Pancreatic neuroendocrine tumors (PNETs), traditionally termed islet cell tumors, are rare cancers occurring in approximately 1000 patients per year in the United States, representing 3% of all pancreatic tumors.¹ The incidence of neuroendocrine tumors has increased over the last three decades, likely from increased use of and improvement in imaging modalities.^2-4 The incidence overall of PNETs is increasing from .17 per 100,000 people in 1973 to .47 per 100,000 people in 2007.⁵ The peak incidence for PNET is between the ages of 40 and 69 years. While survival is significantly longer than patients with pancreatic adenocarcinoma, once patients have metastatic disease cure is not likely. However, surgical treatment plays a very important role in palliation of symptoms from hormone-producing tumors. Overall survival rate of resected tumors is 55%, but is only 15% with metastatic disease. Surgical resection for localized disease is the only curative treatment. The majority of PNETs are nonfunctional; however, some may secrete active gastrointestinal hormones that produce clinical syndromes. Most tumors are sporadic; however, some are associated with syndromes such as multiple endocrine neoplasia (MEN), von Hippel–Lindau syndrome, neurofibromatosis, tuberous sclerosis, and von Recklinghausen syndrome. Tumors associated with MEN syndromes are more likely to be aggressive and multifocal.

PNETs have a wide spectrum of biologic behavior. Some are low grade and indolent, while others behave aggressively and have a propensity to metastasize. Some functional tumors are more likely to be benign, such as insulinomas, while others such as glucagonomas are almost always malignant. Tumors may produce multiple hormones complicating the diagnosis. The functional tumors typically produce symptoms related to the dominant hormone that is produced. This chapter reviews the clinical syndromes, workup, and treatment for pancreatic endocrine tumors.

Endocrine tumors of the pancreas originate from islet cells, hence the traditional name of islet cell tumors. The islets arise from either neural crest cells or embryonic foregut endoderm. They appear histologically similar to carcinoid tumors of the gastrointestinal tract. The tumors are broadly classified into functional and nonfunctional tumors. Nonfunctional tumors compose 40% to 90% of all PNETs and are more common than functional tumors. Functional tumors cause symptoms that are indicative of the hormone the tumor produces. Most commonly these include gastrinomas, vasoactive intestinal polypeptide-secreting tumors (VIPomas), glucagonomas, somatostatinomas, and other rare functional tumors (Table 74-1; Fig. 74-1).

The endocrine portion of the pancreas makes up about 1% to 2% of the gland by weight. Pancreatic islets are composed of four main cell types: alpha cells that secrete glucagon, beta cells that secrete insulin and amylin, delta cells that secrete somatostatin, D₂ cells that secrete vasoactive intestinal peptide (VIP), and F cells that secrete pancreatic polypeptide (PP). The distribution of the endocrine cell types varies within in the gland. Beta and delta cells are distributed evenly throughout the pancreas, whereas alpha cells are concentrated in the body and tail, and F cells are mostly in the uncinate process. This has clinical consequence when partial pancreatectomies are performed.

Endocrine tumors of the pancreas were first described by the symptoms a functional tumor would cause. In 1908, the first description of a pancreatic adenoma was described by Nichols, and subsequently Mayo described a pancreatic islet cell tumor and hyperinsulinemia. This was followed by the Whipple triad in 1935 by Whipple and Frantz.⁶ Next, Becker described what would be a glucagonoma when describing a tumor causing dermatitis, anemia, and diabetes.⁷ Zollinger and Ellison described an islet cell tumor of the pancreas causing peptic ulcer disease and acid hypersecretion in 1955, and later gastrin was found to be the hormone responsible for this syndrome, known as Zollinger–Ellison syndrome (ZES).⁸ VIPomas were described in 1958 by Verner and Morrison, who presented two patients with watery diarrhea and hypokalemia with an associated islet cell tumor.⁹ Most recently, secretin has been confirmed as a diarrheogenic hormone from a case first described in 1968 by Zollinger and Ellison.¹⁰

Multiple endocrine neoplasia type I (MEN-1) is an autosomal dominant inherited disease.¹¹ MEN-1 is characterized by primary hyperparathyroidism in approximately 90% to 100% of patients with the syndrome. Pancreatic neuroendocrine tumors are next most common, and can be functional or nonfunctional. These are usually nonfunctional. Gastrinomas are the most common functional PNET associated with MEN 1.¹² Pituitary adenomas occur less commonly (20%-65%) as do adrenal tumors (10%-73%) and thyroid adenomas (0%-10%).^13,14 MEN-1 gene is a tumor suppressor gene that codes for the protein MENIN and is located on chromosome 11q13, and is responsible for this syndrome.¹⁵ Typically, patients with MEN develop tumors at an earlier age than patients without the inherited disorder—usually between 30 and 40 years old.

Suspicion of MEN-1 should be considered when a patient has a family history of endocrine tumors of the pancreas, family members with pituitary or thyroid disease, kidney stones, young age of diagnosis of functional endocrine tumor, endocrine tumor with associated hypercalcemia, or any patient with ZES. Twenty percent of patients with ZES have MEN-1.¹⁶ Genetic screening should be offered to any patient with two or more MEN-1–related tumors, recurrent hyperparathyroidism at a young age, gastrinoma and hyperparathyroidism, or multiple pancreatic neuroendocrine tumors.¹⁷

Workup of patients with suspected MEN-1 syndrome should include biochemical screening for gastrin, insulin, pancreatic polypeptide, glucagon, and chromogranin A. In addition, calcium level should be obtained. Hyperparathyroidism should be treated first, before treatment of the pancreatic endocrine tumor. ZES is more difficult to cure in patients with MEN-1, as these tumors are often multiple and can have diffuse hyperplasia of the islets and present with metastasis 50% of the time. Other genetic syndromes such as Von Hippel–Lindau and neurofibromatosis type 1 are also associated with pancreatic endocrine tumors.

The majority of pancreatic neuroendocrine tumors are nonfunctional (60%-90%), and many present with distant metastatic disease because they do not have symptoms until late in the course of the disease.^18,19 Tumors that produce PP, neurotensin, and calcitonin are categorized as nonfunctional, as they do not produce a definable hormonal syndrome. Nonfunctional tumors appear similar on cross-sectional imaging. These tumors are often larger and two-thirds are malignant, while up to 80% have metastasized at the time of diagnosis.

Insulinoma

Insulinomas are the most common functional tumor and occur with an annual incidence of 1 per million patients per year, with the average age at diagnosis of 45 years old.²⁰ Only 10% of these tumors are malignant. The tumors are located in equal distribution throughout the pancreas. Most are solitary, however when associated with MEN 1 may be multiple. It should be noted that insulinomas rarely occur in MEN 1. These tumors, like most functional tumors, are diagnosed because of symptoms. The Whipple triad classic diagnostic test and includes symptoms of hypoglycemia, plasma glucose less than 50 mg/dL when symptomatic, and relief of symptoms when given glucose (Table 74-2). The neuroglycopenic symptoms are typically headache, lethargy, dizziness, blurred vision, anxiety, excessive sweating, tachycardia, and nervousness. Patients may eat to relieve these symptoms, and as a result often present with weight gain.

Diagnosis can be confirmed with an elevated insulin-to-glucose ratio greater than 0.3 during fasting, and an associated elevated C-peptide. This ratio can sometimes be found in obese patients but these patients are not hypoglycemic. If the diagnosis cannot be established, a monitored 72-hour fast may be required. The fast should be monitored to prevent life-threatening complications of profound hypoglycemia and to ensure that the hypoglycemia is not factitious. Obtaining sulfonylurea levels and C-peptide may also be necessary if factitious hypoglycemia is suspected. Insulin levels greater than 10 µg/mL and hypoglycemia are very suggestive of insulinomas, however not diagnostic, as these levels of insulin can be seen in other conditions. C-peptide levels greater than 1.2 µg/mL with a glucose less than 40 mL/dL also suggest an insulinomas.²¹ The differential diagnosis includes factitious hypoglycemia, chronic adrenal insufficiency, hypopituitarism, nesidioblastosis, and noninsulinoma pancreatogenous hypoglycemia (NIPH). Nesidioblastosis is not associated with a tumor but patients with this do manifest symptoms of hypoglycemia.²²

Resection is the mainstay of treatment for insulinomas (Fig. 74-2). Preoperative hypoglycemia should be managed with frequent small meals. Octreotide is not typically useful and should be used cautiously, as it can worsen hypoglycemia by suppressing the secretion of glucagon. Diazoxide can also be used to suppress the secretion of insulin. Enucleation is an option for resection of insulinomas given the majority are not malignant. Localization of insulinomas can sometimes be difficult due to the small size of these tumors, averaging 1.0 to 1.5 cm. CT or MRI is usually sufficient to locate the tumor, but endoscopic ultrasound is often a useful adjunct. Determining the relationship of the lesion to the pancreatic duct can help in planning the operative approach. Insulinomas that are in close proximity to the duct may lead to a pancreatic leak if an enucleation is performed, and a more formal pancreatic resection may be indicated if this is a concern. Intraoperative ultrasound can be used if there has been difficultly in identifying the tumor during the surgery, and again may help in determining the location of the pancreatic duct. If the tumor is not located using these methods, blind resection is not indicated. With current imaging techniques and endoscopic ultrasound, angiography or selective portal venous sampling for insulin levels is used rarely. Injection of calcium into the celiac and superior mesenteric arteries can also further increase the sensitivity of this test.

Gastrinoma

ZES was initially described in 1955 in two index cases of refractory ulcer disease and diarrhea.⁸ The mean age at diagnosis is 50 years, with most cases diagnosed between the ages of 20 and 60 with a male predominance (60%). Those with MEN-associated gastrinomas typically present at a younger age. It is important to consider the diagnosis of MEN-1 in patients with ZES, as 20% of them will have MEN-associated disease.¹² Frequently, gastrinomas are not recognized at the initial clinical presentation and are therefore often managed incorrectly. Symptoms that should raise suspicion of a gastrinoma include idiopathic peptic ulcer disease or longstanding diarrhea. The high acid load delivered to the duodenum inactivates pancreatic enzymes, causing malabsorption and diarrhea; thus the diarrhea is relieved by nasogastric suction. The liver is the most common site of metastases, with 70% to 80% of patients diagnosed with liver metastases at the time of diagnosis.

Confirmation of a gastrinoma can be made with a fasting serum gastrin level. A fasting serum gastrin greater than 1000 pg/mL is virtually diagnostic for ZES. This must be drawn while that patient is off protein pump inhibitors (PPIs) for 72 hours prior to the test. Gastrinomas do not secrete gastrin to normal stimuli such as amino acids and peptides or gastric distention. The normal inhibition of gastrin by low luminal pH does not occur, and secretin causes stimulation rather than inhibition of gastrin. Other medical conditions can also cause hypergastrinemia, thus serum gastrin by itself is not diagnostic of ZES. Pernicious anemia, atrophic gastritis, and the use of proton pump inhibitors all can cause elevation of serum gastrin and achlorhydria. Acid hypersecretion and hypergastrinemia may be found with many conditions such as Helicobacter pylori infection, gastric outlet obstruction associated with peptic ulcer, retained antrum, short gut syndrome, or renal failure. A secretin stimulation test can confirm ZES by measuring serum gastrin level after the intravenous injection of 0.4 µg/kg of secretin (Fig. 74-3). Patients can remain on PPIs during this test. Gastrin levels will increase by 200 pg/mL in patients with ZES. A rise in gastrin level by greater than 110 pg/mL over baseline is considered a positive test. Imaging with CT or MRI should be performed to locate the tumor.²³ EUS is very sensitive for detection as is somatostatin scintigraphy using [¹¹¹In-DTPA-DPhe1] octreotide.²⁴ Ninety percent of gastrinomas are located in the gastrinoma triangle (Passaro triangle), which is bounded by cystic duct, the junction of the second and third portions of the duodenum, and the junction of the neck and body of the pancreas (Fig. 74-4).