VIPoma is a very rare neuroendocrine tumor that predominantly originates in the pancreas. It causes symptoms such as profuse watery diarrhea, hypokalemia and achlorhydria. The diagnosis is made by measuring serum levels of vasoactive intestinal polypeptide (VIP) and through use of various imaging studies. Because of nonspecific symptoms, patients are often diagnosed in advanced stages of the disease. Treatment strategies include surgical excision, chemotherapy, octreotide administration and adjuvant therapy.
The hallmark of VIPoma in terms of symptomatology is the presence of prolonged profuse watery diarrhea, usually more than 3000 ml/day. Such profound water loss results in significant hypokalemia, which can have detrimental effects on the cardiac and skeletal system leading to arrhythmias and diffuse muscle weakness. In addition to watery diarrhea and hypokalemia, nausea and vomiting are frequent symptoms, which lead to achlorhydria. These symptoms comprise the WDHA syndrome that describes patients with VIPomas. WDHA syndrome is also known as pancreatic cholera because profuse water loss mimics the syndrome seen in patients with Vibrio cholera infection. Other symptoms that are reported include flushing (which is one of the main features of carcinoid syndrome), weight loss, lethargy, abdominal pain and bloating [12].
Symptoms that appear in patients can be intermittent, which is one of the reasons why establishing the diagnosis may be difficult, although diarrhea is usually a constant finding in these patients.
In order to establish the diagnosis of VIPoma, key steps include detailed patient history, obtaining levels of serum electrolytes and VIP and various imaging techniques to identify the location the tumor.
Patient history may be the key for suspecting VIPoma as a possible etiology for the symptoms. Supporting facts include prolonged diarrhea without an established cause, accompanied by other symptoms that are typical for this tumor. In all patients who suffer from dehydration and severe diarrhea, assessment of serum electrolytes is vital in preventing complications that may be quite severe. Severe dehydration may lead to hypotension, cardiogenic shock and even cardiac arrest, which is why serum potassium, sodium, chloride, bicarbonate and calcium levels should be obtained promptly. Significant hypokalemia and hypochlorhydria may be observed, while hypercalcemia is also a common finding, which presents a significant risk for the cardiac muscle. Additional tests can include evaluation of gastric pH (which will show alkalosis, due to inhibition of gastric acid secretion), while hyperglycemia and anion-gap metabolic acidosis may be reported as well.
Serum VIP levels can confirm the diagnosis of VIPoma. VIP has a very short half-life in the circulation (< 1 min), and its serum levels are usually below 200 pg/ml. Elevated VIP levels together with imaging studies should confirm the diagnosis.
CT and MRI are primary studies of choice for finding the exact location of this tumor, as tumors are up to several centimeters in diameter in a majority of the cases. However, PET scan may be used in patients in whom prior imaging studies have not identified the location of the tumor, while endoscopic ultrasound and scintigraphy using octreotide as contrast have been recommended as well [13]. Imaging studies should also investigate possible metastatic disease, which includes a full body workup with either CT or MRI, with the most common sites being the liver, lungs, lymph nodes proximal to the primary site and kidneys.
Once VIPoma is confirmed and staging completed, initial therapy can be started. This includes management of severe water loss and dehydration. Intravenous administration of fluids supplemented with potassium and bicarbonate is pivotal, thereby preventing further deterioration and potential development of acidosis. Additional therapy includes administration of octreotide, which is an analog of somatostatin. Octreotide exerts its effects by reducing the rate of intestinal motility without further reducing gastric acid secretion. It is usually given intramuscularly as one dose of 20-30 mg per month, while 100–300 μg/day is the standard dosing regimen [14], and shows good results in terms of reducing the burden of diarrhea in patients. Additional drugs that have shown benefit in certain studies include prednisone, loperamide, metoclopramide, and interferon.
Once the fluid loss and electrolyte levels have been stabilized, definite treatment measures may be started. Surgical excision is the only form of treatment that may be curable for the patient and is performed even if metastatic disease is noted. Surgery includes removal of all metastases in addition to the primary tumor. Surgical excision provides significant benefit over chemotherapy, which may be useful only as adjuvant therapy. Streptozocin together with doxorubicin is mentioned as the most favorable combination of chemotherapy. Chemoembolization and embolization of metastatic disease leads to significant improvement in survival rates. [15]. As a last resort, liver transplantation has been also been used in the treatment of liver metastases [16].
This tumor is slow growing in nature and between 50-75% of diagnosed tumors are malignant [10]. This tumor has a very good prognosis if diagnosed in its early stages, with 5-year survival rates exceeding 90% when complete surgical excision is achieved [11]. Unfortunately, only a minority of patients are diagnosed in early stages and between 60-80% of patients have evidence of metastatic disease at the time of diagnosis. As it is a slow growing tumor, even patients with metastasis survive long but the treatment in these patients can present significant challenges.
VIPoma is a tumor that develops in non-β pancreatic islet cells and it was initially described during the 1950s [4], when its connection to refractory diarrhea and hypokalemia was established. However, the exact cause of this tumor remains unknown.
According to reported prevalence rates VIPomas occur in approximately 1 in 10,000,000 individuals every year, suggesting that this neuroendocrine tumor is extremely rare [5]. The vast majority of VIPomas arise in the pancreas, with about 80% occurring in the body and tail, while about 20% originate in the head of the pancreas [6]. Other primary sites that have been reported include the lungs, colon, liver, adrenal glands, and ganglia of the sympathetic system [7], while its association with MEN 1 syndrome has also been reported in rare cases.
This neuroendocrine tumor is seen in both adults and children Extrapancreatic location of the tumor is commonly observed in children, with the adrenal glands and sympathetic ganglia being reported as most frequent sites [8]. Gender predilection has not been established.
Vasoactive intestinal polypeptide (VIP) contains 28 amino acids and is structurally similar to secretin and glucagon. VIP exerts its functions as a neurotransmitter in various parts of the nervous system, including the CNS and nerves of the respiratory, urogenital and enteric systems. Stimulation of enteric smooth muscles, inhibition of gastric acid secretion, regulation of immune system activation, stimulation of exocrine pancreas and modulation of gastrointestinal blood flow are all recognized functions of VIP. Other functions in which VIP may play a role include maintenance of neuronal integrity, glycogen metabolism, prolactin secretion and regulation of catecholamine release [9].
VIP exerts its effect in the intestinal system through stimulation of cyclic adenosine monophosphate (cAMP), and overstimulation of receptors leads to profuse electrolyte and water secretion into the intestinal lumen, ultimately resulting in severe diarrhea and hypokalemia. Inhibition of gastric acid secretion leads to either hypo or achlorhydria, which can have significant effects on bicarbonate concentrations in the circulation, in addition to bicarbonate loss through diarrhea. These factors are combined to form the typical presentation of Watery Diarrhea, Hypokalemia, and Achlorhydria - WDHA syndrome.
Prevention of VIPomas is currently not possible, as the cause of this tumor remains unknown. However, an early diagnosis may be life-saving for many patients, which is why a detailed diagnostic workup should include VIPoma as a possible cause of diarrhea and achlorhydria when all other conditions have been excluded. Regular patient check-ups can reduce the burden of many diseases that are diagnosed in late stages, VIPoma being one of them.
VIPoma is a rare neuroendocrine neoplasia that secretes excessive amounts of vasoactive intestinal polypeptide (VIP) [1]. This hormone acts as a neurotransmitter both in the central and peripheral nervous systems and performs significant functions in the enteric nerves. VIP is classified into a group of hormones and neuropeptides that share similar structures together with secretin, glucagon, growth hormone releasing factor and several others [2]. Its functions in the gastrointestinal tract include smooth muscle stimulation, gastric acid inhibition, and stimulation of exocrine pancreatic secretion. The majority of VIPomas originate as solitary lesions in the pancreas, most commonly in the head and body, but in rare cases, the adrenal glands, liver, colon, and lungs have been reported as its primary site of occurrence. These tumors may be benign, but the majority of tumors are malignant and a significant number of patients have metastatic disease at the time of their diagnosis. Metastases may be identified often in the liver but can also be found in the proximal lymph nodes, kidneys or lungs, as well other organs [3]. The characteristic syndrome of frequent and profuse watery diarrhea, hypokalemia and achlorhydria (known as WDHA syndrome or pancreatic cholera) can be observed in virtually all patients and manifests as severe dehydration, weakness, and lethargy. Flushing may be present as well. The diagnosis may not be established easily, as symptoms tend to be intermittent. VIPoma can be diagnosed through various imaging techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI), because tumors are usually several centimeters in size, while positron emission tomography (PET scan) may be necessary to establish smaller tumors. Serum electrolytes, as well as high levels of VIP in the blood, can confirm that the tumor described through imaging studies is VIPoma. In rare cases, VIPoma can be associated with multiple endocrine neoplasia (MEN) type 1 syndrome, in which hyperparathyroidism and presence of pituitary tumors, most commonly prolactinomas, are present. Initial therapy includes adequate rehydration and correction of serum electrolytes, while a surgical excision is the recommended treatment strategy. Administration of octreotide, a somatostatin analog, chemotherapy and additional drugs including corticosteroids and antimotility agents are part of the adjunctive therapy.
VIPoma is a tumor that predominantly originates in the pancreas and is malignant in most cases. This tumor is very rare and is reported to occur in approximately 1 in 10 million individuals. Although it is often diagnosed when metastases have developed, as it is slow growing, patients continue to live relatively long. It can develop both in adults and in children and the cause remains unknown. The name stems from the fact that cells that undergo malignant transformation secrete vasoactive intestinal polypeptide (VIP), which exerts numerous functions in the body. VIP acts as a neurotransmitter in the nervous system of various organs, including the gastrointestinal system, where most of the symptoms occur. VIP stimulates contraction of smooth muscles in the gut and stimulates the movement of fluids and electrolytes into the intestinal lumen, thus leading to often profuse diarrhea and severe dehydration. A specific term is used for the constellation of symptoms that occur in this condition: the WDHA syndrome (Watery Diarrhea, Hypokalemia, and Achlorhydria). Diarrhea is the main symptom in patients with VIPomas and is usually profuse and causes significant fluid and potassium loss. VIP also inhibits production of gastric acid, which results in reduced acidity of the stomach, thus impairing its normal function. Additional symptoms include nausea, vomiting, abdominal pain, bloating, weakness, and lethargy. Symptoms may be intermittent, which provides a significant challenge in establishing the diagnosis. VIPoma can be diagnosed by obtaining serum levels of VIP, while its location may be identified using various imaging procedures, such as computed tomography (CT scan) and magnetic resonance imaging (MRI) because tumors are usually up to several centimeters in length. Smaller tumors can be identified using positron emission tomography (PET scan). Correction of dehydration and improving levels of potassium and chloride through intravenous fluid administration is very important in managing patients once the diagnosis is made, while administration of various drugs have shown some efficacy in reducing the burden of diarrhea. In most cases, octreotide is the drug of choice, while corticosteroids may provide additional benefit. Definite treatment measures depend on the staging of the tumor, but surgical removal is recommended in all patients, even in those with metastases because it is the only therapeutic strategy that has shown curative effects. Chemotherapy has inferior results compared to surgery and can be used as adjuvant therapy. This tumor can present significant challenges in diagnosis and therapy, but early identification is the key to preventing complications and prolonging the life of the patient.