SCLC 亚型的定义：ASCL1、NEUROD1、POU2F3 和 YAP1：全面的免疫组化和组织病理学特征。
SCLC Subtypes Defined by ASCL1, NEUROD1, POU2F3, and YAP1: A Comprehensive Immunohistochemical and Histopathologic Characterization.
机构信息
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
出版信息
J Thorac Oncol. 2020 Dec;15(12):1823-1835. doi: 10.1016/j.jtho.2020.09.009. Epub 2020 Oct 1.
INTRODUCTION
Recent studies have identified subtypes of small cell lung carcinoma (SCLC) defined by the RNA expression of ASCL1, NEUROD1, POU2F3, and YAP1 transcriptional regulators. There are only limited data on the distribution of these markers at the protein level and associated pathologic characteristics in clinical SCLC samples.
METHODS
The expression of ASCL1, NEUROD1, POU2F3, and YAP1 was analyzed by immunohistochemistry in 174 patient samples with SCLC. Subtypes defined by these markers were correlated with histologic characteristics, expression of classic neuroendocrine markers (synaptophysin, chromogranin A, CD56, INSM1), and other SCLC markers, including the neuroendocrine phenotype-associated markers TTF-1 and DLL3.
RESULTS
ASCL1 and NEUROD1 expression had the following distribution: (1) 41% ASCL1+/NEUROD1-; (2) 37% ASCL1+/NEUROD1+; (3) 8% ASCL1-/NEUROD1+; and (4) 14% ASCL1-/NEUROD1-. On the basis of their relative expression, 69% of cases were ASCL1-dominant and 17% were NEUROD1-dominant. POU2F3 was expressed in 7% of SCLC and was mutually exclusive of ASCL1 and NEUROD1. YAP1 was expressed at low levels, primarily in combined SCLC, and was not exclusive of other subtypes. Both ASCL1-dominant and NEUROD1-dominant subtypes were associated with neuroendocrine marker/TTF-1/DLL3 profile, whereas POU2F3 and other ASCL1/NEUROD1 double-negative tumors were neuroendocrine marker/TTF-1/DLL3.
CONCLUSIONS
This is the first comprehensive immunohistochemical and histopathologic analysis of novel SCLC subtypes in patient samples. We confirm that ASCL1/NEUROD1 double-negative tumors represent a distinct neuroendocrine-low subtype of SCLC, which is either uniquely associated with POU2F3 or lacks a known dominant regulator. The expression profiles of these markers appear more heterogeneous in native samples than in experimental models, particularly with regard to the high prevalence of ASCL1/NEUROD1 coexpression. These findings may have prognostic and therapeutic implications and warrant further clinical investigation.
简介
最近的研究已经确定了小细胞肺癌 (SCLC) 的亚型，这些亚型由 ASCL1、NEUROD1、POU2F3 和 YAP1 转录调节因子的 RNA 表达定义。关于这些标志物在临床 SCLC 样本中的蛋白质水平和相关病理特征的分布，仅有有限的数据。
方法
对 174 例 SCLC 患者样本进行了 ASCL1、NEUROD1、POU2F3 和 YAP1 的免疫组织化学分析。用这些标志物定义的亚型与组织学特征、经典神经内分泌标志物（突触素、嗜铬粒蛋白 A、CD56、INSM1）的表达以及其他 SCLC 标志物（包括与神经内分泌表型相关的标志物 TTF-1 和 DLL3）相关联。
结果
ASCL1 和 NEUROD1 的表达分布如下：（1）41% ASCL1+/NEUROD1-；（2）37% ASCL1+/NEUROD1+；（3）8% ASCL1-/NEUROD1+；和（4）14% ASCL1-/NEUROD1-。基于其相对表达，69%的病例为 ASCL1 优势型，17%为 NEUROD1 优势型。POU2F3 在 7%的 SCLC 中表达，与 ASCL1 和 NEUROD1 均不相关。YAP1 低水平表达，主要见于联合型 SCLC，与其他亚型不相关。ASCL1 优势型和 NEUROD1 优势型均与神经内分泌标志物/TTF-1/DLL3 谱相关，而 POU2F3 和其他 ASCL1/NEUROD1 双阴性肿瘤则与神经内分泌标志物/TTF-1/DLL3 相关。
结论
这是首次对患者样本中新型 SCLC 亚型进行的全面免疫组织化学和组织病理学分析。我们证实，ASCL1/NEUROD1 双阴性肿瘤代表一种独特的神经内分泌低型 SCLC，它要么与 POU2F3 相关，要么缺乏已知的优势调控因子。这些标志物的表达谱在原始样本中比在实验模型中更加异质，尤其是 ASCL1/NEUROD1 共表达的高发生率。这些发现可能具有预后和治疗意义，值得进一步临床研究。
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