In Brief

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Islet cell tumors of the pancreas are relatively rare, accounting for approximately 2% to 4% of all pancreatic tumors. These tumors originate from the neuroendocrine islet cells and are classified by the secretory hormone they produce and the associated clinical syndrome that results. Conversely, many islet cell cancers produce no overt clinical syndrome. The most common islet cell tumors are gastrinomas and insulinomas. Other tumors may produce excess glucagon, vasoactive intestinal polypeptide, somatostatin, or other hormones.

Although the histologic appearance of an islet cell tumor is not usually difficult to distinguish from other pancreatic neoplasms, the differentiation of malignant from benign islet cell tumors may be difficult. The World Health Organization has classified these tumors into a spectrum ranging from benign to uncertain, to low-grade, to high-grade malignancy based on criteria such as tumor size, local or vascular invasion, and the presence of metastases. Other adjuncts such as the finding of DNA aneuploidy or increased expression, by immunohistochemistry, of proliferative markers such as Ki-67 or MIB-1 may portend malignant propensity. For all these neoplasms, surgical resection is the only potentially curative treatment. With the exception of small insulinomas, which are typically benign and may be enucleated, resection with clear margins is recommended.

Gastrinomas were initially described by Zollinger and Ellison in 1955 in a report detailing 2 patients with ulcers in the proximal jejunum, acid hypersecretion, and non-β islet cell tumors of the pancreas. As a result, the clinical syndrome produced by these tumors bears their monikers. The incidence of gastrinomas is 0.2 to 2 per million individuals and these tumors most often manifest in the fifth decade of life. The diagnosis should be suspected in patients who have recurrent ulcer disease after ulcer surgery or in patients whose ulcers prove difficult to treat by medical means. A gastrinoma should also be suspected if ulcers occur distal to the duodenal bulb or in association with diarrhea, or if the patient has a history of other endocrinopathies or family members with ulcer disease. The diagnosis is established if the gastrin level is elevated in the presence of excess acid secretion. For borderline levels of gastrin elevation, a paradoxical rise in serum gastrin level after administration of secretin distinguishes the gastrinoma patient from those with other causes of moderate elevation in gastrin levels. Once the diagnosis is established by biochemical tests, imaging tests are used to locate the tumor and to exclude metastatic diseases. These tests include somatostatin receptor scintigraphy and computerized tomography (CT) or magnetic resonance imaging (MRI). The role of endoscopic ultrasonography is dependent, somewhat, on the skill of the operator and may not show small primary lesions. This modality, however, is quite sensitive for pancreatic tumors or regional adenopathy.

An operative exploration is indicated for patients with a sporadic gastrinoma in the absence of liver metastases. The role of surgery in patients with gastrinoma in the setting of multiple endocrine neoplasia type 1 syndrome (MEN1) is still debated. Up to 30% of patients with sporadic gastrinomas will not have a primary tumor located before exploration, so operation must be conducted in a systematic function. Most tumors occur within the gastrinoma triangle, an anatomic area bordered by the junction of the body and neck of the pancreas, the junction of the second and third portions of the duodenum, and the junction of the cystic duct and the common bile duct. Lymph nodes in the region should be removed and a transduodenal exploration of the wall of the duodenum should be conducted in an effort to find a small submucosal primary tumor. Intraoperative ultrasound is a necessary adjunct to examine the pancreas and the liver. Long-term cure rates reported by the National Institutes of Health (NIH) for patients with sporadic gastrinoma after exploration are 40% and 34% at 5 and 10 years, respectively.

In most series, insulinomas are the most common neuroendocrine tumor of the pancreas. The majority of these tumors are small, benign, and readily curable by surgical removal. Up to 16%, however, are benign. The classic description by Whipple of a clinical triad of findings highlights the presentation. Whipple’s triad includes: (1) signs and symptoms of hypoglycemia during fasting, (2) at the times of symptoms, serum glucose is ≤45 mg/dL, and (3) symptoms are relieved by administration of glucose. The symptoms are often confused as those of a neuropsychiatric disorder so the diagnosis of an insulinoma may be delayed for months or years. The essential diagnostic test is a 72-hour supervised fast. If symptoms develop, simultaneous serum glucose, insulin, and C-peptide levels are drawn. An inappropriately high insulin level in the setting of hypoglycemia (serum glucose below 40 mg/dL) with an insulin-to-glucose ratio greater than 0.3 are associated with an insulinoma. One should exclude other causes of hypoglycemia including surreptitious use of hypoglycemic medications. Once the diagnosis is established, CT or MRI should be used to exclude metastatic disease and possibly locate a primary tumor within the pancreas. Endoscopic ultrasound is more sensitive for insulinomas than for gastrinoma. In the setting of negative tests, selective angiography with injection of secretagogues and hepatic vein sampling of insulin levels is useful to locate the insulinoma within a region of the pancreas and may suggest adult nesidioblastosis.

For small benign insulinomas, enucleation is generally sufficient for cure. For insulinomas larger than 3 cm, tumors with histology suspicious for malignancy or tumors in the tail of the pancreas, resection is preferable. For small insulinomas of the pancreas, intraoperative ultrasound is an important adjunct to careful digital palpation. A small nonpalpable tumor may be seen and relationships to the pancreatic duct and blood vessels assessed. Although they are considered to be advanced procedures, laparoscopic resection and enucleation have both been performed and reported by several authors. Insulinomas of the tail seem more amenable to this approach than are lesions of the pancreatic head. Malignant insulinomas with limited metastatic disease, including liver metastases, can be resected resulting in palliation of hypoglycemic symptoms. The 10-year survival rate was 29% in a Mayo Clinic series.

In general, other islet cell tumors are quite rare and should be considered to have malignant potential and treated accordingly by resection rather than enucleation. Carcinoid tumors of the pancreas comprise only 2% of gastrointestinal carcinoids. Tumors that express excess vasoactive intestinal peptide manifest with the Verner-Morrison syndrome of water diarrhea, hypokalemia, and hypochlorhydria. Glucagonomas manifest with a characteristic rash called necrolytic migratory erythema, but other features include weight loss, hypercalcemia, glossitis, and thromboembolic disease. Somatostatinomas are associated with steattorhea, diarrhea, mild diabetes, and gallstones. Approximately 40% of malignant islet cell tumors produce no overt syndrome of hormone excess. An increasing number are detected as an incidental finding during abdominal imaging for other reasons.

Malignant islet cell tumors are best treated by resection when possible, and although no prospective randomized controlled trials are available to prove that resection prolongs life, retrospective series suggest this is the case. Certainly for patients with disabling symptoms associated with hormone excess, significant palliation can be achieved by debulking of tumor, particularly liver metastases. For patients whose tumors are too extensive to achieve cytoreduction, symptoms can usually be controlled with somatostatin analogues, particularly the long-acting form of octreotide. Hepatic artery embolization or chemoembolization is useful for patients whose primary tumor has been resected and the only remaining disease appears to be confined to the liver. The standard systemic chemotherapy regimen has been based on steptozocin and doxorubicin as reported by Moertel and colleagues in 1992, but recently octreotide in combination with interferon-α and other regimens including paclitaxel, carboplatin, and etoposide have been studied. The possible role of high-energy emitter such as high energy radiation emitters conjugated to octreotide analogues to target metastatic disease is an intriguing one and is being studied in Europe.

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Acknowledgment 

Dr. Demeure would like to thank the authors for their contributions to this work. Drs. Mittendorf and McHenry wrote the section on gastrinomas. Dr. Libutti contributed the section on genetic syndromes and Drs. Shifrin and Inabnet detailed the surgical procedures in their section. It is hoped the readers will find the material presented to be informative and useful in the treatment of patients with these rare tumors.