biomarkers and antibody–drug conjugate targets. NECTIN4 amplification was also assessed by fluorescence in situ hybridization (FISH). Six IHC‐defined subgroups were identified: ASCL1‐driven (41.8%), NEUROD1‐driven (25.3%), POU2F3‐driven (20.3%), YAP1‐driven (6.3%), mixed (5.1%) and full‐negative (1.3%). ASCL1‐driven, NEUROD1‐driven and mixed tumours were classified as High‐NE , with diffuse NE marker expression, whereas POU2F3‐driven, YAP1‐driven and full‐negative tumours were classified as Low‐NE , with weak or absent expression. Overall membranous Nectin‐4 expression was low or absent but significantly higher in Low‐NE tumours ( P < 0.001). NECTIN4 amplification occurred in 21.9% (16/73), comparable to that reported in non‐neuroendocrine urothelial carcinoma. Conversely, DLL3 and SLFN11 were significantly overexpressed in High‐NE tumours, while expression of the remaining targets was almost entirely absent. Conclusions SmCCB may be stratified into two IHC‐defined phenotypic groups with distinctive neuroendocrine differentiation and therapeutic biomarker profiles. Taken together, low membranous Nectin‐4 expression and preferential DLL3 and SLFN11 expression in High‐NE tumours support further investigation of alternative therapeutic strategies.