Practice Essentials
VIPomas are neuroendocrine tumors that secrete vasoactive intestinal peptide (VIP) autonomously. [1, 2, 3] (See the image below.) They originate in amine precursor uptake and decarboxylation (APUD) cells of the gastroenteropancreatic endocrine system and in adrenal or extra-adrenal neurogenic sites. Neural crest cells are precursors of APUDoma and neurogenic cells.
Patient with a large VIPoma. (A) Arteriogram showing vascularity of a large VIPoma preoperatively. (B) Large mass seen intraoperatively. (C) Gross pathologic specimen. Patient subsequently developed liver metastases; he was treated with chemoembolization of liver masses multiple times and finally succumbed to disease 20 years after initial surgical treatment.
Signs and symptoms of VIPomas
The dominant symptom is profuse diarrhea despite fasting. Abdominal discomfort or bloating has been reported. Physical examination may also reveal one or more of the following:
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Tachycardia, decreased skin turgor, and documented weight loss (from volume depletion)
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Muscle weakness (from marked fecal loss of potassium)
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Hepatomegaly (if liver metastasis has occurred)
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Facial flushing (from the vasodilatory effects of VIP)
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Profuse sweating
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Failure to thrive
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Colonic dilatation
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Glucose intolerance
See Presentation for more detail.
Diagnosis of VIPomas
A diagnosis of VIPoma is made when watery diarrhea, hypokalemia, and achlorhydria are present in the setting of elevated serum VIP concentrations.
Laboratory studies
Plasma VIP levels are determined by radioimmunoassay. In cases of VIPoma, VIP levels are usually 2-10 times the normal range (20-30 pmol/L).
Imaging studies
The following imaging modalities have been used in the diagnosis of VIPoma:
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Computed tomography (CT)
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Magnetic resonance imaging (MRI)
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Somatostatin receptor scintigraphy
See Workup for more detail.
Management of VIPomas
Initial treatment of VIPomas is directed toward correcting volume and electrolyte abnormalities. Local tumor resection is the treatment of choice. Systemic chemotherapy may be needed in cases of unresectable or progressive disease.
See Treatment and Medication for more detail.
Background
The symptoms of VIPoma were initially described in 1958, when Verner and Morrison described a syndrome of watery diarrhea, hypokalemia, and achlorhydria (WDHA). [4] In 1970, Said and Nutt extracted the responsible hormone from animal gut [5] ; in 1973, Bloom causally linked this hormone to WDHA syndrome. In 1975, Swift et al was the first to report a child who had watery diarrhea and a ganglioneuroma with secretion of VIP. [6]
VIPomas arise from the pancreas in 90% of cases, but they may also be found in periganglionic tissue or at other sites (eg, colon, bronchus, adrenal glands, and liver), especially in children. [7] They are almost always solitary, with fewer than 5% being multicentric. The tumors are usually greater than 3 cm in diameter at the time of diagnosis and are found primarily in the body and tail of the pancreas.
In children, it is extremely rare for a VIPoma to originate in the pancreas; instead, WDHA syndrome is usually associated with VIP-secreting neurogenic tumors involving the retroperitoneum and mediastinum. Pancreatic non–beta-cell hyperplasia is rare but has been reported in children. Clinical experience is based mainly on case reports (~85 cases before 2005).
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, lungs, or kidneys. [8] Approximately 5% of VIPomas are associated with multiple endocrine neoplasia (MEN) type 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 (GI) tract (except carcinoids) are VIPomas.
Pathophysiology and Etiology
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 (CNS) and in the neurons of the GI, respiratory, and urogenital tracts, where it functions as a neurotransmitter.
VIP regulates the synthesis, secretion, and action of other neuroendocrine hormones; it also regulates cytokines and chemokines. VIP deficiency leads to developmental and behavioral abnormalities (eg, impaired circadian rhythms) in animal models. [9] Overexpression of VIP causes diarrhea and cancer, and overexpression of VIP receptors promotes cancerous growth. In the GI tract, VIP is responsible for relaxation of vascular and nonvascular smooth muscle and secretion of water and electrolytes. It is released in response to distention of the gut 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 the 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 in adults are usually neuroendocrine islet cell tumors of the pancreas that produce high amounts of VIP; other secreted hormones may include secreted gastrin and pancreatic polypeptide. In children and adolescents, VIP is produced mainly by ganglioneuromas, ganglioneuroblastomas, neurofibromas, or other tumors in the adrenal area (the most common location). Only a small fraction of neuroblastomas and ganglioneuroblastomas produce VIP, but VIP production indicates a more favorable prognosis.
Ganglioneuromatosis that affects the entire colon and rectum has been reported in a 7-year-old boy. [10] In contrast to individuals with VIP-secreting pancreatic tumors, patients with neurogenic lesions generally have normal serum levels of pancreatic polypeptide, gastrin, insulin, and somatostatin.
VIPomas can be part of MEN 1 syndrome. This relationship has not been observed with extrapancreatic VIP-secreting tumors of childhood. Somatic point mutations on chromosome 11 of the MEN1 gene have been discovered in sporadic VIPomas and VIPoma cases associated with MEN type 1.
Epidemiology
United States statistics
VIPomas are the third most common neuroendocrine tumor of the pancreas (15%), after insulinomas (50%) and gastrinomas (30%). Annually, 0.05-0.5 new cases per million adults have been reported. No data are available for the incidence of this condition in children.
Age- and sex-related demographics
Peak incidence occurs in the fifth decade of life, but VIPomas may occur in any age group, including young children and elderly persons. In a series of 19 childhood cases, the mean age of onset was 2.5 years. [11] In another series of 10 cases, the mean age of onset was 4 years. The earliest age of onset ever reported is 2 weeks. The male-to-female ratio in children is approximately 1:1, compared with 1:3 in adults.
Prognosis
Approximately 50% of surgical patients with VIPoma are cured after tumor resection. In a large series of 241 adult patients with VIPomas, the 5-year survival rate was 89% among those with pancreatic VIPomas and 68.5% among those with neurogenic VIP-producing tumors. [12] In metastatic disease, the 5-year survival rate was 59.6%. Children with neuroblastomas have a relatively poor overall survival rate (30-40%); children with VIP-secreting ganglioneuroblastomas have a considerably higher survival rate (>90%).
A study by Keutgen et al that evaluated factors affecting survival in malignant-functioning pancreatic neuroendocrine tumors found that the median survival time for VIPomas was 7.9 years. The study also found that primary tumor resection is associated with longer survival in stages I-III as well as stage IV malignant-functioning pancreatic neuroendocrine tumors. [13]
Morbidity from untreated WDHA syndrome is associated with long-standing dehydration and with electrolyte and acid-base disturbances, which may cause chronic renal failure. [14] Death results from renal failure or cardiac arrest caused by volume depletion, hypokalemia, and severe acid-base disturbances.
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Patient with a large VIPoma. (A) Arteriogram showing vascularity of a large VIPoma preoperatively. (B) Large mass seen intraoperatively. (C) Gross pathologic specimen. Patient subsequently developed liver metastases; he was treated with chemoembolization of liver masses multiple times and finally succumbed to disease 20 years after initial surgical treatment.
