Pancreatic neuroendocrine tumors (PNETs) are tumors that originate from the islet cells of the pancreas and are also often referred to as islet cell tumors. With an estimated incidence of about 2.5 to 5 per 100,000 persons per year, these uncommon tumors represent only 1% to 2% of pancreatic malignancies.¹ In contrast to pancreatic adenocarcinoma, the incidence of PNETs appears to have increased over the past decades.^2,3 Autopsy studies have shown that small, asymptomatic PNETs may occur in as many as 10% of people.^4,5 Thus, increased detection, particularly because of increased imaging and advances in imaging technology, may account for much of the rise in the incidence of PNETs.^6–8

In addition to being uncommon, PNETs are also notably heterogeneous with regard to their clinical presentation. PNETs may be classified in several distinct ways: (1) the aggressiveness of malignancy (benign behavior to highly aggressive); (2) the functional status (hormone-producing or not); or (3) the clinical context in which the tumor arises (sporadic or in the context of an inherited syndrome). The overall rarity of PNETs and the heterogeneity of their clinical presentation create challenges in their management. The purpose of this chapter is to present the natural history and basic principles of management of PNETs in their varied forms of presentation.

Pathologic Features

Pancreatic neuroendocrine tumors arise from neuroendocrine cells that are scattered diffusely throughout the pancreas. Their malignant potential varies widely from benign to highly aggressive. From a pathologic perspective, PNETs are classified into four general categories: (1) endocrine microadenomas, (2) well-differentiated neuroendocrine carcinomas, (3) poorly differentiated neuroendocrine carcinomas, and (4) mixed endocrine carcinomas (Table 145-1). Ultimately, the only reliable way of determining malignancy is by identifying local invasion, involved regional lymph nodes, or distant metastatic sites.⁹

ENDOCRINE MICROADENOMAS AND WELL-DIFFERENTIATED NEUROENDOCRINE CARCINOMAS

The vast majority of PNETs are well-differentiated; that is, they retain normal architecture and have a low proliferative rate. Tumors measuring less than 0.5 cm are classified as endocrine microadenomas and are the only PNETs that are considered as a group to be benign. The remainder of well-differentiated PNETs have a low- to intermediate-grade malignant potential.¹⁰

POORLY DIFFERENTIATED ENDOCRINE CARCINOMAS

Poorly differentiated endocrine carcinomas account for a very small percentage of PNETs and have the highest malignant potential. These tumors have a diffuse architecture, high proliferative rate, and abundant necrosis; histologically they are composed of either small or large cells. The main features that distinguish this group from well-differentiated PNETs are the higher proliferative rate (>10 mitoses per high-power field (hpf)) and the presence of abundant necrosis.

MIXED ENDOCRINE NEOPLASMS

Tumors that contain endocrine as well as exocrine components (acinar or ductal) are categorized as “mixed” neoplasms. The presence of at least 25% of each component is required to make the diagnosis. The exocrine component predominates in most cases, which may explain the more aggressive clinical behavior of these tumors compared with classic PNETs. Immunohistochemistry is often helpful to differentiate the various types of mixed endocrine neoplasms: mixed ductal-endocrine carcinoma, mixed acinar-endocrine carcinoma, and mixed acinar-endocrine-ductal carcinoma.^11–16

GRADE

For the purpose of simplification, PNETs are often separated into well-differentiated tumors with an indolent clinical course, and poorly differentiated tumors with a more aggressive clinical course. The World Health Organization (WHO) further subdivides well-differentiated PNETs into low grade (G1) and intermediate grade (G2) categories based upon proliferation rate, whereas poorly differentiated PNETs are considered high grade (G3).⁹

Functional Status

Another method of classification of PNETs is based on the functional status of the tumor; that is, whether or not the tumor produces hormones that lead to clinical signs or symptoms. Functioning tumors produce bioactive compounds that result in very characteristic and well-defined clinical syndromes: insulin, gastrin, glucagon, vasoactive intestinal peptide (VIP), or somatostatin. PNETs that do not produce such hormones are considered nonfunctioning tumors, although they may measurably overexpress hormones such as pancreatic polypeptide (PP), neurotensin, or calcitonin, which are usually clinically silent (however, hypercalcitoninemia can lead to diarrhea and flushing at high levels). Nonfunctioning PNETs are more common than functioning PNETs.^4,17–22 Among the functioning tumors, insulinomas have the highest incidence, followed by gastrinomas. Some PNETs do not cause clinical syndromes in spite of overproduction of hormones that usually do result in clinical syndromes; these are considered nonfunctioning tumors, although the hormone levels can be useful for the detection of tumor recurrence during long-term follow-up.²³

Inherited Syndromes

A final method of classification of PNETs is based upon whether they occur as a component of an inherited syndrome or whether they are sporadic. The management of a patient with a sporadic PNET often differs considerably from the management of a patient with a PNET that occurs as part of an inherited syndrome, and therefore, this distinction is an important one.

The two most common inherited syndromes that include PNETs as component tumors are multiple endocrine neoplasia type 1 (MEN1) and the von Hippel–Lindau (VHL) syndrome. MEN1 is an autosomal-dominant inherited endocrine tumor syndrome characterized primarily by the development of primary hyperparathyroidism, pituitary adenomas, and PNETs. Patients with MEN1 have a 35% to 75% chance of developing a PNET during the course of their lifetime.²⁴ These patients typically develop multiple PNETs and are often diagnosed at a younger age and an earlier stage than are sporadic patients, which may be attributed to the periodic surveillance of at-risk individuals.²⁵ VHL is an autosomal-dominant inherited syndrome that results in retinal, cerebellar, spinal, adrenal, renal, and pancreatic lesions. Approximately 5% to 15% of patients with VHL will develop PNETs.^26,27

Pancreatic neuroendocrine tumors are slightly more common in males with a median age of 60 years at presentation and peak incidence rates in the sixth to eighth decades.^3,4,28–32 Aside from PNETs that occur in the setting of an inherited syndrome, there are no known epidemiological, environmental, or behavioral risk factors for the development of PNETs. Because PNETs are such a diverse group of tumors, the clinical presentation varies widely. Table 145-2 summarizes the typical clinical presentation and initial diagnostic evaluation of the different types of functioning and nonfunctioning PNETs.

Nonfunctioning PNETs

The majority of PNETs do not secrete hormones and remain clinically silent until they are relatively large.³³ Although there are no histologic characteristics that correlate with the functional status of the tumor, functioning tumors are generally smaller than nonfunctioning tumors at the time of diagnosis, presumably because the former become symptomatic due to their hormone overproduction and are hence detected at an earlier stage. Since nonfunctioning PNETs remain clinically silent from a hormonal perspective, they usually present with local symptoms due to their size; that is, with early satiety, abdominal pain or weight loss, or they are incidentally discovered. Many nonfunctional PNETs secrete peptides such as chromogranin A (CgA), neuron-specific enolase (NSE), and pancreatic polypeptide (PP). Serum CgA is considered the best biomarker for nonfunctioning PNETs and is often used during initial evaluation and subsequent surveillance of patients.³⁴ The moderately high specificity and sensitivity, as well as the approximate correlation between tumor burden and plasma levels have also made CgA an occasionally useful tool to monitor tumor response to systemic therapy. A baseline CgA level should be obtained at the time of PNET diagnosis, and serial CgA levels are typically obtained after therapeutic interventions.^34–36

Functioning PNETs

INSULINOMA

Insulinomas are the most common functioning PNETs. The vast majority of insulinomas are sporadic; only approximately 4% to 10% of insulinomas occur in association with MEN1.³⁷ These tumors secrete insulin and present with the very characteristic clinical syndrome known as Whipple’s triad: fasting or exercise-induced hypoglycemia, a plasma glucose level less than 50 mg/dL, and relief of symptoms upon administration of glucose.³⁸

A monitored 72-hour fast, in which plasma glucose and insulin levels are measured every 4 to 6 hours, is used to confirm the diagnosis. In the presence of a low glucose level, an inappropriately high insulin level is indicative of insulinoma (insulin to glucose ratio greater than 0.4). A serum C-peptide level and a screen for sulfonylurea and other antihyperglycemic agents should be obtained to exclude the possibility of factitious use of antihyperglycemic agents.

Insulinomas are evenly distributed throughout the pancreas and are usually small at the time of diagnosis. Therefore, imaging studies are essential to the preoperative workup of the patient. High-quality contrast-enhanced computed tomography (CT) with dedicated pancreas protocol or magnetic resonance imaging (MRI) is useful in detecting lesions greater than 1 cm in diameter.³⁹ Endoscopic ultrasound (EUS) may detect lesions measuring less than 1 cm and can preoperatively identify over 90% of all insulinomas. If the aforementioned modalities fail to localize an insulinoma, visceral angiography with injection of calcium and hepatic venous sampling for insulin may be helpful in regionalizing the source of excess insulin. In contrast to most other PNETs, octreotide scans are of limited value as somatostatin receptors are not highly expressed in insulinomas.

GASTRINOMA

Gastrinomas are the second most common functioning neuroendocrine tumor. They are sporadic in 70% to 80% and associated with MEN1 in 20% to 30% of cases.⁴⁰ These tumors give rise to the Zollinger–Ellison syndrome: overproduction of gastrin yields symptoms of acid hypersecretion that include refractory peptic ulcer disease, abdominal pain, reflux symptoms, and diarrhea.⁴¹

The diagnosis is made by measuring a serum gastrin level and a gastric pH; a gastrin level greater than 1000 pg/mL with a simultaneous gastric pH of less than 2.5 is diagnostic of gastrinoma. The gastrin level must be drawn when the patient has discontinued proton-pump inhibitors for at least 2 weeks and is in the fasting state. If the gastrin level is equivocal, a secretin stimulation test can be performed; the diagnosis is confirmed if the gastrin level increases by 200 pg/mL or more.

Tumor localization is essential in the evaluation of gastrinoma because these tumors can be very small and multiple. Tumor localization is best accomplished by a combination of octreotide scan, CT or MRI, and EUS. More than 75% of gastrinomas occur within the gastrinoma triangle: the area between the confluence of the cystic and common bile duct, the junction of the second and third portions of the duodenum, and the junction of the neck and body of the pancreas.⁴² The remaining 25% of gastrinomas are located in the body of the pancreas and the distal duodenum. Duodenal tumors are 3 to 10 times more common than pancreatic tumors. Although tumors at both locations carry similar rates of malignancy, patients with duodenal tumors have a better prognosis. Lymph node metastases are found in 40% to 70% of patients at the time of diagnosis, and liver metastasis occurs in approximately 5%.⁴³

GLUCAGONOMA

Glucagonomas are ranked behind insulinomas and gastrinomas in terms of frequency of functioning PNETs.^44–46 These tumors are often large, malignant in 80% of cases, and in more than half of patients these tumors have already metastasized at the time of diagnosis.⁴⁷ Multifocal presentation and MEN1 association are very unusual. Glucagonomas present with the syndrome of diabetes, weight loss, anemia, and necrolytic migratory erythema. About 75% to 95% of patients with glucagonoma display glucose intolerance that usually remains undiagnosed or unremarkable until disease progression becomes apparent and patients experience the necrotizing skin rash.^45,48 Other associated symptoms are deep venous thrombosis, stomatitis, glossitis, cheilosis, and vulvovaginitis.

A serum glucagon level greater than 1000 pg/mL confirms the diagnosis of glucagonoma. In cases of an equivocal glucagon level, a secretin stimulation test or skin biopsy may also be useful.

Glucagonomas are always located in the pancreas, and 90% of these are located in the body and tail. They are usually large tumors at presentation and are rich in somatostatin receptors. Thus, localization with CT and staging with somatostatin receptor scintigraphy (octreotide scan) are routine.⁴⁵

VIPOMA

VIPomas are PNETs that secrete VIP. These tumors typically present with severe intermittent watery diarrhea, hypokalemia, and achlorhydria (Verner–Morrison or WDHA syndrome).⁴⁹ Association with MEN1 is rare.