Pulmonary Large-Cell Neuroendocrine Carcinoma: Therapeutic Challenges and Opportunities

Abstract Pulmonary large cell neuroendocrine carcinoma (P-LCNEC) is a rare, poorly differentiated, non-small cell malignancy within the spectrum of neuroendocrine tumors (NETs) of the lung. Despite sharing several similarities with small cell lung cancer (SCLC) in their clinical, immunohistopathological, genomic, and prognostic features, it is a distinct and biologically heterogeneous entity with challenging diagnostic and therapeutic requirements. Given the lack of prospective, randomized data to guide management, it is common practice to pursue thoracic surgery for resectable tumors according to the guidelines for non-small cell lung cancer (NSCLC) and implement systemic chemotherapy as early as at stage I, similar to the treatment of SCLC. However, important issues, such as the optimal timing and combination of therapeutic modalities, the most effective type of chemotherapy for advanced-stage disease, and the benefit from prophylactic cranial irradiation, remain debated. Accumulating evidence from retrospective, molecular profiling studies supports the existence of at least two P-LCNEC subtypes, most notably a SCLC-like and a NSCLC-like phenotype, which presumably underlie the observed differential sensitivity to platinum-based regimens and warrant further validation as predictive biomarkers of efficacy. Furthermore, several potentially actionable, driver molecular alterations have been identified, offering implications for personalized treatment approaches, including targeted therapies and immunotherapy. The current review discusses open questions on the diagnosis and management of P-LCNEC, as well as recent advances in its genomic and transcriptomic characterization that create promising therapeutic opportunities.