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AUTHOR AND EDITOR INFORMATION
Section 1 of 10  
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, 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
Coauthor(s):
Klaus Radebold, MD, PhD, Research Associate, Department of Surgery, Yale University School of Medicine
Editors: 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; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Lynne Lipton Levitsky, MD, Chief, Pediatric Endocrine Unit, Massachusetts General Hospital; Associate Professor, Department of Pediatrics, Harvard University Medical School; Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences; Stephen Kemp, MD, PhD, Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas and Arkansas Children's Hospital
Author and Editor Disclosure
Synonyms and related 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
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.
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.
Carcinoid Tumor
Gastroenteritis
Multiple Endocrine Neoplasia
Neuroblastoma
Sprue
Zollinger-Ellison Syndrome
Other Problems to be Considered
Enteric anendocrinosis
Enteric dysendocrinosis
Lab Studies
- Plasma vasoactive intestinal peptide (VIP) levels are determined by radioimmunoassay. Normal levels are less than 20 pmol/L. Levels in patients with tumors normally range from 160-250 pmol/L.
- Because VIP is rapidly degraded, add aprotinin to the blood sample and keep deep-frozen at -70°C until processed.
- Determine VIP levels when the patient is symptomatic, because VIP release from the tumor fluctuates.
Imaging Studies
- Chest radiography may reveal a paravertebral mass.
- CT scanning is indicated to search for neck, mediastinal, or retroperitoneal masses. No calcifications or bony infiltrations should be found.
- VIPomas are best shown on T1-weighted fat-suppressed MRI as a low-signal intensity mass. Liver metastases may reveal intensive peripheral ring enhancement on immediate postgadolinium gradient echo images.
- Somatostatin receptor scintigraphy has been occasionally used. Experience is limited because of the small number of cases.
- Other previously used techniques include technetium-99m scintigraphy, 123-iodine-VIP receptor scintography, and single photon emission CT (SPECT).
Histologic Findings
- Tumors may be composed of strands of spindled Schwann cells surrounding islands and nests of multinucleated ganglion cells.
- Scattered lymphoid aggregates have been observed.
Staging
- No formal staging criteria have been generally accepted.
- Metastasis most often occurs to the liver or regional lymph nodes.
- Rarely, metastasis to skin has been reported.
Medical Care
Initial treatment is directed toward correcting volume and electrolyte abnormalities by using potassium chloride and sodium bicarbonate.
- Octreotide acetate controls diarrhea in 80% of cases.
- Glucocorticoids reduce symptoms in 50% of patients with vasoactive intestinal peptide tumors (VIPomas).
Surgical Care
Surgical exploration with tumor resection leads to cure in 50% of patients. Surgery is indicated in children without extensive metastatic disease. An exploratory laparotomy may be indicated when imaging studies detect no tumor.
- Local tumor resection is the treatment of choice.
- In advanced states of the disease, tumor debulking may relieve symptoms but is not effective in all cases.
- In adults, selected patients have had orthotopic liver transplantation.
- Serum VIP levels may normalize within an hour after curative tumor resection.
- Repetitive embolization of the hepatic artery may provide palliation over a long period for patients with liver metastases.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Drug Category: Antidiarrheal
These are antisecretory agents used to control acute or chronic diarrhea.
| Drug Name | Octreotide acetate (Sandostatin) |
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| Description | Action similar to natural hormone somatostatin. Suppresses peptide secretion, including VIP, from gastroenteropancreatic tumors. Controls diarrhea in 80% of patients with unresectable or metastatic tumors. High doses may lead to additional antiproliferative effects. Start with small doses in VIPomas. Dose increases during treatment period may become necessary. Novel depot preparations may be useful. |
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| Adult Dose | 1-10 mcg/kg/d SC divided bid, adjust dose q3d prn |
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| Pediatric Dose | Administer as in adults |
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| Contraindications | Documented hypersensitivity |
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| Interactions | May reduce effects of cyclosporine; patients on insulin, PO hypoglycemics, beta-blockers, and CCBs may need dosage adjustments. |
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| Pregnancy | B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
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| Precautions | Adverse effects primarily relate to altered GI motility and include nausea, abdominal pain, diarrhea, and increased incidence of gallstones and biliary sludge; because of alteration in counter-regulatory hormones (eg, insulin, glucagon, GH) hypoglycemia or hyperglycemia may result; bradycardia, cardiac conduction abnormalities, and arrhythmias have been reported; hypothyroidism may occur because of inhibition of TSH secretion; exercise caution in patients with renal impairment; cholelithiasis may occur. |
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Further Inpatient Care
- Embolization of the hepatic artery with doxorubicin HCl and lipiodol may provide palliation in patients with extensive hepatic disease. This treatment may be repeated several times, depending on tumor growth and symptoms.
- External radiation therapy may be indicated in unresectable tumors.
- Laparoscopic surgical resection has been successful in at least one adult with hepatic metastasis.
Further Outpatient Care
- Vasoactive intestinal peptide (VIP) levels may serve as a tumor marker for recurrent disease.
In/Out Patient Meds
- Advanced disease secondary to a pancreatic endocrine tumor may be treated with streptozotocin in combination with 5-fluorouracil. Other chemotherapeutics include dacarbazine and doxorubicin HCl.
- In specific cases, 5-fluorouracil has been combined with interferon-alfa.
Prognosis
- Children with neuroblastomas have a relatively poor overall survival rate (30-40%).
- Children with VIP-secreting ganglioneuroblastomas have a survival rate more than 90%.
- In a large series of 241 adult patients with VIPomas, the 5-year survival rate was 89% among those with pancreatic VIPomas and 68.5% among those with neurogenic VIP-producing tumors.5 In metastatic disease, the 5-year survival rate was 59.6%.
Medical/Legal Pitfalls
- A parathyroidectomy in patients with vasoactive intestinal peptide tumors (VIPomas) does not correct the hypercalcemia unless the VIPoma is resected.
- Severe hypotension may develop temporarily during and after tumor removal, caused by the vasodilatory effect of VIP released during manipulation of the tumor.
- Verner JV, Morrison AB. Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia. Am J Med. 1958;25:374-380. [Medline].
- Swift PG, Bloom SR, Harris F. Watery diarrhoea and ganglioneuroma with secretion of vasoactive intestinal peptide. Arch Dis Child. 1975;50:896-899. [Medline].
- 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].
- 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].
- 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].
- 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].
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- Ammori BJ, El-Dhuwaib Y, Ballester P, Augustine T. Laparoscopic distal pancreatectomy for neuroendocrine tumors of the pancreas. Hepatogastroenterology. 2005;52:620-624. [Medline].
- 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].
- 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].
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- Grier JF. WDHA (watery diarrhea, hypokalemia, achlorhydria) syndrome: clinical features, diagnosis, and treatment. South Med J. Jan 1995;88(1):22-4. [Medline].
- Jackson C, Buchman AL. Calcitonin-secreting VIPoma. Dig Dis Sci. Dec 2005;50(12):2203-6. [Medline].
- 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].
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- 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].
- Moug SJ, Leen E, Horgan PG, Imrie CW. Radiofrequency ablation has a valuable therapeutic role in metastatic VIPoma. Pancreatology. 2005;6:155-159.
- Nijs E, Callahan MJ, Taylor GA. Disorders of the pediatric pancreas: imaging features. Pediatr Radiol. 2005;35:358-373. [Medline].
- 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].
- 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].
- 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].
- 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].
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- 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].
- 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].
- 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].
- Warner RR. Enteroendocrine tumors other than carcinoid: a review of clinically significant advances. Gastroenterology. 2005;128:1668-1684. [Medline].
VIPoma excerpt Article Last Updated: Jul 8, 2008
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