Three familial syndromes are associated with the development of PNETS: (1) multiple endocrine neoplasia type I (MEN1), (2) von Hippel-Lindau disease (VHL), and (3) von Recklinghausen disease (VRH, also termed neurofibromatosis type 1 or NF1). MEN1 is an autosomal dominant syndrome associated with mutation of the MEN1 gene which encodes the menin protein that regulates transcription of a variety of genes involved in cell growth and cell cycle progression. In addition to PNETs, MEN1 is associated with pituitary adenomas (typically prolactin secreting) and hyperparathyroidism (typically four-gland hyperplasia). The PNET most commonly associated with MEN1 is a gastrinoma, though to a lesser degree, insulinomas and glucagonomas are seen; although rare, VIPomas and somatostatinomas can also be associated with MEN 1 syndrome. The hallmark of PNETs associated with MEN1 is the multicentric nature of the tumors distributed throughout the pancreatic gland. A more in-depth discussion of MEN 1 is found in Chap. 25, Multiple Endocrine Neoplasia (MEN) Syndromes.

VHL is an autosomal dominant syndrome associated with mutation of the VHL gene, which encodes for a protein regulating transcription of proteins involved in angiogenesis. VHL is characterized by hemangioblastomas of the eye or cerebral nervous system, renal cell carcinomas, and pheochromocytomas. The PNETs associated with VHL are typically nonfunctional and present in less than 20 % of VHL patients.

VRH is due to mutations in the NF-1 gene which encodes the neurofibromin protein; through binding to microtubules, neurofibromin affects the cellular cytoskeleton. VRH is a relatively common familial syndrome with cutaneous manifestations of café-au-lait spots, neurofibromas, and a variety of cognitive developmental disorders. PNETs are relatively uncommon for VRH patients, though the prototypic tumor is duodenal somatostatinoma.

The World Health Organization (WHO) 2010 classification of PNETs divides tumors into well differentiated and poorly differentiated based on histopathologic grading (mitotic rate and proliferative index as measured by Ki-67 staining). This grading system is useful in determining overall prognosis (Table 24.2). Both the European Neuroendocrine Tumor Society and the American Joint Commission on Cancer have proposed a TNM staging system to predict overall prognosis. These systems incorporate presence of the tumor size (T stage), metastasis to regional lymph nodes (N stage), and absence or presence of distant metastasis (M stage) [8] (Table 24.3).

The liver represents the most common site of distant metastatic disease. Additional adverse prognostic factors (beyond the WHO histologic classification system) include younger age, male gender, and perhaps extent of extrapancreatic disease.

In a patient with suspected PNET, the most important question to answer is whether the disease is resectable as curative resection remains the cornerstone of treatment in nonmetastatic PNETs. Management of PNETs should be based upon a multidisciplinary approach with the surgeon determining resectability. This decision incorporates the ability to achieve a complete resection of disease which is termed an R0 resection. Patients who present with symptomatic hypersecreting tumors may be palliated if an optimal cytoreductive (>85 %) resection can be achieved. It should be stressed that an optimal cytoreduction procedure should not be considered in an asymptomatic patient. A generalized approach to managing PNETs is shown in Fig. 24.2.

The resectability of the tumor depends on the location and extent of the primary disease as well as whether there is any radiologic evidence of metastatic lesions. There are a number of radiographic tools that can be employed to help the surgeon including ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), selective angiography, somatostatin receptor scintigraphy (SRS), positron emission tomography (PET), and single-photon emission computed tomography (SPECT). SRS is useful for localizing all of PNETs except for insulinomas; SRS may miss up to 40 % of insulinomas because these tumors lack sufficient amount of subtype 2 somatostatin receptors [9].

Due to its wide availability and high sensitivity (approaching 90 %), contrast-enhanced triple-phase multidetector CT of the abdomen is the most common and useful imaging modality [10] (see Fig. 24.3). CT has decreased sensitivity for identifying lesions <0.5 cm and if clinical suspicion persists based either on patient symptoms or biochemical evaluation, endoscopic ultrasound (EUS) shows great sensitivity for the identification of PNETs less than 0.5 cm in size, particularly in the head of the pancreas. For radiologically occult functional PNETs, additional selective angiography with provocative testing (secretin for gastrinomas and calcium gluconate for insulinomas) and venous sampling may be helpful for localization of small tumors, but high-resolution radiographic imaging and intraoperative ultrasound have decreased the use of this technique.