G3 GEP NENs category: are basic and clinical investigations well integrated?

Gastroenteropancreatic neuroendocrine neoplasms grade 3, all of them with >20% Ki-67, can be heterogeneous on the basis of their morphological features, comprising well and poorly differentiated neoplasms; the former are named tumors and the latter carcinomas. Several papers about gastroenteropancreatic neuroendocrine neoplasms grade 3 heterogeneity have been reporting over the last years by clinicians and pathologists, indicating that the differential diagnosis between named tumors grade 3 and named carcinomas grade 3 may be relevant in defining a different approach in terms of characterization of disease, staging, and treatment. To well define the sub-type of gastroenteropancreatic neuroendocrine neoplasms grade 3 pathologist's expertise in recognizing tumor morphology, immunohistochemical, and molecular techniques were reported remarkable. Although current evidence about grade 3 gastroenteropancreatic neuroendocrine neoplasms heterogeneity is still far from producing validated specific therapies for specific subcategories, the hypotheses generated from the several retrospective analyses published so far on this topic represent solid bases for designing prospective therapeutic clinical trials in homogenous clinical settings.