6.7 VIPomas

Vasoactive intestinal polypeptide (VIP) secreting tumours are rare neuroendocrine tumours. The associated syndrome was first described by Priest and Alexander in 1957. They reported a case that they thought to be a variant of the Zollinger–Ellison syndrome—a patient with an islet cell tumour associated with diarrhoea, peptic ulceration, and hypokalaemia (1). The following year, Verner and Morrison described a syndrome of profuse, refractory, watery diarrhoea with severe hypokalaemia and dehydration associated with a non-β-cell islet cell tumour (2). Historical terms for this syndrome have included ‘pancreatic cholera’ (as the diarrhoea is similar to the secretory diarrhoea observed in cholera) and the acronym WDHA (watery diarrhoea, hypokalaemia, and achlorhydria). However, these terms are inaccurate descriptions of a syndrome that can be associated with both extrapancreatic tumours and normal gastric acid secretion. In 1973, Bloom first connected the watery diarrhoea with an elevated plasma VIP level and an increased tumour content of VIP, suggesting the term ‘VIPoma syndrome’ (3). There followed a debate as to whether VIP was a marker for the syndrome or the causative agent for the diarrhoea. However, in 1983, Kane infused porcine VIP intravenously in healthy human subjects, achieving VIP levels similar to patients with VIPomas. Profuse watery diarrhoea developed within 4 h of infusion, providing evidence that VIP was indeed the mediator of the syndrome (4).

VIPomas comprise approximately 2% of gastroenteropancreatic neuroendocrine tumours (5) with a reported annual incidence of 1 per 10 million individuals in the general population (6). Most cases present in the fifth decade and some series suggest an increased incidence in females (7–10). In adults, 80 to 90% of VIP-producing tumours originate in the pancreas (5). Reported extrapancreatic locations include the colon, bronchus, adrenals, liver, and sympathetic ganglia (11). Primary tumours are usually greater than 3 cm and solitary. The majority of these tumours are malignant (12) and over 70% of adult patients present with metastatic disease in lymph nodes, liver, or distant sites (9). Despite the severity of the clinical syndrome, symptoms may only present when the tumour reaches a certain size, which may account for the delay in diagnosis and advanced presentation (12). In children, VIP tumours most commonly occur along the autonomic chain and in the adrenal medulla as ganglioneuromas, ganglioblastomas, or neuroblastomas, which only occasionally metastasize.

It is estimated that 2% of VIPoma patients have multiple endocrine neoplasia syndrome type 1. However, VIPoma remains a rare feature of this syndrome with the incidence less than 1% (13). Other tumours, such as carcinoids, phaeochromocytomas, and bronchiogenic carcimonas, are also well recognized to occasionally produce VIP (7–10).

VIP is a 28-amino acid peptide, which normally functions as a neurotransmitter within enteric neurons and neurons of the brain, spinal cord, lung, urogenital system, and other endocrine organs. VIP has close structural homology to secretin and the two cloned VIP receptors (VIP1/VIP2 or VPAC1/VPAC2) are G-protein coupled receptors of the secretin family. The half-life of VIP is less than 1 min in circulation and plasma levels are usually low without prandial fluctuation. VIP is a potent vasodilator and physiological effects of VIP include smooth muscle relaxation (14), stimulation of pancreatic exocrine and gastrointestinal secretion (15), inhibition of gastric acid secretion (16), and modification of immune function and gastrointestinal blood flow (17).

The VIPoma syndrome is caused by excessive VIP secretion from the tumour, although other substances can be cosecreted (18, 19). Watery diarrhoea occurs in nearly all patients (20) and is frequently produced in excess of 3 litres per day (9). The diarrhoea is secretory and typically persists despite 48 to 72 h of fasting. Diarrhoea is the results of the binding of VIP to high-affinity receptors on epithelial cells in all segments of the intestine, leading to secretion of Na⁺, K⁺, Cl⁻, and HCO³⁻ as well as water into the lumen (7). This results in dehydration, severe hypokalaemia (often below 2.5 mmol/l), and hyperchloraemic metabolic acidosis. Diarrhoea-induced hypomagnesasaemia has occasionally been reported and may underlie the infrequent reports of tetany associated with VIPomas. High levels of circulating VIP are known to cause inhibition of gastric acid secretion, stimulation of bone resorption, increased hepatic glucose output, and vasodilation. These effects may clinically result in hypochlorhydria, hypercalcaemia, hyperglycaemia, or flushing (21). Common features are shown in Table 6.7.1.

The diagnosis of VIPoma syndrome can be established in a patient with otherwise unexplained secretory diarrhoea by demonstrating a raised fasting plasma VIP concentration with a localized source of VIP production (7–10). Secretory diarrhoea can be recognized by identifying a low osmotic gap as determined by faecal electrolyte measurement (22). The osmotic gap is calculated by subtracting twice the sum of the concentration of stool potassium and sodium from 290 mOsm/kg to account for unmeasured anions, i.e. measured osmolality = 290–2(Na⁺ + K⁺). An osmotic gap of less than 50 mOsm/kg suggests secretory diarrhoea. Other causes of secretory diarrhoea should be considered (23) and are listed in Box 6.7.1.

The VIPoma syndrome can be difficult to diagnose as other conditions may mimic its presentation, e.g. laxative abuse and Zollinger–Ellison syndrome. These can be differentiated using a careful history and by measurement of gastric pH, acid production, and circulating levels of gastrin and VIP. Fasting plasma VIP levels in healthy volunteers are generally low, whilst many patients with symptomatic VIPoma have levels more than three times the upper limit of normal (20). Chronic diarrhoea from other causes do not generally exhibit raised VIP levels (a rare exception being a carcinoid tumour cosecreting VIP). However, an elevation in plasma VIP can be found following a prolonged fast or in inflammatory bowel disease, small bowel resection, renal failure, or, uncommonly, in the normal population due to reduced clearance of nonbioactive high-molecular-weight VIP. A falsely low VIP level may be found if the hormone is allowed to undergo proteolytic enzymatic degradation prior to measurement. Samples of blood should be collected with the enzyme inhibitor aprotinin, the plasma rapidly separated, and frozen until assayed. It should be noted that patients with VIPoma syndrome may have normal VIP levels in early disease when symptoms are intermittent. Therefore repeated samples should be taken for evaluation of plasma VIP concentration during episodes of diarrhoea.

VIPomas may cosecrete additional peptides including pancreatic polypeptide, calcitonin, gastrin, neurotensin, gastric inhibitory peptide, serotonin, glucagon, insulin, somatostatin, growth hormone-release hormone, chromogranin A, chromogranin B GAWK fragment, and peptide histidine–methionine (PMH) (18, 19). PMH is a 27-amino acid peptide encoded by the same mRNA as VIP in humans. Therefore, PHM is invariably raised in the VIPoma syndrome and often to a greater extent than VIP itself as it has a longer circulating half-life. PMH further stimulates gastrointestinal secretion, although it is significantly less potent than VIP. The biochemical diagnosis of VIPoma should include measurement of general markers of neuroendocrine tumours such as chromogranin A and pancreatic peptide, as well as serum parathyroid hormone, calcium, and prolactin as a baseline screen for multiple endocrine neoplasia type 1 (24).

VIPomas cannot be clearly distinguished from other pancreatic endocrine tumours by histological studies alone. Features are those of epithelial endocrine tumours with either solid, acinar, or trabelular cellular patterns with scant mitosis (25). VIP immunoreactivity is, however, strongly suggestive of a VIPoma, as this is found in less than 10% of other pancreatic endocrine tumours. Tissue examination should include immunohistological staining and histological classification according to the WHO system, which can be an important indicator of malignancy. However, the only method for confirming malignancy is the examination of local lymph nodes and metastatic sites such as the liver.

The optimal treatment for VIPoma is surgical resection and therefore the ability to localize a tumour is integral to a patient’s subsequent management. As for other neuroendocrine tumours, standard imaging procedures include contrast-enhanced helical CT or MRI of the abdomen in combination with endoscopic ultrasonography or somatostatin receptor scintigraphy. The sensitivity of CT can approach 100% for most VIPomas, which are large at presentation (26). Furthermore, most pancreatic neuroendocrine tumours are highly vascular, making contrast-enhanced imaging able to identify up to 92% of lesions (27). MRI is particularly useful to differentiate smaller tumours, with reported sensitivity of 85% and specificity of 100% (28). If cross-sectional imaging is unable to identify the tumour, endoscopic ultrasonography has high sensitivity of up to 100% for detecting small pancreatic tumours, and may also demonstrate extrapancreatic lesions (27). VIPomas are somatostatin receptor positive in 80–90% of cases. Therefore somatostatin receptor scintigraphy is a useful functional scan which complements conventional imaging. Scintigraphy may also identify distant metastases to lymph nodes and rare cases of extra-
abdominal spread to lung or bone (29). Positive scintigraphy may be predictive of the response to octreotide as the degree of VIP suppression is related to the number of high affinity receptors. Gallium-labelled somatostatin analogue positron emission tomography is also a promising method in the detection of small tumours or tumours bearing only a low density of somatostatin receptors (24).

Initial therapeutic intervention in a patient with VIPoma should be focussed at correcting potentially life-threatening dehydration and electrolyte abnormalities. Patients are likely to require intensive fluid and potassium replacement (up to 350 mmol/day) in order to correct the substantial potassium deficit and prevent renal and cardiac dysfunction, which are common causes of death.

Surgical resection is the treatment of choice for nonmetastatic islet cell tumours as half of tumours are resectable and 10% of those patients can be cured (30). In the remaining patients, distal pancreatectomy or tumour debulking can ameliorate symptoms for an extended period. Perioperative administration of a H₂ blocker or proton pump inhibitors is recommended in patients with VIPoma syndrome because of the possibility of rebound gastric acid hypersecretion following tumour removal. Postsurgery there may be profound circulatory changes as the VIP-induced vasodilatory drive is removed, leading to the possibility of circulatory overload. This is particularly problematic as preoperatively the gut is often dilated and contains large quantities of fluid that may be rapidly absorbed once the source of VIP is removed.

The somatostatin analogue, octreotide, is effective at suppressing hormone secretion in neuroendocrine tumours, especially glucagonomas and VIPomas. Symptomatic response occurs in 80 to 90% of patients within days of initiation, and it is therefore the treatment of choice to control diarrhoea in VIPoma syndrome (31, 32). The usual dose of subcutaneous octreotide is 50–100 µg 8 hourly, which can be increased by 50-µg increments up to 200 µg (and occasionally 500 µg) every 8 h (33). Titration should be by clinical response and symptomatic relief is not always accompanied by a reduction in circulating hormone levels. The improvement is mediated by both a direct inhibitory effect of hormone production of the tumour as well as indirect effects, such as the resorption of intestinal fluid and a reduction in bowel motility (34). Although there is some evidence that somatostatin analogues can reduce tumour burden in a minority of patients (32) this has not been clearly shown, but somatostatin therapy may be indicated as an antiproliferative treatment in selected cases base on positive scintigraphy (5).

One-third of patients experience nausea, abdominal discomfort, bloating, loose stools, and fat malabsorption during initial treatment with octreotide (34, 35). These effects on normal tissue usually subside within 2 weeks of initiation of therapy. Initially, diarrhoea can worsen due to steatorrhoea, which is secondary to suppression of pancreatic exocrine secretion; this responds to oral pancreatic enzyme supplements. Mild glucose intolerance rarely occurs due to transient inhibition of insulin secretion. Octreotide reduces postprandial gallbladder contractility and delays gallbladder emptying. One-quarter of patients develop asymptomatic cholesterol gallstones or sludge during the first 18 months of therapy (35). However, only 1% of patients develop symptoms during each year of treatment (34).

Somatostatin analogues can be considered for symptomatic control of the VIP syndrome in patients with unresectable or metastatic disease (12, 31). Treatment should be initiated with short-acting analogues, but once control is achieved the patient can be transferred to a long-acting analogue (e.g. octreotide acetate (Sandostatin-LAR) intramuscularly or Lanreotide autogel subcutaneously) every 4 weeks (36). The availability of long-acting monthly depot forms of octreotide avoids a frequent dosing regimen and improves quality of life in patients who may require pharmacological control over a longer period. The majority of patients have good sustained symptomatic response to octreotide-based therapy (37), but escape from symptomatic control can be seen quite frequently. In this instance an increase in the dose of pharmacotherapy may be temporarily effective. The loss of sensitivity of endocrine cancers to somatostatin analogues may occur due to the growth of tumour cells lacking somatostatin receptors (34).

A number of different pharmacological agents have been reported to control the VIPoma syndrome with varying efficacy (7–10, 31). Prior to the use of somatostatin, glucocorticoids were often used as a first-line agent and patients have been reported to respond to combined glucocorticoid and octreotide therapy (31). α-interferons improve symptom control in up to 50% of patients with pancreatic islet cell tumours (37) and can be effective in VIPomas unresponsive to somatostatin analogues (38). It has also been reported to stabilize or regress tumours in a proportion of patients. The use of interferon is limited by side effects including fatigue, depression, and myelosuppression. Other potential agents, including angiotensin II and clonidine, may enhance sodium absorption in the jejunum, whereas indometacin, lithium carbonate, phenothiazines, propanolol, calcium channel blockers, and opiates may act by inhibition of intestinal secretion.

A wide range of treatment modalities are available for metastatic disease including hepatic resection and transplantation surgery, hepatic artery embolization, radiofrequency ablation, cryotherapy, intravenous chemotherapy, and peptide receptor radionuclide therapy.

Hepatic resection can be undertaken in patients with normal synthetic function and limited hepatic metastases if it is anticipated that 90% of the tumour burden can be removed (24). Although the majority of cases will not be cured by surgery, symptoms of hormone hypersecretion are effectively palliated and prolonged survival is often possible. Liver transplantation may be indicated for a small number of patients without extrahepatic metastases (39) in whom life-threatening hormonal symptoms persist despite maximal medical therapy and where standard surgery is not feasible (24).

Symptomatic liver metastases that are not amenable to surgery may respond to hepatic artery embolization. The goal of this palliative approach is to remove the blood supply to the metastases with only limited damage to normal hepatocytes, which derive most of their blood supply from the portal vein. This procedure can be repeated in metastatic disease with effective prolonged palliation (40). Fever, right upper quadrant pain, nausea, and vomiting are common sequelae postembolization. The possibility of infection must be excluded by regular cultures and, as the cystic artery is a branch of the hepatic artery, inadvertent gallbladder infarction is a possible complication of the procedure. The administration of broad-spectrum antibiotics and octreotide is recommended just prior to embolization and for several days afterwards in order to minimize the risk of infection and peptide release from necrotic tissue. Elevation of liver function tests, particularly liver transaminases, reflect unavoidable hepatic necrosis. However, massive necrosis or abscess formation is rare. Postprocedure hyperuricaemia can occasionally be clinically significant and allopurinol and urine alkalinization can be performed in addition to fluid hydration in order to reduce the risk of urate nephropathy (41).

Hepatic radiofrequency ablation, cryotherapy, or laser therapy can be used to treat hepatic lesions by a percutaneous or laparoscopic route or in combination with surgical debulking (42). This may not be as invasive as resection or embolization, but the technique is less well established and only applicable to limited disease—fewer than eight to ten metastases of less than 4–5 cm diameter (39).

Chemotherapy may be a useful therapeutic option in patients with metastatic and progressive neuroendocrine tumours (10, 31). A combination of streptozocin and doxorubicin has demonstrated response rates in the order of a third (43, 44), but few patients with VIPoma have been included in these series. The orally active agent temozolamide has also demonstrated antitumour activity in advanced neuroendocrine tumour disease (45). However, the relative benefits of these agents are uncertain and systemic chemotherapeutic agents have significant adverse effects with only modest success. An alternative approach is to deliver high doses of cytotoxic agent directly to the tumour in combination with hepatic embolization (chemoembolization). This technique can produce a transient partial remission (46).

Peptide receptor radionuclide therapy utilizes modified somatostatin analogues coupled with trivalent metal ions (indium, gallium, yttrium, lutetium, etc.) at a higher radioactivity than the radiolabelled somatostatin used for imaging. Limited experience is available in the treatment of VIPoma syndrome, but therapy with these agents are efficacious in other endocrine gastroenteropancreatic tumours (47, 48).

Insufficient data are available to provide accurate estimates of survival. However, in one study, the 5-year survival of patients with pancreatic VIPomas was reported as 68.5% (49). Patients with well-differentiated, small tumours and the absence of metastases have a more favourable prognosis (20, 30, 49).