Women's and Perinatal Pathology Division.
Department of Pathology, Stanford University School of Medicine, Stanford, CA.
Am J Surg Pathol. 2020 Nov;44(11):1541-1548. doi: 10.1097/PAS.0000000000001560.
High-grade neuroendocrine carcinomas (NEC) of the endometrium are rare and account for <1% of all endometrial carcinomas. Both small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC) morphologies have been reported. Little is known regarding the molecular features of endometrial NEC including how they compare to pulmonary NEC (the most common site for these neoplasms) and the more common endometrial carcinoma histotypes. In this study, we investigated the molecular alterations in a series of endometrial NEC using a targeted next generation sequencing panel (Oncopanel). Fourteen NEC were sequenced; pure NEC (n=4) and mixed (n=10) with endometrioid adenocarcinoma (n=9) or carcinosarcoma (n=1). The NEC components of mixed tumors comprised LCNEC (n=6) and SCNEC (n=4). The 4 pure NEC comprised LCNEC (n=2) and SCNEC (n=2). Molecular analysis classified tumors into the 4 The Cancer Genome Atlas groups: (1) POLE-mutated/ultramutated (1/14; 7%), (2) microsatellite instability/hypermutated (6/14; 43%), (3) TP53 mutated/copy number high (2/14; 14%), or (4) no specific molecular profile (5/14; 36%). Overall, 50% of cases were ultramutated or hypermutated. In 8 cases of mixed carcinomas, the different histologic components were macrodissected and separately sequenced; molecular alterations were nearly identical among the 2 components, with the non-NEC component harboring slightly increased tumor mutational burden. Only 2 carcinomas (both with pure SCNEC morphology) had a molecular profile that would be expected in typical pulmonary SCNEC (RB1 deletion and TP53 mutations). Our findings, similar to data from NECs of other anatomic sites, suggest that the molecular context may be important when selecting therapies for women with endometrial NEC. Immune checkpoint inhibition may be a reasonable approach to treatment of microsatellite instability-NEC and we thus recommend that all endometrial NEC be tested for mismatch repair abnormalities, either molecularly or by mismatch repair protein immunohistochemistry.
子宫内膜高级别神经内分泌癌（NEC）较为罕见，占子宫内膜癌的比例<1%。已有报道显示，其可呈现小细胞神经内分泌癌（SCNEC）和大细胞神经内分泌癌（LCNEC）的形态学特征。关于子宫内膜 NEC 的分子特征，包括其与最常见的神经内分泌癌（此类肿瘤的最常见部位）和更常见的子宫内膜癌组织学类型的比较，目前知之甚少。在这项研究中，我们使用靶向下一代测序panel（Oncopanel）对一系列子宫内膜 NEC 进行了分子研究。对 14 例 NEC 进行了测序；其中纯 NEC（n=4）和混合性（n=10）肿瘤，与子宫内膜样腺癌（n=9）或癌肉瘤（n=1）混合。混合性肿瘤的 NEC 成分包括 LCNEC（n=6）和 SCNEC（n=4）。4 例纯 NEC 包括 LCNEC（n=2）和 SCNEC（n=2）。分子分析将肿瘤分为 4 个癌症基因组图谱（The Cancer Genome Atlas，TCGA）组：（1）POLE 突变/超突变（1/14；7%），（2）微卫星不稳定/高突变（6/14；43%），（3）TP53 突变/拷贝数高（2/14；14%）或（4）无特定分子谱（5/14；36%）。总体而言，有 50%的病例为超突变或高突变。在 8 例混合性癌中，对不同的组织学成分进行了宏观解剖和分别测序；2 个成分之间的分子改变几乎相同，非 NEC 成分的肿瘤突变负担略有增加。只有 2 例（均为纯 SCNEC 形态）的分子谱与典型的肺 SCNEC 相似（RB1 缺失和 TP53 突变）。与其他解剖部位的 NEC 数据相似，我们的研究结果表明，当为子宫内膜 NEC 女性选择治疗方法时，分子背景可能很重要。免疫检查点抑制可能是治疗微卫星不稳定-NEC 的合理方法，因此我们建议所有子宫内膜 NEC 均应进行错配修复异常的检测，无论是通过分子方法还是错配修复蛋白免疫组化方法。
