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Background: Combined large cell neuroendocrine carcinoma (C-LCNEC) is pulmonary large cell neuroendocrine carcinoma (LCNEC) mixed with other components, such as adenocarcinoma (AD), squamous cell carcinoma (SCC), etc. The clinical characteristics and prognostic factors of C-LCNEC remain unclear. This study aimed to describe the distinct features between C-LCNEC with different components and explore the treatment strategy.Methods: We retrospectively collected data of 114 C-LCNEC patients who underwent surgically resection and analyzed their clinical characteristics and prognosis.Results: In our final cohort, 82 (72%) were LCNEC combined with adenocarcinoma (LCNEC/AD), while 32 (28%) were LCNEC combined with squamous cell carcinoma (LCNEC/SCC). LCNEC/AD was more likely to occur in female, younger adults, with visceral pleural invasion and with driver gene expression. However, univariate analysis showed no significant difference in DFS and OS between them (P¼0.837 and P¼0.852), while adjuvant chemotherapy (P¼0.001 and P¼0.003) and preoperative CEA level (P¼0.026 and P¼0.009) were independent predictors. C-LCNEC patients receiving adjuvant chemotherapy had longer DFS and OS, including stage I patients (P ¼ 0.006 and P ¼ 0.031), and the benefit of etoposide-based chemotherapy in stage II or III patients was greater than the other regimens (P ¼ 0.038 and P¼0.020). EGFR and ALK mutations were present in 5.8% (17/66) and 6.1% (4/66) of C-LCNEC patients, respectively, and they responded well to targeted therapy.Conclusions: LCNEC/AD was the most common type of C-LCNEC, and there were many differences between different combined components. Adjuvant chemotherapy, especially etoposide-based chemotherapy, was a beneficial option for resected C-LCNEC.

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