&NA; Carcinoids and large cell neuroendocrine carcinomas (LCNECs) are rare neuroendocrine lung tumors. Here we provide an overview of the most updated data on the molecular characteristics of these diseases. Recent genomic studies showed that carcinoids generally contain a low mutational burden and few recurrently mutated genes. Most of the reported mutations occur in chromatin‐remodeling genes (e.g., menin 1 gene [MEN1]), and few affect genes of the phosphoinositide 3‐kinase (PI3K)‐AKT‐mechanistic target of rapamycin gene pathway. Aggressive disease has been related to chromothripsis, DNA‐repair gene mutations, loss of orthopedia homeobox/CD44, and upregulation of ret proto‐oncogene gene (RET) gene expression. In the case of LCNECs, which present with a high mutation burden, two major molecular subtypes have been identified: one with biallelic inactivation of tumor protein p53 gene (TP53) and retinoblastoma gene (RB1), a hallmark of SCLC; and the other one with biallelic inactivation of TP53 and serine/threonine kinase 11 gene (STK11)/kelch like ECH associated protein 1 gene (KEAP1), genes that are frequently mutated in NSCLC. These data, together with the identification of common mutations in the different components of combined LCNEC tumors, provide further evidence of the close molecular relation of LCNEC with other lung tumor types. In terms of therapeutic options, future studies should explore the association between mechanistic target of rapamycin pathway mutations and response to mechanistic target of rapamycin inhibitors in carcinoids. For LCNEC, preliminary data suggest that the two molecular subtypes might have a predictive value for chemotherapy response, but this observation needs to be validated in randomized prospective clinical trials. Finally, delta like Notch canonical ligand 3 inhibitors and immunotherapy may provide alternative options for patient‐tailored therapy in LCNEC.

中文翻译：

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肺类癌和大细胞神经内分泌癌的分子特征及其对临床管理的影响的新见解

&NA; 类癌和大细胞神经内分泌癌 (LCNEC) 是罕见的神经内分泌肺肿瘤。在这里，我们概述了有关这些疾病分子特征的最新数据。最近的基因组研究表明，类癌通常含有较低的突变负荷和很少的反复突变基因。大多数报道的突变发生在染色质重塑基因（例如，menin 1 基因 [MEN1]）中，很少影响雷帕霉素基因途径的磷酸肌醇 3 激酶 (PI3K)-AKT 机制靶点的基因。侵袭性疾病与染色体碎裂、DNA 修复基因突变、orthopedia homeobox/CD44 缺失和 ret 原癌基因 (RET) 基因表达上调有关。对于具有高突变负荷的 LCNEC，已经确定了两种主要的分子亚型：一种具有肿瘤蛋白 p53 基因 (TP53) 和视网膜母细胞瘤基因 (RB1) 的双等位基因失活，这是 SCLC 的标志；另一个是双等位基因失活的 TP53 和丝氨酸/苏氨酸激酶 11 基因 (STK11)/kelch 样 ECH 相关蛋白 1 基因 (KEAP1)，这些基因在 NSCLC 中经常发生突变。这些数据，连同对联合 LCNEC 肿瘤不同成分中常见突变的鉴定，为 LCNEC 与其他肺肿瘤类型的密切分子关系提供了进一步的证据。在治疗选择方面，未来的研究应探讨雷帕霉素通路突变的机制靶点与类癌中雷帕霉素抑制剂机制靶点的反应之间的关联。对于 LCNEC，初步数据表明这两种分子亚型可能对化疗反应具有预测价值，但这一观察结果需要在随机前瞻性临床试验中得到验证。最后，像 Notch 经典配体 3 抑制剂和免疫疗法的 delta 可能为 LCNEC 中的患者量身定制治疗提供替代选择。