Molecular Biology of Neuroendocrine Tumors

Neuroendocrine tumors (NETs) are diagnostically challenging tumors, as they comprehend a heterogeneous group of epithelial neoplasms with neuroendocrine differentiation. They are molecularly different from neuroendocrine carcinomas (NECs), as they rarely display inactivation of RB1 and TP53, which instead are characteristic driver events in NECs. In the past, medical treatment has been mostly based on chemotherapy and has not taken into consideration varying tumor biology. In fact, the molecular study of NETs has been significantly limited for many years, due in large part to their relative scarcity. As a result, the knowledge on their cellular and molecular biology was significantly limited in comparison to that of other more common cancers. This limitation has been counteracted in recent years by a steady increase in the prevalence of these tumors, deriving from both longer survival of patients compared toother neoplasms and increased diagnosis rates thanks to improved imaging techniques. Additionally, the clinical-therapeutic management of NET patients considerably suffered by the lack of universally accepted standards for the disease, including both a diagnostic nomenclature and a staging system. This significantly limited the conduction of appropriate clinical trials, and thus survival rates remained virtually unchanged for decades. While efforts on classification and staging have provided a better grouping of NETs according to clinicopathologic and histologic features, recent genomic and epigenomic findings have significantly expanded our knowledge of NETs molecular landscape, allowing finer patient stratification and improved targeted therapies to achieve personalized patient care.