Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
Changzhou Tongshu Biotechnology Co., Ltd., Shanghai 200120, China.
Hum Pathol. 2023 Dec;142:81-89. doi: 10.1016/j.humpath.2023.09.002. Epub 2023 Sep 22.
Molecular research on large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC) has progressed significantly. However, there are still fewer molecular markers related to prognostic/therapeutic strategies for these conditions compared to those for adenocarcinoma. We therefore investigated the molecular characteristics of neuroendocrine carcinomas (NECs). We enrolled patients surgically diagnosed with NECs between 2011 and 2019, with complete follow-up records. All were analyzed using whole exome sequencing and p53/Rb immunohistochemistry (IHC). A total of 92 cases, comprising 45 pure SCLC, 15 combined SCLC, 27 pure LCNEC, and 5 combined LCNEC, were included. TP53 (78.3%) and RB1 (34.8%) were the most common molecular alterations, followed by KMT2D, LRP1B, FAT3, NCOR2, SPTA1, and NOTCH1. The mutation frequency for EGFR was 10.9%. Sixteen patients with LCNEC who had TP53/RB1 co-alterations were SCLC-like, while the remaining were NSCLC-like. There was no statistically significant difference between the groups regarding overall survival (OS; p = 0.458) and progression-free survival (PFS; p = 0.157). The frequency of the loss of Rb expression by IHC in SCLC-like LCNEC was 100%. Significant pathway alterations unique to SCLC included Notch and AMPK, while HIF-1 was enriched exclusively in LCNEC. NCOR2 mutation was linked to worse OS (p = 0.029) and PFS (p = 0.015), while wild-type SPTA1 was associated with poor PFS (p = 0.018). IHC for Rb was reliable for predicting LCNEC molecular subtypes, indicating its clinical value. NCOR2 and SPTA1 alterations were identified as prognostic factors that may provide therapeutic targets for patients with NEC.
大细胞神经内分泌癌（LCNEC）和小细胞肺癌（SCLC）的分子研究取得了显著进展。然而，与腺癌相比，这些疾病的预后/治疗策略相关的分子标志物仍然较少。因此，我们研究了神经内分泌癌（NEC）的分子特征。我们纳入了 2011 年至 2019 年间手术诊断为 NEC 且具有完整随访记录的患者。所有患者均采用全外显子测序和 p53/Rb 免疫组化（IHC）进行分析。共纳入 92 例患者，其中 45 例为单纯 SCLC，15 例为合并 SCLC，27 例为单纯 LCNEC，5 例为合并 LCNEC。最常见的分子改变是 TP53（78.3%）和 RB1（34.8%），其次是 KMT2D、LRP1B、FAT3、NCOR2、SPTA1 和 NOTCH1。EGFR 突变频率为 10.9%。16 例存在 TP53/RB1 共改变的 LCNEC 患者为 SCLC 样，其余为 NSCLC 样。两组患者的总生存（OS；p=0.458）和无进展生存（PFS；p=0.157）无统计学差异。SCLC 样 LCNEC 中 IHC 检测到 Rb 表达缺失的频率为 100%。SCLC 中特有的显著通路改变包括 Notch 和 AMPK，而 HIF-1 仅在 LCNEC 中富集。NCOR2 突变与较差的 OS（p=0.029）和 PFS（p=0.015）相关，而野生型 SPTA1 与较差的 PFS 相关（p=0.018）。Rb 的 IHC 对于预测 LCNEC 分子亚型是可靠的，表明其具有临床价值。NCOR2 和 SPTA1 的改变被确定为预后因素，可能为 NEC 患者提供治疗靶点。
