- 88 例膀胱小细胞癌（SmCCB）多中心回顾队列中，79 例完成 ASCL1/NEUROD1/POU2F3/YAP1/HNF4α 等 IHC 分层，可分为 High-NE 与 Low-NE 两大表型。
- High-NE（ASCL1、NEUROD1、mixed）神经内分泌标志弥漫阳性；Low-NE（POU2F3、YAP1、full-negative）表达弱或缺失。
- 膜性 Nectin-4 总体低/缺，但 Low-NE 显著更高；High-NE 优先过表达 DLL3 与 SLFN11，提示可探索替代治疗策略。
摘要
目的
膀胱小细胞癌（SmCCB）罕见且侵袭性强，目前界定仍不充分。我们借助小细胞肺癌（SCLC）的转录分型框架，按主导转录因子对 SmCCB 分层，并评估免疫组化（IHC）定义的表型、神经内分泌分化与治疗相关生物标志物表达之间的关联。
方法与结果
组装了 88 例 SmCCB 的回顾性多中心队列。其中 79 例完成 ASCL1、NEUROD1、POU2F3、YAP1 与 HNF4α 的免疫组化表征，并同步检测经典型神经内分泌标志物、治疗相关生物标志物及抗体–药物偶联物（ADC）靶点。亦以荧光原位杂交（FISH）评估 NECTIN4 扩增。共识别六个 IHC 定义亚组：ASCL1 驱动（41.8%）、NEUROD1 驱动（25.3%）、POU2F3 驱动（20.3%）、YAP1 驱动（6.3%）、混合型（5.1%）与全阴性（1.3%）。ASCL1 驱动、NEUROD1 驱动与混合型归为 High-NE，神经内分泌标志弥漫表达；POU2F3 驱动、YAP1 驱动与全阴性归为 Low-NE，表达弱或缺失。总体膜性 Nectin-4 表达低或缺失，但在 Low-NE 肿瘤中显著更高（P<0.001）。NECTIN4 扩增见于 21.9%（16/73），与非神经内分泌尿路上皮癌报道比例相近。相反，DLL3 与 SLFN11 在 High-NE 肿瘤中显著过表达，其余靶点表达几乎完全缺失。
结论
SmCCB 可分层为两个 IHC 定义表型组，神经内分泌分化与治疗生物标志物谱各具特点。综合来看，膜性 Nectin-4 表达偏低，以及 High-NE 肿瘤优先表达 DLL3 与 SLFN11，支持进一步探索替代治疗策略。
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.