Pathology, molecular biology, medical oncology, and radiotherapy implications of lung neuroendocrine neoplasm classification: a multidisciplinary perspective

INTRODUCTION: Neuroendocrine neoplasms (NENs) of the lung make up a heterogeneous clinicopathologic ensemble, encompassing well-differentiated neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). Despite being characterized since decades, they still continue to embody diagnostic and therapeutic challenges, where establishing correlations among tumor nomenclature, molecular alterations, and therapeutic options is essential for the best clinical decision making. AREAS COVERED: Lung NENs were dissected according to five conveying perspectives (available English literature in PubMed, National Library of Medicine): (i) pathologic and molecular grounds for clinical decision making; (ii) tumor microenvironment and tumor immune microenvironment; (iii) how to manage NETs, especially in the metastatic setting; iv) handling life-threatening NECs, especially in light of emerging therapeutic protocols; (v) radiotherapy with some hints at the surgery's role. EXPERT OPINION: Diagnosis of NETs and NECs has precise clinical implications, which influences tumor nomenclature and clinical decision making (surgery, chemotherapy, radiotherapy, immuno-oncology). However, unexpected subtypes are currently emerging, which question the traditional segregation of NETs and NECs as separate and non-communicating tumor subsets, with no pathogenetic link. This paradigm shift could not only affect our outlook on lung NENs, but even modify the essence of the patient clinical management.