Neoplasms of the Endocrine Pancreas Treatment & Management
- Author: Evan S Ong, MD, MS; Chief Editor: Jules E Harris, MD, FACP, FRCPC more...
Treatment must be individualized in patients with a neoplasm of the endocrine pancreas, in order to balance management of the effects of hormone production with management of the symptoms related to the bulk of the tumor. Many pancreatic endocrine tumor syndromes are potentially life-threatening upon presentation; therefore, initial medical therapy is aimed at stabilization of the patient adequate enough for a complete preoperative evaluation.
The only effective medication for functional pancreatic endocrine neoplasms in general is a long-acting somatostatin analog (eg, octreotide). Somatostatin analog treatment can improve symptoms and quality of life in all the functional pancreatic endocrine neoplasms except somatostatinoma. Otherwise, the specific therapy for each syndrome depends on the action of the particular hormone product secreted. The use of specific pharmacologic agents (including chemotherapeutic agents) in the treatment of patients with endocrine neoplasms of the pancreas is discussed in Medication.
A study by Yao et al found that everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), significantly prolonged progression-free survival among parents with progressive advanced pancreatic neuroendocrine tumors when compared with placebo. It was associated with a low rate of severe adverse affects.
A study by Raymond et al found that continuous daily administration of sunitinib (37.5 mg) improved progression-free survival, overall survival, and objective response rate among patients with advanced pancreatic neuroendocrine tumors, compared with placebo.
A retrospective chart review by Anthony et al looked at patients with pancreatic neuroendocrine tumors with and without carcinoid syndrome and their response to treatment with octreotide LAR. Approximately 57% of patients demonstrated stable disease on octreotide LAR (dose range, 20-60 mg). Although this is a cancer not frequently seen in general endocrinology practice, its management with octreotide LAR is a helpful finding.
In a phase II study of 58 patients with well or moderately differentiated pancreatic neuroendocrine tumors, the response rate to combination treatment with the mTOR inhibitor temsirolimus and the vascular endothelial growth factor (VEGF)-A monoclonal antibody bevacizumab was 41%. At 6 months, the progression-free survival rate was 79%. Median progression-free survival was 13.2 months, and median overall survival was 34 months. The most common treatment-related adverse events were hypertension, fatigue, lymphopenia, and hyperglycemia.
Combination treatment with bevacizumab and streptozocin plus 5-fluorouracil (5-FU) in an open-label study of 34 patients with progressive, metastatic, well-differentiated pancreatic neuroendocrine tumors resulted in median progression-free survival of 23.7 months after a maximum of 24 months of follow-up. A partial response was seen in 19 (56%) patients, and 15 (44%) patients had stable disease. Overall survival at 24 months was 88%. The most common adverse events were hypertension, abdominal pain, and thromboembolic events.
Treatments for specific syndromes may include the following:
Insulinoma - Upon initial presentation, patients with insulinoma may require immediate potassium replacement and dextrose administration. Hypoglycemia can often be managed in the preoperative period by administering diazoxide, which inhibits insulin release from both normal beta cells and insulinoma cells. [88, 28]
Gastrinoma - The two main goals in the initial treatment of a patient with a gastrinoma are (1) to stabilize the general hemodynamic condition of the patient and control bleeding from gastrointestinal ulcers and (2) to establish a nonacidic gastric pH with the use of proton pump inhibitors (eg, omeprazole). 
VIPoma - The primary initial concern in the treatment of a patient who presents first with VIPoma-associated diarrhea is the replacement of volume losses and the correction of acid-base and electrolyte abnormalities. 
Glucagonoma - Patients with glucagonomas generally have nutritional depletion and often require blood transfusions, total parenteral nutrition, and preoperative control of hyperglycemia. 
Somatostatinoma - Nutritional repletion and control of hyperglycemia are important aspects of good medical care in patients with somatostatinoma syndrome.
Extralymphatic metastatic spread of pancreatic endocrine neoplasms primarily involves the liver. Therefore, cytoreductive techniques that lower serum levels of the offending gastroenteropancreatic hormone by decreasing hepatic tumor bulk often improve the patient's quality of life. Similar to surgical resection of hepatic metastases (discussed below), hepatic arterial embolization with or without chemotherapy yields impressive results in terms of tumor, hormone, and symptom regression. Cryosurgery is reported to ameliorate symptoms in patients with hepatic metastases that are resistant to chemotherapy, and the successful treatment of these lesions with radiofrequency ablation has also been reported.
Practice guidelines from the National Comprehensive Cancer Network recommend that patients being considered for surgery with possible splenectomy (eg, for treatment of glucagonoma) receive trivalent vaccine (ie, pneumococcus, Haemophilus influenzae type b, and meningococcus group C).
At the time of surgical exploration for pancreatic endocrine neoplasms, the pancreas and peripancreatic regions are completely evaluated. Dividing the gastrocolic ligament exposes the body and tail of the pancreas. This portion of the pancreas can be partially elevated out of the retroperitoneum by dividing the inferior retroperitoneal attachments to the gland. After the second portion of the duodenum is elevated out of the retroperitoneum by means of the Kocher maneuver, the pancreatic head and uncinate process are palpated bimanually. The liver is carefully assessed for evidence of metastatic disease. Potential extrapancreatic sites of tumoral involvement are evaluated in all cases, with particular attention to the duodenum; splenic hilum; small intestine and its mesentery; peripancreatic lymph nodes; and, in women, the reproductive tract.
The goals of surgical therapy for pancreatic endocrine neoplasms include (1) controlling the symptoms of hormone excess, (2) safely resecting the maximal amount of tumor mass possible, and (3) preserving the maximal amount of pancreatic parenchyma possible. Surgical management of the primary tumor is similar for the different types of pancreatic endocrine neoplasms. Surgical treatments may include the following:
Small benign lesions remote from the main pancreatic duct can be enucleated. [24, 10]
Tumors deep in the substance of the pancreatic gland, and therefore close to the main duct, have ill-defined capsules, and tumors larger than 2 cm in diameter should be treated with regional pancreatectomy.
Tumors in the body or tail of the pancreas can be managed with distal pancreatectomy. 
Lesions in the head or uncinate process of the pancreas can be resected with pancreaticoduodenectomy. [93, 94]
Tumors in the neck of the pancreas can now be managed with middle-segment pancreatectomy by oversewing the proximal pancreatic stump and draining the distal pancreatic duct via a pancreaticogastrostomy or pancreaticojejunostomy.
When a preoperatively occult gastrinoma is not found during surgical exploration, despite the use of intraoperative ultrasonography and endoscopic transduodenal illumination, longitudinal duodenotomy can be performed at the level of the second portion of the duodenum to allow eversion of the duodenum to assess duodenal microgastrinomas.  Then, the localized microgastrinomas can be resected and the duodenal defect closed. 
Rather than performing a blind regional pancreatectomy for an occult insulinoma or gastrinoma, selective provocative angiography (see Other Tests) should be performed so that the appropriate pancreatic segment can be resected, eg, distal pancreatectomy versus pancreaticoduodenectomy. 
Metastatic disease to the liver should be resected when possible. In patients with unresectable disease, radiofrequency or cryosurgical ablation should be considered.
In the past, most patients with metastatic neoplasms of the endocrine pancreas died of the hormone-excess states, but with the development of increasingly effective medical therapies to control this pathophysiologic condition (ie, proton pump inhibitors for gastrinomas; octreotide for other endocrine tumors), the major determinant of long-term patient survival is becoming the malignant nature of the tumors. For this reason, hepatic metastases are debulked with cytoreductive surgical resection. However, most surgeons believe that this aggressive approach should be reserved for patients in whom near 100% tumor removal can be achieved with reasonable safety. 
See the list below:
Pancreatic or oncologic surgeon
Patients with unresectable insulinoma may gain some symptomatic relief by eating frequent small meals with a high starch and complex carbohydrate content. In contrast to the symptoms of routine dyspepsia, diet modification rarely ameliorates the symptoms or complications of gastrinoma-associated hyperchlorhydria. Patients with VIPomas, glucagonomas, and somatostatinomas frequently have fluid, electrolyte, and nutritional deficits, and they often require parenteral supplementation.
Zollinger RM, Ellison EH. Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas. Ann Surg. 1955. 142:709.
Verner JV, Morrison AB. Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia. Am J Med. 1958. 25:374.
Ganda OP, Weir GC, Soeldner JS, et al. "Somatostatinoma": a somatostatin-containing tumor of the endocrine pancreas. N Engl J Med. 1977 Apr 28. 296(17):963-7. [Medline].
Larsson LI, Hirsch MA, Holst JJ, et al. Pancreatic somatostatinoma. Clinical features and physiological implications. Lancet. 1977 Mar 26. 1(8013):666-8. [Medline].
Howard JM, Gohara AF, Cardwell RJ. Malignant islet cell tumor of the pancreas associated with high plasma calcitonin and somatostatin levels. Surgery. 1989 Feb. 105(2 Pt 1):227-9. [Medline].
McLeod MK, Vinik AI. Calcitonin immunoreactivity and hypercalcitoninemia in two patients with sporadic, nonfamilial, gastroenteropancreatic neuroendocrine tumors. Surgery. 1992 May. 111(5):484-8. [Medline].
Mao C, Carter P, Schaefer P, et al. Malignant islet cell tumor associated with hypercalcemia. Surgery. 1995 Jan. 117(1):37-40. [Medline].
Meko JB, Norton JA. Endocrine tumors of the pancreas. Curr Opin Gen Surg. 1994. 186-94. [Medline].
Langstein HN, Norton JA, Chiang V, et al. The utility of circulating levels of human pancreatic polypeptide as a marker for islet cell tumors. Surgery. 1990 Dec. 108(6):1109-15; discussion 1115-6. [Medline].
Yeo CJ. Neoplasms of the endocrine pancreas. In: Greenfield LJ, Mulholland MW, Oldham KT, eds. Surgery: Scientific Principles and Practice, 3rd ed. Philadelphia, Pa: Lippincott. 2001: 899-913.
Pearse AG. Common cytochemical and ultrastructural characteristics of cells producing polypeptide hormones (the APUD series) and their relevance to thyroid and ultimobranchial C cells and calcitonin. Proc R Soc Lond B Biol Sci. 1968 May 14. 170(18):71-80. [Medline].
Andrew A, Kramer B, Rawdon BB. The origin of gut and pancreatic neuroendocrine (APUD) cells--the last word?. J Pathol. 1998 Oct. 186(2):117-8. [Medline].
Kloppel G, Heitz PU. Pancreatic endocrine tumors. Pathol Res Pract. 1988 Apr. 183(2):155-68. [Medline].
Heitz PU, Kasper M, Polak JM, Kloppel G. Pancreatic endocrine tumors. Hum Pathol. 1982 Mar. 13(3):263-71. [Medline].
Metz DC. Diagnosis and treatment of pancreatic neuroendocrine tumors. Semin Gastrointest Dis. 1995 Apr. 6(2):67-78. [Medline].
Norton JA, Levin B, Jensen RT. Cancer of the endocrine system. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 4th ed. Philadelphia, Pa:. Lippincott-Raven. 1993:1333-435.
Helmrath MA. Miscellaneous endocrine disorders. In: Berry SM, Bass RC, Heaton KM, eds. The Mont Reid Surgical Handbook. 4th ed. St Louis, Mo:. Mosby. 1997: 355-67.
Buchanan KD, Johnston CF, O''Hare MM, et al. Neuroendocrine tumors. A European view. Am J Med. 1986 Dec 22. 81(6B):14-22. [Medline].
Eriksson B, Oberg K, Skogseid B. Neuroendocrine pancreatic tumors. Clinical findings in a prospective study of 84 patients. Acta Oncol. 1989. 28(3):373-7. [Medline].
Weil C. Gastroenteropancreatic endocrine tumors. Klin Wochenschr. 1985 May 15. 63(10):433-59. [Medline].
Jensen RT, Norton JA. Endocrine tumors of the pancreas. In: Feldman M, Scharschmidt BF, Sleisenger M, eds. Sleisenger and Fordtran's Gastrointestinal and Liver Disease. 6th ed. Philadelphia, Pa:. WB Saunders. 1998: 871-94.
Eriksson B, Oberg K. PPomas and nonfunctioning endocrine pancreatic tumors: clinical presentation, diagnosis, and advances in management. In: Mignon M, Jensen RT, eds. Endocrine Tumors of the Pancreas. Frontiers of Gastrointestinal Research. Vol 23. Basel, Switzerland:. Karger. 1995: 208.
Phan GQ, Yeo CJ, Hruban RH, et al. Surgical experience with pancreatic and peripancreatic neuroendocrine tumors: review of 125 patients. J Gastrointest Surg. 1998 Sep-Oct. 2(5):472-82. [Medline].
Menegaux F, Schmitt G, Mercadier M, Chigot JP. Pancreatic insulinomas. Am J Surg. 1993 Feb. 165(2):243-8. [Medline].
Thompson GB, Service FJ, van Heerden JA, et al. Reoperative insulinomas, 1927 to 1992: an institutional experience. Surgery. 1993 Dec. 114(6):1196-204; discussion 1205-6. [Medline].
Metz DC, Jensen RT. Endocrine tumors of the pancreas. In: Haubrich WB, Berk F, Schaffner JE, eds. Bockus Gastroenterology. 5th ed. Philadelphia, Pa:. WB Saunders. 1994: 3002-34.
Whipple AO, Frantz VK. Adenoma of islet cells with hyperinsulinism: a review. Ann Surg. 1935. 101:1299.
Fajans SS, Vinik AI. Insulin-producing islet cell tumors. Endocrinol Metab Clin North Am. 1989 Mar. 18(1):45-74. [Medline].
Service FJ. Hypoglycemic disorders. N Engl J Med. 1995 Apr 27. 332(17):1144-52. [Medline].
Wolfe MM, Jensen RT. Zollinger-Ellison syndrome. Current concepts in diagnosis and management. N Engl J Med. 1987 Nov 5. 317(19):1200-9. [Medline].
Way L, Goldman L, Dunphy JE. Zollinger-Ellison syndrome. An analysis of twenty-five cases. Am J Surg. 1968 Aug. 116(2):293-304. [Medline].
Orloff SL, Debas HT. Advances in the management of patients with Zollinger-Ellison syndrome. Surg Clin North Am. 1995 Jun. 75(3):511-24. [Medline].
Miller LS, Vinayek R, Frucht H, et al. Reflux esophagitis in patients with Zollinger-Ellison syndrome. Gastroenterology. 1990 Feb. 98(2):341-6. [Medline].
Bieligk S, Jaffe BM. Islet cell tumors of the pancreas. Surg Clin North Am. 1995 Oct. 75(5):1025-40. [Medline].
Stabile BE, Passaro E Jr. Recurrent peptic ulcer. Gastroenterology. 1976 Jan. 70(1):124-35. [Medline].
Vinik AI, Thompson NW, Averbuch SD. Neoplasms of the gastroenteropancreatic endocrine system. In: Holland JF, Frei E, Bast RC, eds. Cancer Medicine. Philadelphia, Pa: Lea & Febiger. 1993: 1180-209.
Shimoda SS, Saunders DR, Rubin CE. The Zollinger-Ellison syndrome with steatorrhea. II. The mechanism of fat and vitamin B 12 malabsorption. Gastroenterology. 1968 Dec. 55(6):705-23. [Medline].
Wynick D, Williams SJ, Bloom SR. Symptomatic secondary hormone syndromes in patients with established malignant pancreatic endocrine tumors. N Engl J Med. 1988 Sep 8. 319(10):605-7. [Medline].
Chiang HC, O''Dorisio TM, Huang SC, et al. Multiple hormone elevations in Zollinger-Ellison syndrome. Prospective study of clinical significance and of the development of a second symptomatic pancreatic endocrine tumor syndrome. Gastroenterology. 1990 Dec. 99(6):1565-75. [Medline].
O''Dorisio TM, Mekhjian HS, Gaginella TS. Medical therapy of VIPomas. Endocrinol Metab Clin North Am. 1989 Jun. 18(2):545-56. [Medline].
Higgins GA, Recant L, Fischman AB. The glucagonoma syndrome: surgically curable diabetes. Am J Surg. 1979 Jan. 137(1):142-8. [Medline].
Wilkinson DS. Necrolytic migratory erythema with carcinoma of the pancreas. Trans St Johns Hosp Dermatol Soc. 1973. 59(2):244-50. [Medline].
Stacpoole PW. The glucagonoma syndrome: clinical features, diagnosis, and treatment. Endocr Rev. 1981 Summer. 2(3):347-61. [Medline].
Leichter SB. Clinical and metabolic aspects of glucagonoma. Medicine (Baltimore). 1980 Mar. 59(2):100-13. [Medline].
Guillausseau PJ, Guillausseau C, Villet R, et al. [Glucagonomas. Clinical, biological, anatomopathological and therapeutic aspects (general review of 130 cases]. Gastroenterol Clin Biol. 1982 Dec. 6(12):1029-41. [Medline].
Vinik AI, Strodel WE, Eckhauser FE, et al. Somatostatinomas, PPomas, neurotensinomas. Semin Oncol. 1987 Sep. 14(3):263-81. [Medline].
Brodish RJ, Kuvshinoff BW, McFadden DW, Fink AS. Somatostatin inhibits cholecystokinin-induced pancreatic protein secretion via cholinergic pathways. Pancreas. 1995 May. 10(4):401-6. [Medline].
Boden G, Shimoyama R. Somatostatinoma. In: Cohen S, Soloway RD, eds. Hormone-Producing Tumors of the Gastrointestinal Tract. New York, NY: Churchill Livingstone. 1985: 85.
Long PP, Hruban RH, Lo R, et al. Chromosome analysis of nine endocrine neoplasms of the pancreas. Cancer Genet Cytogenet. 1994 Oct. 77(1):55-9. [Medline].
Zeiger MA, Norton JA. Gs alpha--identification of a gene highly expressed by insulinoma and other endocrine tumors. Surgery. 1993 Aug. 114(2):458-62; discussion 462-3. [Medline].
Eubanks PJ, Sawicki MP, Samara GJ, et al. Pancreatic endocrine tumors with loss of heterozygosity at the multiple endocrine neoplasia type I locus. Am J Surg. 1997 Jun. 173(6):518-20. [Medline].
Miller JA, Norton JA. Multiple endocrine neoplasia. Cancer Treat Res. 1997. 90:213-25. [Medline].
Nakeeb A, Lillemoe KD, Yeo CJ. Neoplasms of the exocrine pancreas. In: Greenfield LJ, Mulholland MW, Oldham KT, eds. Surgery: Scientific Principles and Practice. 3rd ed. Philadelphia, Pa:. Lippincott-Raven. 2001:885-99.
[Guideline] NCCN Clinical Practice Guidelines in Oncology. Neuroendocrine Tumors Version 1.2015. National Comprehensive Cancer Network. Available at http://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf. Accessed: December 21, 2014.
Ekeblad S, Skogseid B, Dunder K, Oberg K, Eriksson B. Prognostic factors and survival in 324 patients with pancreatic endocrine tumor treated at a single institution. Clin Cancer Res. 2008 Dec 1. 14(23):7798-803. [Medline]. [Full Text].
Warner RR, Curran T, Shafir MK, et al. Serum and ascites chromogranin-A in patients with metastatic neuroendocrine tumors. Pancreas. 2011 May. 40(4):622-6. [Medline].
Mekhjian HS, O''Dorisio TM. VIPoma syndrome. Semin Oncol. 1987 Sep. 14(3):282-91. [Medline].
Krejs GJ. VIPoma syndrome. Am J Med. 1987 May 29. 82(5B):37-48. [Medline].
Krejs GJ, Orci L, Conlon JM, et al. Somatostatinoma syndrome. Biochemical, morphologic and clinical features. N Engl J Med. 1979 Aug 9. 301(6):285-92. [Medline].
Naswa N, Sharma P, Kumar A, et al. Gallium-68-DOTA-NOC PET/CT of patients with gastroenteropancreatic neuroendocrine tumors: a prospective single-center study. AJR Am J Roentgenol. 2011 Nov. 197(5):1221-8. [Medline].
Pelley RJ, Bukowski RM. Recent advances in diagnosis and therapy of neuroendocrine tumors of the gastrointestinal tract. Curr Opin Oncol. 1997 Jan. 9(1):68-74. [Medline].
Moore NR, Rogers CE, Britton BJ. Magnetic resonance imaging of endocrine tumours of the pancreas. Br J Radiol. 1995 Apr. 68(808):341-7. [Medline].
Berger JF, Laissy JP, Limot O, et al. Differentiation between multiple liver hemangiomas and liver metastases of gastrinomas: value of enhanced MRI. J Comput Assist Tomogr. 1996 May-Jun. 20(3):349-55. [Medline].
Gibril F, Reynolds JC, Doppman JL, et al. Somatostatin receptor scintigraphy: its sensitivity compared with that of other imaging methods in detecting primary and metastatic gastrinomas. A prospective study. Ann Intern Med. 1996 Jul 1. 125(1):26-34. [Medline].
Mitchell DG. Diagnosis and staging of pancreatic tumors by magnetic resonance imaging. Neoplasms of the Digestive System. 1998. Lippincott Raven:
Krausz Y, Bar-Ziv J, de Jong RB, et al. Somatostatin-receptor scintigraphy in the management of gastroenteropancreatic tumors. Am J Gastroenterol. 1998 Jan. 93(1):66-70. [Medline].
Frilling A, Malago M, Martin H, Broelsch CE. Use of somatostatin receptor scintigraphy to image extrahepatic metastases of neuroendocrine tumors. Surgery. 1998 Dec. 124(6):1000-4. [Medline].
Glover JR, Shorvon PJ, Lees WR. Endoscopic ultrasound for localisation of islet cell tumours. Gut. 1992 Jan. 33(1):108-10. [Medline].
Rosch T, Lightdale CJ, Botet JF, et al. Localization of pancreatic endocrine tumors by endoscopic ultrasonography. N Engl J Med. 1992 Jun 25. 326(26):1721-6. [Medline].
Imamura M, Takahashi K, Adachi H, et al. Usefulness of selective arterial secretin injection test for localization of gastrinoma in the Zollinger-Ellison syndrome. Ann Surg. 1987 Mar. 205(3):230-9. [Medline].
Thom AK, Norton JA, Doppman JL, et al. Prospective study of the use of intraarterial secretin injection and portal venous sampling to localize duodenal gastrinomas. Surgery. 1992 Dec. 112(6):1002-8; discussion 1008-9. [Medline].
Pereira PL, Roche AJ, Maier GW, et al. Insulinoma and islet cell hyperplasia: value of the calcium intraarterial stimulation test when findings of other preoperative studies are negative. Radiology. 1998 Mar. 206(3):703-9. [Medline].
Vinik AI, Delbridge L, Moattari R, et al. Transhepatic portal vein catheterization for localization of insulinomas: a ten-year experience. Surgery. 1991 Jan. 109(1):1-11; discussion 111. [Medline].
Fraker DL, Alexander HR. The surgical approach to endocrine tumors of the pancreas. Semin Gastrointest Dis. 1995 Apr. 6(2):102-13. [Medline].
Gooding GA. Adrenal, pancreatic, and scrotal ultrasound in endocrine disease. Radiol Clin North Am. 1993 Sep. 31(5):1069-83. [Medline].
Norton JA, Sigel B, Baker AR, et al. Localization of an occult insulinoma by intraoperative ultrasonography. Surgery. 1985 Mar. 97(3):381-4. [Medline].
Grant CS, van Heerden J, Charboneau JW, et al. Insulinoma. The value of intraoperative ultrasonography. Arch Surg. 1988 Jul. 123(7):843-8. [Medline].
Nasir A, Helm J, Turner L, et al. RUNX1T1: a novel predictor of liver metastasis in primary pancreatic endocrine neoplasms. Pancreas. 2011 May. 40(4):627-33. [Medline].
Somogyi L, Mishra G. Diagnosis and staging of islet cell tumors of the pancreas. Curr Gastroenterol Rep. 2000 Apr. 2(2):159-64. [Medline].
Macdonald JS, Haller D, McDougall IR. Endocrine system: pancreatic islet cell tumors. In: Abeloff MD, Armitage JO, Lichter AS, eds. Clinical Oncology. 2nd ed. New York, NY:. Churchill-Livingstone. 2000: 1384-97.
Modlin IM, Kidd M, Drozdov I, Siddique ZL, Gustafsson BI. Pharmacotherapy of neuroendocrine cancers. Expert Opin Pharmacother. 2008 Oct. 9(15):2617-26. [Medline].
Vinik AI, Moattari AR. Treatment of endocrine tumors of the pancreas. Endocrinol Metab Clin North Am. 1989 Jun. 18(2):483-518. [Medline].
Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10. 364(6):514-23. [Medline].
Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10. 364(6):501-13. [Medline].
Anthony L, Vinik AI. Evaluating the characteristics and the management of patients with neuroendocrine tumors receiving octreotide LAR during a 6-year period. Pancreas. 2011 Oct. 40(7):987-94. [Medline].
Hobday TJ, Qin R, Reidy-Lagunes D, Moore MJ, Strosberg J, Kaubisch A, et al. Multicenter Phase II Trial of Temsirolimus and Bevacizumab in Pancreatic Neuroendocrine Tumors. J Clin Oncol. 2014 Dec 8. [Medline].
Ducreux M, Dahan L, Smith D, O'Toole D, Lepère C, Dromain C, et al. Bevacizumab combined with 5-FU/streptozocin in patients with progressive metastatic well-differentiated pancreatic endocrine tumours (BETTER trial) - A phase II non-randomised trial. Eur J Cancer. 2014 Dec. 50(18):3098-106. [Medline].
Boden G. Glucagonomas and insulinomas. Gastroenterol Clin North Am. 1989 Dec. 18(4):831-45. [Medline].
Moertel CG, Johnson CM, McKusick MA, et al. The management of patients with advanced carcinoid tumors and islet cell carcinomas. Ann Intern Med. 1994 Feb 15. 120(4):302-9. [Medline].
Bilchik AJ, Sarantou T, Foshag LJ, et al. Cryosurgical palliation of metastatic neuroendocrine tumors resistant to conventional therapy. Surgery. 1997 Dec. 122(6):1040-7; discussion 1047-8. [Medline].
Mazzaglia PJ, Berber E, Milas M, Siperstein AE. Laparoscopic radiofrequency ablation of neuroendocrine liver metastases: a 10-year experience evaluating predictors of survival. Surgery. 2007 Jul. 142(1):10-9. [Medline].
Lillemoe KD, Kaushal S, Cameron JL, et al. Distal pancreatectomy: indications and outcomes in 235 patients. Ann Surg. 1999 May. 229(5):693-8; discussion 698-700. [Medline].
Phan GQ, Yeo CJ, Cameron JL, et al. Pancreaticoduodenectomy for selected periampullary neuroendocrine tumors: fifty patients. Surgery. 1997 Dec. 122(6):989-96; discussion, 996-7. [Medline].
Udelsman R, Yeo CJ, Hruban RH, et al. Pancreaticoduodenectomy for selected pancreatic endocrine tumors. Surg Gynecol Obstet. 1993 Sep. 177(3):269-78. [Medline].
Sugg SL, Norton JA, Fraker DL, et al. A prospective study of intraoperative methods to diagnose and resect duodenal gastrinomas. Ann Surg. 1993 Aug. 218(2):138-44. [Medline].
Farley DR, van Heerden JA, Grant CS, Thompson GB. Extrapancreatic gastrinomas. Surgical experience. Arch Surg. 1994 May. 129(5):506-11; discussion 511-2. [Medline].
Gibril F, Doppman JL, Jensen RT. Recent advances in the treatment of metastatic pancreatic endocrine tumors. Semin Gastrointest Dis. 1995 Apr. 6(2):114-21. [Medline].
Stefanini P, Carboni M, Patrassi N, Basoli A. Beta-islet cell tumors of the pancreas: results of a study on 1,067 cases. Surgery. 1974 Apr. 75(4):597-609. [Medline].
Fjallskog ML, Sundin A, Westlin JE. Treatment of malignant endocrine pancreatic tumors with a combination of alpha-interferon and somatostatin analogs. Med Oncol. 2002. 19(1):35-42.
Moertel CG, Hanley JA, Johnson LA. Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1980 Nov 20. 303(21):1189-94. [Medline].
Moertel CG, Lefkopoulo M, Lipsitz S, et al. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992 Feb 20. 326(8):519-23. [Medline].
Fjallskog ML, Janson ET, Falkmer UG, Vatn MH, Oberg KE, Eriksson BK. Treatment with combined streptozotocin and liposomal doxorubicin in metastatic endocrine pancreatic tumors. Neuroendocrinology. 2008. 88(1):53-8. [Medline].
Rivera E, Ajani JA. Doxorubicin, streptozocin, and 5-fluorouracil chemotherapy for patients with metastatic islet-cell carcinoma. Am J Clin Oncol. 1998 Feb. 21(1):36-8. [Medline].
Arvold ND, Willett CG, Fernandez-Del Castillo C, Ryan DP, Ferrone CR, Clark JW, et al. Pancreatic Neuroendocrine Tumors With Involved Surgical Margins: Prognostic Factors and the Role of Adjuvant Radiotherapy. Int J Radiat Oncol Biol Phys. 2012 Mar 11. [Medline].
Welbourne RB, Wood SM, Polak JM. Pancreatic endocrine tumors. In: Bloom SR, Polak JM, eds. Gut Hormones. 2nd ed. New York, NY: Churchill-Livingstone. 1981: 547-54.
Rothmund M, Angelini L, Brunt LM, et al. Surgery for benign insulinoma: an international review. World J Surg. 1990 May-Jun. 14(3):393-8; discussion 398-9. [Medline].
McGuigan JE. Zollinger-Ellison syndrome and other hypersecretory states. In: Feldman M, Scharschmidt BF, Sleisenger M, eds. Sleisenger and Fordtran's Gastrointestinal and Liver Disease. 6th ed. Philadelphia, Pa:. WB Saunders. 1998:679-95.
Stabile BE, Passaro E Jr. Benign and malignant gastrinoma. Am J Surg. 1985 Jan. 149(1):144-50. [Medline].
Fraker DL, Norton JA, Alexander HR, et al. Surgery in Zollinger-Ellison syndrome alters the natural history of gastrinoma. Ann Surg. 1994 Sep. 220(3):320-8; discussion 328-30. [Medline].
Weber HC, Venzon DJ, Lin JT, et al. Determinants of metastatic rate and survival in patients with Zollinger- Ellison syndrome: a prospective long-term study. Gastroenterology. 1995 Jun. 108(6):1637-49. [Medline].
Jensen RT, Fraker DL. Zollinger-Ellison syndrome. Advances in treatment of gastric hypersecretion and the gastrinoma. JAMA. 1994 May 11. 271(18):1429-35. [Medline].
Holst JJ. Glucagon-producing tumors. In: Cohen S, Soloway RD, eds. Hormone-Producing Tumors of the Gastrointestinal Tract. New York, NY: Churchill-Livingstone. 1985: 57.
Verner JV, Morrison AB. Endocrine pancreatic islet disease with diarrhea. Report of a case due to diffuse hyperplasia of nonbeta islet tissue with a review of 54 additional cases. Arch Intern Med. 1974 Mar. 133(3):492-9. [Medline].
Long RG, Bryant MG, Mitchell SJ, et al. Clinicopathological study of pancreatic and ganglioneuroblastoma tumours secreting vasoactive intestinal polypeptide (vipomas). Br Med J (Clin Res Ed). 1981 May 30. 282(6278):1767-71. [Medline].
Kent RB 3rd, van Heerden JA, Weiland LH. Nonfunctioning islet cell tumors. Ann Surg. 1981 Feb. 193(2):185-90. [Medline].
Tomassetti P, Campana D, Piscitelli L. Endocrine pancreatic tumors: factors correlated with survival. Ann Oncol. 2005 Nov. 16(11):1806-10.
Abood GJ, Go A, Malhotra D, Shoup M. The surgical and systemic management of neuroendocrine tumors of the pancreas. Surg Clin North Am. 2009 Feb. 89(1):249-66, x. [Medline].
Becker M, Aron DC. Ectopic ACTH syndrome and CRH-mediated Cushing''s syndrome. Endocrinol Metab Clin North Am. 1994 Sep. 23(3):585-606. [Medline].
Canavese G, Azzoni C, Pizzi S. p27: a potential main inhibitor of cell proliferation in digestive endocrine tumors but not a marker of benign behavior. Hum Pathol. 2001 Oct. 32(10):1094-101. [Medline].
Evers BM, Rady PL, Sandoval K, et al. Gastrinomas demonstrate amplification of the HER-2/neu proto-oncogene. Ann Surg. 1994 Jun. 219(6):596-601; discussion 602-4. [Medline].
Fedorak IJ, Ko TC, Gordon D, et al. Localization of islet cell tumors of the pancreas: a review of current techniques. Surgery. 1993 Mar. 113(3):242-9. [Medline].
Mallinson CN, Bloom SR, Warin AP, et al. A glucagonoma syndrome. Lancet. 1974 Jul 6. 2(7871):1-5. [Medline].
Maton PN. The use of the long-acting somatostatin analogue, octreotide acetate, in patients with islet cell tumors. Gastroenterol Clin North Am. 1989 Dec. 18(4):897-922. [Medline].
Mazzaglia PJ, Berber E, Milas M, Siperstein AE. Laparoscopic radiofrequency ablation of neuroendocrine liver metastases: a 10-year experience evaluating predictors of survival. Surgery. 2007 Jul. 142(1):10-9. [Medline].
Oberg K, Eriksson B. Medical treatment of neuroendocrine gut and pancreatic tumors. Acta Oncol. 1989. 28(3):425-31. [Medline].
Pless J, Bauer W, Briner U, et al. Chemistry and pharmacology of SMS 201-995, a long-acting octapeptide analogue of somatostatin. Scand J Gastroenterol Suppl. 1986. 119:54-64. [Medline].
Rivier J, Spiess J, Thorner M, Vale W. Characterization of a growth hormone-releasing factor from a human pancreatic islet tumour. Nature. 1982 Nov 18. 300(5889):276-8. [Medline].
Schein P, Kahn R, Gorden P, et al. Streptozotocin for malignant insulinomas and carcinoid tumor. Report of eight cases and review of the literature. Arch Intern Med. 1973 Oct. 132(4):555-61. [Medline].
Thorner MO, Perryman RL, Cronin MJ, et al. Somatotroph hyperplasia. Successful treatment of acromegaly by removal of a pancreatic islet tumor secreting a growth hormone-releasing factor. J Clin Invest. 1982 Nov. 70(5):965-77. [Medline].
Wilder RM, Allan FN, Power WH. Carcinoma of the islands of the pancreas: Hyperinsulinism and hypoglycemia. JAMA. 1927. 89:348.
Yeo CJ. Islet cell tumors of the pancreas. In: Niederhuber JE, ed. Current Therapy in Oncology. St. Louis, Mo: Mosby-Year Book; 1993:. 272.