Author(s): Miral R Sadaria 1 , Ralph H Hruban 2 , Barish H Edil [*] 3
endocrine tumor; everolimus; islet cell tumor; liver metastases; pancreatectomy; pancreatic neuroendocrine tumor; sunitinib; targeted therapy
Although pancreatic neuroendocrine tumors (PanNETs) are relatively rare, their incidence has been rising over the last 20 years. PanNETs represent approximately 1-2% of all pancreatic neoplasms [1-4] and comprise 7.0% of all neuroendocrine tumors  , making them the second most common clinically important neuroendocrine tumor after gastrointestinal carcinoid. The National Cancer Institute Surveillance, Epidemiology and End Results (SEER) program registries reports that the annual incidence of PanNETs from 2003-2007 was 0.43 per 100,000 people in the USA, demonstrating a greater than twofold increase in the incidence of PanNETs since the 1980s  . A portion of this increase is attributable to improved awareness among physicians and enhanced diagnostic testing  , but even these numbers may underestimate the true occurrence of PanNET. For instance, autopsy series indicate the prevalence of PanNETs varied between 0.8 to 3% [3,6-9] with one study even as high as 10% for pancreatic specimens undergoing extensive pathologic assessment [7-9] , validating that people frequently harbor asymptomatic disease.
Neuroendocrine tumors of the pancreas, traditionally called islet cell tumors, were recently re-designated by the WHO as PanNETs, and PanNETs can be further categorized as functional or nonfunctional tumors. Functional PanNETs hypersecrete hormones such as insulin, gastrin, glucagon, vasoactive intestinal peptide (VIP) and somatostatin to produce clinical symptoms [10,11] , whereas nonfunctional PanNETs do not secrete enough hormones to produce hormone-related clinical findings and are generally detected secondary to a mass effect [10,11] . According to the SEER database, from 1973 to 2000 the majority of PanNETs diagnosed were nonfunctional tumors (90.8%) and the remaining 9% included malignant functional tumors such as gastrinomas (4.2%), insulinomas (2.5%), glucagonomas (1.6%) and VIPomas (0.9%  ). Furthermore, patients with functional tumors tend to present at a younger age than patients with non-functional tumors (55.2 years vs 58.8 years), and they have an improved survival compared to those diagnosed with nonfunctional tumors (54 months vs 26 months  ).
Despite the misconception that PanNETs are indolent tumors as they have a far favorable prognosis over pancreatic adenocarcinoma, most PanNET patients (60-70%) present with metastatic disease [10-12] . Even when they are resectable, many patients succumb to the disease. Following surgical resection of PanNETs, the 5-year survival for PanNETs other than insulinomas is roughly 65% with a 10-year survival of 45%  .
In 2010, the WHO updated its classification system and re-designated neuroendocrine neoplasms using a proliferation-based grading system in conjunction with the traditional histopathological diagnostic criteria, acknowledging and enforcing the malignant potential of these neoplasms [13-15] . Of note, proliferation activity of these neoplasms is assessed based on the mitotic count and the expression of the nuclear antigen Ki-67, a well-known cellular marker for proliferation  . The 2010 WHO classification has a three-tiered grading system for pancreatic neuroendocrine neoplasms. Grade 1 and grade 2 neoplasms are classified as neuroendocrine tumors to include both well-s and intermediate-differentiated lesions, and grade 3 neoplasms,...