eMedicine Specialties > Endocrinology > Multiple Endocrine Disease and Miscellaneous Endocrine Disease

VIPomas: Differential Diagnoses & Workup

Author: Daniel S Tung, MD, Fellow in Endocrinology, Department of Internal Medicine, Baylor College of Medicine
Coauthor(s): Sai-Ching Jim Yeung, MD, PhD, FACP, Deputy Section Chief of Emergency Care, Assistant Professor, Department of General Internal Medicine, Ambulatory Treatment and Emergency Care, University of Texas MD Anderson Cancer Center; Klaus Radebold, MD, PhD, Research Associate, Department of Surgery, Yale University School of Medicine
Contributor Information and Disclosures

Updated: Dec 18, 2008

Differential Diagnoses

Carcinoid Tumor, Intestinal
Thyroid, Medullary Carcinoma
Gastrinoma
Villous Adenoma
Gastroenteritis, Bacterial
Wermer Syndrome (MEN Type 1)
Pancreatic Cancer
Zollinger-Ellison Syndrome
Somatostatinomas
Sprue, Tropical

Other Problems to Be Considered

All conditions with diarrhea
Ganglioneuroblastoma (similar symptoms mainly in children)
Infectious diseases of the intestines
Laxative abuse
Villous adenoma of the rectum

Workup

Laboratory Studies

  • A diagnosis of VIPoma is made when watery diarrhea, hypokalemia, and achlorhydria are present in the setting of elevated serum vasoactive intestinal polypeptide (VIP) concentrations.
  • A normal plasma VIP level is 20-30 pmol/L or less, as determined by radioimmunoassay. VIP levels in patients with VIPoma are markedly elevated, often to levels of 160-250 pmol/L or higher. VIP levels are usually 2-10 times the normal range. VIP levels should be drawn after fasting.8
    • Because VIP is degraded rapidly, a protease inhibitor, such as aprotinin, is added to the blood sample, which must be kept frozen at -70°C until processed.
    • Because VIP secretion from the tumor may be episodic, collect serum VIP levels during bouts of severe diarrhea. 
  • Hypokalemia and non–anion gap acidosis are the main diagnostic features of VIPomas. Hypokalemia may require aggressive replacement.
  • Hypercalcemia may occur in the absence of MEN 1 syndrome or elevated parathyroid hormone levels. The mechanism of action is not clear but is believed to be through increased bone resorption. The dehydration from severe diarrhea certainly may exacerbate the hypercalcemia. 
  • Hyperglycemia may be caused by the direct glycogenolytic effect of VIP on the liver and by the inhibitory effect of hypokalemia on pancreatic islet cell insulin release.  
  • Renal function should be assessed with blood urea nitrogen and serum creatinine levels. 
  • Other electrolytes, including magnesium, should be checked and replaced.
  • VIPomas may cosecrete other hormones, including pancreatic polypeptide, calcitonin, and neurotensin. 
  • Stool weight with potassium measurements verifies high gastrointestinal potassium losses.

Imaging Studies

Imaging studies are focused primarily on the pancreas, where 90% of VIPomas are located. Tumor localization is normally not difficult, because these tumors are generally larger than 3 cm in the longest dimension at the time of diagnosis. The following modalities can be used for imaging VIPomas:

  • Computed tomography (CT) scanning
    • CT scanning will successfully identify the primary tumor in most cases.
    • It also assists in including or excluding liver metastasis.
    • In a series of 31 patients from China, Peng and colleagues reported that all VIPomas of the pancreatic body and tail were identified through CT scanning but that only 71% of VIPomas in the pancreatic head were successfully identified with this modality.7   
  • Magnetic resonance imaging (MRI)
    • MRI may be used if a CT scan is contraindicated, eg, if the patient is allergic to iodine contrast dyes or in cases of renal failure. 
    • VIPomas are observed best on T1-weighted, fat-suppressed images as low – signal-intensity masses.9
    • Liver metastases may demonstrate intensive peripheral ring enhancement on immediate post-gadolinium spoiled gradient-echo images.9
  • Somatostatin receptor scintigraphy
    • Somatostatin receptor scintigraphy may be useful to characterize an abnormality found on a CT scan or to identify occult or distant metastatic disease. It may also be used if postsurgical changes diminish the clarity of a CT scan’s image. 
    • Sensitivity for localization of all pancreatic endocrine tumors has been reported at 80-90%, with 92% sensitivity for tumors larger than 1 cm.
    • Investigations suggest that the use of somatostatin receptor scintigraphy for the localization of neuroendocrine tumors, including VIPomas, may be improved in the future through the employment of single-photon emission CT (SPECT) scanning.10
  • Technetium-99m (99m Tc) sestamibi - Reports demonstrate successful VIPoma localization with99m Tc sestamibi.11
  • Transabdominal ultrasonography - This may be used for early screening to exclude liver metastases, which may be present as hepatic calcifications.

Other Tests

  • Hypochlorhydria or achlorhydria is seen in at least 75% of patients with VIPoma, because vasoactive intestinal polypeptide inhibits the histamine- and pentagastrin-stimulated gastric acid secretion. This can be determined by measuring gastric pH or basal gastric acid output.
  • Stool volumes of less than 700 mL virtually exclude the diagnosis. Typical stool volumes are more than 3 L per day.

Procedures

  • Endoscopic retrograde cholangiopancreatography
    • This modality may demonstrate occlusion of the major pancreatic duct.
    • Endoscopic retrograde cholangiopancreatography may also demonstrate calcifications in the body of the pancreas.
  • Colonoscopy

    • This may be useful as a means of evaluating for a possible villous adenoma as an alternative cause of potassium-losing diarrhea.

Histologic Findings

VIPomas, like other pancreatic endocrine tumors, are thought to arise from the pluripotent cells in ductal epithelium. Histologic examination usually reveals, as is typical for neuroendocrine tumors, sheets of nested, uniform-appearing cells with round nuclei and a low mitotic rate. Immunohistochemistry staining is positive for chromogranin A and vasoactive intestinal polypeptide. Under electron microscopy, neurosecretory granules may be seen clustering around Golgi complexes and the endoplasmic reticulum. Classifying a tumor as malignant or benign based on microscopic appearance alone is difficult.

More on VIPomas

Overview: VIPomas
Differential Diagnoses & Workup: VIPomas
Treatment & Medication: VIPomas
Follow-up: VIPomas
Multimedia: VIPomas
References
Further Reading
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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. Sep 1958;25(3):374-80. [Medline].

  2. Said SI, Mutt V. Polypeptide with broad biological activity: isolation from small intestine. Science. Sep 18 1970;169(951):1217-8. [Medline].

  3. Aton SJ, Colwell CS, Harmar AJ, et al. Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons. Nat Neurosci. Apr 2005;8(4):476-83. [Medline]. [Full Text].

  4. Doherty GM. Rare endocrine tumours of the GI tract. Best Pract Res Clin Gastroenterol. Oct 2005;19(5):807-17. [Medline].

  5. Ayub A, Zafar M, Abdulkareem A, et al. Primary hepatic vipoma. Am J Gastroenterol. Jun 1993;88(6):958-61. [Medline].

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

  7. Peng SY, Li JT, Liu YB, et al. Diagnosis and treatment of VIPoma in China: (case report and 31 cases review) diagnosis and treatment of VIPoma. Pancreas. Jan 2004;28(1):93-7. [Medline].

  8. de Herder WW. Biochemistry of neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab. Mar 2007;21(1):33-41. [Medline].

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

  10. Schillaci O, Corleto VD, Annibale B, et al. Single photon emission computed tomography procedure improves accuracy of somatostatin receptor scintigraphy in gastro-entero pancreatic tumours. Ital J Gastroenterol Hepatol. Oct 1999;31 Suppl 2:S186-9. [Medline].

  11. Cesani F, Ernst R, Walser E, et al. 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. Ruiz-Tovar J, Priego P, Martínez-Molina E, et al. Pancreatic neuroendocrine tumours. Clin Transl Oncol. Aug 2008;10(8):493-7. [Medline].

  13. Ghaferi AA, Chojnacki KA, Long WD, et al. Pancreatic VIPomas: subject review and one institutional experience. J Gastrointest Surg. Feb 2008;12(2):382-93. [Medline].

  14. Akerstrom G, Hellman P. Surgery on neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab. Mar 2007;21(1):87-109. [Medline].

  15. King J, Quinn R, Glenn DM, et al. Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases. Cancer. Sep 1 2008;113(5):921-9. [Medline].

  16. Bramley PN, Lodge JP, Losowsky MS, et al. Treatment of metastatic Vipoma by liver transplantation. Clin Transplant. Oct 1990;4(5 part 1):276-8; discussion 279. [Medline].

  17. 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].

  18. 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].

  19. Jensen RT. Pancreatic endocrine tumors: recent advances. Ann Oncol. 1999;10 Suppl 4:170-6. [Medline].

  20. Mansour JC, Chen H. Pancreatic endocrine tumors. J Surg Res. Jul 2004;120(1):139-61. [Medline].

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

  22. Remme CA, de Groot GH, Schrijver G. Diagnosis and treatment of VIPoma in a female patient. Eur J Gastroenterol Hepatol. Jan 2006;18(1):93-9. [Medline].

  23. 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].

  24. Shan L, Nakamura Y, Nakamura M, et al. Somatic mutations of multiple endocrine neoplasia type 1 gene in the sporadic endocrine tumors. Lab Invest. Apr 1998;78(4):471-5. [Medline].

  25. Swift PG, Bloom SR, Harris F. Watery diarrhoea and ganglioneuroma with secretion of vasoactive intestinal peptide. Arch Dis Child. Nov 1975;50(11):896-9. [Medline]. [Full Text].

  26. Tennvall J, Ljungberg O, Ahren B, et al. Radiotherapy for unresectable endocrine pancreatic carcinomas. Eur J Surg Oncol. Feb 1992;18(1):73-6. [Medline].

  27. 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. Mar 1974;133(3):492-9. [Medline].

  28. 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]. [Full Text].

  29. Warner RR. Enteroendocrine tumors other than carcinoid: a review of clinically significant advances. Gastroenterology. May 2005;128(6):1668-84. [Medline].

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Keywords

VIPoma, pancreatic cancer, cancer pancreas, pancreatic cancer symptoms, neuroendocrine tumor, neuroendocrine carcinoma, pancreatic tumor, pancreas tumor, multiple endocrine neoplasia, pancreas tumors, pancreatic tumors, Verner-Morrison syndrome, pancreatic cholera, watery diarrhea-hypokalemia-achlorhydria syndrome, WDHA syndrome, vasoactive intestinal polypeptide, VIP, pancreatic endocrine tumor, multiple endocrine neoplasia type 1 syndrome, MEN 1

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Contributor Information and Disclosures

Author

Daniel S Tung, MD, Fellow in Endocrinology, Department of Internal Medicine, Baylor College of Medicine
Daniel S Tung, MD is a member of the following medical societies: American Association of Clinical Endocrinologists and American Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Sai-Ching Jim Yeung, MD, PhD, FACP, Deputy Section Chief of Emergency Care, Assistant Professor, Department of General Internal Medicine, Ambulatory Treatment and Emergency Care, University of Texas MD Anderson Cancer Center
Sai-Ching Jim Yeung, MD, PhD, FACP is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Medical Association, American Thyroid Association, and Endocrine Society
Disclosure: Nothing to disclose.

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

Frederick H Ziel, MD, Associate Professor of Medicine, David Geffen School of Medicine at UCLA; Physician-In-Charge, Endocrinology/Diabetes Center, Director of Medical Education, Kaiser Permanente Woodland Hills; Chair of Endocrinology, Co-Chair of Diabetes Complete Care Program, Southern California Permanente Medical Group
Frederick H Ziel, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Federation for Medical Research, American Medical Association, American Society for Bone and Mineral Research, California Medical Association, Endocrine Society, and International Society for Clinical Densitometry
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS, Professor of Medicine (Endocrinology, Adj), Johns Hopkins School of Medicine; Affiliate Research Professor, Bioinformatics and Computational Biology Program, School of Computational Sciences, George Mason University; Principal, C/A Informatics, LLC
Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Nutrition, American College of Physician Executives, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Informatics Association, American Society for Bone and Mineral Research, American Society of Law Medicine and Ethics, Endocrine Society, and International Society for Clinical Densitometry
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

 
 
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