Insulinomas

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Although insulinomas are the most common of the functional endocrine tumors of the pancreas, they are rare tumors, with an incidence of four per million person-years. A 60-year review including 224 patients provides epidemiologic data.3 In this series, the median age was 47 years (range 8 to 82 years), and 59% were women. Of these patients, 5.8% had malignant insulinomas and 7.6% had MEN type I. Symptoms include blurred vision, confusion, abnormal behavior, sweating, weakness, hunger, anxiety, and palpitations. The diagnosis may not be made for years in symptomatic patients, many of whom are treated for seizures or psychiatric disturbances before the possibility of an insulinoma is entertained. The mean interval from onset of symptoms to diagnosis is approximately 3 years.4

The discovery of insulin as a hormone by Banting and Best in 1922 was followed by a description of the pathophysiology of excess insulin by Harris in 1924.5 Graham performed the first successful resection of an insulin-secreting tumor in 1929. In 1935, Whipple and Franz wrote the classic description of the clinical manifestations of an insulinoma in what is now known as Whipple's triad6:

1. The patient exhibits signs and symptoms of hypoglycemia during fasting.

2. At the time of symptoms, serum glucose is < 45 mg/dL.

3. Symptoms are relieved by oral or intravenous administration of glucose.

The diagnosis, in current times, is generally established by the demonstration of low serum glucose with a simultaneous inappropriately elevated serum insulin level. The ratio of serum insulin to glucose in this setting is greater than 0.4.7 The gold standard test to establish the diagnosis of an insulinoma is a supervised fast for up to 72 hours. Most patients (80%) will become symptomatic within 24 hours, at which time simultaneous levels of glucose and insulin should be drawn. In unusual or equivocal cases, a provocative test with tolbutamide or glucagon may be useful to establish the presence of an insulinoma.8 Adjunctive tests to confirm the diagnosis of insulinoma include an assay for elevated levels of proinsulin and C peptide. Proinsulin is the precursor of insulin.9,10 Proteolytic cleavage of this protein results in production of C peptide. The differential diagnosis should include other causes of hypoglycemia such as postprandial hypoglycemia, alimentary hyperinsulinism, adrenal insufficiency, hepatitis or cirrhosis, and sulfonylurea overuse (Table 15-1). The presence of circulating insulin-binding antibodies should alert the clinician that the patient is surreptitiously taking insulin.11

Once the diagnosis of an insulinoma is established by biochemical means, there exists some debate as to whether localizing studies are necessary before operation. Some authors, myself included, recommend only magnetic resonance imaging (MRI) to evaluate the liver for possible metastatic disease. Of course, a carefully done MRI can demonstrate the primary lesion in about 43% of cases (Figure 15-1). Insulinomas are usually small, with a mean size of 1.5 cm.

Patients usually have initiated treatment prior to seeking medical attention. They find that they can

Table 15-1. CAUSES OF HYPOGLYCEMIA

Insulin excess Insulinoma

Surreptitious use of insulin Sulfonylureas

Insulin or insulin receptor autoantibodies Quinine

Glucose deficiency

Drugs

Ethanol

Propranolol

Salicylates

Haloperidol

Hormone deficiencies

Adrenal insufficiency

Hypopituitarism

Catecholamine deficiency

Enzyme deficiencies

Liver failure

Renal failure

Congestive heart failure

Sepsis and shock

Severe malnutrition or starvation

Intensive exercise

Late pregnancy

Adapted from Cryer PE. Hypoglycemia. In: Braunwald E, Fauci AS, Kosper DL, et al, editors. Harrison's principles of internal medicine. 15th ed. New York: McGraw-Hill; 2001. p. 2138.

Figure 15-1. An insulinoma is demonstrated in the head of the pancreas by T2-weighted magnetic resonance imaging.

treat their symptoms by eating frequent small meals or waking during the night to have a snack. Many patients report moderate weight gain. The use of pharmacologic agents to control hypoglycemia is usually reserved for patients with unresectable metastatic tumors or in preparation for surgery. Diaz-oxide suppresses insulin secretion by direct inhibition of the beta islet cells. Control of hypoglycemia is achieved in over 50% of patients, but a significant number suffer adverse effects from the medication, including weight gain from fluid retention, nausea, and hirsutism. A limited number of reports suggest that verapamil may also be effective. Octreotide has been used to control hypoglycemia in patients not well treated by other agents. It requires parenteral dosing and is relatively expensive.

Because approximately 20% of insulinomas cannot be felt or seen by the surgeon at the time of laparotomy, it is essential for any surgeon exploring a patient for an insulinoma to be skillful in the use of high-resolution intraoperative ultrasonography (Figure 15-2). Most common small benign neuroendocrine tumors, including most insulinomas, are amenable to cure by enucleation from the pancreatic parenchyma. Insulinomas arising in the pancreatic head or uncinate process can almost always be removed in this manner. To accomplish this, a thorough Kocher maneuver is needed to allow complete mobilization and bimanual palpation of the pancreatic head. On occasion, to gain access to the unci-nate, it is necessary to ligate and divide small branches from the superior mesenteric artery and

Figure 15-2. This insulinoma is demonstrated in the tail of the pancreas near the splenic artery and vein. The lesion is hypoechoic on intraoperative ultrasonography.

vein. Here high-resolution intraoperative ultrasonography is useful to plan an incision into the pancreatic parenchyma and avoid the major pancreatic duct. The incision may be in either the anterior or posterior surface of the pancreas, but an anterior leak, should it develop after surgery, is easier to repair than a posterior fistula by means of a Roux-en-Y pancreaticojejunostomy. Once the tumor capsule is reached, a fine hemostat is used to develop a plane between the tumor and the surrounding pancreatic parenchyma. At the completion of the procedure, some have suggested administering secretin to assess for leakage of pancreatic juice from the enu-cleation. No attempt is made to close the site with sutures, but some place an omental pedicle into the pancreatic defect. A closed suction drain should be placed to control a possible pancreatic leak.

Small benign lesions in the body and tail of the pancreas may be treated by either enucleation or resection (Figure 15-3). For large or malignant tumors at the head of the pancreas, a pancreaticoduo-denectomy may be required (Figure 15-4). Large or posterior surface neuroendocrine tumors in the pancreas should be removed by means of a distal pancreatectomy with an effort to preserve the spleen. If a lesion is suspected to be malignant, however, the dis tal pancreas, spleen, and regional lymph nodes along the splenic artery should be resected en bloc. I do not advocate a blind distal pancreatectomy if the insulinoma is not found during intraoperative exploration but prefer to close the patient's incision, reconfirm the diagnosis, and do further investigations to locate the tumor. Recently, a small series was reported consisting of 12 patients undergoing attempted laparoscopic distal pancreatectomy or enucleation for endocrine tumors of the pancreas.12 Of these patients, 8 had insulinomas. Laparoscopic removal was accomplished in 6 of the 12 patients. The reasons for conversion to open surgery were identification of metastatic disease, inability to find a tumor, and the need to perform a Whipple's operation. The mean operative time for the laparoscopic procedures was 4.5 hours. I have successfully performed a distal pan-createctomy for a benign pancreatic cystic neoplasm using a hand-assisted laparoscopic technique. Although these preliminary efforts suggest great promise for future possibilities, the utility of minimally invasive approaches has yet to be established.

Patients with MEN type I tend to have multiple islet cell tumors of the pancreas that may produce a variety of peptides. One syndrome will, however, predominate. Demeure and colleagues and others have recommended a different operative approach for the MEN type I patient with an insulinoma13: a subtotal distal pancreatectomy with enucleation of any tumors seen in the head of the gland.

Intraoperative glucose monitoring with a rapid glucose assay can reassure the surgeon and add a measure of safety by detecting hypoglycemia. A baseline glucose level is obtained soon after induction of anesthesia and at 15- to 20-minute intervals until the insulinoma tumor is removed. Following removal, a rise in serum glucose is indicative of a successful operation. It is common for patients to have mild hyperglycemia for the first 2 to 3 postoperative days, but normal glucose metabolism then returns.

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