The pancreas is a retroperitoneal organ that is composed of multiple lineages of neuroendocrine cells interspersed within the larger structure of its exocrine ductal system. The neuroendocrine cells are histologically grouped into islands known as islets of Langerhaans. These islet cells are differentiated such that they each synthesize and secrete only one of six pancreatic endocrine hormones. These hormones play an integral role in the fine balance of normal physiology. Both benign and malignant neoplastic processes can affect the pancreatic neuroendocrine cells. This tumor formation may be the result of a sporadic, somatic mutation or an inherited genetic predisposition to tumorigenesis. Although some of the tumors that develop retain sufficient differentiation to elicit the specific hormone made by the cell of origin, defects are often present in the normal feedback control of hormone release. This may result in a clinically detectable syndrome of hormone excess that may be diagnostically useful before detection of symptoms related to the primary tumor mass or metastatic burden. Pancreatic neuroendocrine tumors (PNETs) are relatively rare, with approximately five cases occurring per 1 million people annually.

PNETs are named relative to the chief hormone produced by the tumor cells. For example, there are insulinomas, gastrinomas, glucagonomas, somatostatinomas, and vasoactive intestinal peptide (VIP)-omas. Insulinomas and gastrinomas are discussed elsewhere in this manual. Occasional functional PNETs elicit hormones not normally produced by the pancreatic islet cells, including neurotensin, adrenocorticotropic hormone, parathyroid hormone–related protein, and growth hormone–releasing factor. Tumors that do not produce a specific hormone product and yet are derived from a neuroendocrine progenitor cell are known as nonfunctional neuroendocrine tumors.1 Roughly 75% of the nonfunctional neuroendocrine tumors produce pancreatic polypeptide but have no associated endocrine syndrome. Hence, these tumors could be referred to as pancreatic polypeptide or PP-omas. These nonfunctional tumors can be identified based on their histologic appearance, cell surface markers, and the presence of immunohistochemical staining for markers such as chromogranin A and neuron-specific enolase.2 Each PNET can be characterized by a unique endocrine syndrome that includes hormone overproduction (with the exception of nonfunctional neuroendocrine tumors), the location of the tumor, the frequency of the tumor being malignant, and the relative efficacy of medical management to control the associated endocrinopathy (Table 20-1).

Nonfunctional PNETs represent approximately 30% of pancreatic endocrine tumors. Because these tumors do not have a clinically detectable endocrinopathy, they are often diagnosed at a late stage.3 The tumors are often large and located in the head of the pancreas. The majority are sporadic tumors and are malignant. In fact, nearly 80% of these tumors have locoregional or distant metastases present at the time of diagnosis. Glucagonomas are rare tumors that predominantly arise in the body and tail of the pancreas.4 They often present late, and most are solitary and large (>4 cm). Nearly 75% of glucagonomas are malignant.

Somatostatinomas are among the rarest endocrine neoplasms, with an estimated annual incidence of only one case in 40 million.5 The mean age at presentation is 50 years, and there does not appear to be any gender predilection. Nearly 75% of these tumors are malignant, and regional lymph node, hepatic, or bone metastases at the time of diagnosis are common. Roughly 30% of somatostatinomas are located outside the pancreatic parenchyma. Common sites include the duodenum, small bowel, and ampulla of Vater.

VIPomas are also rare PNETs.6,7 Extrapancreatic sites of disease include the bronchi, colon, adrenal glands, liver, and sympathetic ganglia. Most of these tumors are solitary and located in the body or tail of the pancreas. About 60% to 80% of VIPomas are malignant, and 75% have metastasized by the time of surgical exploration.

PNETs may arise in an isolated, sporadic fashion or as a manifestation of a more systemic, inherited predisposition to tumor formation. After a diagnosis of a PNET is confirmed, it is imperative to assess the possibility that the patient has a familial cause for the tumor. The presence of an endocrine neoplasia syndrome often guides the overall treatment planning.

The most frequent inherited endocrinopathy associated with PNETs is multiple endocrine neoplasia type 1 (MEN1). This is an autosomal dominant syndrome classically characterized by anterior pituitary micro- and macroadenomas, multiglandular parathyroid adenomas, and PNETs. More detailed studies, however, reveal an increased incidence of benign and malignant tumors of other tissues such as the subcutaneous fat (lipomas), thymus and bronchi (carcinoids), thyroid gland, adrenal glands, and skin. The syndrome has nearly 100% penetrance but variable expressivity. The etiologic genetic mutation for MEN1 has been identified to be the menin tumor suppressor gene on the long arm of chromosome 13.8 The menin gene product is a 610 amino acid nuclear protein thought to repress JUN-D–mediated RNA transcription. This gene product has also been found to be altered in some cases of apparently sporadic cases of PNETs. Direct DNA testing for menin is now available but should be accompanied by qualified genetic counseling to interpret the results and plan for screening and intervention for the proband and family members.9

Another less common inherited tumor syndrome that should be considered when evaluating a PNET is von Hippel-Lindau (VHL) syndrome. This diagnosis should especially be considered if the pancreatic tumors are cystic. VHL is an autosomal dominant condition caused by a mutation on the short arm of chromosome 3 that leads to angiomatous tumors of the central nervous system (specifically, the internal auditory canal and retina) as well as cystic tumors of the pancreas, adrenals, and kidneys. These patients carry an increased risk of developing renal cell carcinoma.

Because of the remote location of the pancreas, PNETs do not produce symptoms from mass effect until later stages. However, the symptoms associated with hormone overproduction often bring these tumors to clinical attention. Each functional PNET has a unique endocrinopathy, and although subtle and nonspecific, attentive and suspecting clinicians can use these signs and symptoms together to arrive at an accurate diagnosis.

Glucagon is a peptide produced by the α cells of pancreatic islets. Tumors that produce excessive glucagon may lead to altered glucose tolerance and frank diabetes mellitus. In fact, new-onset type II diabetes in a thin patient older than age 60 years should prompt investigation into the presence of a pancreatic glucagonoma. If present, a characteristic skin rash, named necrolytic migratory erythema, is pathognomonic for glucagonoma4 and is present in two thirds of patients with glucagonomas. The rash consists of painful, pruritic lesions that begin as blistering, erythematous plaques and slowly spread outward. The edges appear to erode and then crust over. Hyperpigmentation may be seen at the location of a prior lesion. These lesions generally appear in areas subject to great friction and pressure, such as the perineum, lower abdomen, buttocks, and groin. Patients with glucagonomas often have other signs of nutritional deficiencies, such as hypoaminoacidemia and zinc deficiency. They may present with stomatitis, glossitis, cheilosis, and vulvovaginitis. Other symptoms may include weight loss, depression, and anemia that is normochromic and normocytic. Finally, patients with a glucagonoma may have a marked risk of hypercoagulability and deep venous thrombosis.

The endocrine syndrome produced by excess somatostatin release is quite subtle.5 Patients may present with weight loss, diarrhea, and steatorrhea. These symptoms are partly caused by impaired secretion of cholecystokinin and pancreatic exocrine enzymes. Furthermore, one may find cholelithiasis upon workup for a somatostatinoma, or conversely, may discover a pancreatic or duodenal somatostatinoma upon evaluation of a patient with gallstones. On detailed gastric acid analysis, one may find patients with a somatostatinoma to have hypochlorhydria. Finally, excess somatostatin release may impair glucose tolerance and lead to both fasting and postprandial hyperglycemia. This “classic” syndrome, however, is typically absent in patients with duodenal somatostatinomas.10