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

IF 3.8 2区医学 Q2 CELL BIOLOGY

Histopathology Pub Date : 2026-09-16 DOI:10.1111/his.70284

Nazario P Tenace, Maurizio Colecchia, Arndt Hartmann, Maurilio Ponzoni, Claudio Doglioni, Sebastian Rauch, Marco Moschini, Andrea Necchi, Alberto Briganti, Francesco Montorsi, Markus Eckstein

{"title":"Immunohistochemical stratification of bladder small cell carcinoma reveals two major phenotypes with distinct therapeutic biomarker profiles.","authors":"Nazario P Tenace, Maurizio Colecchia, Arndt Hartmann, Maurilio Ponzoni, Claudio Doglioni, Sebastian Rauch, Marco Moschini, Andrea Necchi, Alberto Briganti, Francesco Montorsi, Markus Eckstein","doi":"10.1111/his.70284","DOIUrl":null,"url":null,"abstract":"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.","PeriodicalId":13219,"journal":{"name":"Histopathology","volume":" ","pages":""},"PeriodicalIF":3.8000,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Histopathology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/his.70284","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

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.

查看原文本刊更多论文

膀胱小细胞癌的免疫组织化学分层揭示了两种具有不同治疗生物标志物特征的主要表型。

目的：膀胱小细胞癌（SmCCB）是一种罕见的侵袭性恶性肿瘤，目前尚未明确定义。利用小细胞肺癌（SCLC）的转录分类学，我们旨在通过优势转录因子对SmCCB进行分层，并评估ihc定义的表型、神经内分泌分化和治疗性生物标志物表达之间的关系。方法和结果：对88家中小工商银行进行了回顾性研究。其中，79例患者进行了ASCL1、NEUROD1、POU2F3、YAP1和HNF4α的免疫组织化学鉴定，以及经典的神经内分泌标志物、治疗性生物标志物和抗体-药物偶联靶点。用荧光原位杂交（FISH）检测NECTIN4扩增情况。确定了六个ihc定义的亚组：ascl1驱动（41.8%），neurod1驱动（25.3%），pou2f3驱动（20.3%），yap1驱动（6.3%），混合（5.1%）和全阴性（1.3%）。ascl1驱动、neurod1驱动和混合驱动肿瘤被归类为High-NE， NE标记物表达弥漫；而pou2f3驱动、yap1驱动和全阴性肿瘤被归类为Low-NE， NE标记物表达弱或不表达。结论：SmCCB可能分为两个ihc定义的表型组，具有独特的神经内分泌分化和治疗性生物标志物特征。综上所述，在高ne肿瘤中，低膜性Nectin-4表达和优先的DLL3和SLFN11表达支持进一步研究替代治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Histopathology 医学-病理学

CiteScore

10.20

自引率

4.70%

发文量

239

审稿时长

1 months

期刊介绍： Histopathology is an international journal intended to be of practical value to surgical and diagnostic histopathologists, and to investigators of human disease who employ histopathological methods. Our primary purpose is to publish advances in pathology, in particular those applicable to clinical practice and contributing to the better understanding of human disease.