VIPoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Madhu Sigdel M.B.B.S.[2]Parminder Dhingra, M.D. [3] Homa Najafi, M.D.[4]

VIPoma is a rare tumor of the non-beta cells of the pancreas that results in the overproduction of the hormone vasoactive intestinal peptide (VIP). On histopathological analysis, composition of uniform, small to intermediate-sized cells in clusters, nests, and trabecular growth patterns with hyperchromatic nuclei and scant cytoplasm are seen. VIPoma must be differentiated from ganglioneuroblastoma, ganglioneuroma, factitious diarrhea, bile salt enteropathy, rectal vilous adenomas, and laxative abuse. The incidence VIPoma is approximately 0.01 per 100,000 individuals worldwide, and females are more commonly affected than males. If left untreated, patients with VIPoma may progress to develop watery diarrhea, abdominal pain, bloating, nausea, vomiting, skin rash, backache, flushing, and lethargy. Common complications of VIPoma include metastasis, cardiac arrest from low blood potassium level, and dehydration. The presence of metastasis is associated with a particularly poor prognosis, with a 5 year survival rate of 60%. The hallmark of VIPoma is watery diarrhea. A positive history of abdominal pain, weight loss, numbness, and weakness is suggestive of VIPoma. Common physical examination findings of VIPoma include tachycardia, rash, facial flushing, abdominal tenderness, and abdominal distention. Laboratory tests used in the diagnosis of VIPoma include serum vasoactive intestinal polypeptide (VIP) levels, basal gastric acid output, and basic metabolic pannel for potassium, bicarbonate, magnesium, and calcium levels. On CT scan VIPoma is characterized by hypervascularity with diffuse multiple metastatic nodulation. Abdominal MRI is helpful in the diagnosis of VIPoma which is characterized by a mass that is hypointense on T1-weighted and hyperintense on T2-weighted MRI. Initial treatment in patient with VIPoma is prompt replacement of fluid and electrolyte losses, steroids may be used to provide symptomatic relief. Surgery is the mainstay of treatment.

VIPoma which is also known as Verner-Morrison syndrome was first described in 1958 by Verner and Morrison.

A VIPoma is a rare tumor of the non-beta cells of the pancreas that results in the overproduction of the hormone vasoactive intestinal peptide (VIP). On microscopichistopathological analysis, findings of VIPoma are composition of uniform, small to intermediate-sized cells in clusters, nests, and trabecular growth patterns with hyperchromatic nuclei and scant cytoplasm.

The cause of VIPoma has not been identified.

VIPoma must be differentiated from ganglioneuroblastoma, ganglioneuroma, factitious diarrhea, bile salt enteropathy, rectal vilous adenomas, and laxative abuse.

The annual incidence of VIPoma is approximately 0.01 per 100,000 (approx. 1 in 10 million) individuals worldwide. Female are more commonly affected by VIPoma than male. The incidence of VIPoma increases with age, the median age at diagnosis in adults is 50 years. VIPoma in children is usually diagnosed between age 2 to 4.

The most important risk factor in the development of VIPoma is a positive family history of multiple endocrine neoplasia type 1.

According to the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for VIPoma.

If left untreated, patients with VIPoma may progress to develop watery diarrhea, abdominal pain, bloating, nausea, vomiting, skin rash, backache, flushing, and lethargy. Common complications of VIPoma include metastasis, cardiac arrest from low blood potassium level, and dehydration. The presence of metastasis is associated with a particularly poor prognosis among patients with VIPoma, with a 5 year survival rate of 60%.

The diagnostic study of choice for Vipoma is the measurement of serum vasoactive intestinal polypeptide (VIP) concentration.

The hallmark of Vipoma is watery diarrhea. A positive history of abdominal pain, weight loss, numbness, and weakness is suggestive of VIPoma . The most common symptoms of VIPoma include watery diarrhea like cholera, dehydration, lethargy, muscle weakness, weight loss, numbness, and flushing.

Common physical examination findings of VIPoma include tachycardia, rash, facial flushing, abdominal tenderness, muscle weakness, and abdominal distention.

Laboratory tests used in the diagnosis of VIPoma include serum vasoactive intestinal polypeptide (VIP) levels, basal gastric acid output, and CMP for potassium, bicarbonate, magnesium, and calcium levels.

There are no ECG findings associated with VIPoma.

There are no x-ray findings associated with VIPoma.

On CT scan VIPoma is characterized by hypervascularity with diffuse multiple metastatic nodulation. CT scan are highly accurate for tumor localization of primary neuroendocrine pancreatic tumor. Since most of them are more than 3cm in size at the time of presentation. Sensitivity of contrast enhanced CT for VIPoma approaches 100%.

Abdominal MRI is helpful in the diagnosis of VIPoma. On abdominal MRI, VIPoma is characterized by a mass which is hypointense on T1-weighted MRI and hyperintense on T2-weighted MRI.

Endoscopic ultrasound may be helpful in the diagnosis of VIPoma. Finding on ultrasound suggestive of VIPoma is hypoechoic tumor in the distal part of pancreas.

Other imaging studies for VIPoma include somatostatin receptor scintigraphy and PET scan using radiolabeled somatostatin analogs.

Other diagnostic studies for VIPoma include immunohistochemical staining test, which demonstrates staining for markers such as chromogranin A, cytokeratin 19, synaptophysin, Ki-67, neuron specific enolase, PGP 9.5.

Initial treatment in patient with VIPoma is prompt replacement of fluid and correction of electrolyte imbalance and acid-base disturbance. Somatostatin analogues like short acting octreotide is useful for controlling diarrhea by blocking the release of VIP. Octreotide is later replaced by longer acting depot preparation of somatostatin analogues like sandostatin or lanreotide.

The mainstay of treatment for VIPoma is surgery. Hepatic artery embolization or transcatheter chemoembolization with doxorubicin or cisplatin is usually reserved for patients with liver metastases. Moreover, in patients with liver metastases less than 3 cm radiofrequency ablation and cryoablation can be used.

Surgery is the mainstay of treatment for VIPoma. Surgery should be considered after initial symptomatic management of VIPoma inoperable cases. Complete surgical resection of the tumor is the only curative treatment for VIPoma. If the tumor cannot be removed completely, surgical debulking may have palliative effect for control of hormonal symptoms.

There are no established measures for the primary prevention of VIPoma.

Effective measures for the secondary prevention of VIPoma include history and physical examination, serum VIP levels and indicated markers, and multi-phasic CT scan or MRI.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Madhu Sigdel M.B.B.S.[2]Parminder Dhingra, M.D. [3] Homa Najafi, M.D.[4]

VIPoma which is also known as Verner-Morrison syndrome was first described in 1958 by Verner and Morrison.

• In 1870, Rudolf Heidenhain was the first to discover and describe the neuroendocrine tumors of the gastrointestinal tract and pancreas.
• In 1958, American physicians, John U. Verner and Ashton B. Morrison discovered VIPoma for the first time in a patient presenting with profuse diarrhea and hypokalemia.
• John U. Verner and Ashton B also described the pathogenesis of VIPoma (due to malignancy of non-insulin producing pancreatic islets) in detail.
• VIPoma is also known as Verner-Morrison syndrome.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Madhu Sigdel M.B.B.S.[2]Parminder Dhingra, M.D. [3] Homa Najafi, M.D.[4]

A VIPoma is a rare tumor of the non-beta cells of the pancreas that results in the overproduction of the hormone vasoactive intestinal peptide (VIP). On microscopic histopathological analysis, findings of VIPoma are composition of uniform, small to intermediate-sized cells in clusters, nests, and trabecular growth patterns with hyperchromatic nuclei and scant cytoplasm. BKJHKJJFHKH

• VIPomas are neuroendocrine neoplasms arising from the pancreas in 90% of the cases, while the remaining 10% occur in extra pancreatic tissues like bronchus, colon, liver, and neural crest-derived tissues.^[1][2][3]
• When VIPoma is found in the pancreas, 75% of the tumors occur in the tail of pancreas, while 25% occur in the pancreatic head and body.
• VIPomas originate in amine precursor uptake and decarboxylation (APUD) cells of the gastroenteropancreatic endocrine system and in adrenal or extra-adrenal neurogenic sites.
• VIPoma causes cells in the pancreas to produce high levels of a hormone called vasoactive intestinal peptide (VIP).

• Vasoactive intestinal peptide hormone has three important functions^[4][5]
  • Stimulates secretions from the intestine and pancreas
  • Inhibits gastric acid secretion
  • Increases glycogenolysis
  • Causes hypercalcemia and relaxes sphincters and circular smooth muscles of gut.
• VIP hormone in CNS has effect on behavior and learning as well as secretagouge.
  • It induces release of prolactin, luteinizing hormone and growth hormone from the pituitary as well as regulates the release of insulin and glucagon from the pancreas.

• Vasoactive intestinal peptide (VIP) is a structural homologue of secretin.^[6]
• VIP innervates on both VPAC1 and VPAC2.
• When VIP binds to VPAC2 receptors in intestinal cells, a G-alpha-mediated signalling cascade is triggered.
• In a number of systems, VIP binding activates adenyl cyclase activity leading to increases in cAMP and PKA.
• The PKA then activates other intracellular signaling pathways like the phosphorylation of CREB and other transcriptional factors.
• Elevated serum VIP levels leading to increased intracellular cAMP causes increased intestinal secretion of water along with Na+, K+, HCO3 -, and Cl- in the intestinal lumen, as well as bone resorption, vasodilation, and inhibition of gastric acid secretion.

On gross pathology, circumscribed, solid mass composed of white tan, irregular and firm mass within fleshy parenchyma are characteristic findings of VIPoma.^[7]

• Histologically, a VIPoma demonstrates a composition of uniform, small to intermediate-sized cells in clusters, nests, and trabecular growth patterns with hyperchromatic nuclei and scant cytoplasm. A few nests may also exhibit psuedorosettes.^[6][3]
• Immunohistochemistry of VIPoma typically demonstrates positive immunoreactivity for vasoactive intestinal peptide, cytokeratin, neuron specific enolase, chromogranin, synaptophysin, and somatostatin, with negative reactivity for S100, calcitonin, PSA, CEA, insulin, glucagon, and growth hormone.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Madhu Sigdel M.B.B.S.[2]Parminder Dhingra, M.D. [3] Homa Najafi, M.D.[4]

The cause of VIPoma has not been identified.

The cause of VIPoma has not been identified. However, 5 % of VIPomas are associated with MEN-1 syndrome.^[1][2][3][4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Madhu Sigdel M.B.B.S.[2]Parminder Dhingra, M.D. [3] Homa Najafi, M.D.[4]

VIPoma must be differentiated from ganglioneuroblastoma, ganglioneuroma, factitious diarrhea, bile salt enteropathy, rectal vilous adenomas, and laxative abuse.

VIPoma must be differentiated from:^[1]

• Ganglioneuroblastoma
• Ganglioneuroma
• Enterotoxin production by Vibrio cholera and E.coli
• Rectal vilous adenomas
• Bile salt enteropathy
• Factitious diarrhea
• Laxative abuseThe table below summarizes the findings that differentiate watery causes of chronic diarrhea^[2][3][4][5]

Cause			Osmotic gap		History	Physical exam	Gold standard	Treatment
			< 50 mOsm per kg	> 50 mOsm per kg*
Watery	Secretory	Crohns	+	–	Abdominal pain followed by diarrhea	Abdominal tenderness when palpated in severe disease Blood seen on rectal exam Fever Tachycardia Hypotension	Colonoscopy with biopsy	Topical mucosamine and corticosteroids are preferred Mesalamine and sulfasalazine are used for remission
		Hyperthyroidism	+	–	Excessive sweating Heat intolerance Increased bowel movements	Lump in the neck Proptosis Tremors Increased DTR	TSH with T3 and T4	Carbimazole and methimazole Beta blockers like propylthiouracil Iodine-131
		VIPoma	+	–	Watery diarrhea Dehydration (thirst, dry skin, dry mouth, tiredness, headaches, and dizziness) Lethargy, muscle weakness Nausea, vomiting Crampy abdominal pain Weight loss Flushing	Tachycardia Rash Facial flushing Abdominal distention Abdominal tenderness in the right upper abdominal quadrant	Elevated VIP levels Followed by imaging	Sandostatin or chemotherapy for malignant tumors Surgical removal of the tumor
	Osmotic	Lactose intolerance	–	+	Abdominal pain Bloating Diarrhea Flatulence	Abdominal tenderness	Intestinal biopsy	Avoidance of dietary lactose Substitution to maintain nutrient intake Regulation of calcium intake Use of enzyme lactase
		Celiac disease	–	+	May be asymptomatic Vague abdominal pain Diarrhea Weight loss Malabsorption / steatorrhea Bloatedness	Abdominal pain and cramping Abdominal distention Tetany Mouth ulcers Dermatitis herpetiformis Signs of the fat-soluble vitamins A, D, E, and K deficiency	IgA tissue transglutaminase Ab	Gluten-free diet
	Functional	Irritable bowel syndrome	–	–	Abdominal pain or discomfort recurring at least 3 days per month in the past 3 months and associated with 2 or more of the following: Improves with defecation Onset associated with change in frequency of stool Onset associated with change in appearance of stool 25% of bowel movements are loose stools History of straining is also common	Abdominal tenderness Hard stool in the rectal vault	Clinical diagnosis ROME III criteria Pharmacologic studies based criteria	High dietary fiber Osmotic laxatives such as polyethylene glycol, sorbitol, and lactulose Antispasmodic drugs (e.g. anticholinergics such as hyoscyamine or dicyclomine)

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VIPoma must be differentiated from diseases that cause abdominal pain and chronic diarrhea. The table below summarizes the findings that differentiate watery causes of chronic diarrhea:^{[6][2][3][4][5]}

Cause	Osmotic gap		History	Physical exam	Gold standard for diagnosis
	< 50 mOsm per kg	> 50 mOsm per kg*
Zollinger-Ellison syndrome	+	–	Abdominal pain and diarrhea Dyspepsia Upper or Lower gastrointestinal bleeding	Abdominal tenderness Hematochezia Hematemesis Tachycardia Hypotension	Gastrin levels
Crohn’s disease	+	–	Abdominal pain followed by diarrhea	Abdominal tenderness when palpated in severe disease Blood seen on rectal exam Fever Tachycardia Hypotension	Colonoscopy with biopsy
Hyperthyroidism	+	–	Excessive sweating Heat intolerance Increased bowel movements	Lump in the neck Proptosis Tremors Increased DTR	TSH with T3 and T4
VIPoma	+	–	Watery diarrhea Dehydration (thirst, dry skin, dry mouth, tiredness, headaches, and dizziness) Lethargy, muscle weakness Nausea, vomiting Cramping abdominal pain Weight loss Flushing	Tachycardia Rash Facial flushing Abdominal distention Abdominal tenderness in the right upper abdominal quadrant	Elevated VIP levels Followed by imaging
Lactose intolerance	–	+	Abdominal pain Bloating Diarrhea Flatulence	Abdominal tenderness	Intestinal biopsy
Celiac disease	–	+	May be asymptomatic Vague abdominal pain Diarrhea Weight loss Malabsorption/steatorrhea Bloatedness	Abdominal pain and cramping Abdominal distention Tetany Mouth ulcers Dermatitis herpetiformis Signs of the fat-soluble vitamins A, D, E, and K deficiency	IgA tissue transglutaminase Ab
Irritable bowel syndrome	–	–	Abdominal pain or discomfort recurring at least 3 days per month in the past 3 months and associated with 2 or more of the following: Improves with defecation Onset associated with change in frequency of stool Onset associated with change in appearance of stool 25% of bowel movements are loose stools History of straining is also common.	Abdominal tenderness Hard stool in the rectal vault	Clinical diagnosis ROME III criteria Pharmacologic studies based criteria

References

1. ↑ Reindl T, Degenhardt P, Luck W, Riebel T, Sarioglu N, Henze G; et al. (2004). “[The VIP-secreting tumor as a differential diagnosis of protracted diarrhea in pediatrics]”. Klin Padiatr. 216 (5): 264–9. doi:10.1055/s-2004-44901. PMID 15455292.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
2. ↑ ^{2.0 2.1} Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR; et al. (2005). “Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology”. Can J Gastroenterol. 19 Suppl A: 5A–36A. PMID 16151544.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
3. ↑ ^{3.0 3.1} Sauter GH, Moussavian AC, Meyer G, Steitz HO, Parhofer KG, Jüngst D (2002). “Bowel habits and bile acid malabsorption in the months after cholecystectomy”. Am J Gastroenterol. 97 (7): 1732–5. doi:10.1111/j.1572-0241.2002.05779.x. PMID 12135027.CS1 maint: Multiple names: authors list (link)
4. ↑ ^{4.0 4.1} Maiuri L, Raia V, Potter J, Swallow D, Ho MW, Fiocca R; et al. (1991). “Mosaic pattern of lactase expression by villous enterocytes in human adult-type hypolactasia”. Gastroenterology. 100 (2): 359–69. PMID 1702075.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
5. ↑ ^{5.0 5.1} RUBIN CE, BRANDBORG LL, PHELPS PC, TAYLOR HC (1960). “Studies of celiac disease. I. The apparent identical and specific nature of the duodenal and proximal jejunal lesion in celiac disease and idiopathic sprue”. Gastroenterology. 38: 28–49. PMID 14439871.CS1 maint: Multiple names: authors list (link)
6. ↑ SCOBIE BA, MCGILL DB, PRIESTLEY JT, ROVELSTAD RA (1964). “EXCLUDED GASTRIC ANTRUM SIMULATING THE ZOLLINGER-ELLISON SYNDROME”. Gastroenterology. 47: 184–7. PMID 14201408.CS1 maint: Multiple names: authors list (link)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Madhu Sigdel M.B.B.S.[2]Parminder Dhingra, M.D. [3] Homa Najafi, M.D.[4]

The annual incidence of VIPoma is approximately 0.01 per 100,000 (approx. 1 in 10 million) individuals worldwide. Female are more commonly affected by VIPoma than male. The incidence of VIPoma increases with age, the median age at diagnosis in adults is 50 years. VIPoma in children is usually diagnosed between age 2 to 4.

• The annual incidence of VIPoma is approximately 0.01 per 100,000 (approx. 1 in 10 million) individuals worldwide .^[1]

• Female are more commonly affected by VIPoma than male. The female to male ratio is approximately 3 to 1 in adults. ^[1]

• The incidence of VIPoma increases with age, the median age at diagnosis in adults is 50 years.^[1][2][3]
• VIPoma in children is usually diagnosed between age 2 to 4.
• VIPoma in children though uncommon, is usually ganglioneuromas or ganglioneuroblastomas which develop from neural crest tissue of sympathetic ganglia or adrenal medulla.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Madhu Sigdel M.B.B.S.[2]Parminder Dhingra, M.D. [3] Homa Najafi, M.D.[4]

The most important risk factor in the development of VIPoma is a positive family history of multiple endocrine neoplasia type 1.

• The most important risk factor in the development of VIPoma is a positive family history of multiple endocrine neoplasia type 1.^[1]
• The most cases of VIPoma are sporadic whereas in 5% of cases are associated with MEN-1.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Madhu Sigdel M.B.B.S.[2]Parminder Dhingra, M.D. [3] Homa Najafi, M.D.[4]

According to the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for VIPoma.

According to the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for VIPoma..^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Madhu Sigdel M.B.B.S.[2]Parminder Dhingra, M.D. [3] Homa Najafi, M.D.[4]

If left untreated, patients with VIPoma may progress to develop watery diarrhea, abdominal pain, bloating, nausea, vomiting, skin rash, backache, flushing, and lethargy. Common complications of VIPoma include metastasis, cardiac arrest from low blood potassium level, and dehydration. The presence of metastasis is associated with a particularly poor prognosis among patients with VIPoma, with a 5 year survival rate of 60%.

• If left untreated, patients with VIPoma may progress to develop watery diarrhea, abdominal pain, bloating, nausea, vomiting, skin rash, backache, flushing, and lethargy.^[1]
• VIPoma have a very slow growth rate compared to the most malignant tumors.

Common complications of VIPoma include:^[2][3]

• Metastasis
• Cardiac arrest from low blood potassium level
• Dehydration

• Surgery can usually cure VIPomas. However, in one-third to one-half of patients, the tumor has spread by the time of diagnosis and cannot be cured.^[4]
• The 5-year survival for patients with localized VIPoma is 94% whereas metastatic pancreatic VIPomas is 60%, respectively.

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