Gastrinoma

Gastrinoma is a gastrin secreting neuroendocrine tumour that causes Zollinger-Ellison syndrome: severe gastric acid hypersecretion with refractory peptic ulceration, reflux disease and diarrhoea. About half are malignant, and the two aims are immediate control of acid secretion and removal or control of the tumour.

It is the commonest functional malignant pancreatic region neuroendocrine tumour, with an incidence of about 0.5 to 2 cases in 1,000,000 people each year. Median age at diagnosis is 40 to 60, with a slight male predominance. About 75% are sporadic and 25% occur in multiple endocrine neoplasia type 1 (MEN1).

Most tumours lie in the gastrinoma triangle (junction of the cystic and common bile ducts, the second and third parts of the duodenum, and the neck and body of the pancreas). In sporadic disease the duodenum is the commonest site (60% to 70%), usually with tumours under 1 cm, and the pancreas accounts for 25% to 40%. In MEN1 the tumours are mainly duodenal, small and multiple.

Pathophysiology. Gastrin stimulates parietal cell hyperplasia and acid output (basal acid output over 15 mmol/h, or over 5 mmol/h after gastric surgery). Acid injures the mucosa and inactivates pancreatic enzymes and bile salts, causing diarrhoea and steatorrhoea.

Behaviour and prognosis. Lymph node and liver metastases occur in 30% to 50%. Liver metastasis is the main prognostic factor: 10-year survival is about 90% to 95% without liver metastases and about 30% with them. Duodenal tumours are smaller but metastasise to nodes early.

• Epigastric pain from peptic ulcer (75% to 90%), often multiple, in unusual sites (distal duodenum, jejunum) or recurrent after surgery or low dose acid suppression.
• Diarrhoea (50% to 70%), which may precede ulcer symptoms, with steatorrhoea and weight loss, and which improves with acid suppression.
• Reflux with oesophagitis, stricture or Barrett oesophagus.
• Complications: gastrointestinal bleeding, perforation, gastric outlet obstruction.
• MEN1 features: primary hyperparathyroidism (hypercalcaemia, renal stones, which can raise gastrin and acid output), pituitary tumours.

Red flags.

• Haematemesis or melaena, peritonism or haemodynamic instability.
• Severe diarrhoea with hypokalaemia.
• Sudden worsening after interruption of acid suppression.

• Fasting serum gastrin with gastric pH: gastrin over 10 times the upper limit with gastric pH under 2 is diagnostic (about 40% to 60% of patients). Proton pump inhibitors raise gastrin, and stopping them for testing is dangerous, so it is done only in a specialist unit with monitoring and with gastric pH measurement.
• Secretin stimulation test when gastrin is lower: secretin 0.4 micrograms/kg IV over 1 minute with gastrin measured at baseline and at 2, 5, 10, 15 and 20 minutes. A rise of 120 pg/mL or more over baseline is positive (sensitivity about 90%).
• Localisation and staging: 68Ga-DOTATATE PET-CT (most sensitive), multiphasic CT or MRI, endoscopic ultrasound with biopsy, and upper endoscopy (ulcers, thick gastric folds, duodenal nodules). Intraoperative duodenotomy with palpation and ultrasound for occult tumours.
• Ki-67 and mitotic count for grade. Calcium, parathyroid hormone, prolactin and IGF-1, and genetic testing for MEN1.

Differential diagnosis.

• Hypergastrinaemia with high gastric pH: atrophic gastritis, pernicious anaemia, proton pump inhibitor use
• Hypergastrinaemia with low gastric pH: Helicobacter pylori infection, retained gastric antrum, G-cell hyperplasia, gastric outlet obstruction, renal failure
• Idiopathic peptic ulcer disease and NSAID ulcer
• Other causes of chronic diarrhoea (VIPoma, carcinoid syndrome, coeliac disease)

Control of acid secretion (start at once in every patient).

• Proton pump inhibitor: omeprazole 60 mg orally once daily initially, adjusted every 1 to 2 weeks to control symptoms and acid output (usual range 40 to 120 mg daily, with doses over 80 mg daily given in 2 divided doses); maximum 120 mg daily in routine use (higher doses only under specialist supervision with acid output measurement); monitoring: symptom control, basal acid output (target under 10 mmol/h, or under 5 mmol/h after gastric surgery), magnesium, vitamin B12, FBC, bone health; adjustment: reduce the dose gradually only when acid output stays controlled, never stop abruptly because acid hypersecretion rebounds within days, monitor closely and reduce the dose in severe hepatic impairment, separate from drugs that need gastric acid for absorption
• Intravenous cover when oral intake is not possible: pantoprazole 80 mg IV once, then 40 mg IV every 12 hours (up to 80 mg every 12 hours for severe hypersecretion) until oral therapy is possible, for no longer than 7 days; maximum 240 mg daily; monitoring: gastric pH or acid output, magnesium, liver tests, infusion site; adjustment: no renal adjustment, reduce in severe hepatic impairment, return to oral omeprazole as soon as swallowing and gut absorption allow

Surgery. Sporadic tumours: exploration with duodenotomy and resection of tumour with regional lymph node dissection (curative in 30% to 60%). Pancreatic tumours are enucleated or resected (distal pancreatectomy or pancreatoduodenectomy). MEN1: surgery is offered for pancreatic tumours over 2 cm, since duodenal disease is rarely cured. Liver metastases are resected or ablated when feasible.

Metastatic or progressive disease.

• Somatostatin analogue (also antiproliferative in grade 1 and 2 tumours): 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
• Lutetium dotatate (somatostatin receptor positive): 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 (embolisation, radioembolisation, ablation) 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

Monitoring. Fasting gastrin and gastric acid output at 3 to 6 months, then yearly. Imaging every 6 to 12 months for at least 10 years. Magnesium, vitamin B12 and bone health on long term acid suppression. Annual MEN1 screening.

Referral and escalation.

• Referral to a neuroendocrine tumour centre on suspicion.
• Emergency admission for gastrointestinal bleeding, perforation or severe diarrhoea with hypokalaemia.

Special groups.

• MEN1: parathyroidectomy first when hypercalcaemic, since it lowers gastrin, then tumour surgery decisions at a specialist centre.
• Pregnancy: continue acid suppression with specialist advice, and defer tumour surgery.
• Renal and hepatic impairment: adjust drug doses and monitor closely.