Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Department of Gastrointestinal Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Histopathology. 2021 Feb;78(3):381-391. doi: 10.1111/his.14230. Epub 2020 Sep 26.
Gastric neuroendocrine carcinoma (NEC) is a rare and aggressive subtype with a poor prognosis. We aim to investigate expression profiles of HER2 and programmed death ligand 1 (PD-L1) in gastric NEC to test the potential applicability of drugs targeting these molecules.
Expression levels of HER2 and PD-L1 were evaluated in 25 gastric NECs, including 10 pure NECs and 15 mixed adenocarcinoma-NECs, and a combined positive score (CPS) was used to evaluate PD-L1 expression. The correlations of expression levels with both clinicopathological features and the expression of p53, retinoblastoma protein (Rb) and mismatch repair proteins were also analysed. Eighteen of the 25 (72%) cases showed a PD-L1 CPS of ≥ 1, which was previously shown to be associated with response to pembrolizumab. Positive nodal metastasis and low tumour-infiltrating lymphocyte (TIL) levels at the invasive margin were significantly associated with a PD-L1 CPS of < 1. The NEC component was HER2-negative in all cases, whereas HER2 positivity was observed in the adenocarcinoma component of six of 15 (40%) mixed adenocarcinoma-NECs. Mismatch repair deficiency, a mutant pattern of p53 expression and loss of Rb expression were observed in four (16%), 17 (68%) and nine (36%) cases, respectively, although these alterations were not associated with the PD-L1 CPS or other clinicopathological characteristics.
HER2 is unlikely to be an effective target in gastric NEC owing to the lack of HER2 expression, whereas the PD-1/PD-L1 pathway is a potential therapeutic target for gastric NEC because of the relatively high prevalence of a PD-L1 CPS of ≥ 1 in this subtype.
胃神经内分泌癌（NEC）是一种罕见且侵袭性强的亚型，预后不良。本研究旨在探讨胃 NEC 中 HER2 和程序性死亡配体 1（PD-L1）的表达谱，以检验针对这些分子的药物的潜在适用性。
评估了 25 例胃 NEC（包括 10 例纯 NEC 和 15 例混合性腺癌-NEC）中 HER2 和 PD-L1 的表达水平，并使用综合阳性评分（CPS）评估 PD-L1 的表达。还分析了表达水平与临床病理特征以及 p53、视网膜母细胞瘤蛋白（Rb）和错配修复蛋白表达的相关性。25 例中有 18 例（72%）的 PD-L1 CPS≥1，之前的研究表明这与对 pembrolizumab 的反应相关。阳性淋巴结转移和浸润性边缘的低肿瘤浸润淋巴细胞（TIL）水平与 PD-L1 CPS<1 显著相关。所有病例的 NEC 成分均为 HER2 阴性，而 15 例混合性腺癌-NEC 中有 6 例（40%）的腺癌成分 HER2 阳性。观察到 4 例（16%）存在错配修复缺陷、17 例（68%）存在 p53 表达突变模式和 9 例（36%）存在 Rb 表达缺失，但这些改变与 PD-L1 CPS 或其他临床病理特征无关。
由于缺乏 HER2 表达，HER2 不太可能成为胃 NEC 的有效靶点，而 PD-1/PD-L1 通路可能是胃 NEC 的潜在治疗靶点，因为这种亚型中 PD-L1 CPS≥1 的比例相对较高。
