Non-Functioning Pancreatic Neuroendocrine Tumors

Non-functioning pancreatic neuroendocrine tumors are quite rare, representing 2% of all pancreatic malignancies and 85% of all pancreatic neuroendocrine tumors. They are classified based on Ki-67 labelling index and the grade of differentiation according to the WHO 2019 histopathologic classification. On a molecular basis, they are different from pancreatic adenocarcinoma, expressing menin-1, death domain-associated protein, alpha thalassemia/mental retardation syndrome X-linked, and mammalian target of rapamycin, as the main mutated genes. As for treatment, surgery represents the only curative option, related to localized stage of disease but regards a minority of patients. In the more frequent advanced stage, several non-surgical options can be discussed and even cytoreductive surgery. Somatostatin analogues are recommended in progressing non-functioning pancreatic neuroendocrine tumors. Streptozotocin-based chemotherapy was approved in the 1970s. Over the last decade, several molecular-targeted agents and novel chemotherapeutics have been developed. In 2011 everolimus, a mammalian target of rapamycin inhibitor, and sunitinib, a multitargeted inhibitor, were approved for progressing well/moderately differentiated pancreatic neuroendocrine tumors. Evidence accumulates on the beneficial role of immunotherapy in selected patients. Peptide radioreceptor therapy with 177Lutetium-Dotatate is a promising systemic therapy for tumors highly expressing subtype-2 somatostatin receptors. Finally, a number of locoregional treatments, mainly liver-directed and interventional radiology based, have been demonstrated to be useful within a global therapeutic strategy including cytoreduction. Patients with distant metastases have a median survival of 23 months compared with 124 and 70 months of those with localized and regional disease, respectively. Several clinical studies are ongoing to evaluate novel agents in tumors resistant to everolimus and sunitinib or as an alternative to them against different targets. Biological predictive markers of response are needed and they should be included in the design of the new clinical trials.