VIPomas represent 1.4 % of Gastro entero pancreatic (GEP) neuroendocrine tumours (NETs), corresponding to an incidence of 0.01/1,000,000 yearly. About 85 % are pancreatic, and amongst islet cell tumours, they are about 2 % [1]. Rare extrapancreatic types exist including oesophagus, liver and retroperitoneum, but these forms are mainly present in paediatric age and are attributable to neuroblastomas, which produce also VIP. In adults the extrapancreatic types have low malignant phenotype.

In the pancreas VIPoma usually arises as a unique tumour. It may reach great dimensions, 3 cm as diameter (range of 1–7 cm) on the average, but one case report describes also a 20 cm VIPoma [2]. The main location is (75 %) within the pancreatic body and tail. It is more frequent in female (about 56 %) and the mean age at diagnosis is 49 years.

The pure secreting VIPoma is rare, because about 75 % of VIPomas produce also pancreatic polypeptide (PP), neurotensin, gastrin and GIP. However, it is nearly always biologically active [3, 4]. Four to ten percent of VIPomas belong to the MEN syndrome. Wermer syndrome, induced by VIP production, arises in 1–7 % of islet cell tumours.

To date we can find in the literature 133 case reports and 161 patients grouped in 8 cohorts on VIPoma. Amongst all publications, a small number of them report the investigation about the molecular mechanisms for the development of VIPoma.

In particular, a study investigated benign and malignant NETs for microsatellite loss of heterozygosity (LOH) analysis and fluorescence in situ hybridization (FISH) in order to evaluate the importance of chromosome 3p deletions in the molecular pathogenesis and biological behaviour. Amongst these patients a VIPoma showed LOH at all informative microsatellite markers. This finding could indicate that the tumour cells initially had a 3p deletion which was followed by duplication of the remaining allele. Such endoreduplication was also reported for colorectal cancer [5, 6]. In a similar case series, chromosome 6q losses were observed. Some tumour suppressor genes are located in this region of deletion. These genes include “absent in melanoma 1” (AIM1), “cyclin C” (CCNC) and “receptor-type protein-tyrosine phosphatase kappa” (PTPRK). AIM1 and CCNC were mapped to 6q21 and PTPRK to 6q22.2-q22.3. The first one exerts its effects through interactions with the cytoskeleton. The CCNC is upregulated by 1α,25-dihydroxyvitamin D3, inhibits cellular growth and induces apoptosis. The PTPRK gene seems to be involved in the regulation of cell adhesion by dephosphorylation of β-catenin and γ-catenin/plakoglobin or cadherins, thereby contributing to the formation and maintenance of intact adherens junctions [7].

Another report of pancreatic NETs including VIPomas evaluated the putative tumour suppressor gene DPC4 located at the chromosome 18q21.1. This gene, also indicated as Smad4, is a member of the highly conserved family of Smad proteins that are involved in the transduction of signals from the transforming growth factor family of cytokines. This study found out no mutations in this gene for VIPomas [8].

A study about the role of sex chromosome in NET development included 1 VIPoma. This analysis showed a loss of chromosome X in 40 % of female patients whereas loss of chromosome Y in 36 % of male patients without loss of the X chromosome. Sex chromosome loss is associated with aggressiveness of pancreatic NETs and may also predict a poorer clinical outcome. This phenomenon could be explained by the role of genes on the X chromosome in the induction of senescence and control of cell proliferation [9].

BRAF mutations were also investigated in NET, but these genetic alterations were really low (3 %). However, none of the two VIPomas of this case series bore BRAF gene impairment [10].

Recently, in a patient with VIPoma, LOH downregulation was observed by the microarray analysis for the mismatch repair gene MSH2 in the primary tumour. Besides, in the same case, a strong overexpression of the chemokine CXCR4 gene was found in the liver metastases. On the basis of these findings, the authors argued a role for MSH2 gene impairment in carcinogenesis and for CXCR4 dysregulation in metastasis development [11].

In 1958 Verner and Morrison described in two patients a syndrome including diarrhoea, hypokalaemia, hypochlorhydria and metabolic acidosis [12, 13]. For this syndrome an acronym was used: WDHH (watery diarrhoea, hypokalaemia, hypochlorhydria). It was also defined as “pancreatic cholera”, but this definition is not proper when it arises from an extrapancreatic origin. The term VIPoma was suggested by the elevated plasma levels of the vasoactive intestinal polypeptide (VIP), which are associated with this kind of tumour. VIP is a 28-amino acid polypeptide which is distributed throughout the body and normally functions as a neurotransmitter. In the gut it regulates the blood flow, smooth muscle activity, pancreatic and intestinal secretions and inhibits gastric acid production. Excessive circulating VIP concentrations induce secretion in all intestinal segments of Na+, K+, Cl- and HCO3- as well as water, but also gastric acid secretion, bone resorption, glycogenolysis and vasodilation.

The Verner-Morrison syndrome is characterized by sizeable diarrhoea (1–6 l/die), which is watery and increasing. The diarrhoea associated with VIPoma is characterized by its persistence for 48–72 h after fasting and by great faecal volumes of 6–8 l/die. The secretory nature of the diarrhoea is confirmed if it is refractory to fasting. The hydro-electrolytic disequilibrium is a consequence of diarrhoea and includes hypokalaemia, hypomagnesaemia, hypovolaemia and metabolic acidosis. These events induce lethargy, muscular weakness, cardiac conduction disturbances, weight loss, abdominal pain, paralytic ileus, dyspepsia and gallbladder hypotonia. Flushing could be found in about 20 % of VIPomas, and rarely acute kidney tubular necrosis was reported. In 75 % of VIPoma patients, hypercalcaemia was described, and hypophosphataemia could be associated because of hyperparathyroidism. Hypercalcaemia could be a consequence of paraneoplastic hormonal secretion. The development of hypercalcaemia was attributed to the release of PTHrp by tumour cells. Half of VIPoma patients develop hyperglycaemia because of reduced glucose tolerance, and an increased hepatic glycogenolysis has been hypothesized as a possible explanation for this finding. In 40 % of those patients, hypochlorhydria has been reported. Hypochlorhydria is due to the inhibition of gastric acid production by VIP. Hyperchloremic acidosis can also develop because of low bicarbonate levels as a consequence of severe intestinal loss [14].

In earlier stages the Verner-Morrison syndrome could be confused with diarrhoeas from different origin, including those related with bacterial, viral and parasitic infections and with inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease. Since also other neuroendocrine tumours could induce diarrhoea, the one that is related to VIPoma needs to be distinguished. VIP plasma levels allow to recognize those patients affected by this NET. However, VIP could be present in various molecular forms, and its levels could exceed 170 pg/ml. These high VIP levels are often associated with high plasma levels of other diarrhoea-inducing molecules, such as pancreatic polypeptide (PP), gastric inhibiting polypeptide (GIP) and prostaglandin E2 (PGE2) [15]. For this reason the already-known role of VIP as the main inducer of diarrhoea has been limited. Besides some VIPoma patients without diarrhoea showed high VIP plasma levels.

Of malignant VIPomas clinical onset is usually accompanied by advanced stage of neoplastic disease. In these patients the clinical management of hydro-electrolytic disequilibrium needs to precede any other treatment. Since the past decades, the use of prednisone has been revealed as a quite efficacious way to manage diarrhoea. Anyway this symptom could be properly contrasted by the treatment with anti-diarrhoeal drugs, prostaglandin inhibitors and indole derivatives, since early phases. The treatment with octreotide, a somatostatin analogue, achieved the best control of diarrhoea with subsequent improvement of hydro-electrolytic disequilibrium. In some patients in whom octreotide was delivered for diarrhoea control, a benefit in metastases regression was also obtained [16]. These results have been subsequently implemented by the findings from the PROMID trial about the antitumour benefit on efficacy end point by octreotide in GEP NET patients.

VIPomas are characterized by hypokalaemia in 100 % of patients and hypochlorhydria in 70 %, as a consequence of electrolytic loss by secretory diarrhoea, hypercalcaemia in 40 % and hyperglycaemia in 20 %. However, this biochemical changes are not sufficient for diagnosis, because only high VIP plasma levels are really mandatory for VIPoma’s diagnosis. Since fasting normal VIP values are ranged between 150 and 170 pg/ml, in VIPoma patients hugely higher levels are found in plasma [14]. The VIP levels are usually found elevated in almost all cases, but it could also be found normal between the episodes of diarrhoea. However, the evaluation of VIP plasma levels needs some particular technical devices to guarantee its accuracy and its right interpretation. In fact VIP is a highly unstable protein which easily undergoes a proteolytic degradation [17].

Anyway high VIP plasma levels could be found in patients affected by liver and kidney failure, myocardial infarction, intestinal ischemia, AIDS and laxative-induced diarrhoea.

Besides VIPomas are able to produce other peptides such as PP, calcitonin, gastrin, neurotensin, gastric inhibitory peptide (GIP), serotonin, glucagon, insulin, somatostatin, growth hormone-releasing hormone and peptide histidine-methionine [18].

When a NET has a dimension less than 1 cm, CT scan reaches a sensitivity less than 10 %. However, VIPomas are usually found when they are greater than 3 cm, so that CT sensitivity could reach 100 % [19]. The magnetic resonance imaging (MRI) could help differentiating the small pancreatic tumours from the surrounding normal pancreatic tissue. This imaging technique has reached a sensitivity of 85 and 100 % specificity [20]. On the basis of the high expression of somatostatin receptors in VIPomas, OctreoScan has been considered as a reliable evaluation for this kind of tumours. Somatostatin receptors are expressed in 80–90 % of VIPomas.

The histological examination of VIPoma show some molecular patterns, such as solid, acinar or trabecular tissue architecture with scant mitoses. The cells are cytologically bland, with modest amount of cytoplasm and round nuclei without visible nucleoli. Few mitotic figures can be found. However, since 60–80 % of VIPomas are metastatic diagnosis, locoregional lymph nodes and suspicious distant metastases could confirm that those histological features are associated with a malignancy [21].

The suspicion of this neuroendocrine tumour in patients with chronic diarrhoea could help to diagnose early this rare disease. Before any curative or palliative treatment is started, the life-threatening hydro-electrolytic disorders must be corrected. Some patients could require a massive intravenous potassium replacement because a consistent potassium deficit induced by chronic gastrointestinal losses.

More than half of VIPomas are resectable at diagnosis. Curable rate by resection reached 10 % [22]. The localization of VIPomas is relatively easy because 80 % have a single site and range between 1 and 7 cm. Pancreatic forms are usually localized in the pancreatic tail. For this reason in these cases, the surgical treatment is represented by a distal pancreatectomy. When pancreatic lesions could not be identified, the exploration of adrenal glands and sympathetic plexus for extrapancreatic forms is necessary. Cytoreductive surgery includes palliative debulking of the primary tumour. This treatment achieves a tumour bulk reduction, the improvement of hormone-mediated symptoms and the prevention of local and systemic tumour effects. A complete resection of the primary tumour improves the prognosis greatly.

In metastatic patients with low risk, the surgical option could be taken into account for symptoms control, which could be reached in 40 % of patients. In high-risk patients with multiple metastatic sites, a systemic treatment is overriding. However, in these patients a palliative debulking surgery should be considered, since patients’ outcomes could be improved.