Continuing Education Activity

Vasoactive intestinal peptide tumors (VIPoma) are neuroendocrine tumors secreting vasoactive intestinal peptide (VIP) in an unregulated manner. The VIPoma syndrome is also known as Verner-Morrison syndrome, watery diarrhea, hypokalemia, and hypochlorhydria or achlorhydria (WDHA) syndrome, and pancreatic cholera syndrome. This activity reviews the clinical presentation, diagnosis, and management of VIPomas and highlights the role of the interprofessional team in caring for patients affected by this condition.

Objectives:

• Describe the symptoms of VIPomas in adults and children.
• Review the importance of laboratory tests and imaging studies in diagnosing VIPomas.
• Explain the need for follow-up in patients with VIPomas.
• Summarize the significance of an integrated interprofessional approach to the medical and surgical management of VIPomas.

Introduction

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 [1]. In 1973, the team of Bloom, Polak, and Pearse confirmed that the mediator was VIP [2]. The VIPoma syndrome is also known as Verner-Morrison syndrome, watery diarrhea, hypokalemia, and hypochlorhydria or achlorhydria (WDHA) syndrome, and pancreatic cholera syndrome [3]. This review highlights the clinical presentation, diagnosis, and management.

Etiology

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.

Epidemiology

VIPomas are rare tumors with an incidence of 0.05% to 2.0% and can occur both in children and adults [4]. 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 [5].

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 [6].

Pathophysiology

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 an 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.

History and Physical

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 [7] [8]. 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.

Evaluation

Laboratory Studies

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.

Imaging Studies

Tumor localization is typically started with a helical multiphasic contrast-enhanced CT scan. The sensitivity of multiphasic CT scans is significantly high at greater than 80% for detecting intrapancreatic neuroendocrine tumors [9] [10]. 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.

Treatment / Management

Initial Management

The management of VIPoma involves medical management and surgery.

• Initial medical management is aimed mainly at controlling the symptoms and prompt and aggressive replacement of fluids and electrolytes. 
• Somatostatin analogs like octreotide and lanreotide inhibit secretion of VIP and are used for symptomatic control. Octreotide is usually started at 50 to 100 mcg subcutaneous every 8 hours and titrated for symptom control. A long-acting formulation of octreotide is initiated at a dose of 20 mg intramuscularly (IM) monthly and titrated as needed for optimal symptom control.
• Glucocorticoids are used in patients refractory to somatostatin analogs [11].
• Interferon-alpha has also been used in patients in patients not responding to the above medications.
• Complete surgical resection is the treatment of choice for primary tumors and is usually a distal pancreatectomy. If the tumor cannot be excised completely, surgical debulking may provide palliative benefit [12].

Management of Metastatic/Progressive Disease

Metastases at the time of detection of VIPoma have been noted in as high as 60% of the cases [13]. The metastases most commonly occur in the liver, lymph nodes, bones, and kidney [14].

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 [15].  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 [16]. 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 [17] [18].

Differential Diagnosis

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 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.

Prognosis

The median survival of patients with VIPoma is 96 months [19]. 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.

Enhancing Healthcare Team Outcomes

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]