ArticleModern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc2024
Differential NEUROD1, ASCL1, and POU2F3 Expression Defines Molecular Subsets of Bladder Small Cell/Neuroendocrine Carcinoma With Prognostic Implications.
Article in Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers, 1 of them a synthesis that pooled it.
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Who cites it
14 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Prognostic values and clinical significance of POU2F3 expression in neuroendocrine carcinomas: a meta-analysis with a focus on small cell lung cancer.Annals of medicine · 2025Pooled it
- Article
- Small Cell Lung Cancer Classification: Unraveling Heterogeneity to Enable Personalized Treatments.Cancer research · 2026Review
- POU2F3-positive neuroendocrine carcinoma of the urinary bladder showing basaloid morphology: expanding the morphologic spectrum of tuft cell-like carcinoma.Virchows Archiv : an international journal of pathology · 2026Article
- PLCG2 across human disease: genetic variants, signaling mechanisms, and clinical implications.Journal of translational medicine · 2026Review
- Case Report: Clinicopathological features of bladder neuroendocrine neoplasm: a retrospective case series of nine cases and literature review.Frontiers in oncology · 2026Article
- Concept of neuroendocrine neoplasms of all organs with a focus on grading, subtyping.Virchows Archiv : an international journal of pathology · 2026Review
- Adjunctive diagnostic utility of POU2F3 in predominantly pulmonary high-grade neuroendocrine carcinomas with limited or discordant conventional marker expression: a case-control study.Frontiers in medicine · 2026Article
- Article
- Lineage plasticity and histological transformation: tumor histology as a spectrum.Cell research · 2025Review
- Review
- Clinicopathological characteristics of transcription factor-defined subtypes in bladder small cell carcinoma.BMC cancer · 2025Article
- Molecular Characteristics, Heterogeneity, Plasticity, and Cell of Origin of Neuroendocrine Bladder Cancer.Cancer heterogeneity and plasticity · 2025Article
- Harnessing delta-like ligand 3: bridging biomarker discovery to next-generation immunotherapies in refractory small cell lung cancer.Frontiers in immunology · 2025Review
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Abstract
Small cell carcinomas (SMC) of the lung are now molecularly classified based on the expression of transcriptional regulators (NEUROD1, ASCL1, POU2F3, and YAP1) and DLL3, which has emerged as an investigational therapeutic target. PLCG2 has been shown to identify a distinct subpopulation of lung SMC with stem cell-like and prometastasis features and poor prognosis. We analyzed the expression of these novel neuroendocrine markers and their association with traditional neuroendocrine markers and patient outcomes in a cohort of bladder neuroendocrine carcinoma (NEC) consisting of 103 SMC and 19 large cell NEC (LCNEC) assembled in tissue microarrays. Coexpression patterns were assessed and integrated with detailed clinical annotation including overall (OS) and recurrence-free survival (RFS) and response to neoadjuvant/adjuvant chemotherapy. We identified 5 distinct molecular subtypes in bladder SMC based on the expression of ASCL1, NEUROD1, and POU2F3: ASCL1+/NEUROD1- (n = 33; 34%), ASCL1- /NEUROD1+ (n = 21; 21%), ASCL1+/NEUROD1+ (n = 17; 17%), POU2F3+ (n = 22, 22%), and ASCL1- /NEUROD1- /POU2F3- (n = 5, 5%). POU2F3+ tumors were mutually exclusive with those expressing ASCL1 and NEUROD1 and exhibited lower expression of traditional neuroendocrine markers. PLCG2 expression was noted in 33 tumors (32%) and was highly correlated with POU2F3 expression (P < .001). DLL3 expression was high in both SMC (n = 72, 82%) and LCNEC (n = 11, 85%). YAP1 expression was enriched in nonneuroendocrine components and negatively correlated with all neuroendocrine markers. In patients without metastatic disease who underwent radical cystectomy, PLCG2+ or POU2F3+ tumors had shorter RFS and OS (P < .05), but their expression was not associated with metastasis status or response to neoadjuvant/adjuvant chemotherapy. In conclusion, the NEC of the bladder can be divided into distinct molecular subtypes based on the expression of ASCL1, NEUROD1, and POU2F3. POU2F3-expressing tumors represent an ASCL1/NEUROD1-negative subset of bladder NEC characterized by lower expression of traditional neuroendocrine markers. Marker expression patterns were similar in SMC and LCNEC. Expression of PLCG2 and POU2F3 was associated with shorter RFS and OS. DLL3 was expressed at high levels in both SMC and LCNEC of the bladder, nominating it as a potential therapeutic target.
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