Clinical utility of molecular profiling in rare lung neuroendocrine neoplasms.

Rare lung neuroendocrine neoplasms (LNENs), including pulmonary carcinoids and large-cell neuroendocrine carcinomas (LCNEC), are heterogeneous tumors. Current World Health Organization (WHO) classification primarily relies on morphological features, leading to important inter-observer variability and sub-optimal prognostic accuracy. This review highlights the clinical utility of molecular profiling to overcome these diagnostic and prognostic challenges. Recent multi-omics studies have demonstrated that pulmonary carcinoids are not a uniform entity but comprise distinct molecular subgroups (A1, A2, B, and supra-carcinoids) with unique clinical and genomic features. Furthermore, the recently described atypical SCLC adds another layer of heterogeneity to this spectrum. For clinical practice, a biomarker panel consisting of OTP, CD44, and Ki-67 can improve the prediction of disease recurrence in pulmonary carcinoids, enabling personalized follow-up strategies. Furthermore, subgroup-specific markers, such as OTP, ASCL1, and HNF1A, may facilitate clinical implementation of molecular profiles. Within LCNEC molecular profiles are heterogenous, generally defining two major subgroups (SCLC-like and NSCLC-like). Emerging therapies targeting DLL3 and SEZ6 show potential relevance for clinical screening of these targets. Integration of subgroup-specific molecular markers into routine diagnostics is essential. This approach may allow clinicians to refine risk stratification, prevent unnecessary long-term surveillance, and develop personalized treatment approaches for patients with pulmonary NENs.