Incidence and Mortality
They are uncommon cancers with about 1,000 new cases per year in the United States. They account for 3% to 5% of pancreatic malignancies and overall have a better prognosis than the more common pancreatic exocrine tumors.[1,2] Five-year survival is about 55% when the tumors are localized and resected but only about 15% when the tumors are not resectable. Overall 5-year survival rate is about 42%.
Figure 1. Cancer of the Pancreas: Relative Survival Rates (%) by Histologic Subtype, Ages 20+, 12 SEER Areas, 1988-2001. Key, C. Ch 7: Cancer of the pancreas. In: Ries LAG, Young JL, Keel GE, et al. (eds). SEER Survival Monograph: Cancer Survival Among Adults: U.S. SEER Program, 1988-2001, Patient and Tumor Characteristics. National Cancer Institute, SEER Program, NIH Pub. No. 07-6215, Bethesda, MD, 2007.
Tumors of the endocrine pancreas are a collection of tumor cell types collectively referred to as pancreatic neuroendocrine tumors (NETs). These tumors originate in islet cells. Although they may be similar or identical in histologic appearance to carcinoid tumors of the gastrointestinal tract, differences in their underlying biology and likely differences in response to therapeutic agents suggest that they should be treated and investigated as a distinct entity.
Most pancreatic NETs are sporadic, but some occur as part of the autosomal dominant multiple endocrine neoplasia type-1 (MEN-1) inherited syndrome consisting of tumors of the anterior pituitary, parathyroid, and endocrine pancreas glands, which results from the inactivation of the tumor suppressor gene Menin located on chromosome 11q13. When part of the MEN-1 syndrome, there may be multiple pancreatic tumors.
Islet tumors may either be functional (produce one or more active hormones) or nonfunctional. The functional tumors, which usually present with symptoms of hormone hypersecretion, include:
Most islet cell cancers are functional, but about 15% are nonfunctional, with presentations similar to the far more common exocrine adenocarcinomas of the pancreas.[5,6,7] Because of the presence of several cell types in the pancreatic islets (alpha, beta, delta, A, B, C, D, E, F), the term, islet cell tumors, refers to at least five distinct cancers that, when functional, produce unique metabolic and clinical characteristics. The clinical manifestations in functional tumors may result from the distinctive metabolic effects of the polypeptide(s) secreted by the cancer cells rather than from tumor bulk or metastatic disease. Functional tumors may even be too small to be detected by conventional imaging techniques.
Nonfunctional tumors tend to present at later clinical stages with symptoms attributable to mass effect or metastases. Although nonfunctional tumors do not produce specific clinical syndromes, they may secrete inactive amine and peptide products such as the following:
- Alpha-subunit of human chorionic gonadotropin (alpha-hCG).
- Neuron-specific enolase.
- Pancreatic polypeptide.
- Chromogranin A.
The frequent long delays between initial symptoms and diagnosis and the varied effects of the polypeptides secreted often necessitate involvement of multiple surgical and medical subspecialties. Surgery is the only curative modality. Surgery is often used even in the setting of metastatic disease to alleviate the symptoms of hormonal hypersecretion. Effective palliation may be achieved because of the slow-growing nature of the majority of these tumors and the potential use of antihormonal pharmacologic therapy (e.g., cimetidine in the ulcer-producing Zollinger-Ellison syndrome). In patients with indolent, slow-growing metastatic islet cell tumors, the best therapy may be careful observation, and no treatment until palliation is required. In patients with MEN-1 in which 85% have pancreatic islet cell tumors, 90% have hyperparathyroidism, and 65% have pituitary tumors, and they are less likely to be cured by pancreatic resection than are patients with sporadic islet cell tumors. With the exception of pain relief from bone metastases, radiation therapy has a limited role in this disease.
Tumor localization and staging studies include imaging with computed tomography (CT) with or without magnetic resonance imaging (MRI), and endoscopic ultrasound. In addition, somatostatin-receptor scintigraphy and single-photon emission CT may be useful adjuncts. However, somatostatin-receptor scintigraphy has diminished utility in localizing insulinomas versus other pancreatic NETs, since insulinomas often have a low density of somatostatin receptors. If the noninvasive tests do not reveal a tumor, but clinical suspicion remains high, more invasive and technically demanding tests, such as selective arteriography or selective arterial stimulation (with a secretagogue specific for the suspected tumor type), may be useful.
Some of the tumor types have unique characteristics that require specific approaches in their diagnosis and initial evaluation.
Diagnosis is dependent on elevated serum gastrin and elevated gastric acid levels. Provocative testing with calcium and secretin shows considerable overlap, and the value of these tests is limited. Zollinger-Ellison syndrome (ZES) is a syndrome of unrelenting peptic ulcer disease, diarrhea, and gastric hyperacidity, associated with a gastrin-producing tumor. (Refer to the Diarrhea section in the PDQ summary on Gastrointestinal Complications for more information.) It accounts for less than 1% of all peptic ulcer disease. About 15% to 35% of gastrinomas are associated with the MEN-1 syndrome and up to 50% are malignant. Up to 33% of gastrinomas have liver metastases.
- BAO:MAO ≥ = 0.6 (Basal Acid Output:Maximal Acid Output).
- Overnight AO ≥ = 100 mmol.
- BAO ≥ = 10 mmol/hr.
- Serum gastrin 10 times normal or >500 pg/mL (the accuracy of gastrin assays may vary widely).
- Secretin test: 1 unit/kg IV rapid injection: Positive = 100% increase in gastrin within 10 minutes; 2 units/kg: Positive = 100% increase over baseline.
- Elevated human chorionic gonadotropin levels.
Insulinomas are far more likely to be benign than malignant. Only 10% are multiple, and only 10% are malignant. About 5% to 8% are associated with MEN-1 syndrome. The clinical manifestations are those of hypoglycemia, which results from inappropriate secretion of insulin by the tumor. Fasting hypoglycemia (<40 mg/dL) associated with an elevated insulin level (in the absence of exogenous administration of insulin) is pathognomonic. Measurement of plasma proinsulin may be helpful for diagnosing insulin-secreting carcinomas. These tumors are usually slow-growing tumors and, when localized to the pancreas or regional lymph nodes, can be cured with pancreatic resection.
The approach to management depends on carefully performed preoperative localization studies and the findings at exploratory laparotomy. In a retrospective case series of 30 patients with 32 pancreatic insulinomas, the combination of preoperative dual-phase thin-section multidetector CT and endoscopic sonography correctly identified and localized all of the tumors. These tests, with or without MRI, have replaced older, more invasive, and technically challenging tests, such as percutaneous transhepatic portal venous sampling and arterial stimulation with venous sampling except for unusual circumstances in which the imaging tests are unsuccessful.[4,9]
Glucagonoma is the third most common endocrine-secreting islet cell tumor. About 75% of glucagonomas are malignant. Necrolytic migratory erythema, hyperglycemia, and venous thrombosis comprise a virtually diagnostic triad. A serum glucagon level greater than 1000 pg/mL confirms the diagnosis. These tumors tend to be large and easily visible on CT scan. Somatostatin receptor scintigraphy scanning may be a useful adjunct in detecting metastases.
Miscellaneous islet cell tumors
These tumors are rare but have defined clinical syndromes associated with specific production of polypeptide hormone production by islet cell tumors. Because of their rarity and similar approaches to management, they are grouped in the section on treatment. Miscellaneous tumors include the following:
- VIPoma (Verner-Morrison Syndrome) is characterized by watery diarrhea, hypokalemia, and achlorhydria.
A serum vasoactive intestinal peptide (VIP) greater than 200 pg/mL is diagnostic. These tumors can generally be easily localized by CT scan. Somatostatin receptor scintigraphy scanning may be a useful adjunct in detecting metastases.
These tumors are particularly rare. They often present with diarrhea, steatorrhea, diabetes, and/or gallstones. Decreased pancreatic secretion of enzymes and bicarbonate accounts for the diarrhea and steatorrhea. Somatostatin-mediated inhibition of cholecystokinin leads to gallstone formation. Somatostatin also inhibits insulin, producing hyperglycemia. The diagnosis is made by a fasting serum somatostatin level greater than 100 pg/mL. CT scan, MRI, and endoscopic ultrasound can usually help localize and stage the tumor. Most of these tumors are malignant and have metastases at diagnosis.
- Ries LAG, Young JL, Keel GE, et al., eds.: SEER Survival Monograph: Cancer Survival Among Adults: U. S. SEER Program, 1988-2001, Patient and Tumor Characteristics. Bethesda, MD: National Cancer Institute, 2007. NIH Pub. No. 07-6215.
- Exocrine and endocrine pancreas. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 241-9.
- Kulke MH, Siu LL, Tepper JE, et al.: Future directions in the treatment of neuroendocrine tumors: consensus report of the National Cancer Institute Neuroendocrine Tumor clinical trials planning meeting. J Clin Oncol 29 (7): 934-43, 2011.
- Davies K, Conlon KC: Neuroendocrine tumors of the pancreas. Curr Gastroenterol Rep 11 (2): 119-27, 2009.
- Hochwald SN, Zee S, Conlon KC, et al.: Prognostic factors in pancreatic endocrine neoplasms: an analysis of 136 cases with a proposal for low-grade and intermediate-grade groups. J Clin Oncol 20 (11): 2633-42, 2002.
- O'Grady HL, Conlon KC: Pancreatic neuroendocrine tumours. Eur J Surg Oncol 34 (3): 324-32, 2008.
- King CM, Reznek RH, Dacie JE, et al.: Imaging islet cell tumours. Clin Radiol 49 (5): 295-303, 1994.
- Gouya H, Vignaux O, Augui J, et al.: CT, endoscopic sonography, and a combined protocol for preoperative evaluation of pancreatic insulinomas. AJR Am J Roentgenol 181 (4): 987-92, 2003.
- Nikfarjam M, Warshaw AL, Axelrod L, et al.: Improved contemporary surgical management of insulinomas: a 25-year experience at the Massachusetts General Hospital. Ann Surg 247 (1): 165-72, 2008.