Neuroendocrine Tumors of the Pancreas

Symptoms and Diagnosis

Diagnosis of insulinoma is suggested by the presence of Whipple triad: neuroglycopenic symptoms, low blood glucose levels (<45 mg/dL), and relief of symptoms with glucose administration. Acute neuroglycopenic symptoms include anxiety, dizziness, obtundation, confusion, unconsciousness, personality changes, and seizures. Symptoms are typically worse following exercise or fasting. Eighty percent of patients gain weight. The majority (60% to 75%) of patients are female, and many have undergone extensive psychiatric evaluation. Many have been diagnosed with a neurologic condition such as seizure disorder, cerebrovascular accident, or transient ischemic attack. In a review of 59 patients with insulinoma, the interval from the onset of symptoms to the time of diagnosis ranged from 1 month to 30 years, with the median time to diagnosis being 2 years. Approximately 5% to 10% of patients with insulinoma also have MEN-1, which should be excluded or included based on history, symptoms, physical examination, and biochemical findings.

Patients with a suspicion of having insulinoma should undergo a 72-hour diagnostic fast. Factitious hypoglycemia, in which exogenous insulin or oral hypoglycemic drugs are administered clandestinely, may present with exactly the same symptoms as an insulinoma and must be excluded. Factitious hypoglycemia is seen more commonly in women and may be suspected in individuals with access to insulin or oral hypoglycemic drugs. Urinary sulfonylurea concentration should be measured by gas chromatography–mass spectroscopy to detect abuse of oral hypoglycemic drugs. Antiinsulin antibodies should not be detectable in patients with insulinoma. An increased serum concentration of proinsulin or C-peptide during hypoglycemia effectively excludes the diagnosis of factitious hypoglycemia because exogenously administered insulin does not contain these proteins and actually suppresses their endogenous production. The diagnosis of insulinoma is difficult in patients with chronic renal failure because hypoglycemia may develop for other reasons.

Any patient with a history of neuroglycopenic symptoms and hypoglycemia should undergo a diagnostic 72-hour fast in the inpatient hospital setting under close supervision. During the fast, the patient may drink only water or noncaloric beverages. The study is designed to induce symptoms of hypoglycemia in a controlled setting so that serum levels of glucose and insulin can be measured during symptoms. Blood is tested for serum glucose and immunoreactive insulin concentration every 6 hours and when symptoms develop. If the patient develops neuroglycopenic symptoms, such as confusion, altered mental status, dizziness, or seizure, serum levels of glucose, insulin, C-peptide, and proinsulin are drawn and the fast is terminated. At termination, dextrose is administered intravenously to relieve the symptoms of hypoglycemia.

The diagnosis of insulinoma is made if the patient develops neuroglycopenic symptoms, the serum glucose level is lower than 45 mg/dL, and the concomitant serum level of insulin is higher than 5 µU/L. The symptoms should be ameliorated with the administration of glucose. Elevated serum levels of C-peptide (>0.7 ng/mL) and proinsulin are confirmatory and exclude factitious hypoglycemia. Sixty percent of patients with insulinoma develop symptoms within 24 hours after fasting, and almost all patients develop symptoms within 72 hours.

Preoperative Localization

Sporadic nonfamilial insulinomas may be difficult to localize precisely preoperatively. For this reason the diagnosis must be unequivocal before contemplating an operation. Ultrasonography is an initial study to try to localize the insulinoma. The tumor appears sonolucent compared with the more echo-dense pancreas. However, ultrasound images only approximately 20% of insulinomas. It is especially limited by overlying bowel gas and obesity.

Thin-cut pancreatic protocol CT with intravenous contrast and serial sections at small intervals through the pancreas ( Fig. 97.2 ) is the noninvasive study of choice. Tumors are hypervascular compared with the surrounding pancreatic parenchyma. CT can demonstrate at least 80% of insulinomas and may be useful for demonstrating liver metastases. Magnetic resonance imaging (MRI) is a newer but similarly sensitive modality for imaging insulinomas. Insulinomas appear bright on T2-weighted images. The sensitivity of MR is equivalent to that of CT and increases with tumor size.

Somatostatin receptor scintigraphy (SRS) or Octreoscan has become an important imaging modality for neuroendocrine tumors of the pancreas. It images tumors based on the density of type 2 somatostatin receptors. Radiolabeled octreotide binds to tumors with somatostatin receptors, causing the tumor to appear as a “hot spot” on whole-body gamma camera scintigraphy. Although SRS correctly identifies 90% of NETs and carcinoid tumors, small insulinomas often are not visible on SRS, although combined with endoscopic ultrasound (EUS) the sensitivity for the diagnosis of insulinoma is reported to be higher than 90%. DOTA scan is a newer type of SRS. It is able to image PNETs better than Octreoscan and has replaced it as the preoperative imaging study of choice.

Invasive Localization Studies

Approximately 50% of patients have small (<2 cm) insulinomas that are not detected by noninvasive imaging tests. EUS ( Fig. 97.3 ) is an important study that can identify tumors as small as 2 to 3 mm. PNETs can be biopsied by fine-needle aspiration for an unequivocal diagnosis and localization. Sensitivity for EUS ranges from 70% to 90%, and specificity is near 100%. It is more accurate in the head of the pancreas than in the body and the tail. Despite the tremendous potential, there are some limitations, including false-positive findings, such as accessory spleens and intrapancreatic lymph nodes. CT is a useful adjunct to EUS to image the liver and rule out disseminated malignancy.

A small number of insulinomas remain occult despite extensive preoperative imaging studies. When the diagnosis is certain based on the result of the 72-hour fast, surgical exploration with careful inspection, palpation, and intraoperative ultrasound (IOUS) is indicated. Studies have shown that the combination of surgical exploration with IOUS identifies nearly all insulinomas.

Therapy

Medical treatment should prevent hypoglycemia. Acute hypoglycemia is initially treated with intravenous glucose infusion. Hypoglycemia can be prevented while establishing the diagnosis and tumor localization by giving frequent feeds of high-carbohydrate diet, including a night meal. Cornstarch added to the diet may prolong and slow down absorption of glucose. For patients who continue to become hypoglycemic between feedings, diazoxide may be added to the treatment regimen at a dose of 400 to 600 mg orally each day. Diazoxide inhibits insulin release in approximately 50% of patients with insulinoma. In some patients, calcium channel blockers or phenytoin may suppress insulin production. Octreotide binds to and activates somatostatin receptors on cells expressing them. However, its usefulness to inhibit insulin release has been disappointing and unpredictable.

Long-term medical management of hypoglycemia in patients with insulinomas is generally reserved for the few patients (<5%) with unlocalized, unresected tumors after thorough preoperative testing and exploratory laparotomy and for patients with metastatic, unresectable malignant insulinoma. Patients with malignant insulinomas and refractory hypoglycemia may even require the placement of implantable glucose pumps for continuous glucose infusion.

Surgery is the only curative therapy for insulinoma. Because most insulinomas are benign and small, the goal of surgery is to precisely localize the tumor and remove it with minimal morbidity. The major breakthrough in surgery for insulinoma is IOUS. It is the single best intraoperative method to localize insulinomas, although in most cases the tumor is localized by other techniques preoperatively or is visualized or palpated by the surgeon.

Midline or bilateral subcostal incisions allow for good exposure. Because virtually all insulinomas are located within the pancreas, an extended Kocher maneuver is performed and the lesser sac is opened, such that the entire pancreas can be examined. The tumor feels like a firm, nodular, and discrete mass. It may appear brownish-red purple, like a cherry. IOUS should be performed with a high-resolution near-field transducer (10 to 15 MHz). The neuroendocrine tumor is sonolucent compared with the more echodense pancreas ( Fig. 97.4 ). The tumor should be imaged in two directions to identify it as a real structure. A recent study of 37 consecutive patients showed that IOUS identified tumors in 35 (95%), and the 2 that were missed were in the pancreatic tail. The liver is examined, and suspicious lesions are biopsied or excised.

Patients who have clear-cut preoperative localization including CT may be candidates for laparoscopic resection. This has been done with good results in these patients using laparoscopic ultrasound to image the tumor and guide the resection. Patients who undergo laparoscopic resection of insulinomas have less postoperative pain, shorter hospitalization, and faster return to work. Insulinomas presenting during pregnancy have been reported and are usually managed medically until the fetus can be delivered or the pregnancy is terminated.

Diagnosis

The possibility of MEN-1 should be considered during the evaluation of all patients presenting with pancreatic NET. A careful family history of first-degree relatives should be taken, and suspicious comorbidities, such as kidney stones, hyperparathyroidism, hypoglycemia, peptic ulcer disease, diarrhea, Cushing syndrome, and prolactinoma should be queried. All patients younger than age 40 years presenting with primary hyperparathyroidism due to multiple gland disease should be screened for pancreatic endocrine tumors even if their family history is negative for MEN-1 syndrome. Physical examination should be done to exclude lipomas that may be present in MEN-1. Screening of other family members is indicated, if suspicion for MEN-1 exists. Evaluation should include serum levels of calcium, gastrin, glucose, PP, chromogranin A, and prolactin.

Each patient with biochemical evidence of a neuroendocrine tumor should undergo complete radiologic assessment of disease to determine the feasibility of surgery. During the radiologic evaluation, medical management should be used to ameliorate symptoms secondary to excessive hormone secretion. It is clear that in some patients with neuroendocrine tumors (e.g., VIPoma) advances in medical control of the hormone production have improved the surgical outcome and reduced the operative complication rate.

Therapy

In MEN-1 patients with primary hyperparathyroidism and Zollinger-Ellison syndrome, surgery to correct the primary hyperparathyroidism (three and one-half gland parathyroidectomy) should be performed prior to pancreatic surgery because correction of the hypercalcemia will greatly ameliorate the signs and symptoms of Zollinger-Ellison syndrome. If MEN-1 is present, the pathologist will identify multiple neuroendocrine tumors within the pancreas, so patients are seldom cured by surgery, but most experts recommend that patients with neuroendocrine tumors greater than 2 cm undergo surgery because these tumors have a higher probability of developing liver metastases. Medical management can only control the signs and symptoms, and tumor resection is the only potentially curative treatment for malignant PNET. Resection is better in MEN-1 patients because of multiple tumors. Therefore, in patients with localized, potentially resectable, imageable (2 cm or larger) tumors, pancreatic resection by either a Whipple procedure (for pancreatic head tumors) or distal pancreatectomy (for pancreatic body and tail tumors) is indicated.

Prognosis

Many variables associated with an individual patient have an impact on the surgical outcome. These include the extent of disease on preoperative imaging studies, whether the primary tumor is within the pancreas or duodenum, the exact area of the pancreas involved (head, body, or tail), the presence of liver or other distant metastases and whether they are resectable, the occurrence of the neuroendocrine tumor in a familial or a sporadic setting, and the simultaneous occurrence of other medical conditions that may limit the ability of a patient to undergo major surgery. The definition of success need not be equated with cure because decreased medication requirement, decreased symptoms, and increased length of survival may be of considerable clinical value. In each patient, it is clear that neuroendocrine tumors may be malignant, that surgery is an effective way of accurately staging the true extent of disease, and that surgery may be curative, even in the patients with metastatic neuroendocrine tumor.

Genetic counseling and screening should be provided to families at high risk of developing MEN-1. These patients should enter a clinical screening program, which can enable earlier detection and treatment of MEN-1–associated tumors and prompt treatment of hyperparathyroidism.