Vipoma

VIPoma is a neuroendocrine tumour secreting vasoactive intestinal peptide (VIP) that causes Verner-Morrison syndrome (watery diarrhoea, hypokalaemia and achlorhydria, WDHA). The diarrhoea is a large volume secretory diarrhoea that persists on fasting and can be life threatening through dehydration, hypokalaemia and acidosis.

It is rare, with an incidence of about 1 case in 10,000,000 people each year. In adults, 90% are pancreatic (usually in the body or tail), with a median age of 40 to 60 and a slight female predominance. In children (aged 2 to 4), the source is more often a ganglioneuroblastoma or neuroblastoma.

About 60% to 80% of pancreatic VIPomas are malignant, and most have liver or nodal metastases at diagnosis. Only 5% are linked with MEN1.

Pathophysiology. VIP stimulates intestinal secretion of water and electrolytes through cyclic AMP, with inhibition of gastric acid secretion and vasodilatation. Stool is large volume and isotonic, with high potassium and bicarbonate loss, leading to hypokalaemia and non-anion-gap metabolic acidosis.

Prognosis. Median survival is about 5 years after resection and shorter with unresectable metastases. Mortality is mostly from the tumour, though electrolyte emergencies are also lethal.

• Profuse watery diarrhoea (usually over 3 L daily and up to 20 L), continuing during fasting.
• Dehydration with weakness, lethargy, muscle cramps, postural hypotension and renal impairment.
• Hypokalaemia (cardiac arrhythmias, myopathy, ileus), hypomagnesaemia and hypercalcaemia (about 50%).
• Hypochlorhydria or achlorhydria, flushing (20%), and glucose intolerance (25% to 50%).
• Abdominal pain, weight loss and gallbladder atony.

Red flags.

• Severe dehydration, shock or acute kidney injury.
• Potassium under 2.5 mmol/L, arrhythmia or paralytic ileus.
• Severe metabolic acidosis.

• Stool volume over 700 mL daily on a fast, with a stool osmotic gap under 50 mOsm/kg (secretory diarrhoea), and electrolytes (sodium, potassium over 40 mmol/L).
• Plasma VIP: over 75 pg/mL (many laboratories use over 200 pg/mL) with watery diarrhoea. Collect on ice and after the diarrhoea has been active, since levels can be intermittently normal.
• Blood tests: potassium, magnesium, calcium, bicarbonate, glucose, creatinine, and exclusion of laxative abuse, infections, carcinoid syndrome and gastrinoma (gastrin, 5-HIAA).
• Multiphasic CT or MRI and endoscopic ultrasound, 68Ga-DOTATATE PET-CT, with biopsy for Ki-67 and grade. Calcium, PTH and genetic testing for MEN1. In children, MIBG and urinary catecholamines.

Differential diagnosis.

• Laxative abuse and infective diarrhoea
• Carcinoid syndrome, gastrinoma and medullary thyroid carcinoma
• Bile acid diarrhoea, villous adenoma and microscopic colitis
• Chronic diarrhoea from coeliac disease, HIV and enteropathy

Resuscitation comes first, then control of secretion, then tumour surgery.

Fluid and electrolyte replacement.

• Intravenous fluids and potassium: sodium chloride 0.9% IV 2 to 6 L daily, adjusted to replace measured stool loss plus 2 L maintenance, with potassium chloride 20 to 40 mmol added to each litre; maximum potassium infusion rate 10 mmol/h by a peripheral line (up to 20 mmol/h by a central line with continuous ECG monitoring) and 200 mmol in 24 hours; monitoring: potassium, sodium, bicarbonate, creatinine and magnesium every 6 to 12 hours initially, daily weight, fluid balance, ECG; adjustment: reduce the potassium dose in renal impairment and with potassium sparing drugs, replace bicarbonate loss with sodium bicarbonate when pH is under 7.2, correct magnesium first when hypokalaemia is refractory
• Magnesium replacement: magnesium sulfate 8 to 20 mmol IV over 12 to 24 hours, repeated as needed to keep serum magnesium over 0.7 mmol/L; maximum about 40 mmol in 24 hours; monitoring: serum magnesium, calcium and potassium, deep tendon reflexes, respiratory rate, ECG; adjustment: halve the dose when creatinine clearance is under 30 mL/min, stop for loss of reflexes or respiratory depression, switch to oral magnesium when the level is stable

Control of diarrhoea.

• Octreotide (short acting): octreotide 100 micrograms subcutaneously three times daily, increased every 2 to 3 days in response to stool volume to 200 to 300 micrograms three times daily; maximum 1500 micrograms daily in routine use (higher doses only under specialist supervision); monitoring: stool volume, potassium, magnesium, fasting glucose, gallbladder ultrasound at baseline and yearly, heart rate, thyroid function, vitamin B12 and fat soluble vitamins; adjustment: halve the dose in severe renal impairment (creatinine clearance under 10 mL/min), reduce the dose once diarrhoea is controlled, move to a long acting analogue after response and continue short acting cover for the first 2 weeks, and expect escape that needs a higher dose or a shorter interval
• Long acting somatostatin analogue (also antiproliferative): lanreotide 120 mg deep subcutaneously every 28 days until progression; maximum 120 mg every 28 days; monitoring: glucose and HbA1c, gallbladder ultrasound, thyroid function, heart rate, steatorrhoea; adjustment: start at 60 mg in moderate to severe renal or hepatic impairment, extend the interval to 42 or 56 days for stable disease
• Loperamide as an adjunct: loperamide 4 mg orally after the first loose stool, then 2 mg after each further loose stool; maximum 16 mg daily; monitoring: stool frequency, abdominal distension, QTc at doses over 16 mg or with other QT-prolonging drugs; adjustment: stop for ileus, bloody diarrhoea or fever, avoid with strong CYP3A4 or P-glycoprotein inhibitors, reduce the dose in severe hepatic impairment
• Corticosteroids such as prednisolone 40 to 60 mg daily by mouth are used for refractory diarrhoea only under specialist supervision (tapered over several weeks, with glucose, blood pressure and infection monitoring).

Surgery. Resection with lymph node dissection (distal pancreatectomy, enucleation or pancreatoduodenectomy) for localised disease, with debulking and resection or ablation of liver metastases, because tumour reduction relieves diarrhoea. Resection is urgent after stabilisation.

Metastatic or progressive disease.

• Lutetium dotatate: lutetium (177Lu) dotatate 7.4 GBq IV over 30 minutes every 8 weeks for 4 doses, with an amino acid infusion for renal protection starting 30 minutes before; maximum 4 doses; monitoring: FBC, creatinine and liver tests before each dose, delayed myelodysplasia; adjustment: withhold for grade 2 or worse toxicity and resume at 3.7 GBq, avoid when creatinine clearance is under 30 mL/min, use contraception during and for 7 months after treatment (4 months for men)
• Everolimus: everolimus 10 mg orally once daily, at the same time each day, until progression or unacceptable toxicity; maximum 10 mg daily; monitoring: glucose and lipids at baseline and every 3 months, FBC, creatinine, symptoms and imaging for non-infectious pneumonitis, stomatitis, infection and wound healing; adjustment: 5 mg daily in moderate hepatic impairment (2.5 mg daily in severe), reduce to 5 mg daily with moderate CYP3A4 inhibitors and avoid strong inhibitors and inducers, hold for grade 3 toxicity until grade 1 and resume at 5 mg, stop for grade 4 pneumonitis
• Sunitinib: sunitinib 37.5 mg orally once daily continuously until progression or unacceptable toxicity; maximum 50 mg daily; monitoring: blood pressure at each visit, liver tests, thyroid function, FBC, left ventricular ejection fraction, QTc, hand foot skin reaction; adjustment: reduce in 12.5 mg steps (to 25 mg then 12.5 mg), reduce to 25 mg daily with strong CYP3A4 inhibitors, hold for grade 3 to 4 toxicity or ejection fraction fall, stop for hepatotoxicity with ALT over 3 times the upper limit and bilirubin raised
• Capecitabine with temozolomide: capecitabine 750 mg/m2 orally twice daily on days 1 to 14 with temozolomide 200 mg/m2 orally once daily on days 10 to 14, every 28 days for 4 to 6 months or until progression; maximum capecitabine 1500 mg/m2 daily and temozolomide 200 mg/m2 daily; monitoring: FBC, creatinine, liver tests, hand foot syndrome, diarrhoea; adjustment: reduce capecitabine to 75% when creatinine clearance is 30 to 50 mL/min and avoid under 30, test DPYD before starting, avoid warfarin, caution with temozolomide when creatinine clearance is under 36 mL/min
• Liver directed therapy for liver dominant disease.

Grade 3 neuroendocrine carcinoma.

• Cisplatin with etoposide: cisplatin 75 mg/m2 IV on day 1 with etoposide 100 mg/m2 IV daily on days 1 to 3, every 21 days for 4 to 6 cycles; maximum cisplatin 100 mg/m2 each cycle; monitoring: FBC, creatinine, potassium, magnesium, audiometry, neuropathy; adjustment: give cisplatin only when creatinine clearance is 60 mL/min or more (carboplatin AUC 5 is the alternative), etoposide 75% of the dose when creatinine clearance is 15 to 50 mL/min and 50% when under 15, reduce for hepatic impairment

Paediatric tumours. Ganglioneuroblastoma and neuroblastoma are managed by a paediatric oncology team with surgery and risk adapted therapy.

Monitoring. Stool volume, potassium, magnesium and creatinine daily in hospital, then at every visit. VIP and imaging every 3 to 6 months, and gallbladder ultrasound yearly while on somatostatin analogues.

Referral and escalation.

• Referral to a neuroendocrine tumour centre on suspicion.
• Emergency admission for dehydration, arrhythmia or severe hypokalaemia.

Special groups.

• Children: weight based fluid and potassium replacement with paediatric specialist care.
• Renal impairment: lower potassium and magnesium doses with close monitoring.
• Pregnancy: stabilise electrolytes and plan surgery in the second trimester.