Approach

VIPoma is characterised by profuse watery diarrhoea, hypokalaemia, metabolic acidosis, and hypochlorhydria or achlorhydria, in the presence of raised serum vasoactive intestinal peptide (VIP). The clinical syndrome associated with VIPomas is sometimes referred to as WDHA syndrome (watery diarrhoea, hypokalaemia, and achlorhydria), Verner-Morrison syndrome, or pancreatic cholera.[17]

Multi-phase contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scan is recommended to identify the primary tumour.[3]

History

Patients usually present with profuse watery diarrhoea (100% >700 mL/day); stool volumes typically exceed 3 L/day (70% to 80% of patients).[18][19][20] Large tumours can result in 6-8 L stool volumes per day.[21] Characteristically, the diarrhoea is odourless and tea-coloured, and persists even after 48-72 hours of fasting. 

Patients may complain of headache and other dehydration-related symptoms. Flushing, secondary to vasodilation, may occur in up to 33% of patients.[9]

Medical history may reveal a history or family history of multiple endocrine neoplasia type 1 (MEN1). However, this is an uncommon finding; VIPoma is reported in <1% of patients with MEN1.[10][17]

Physical examination

Physical examination findings will reflect hypokalaemia (e.g., muscle weakness, muscle cramps), and volume depletion (e.g., weight loss, poor skin turgor, dry mucus membranes). There may be evidence to suggest metastasis (e.g., hepatomegaly, weight loss).[9]

Laboratory investigations

A chemistry panel is the initial laboratory investigation in patients presenting with severe and persistent watery diarrhoea.

Chemistry panel will typically reveal hypokalaemia and low bicarbonate levels; hypercalcaemia and hyperglycaemia may also be present. Low bicarbonate levels may result in non-anion gap metabolic acidosis, which can be confirmed by arterial blood gas analysis.

Liver function tests are recommended; abnormal results may suggest hepatic metastasis.[17]

Gastric pH is increased in patients with VIPoma due to inhibition of gastric acid secretion by VIP.[21]​ Gastric pH (via nasogastric tube aspiration) is rarely measured, but useful to assess for hypochlorhydria or achlorhydria if there is diagnostic uncertainty.[20]

Vasoactive intestinal peptide (VIP) levels

VIPoma patients usually have markedly raised levels of VIP (reference value <75 picograms/mL).[9] One review of case reports and case series reported serum VIP levels ranging from 293 to 1500 picograms/mL.[9]

Diagnosis of VIPoma can be made based on raised VIP levels and the presence of clinical syndrome. The only pancreatic neuroendocrine tumour to secrete VIP is VIPoma.[17]​ VIP levels are measured by radioimmunoassay in symptomatic fasting patients (ideally during a bout of diarrhoea). If VIP levels are normal, the test should be repeated because VIP secretion from the tumour may be episodic.[22]

Neuroendocrine tumour markers

Neuroendocrine tumour markers (chromogranin A and pancreatic polypeptide) have limited utility as they are non-specific and secreted by a broad variety of neuroendocrine tumours.[23]​​ If VIP levels are normal but concerns regarding neuroendocrine tumour persist, chromogranin A and pancreatic polypeptide can be measured to aid diagnosis.

Imaging

Accurately locating the tumour and metastases is important for staging and guiding management.[17]​ Anatomical and functional imaging techniques should be used where available and as clinically indicated.

Anatomical imaging

Due to the hypervascular nature of pancreatic neuroendocrine tumours, multi-phasic CT and MRI scans are recommended to identify primary tumours and metastatic disease.[24][25]

CT

VIPomas are usually solitary tumours, >3 cm in diameter at diagnosis. Therefore, most can be located by multi-phase abdominal contrast-enhanced CT scan.[26]

MRI

Multi-phase MRI of the abdomen effectively locates VIPomas, and is warranted if radiation exposure is to be avoided (e.g., pregnancy).[26] MRI is superior to CT scan in identifying hepatic metastasis.[26]

Endoscopic ultrasound

For smaller tumours that prove elusive (rare), endoscopic ultrasound can allow for a definitive diagnosis via ultrasound-guided fine needle aspiration of the mass.[17][24]

Functional imaging

If imaging from CT and MRI is inconclusive, then functional somatostatin receptor-based imaging techniques should be considered if available. Somatostatin receptors are expressed in 80% to 90% of VIPomas.[9]

Somatostatin receptor-based imaging techniques have increased sensitivity for detecting neuroendocrine tumours (including metastases) compared with CT and MRI, making them particularly useful for staging and guiding treatment.[26][27] These modalities can identify patients with sufficient tumour somatostatin receptor expression who may benefit from treatment with somatostatin analogues.[26][27]

Somatostatin receptor scintigraphy (using a radiolabelled somatostatin analogue, e.g., octreotide) can confirm the location of the tumour and detect occult hepatic metastasis. However, it has been mostly replaced by positron emission tomography (PET)-CT/MRI.

PET-CT/MRI employing novel somatostatin receptor PET tracers (e.g., 68Ga-DOTATATE; 64Cu-DOTATATE; 68Ga-DOTATOC) has increased sensitivity for detecting neuroendocrine tumours and metastases compared with conventional CT, MRI, and scintigraphy.[3]​​[17]​​[26][27][28][29]

Biopsy

In patients with surgically resectable disease, preoperative biopsy is not indicated. For unresectable disease tissue diagnosis is recommended with endoscopic ultrasound-guided fine needle aspiration. Pathological evaluation focuses on Ki-67 and mitosis per high power field to determine tumour grade and prognosis.[17]

Operative exploration

Intraoperative ultrasound can be used during operative exploration to localise smaller tumours. However, most tumours are easily visualised and palpated at pancreatic exploration.

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