VIPomas 

Updated: Mar 16, 2017
Author: Sai-Ching Jim Yeung, MD, PhD, FACP; Chief Editor: George T Griffing, MD 

Overview

Background

VIPomas are neuroendocrine tumors that secrete vasoactive intestinal peptide (VIP) autonomously.[1, 2, 3] 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.

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.

 

Presentation

History

The onset of VIPoma is insidious. The dominant symptom is profuse diarrhea despite fasting; this symptom may persist for years before the diagnosis is established. Diarrhea may be episodic initially, but it becomes continuous as the tumor progresses. The stool is typically odorless and tea-colored, without blood or mucus.

Clinical diagnosis is based on a history of approximately 10 watery stools per day. Fecal losses during fasting are at least 20 mL/kg/day but exceed 50 mL/kg/day in most cases. Fecal osmolality is entirely accounted for by twice the sum of the concentrations of sodium and potassium, indicating the electrolyte loss.

The loss of water, sodium, and chloride may lead to volume depletion, dehydration, and exhaustion among patients who are unable to replace the lost fluid and electrolytes. 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 or weakness.

Abdominal discomfort or bloating has been reported. In a 31-case series from China, facial flushing was observed in one third of patients.[15] Other studies have also reported facial flushing, but without specifying its frequency.

One patient in China reportedly suffered from 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 Examination

Aside from a mildly extended abdomen, no relevant abnormalities may be apparent on physical evaluation of patients with VIPomas. However, physical examination may also reveal one or more of the following:

  • Tachycardia, decreased skin turgor, and documented weight loss (from volume depletion)

  • Muscle weakness (from marked fecal loss of potassium)

  • Hepatomegaly (if liver metastasis has occurred)

  • Facial flushing (from the vasodilatory effects of vasoactive intestinal polypeptide [VIP])

  • Profuse sweating

  • Failure to thrive

  • Colonic dilatation

  • Glucose intolerance

Electrolyte abnormalities (see Workup) are commonly noted.

 

DDx

Diagnostic Considerations

In addition to the conditions listed in the differential diagnosis, other problems to be considered include the following:

  • Enteric anendocrinosis

  • Enteric dysendocrinosis

  • All conditions with diarrhea

  • Ganglioneuroblastoma (similar symptoms; mainly found in children)

  • Infectious diseases of the intestines

  • Laxative abuse

  • Villous adenoma of the rectum

Differential Diagnoses

 

Workup

Approach Considerations

Plasma vasoactive intestinal peptide (VIP) levels are determined by radioimmunoassay. In cases of VIPoma, VIP levels are usually 2-10 times the normal range (20-30 pmol/L). VIP levels must be determined when the patient is symptomatic because VIP release from the tumor fluctuates.

Imaging studies focus primarily on the pancreas, where 90% of VIPomas are located. Tumor localization normally is not difficult, because at the time of diagnosis, these tumors are generally larger than 3 cm in their longest dimension. Computed tomography (CT), magnetic resonance imaging (MRI), and somatostatin receptor scintigraphy are imaging modalities that can be used in the diagnosis of VIPoma. Reports have demonstrated successful VIPoma localization with99m Tc sestamibi.[16]

No formal staging criteria for VIPoma have been generally accepted. Metastasis most often occurs to the liver or regional lymph nodes. Rarely, metastasis to skin has been reported.

Laboratory Studies

A diagnosis of VIPoma is made when watery diarrhea, hypokalemia, and achlorhydria are present in the setting of elevated serum VIP concentrations. Stool volumes of less than 700 mL/day virtually exclude the diagnosis; typical stool volumes in the presence of a VIPoma exceed 3 L/day.

A normal plasma VIP level is 20-30 pmol/L or less, as determined by radioimmunoassay. VIP levels in patients with VIPoma often reach 160-250 pmol/L or higher. VIP levels should be drawn after fasting.[17] 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, serum VIP levels should be collected during bouts of severe diarrhea.

Hypokalemia and non–anion gap acidosis are the main diagnostic features of VIPomas. Hypokalemia may necessitate aggressive potassium replacement.

Hypercalcemia may occur in the absence of multiple endocrine neoplasia (MEN) type 1 syndrome or elevated parathyroid hormone levels. The mechanism of action is not clear but is believed to involve 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.

Hypochlorhydria or achlorhydria is seen in at least 75% of patients with VIPoma because VIP inhibits histamine- and pentagastrin-stimulated gastric acid secretion. This abnormality can be evaluated by measuring gastric pH or basal gastric acid output.

Renal function should be assessed by measuring blood urea nitrogen (BUN) and serum creatinine levels. Other electrolytes, including magnesium, should be checked and replaced. Stool weight with potassium measurements verifies high gastrointestinal (GI) potassium losses.

VIPomas may cosecrete other hormones, including pancreatic polypeptide, calcitonin, and neurotensin.

Computed Tomography

CT is indicated to search for neck, mediastinal, or retroperitoneal masses. No calcifications or bony infiltrations should be found. CT 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 CT successfully identified all VIPomas in the pancreatic body and tail but only 71% of VIPomas in the pancreatic head.[15]

Magnetic Resonance Imaging

MRI may be used if CT is contraindicated (eg, if the patient is allergic to iodine contrast dyes or is in a state of renal failure). VIPomas are best observed on T1-weighted, fat-suppressed images as low-signal-intensity masses. Liver metastases may demonstrate intensive peripheral ring enhancement on immediate postgadolinium spoiled gradient-echo images.[18]

Somatostatin Receptor Scintigraphy

Somatostatin receptor scintigraphy using radionuclide-labeled octreotide (111 In-pentetreotide (ie, DTPA-D-Phe-1-octreotide),111 In-DOTA-DPhe1 -Tyr3 -octreotide), or lanreotide (111 In -DOTA-lanreotide) may be useful for characterizing an abnormality found on a CT scan or for identifying occult or distant metastatic disease. It may also be used if postoperative changes diminish the clarity of a CT scan. Sensitivity for localization of all pancreatic endocrine tumors has been reported at 80-90%, with 92% sensitivity for tumors larger than 1 cm.

Other previously employed techniques include technetium-99m scintigraphy, 123-iodine-VIP receptor scintigraphy, and single-photon emission CT (SPECT). Investigations have suggested that in the future, the use of SPECT scanning may improve the value of somatostatin receptor scintigraphy for the localization of neuroendocrine tumors, including VIPomas.[19]

Other Studies

18 F-deoxyglucose (FDG)-PET scan has also been used to diagnose neuroendocrine tumors. However, it may not be as sensitive as somatostatin receptor scintigraphy.[20]

Chest radiography may reveal a paravertebral mass. Endoscopic retrograde cholangiopancreatography may demonstrate occlusion of the major pancreatic duct. It may also reveal calcifications in the body of the pancreas. Transabdominal ultrasonography may be used for early screening to exclude liver metastases, which may be present as hepatic calcifications.

Electrocardiography may reveal QRS widening and T-wave flattening if hypokalemia is severe. Colonoscopy may be useful as a means of evaluating for a villous adenoma as an alternative cause of potassium-losing diarrhea.

Histology

VIPomas, like other pancreatic endocrine tumors, are thought to arise from the pluripotent cells in ductal epithelium. Histologic examination usually reveals, as is typical for neuroendocrine tumors, sheets of nested, uniform-appearing cells with round nuclei and a low mitotic rate.

Immunohistochemical staining is positive for chromogranin A and VIP. Under electron microscopy, neurosecretory granules may be seen clustering around Golgi complexes and the endoplasmic reticulum. Classifying a tumor as malignant or benign on the basis of microscopic appearance alone is difficult.

 

Treatment

Approach Considerations

Initial treatment of VIPomas is directed toward correcting volume and electrolyte abnormalities. Octreotide acetate controls diarrhea in up to 90% of patients with VIPomas. Glucocorticoids reduce symptoms in 50%.

Systemic chemotherapy may be needed in cases of unresectable or progressive disease. Streptozocin, doxorubicin, fluorouracil, or a combination of these appears to be beneficial, though the number of treated cases has been limited.

Local tumor resection is the treatment of choice. In advanced disease, tumor debulking may relieve symptoms, but it is not effective in all cases. Transarterial chemoembolization (TACE) with chemotherapy-loaded materials may provide palliation in patients with extensive hepatic disease.[21] This treatment may be repeated several times, depending on tumor growth and symptoms. External radiation therapy may be indicated in unresectable tumors. Laparoscopic surgical resection has been successful in at least one adult with hepatic metastasis. Irreversible electroporation (IRE) for the management of unresectable pancreatic VIPoma has been reported.[22]

In patients with VIPoma, parathyroidectomy does not correct hypercalcemia. (VIP and its parathyroid hormone–like action cause hypercalcemia.)

Pharmacologic Therapy

Initial treatment for VIPoma is aimed at correcting any volume, electrolyte, and acid-base abnormalities with intravenous (IV) normal saline, potassium chloride, and, if acidosis is severe, sodium bicarbonate. In many cases, these abnormalities are pronounced enough to necessitate hospital admission.

In more than 90% of patients, somatostatin effectively reduces serum vasoactive intestinal peptide (VIP) levels and promptly controls diarrhea.[15] To circumvent the short serum half-life of somatostatin, the derivative octreotide is used. A long-acting octreotide formulation is available that allows once-monthly intragluteal administration. (Patients may have to make monthly clinic visits to receive the injections.) Diarrhea recurs when treatment is discontinued. It is currently debated whether somatostatin analogues also diminish tumor size.

Unless a surgical cure has been achieved (see Surgical Intervention), octreotide dosing is continued in most patients. Long-term octreotide treatment frequently results in gradually increasing resistance to this therapy. When the highest tolerable dosages of octreotide are unable to control symptoms, interferon alfa may be added to control diarrhea (and, possibly, achieve a modest reduction in tumor size).

Glucocorticoids are less effective, reducing symptoms in approximately 50% of patients. However, they are also less expensive.

In patients with advanced disease, tumors may respond to treatment with streptozocin-based chemotherapy (eg, streptozocin combined with 5-fluorouracil [5-FU]). If conventional chemotherapy and somatostatin are not effective, 5-FU may be combined with interferon alfa. Other chemotherapy agents that may be considered include dacarbazine and doxorubicin HCl.

Radiation Therapy

The use of radiolabeled octreotide to target radiation treatment toward a VIPoma is based on the affinity of octreotide for 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.[23] This therapeutic approach may be applied to advanced neuroendocrine tumors in general.

Occasionally, external radiation therapy may be indicated for locally advanced unresectable tumors; however, experience with this treatment is limited.

Surgical Intervention

Surgical exploration with tumor resection (see the image below) leads to cure in 50% of patients. 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.

Patient with a large VIPoma. (A) Arteriogram showi 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.

Local tumor resection is the treatment of choice.[15, 24, 25, 26] 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. Serum VIP levels may normalize within an hour after curative tumor resection. Preoperative treatment with a proton pump inhibitor is advisable to prevent rebound gastric acid hypersecretion after surgical tumor removal.

Severe hypotension may develop temporarily during and after tumor removal as a consequence of the vasodilatory effect of the VIP released during manipulation of the tumor. Severe hypertension may develop temporarily after tumor removal. Postoperatively, octreotide therapy will usually be needed indefinitely to control symptoms of VIP hypersecretion from residual tumor.[25]

In most cases, at the time of diagnosis of VIPoma, metastatic disease is already present. For these patients, tumor debulking may reduce clinical symptoms,[15, 26] but for substantial clinical benefit to be achieved, operative planning ought to include resection of more than 90% of tumor volume.

Unresectable liver metastases may be treated with hepatic artery radioembolization or transcatheter chemoembolization with doxorubicin or cisplatin.[27] When embolization is unsuccessful or not feasible for liver metastases, percutaneous or intraoperative radiofrequency tumor ablation may be attempted, though it is not ideal for large metastatic tumors.

All patients being surgically treated for a VIPoma should undergo a cholecystectomy to alleviate concerns of gallstones with somatostatin analogue therapy, in case such therapy is needed in the future. In patients with VIPomas, a parathyroidectomy does not correct hypercalcemia unless the VIPoma is resected.

Orthotopic liver transplantation has been performed in a small number of adult patients with pancreatic endocrine tumors; the 5-year survival rate has been approximately 50%.[28]

Consultations

Consultations with the following specialists may be warranted:

  • Endocrinologist - Consultation with an endocrinologist is indicated, particularly in MEN 1 or other polyhormonal secretion states or in cases where long-term hormonal suppression is required

  • Gastroenterologist - Consultation with a gastroenterologist may be indicated for evaluation of long-term diarrhea or for colonoscopic evaluation for villous adenoma

  • Surgeon - Consultation with a surgeon experienced in pancreatic surgery may be indicated if the evaluation suggests a resectable or debulkable tumor or if exploratory surgery is contemplated

Long-Term Monitoring

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 long-term central venous access device may be implanted; the patient may be trained to replace fluid and electrolytes at home or in an ambulatory setting.

Posttreatment VIP levels may serve as a tumor marker for recurrent disease.

 

Medication

Medication Summary

Somatostatin reduces serum vasoactive intestinal polypeptide (VIP) levels and controls diarrhea in patients with VIPomas. To circumvent the short serum half-life of somatostatin, the derivative octreotide is used. An available long-acting formulation of octreotide allows once-monthly intragluteal administration. Long-term treatment with octreotide often causes resistance to the drug. When maximum tolerable octreotide doses cannot control symptoms, interferon alfa may be added to control diarrhea.

Glucocorticoids are less effective but also less expensive.

Somatostatin Analogues

Class Summary

Somatostatin analogues 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 downregulate receptor expression levels, resulting in decreased efficiency despite increasing doses. Short-acting and long-acting depot preparations are available.

Octreotide acetate (Sandostatin, Sandostatin LAR)

Octreotide acetate acts similarly to the natural hormone somatostatin and has the ability to suppress the secretion of gastroenteropancreatic peptides, including VIP. Octreotide treatment in patients with VIPomas should start with low dosages, which are then titrated on the basis of patient response. Sandostatin LAR is a long-acting depot dosage formulation intended for intramuscular injection.

Lanreotide (Somatuline)

Lanreotide is a long-acting synthetic analogue of somatostatin. It binds to the same receptors as somatostatin but with higher affinity to peripheral receptors. It has a much longer biological half-life than octreotide, and its pharmacological effects are longer than octreotide.

Lanreotide's action is similar to the natural hormone somatostatin, but it is long-acting. It suppresses peptide secretion, including VIP, from gastroenteropancreatic tumors. It controls diarrhea in 80% of patients with unresectable or metastatic tumors. It is available in two formulations: sustained-release Somatuline La for IM injection every 10-14 days, and a depot formulation Somatuline Depot injected SC monthly.

Corticosteroids

Class Summary

Glucocorticoids have anti-inflammatory properties and cause profound and varied metabolic effects, modifying the body’s immune response to diverse stimuli. In the treatment of VIPomas, these agents are less expensive than octreotide but also less effective; they reduce symptoms in approximately 50% of patients.

Prednisone (Rayos)

Prednisone is an immunosuppressant used to treat autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte (PMN) activity. It stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production.

Prednisolone (Pediapred, Prelone, Orapred, Millipred, Flo-Pred)

Prednisolone may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. It is a commonly used oral agent.