Current understanding of pathogenetic mechanisms in neuroendocrine neoplasms.

Despite the fact that important advances in research on neuroendocrine neoplasms (NENs) have been made, consistent data about their pathogenetic mechanism are still lacking. Furthermore, different primary sites may recognize different pathogenetic mechanisms. This review analyzes the possible biological and molecular mechanisms that may lead to NEN onset and progression in different organs. Through extensive research of the literature, risk factors including hypercholesterolemia, inflammatory bowel disease, chronic atrophic gastritis are evaluated as potential pathogenetic mechanisms. Consistent evidence is available regarding sporadic gastric NENs and MEN1 related duodenopancreatic NENs precursor lesions, and genetic-epigenetic mutations may play a pivotal role in tumor development and bone metastases onset. In lung neuroendocrine tumors (NETs), diffuse proliferation of neuroendocrine cells on the bronchial wall (DIPNECH) has been proposed as a premalignant lesion, while in lung neuroendocrine carcinoma nicotine and smoke could be responsible for carcinogenic processes. Also, rare primary NENs such as thymic (T-NENs) and Merkel cell carcinoma (MCC) have been analyzed, finding different possible pathogenetic mechanisms. New technologies in genomics and epigenomics are bringing new light to the pathogenetic landscape of NENs, but further studies are needed to improve both prevention and treatment in these heterogeneous neoplasms.