Pulmonary Large-Cell Neuroendocrine Carcinoma: Molecular Heterogeneity, Current Treatment and the Emerging Precision-Oncology Paradigm

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive malignancy with substantial biological heterogeneity. Genomic studies identify SCLC-like and NSCLC-like spectra, but genomic categories overlap incompletely with transcriptional states. Morphology remains essential: neither neuroendocrine marker positivity nor RB1 status alone distinguishes LCNEC from small-cell lung cancer (SCLC). This narrative review integrates diagnostic limitations, stage-based management, and the clinical implications of profiling. Surgery with systematic nodal assessment is central for resectable disease; postoperative platinum chemotherapy has greater support than perioperative immunotherapy. In advanced disease, platinum-etoposide is a commonly used reference regimen. Retrospective associations involving platinum-gemcitabine or platinum-taxanes in RB1-wild-type tumors remain hypothesis-generating and should not be extended to pemetrexed. LANCE, a durvalumab phase II trial, and preliminary NEJ044 findings provide prospective chemo-immunotherapy observations, although randomized LCNEC-specific evidence remains absent. No standard second-line regimen is established. Rare actionable drivers may support matched treatment, whereas DLL3-directed approaches and FGL1/SPINK1-associated strategies require clinical validation. We propose an evidence-qualified framework separating stage-based care, individualized molecular considerations, and clinical-trial strategies.