VIPoma: Clinical manifestations, diagnosis, and management
- Stephen E Goldfinger, MD
Stephen E Goldfinger, MD
- Professor of Medicine Emeritus
- Harvard Medical School
- Section Editors
- Kenneth K Tanabe, MD
Kenneth K Tanabe, MD
- Section Editor — Gastrointestinal Malignancies
- Professor of Surgery
- Harvard Medical School
- David C Whitcomb, MD, PhD
David C Whitcomb, MD, PhD
- Section Editor — Pancreatic Diseases
- Professor of Medicine
- University of Pittsburgh School of Medicine
VIPomas are rare functioning neuroendocrine tumors that secrete vasoactive intestinal polypeptide (VIP). This topic will review the clinical manifestations, diagnosis, and management of VIPomas. An overview of the clinical manifestations, diagnosis, and management of pancreatic neuroendocrine tumors and other functioning pancreatic neuroendocrine tumors are discussed in detail, separately. (See "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine tumors (islet-cell tumors)" and "Surgical resection of sporadic pancreatic neuroendocrine tumors" and "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion" and "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion" and "Insulinoma" and "Somatostatinoma: Clinical manifestations, diagnosis, and management" and "Glucagonoma and the glucagonoma syndrome" and "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis" and "Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)".)
VIPomas are detected in 1 in 10 million people per year . The majority of VIPomas arise within the pancreas, and are classified as functioning pancreatic neuroendocrine (islet cell) tumors. In adults, VIPomas are intrapancreatic in over 95 percent of cases. However, other VIP-secreting tumors have been reported, including lung cancer, colorectal cancer, ganglioneuroblastoma, pheochromocytoma, hepatoma, and adrenal tumors. In children, VIPomas can occur in sympathetic ganglia and the adrenal glands . (See "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine tumors (islet-cell tumors)", section on 'Classification and nomenclature'.)
VIPomas are usually diagnosed between 30 and 50 years of age in adults and between two and four years of age in children. Symptomatic pancreatic VIPomas are usually solitary, more than 3 cm in diameter, and occur in the tail of the pancreas in 75 percent of patients. Approximately 60 to 80 percent of VIPomas have metastasized by the time of diagnosis [2,3]. VIPomas usually occur as isolated tumors, but in 5 percent of patients they are part of the multiple endocrine neoplasia syndrome type 1 (MEN1) and occur in association with parathyroid and pituitary tumors, gastrinoma, and other tumors . (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis".)
The VIPoma syndrome is caused by excessive, unregulated secretion of vasoactive intestinal polypeptide (VIP) by the tumor. However, other substances, such as prostaglandin E2, may occasionally be secreted by the tumors . VIP is a 28 amino acid polypeptide that binds to high affinity receptors on intestinal epithelial cells, leading to activation of cellular adenylate cyclase and cAMP production. This results in net fluid and electrolyte secretion into the lumen, resulting in secretory diarrhea and hypokalemia [5,6]. Other biologic actions of VIP including vasodilation, inhibition of gastric acid secretion, bone resorption, and enhanced glycogenolysis are responsible for flushing as well as laboratory findings of hypochlorhydria, hypercalcemia, and hyperglycemia in patients with VIPomas (table 1). (See "Vasoactive intestinal polypeptide" and 'Clinical features' below and "Physiology of gastric acid secretion".)
Clinical manifestations — The majority of patients with VIPoma have VIPoma syndrome, which is also called the pancreatic cholera syndrome, Verner-Morrison syndrome, and the watery diarrhea, hypokalemia, and hypochlorhydria or achlorhydria (WDHA) syndrome. VIPoma syndrome is characterized by watery diarrhea that persists with fasting. Stools are tea-colored and odorless with stool volumes exceeding 700 mL/day. In 70 percent of patients, stool volume can exceed 3000 mL/day [7-9]. Abdominal pain is mild or absent. Associated symptoms include flushing episodes in 20 percent of patients and symptoms related to hypokalemia and dehydration, such as lethargy, nausea, vomiting, muscle weakness, and muscle cramps (table 1). (See "Clinical manifestations and treatment of hypokalemia in adults".)
- Friesen SR. Update on the diagnosis and treatment of rare neuroendocrine tumors. Surg Clin North Am 1987; 67:379.
- Perry RR, Vinik AI. Clinical review 72: diagnosis and management of functioning islet cell tumors. J Clin Endocrinol Metab 1995; 80:2273.
- Smith SL, Branton SA, Avino AJ, et al. Vasoactive intestinal polypeptide secreting islet cell tumors: a 15-year experience and review of the literature. Surgery 1998; 124:1050.
- Lecorguillé M, Hammel P, Couvelard A, et al. [Jejunal vipoma]. Gastroenterol Clin Biol 2004; 28:797.
- Meriney DK. Pathophysiology and management of VIPoma: a case study. Oncol Nurs Forum 1996; 23:941.
- Bloom SR, Yiangou Y, Polak JM. Vasoactive intestinal peptide secreting tumors. Pathophysiological and clinical correlations. Ann N Y Acad Sci 1988; 527:518.
- Krejs GJ. VIPoma syndrome. Am J Med 1987; 82:37.
- Grier JF. WDHA (watery diarrhea, hypokalemia, achlorhydria) syndrome: clinical features, diagnosis, and treatment. South Med J 1995; 88:22.
- Mekhjian HS, O'Dorisio TM. VIPoma syndrome. Semin Oncol 1987; 14:282.
- Donowitz M, Kokke FT, Saidi R. Evaluation of patients with chronic diarrhea. N Engl J Med 1995; 332:725.
- Khashab MA, Yong E, Lennon AM, et al. EUS is still superior to multidetector computerized tomography for detection of pancreatic neuroendocrine tumors. Gastrointest Endosc 2011; 73:691.
- Legmann P, Vignaux O, Dousset B, et al. Pancreatic tumors: comparison of dual-phase helical CT and endoscopic sonography. AJR Am J Roentgenol 1998; 170:1315.
- Dromain C, de Baere T, Baudin E, et al. MR imaging of hepatic metastases caused by neuroendocrine tumors: comparing four techniques. AJR Am J Roentgenol 2003; 180:121.
- Kirkwood KS, Debas HT. Neuroendocrine tumors: common presentations of uncommon diseases. Compr Ther 1995; 21:719.
- King CM, Reznek RH, Dacie JE, Wass JA. Imaging islet cell tumours. Clin Radiol 1994; 49:295.
- Wang SC, Parekh JR, Zuraek MB, et al. Identification of unknown primary tumors in patients with neuroendocrine liver metastases. Arch Surg 2010; 145:276.
- Reidy-Lagunes DL, Gollub MJ, Saltz LB. Addition of octreotide functional imaging to cross-sectional computed tomography or magnetic resonance imaging for the detection of neuroendocrine tumors: added value or an anachronism? J Clin Oncol 2011; 29:e74.
- Nikou GC, Toubanakis C, Nikolaou P, et al. VIPomas: an update in diagnosis and management in a series of 11 patients. Hepatogastroenterology 2005; 52:1259.
- Falconi M, Bartsch DK, Eriksson B, et al. ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms of the digestive system: well-differentiated pancreatic non-functioning tumors. Neuroendocrinology 2012; 95:120.
- Ramage JK, Ahmed A, Ardill J, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut 2012; 61:6.
- Öberg K, Knigge U, Kwekkeboom D, et al. Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23 Suppl 7:vii124.
- Rindi G, Klöppel G, Alhman H, et al. TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2006; 449:395.
- Strosberg JR, Cheema A, Weber JM, et al. Relapse-free survival in patients with nonmetastatic, surgically resected pancreatic neuroendocrine tumors: an analysis of the AJCC and ENETS staging classifications. Ann Surg 2012; 256:321.
- Strosberg JR, Cheema A, Weber J, et al. Prognostic validity of a novel American Joint Committee on Cancer Staging Classification for pancreatic neuroendocrine tumors. J Clin Oncol 2011; 29:3044.
- Eriksson B, Oberg K. An update of the medical treatment of malignant endocrine pancreatic tumors. Acta Oncol 1993; 32:203.
- O'Dorisio TM, Mekhjian HS, Gaginella TS. Medical therapy of VIPomas. Endocrinol Metab Clin North Am 1989; 18:545.
- Kraenzlin ME, Ch'ng JL, Wood SM, et al. Long-term treatment of a VIPoma with somatostatin analogue resulting in remission of symptoms and possible shrinkage of metastases. Gastroenterology 1985; 88:185.
- Pavel M, Baudin E, Couvelard A, et al. ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology 2012; 95:157.
- Rubin J, Ajani J, Schirmer W, et al. Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome. J Clin Oncol 1999; 17:600.
- Eriksson B, Renstrup J, Imam H, Oberg K. High-dose treatment with lanreotide of patients with advanced neuroendocrine gastrointestinal tumors: clinical and biological effects. Ann Oncol 1997; 8:1041.
- Tomassetti P, Migliori M, Gullo L. Slow-release lanreotide treatment in endocrine gastrointestinal tumors. Am J Gastroenterol 1998; 93:1468.
- Toumpanakis C, Caplin ME. Update on the role of somatostatin analogs for the treatment of patients with gastroenteropancreatic neuroendocrine tumors. Semin Oncol 2013; 40:56.
- Lamberts SW, van der Lely AJ, de Herder WW, Hofland LJ. Octreotide. N Engl J Med 1996; 334:246.
- Newman CB, Melmed S, Snyder PJ, et al. Safety and efficacy of long-term octreotide therapy of acromegaly: results of a multicenter trial in 103 patients--a clinical research center study. J Clin Endocrinol Metab 1995; 80:2768.
- Fernández-Cruz L, Blanco L, Cosa R, Rendón H. Is laparoscopic resection adequate in patients with neuroendocrine pancreatic tumors? World J Surg 2008; 32:904.
- Swärd C, Johanson V, Nieveen van Dijkum E, et al. Prolonged survival after hepatic artery embolization in patients with midgut carcinoid syndrome. Br J Surg 2009; 96:517.
- Ruszniewski P, Rougier P, Roche A, et al. Hepatic arterial chemoembolization in patients with liver metastases of endocrine tumors. A prospective phase II study in 24 patients. Cancer 1993; 71:2624.
- Eriksson BK, Larsson EG, Skogseid BM, et al. Liver embolizations of patients with malignant neuroendocrine gastrointestinal tumors. Cancer 1998; 83:2293.
- Christante D, Pommier S, Givi B, Pommier R. Hepatic artery chemoinfusion with chemoembolization for neuroendocrine cancer with progressive hepatic metastases despite octreotide therapy. Surgery 2008; 144:885.
- Drougas JG, Anthony LB, Blair TK, et al. Hepatic artery chemoembolization for management of patients with advanced metastatic carcinoid tumors. Am J Surg 1998; 175:408.
- Loewe C, Schindl M, Cejna M, et al. Permanent transarterial embolization of neuroendocrine metastases of the liver using cyanoacrylate and lipiodol: assessment of mid- and long-term results. AJR Am J Roentgenol 2003; 180:1379.
- de Baere T, Deschamps F, Teriitheau C, et al. Transarterial chemoembolization of liver metastases from well differentiated gastroenteropancreatic endocrine tumors with doxorubicin-eluting beads: preliminary results. J Vasc Interv Radiol 2008; 19:855.
- Kennedy AS, Dezarn WA, McNeillie P, et al. Radioembolization for unresectable neuroendocrine hepatic metastases using resin 90Y-microspheres: early results in 148 patients. Am J Clin Oncol 2008; 31:271.
- Rhee TK, Lewandowski RJ, Liu DM, et al. 90Y Radioembolization for metastatic neuroendocrine liver tumors: preliminary results from a multi-institutional experience. Ann Surg 2008; 247:1029.
- King J, Quinn R, Glenn DM, et al. Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases. Cancer 2008; 113:921.
- Gaur SK, Friese JL, Sadow CA, et al. Hepatic arterial chemoembolization using drug-eluting beads in gastrointestinal neuroendocrine tumor metastatic to the liver. Cardiovasc Intervent Radiol 2011; 34:566.
- Arrese D, McNally ME, Chokshi R, et al. Extrahepatic disease should not preclude transarterial chemoembolization for metastatic neuroendocrine carcinoma. Ann Surg Oncol 2013; 20:1114.
- Gupta S, Johnson MM, Murthy R, et al. Hepatic arterial embolization and chemoembolization for the treatment of patients with metastatic neuroendocrine tumors: variables affecting response rates and survival. Cancer 2005; 104:1590.
- Cao CQ, Yan TD, Bester L, et al. Radioembolization with yttrium microspheres for neuroendocrine tumour liver metastases. Br J Surg 2010; 97:537.
- Memon K, Lewandowski RJ, Mulcahy MF, et al. Radioembolization for neuroendocrine liver metastases: safety, imaging, and long-term outcomes. Int J Radiat Oncol Biol Phys 2012; 83:887.
- Gupta S, Yao JC, Ahrar K, et al. Hepatic artery embolization and chemoembolization for treatment of patients with metastatic carcinoid tumors: the M.D. Anderson experience. Cancer J 2003; 9:261.
- Moug SJ, Leen E, Horgan PG, Imrie CW. Radiofrequency ablation has a valuable therapeutic role in metastatic VIPoma. Pancreatology 2006; 6:155.
- National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in oncology. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (Accessed on April 01, 2014).
- Roland CL, Bian A, Mansour JC, et al. Survival impact of malignant pancreatic neuroendocrine and islet cell neoplasm phenotypes. J Surg Oncol 2012; 105:595.
- Bilimoria KY, Bentrem DJ, Merkow RP, et al. Application of the pancreatic adenocarcinoma staging system to pancreatic neuroendocrine tumors. J Am Coll Surg 2007; 205:558.
- CLINICAL FEATURES
- Clinical manifestations
- Laboratory findings
- DIFFERENTIAL DIAGNOSIS
- TUMOR LOCALIZATION
- Approach to imaging
- Symptomatic treatment
- - Repletion of fluid and electrolytes
- - Somatostatin analogs
- - Glucocorticoids
- Pancreatic resection
- Management of advanced/metastatic disease
- - Liver-directed therapy for metastatic disease
- - Molecularly targeted therapy
- - Cytotoxic chemotherapy
- POST-TREATMENT SURVEILLANCE
- SUMMARY AND RECOMMENDATIONS