Mutational analysis of pulmonary large cell neuroendocrine carcinoma: APC gene mutations identify a good prognostic factor.

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-APC, 6/19) and APC-mutated (LCNEC-APC, 13/19) subgroups. In comparison with LCNEC-APC, LCNEC-APC displayed lower TMB (median: 12.64 vs 4.20, P = 0.045), and relatively mild cytologic atypia. In addition, LCNEC-APC distinguished itself from AC and LCNEC-APC 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-APC was numerically intermediate between AC and LCNEC-APC. We first proposed that APC alterations were common in LCNEC with wild-type RB1 and that LCNEC-APC was associated with lower TMB and better OS in comparison with LCNEC-APC.