VIPoma

A VIPoma is a rare neuroendocrine tumor arising primarily in the pancreas that releases large amounts of vasoactive intestinal polypeptide (VIP). This process leads to chronic watery diarrhea with concomitant hypokalemia and dehydration, as well as wheezing and flushing (known as Verner-Morrison or WDHA (chronic Watery Diarrhea, Hypokalemia, Achlorhydria) syndrome). Most tumors arise sporadically, but some are associated with MEN 1. Diagnosis is established by measuring serum VIP levels. Treatment consists of medical management of symptoms and complete surgical removal of the tumor when possible.

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Overview

Definition

A VIPoma is a rare neuroendocrine tumor that secretes vasoactive intestinal polypeptide (VIP).

Epidemiology

  • Incidence: 1 in 1,000,000 people per year
  • 95% arise in the pancreas, and 75% of symptomatic cases arise in the tail of the pancreas.
  • 3rd most common pancreatic neuroendocrine tumor (after insulinoma and gastrinoma)
  • Age of onset: 30–50 in adults and 2–4 in children

Etiology

  • Arise from neuroendocrine cells, most commonly islet cells in pancreas
  • Most are isolated and sporadic, but 5% are associated with MEN 1.

Pathophysiology and Clinical Presentation

Anatomy

  • 95% arise within the pancreas, and 75% within the tail of the pancreas.
  • Usually solitary and > 3 cm
  • Other locations common in children:
    • Adrenal glands
    • Sympathetic ganglia
  • Less common locations:
    • Lung
    • Colon/rectum
    • Liver

Anatomy of the pancreas

Image: “Blausen 0699 PancreasAnatomy2” by Blausen. License: CC BY 3.0

VIPoma syndrome

  • Also known as Verner-Morrison syndrome or WDHA syndrome:
    • Chronic Watery Diarrhea
    • Hypokalemia (causes muscle cramps, weakness, and arrhythmias)
    • Achlorhydria
  • Caused by excessive unregulated secretion of VIP:
    • VIP binds to receptors on intestinal epithelial cells.
    • Activation of cellular adenylate cyclase and cAMP production result in fluid and electrolyte secretion into lumen.
    • Other effects:
      • Vasodilation
      • Inhibition of gastric acid secretion
      • Bone resorption
      • Enhanced glycogenolysis

Clinical presentation

  • Watery diarrhea:
    • Usually intermittent
    • Not affected by fasting
    • Tea-colored stools (> 700 mL/day, up to 5 L)
    • Abdominal pain is mild or minimal.
  • Flushing episodes (in 20% of patients)
  • Symptoms related to hypokalemia and dehydration:
    • Lethargy
    • Nausea/vomiting
    • Muscle weakness/cramps

Diagnosis

History

  • Unexplained high-volume diarrhea (often intermittent)
  • Flushing episodes
  • Family or personal history of MEN 1

Laboratory studies

  • Elevated serum VIP > 75 pg/mL (should be confirmed with repeat testing)
  • Abnormal electrolyte levels:
    • Hypokalemia
    • Metabolic alkalosis
    • Hypercalcemia: can be intermittent and correspond to diarrheal episodes
    • Hyperglycemia
    • Hypochlorhydria
    • Iron and B12 deficiency

Imaging

  • CT scan with contrast: Sensitivity approaches 100%.
  • MRI: more sensitive than CT for detecting liver metastases
  • Somatostatin receptor scintigraphy: whole-body scan using radioactively labeled octreotide
  • Endoscopic ultrasound (EUS): rarely used
  • PET scan: good for localization and staging

Computed tomography scan showing large necrotic pancreatic VIPoma

Image: “Multi-visceral resection of pancreatic VIPoma in a patient with sinistral portal hypertension” by Joyce DL, Hong K, Fishman EK, Wisell J, Pawlik TM. License: CC BY 2.0

Management

Primary mass

  • Medical:
    • Repletion of fluid and electrolytes
    • Somatostatin analogs (octreotide, lanreotide)
      • Bind to somatostatin receptors
      • Inhibit serotonin release
    • 2nd-line treatments for diarrhea refractory to somatostatin analogs:
      • Glucocorticoids
      • Clonidine
      • Loperamide
  • Surgical: distal pancreatectomy for primary tumors

Metastatic disease

  • Liver resection
  • Hepatic artery embolization
  • Ablations (radiofrequency and cryoablation)
  • Drugs:
    • Somatostatin analogs
    • Streptozocin
    • Sunitinib
    • Everolimus

Prognosis

  • 60%–80% are metastatic at diagnosis.
  • Prognosis depends on grade, stage, and surgical resectability.
  • Median survival of VIPoma patients is 96 months.

Differential Diagnosis

  • Infectious diarrhea: diarrhea caused by a variety of bacteria and viruses (e.g., Vibrio cholerae, Escherichia coli). Usually acute onset and frequently self-limited. Diagnosis established by history and stool cultures. Treatment entails supportive management and antibiotics in certain cases.
  • Malabsorption: malfunction of intestinal wall that results in insufficient absorption of breakdown products. May present as diarrhea, steatorrhea, abdominal distention, flatulence, weight loss, anemia, vitamin deficiencies, and/or failure to thrive. Diagnosis established by a combination of stool studies, blood work, and sometimes endoscopy and imaging. Treatment is usually supportive.
  • Carcinoid syndrome: constellation of symptoms associated with production of serotonin and other substances by carcinoid tumors. Usually presents with diarrhea, flushing, and wheezing. Diagnosis established by measurement of serotonin metabolites and imaging to confirm presence of tumor. Treatment includes surgical resection and symptomatic management.
  • Gastrinoma: gastrin-secreting tumor that causes Zollinger-Ellison syndrome. Arises from pancreas, stomach, duodenum, jejunum, and/or even lymph nodes. Symptoms include refractory peptic ulcers and diarrhea. Diagnosis established by fasting gastrin levels. Treatment includes surgical resection and symptomatic management.

References

  1. Bergsland E. (2020). VIPoma: Clinical manifestations, diagnosis, and management. Retrieved January 27, 2021, from https://www.uptodate.com/contents/vipoma-clinical-manifestations-diagnosis-and-management
  2. Cameron J.L. (2004). Current Surgical Therapy. 8th Edition. 
  3. Grier J.F. (1995). WDHA (watery diarrhea, hypokalemia, achlorhydria) syndrome: clinical features, diagnosis, and treatment. Southern Medical Journal. 88(1), 22–24. https://doi.org/10.1097/00007611-199501000-00002
  4. Smith S.L., et al. (1998). Vasoactive intestinal polypeptide secreting islet cell tumors: a 15-year experience and review of the literature. Surgery. 124(6), 1050–1055. https://doi.org/10.1067/msy.1998.92005

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