Pancreatic endocrine tumors arise from islet and gastrin-producing cells and often produce many hormones. Although these tumors develop most often in the pancreas, they may appear in other organs, particularly the duodenum, jejunum, and lung.
These tumors have two general manifestations. Nonfunctioning tumors may cause obstructive symptoms of the biliary tract or duodenum, bleeding into the GI tract, or abdominal masses. Functioning tumors hypersecrete a particular hormone, causing various syndromes (see see Pancreatic Endocrine Tumors). These clinical syndromes can also occur in multiple endocrine neoplasia, in which tumors or hyperplasia affects two or more endocrine glands, usually the parathyroid, pituitary, thyroid, or adrenals (see Multiple Endocrine Neoplasia (MEN) Syndromes).
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Treatment for functioning and nonfunctioning tumors is surgical resection. If metastases preclude curative surgery, various antihormone treatments may be tried for functioning tumors. Because of tumor rarity, chemotherapy trials have not identified definitive treatment. However, streptozotocin has selective activity against pancreatic islet cells and is commonly used, either alone or in combination with 5-fluorouracil or doxorubicin. Some centers use chlorozotocin and interferon.
An insulinoma is a rare pancreatic β-cell tumor that hypersecretes insulin. The main symptom is fasting hypoglycemia. Diagnosis is by a 48- or 72-h fast with measurement of glucose and insulin levels, followed by endoscopic ultrasound. Treatment is surgery when possible. Drugs that block insulin secretion (eg, diazoxide, octreotide, Ca channel blockers, β-blockers, phenytoin) are used for patients not responding to surgery.
Of all insulinomas, 80% are single and may be curatively resected if identified. Only 10% of insulinomas are malignant. Insulinoma occurs in 1/250,000 at a median age of 50 yr, except in multiple endocrine neoplasia (MEN) type I (about 10% of insulinomas), when it occurs in the 20s. Insulinomas associated with MEN type I are more likely to be multiple.
Surreptitious administration of exogenous insulin can cause episodic hypoglycemia mimicking insulinoma.
Symptoms and Signs
Hypoglycemia secondary to an insulinoma occurs during fasting. Symptoms are insidious and may mimic various psychiatric and neurologic disorders. CNS disturbances include headache, confusion, visual disturbances, motor weakness, palsy, ataxia, marked personality changes, and possible progression to loss of consciousness, seizures, and coma. Symptoms of sympathetic stimulation (faintness, weakness, tremulousness, palpitation, sweating, hunger, and nervousness) are often present.
Plasma glucose should be measured during symptoms. If hypoglycemia is present (glucose < 40 mg/dL [2.78 mmol/L]), an insulin level should be measured on a simultaneous sample. Hyperinsulinemia of > 6 μU/mL (42 pmol/L) suggests an insulin-mediated cause, as does a serum insulin to plasma glucose ratio > 0.3 (μU/mL)/(mg/dL).
Insulin is secreted as proinsulin, consisting of an α chain and β chain connected by a C peptide. Because pharmaceutical insulin consists only of the β chain, surreptitious insulin administration can be detected by measuring C-peptide and proinsulin levels. In patients with insulinoma, C peptide is ≥ 0.2 nmol/L and proinsulin is ≥ 5 pmol/L. These levels are normal or low in patients with surreptitious insulin administration.
Because many patients have no symptoms (and hence no hypoglycemia) at the time of evaluation, diagnosis requires admission to the hospital for a 48- or 72-h fast. Nearly all (98%) patients with insulinoma develop symptoms within 48 h of fasting; 70 to 80% within 24 h. Hypoglycemia as the cause of the symptoms is established by the Whipple triad: (1) Symptoms occur during the fast; (2) symptoms occur in the presence of hypoglycemia; and (3) ingestion of carbohydrates relieves the symptoms. Hormone levels are obtained as described above when the patient is having symptoms.
If the Whipple triad is not observed after prolonged fasting and the plasma glucose after an overnight fast is > 50 mg/dL (> 2.78 mmol/L), a C-peptide suppression test can be done. During insulin infusion (0.1 U/kg/h), patients with insulinoma fail to suppress C peptide to normal levels (≤ 1.2 ng/ mL [≤ 0.40 nmol/L]).
Endoscopic ultrasonography has > 90% sensitivity and helps localize the tumor. PET also may be used. CT has not proved useful, and arteriography or selective portal and splenic vein catheterization is generally unnecessary.
Overall surgical cure rates approach 90%. A small, single insulinoma at or near the surface of the pancreas can usually be enucleated surgically. If a single large or deep adenoma is within the pancreatic body or tail, if there are multiple lesions of the body or tail (or both), or if no insulinoma is found (an unusual circumstance), a distal, subtotal pancreatectomy is done. In < 1% of cases, the insulinoma is ectopically located in peripancreatic sites of the duodenal wall or periduodenal area and can be found only by diligent search during surgery. Pancreatoduodenectomy (Whipple procedure) is done for resectable malignant insulinomas of the proximal pancreas. Total pancreatectomy is done if a previous subtotal pancreatectomy proves inadequate.
If hypoglycemia continues, diazoxide starting at 1.5 mg/kg po bid with a natriuretic can be used. Doses can be increased up to 4 mg/kg. A somatostatin analog, octreotide (100 to 500 μg sc bid to tid), is variably effective and should be considered for patients with continuing hypoglycemia refractory to diazoxide. Patients who respond may be converted to a long-acting octreotide formulation given as 20 to 30 mg IM once/mo. Patients using octreotide may also need to take supplemental pancreatic enzymes because octreotide suppresses pancreatic enzyme secretion. Other drugs that have modest and variable effect on insulin secretion include verapamil, diltiazem, and phenytoin.
If symptoms are not controlled, chemotherapy may be tried, but response is limited. Streptozotocin has a 30 to 40% response rate and, when combined with 5-fluorouracil, a 60% response rate lasting up to 2 yr. Other agents include doxorubicin, chlorozotocin, and interferon.
(Zollinger-Ellison Syndrome; Z-E Syndrome)
A gastrinoma is a gastrin-producing tumor usually located in the pancreas or the duodenal wall. Gastric acid hypersecretion and aggressive, refractory peptic ulceration result (Zollinger-Ellison syndrome). Diagnosis is by measuring serum gastrin levels. Treatment is proton pump inhibitors and surgical removal.
Gastrinomas occur in the pancreas or duodenal wall 80 to 90% of the time. The remainder occur in the splenic hilum, mesentery, stomach, lymph node, or ovary. About 50% of patients have multiple tumors. Gastrinomas usually are small (< 1 cm in diameter) and grow slowly. About 50% are malignant. About 40 to 60% of patients with gastrinoma have multiple endocrine neoplasia (see Multiple Endocrine Neoplasia (MEN) Syndromes).
Symptoms and Signs
Zollinger-Ellison syndrome typically manifests as aggressive peptic ulcer disease, with ulcers occurring in atypical locations (up to 25% are located distal to the duodenal bulb). However, as many as 25% do not have an ulcer at diagnosis. Typical ulcer symptoms and complications (eg, perforation, bleeding, obstruction) can occur. Diarrhea is the initial symptom in 25 to 40% of patients.
Gastrinoma is suspected by history, particularly when symptoms are refractory to standard acid suppressant therapy.
The most reliable test is serum gastrin. All patients have levels > 150 pg/mL; markedly elevated levels of > 1000 pg/mL in a patient with compatible clinical features and gastric acid hypersecretion of > 15 mEq/h establish the diagnosis. However, moderate hypergastrinemia can occur with hypochlorhydric states (eg, pernicious anemia, chronic gastritis, use of proton pump inhibitors), in renal insufficiency with decreased clearance of gastrins, in massive intestinal resection, and in pheochromocytoma.
A secretin provocative test may be useful in patients with gastrin levels < 1000 pg/mL. An IV bolus of secretin 2 μg/kg is given with serial measurements of serum gastrin (10 and 1 min before, and 2, 5, 10, 15, 20, and 30 min after injection). The characteristic response in gastrinoma is an increase in gastrin levels, the opposite of what occurs in patients with antral G-cell hyperplasia or typical peptic ulcer disease. Patients also should be evaluated for Helicobacter pylori infection, which commonly results in peptic ulceration and moderate excess gastrin secretion.
Once the diagnosis has been established, the tumor or tumors must be localized. The first test is abdominal CT or somatostatin receptor scintigraphy, which may identify the primary tumor and metastatic disease. PET or selective arteriography with magnification and subtraction is also helpful. If no signs of metastases are present and the primary is uncertain, endoscopic ultrasonography should be done. Selective arterial secretin injection is an alternative.
Five- and 10-yr survival is > 90% when an isolated tumor is removed surgically vs 43% at 5 yr and 25% at 10 yr with incomplete removal.
Proton pump inhibitors are the drugs of choice: omeprazole or esomeprazole 40 mg po bid. The dose may be decreased gradually once symptoms resolve and acid output declines. A maintenance dose is needed; patients need to take these drugs indefinitely unless they undergo surgery.
Octreotide injections, 100 to 500 μg sc bid to tid, may also decrease gastric acid production and may be palliative in patients not responding well to proton pump inhibitors. A long-acting form of octreotide (20 to 30 mg IM once/mo) can be used.
Surgical removal should be attempted in patients without apparent metastases. At surgery, duodenotomy and intraoperative endoscopic transillumination or ultrasonography help localize tumors. Surgical cure is possible in 20% of patients if the gastrinoma is not part of a multiple endocrine neoplasia syndrome.
In patients with metastatic disease, streptozocin in combination with 5-fluorouracil or doxorubicin is the preferred chemotherapy for islet cell tumors. It may reduce tumor mass (in 50 to 60%) and serum gastrin levels and is a useful adjunct to omeprazole. Patients with metastatic disease are not cured by chemotherapy.
A vipoma is a non-β pancreatic islet cell tumor secreting vasoactive intestinal peptide (VIP), resulting in a syndrome of watery diarrhea, hypokalemia, and achlorhydria (WDHA syndrome). Diagnosis is by serum VIP levels. Tumor is localized with CT and endoscopic ultrasound. Treatment is surgical resection.
Of these tumors, 50 to 75% are malignant, and some may be quite large (7 cm) at diagnosis. In about 6%, vipoma occurs as part of multiple endocrine neoplasia (see Multiple Endocrine Neoplasia (MEN) Syndromes).
Symptoms and Signs
The major symptoms are prolonged massive watery diarrhea (fasting stool volume > 750 to 1000 mL/day and nonfasting volumes of > 3000 mL/day) and symptoms of hypokalemia, acidosis, and dehydration. In half of patients, diarrhea is constant; in the rest, diarrhea severity varies over time. About 33% of patients have diarrhea < 1 yr before diagnosis, but 25% have diarrhea ≥ 5 yr before diagnosis. Lethargy, muscular weakness, nausea, vomiting, and crampy abdominal pain occur frequently. Flushing similar to the carcinoid syndrome occurs in 20% of patients during attacks of diarrhea.
Diagnosis requires demonstration of secretory diarrhea (stool osmolality is close to plasma osmolality, and twice the sum of Na and K concentration in the stool accounts for all measured stool osmolality). Other causes of secretory diarrhea and, in particular, laxative abuse must be excluded (see Diarrhea). In such patients, serum VIP levels should be measured (ideally during a bout of diarrhea). Markedly elevated levels establish the diagnosis, but mild elevations may occur with short bowel syndrome and inflammatory diseases. Patients with elevated VIP levels should have tumor localization studies, such as endoscopic ultrasonography, PET, and octreotide scintigraphy or arteriography to localize metastases.
Electrolytes and CBC should be measured. Hyperglycemia and impaired glucose tolerance occur in ≤ 50% of patients. Hypercalcemia occurs in 50% of patients.
Initially, fluids and electrolytes must be replaced. Bicarbonate must be given to replace fecal loss and avoid acidosis. Because fecal losses of water and electrolytes increase as rehydration is achieved, continual IV replacement may become difficult.
Octreotide usually controls diarrhea, but large doses may be needed. Responders may benefit from a long-acting octreotide formulation given 20 to 30 mg IM once/mo. Patients using octreotide may also need to take supplemental pancreatic enzymes because octreotide suppresses pancreatic enzyme secretion.
Tumor resection is curative in 50% of patients with a localized tumor. In patients with metastatic tumor, resection of all visible tumor may provide temporary relief of symptoms. The combination of streptozocin and doxorubicin may reduce diarrhea and tumor mass if objective response occurs (in 50 to 60%). Chemotherapy is not curative.
A glucagonoma is a pancreatic α-cell tumor that secretes glucagon, causing hyperglycemia and a characteristic skin rash. Diagnosis is by elevated glucagon levels and imaging studies. Tumor is localized with CT and endoscopic ultrasound. Treatment is surgical resection.
Glucagonomas are very rare but similar to other islet cell tumors in that the primary and metastatic lesions are slow-growing: 15-yr survival is common. Eighty percent of glucagonomas are malignant. The average age at symptom onset is 50 yr; 80% of patients are women. A few patients have multiple endocrine neoplasia type I (see Multiple Endocrine Neoplasia, Type 1 (MEN 1)).
Symptoms and Signs
Because glucagonomas produce glucagon, the symptoms are the same as those of diabetes. Frequently, weight loss, normochromic anemia, hypoaminoacidemia, and hypolipidemia are present, but the most distinctive clinical feature is a chronic eruption involving the extremities, often associated with a smooth, shiny, vermilion tongue and cheilitis. The exfoliating, brownish red, erythematous lesion with superficial necrolysis is termed necrolytic migratory erythema.
Most patients with glucagonoma have glucagon levels > 1000 pg/mL (normal < 200). However, moderate elevations occur in renal insufficiency, acute pancreatitis, severe stress, and fasting. Correlation with symptoms is required. Patients should have abdominal CT followed by endoscopic ultrasonography; MRI or PET may be used if CT is unrevealing.
Resection of the tumor alleviates all symptoms. Unresectable, metastatic, or recurrent tumors are treated with combination streptozocin and doxorubicin, which may decrease levels of circulating immunoreactive glucagon, lessen symptoms, and improve response rates (50%) but are unlikely to improve survival. Octreotide injections partially suppress glucagon production and relieve the erythema, but glucose tolerance may also decrease because octreotide decreases insulin secretion. Octreotide may quickly reverse anorexia and weight loss caused by the catabolic effect of glucagon excess. Patients who respond may be converted to a long-acting octreotide formulation given 20 to 30 mg IM once/mo. Patients using octreotide may also need to take supplemental pancreatic enzymes because octreotide suppresses pancreatic enzyme secretion.
Locally applied, oral, or parenteral zinc may cause the erythema to disappear, but resolution may occur after simple hydration or IV administration of amino or fatty acids, suggesting that the erythema is not solely caused by zinc deficiency.
Last full review/revision October 2012 by Elliot M. Livstone, MD
Content last modified September 2013