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AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Daniel S Tung, MD, Fellow in Endocrinology, Department of Internal Medicine, Baylor College of Medicine
Daniel S Tung is a member of the following medical societies: American Association of Clinical Endocrinologists and American Medical Association
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, The University of Texas MD Anderson Cancer Center;
Klaus Radebold, MD, PhD, Research Associate, Department of Surgery, Yale University School of Medicine
Editors: Frederick H Ziel, MD, Chief of Endocrinology, Kaiser Permanente Woodland Hills, Department of Internal Medicine, Division of Diabetes and Endocrinology, Associate Professor, University of California at Los Angeles; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS, Affiliate Research Professor, School of Computational Sciences; Principal, Bioinformatics and Computational Biology Program, C/A Informatics, LLC; Mark Cooper, MD, Head, Vascular Division, Baker Medical Research Institute; Professor of Medicine, Monash University; George T Griffing, MD, Professor of Medicine, Director of General Internal Medicine, St Louis University
Author and Editor Disclosure
Synonyms and related keywords:
Verner-Morrison syndrome, pancreatic cholera, watery diarrhea-hypokalemia-achlorhydria syndrome, WDHA, vasoactive intestinal polypeptide, VIP, VIPoma, neuroendocrine tumor, pancreatic endocrine tumor, multiple endocrine neoplasia type 1 syndrome, MEN 1
Background
In 1958, Verner and Morrison described a syndrome of watery diarrhea, hypokalemia, and achlorhydria (WDHA) in 2 patients. These patients eventually succumbed to the condition from dehydration and renal failure despite attempted intravenous hydration. In 1970, Said and Mutt extracted the putative hormone causing WDHA from pig gut tissue. Finally, in 1973, this hormone was causally linked to WDHA when Bloom reported 6 patients with watery diarrhea that was due to pancreatic tumors associated with raised plasma levels of this hormone. The extirpated tumors from these cases were found to contain large amounts of what is now known as vasoactive intestinal polypeptide (VIP).
Pathophysiology
VIPoma is a neuroendocrine tumor, mainly found in the pancreas, that secretes VIP autonomously.
VIP has a molecular weight of 3381, consists of 28 amino acids, and belongs to the secretin-glucagon family. The VIP gene is located on chromosome 6. VIP is normally expressed in the central nervous system and in the neurons of the gastrointestinal, respiratory, and urogenital tracts, where it functions as a neurotransmitter. VIP regulates the synthesis, secretion, and action of other neuroendocrine hormones as well as cytokines and chemokines. Deficiency of VIP leads to developmental and behavioral abnormalities, including impaired circadian rhythms, in animal models. Overexpression of VIP causes diarrhea and cancer, and overexpression of VIP receptors promotes cancerous growth. In the gastrointestinal tract, VIP is largely responsible for the relaxation of vascular and nonvascular smooth muscle and for water and electrolyte secretion. VIP is released in response to gut distension by food.
VIP is a potent stimulator of gut cyclic adenosine monophosphate (cAMP) production, which leads to massive secretion of water and electrolytes (mainly potassium). VIP resembles secretin, which stimulates secretion of alkaline pancreatic juices. In the stomach, VIP inhibits histamine and pentagastrin-stimulated acid secretion. Like glucagon, VIP stimulates lipolysis and glycogenolysis and has an inotropic effect on the myocardium. It also has anti-inflammatory properties and modulates the immune system. VIPomas arise from the pancreas in 90% of cases, but they may also be found in periganglionic tissue or other sites including the colon, bronchus, adrenal glands, and liver, especially in children. These tumors are almost always solitary, with only less than 5% of cases being multicentric. These tumors are usually greater than 3 cm at the time of diagnosis and are mostly found in the body and tail of the pancreas.
Approximately 60-80% of VIPomas are malignant and have metastasized at the time of diagnosis. Metastasis occurs most frequently in the liver but may also occur in the lymph nodes, lung, or kidneys. Approximately 5% of VIPomas are associated with multiple endocrine neoplasia type 1 (MEN 1) syndrome. Conversely, 17% of patients with MEN 1 develop VIPomas at some stage of their disease. Approximately 10% of neuroendocrine tumors of the gastrointestinal tract (except carcinoids) are VIPomas.
Frequency
International
The incidence of new cases of VIPomas is 0.05-0.5 per million people per year.
Mortality/Morbidity
- Morbidity from untreated WDHA syndrome is related to long-standing dehydration and electrolyte and acid-base disturbances, which may result in chronic renal failure.
- Death results from renal failure or cardiac arrest caused by volume depletion, hypokalemia, and severe acid-base disturbances.
Sex
- The male-to-female ratio is approximately 1:1.
Age
- Peak incidence occurs in the fifth decade of life, but VIPomas may occur in all ages including young children and elderly persons.
History
- The onset of VIPoma is insidious.
- The dominant symptom is profuse diarrhea despite fasting that may persist for years before the diagnosis is established. Diarrhea may be episodic initially but becomes continuous as the tumor progresses. Stool volumes are typically profound, with volumes greater than 3 L per day in 70% of cases. The stool is typically odorless and tea-colored, without blood or mucus.
- The loss of water, sodium, and chloride may lead to volume depletion, dehydration, and exhaustion among patients unable to replace fluid and electrolyte losses. Weight loss and even renal failure have been reported in some patients.
- Excretion of large amounts of potassium and bicarbonate in the stool causes hypokalemia and non–anion gap acidosis. Hypokalemia may present as muscle cramps, weakness, or both.
- Abdominal discomfort or bloating has been reported.
- Facial flushing involved one third of patients from a 31-case series in China. Other studies have also reported facial flushing without a reported frequency.
- One reported case in China involved periodic backache and a rash involving the chest, back, and upper limb. These 2 symptoms occurred before or after the diarrhea, worsened over 6 years, and resolved after surgical resection.
Physical
- Volume depletion may lead to tachycardia, decreased skin turgor, and documented weight loss.
- Because of marked fecal loss of potassium, patients may have muscle weakness on examination.
- Patients may present with a mildly distended abdomen.
- Hepatomegaly may be detected if liver metastasis has occurred.
- Facial flushing may be seen because of the vasodilatory effects of VIP.
- An electrocardiogram may reveal QRS widening and T-wave flattening if hypokalemia is severe.
Causes
Point mutations on chromosome 11 of the MEN1 gene have been identified in cases where VIPomas are part of MEN 1 and, to a lesser extent, in sporadic tumors.
Carcinoid Tumor, Intestinal
Gastrinoma
Gastroenteritis, Bacterial
Pancreatic Cancer
Somatostatinomas
Sprue, Tropical
Thyroid, Medullary Carcinoma
Villous Adenoma
Wermer Syndrome (MEN Type 1)
Zollinger-Ellison Syndrome
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
Lab Studies
- Diagnosis is made when watery diarrhea, hypokalemia, and achlorhydria are present in the setting of elevated serum 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.
- 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 primarily focused on the pancreas because 90% of VIPoma tumors are located in the pancreas. Tumor localization is generally not difficult as these tumors are generally larger than 3 cm in the longest dimension at the time of diagnosis.
- CT scan
- CT scan 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 et al reported that all VIPomas of the pancreatic body and tail were identified on CT, but only 71% of VIPomas in the pancreatic head were successfully identified on CT.
- MRI
- MRI may be used if a CT scan is contraindicated, eg, allergy to iodine contrast dyes or renal failure.
- VIPomas are observed best on T1-weighted, fat-suppressed images as low-signal intensity masses.
- Liver metastases may demonstrate intensive peripheral ring enhancement on immediate post-gadolinium spoiled gradient-echo images.
- Somatostatin receptor scintigraphy
Somatostatin receptor scintigraphy may be useful to characterize an abnormality found on 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. - Use for localization of neuroendocrine tumors, including VIPomas, may be improved in the near future by single-photon emission CT, as suggested by recent investigations.
- Technetium 99m sestamibi: Reports demonstrate successful VIPoma localization with technetium 99m sestamibi.
- 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 because VIP 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
- Endoscopic retrograde cholangiopancreatography may demonstrate occlusion of the major pancreatic duct.
- It also may demonstrate calcifications in the body of the pancreas.
- Colonoscopy
- This may be useful to evaluate for a possible villous adenoma as an alternative cause of potassium-losing diarrhea.
Histologic Findings
These tumors, like other pancreatic endocrine tumors, are felt to arise from the pluripotent cells in ductal epithelium. Histologic examination usually reveals sheets of nested, uniform-appearing cells with round nuclei and low mitotic rate, typical for neuroendocrine tumors. Immunohistochemistry staining is positive for VIP and chromogranin A. Under electron microscopy, neurosecretory granules may be seen clustering around Golgi complexes and the endoplastic reticulum. Classifying a tumor as malignant or benign based on microscopic appearance alone is difficult.
Medical Care
- Initial treatment is aimed at correcting any volume, electrolyte, and acid-base abnormalities with intravenous normal saline, potassium chloride, and, if acidosis is severe, sodium bicarbonate. In many cases, these abnormalities are severe, requiring hospital admission.
- Somatostatin is highly effective in reducing serum VIP levels and promptly controlling diarrhea in more than 90% of patients. To circumvent the short serum half-life of somatostatin, the derivative octreotide is used. Octreotide is delivered subcutaneously at an initial dose of 50-100 mcg 3 times a day, which may be titrated up for symptom control to a maximum of 500 mcg 3 times a day. A long-acting formulation of octreotide called Sandostatin LAR allows for once monthly intragluteal administration and is now available. The starting dose of Sandostatin LAR is 10-20 mg per month. The dose can subsequently be titrated up to a maximum of 40 mg monthly. Diarrhea recurs when Sandostatin treatment is discontinued. It is currently debated whether somatostatin analogues also diminish tumor size.
- Long-term octreotide treatment frequently results in gradual resistance to this treatment. When maximum tolerable doses of octreotide are unable to control symptoms, interferon alpha may be added to control diarrhea, with possible modest reduction in tumor size.
- Glucocorticoids are less effective but less expensive, reducing symptoms in approximately 50% of patients.
- Preoperative treatment with a proton pump inhibitor is advisable to prevent rebound gastric acid hypersecretion after surgical removal of tumor.
- Systemic chemotherapy may be needed in cases of unresectable or progressive disease. Streptozocin, doxorubicin, fluorouracil, or their combination appears to be beneficial, although the number of treated cases has been limited.
The use of radiolabeled octreotide to target radiation treatment to VIPoma is based on the affinity of octreotide to the somatostatin receptors on the VIPoma cells. In one trial, half of the patients achieved stabilization of previously progressive tumors, with minimal bone marrow toxicity. This therapeutic approach is still considered experimental.
Surgical Care
- After appropriate fluid and electrolyte replacement, all operable patients with apparently resectable disease should receive abdominal exploration with careful staging. Intraoperative ultrasonography of the pancreas may aid in locating an otherwise unidentified tumor. For patients without nodal or distant metastasis, complete surgical resection offers the only chance for a cure.
- Local tumor resection is the treatment of choice.
- Pancreatoduodenectomy is indicated when the tumor is in the pancreatic head or processus uncinatus.
- If no tumor is found at surgery, a blind pancreatic tail resection may be performed. A total pancreatectomy no longer is recommended.
- In most cases, metastatic disease is found at the time of diagnosis. For these patients, tumor debulking may reduce clinical symptoms, but surgical plans ought to include resection of more than 90% of tumor volume for substantial clinical benefit.
- Postoperative octreotide therapy will usually be needed indefinitely to control symptoms of VIP hypersecretion from residual tumor.
- Unresectable liver metastases may be treated with bland hepatic artery embolization or transcatheter chemoembolization with doxorubicin or cisplatin.
- When embolization is unsuccessful or not feasible for liver metastases, percutaneous or intraoperative radiofrequency tumor ablation may be attempted, although not ideal for large metastatic tumors.
- All patients having surgery should undergo a cholecystectomy to alleviate concerns of gallstones with somatostatin analogue therapy in case such therapy may be needed in the future.
- Orthotopic liver transplantation has been performed in a small number of select patients with pancreatic endocrine tumors with approximately a 50% survival rate at 5 years.
Consultations
- Consultation with an endocrinologist is indicated, particularly in MEN 1 or other polyhormonal secretion states or if long-term hormonal suppression is required.
- Consultation with a gastroenterologist may be indicated for evaluation of long-term diarrhea or colonoscopy evaluation for villous adenoma.
- Consultation with a surgeon experienced in pancreatic surgery may be indicated if the evaluation suggests a resectable or debulkable tumor or exploratory surgery is contemplated.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Drug Category: Somatostatin analogs
These agents may control diarrheal symptoms in as many as 80% of patients with unresectable or metastatic tumors. High-dose treatment may lead to additional antiproliferative effects. However, long-term application of somatostatin may down-regulate receptor expression levels, resulting in decreased efficiency despite increasing doses. Both short-acting and long-acting depot preparations are available.
| Drug Name | Octreotide acetate (Sandostatin) |
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| Description | Acts similarly to the natural hormone somatostatin and has the ability to suppress secretion of gastroenteropancreatic peptides, including VIP. Start with small doses in patients with VIPomas. |
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| Adult Dose | 150-300 mcg/24 h SC divided bid/qid (range 150-750 mcg) during initial 2 wk; adjust dose to individual; doses >450 mcg usually not required; LAR long-acting preparation can be used intragluteally once/mo with initial dose of 10-20 mg to maximum of 40 mg monthly; long-acting preparation not for IV/SC administration |
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| Pediatric Dose | Not established |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Associated with alterations in nutrient absorption; carefully consider effect on any PO drug |
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| Pregnancy | B - Usually safe but benefits must outweigh the risks.
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| Precautions | Dosage adjustments may be required to control symptoms; patients may develop hypoglycemia or hyperglycemia due to alterations in balance between counter regulatory hormones; baseline and periodic thyroid function tests advised; gallstones may develop; half-life may be increased in patients with renal failure |
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Drug Category: Glucocorticoids
Elicit anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli. Glucocorticoids are less effective but less expensive, reducing symptoms in approximately 50% of patients.
| Drug Name | Prednisone (Deltasone, Meticorten, Orasone) |
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| Description | Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production. |
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| Adult Dose | 30-50 mg/d PO qd; gradually taper dose following resolution of symptoms |
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| Pediatric Dose | Disease rarely occurs in children |
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| Contraindications | Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI disease |
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| Interactions | Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics |
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| Pregnancy | B - Usually safe but benefits must outweigh the risks.
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| Precautions | Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use |
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Further Inpatient Care
- Hepatic artery embolization or chemoembolization may be required as described in Surgical Care.
- Occasionally, external radiation therapy may be indicated in locally unresectable tumors; however, experience is limited to a few cases.
Further Outpatient Care
- Patients with VIPomas need frequent outpatient follow-up to monitor hydration status and serum electrolyte levels.
- In patients with continuing fluid loss that is not controlled effectively by medical and surgical treatment options, a Port-a-Cath or other long-term central venous access devices may be implanted, and the patient may be trained to perform replacement of fluid and electrolytes at home or in an ambulatory setting.
- Patients on Sandostatin LAR may need monthly clinic visits to receive the injections.
In/Out Patient Meds
- Octreotide dosing is continued in most patients, unless surgical cure has been achieved.
- In patients with advanced disease, tumors may respond to treatment with streptozotocin-based chemotherapy.
- If conventional chemotherapy and somatostatin are not effective, 5-flourouracil may be combined with interferon alpha.
Prognosis
- Approximately 50% of surgical patients are cured after tumor resection.
- In a series of 241 patients with VIPomas, the 5-year survival rate was 89% for patients with pancreatic VIPomas and 68.5% for those with extrapancreatic neurogenic VIP-producing tumors. The 5-year survival rate of patients without metastatic disease was reported as up to 95%. In patients with metastases, the 5-year survival rate was approximately 60%.
Medical/Legal Pitfalls
- In patients with VIPomas, parathyroidectomy does not correct hypercalcemia. VIP and its PTH-like action cause hypercalcemia.
- Some patients have hypotension due to peripheral vasodilation. Severe hypertension may develop temporarily after tumor removal.
| Media file 1:
A patient with a large VIPoma. (A) Arteriogram showing the vascularity of the large VIPoma preoperatively. (B) Large mass seen during surgery. (C) The gross pathologic specimen. The patient subsequently developed liver metastases. He was treated with chemoembolization of the liver masses multiple times and finally succumbed to the disease 20 years after the initial surgical treatment. |
 |  View Full Size Image | |
Media type: Photo
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VIPomas excerpt Article Last Updated: Aug 10, 2006
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