eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

VIPoma

Author: Robert J Ferry Jr, MD, Chief, Division of Pediatric Endocrinology and Diabetes, Le Bonheur Children's Medical Center, University of Tennessee Health Science Center at Memphis and St Jude Children's Research Hospital; Lieutenant Colonel (Medical Corps), 162nd Area Support Medical Company, Army National Guard
Coauthor(s): Klaus Radebold, MD, PhD, Research Associate, Department of Surgery, Yale University School of Medicine
Contributor Information and Disclosures

Updated: Jul 8, 2008

Introduction

Background

In 1958, Verner and Morrison described a syndrome of watery diarrhea, hypokalemia, and achlorhydria (WDHA).1 Siad and Nutt extracted the responsible hormone in 1970 from animal gut. In 1975, Swift et al was the first to report a child who had watery diarrhea and a ganglioneuroma with secretion of vasoactive intestinal peptide (VIP).2

VIPomas originate in amine precursor uptake and decarboxylation (APUD) cells of the gastroenteropancreatic endocrine system and in adrenal or extra-adrenal neurogenic sites. Neural crest cells are precursors of APUDoma and neurogenic cells.

VIPomas in adults commonly originate in the pancreas but extremely rarely originate in the pancreas of affected children. Instead, WDHA syndrome is usually associated with VIP-secreting neurogenic tumors involving the retroperitoneum and mediastinum in children. Pancreatic non–beta-cell hyperplasia is rare, but has been reported in children. Clinical experience is based mainly on case reports (about 85 cases prior to 2005).

Pathophysiology

VIPomas in adults are usually neuroendocrine islet cell tumors of the pancreas that produce high amounts of VIP. Other secreted hormones may include secreted gastrin and pancreatic polypeptide.

In children and adolescents, VIP is produced mainly by ganglioneuromas, ganglioneuroblastomas, neurofibromas, or other tumors in the adrenal area (most common location). Only a small fraction of neuroblastomas and ganglioneuroblastomas produce VIP, but VIP production indicates a more favorable prognosis.

Ganglioneuromatosis that affects the entire colon and rectum has been reported in a 7-year-old boy.3 In contrast to individuals with VIP-secreting pancreatic tumors, patients with neurogenic lesions generally have normal serum levels of pancreatic polypeptide, gastrin, insulin, and somatostatin.

VIP, a 28-aminoacid neuropeptide, is expressed in neurons of the GI, respiratory, and urogenital tracts, as well as in the CNS (ie, hypothalamus, hippocampus, cortex).

Physiological actions of VIP include relaxation of vascular and nonvascular smooth muscles and escalation of gut secretions.

VIP is a potent stimulator of adenosine 3',5'-cyclic phosphate (cAMP) production by the gut. Thus, overproduction leads to massive secretion of water and electrolytes, mainly potassium.

Other important VIP effects include stimulation of alkaline pancreatic juice secretion and lipolysis and glycogenolysis, and inhibition of histamine release and pentagastrin-stimulated acid secretion.

VIPomas can be part of multiple endocrine neoplasia (MEN) type 1 syndrome. This relationship has not been observed with extrapancreatic VIP-secreting tumors of childhood.

Frequency

United States

No data are available for incidence in children. Annually, 0.05-0.2 new cases per million adults have been reported. VIPomas are the third most common neuroendocrine tumor of the pancreas (15%), after insulinomas (50%) and gastrinomas (30%).

Mortality/Morbidity

Death may result from renal failure or cardiac arrest caused by volume depletion and acidosis.

Sex

Male-to-female ratio in children is approximately 1:1, compared with 1:3 in adults.

Age

In a series of 19 childhood cases, the mean age of onset was 2.5 years.4 In another series of 10 cases, the mean age of onset was 4 years. The earliest age of onset ever reported is 2 weeks.

Clinical

History

The onset of symptoms is insidious. Diarrhea may persist for years before the diagnosis is made. Diarrhea typically occurs in episodes. Secretory diarrhea persists even when the patient is restricted to nothing by mouth.

  • Fecal loss of large amounts of potassium and bicarbonate cause hypokalemia, acidosis, and volume depletion.
  • Clinical diagnosis is based on a history of approximately 10 watery stools per day. Fecal losses while fasting are at least 20 mL/kg/d but exceed 50 mL/kg/d in most cases. Fecal osmolality is entirely accounted for by twice the sum of the concentrations of sodium and potassium, indicating the electrolyte loss.
  • Patients may complain about colicky abdominal pain or pain in the upper abdominal area radiating to the back.

Physical

Physical evaluation may reveal no relevant abnormalities other than a mildly extended abdomen.

  • Features of vasoactive intestinal peptide (VIP) syndrome include watery diarrhea (100%), hypochlorhydria (70% in adults), hyperglycemia (20-50% in adults), hypercalcemia (20-50% in adults), and flushing (20% in adults).
  • Extensive fecal loss of potassium and subsequent hypokalemia may cause ECG changes, muscle weakness, and nephrosis.
  • VIP normally inhibits acid secretion; therefore, patients are hypochlorhydric or achlorhydric. Achlorhydria, however, has been observed only occasionally in children.
  • Hypercalcemia due to VIP's parathyroid hormone–like action occurs in as many as 50% of adult patients.
  • Glucose intolerance develops in as many as 50% of adult patients.
  • Flushing is occasionally observed.
  • Profuse sweating, failure to thrive, and colonic dilatation have been reported.

Causes

Somatic point mutations on chromosome 11 of the MEN1 gene have been discovered in sporadic VIPomas and VIPoma cases associated with MEN type 1.

More on VIPoma

Overview: VIPoma
Differential Diagnoses & Workup: VIPoma
Treatment & Medication: VIPoma
Follow-up: VIPoma
References
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References

  1. Verner JV, Morrison AB. Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia. Am J Med. 1958;25:374-380. [Medline].

  2. Swift PG, Bloom SR, Harris F. Watery diarrhoea and ganglioneuroma with secretion of vasoactive intestinal peptide. Arch Dis Child. 1975;50:896-899. [Medline].

  3. Rescorla FJ, Vane DW, Fitzgerald JF, et al. Vasoactive intestinal polypeptide-secreting ganglioneuromatosis affecting the entire colon and rectum. J Pediatr Surg. Jul 1988;23(7):635-7. [Medline].

  4. Quak SH, Prabhakaran K, Kwok R, O'Reilly AP. Vasoactive intestinal peptide secreting tumours in children: a case report with literature review. Aust Paediatr J. Feb 1988;24(1):55-8. [Medline].

  5. Soga J, Yakuwa Y. Vipoma/diarrheogenic syndrome: a statistical evaluation of 241 reported cases. J Exp Clin Cancer Res. Dec 1998;17(4):389-400. [Medline].

  6. Adham M, Giunippero A, Hervieu V, Courbière M, Partensky C. Central pancreatectomy: single-center experience of 50 cases. Arch Surg. 2008;143:175-80; discussion 180-1. [Medline].

  7. Akerström G, Hellman P. Surgery on neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab. 2007;21:87-109. [Medline].

  8. Ammori BJ, El-Dhuwaib Y, Ballester P, Augustine T. Laparoscopic distal pancreatectomy for neuroendocrine tumors of the pancreas. Hepatogastroenterology. 2005;52:620-624. [Medline].

  9. Bartsch DK, Fendrich V, Langer P, Celik I, Kann PH, Rothmund M. Outcome of duodenopancreatic resections in patients with multiple endocrine neoplasia type 1. Ann Surg. Dec 2005;242(6):757-64, discussion 764-6. [Medline].

  10. Cellier C, Yaghi C, Cuillerier E, et al. Metastatic jejunal VIPoma: beneficial effect of combination therapy with interferon-alpha and 5-fluorouracil. Am J Gastroenterol. Jan 2000;95(1):289-93. [Medline].

  11. Cesani F, Ernst R, Walser E, Villanueva-Meyer J. Tc-99m sestamibi imaging of a pancreatic VIPoma and parathyroid adenoma in a patient with multiple type I endocrine neoplasia. Clin Nucl Med. Jun 1994;19(6):532-4. [Medline].

  12. Cooney DR, Voorhess ML, Fisher JE, et al. Vasoactive intestinal peptide producing neuroblastoma. J Pediatr Surg. Dec 1982;17(6):821-25. [Medline].

  13. Cugat E, Olsina JJ, Rotellar F, et al. Initial results of the National Registry of Laparoscopic Liver Surgery [Spanish]. Cir Esp. 2005;78:152-160. [Medline].

  14. Doherty GM. Rare endocrine tumours of the GI tract. Best Pract Res Clin Gastroenterol. 2005;19:807-817. [Medline].

  15. Ghaferi AA, Chojnacki KA, Long WD, Cameron JL, Yeo CJ. Pancreatic VIPomas: subject review and one institutional experience. J Gastrointest Surg. 2008;12:382-93. [Medline].

  16. Grier JF. WDHA (watery diarrhea, hypokalemia, achlorhydria) syndrome: clinical features, diagnosis, and treatment. South Med J. Jan 1995;88(1):22-4. [Medline].

  17. Jackson C, Buchman AL. Calcitonin-secreting VIPoma. Dig Dis Sci. Dec 2005;50(12):2203-6. [Medline].

  18. Keller J, Mueller-Wolf JC, Ahmadi-Simab K, et al. Do elevated plasma vasoactive intestinal polypeptide (VIP) levels cause small intestinal motor disturbances in humans?. Dig Dis Sci. 2005;50:276-282. [Medline].

  19. Marks IN, Bank S, Louw JH. Islet cell tumor of the pancreas with reversible watery diarrhea and achylorhydraia. Gastroenterology. Apr 1967;52(4):695-708. [Medline].

  20. Matthews BD, Smith TI, Kercher KW, et al. Surgical experience with functioning pancreatic neuroendocrine tumors. Am Surg. Aug 2002;68(8):660-5; discussion 665-6. [Medline].

  21. Moug SJ, Leen E, Horgan PG, Imrie CW. Radiofrequency ablation has a valuable therapeutic role in metastatic VIPoma. Pancreatology. 2005;6:155-159.

  22. Nijs E, Callahan MJ, Taylor GA. Disorders of the pediatric pancreas: imaging features. Pediatr Radiol. 2005;35:358-373. [Medline].

  23. Nikou GC, Toubanakis C, Nikolaou P, et al. VIPomas: an update in diagnosis and management in a series of 11 patients. Hepatogastroenterology. Jul-Aug 2005;52(64):1259-65. [Medline].

  24. Ram R, Natanzi N, Saadat P, Eliav D, Vadmal MS. Skin metastasis of pancreatic vasoactive intestinal polypeptide tumor: case report and review of the literature. Arch Dermatol. 2006;142:946-7. [Medline].

  25. Robichon A, Marie JC. Selective photolabeling of high and low affinity binding sites for vasoactive intestinal peptide (VIP): evidence for two classes of covalent VIP-receptor complexes in intestinal cell membranes. Endocrinology. Mar 1987;120(3):978-85. [Medline].

  26. Sandoval C, Oiseth S, Slim M, et al. Gastric ganglioneuroblastoma: a rare finding in an infant with multifocal ganglioneuroblastoma. J Pediatr Hematol Oncol. Nov 1996;18(4):409-12. [Medline].

  27. Sofka CM, Semelka RC, Marcos HB, Woosley JT. MR imaging of metastatic pancreatic VIPoma. Magn Reson Imaging. 1997;15(10):1205-8. [Medline].

  28. Tauber MT, Harris AG, Rochiccioli P. Clinical use of the long acting somatostatin analogue octreotide in pediatrics. Eur J Pediatr. May 1994;153(5):304-10. [Medline].

  29. Virgolini I, Kurtaran A, Leimer M, et al. Location of a VIPoma by iodine-123-vasoactive intestinal peptide scintigraphy. J Nucl Med. Sep 1998;39(9):1575-9. [Medline].

  30. Wang J, Cortina G, Wu SV, et al. Mutant neurogenin-3 in congenital malabsorptive diarrhea. N Engl J Med. Jul 20 2006;355(3):270-80. [Medline].

  31. Warner RR. Enteroendocrine tumors other than carcinoid: a review of clinically significant advances. Gastroenterology. 2005;128:1668-1684. [Medline].

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Further Reading

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Keywords

VIPoma, vipoma, pancreatic cholera, Verner-Morrison syndrome, watery diarrhea, hypokalemia, achlorhydria, WDHA syndrome, ganglioneuromas, ganglioneuroblastomas, neurofibromas, neuroblastomas, multiple endocrine neoplasia type 1 syndrome, MEN, acidosis, hypochlorhydria, hyperglycemia, hypercalcemia, nephrosis, failure to thrive

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Contributor Information and Disclosures

Author

Robert J Ferry Jr, MD, Chief, Division of Pediatric Endocrinology and Diabetes, Le Bonheur Children's Medical Center, University of Tennessee Health Science Center at Memphis and St Jude Children's Research Hospital; Lieutenant Colonel (Medical Corps), 162nd Area Support Medical Company, Army National Guard
Robert J Ferry Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, American Medical Association, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, Society for Pediatric Research, and Texas Pediatric Society
Disclosure: Nutropin Speakers Bureau Honoraria Speaking and teaching

Coauthor(s)

Klaus Radebold, MD, PhD, Research Associate, Department of Surgery, Yale University School of Medicine
Klaus Radebold, MD, PhD is a member of the following medical societies: American Gastroenterological Association and New York Academy of Sciences
Disclosure: Nothing to disclose.

Medical Editor

Arlan L Rosenbloom, MD, Adjunct Distinguished Service Professor Emeritus of Pediatrics, University of Florida; Fellow of the American Academy of Pediatrics; Fellow of the American College of Epidemiology
Arlan L Rosenbloom, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Epidemiology, American Pediatric Society, Endocrine Society, Florida Pediatric Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Lynne Lipton Levitsky, MD, Chief, Pediatric Endocrine Unit, Massachusetts General Hospital; Associate Professor, Department of Pediatrics, Harvard University Medical School
Lynne Lipton Levitsky, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Diabetes Association, American Pediatric Society, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences
Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Lawson-Wilkins Pediatric Endocrine Society
Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD, Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas and Arkansas Children's Hospital
Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research
Disclosure: Genentech, Inc. Honoraria Speaking and teaching; Pfiser, Inc. Honoraria Consulting

 
 
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