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Pancreatic Neuroendocrine Tumors (Islet Cell Tumors)
Pancreatic neuroendocrine tumors (PNETs), also known as “islet cell tumors,” represent a group of rare neoplasms of the neuroendocrine cells of the gastropancreatic system ( Fig. 132.1 ). PNETs constitute fewer than 5% of the pancreatic tumors. They may be functioning tumors producing distinct clinical syndromes based on the hormone (gastrin, insulin, and glucagon) produced, or nonfunctioning tumors (60%–90%), diagnosed because of their mass effect or malignant behavior. The incidence of PNET is increasing.
Pancreatic Neuroendocrine (Islet Cell) Tumors: Adenoma and Carcinoma.
Polypeptide hormone–producing cells of the pancreatic islets (islets of Langerhans) have a common embryologic origin within the neural crest and subsequently migrate to the foregut enlargement of the pancreas. These tumors have similar histology but can be distinguished by immunohistochemistry.
PNETs constitute four familial syndromes: multiple endocrine neoplasia type 1 (MEN-1), von Hippel-Lindau syndrome (VHL), neurofibromatosis type 1, and tuberous sclerosis complex (TSC). These tumors are benign or malignant. PNETs may occur with an autosomal dominant inheritance as part of MEN-1 syndrome. MEN-1 syndrome is a disorder of three glands: parathyroid, pancreatic islets, and pituitary. MEN-2 tumors include pheochromocytoma and adenoma or hyperplasia of parathyroid glands. Insulinomas and gastrinomas are the most common functioning PNETs. Other functioning tumors are less than 3% and are vasoactive intestinal peptide–secreting tumor (VIPoma), glucagonoma, and somatostatinoma.
Clinical picture, diagnosis, and treatment of PNETs vary greatly depending on the syndrome and secretory production, as discussed under insulinoma, gastrinoma, and glucagonoma.
The diagnostic studies include serum levels of hormones in functioning PNETs. There are several tumor markers available. Chromogranin A (CgA) is an acidic glycoprotein that is produced and excreted by PNETs. Circulating CgA levels are useful markers with a high specificity and a sensitivity ranging from 27% to 81%.
Computed tomography (CT) scan of the abdomen, magnetic resonance imaging (MRI), endoscopic ultrasound (EUS), somatostatin-receptor scintigraphy (SRS, octreotide scan), positron emission tomography (PET) scan are useful. EUS is particularly helpful in detecting small lesions such as gastrinomas and insulinomas.
Insulinoma
Insulinoma is the most common functional PNET. Almost 60% occur in middle-aged women. Insulinomas can be sporadic or familial, a component of MEN-1 syndrome. Approximately 10% of patients with insulinoma have the MEN-1 syndrome. Most of the tumors are solitary, relatively benign, less than 2.5 cm in diameter, and evenly distributed throughout the pancreas.
Fasting hypoglycemia is a common clinical manifestation of insulinoma. Headache, visual disturbances, dizziness, lightheadedness, confusion, weakness, grand mal seizures, and coma are the neuroglycopenic symptoms. Hypoglycemia-induced catecholamine response causes diaphoresis, tremulousness, palpitations, irritability, and hunger. Hypoglycemic symptoms are precipitated by fasting or exercise and respond to carbohydrate ingestion. Obesity is a consequence of hunger and increased eating.
Diagnosis
After 72 hours of supervised fasting, the patient displays the Whipple triad: (1) hypoglycemic symptoms (central nervous system, vasomotor), (2) documented hypoglycemia, and (3) relief of symptoms after glucose intake. Hypoglycemia usually develops within 24 hours of fasting. A serum insulin level of 5 mU/mL or more with concomitant plasma glucose level less than 45 mg/dL (2.5 mmol/L) indicates insulinoma. Factitious hypoglycemia is ruled out by fasting plasma levels, C-peptide, and proinsulin.
Abdominal CT, MRI, and EUS are all useful in diagnosing. Visceral angiography and indium 111–labeled octreotide nuclear imaging are other diagnostic modalities.
Treatment and Management
The goal of management is to prevent hypoglycemia through frequent small meals. Diazoxide, 100 to 150 mg every 8 hours, prevents insulin release. Other therapies include calcium channel blockers, corticosteroids, and glucagon. Octreotide therapy is useful in some patients with insulinoma.
Surgical exploration and enucleation of the tumor are needed in most patients. Insulinomas are often single and benign, and the surgical cure rate is high.
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