Neuroendocrine tumors of the pancreas: molecular pathogenesis and current surgical management

Neuroendocrine tumors (NET) of the pancreas are uncommon neoplasms that arise from the pancreatic islet cells. The clinical presentation of specific tumors is characterized by unique signs and symptoms related to the overproduction of any of a number of peptide hormone products. Functional NET may cause significant manifestations when the primary tumor is small and even occult radiographically, and the diagnosis is confirmed by directed biochemical testing for the hormone produced. Non-functional pancreatic NET cause symptoms due to the effects of tumor progression locally, and may present at a later stage with overall worse outcomes. Importantly, pancreatic NET occur as a component of a number of hereditary endocrine cancer syndromes, and the diagnosis and optimal management in these patients is associated with special considerations. Complete surgical resection is the optimal and only potentially curative treatment, because NET in general has limited responsiveness to cytotoxic chemotherapy. Functionally based medical therapies for NET include somatostatin analogs to control symptoms, and administration of radiolabeled somatostatin analogs for targeted antitumor effects (peptide receptor radionuclide therapy). Importantly, new therapies based on specific molecular targets have recently shown efficacy in patients with metastatic well-differentiated NET not amenable to complete surgical resection. These include an inhibitor of the mammalian target of rapamycin pathway termed everolimus, and angiogenesis inhibitors such as sunitinib that target vascular endothelial growth factor receptor (VEGFR) and other growth factor receptors. The development of new more effective therapeutic options based on the further elucidation of critical pathways in the pathogenesis of NET is needed.