Insulinoma - Pancreatic cancers

• Tumors of the Gastrointestinal tract • • Pancreatic cancers • Jan 20, 08

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, nervousness) are often absent.

Diagnosis
Serum 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 serum 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 ≥ 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%) 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 Whipple’s triad: (1) Symptoms occur during the fast; (2) symptoms occur in the presence of hypoglycemia; (3) ingestion of carbohydrates relieves the symptoms. Hormone levels are obtained as described above when the patient is having symptoms.

If Whipple’s 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 performed. 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 ultrasound has > 90% sensitivity and helps localize the tumor. CT has not proven useful, and arteriography or selective portal and splenic vein catheterization is generally unnecessary.

Treatment
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 performed. 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. Pancreaticoduodenectomy (Whipple’s operation) is performed for resectable malignant insulinomas of the proximal pancreas. Total pancreatectomy is performed 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 administered 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.

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