Clinical presentation, diagnosis, and management of VIPoma

Author:: Emily Bergsland, MD
Section Editors:: Kenneth K Tanabe, MD; David C Whitcomb, MD, PhD
Deputy Editor:: Sonali M Shah, MD

Literature review current through: Apr 2025. | This topic last updated: Apr 24, 2025.

INTRODUCTION —

VIPomas are rare functioning neuroendocrine tumors (NETs) that secrete vasoactive intestinal polypeptide (VIP) [1,2]. This topic will review the clinical manifestations, diagnosis, and management of VIPomas. An overview of the clinical manifestations, diagnosis, and management of pancreatic NETs and other functioning pancreatic NETs are discussed in detail, separately.

●(See "Classification, clinical presentation, diagnosis, and staging of pancreatic neuroendocrine neoplasms".)

●(See "Surgical resection of sporadic pancreatic neuroendocrine neoplasms".)

●(See "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors".)

●(See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion".)

●(See "Insulinoma".)

●(See "Somatostatinoma: Clinical manifestations, diagnosis, and management".)

●(See "Glucagonoma and the glucagonoma syndrome".)

●(See "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis".)

●(See "Management and prognosis of gastrinoma (Zollinger-Ellison syndrome)".)

EPIDEMIOLOGY —

VIPomas are detected in 1 in a million people per year [3,4]. The majority of VIPomas arise within the pancreas, and are classified as functioning pancreatic neuroendocrine (islet cell) tumors. In adults, VIPomas are intrapancreatic in over 95 percent of cases. However, other vasoactive intestinal polypeptide (VIP)-secreting tumors have been reported, including lung cancer, colorectal cancer, ganglioneuroblastoma, pheochromocytoma, hepatoma, and adrenal tumors. In children, VIPomas rarely arise in the pancreas [5]. Instead, VIP-secreting tumors typically occur in the sympathetic ganglia (eg, ganglioneuroblastomas or ganglioneuromas) and the adrenal glands [6-8]. (See "Classification, clinical presentation, diagnosis, and staging of pancreatic neuroendocrine neoplasms", section on 'Classification'.)

VIPomas are usually diagnosed between 30 and 50 years of age in adults and between two and four years of age in children. Symptomatic pancreatic VIPomas are usually solitary, more than 3 cm in diameter, and occur in the tail of the pancreas in 75 percent of patients. Approximately 60 to 80 percent of VIPomas have metastasized by the time of diagnosis [9,10]. VIPomas usually occur as isolated tumors, but in 5 percent of patients they are part of the multiple endocrine neoplasia syndrome type 1 (MEN1) and occur in association with parathyroid and pituitary tumors, gastrinoma, and other tumors [11,12]. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis".)

PATHOPHYSIOLOGY —

The VIPoma syndrome is caused by excessive, unregulated secretion of vasoactive intestinal polypeptide (VIP) by the tumor. However, other substances, such as prostaglandin E2, may occasionally be secreted by the tumors [13]. VIP is a 28 amino acid polypeptide that binds to high affinity receptors on intestinal epithelial cells, leading to activation of cellular adenylate cyclase and cAMP production. This results in net fluid and electrolyte secretion into the lumen, resulting in secretory diarrhea and hypokalemia [13,14]. Other biologic actions of VIP including vasodilation, inhibition of gastric acid secretion, bone resorption, and enhanced glycogenolysis are responsible for flushing as well as laboratory findings of hypochlorhydria, hypercalcemia, and hyperglycemia in patients with VIPomas (table 1). (See "Vasoactive intestinal polypeptide" and 'Clinical features' below and "Physiology of gastric acid secretion".)

CLINICAL FEATURES

Clinical presentation — The majority of patients with VIPoma have VIPoma syndrome, which is also called the pancreatic cholera syndrome, Verner-Morrison syndrome, and the watery diarrhea, hypokalemia, and hypochlorhydria or achlorhydria (WDHA) syndrome. VIPoma syndrome is characterized by watery diarrhea that persists with fasting [15]. Stools are tea-colored and odorless with stool volumes exceeding 700 mL/day. In 70 percent of patients, stool volume can exceed 3000 mL per day [16-18]. Abdominal pain is mild or absent. Associated symptoms include flushing episodes in 20 percent of patients and symptoms related to hypokalemia and dehydration, such as lethargy, nausea, vomiting, muscle weakness, and muscle cramps (table 1). (See "Clinical manifestations and treatment of hypokalemia in adults".)

Laboratory findings — Patients with VIPoma have secretory diarrhea with a low osmotic gap (<50 mOsm/kg) (calculator 1) [19]. Hypochlorhydria occurs in 75 percent of patients and can result in iron and B12 deficiency. Other findings may include hyperglycemia and hypercalcemia (table 1). Hypercalcemia may be due to coexistent hyperparathyroidism as part of the multiple endocrine neoplasia syndrome type 1 (MEN1) syndrome or to hyperalbuminemia caused by dehydration. In patients with dehydration, the serum total calcium concentration is increased, but the serum ionized (or free) calcium concentration is normal. (See "Diagnostic approach to hypercalcemia", section on 'Verify elevated calcium' and "Approach to the adult with chronic diarrhea in resource-abundant settings".)

DIAGNOSIS —

The diagnosis of a VIPoma is suspected in patients with unexplained high-volume secretory diarrhea (>700 mL/day). The diagnosis is established by elevated serum vasoactive intestinal polypeptide (VIP) [15] levels. In one observational series of 52 patients with VIPoma, the median VIP level was 630 pictograms/mL [2]. However, a single elevated VIP level should be confirmed by repeat testing, taking care to observe the laboratory collection and processing instructions.

Evaluation of the patient with secretory diarrhea to exclude other causes is discussed in detail, separately. (See 'Differential diagnosis' below and "Approach to the adult with chronic diarrhea in resource-abundant settings".)

DIFFERENTIAL DIAGNOSIS —

Other disorders that can cause secretory diarrhea include surreptitious abuse of saline cathartics, enteritis caused by enterotoxigenic Escherichia coli or Vibrio cholera, microscopic colitis, bile salt malabsorption due to ileal resection, and the carcinoid syndrome (table 2). (See "Approach to the adult with chronic diarrhea in resource-abundant settings".)

TUMOR LOCALIZATION

Approach to imaging — After diagnosis, imaging studies are required to accurately localize the tumor. Cross-sectional imaging with multiphasic computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen can localize the tumor and stage the extent of disease. We begin with multiphasic contrast-enhanced CT for evaluation of patients with a VIPoma. We perform gadolinium-enhanced MRI when CT shows indeterminate lesions that need further characterization.

If cross-sectional imaging is inconclusive, endoscopic ultrasound (EUS) or integrated somatostatin-receptor (SSTR)-based positron emission tomography (PET)-CT or PET-MRI using gallium Ga-68 dotatate or copper Cu-64 dotatate should be performed to identify the tumor [20,21]. In addition, we perform integrated SSTR PET-CT or PET-MRI in a patient with VIPoma if the finding of extra-abdominal metastases would change treatment. (See "Classification, clinical presentation, diagnosis, and staging of pancreatic neuroendocrine neoplasms", section on 'Somatostatin receptor-based imaging studies'.)

●Computed tomography – CT scan is noninvasive and readily available. Intravenous contrast enhances the detection of smaller lesions, especially when images are obtained during the arterial phase. In addition, arterial phase and portal venous phase sequences can be used to maximize the conspicuity of liver metastases compared with the surrounding normal liver parenchyma. CT scans are highly accurate for detecting primary pancreatic neuroendocrine tumors (NETs), and, using multiphase imaging techniques, sensitivity is >80 percent [22-24]. Since most pancreatic VIPomas are more than 3 cm in size at presentation, a pancreatic mass can usually be identified by CT in the majority of cases [25]. The sensitivity of contrast-enhanced CT for these tumors approaches 100 percent [26,27]. (See "Classification, clinical presentation, diagnosis, and staging of pancreatic neuroendocrine neoplasms", section on 'Computed tomography'.)

●Magnetic resonance imaging – On MRI, pancreatic NETs are typically characterized by low signal intensity on T1-weighted images and high signal intensity on T2-weighted images (image 1 and image 2). MRI may have a higher sensitivity for liver metastases as compared with CT [28]. (See "Classification, clinical presentation, diagnosis, and staging of pancreatic neuroendocrine neoplasms", section on 'Magnetic resonance imaging'.)

●Endoscopic ultrasound – EUS can detect pancreatic tumors as small as 2 to 3 mm, provide accurate information on the local extent of disease, and allow for transmucosal needle biopsy of pancreatic lesions. However, EUS is rarely used in the evaluation of VIPomas as these tumors are diagnosed by hormonal assays and VIPomas are usually detectable on CT/MRI at diagnosis. (See "Classification, clinical presentation, diagnosis, and staging of pancreatic neuroendocrine neoplasms".)

●Functional PET imaging – Most VIPomas express SSTRs (between 80 to 100 percent of tumors) [29]. SSTR analogs, such as Ga-68 dotatate and Cu-64 dotatate, can detect SSTR expression on NETs. These tracers are approved for use with PET imaging for the localization of SSTR-positive NETs. Such SSTR-based PET-CT or PET-MRI scanning is the functional imaging modality of choice for staging and localization of most well-differentiated NETs [4,30-32]. Further details are discussed separately. (See "Clinical presentation, imaging and biomarker monitoring, and prognosis of metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors", section on 'Somatostatin receptor-based imaging studies'.)

STAGING —

Pancreatic neuroendocrine tumors (NETs), including VIPomas, are staged using the ninth version of the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system (table 3). The AJCC staging system for NETs of the pancreas is separate from that used for exocrine pancreatic tumors. Further details are discussed separately. (See "Classification, clinical presentation, diagnosis, and staging of pancreatic neuroendocrine neoplasms", section on 'Staging system'.)

TREATMENT

Symptomatic treatment

Repletion of fluid and electrolytes — Treatment of a patient with a VIPoma begins with replacement of fluid losses and correction of electrolyte abnormalities [15]. Many patients require more than 5 L of fluid and 350 mEq of potassium daily. (See "Maintenance and replacement fluid therapy in adults", section on 'Replacement fluid therapy' and "Clinical manifestations and treatment of hypokalemia in adults", section on 'Treatment' and "Treatment of hypovolemia (dehydration) in children in resource-abundant settings".)

Somatostatin analogs — Somatostatin and its analogs (eg, octreotide, lanreotide) inhibit the secretion of vasoactive intestinal polypeptide (VIP) [3,33-36]. For patients with VIPoma and diarrhea, we suggest a somatostatin analog (SSA). (See "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors".)

Symptomatic patients may be initiated on short-acting octreotide (50 to 100 micrograms subcutaneously every eight hours), if needed, with rapid transition to a long-acting formulation and subsequent titration of dose to optimize symptom control [37,38]. Sandostatin long-acting release (LAR), a depot preparation, is typically initiated at a dose of 20 to 30 mg IM monthly with gradual dose escalation as needed for optimal symptom control [39]. Patients may use additional short-acting octreotide for breakthrough symptoms while doses are being titrated; therapeutic levels of octreotide are not reached until 10 to 14 days after initiating the LAR injection. Lanreotide, another long-acting SSA, can be self-administered once monthly using a deep subcutaneous injection (typically 120 mg) and appears to have similar efficacy to octreotide [40-42].

SSAs are usually well tolerated, and side effects are generally mild. Potential side effects include symptoms of pancreatic malabsorption, mild glucose intolerance, and gallstones. Further details on the side effects of SSAs are discussed separately. (See "Treatment of the carcinoid syndrome", section on 'Side effects'.)

Other agents — The use of glucocorticoids (eg, prednisone 60 mg), clonidine, and loperamide and other antidiarrheals are generally reserved for patients with diarrhea that is refractory to SSAs [3,34,36,43]. Data suggest that cinacalcet may be useful for treating cystic fibrosis transmembrane conductance regulator (CTFR)-mediated secretory diarrhea as seen in VIPoma [44,45].

Pancreatic resection — Primary tumors can be managed with distal pancreatectomy. However, up to 60 percent have metastasized to lymph nodes, liver, kidneys, or bone at diagnosis [10,46]. Lack of symptomatic improvement after resection of functional neuroendocrine tumors (NETs) is associated with worse relapse-free survival [47]. (See "Surgical resection of lesions of the body and tail of the pancreas".)

Management of advanced/metastatic disease

Liver-directed therapy for metastatic disease

●Surgery – Hepatic resection is indicated for the treatment of metastatic liver disease in the absence of diffuse bilobar involvement, compromised liver function, or extrahepatic metastases (eg, pulmonary, peritoneal). Although eventual recurrence is the rule, palliation of symptoms stemming from hormone hypersecretion can be achieved, and prolonged survival is often possible given the slow-growing nature of these tumors [48-51].

Note that life-threatening fluid losses and electrolyte abnormalities should be corrected before surgery with SSA treatment, plus intravenous and electrolyte therapy [52]. Surgical resection for patients with metastases from pancreatic NETs is discussed separately. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Surgical resection'.)

●Hepatic artery embolization – Hepatic arterial embolization with or without selective hepatic artery infusion of chemotherapy is a palliative technique in patients with symptomatic hepatic metastases who are not candidates for surgical resection. Embolization can be performed via the infusion of gel foam powder into the hepatic artery through an angiography catheter (bland embolization) or in conjunction with chemotherapy (eg, doxorubicin, cisplatin) administered via the hepatic artery (chemoembolization). Chemoembolization with drug-eluting beads (DEB) has emerged as a more controversial option, with some studies suggesting more complications with DEB compared with bland or chemoembolization [53,54]. Another embolization technique uses radioactive isotopes (eg, yttrium-90 [90-Y]) tagged to glass or resin microspheres and delivered selectively to the tumor via the hepatic artery. Response rates, as measured by a decrease in hormonal secretion or radiographic regression, are generally over 50 percent [55-70]. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Hepatic arterial embolization'.)

●Radiofrequency ablation and cryoablation – Ablation can be used as a primary treatment modality for neuroendocrine liver metastases or as an adjunct to surgical resection [71]. Ablation can be performed percutaneously or laparoscopically and is less invasive than either hepatic resection or hepatic artery embolization. However, ablation is applicable only to smaller lesions (typically <3 cm), and its long-term efficacy is uncertain [72]. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Ablation'.)

●Liver transplantation – Liver transplantation is considered an investigational approach for metastatic pancreatic NETs, including VIPoma, as the number of patients with liver-isolated metastatic disease in whom orthotopic liver transplantation has been attempted is small, and follow-up data are insufficient to judge whether cure has been achieved [73-77]. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Liver transplantation'.)

Somatostatin analogs — In addition to decreasing hormone secretion and improving symptom control, SSAs have cytostatic activity in well-differentiated NETs [78,79]. Given their favorable safety profile, SSAs are considered the treatment of choice in patients with slow-growing, unresectable, metastatic well-differentiated NETs.

Molecularly targeted therapy and other novel agents — Molecularly targeted agents (eg, everolimus, sunitinib) have a role in the management of patients with progressive, advanced VIPomas [80-82]. Cabozantinib also has activity in patients with advanced pancreatic NETs [83]. Further details are discussed separately. (See "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors".)

Chemotherapy — For patients who are highly symptomatic due to tumor bulk or who have rapidly enlarging metastases, chemotherapy has been used as initial treatment together with a SSA. The options for therapy typically include a streptozocin-based combination or a temozolomide-containing regimen [84-86]. However, experience with systemic chemotherapy in patients with VIPomas is limited, and few patients have been included in contemporary clinical studies. Further details are discussed separately. (See "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors".)

Peptide receptor radionuclide therapy — Peptide receptor radionuclide therapy (PRRT) is another option for progressive SSTR-positive pancreatic NETs [87,88]. Symptomatic and radiologic responses have been noted in treating functional pancreatic NETs, including VIPoma, with lutetium Lu-177 dotatate PRRT [36,43,50,82,89,90]. Further details are discussed separately. (See "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors".)

POSTTREATMENT SURVEILLANCE —

There are limited data on the optimal posttreatment surveillance following resection of a VIPoma. Our approach for follow-up after treatment of a VIPoma consists of the following, which is generally consistent with guidelines from the National Comprehensive Cancer Network and others [36,91]:

●3 to 12 months postresection – History and physical examination, serum vasoactive intestinal polypeptide (VIP) level, and abdominal contrast-enhanced multiphasic CT or gadolinium-enhanced MRI. Obtain chest CT scan with or without contrast as clinically indicated.

●Greater than one year postresection to a maximum of 10 years – History and physical examination, serum VIP level, and abdominal contrast-enhanced multiphasic CT or gadolinium-enhanced MRI every 6 to 12 months. Obtain chest CT scan with or without contrast as clinically indicated.

PROGNOSIS —

The median survival of patients with VIPomas is 96 months [92]. Prognosis largely depends on VIPoma tumor grade, staging, and surgical resectability.

SOCIETY GUIDELINE LINKS —

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuroendocrine neoplasms".)

SUMMARY AND RECOMMENDATIONS

●Definition – VIPomas are rare neuroendocrine tumors (NETs) that secrete vasoactive intestinal polypeptide (VIP). (See 'Introduction' above.)

●Epidemiology – VIPomas are usually diagnosed between 30 and 50 years of age in adults and between two and four years of age in children. Pancreatic VIPomas are usually solitary, more than 3 cm in diameter, and occur in the tail of pancreas in 75 percent of patients. Approximately 60 to 80 percent of VIPomas have metastasized by the time of diagnosis. (See 'Epidemiology' above.)

●Association with MEN1 – VIPomas usually occur as isolated tumors, but in 5 percent of patients they are part of the multiple endocrine neoplasia syndrome type 1 (MEN1). (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Other functioning pancreatic NETs'.)

●Clinical presentation

•Clinical features – VIPoma syndrome is characterized by watery diarrhea that persists even during fasting. The stools are tea-colored, odorless with stool volumes exceeding 700 mL/day. In 70 percent of patients, stool volume can exceed 3000 mL/day. Abdominal pain is mild or absent. Associated symptoms include flushing, lethargy, nausea, vomiting, muscle weakness, and muscle cramps. (See 'Clinical features' above.)

•Laboratory findings – Patients with VIPoma have secretory diarrhea with a low osmotic gap (<50 mOsm/kg) (calculator 1). Hypochlorhydria occurs in 75 percent of patients. Other common laboratory findings include hyperglycemia and hypercalcemia. (See 'Laboratory findings' above.)

●Diagnosis – The diagnosis of a VIPoma is suspected in patients with unexplained high-volume secretory diarrhea. The diagnosis is established by an elevated serum VIP. However, a single elevated VIP level should be confirmed by repeat testing. (See 'Diagnosis' above.)

●Staging imaging studies and tumor localization – Multiphasic contrast-enhanced CT or gadolinium-enhanced MRI of the abdomen can localize the tumor and stage the extent of disease. If cross-sectional imaging is inconclusive, endoscopic ultrasound (EUS) or integrated somatostatin-receptor (SSTR)-based positron emission tomography (PET)-CT or PET-MRI using gallium Ga-68 dotatate or copper Cu-64 dotatate should be performed to identify the tumor. In addition, we perform integrated SSTR PET-CT or PET-MRI in patients with VIPomas if the finding of extra-abdominal metastases would change treatment. (See 'Tumor localization' above.)

●Management

•Fluid and electrolyte repletion – Treatment of hormone-mediated symptoms in a patient with a VIPoma begins with replacement of fluid losses and correction of electrolyte abnormalities. (See 'Repletion of fluid and electrolytes' above.)

•Somatostatin analog – For patients with VIPoma and diarrhea, we suggest a somatostatin analog (SSA) (Grade 2B). (See 'Somatostatin analogs' above.)

-Treatment is initiated with short-acting octreotide (50 to 100 micrograms subcutaneously every eight hours) with rapid transition to a long-acting octreotide formulation and subsequent dose titration to optimize symptom control. Alternatively, lanreotide may be used.

-Furthermore, use of anticancer therapy, particularly in the form of debulking surgery, liver-directed therapy, chemotherapy, or another systemic agent, may also lead to improved symptom control.

•Pancreatic resection – Primary tumors arising in the tail of the pancreas can be managed with distal pancreatomy. However, up to 60 percent of VIPomas have metastasized to lymph nodes, liver, kidneys, or bone at diagnosis. (See "Surgical resection of sporadic pancreatic neuroendocrine neoplasms" and 'Pancreatic resection' above.)

•Treatment of metastatic disease – Hepatic resection and/or ablation can be considered in patients with metastatic disease in the absence of diffuse bilobar involvement, compromised liver function, or extensive extrahepatic metastases. Hepatic arterial embolization with or without selective hepatic artery infusion of chemotherapy may be used for palliation in patients with symptomatic hepatic metastases who are not candidates for surgical resection. Tumor control can also be achieved with SSAs, chemotherapy, and molecularly targeted agents such as sunitinib, everolimus, and cabozantinib. Lutetium Lu-177 dotatate peptide receptor radionuclide therapy (PRRT) is also used to treat well-differentiated pancreatic NETs. (See 'Management of advanced/metastatic disease' above and "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors" and "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion".)

●Posttreatment surveillance – Our approach for follow-up after treatment of a VIPoma consists of the following (see 'Posttreatment surveillance' above):

•3 to 12 months postresection – History and physical examination, serum VIP level, and abdominal multiphasic CT or MRI. Obtain chest CT scan with or without contrast as clinically indicated.

•Greater than one year postresection to a maximum of 10 years – History and physical examination with serum VIP level every 6 to 12 months. Obtain abdominal multiphasic CT or MRI every 6 to 12 months. Obtain chest CT scan with or without contrast as clinically indicated.

ACKNOWLEDGMENT —

The UpToDate editorial staff thank Dr. Stephen E. Goldfinger, MD, for his past contributions as an author to this topic review.

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Topic 2610 Version 41.0

خرید پکیج

Clinical presentation, diagnosis, and management of VIPoma

References