Vasoactive intestinal peptide tumors (VIPoma) are neuroendocrine tumors secreting vasoactive intestinal peptide (VIP) in an unregulated manner. Werner and Morrison first described them in 1958 as a pancreatic tumor resulting in watery diarrhea and hypokalemia . In 1973, the team of Bloom, Polak, and Pearse confirmed that the mediator was VIP . The VIPoma syndrome is also known as Verner-Morrison syndrome, watery diarrhea, hypokalemia, and hypochlorhydria or achlorhydria (WDHA) syndrome and pancreatic cholera syndrome . This review highlights the clinical presentation, diagnosis, and management.
VIP is a neurohormone produced in the central nervous system as well as in the neurons of the gastrointestinal (GI), respiratory, and urogenital tracts. It functions as a vasodilator and regulator of smooth muscle activity, stimulator of water and electrolyte secretion from the intestinal tract, an inhibitor of gastric acid secretion, and promotor of blood flow mainly in the GI tract.
VIPomas are rare tumors with an incidence of 0.05% to 2.0% and can occur both in children and adults . In adults, they occur most commonly between the ages of 30 to 50 years and are mostly intrapancreatic (95%). A small proportion of tumors secreting VIP have been reported as colorectal cancer, lung cancer, pheochromocytoma, neurofibroma, and ganglioneuroblastoma. The majority of VIPomas occur as isolated tumors, but in about 5% of patients, they are part of the multiple endocrine neoplasia type 1 (MEN1) syndromes. More than 50% of VIPomas have metastasized by the time of diagnosis .
In children, they are typically diagnosed between the ages of 2 to 4 years. The majority of VIPomas in children are either ganglioneuromas or ganglioneuroblastomas, arising from the neural crest tissue of the sympathetic ganglia, in the mediastinum or retroperitoneum. They may also arise from the adrenal medulla .
Excessive secretion of VIP from the tumor has multiple effects on different organ systems, with its primary effects being on the GI system. VIP is a neurotransmitter belonging to the secretin-glucagon family and consists of 28 amino acids. It is a potent stimulator of intestinal cyclic adenosine monophosphate (cAMP) production and inhibitor of gastric acid secretion. It promotes vasodilation, glycogenolysis, lipolysis, and bone resorption. Effects secondary to these actions of VIP include huge secretion of water and electrolytes from the GI epithelial cells, hypokalemia, facial flushing, decreased gastric acidity, elevated blood glucose, and hypercalcemia.
Patients with VIPoma most commonly present with watery diarrhea, which is secretory (it persists after a 48 hour fast). Diarrhea may be present for several years before diagnosis. Typically, stool amount exceeds 700 ml per day despite fasting and can exceed over 3000 ml per day in 70% of patients  . These stools are odorless and tea-colored and result in substantial losses of fluid and electrolytes such as potassium.
Other symptoms include lethargy, nausea, vomiting, muscle weakness, and cramps, which occur due to dehydration and hypokalemia. Flushing has been reported in about 8% to 20% of the patients. Tetany has been reported and is due to hypomagnesemia. If severe, the loss of fluid and electrolytes can result in cardiac arrhythmias, myopathy, tetany, and hypovolemic shock.
Children with VIPoma may present with failure to thrive in addition to chronic diarrhea.
Diagnosis of VIPoma is made in patients with secretory diarrhea usually greater than 3.0 liters per day with a serum VIP level around 250 to 500 pg/ml (reference range is less than 190 pg/ml). Secretory diarrhea has a low fecal osmotic gap of less than 50 mOsm/kg. It is important to repeat levels of VIP to confirm diagnosis since levels may not be elevated between episodes of watery diarrhea. It is also imperative to determine VIP levels when the patient is symptomatic, as the VIPoma may only secrete VIP intermittently. Hence, a normal level may be a false negative. Among children suspected of having VIPoma, catecholamine levels should also need to be measured. Levels of pancreatic polypeptide are elevated in tumors originating from the pancreas.
Electrolyte abnormalities include hypokalemia, hypochlorhydria, hypomagnesemia, hyperglycemia, and hypercalcemia. Hypokalemia and hyperchloremic metabolic acidosis occur due to a large amount of GI loss and bicarbonate wasting. Hypochlorhydria occurs secondary to the direct gastric acid inhibitory effect of VIP. Hypercalcemia may be due to dehydration, coincidental MEN1 syndrome, or secretion by the tumor of a calcitrophic peptide. Hypomagnesemia may occur from profound diarrhea. Hyperglycemia is due to the increased glycogenolytic activity of VIP.
Tumor localization is typically started with helical multiphasic contrast-enhanced CT scan. The sensitivity of multiphasic CT scans is significantly high at greater than 80% for detecting intrapancreatic neuroendocrine tumors  . Intravenous (IV) contrast further aids with detecting smaller lesions.
MRI is performed in case of indeterminate lesions and may have a better sensitivity to detect liver metastases.
Somatostatin receptor scintigraphy using radiolabeled somatostatin analog octreotide or lanreotide has the advantage of detecting small, occult metastases within and outside of the abdomen.
Other techniques include endoscopic ultrasound, which helps determine the accurate extent of the disease. A biopsy of the pancreatic lesions can also be performed with this technique.
The FDA approves functional PET imaging technique with 68-Ga DOTATATE injection as the radioactive diagnostic agent for the detection of somatostatin receptor-positive neuroendocrine tumors in both adult and pediatric patients.
The management of VIPoma involves medical management and surgery.
Management of Metastatic/Progressive Disease
Surgical resection of the liver is indicated in cases of liver metastases in the absence of diffuse involvement of both the lobes, decreased liver function, or extrahepatic metastases.
Radiofrequency ablation and cryoablation have also been the choice of the modality of treatment in cases of small metastases less than 3 cm . Hepatic artery embolization is a palliative treatment measure in patients with unresectable hepatic metastases.
Systemic chemotherapy is a treatment modality used in patients with large, bulky tumors or patients extrahepatic metastases. A combination regimen with streptozocin or temozolomide-based regimen has been tried . The overall response to systemic chemotherapy is not encouraging.
Novel agents like sunitinib, a tyrosine kinase inhibitor, and everolimus, an mTOR inhibitor, are approved in the United States for treatment of advanced, well-differentiated pancreatic neuroendocrine tumors including VIPomas  .
Causes of secretory diarrhea in adults of the developed countries include laxative abuse, carcinoid syndrome, microscopic colitis, and bile salt malabsorption due to ileal resection. Though more common in the developing countries, diarrhea due to infection from Vibrio cholera, enterotoxigenic Escherichia coli may also need to be ruled out after careful assessment of the history. Secretory diarrhea may occasionally occur in association with gastrointestinal disorders like Crohn disease and short bowel syndrome. In rare cases, Munchausen syndrome by proxy may also need to be ruled out.
In children, rarely inherited electrolyte transport defects, like congenital chloride diarrhea and congenital sodium diarrhea may cause secretory diarrhea. These present in early infancy.
The median survival of patients with VIPoma is 96 months . It is mostly dependent on tumor grade, stage, and surgical resectability.
As per recent National Comprehensive Cancer Network (NCCN) guidelines, the post-resection follow up includes history and physical examination, multiphasic CT or MRI and serum VIP level in the initial 3 to 12 month period. After one year, it is recommended to follow the same measures every 6 to 12 months.
A VIPoma is a rare and challenging tumor to diagnose and treat. Successful care will be enhanced by a coordinated interprofessional team of an endocrinologist, gastroenterologist, gastroenterology nurse, surgeon, pharmacist, oncologist, and oncology nurse managing the treatment of a patient with this condition. Nurses monitor patients, notify the team of changes in status, and educate the patients and family about the condition. Pharmacists review prescriptions and check for interactions. [Level 5]
|||Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia., VERNER JV,MORRISON AB,, The American journal of medicine, 1958 Sep [PubMed PMID: 13571250]|
|||Vasoactive intestinal peptide and watery-diarrhoea syndrome., Bloom SR,Polak JM,Pearse AG,, Lancet (London, England), 1973 Jul 7 [PubMed PMID: 4123289]|
|||Vasoactive Intestinal Peptide Tumor (VIPoma), Vinik A,,, 2000 [PubMed PMID: 25905195]|
|||Ito T,Igarashi H,Jensen RT, Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances. Best practice & research. Clinical gastroenterology. 2012 Dec [PubMed PMID: 23582916]|
|||Perry RR,Vinik AI, Clinical review 72: diagnosis and management of functioning islet cell tumors. The Journal of clinical endocrinology and metabolism. 1995 Aug [PubMed PMID: 7629220]|
|||Belei OA,Heredea ER,Boeriu E,Marcovici TM,Cerbu S,Mărginean O,Iacob ER,Iacob D,Motoc AGM,Boia ES, Verner-Morrison syndrome. Literature review. Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie. 2017 [PubMed PMID: 28730220]|
|||Grier JF, WDHA (watery diarrhea, hypokalemia, achlorhydria) syndrome: clinical features, diagnosis, and treatment. Southern medical journal. 1995 Jan [PubMed PMID: 7817223]|
|||Mekhjian HS,O'Dorisio TM, VIPoma syndrome. Seminars in oncology. 1987 Sep [PubMed PMID: 2820063]|
|||Legmann P,Vignaux O,Dousset B,Baraza AJ,Palazzo L,Dumontier I,Coste J,Louvel A,Roseau G,Couturier D,Bonnin A, Pancreatic tumors: comparison of dual-phase helical CT and endoscopic sonography. AJR. American journal of roentgenology. 1998 May [PubMed PMID: 9574609]|
|||Khashab MA,Yong E,Lennon AM,Shin EJ,Amateau S,Hruban RH,Olino K,Giday S,Fishman EK,Wolfgang CL,Edil BH,Makary M,Canto MI, EUS is still superior to multidetector computerized tomography for detection of pancreatic neuroendocrine tumors. Gastrointestinal endoscopy. 2011 Apr [PubMed PMID: 21067742]|
|||O'Dorisio TM,Mekhjian HS,Gaginella TS, Medical therapy of VIPomas. Endocrinology and metabolism clinics of North America. 1989 Jun [PubMed PMID: 2545444]|
|||Friesen SR, The development of endocrinopathies in the prospective screening of two families with multiple endocrine adenopathy, type I. World journal of surgery. 1979 Nov [PubMed PMID: 43626]|
|||Smith SL,Branton SA,Avino AJ,Martin JK,Klingler PJ,Thompson GB,Grant CS,van Heerden JA, Vasoactive intestinal polypeptide secreting islet cell tumors: a 15-year experience and review of the literature. Surgery. 1998 Dec [PubMed PMID: 9854582]|
|||Fernández-Cruz L,Blanco L,Cosa R,Rendón H, Is laparoscopic resection adequate in patients with neuroendocrine pancreatic tumors? World journal of surgery. 2008 May [PubMed PMID: 18264824]|
|||Moug SJ,Leen E,Horgan PG,Imrie CW, Radiofrequency ablation has a valuable therapeutic role in metastatic VIPoma. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]. 2006 [PubMed PMID: 16354964]|
|||Krug S,Boch M,Daniel H,Nimphius W,Müller D,Michl P,Rinke A,Gress TM, Streptozocin-Based Chemotherapy in Patients with Advanced Neuroendocrine Neoplasms--Predictive and Prognostic Markers for Treatment Stratification. PloS one. 2015 [PubMed PMID: 26630134]|
|||Raymond E,Dahan L,Raoul JL,Bang YJ,Borbath I,Lombard-Bohas C,Valle J,Metrakos P,Smith D,Vinik A,Chen JS,Hörsch D,Hammel P,Wiedenmann B,Van Cutsem E,Patyna S,Lu DR,Blanckmeister C,Chao R,Ruszniewski P, Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. The New England journal of medicine. 2011 Feb 10 [PubMed PMID: 21306237]|
|||Yao JC,Shah MH,Ito T,Bohas CL,Wolin EM,Van Cutsem E,Hobday TJ,Okusaka T,Capdevila J,de Vries EG,Tomassetti P,Pavel ME,Hoosen S,Haas T,Lincy J,Lebwohl D,Öberg K, Everolimus for advanced pancreatic neuroendocrine tumors. The New England journal of medicine. 2011 Feb 10 [PubMed PMID: 21306238]|
|||Roland CL,Bian A,Mansour JC,Yopp AC,Balch GC,Sharma R,Xie XJ,Schwarz RE, Survival impact of malignant pancreatic neuroendocrine and islet cell neoplasm phenotypes. Journal of surgical oncology. 2012 May [PubMed PMID: 22006521]|