Approach

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

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

History

Patients usually present with profuse watery diarrhea (100% >700 mL/day); stool volumes typically exceed 3 L/day (70% to 80% of patients).[18][19][20] Large tumors can result in 6-8 L stool volumes per day.[21] Characteristically, the diarrhea is odorless and tea-colored, 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 hypokalemia (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 diarrhea.

Chemistry panel will typically reveal hypokalemia and low bicarbonate levels; hypercalcemia and hyperglycemia 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 elevated 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 elevated VIP levels and the presence of clinical syndrome. The only pancreatic neuroendocrine tumor to secrete VIP is VIPoma.[17]​ VIP levels are measured by radioimmunoassay in symptomatic fasting patients (ideally during a bout of diarrhea). If VIP levels are normal, the test should be repeated because VIP secretion from the tumor may be episodic.[22]

Neuroendocrine tumor markers

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

Imaging

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

Anatomic imaging

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

CT

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

MRI

Multiphase 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 tumors 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 tumors (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 tumor somatostatin receptor expression who may benefit from treatment with somatostatin analogs.[26][27]

Somatostatin receptor scintigraphy (using a radiolabeled somatostatin analog, e.g., octreotide) can confirm the location of the tumor 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 tumors 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. Pathologic evaluation focuses on Ki-67 and mitosis per high power field to determine tumor grade and prognosis.[17]

Operative exploration

Intraoperative ultrasound can be used during operative exploration to localize smaller tumors. However, most tumors are easily visualized and palpated at pancreatic exploration.

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