肺大细胞神经内分泌癌（LCNEC）是一种具有生物异质性的高度侵袭性肿瘤。 LCNEC 中已发现多个基因突变。然而，基因改变、组织病理学特征和预后之间的关联仍然不明确。在此，我们研究了 19 名 LCNEC 患者和 9 名非典型类癌 (AC) 患者的临床病理学、免疫组织化学和基因组特征。我们发现 LCNEC 中 TP53 (89.5%)、RB1 (42.1%)、APC (31.6%) 和 MCL1 (31.6%) 的突变频率很高，而 AC 中很少发现基因改变。 APC 改变主要发生在外显子 16，并且仅在具有野生型 RB1 的 LCNEC 中被发现。 19 个 LCNEC 进一步分为 APC 野生型 (LCNEC-APCMT, 6/19) 和 APC 突变 (LCNEC-APCWT, 13/19) 亚组。与 LCNEC-APCWT 相比，LCNEC-APCMT 显示出较低的 TMB（中位数：12.64 vs 4.20，P = 0.045），且细胞学异型性相对较轻。此外，LCNEC-APCMT 与 AC 和 LCNEC-APCWT 的区别在于神经内分泌标志物（CD56 和 Syn，P < 0.01）的表达明显下调，并且 APC 下游基因的表达显着改变（β-连环蛋白迁移到细胞质和细胞核中， P < 0.001；c-Myc 上调，P = 0.005)。 LCNEC-APCMT 的 OS 在数值上介于 AC 和 LCNEC-APCWT 之间。我们首先提出，APC 改变在野生型 RB1 的 LCNEC 中很常见，并且与 LCNEC-APCWT 相比，LCNEC-APCMT 与更低的 TMB 和更好的 OS 相关。版权所有 © 2024。由 Elsevier B.V 出版。

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a highly aggressive neoplasm with biological heterogeneity. Mutations in multiple genes have been identified in LCNEC. However, associations between gene alterations, histopathological characteristics, and prognosis remain ambiguous. Here, we investigated the clinicopathologic, immunohistochemical, and genomic characteristics of 19 patients with LCNEC and 9 patients with atypical carcinoid (AC). We revealed high mutation frequencies of TP53 (89.5 %), RB1 (42.1 %), APC (31.6 %), and MCL1 (31.6 %) in LCNEC, while genetic alterations were rarely found in AC. APC alterations mainly occurred to the exon 16 and were only identified in LCNEC with wild-type RB1. The 19 LCNEC were further subgrouped into APC wild-type (LCNEC-APCMT, 6/19) and APC-mutated (LCNEC-APCWT, 13/19) subgroups. In comparison with LCNEC-APCWT, LCNEC-APCMT displayed lower TMB (median: 12.64 vs 4.20, P = 0.045), and relatively mild cytologic atypia. In addition, LCNEC-APCMT distinguished itself from AC and LCNEC-APCWT by obviously downregulated expression of neuroendocrine markers (CD56 and Syn, P < 0.01) and significantly altered expression of genes downstream of APC (β-catenin migrating into the cytoplasm and nucleus, P < 0.001; c-Myc upregulating, P = 0.005). The OS of LCNEC-APCMT was numerically intermediate between AC and LCNEC-APCWT. We first proposed that APC alterations were common in LCNEC with wild-type RB1 and that LCNEC-APCMT was associated with lower TMB and better OS in comparison with LCNEC-APCWT.Copyright © 2024. Published by Elsevier B.V.