Clinicopathological features of gastric neuroendocrine carcinomas and the roles of hASH1/HES1 in neuroendocrine differentiation of gastric cancers

目前的胃癌组织学分类仅定义为神经内分泌(NE)类别的类癌和小细胞癌。本研究旨在探讨非小细胞型高级别胃NE癌的组织学和临床特征，暂定为大细胞神经内分泌癌(LCNEC)。通过对2835例切除的胃癌的组织学回顾，筛选出组织学特征可疑NE分化的肿瘤，其中NE表型在嗜铬粒素A和/或突触素表达的肿瘤细胞中分别占50%和1%~50%，分别定义为LCNEC和伴有神经内分泌分化的腺癌(ACNED)。在199个肿瘤中，嗜铬粒素A和/或突触素阳性的肿瘤中，42个和44个肿瘤分别符合喉癌和痤疮的诊断标准。一般来说，LCNEC的NE形态不如类癌明显，根据其主要生长方式可大致分为实性(30例)、管型(7例)和硬型(5例)。喉癌的预后明显差于常规腺癌(P&lt；0.0001)。因此，这项研究表明，胃NE肿瘤的范围比以前认识的更广泛，LCNEC不仅是一个独特的组织病理学实体，而且是一个独特的临床实体。此外，ACNEDs的预后也明显比腺癌差(P&lt；0.0001)，有些ACNEDs实际上可能是LCNEC，生存分析表明，只要肿瘤中存在光镜下的NE形态，&gt；20%的NE标志物阳性就足以表征LCNEC。

The current histologic classifications of gastric cancers define only carcinoids and small cell carcinomas in the neuroendocrine (NE) category. This study aimed to characterize the histologic and clinical features of high-grade gastric NE carcinomas of nonsmall cell type, tentatively named large cell neuroendocrine carcinoma (LCNEC). Tumors with histologic features suspicious of NE differentiation were selected by a histologic review of 2835 resected gastric cancers, and those with a NE phenotype in >50% and 1% to 50% tumor cells assessed by expressing chromogranin A and/or synaptophysin were defined as LCNEC and adenocarcinoma with neuroendocrine differentiation (ACNED), respectively. One hundred ninety-nine tumors were selected and of the 109 positive for chromogranin A and/or synaptophysin, 42 and 44 met the criteria for LCNEC and ACNED, respectively. Generally, LCNECs demonstrated less predominant NE morphology than carcinoids, and could be roughly divided into solid (30 cases), tubular (7 cases), and scirrhous (5 cases) subtypes with reference to their main growth pattern. The prognosis of LCNECs was significantly worse than that of conventional adenocarcinomas (P<0.0001). Thus, this study shows that the spectrum of gastric NE tumors is broader than has previously been recognized and LCNEC is not only a distinct histopathologic entity, but also a distinct clinical entity. Furthermore, the prognosis of ACNEDs was also significantly worse than that of adenocarcinomas (P<0.0001), and some ACNEDs might actually have been LCNECs, and survival analysis showed that >20% positivity of NE markers could be enough to characterize LCNEC, as long as light microscopic NE morphology was present in the tumor.