The genotypic-phenotypic approach redefines the prognostic evaluation of lung neuroendocrine neoplasms

Lung neuroendocrine neoplasms are heterogeneous in terms of morphological features and clinical behavior. The four-tired WHO classification scheme, together with TNM stage, are currently the most effective prognostic indicators and, to date, they define the clinical management and therapeutic strategies in these neoplasms. However, in the last decade novel information on the phenotypical characteristics and molecular background of these tumors resulted in the proposal of novel biomarkers indicative of biological or clinical behavior. Although most of them are strongly histotype-dependent, some others have been proposed to be significantly associated to tumor characteristics also within individual tumor groups, and are therefore potential additional and complementary tools, with special reference to the carcinoid patients group whose prognostic prediction is still very uneffective. Indeed, these candidate biomarkers are still to be integrated in a multimodal approach and are in the vast majority of cases not validated in independent or prospective series and have been analyzed, with special reference to the molecular ones, on relatively small case series. Once the characterization of these tumors will be further refined, the clinical impact of these information will be strongly determined by their potentiality to be integrated with the current classification, and the tight collaboration between those who are active in this subject (diagnostic pathologists, molecular pathologists/biologists, clinicians) is necessary for a validation in the clinical practice.