Somatostatinoma

Somatostatinoma is a rare neuroendocrine tumour of delta cells that secretes somatostatin. It occurs in the pancreas or the duodenum and ampulla. The classic somatostatinoma syndrome (diabetes mellitus, gallstones and steatorrhoea) is uncommon, and most tumours are found incidentally or after complications.

It is the rarest functional neuroendocrine tumour, with an incidence of about 1 case in 40,000,000 people each year. Median age at diagnosis is 50 to 60, with a slight female predominance. About 55% arise in the pancreas (mainly the head) and 45% in the duodenum or ampulla.

Duodenal somatostatinomas are linked with neurofibromatosis type 1 and often have psammoma bodies, and rarely cause the syndrome. Associations with MEN1 and von Hippel-Lindau disease are described.

Pathophysiology. Somatostatin inhibits insulin, glucagon, gastrin, cholecystokinin and pancreatic enzyme release, causing mild diabetes, gallbladder hypomotility with stones, reduced pancreatic exocrine function with steatorrhoea, and hypochlorhydria.

Behaviour and prognosis. Pancreatic tumours are mostly large (over 4 cm) and metastatic (about 70% to 90%) at diagnosis. Duodenal tumours are smaller, with lower metastatic rates (about 30% to 50%). Five year survival is about 60% overall, and about 15% to 40% with metastases.

• Syndrome (only 10% to 15%): diabetes mellitus, cholelithiasis, steatorrhoea and diarrhoea, weight loss, hypochlorhydria and anaemia.
• Most patients present with non-specific features of a mass: abdominal pain, jaundice (ampullary or head tumours), weight loss, nausea, or acute cholecystitis and pancreatitis.
• Incidental finding at cholecystectomy, endoscopy or imaging.
• Neurofibromatosis features (café-au-lait macules, neurofibromas) in the duodenal subtype.

Red flags.

• Obstructive jaundice with cholangitis.
• Gastrointestinal bleeding or gastric outlet obstruction.

• Fasting plasma somatostatin (raised against the assay specific upper limit), but the test is neither sensitive nor widely available, and diagnosis often follows tissue examination.
• Multiphasic CT or MRI, endoscopic ultrasound with biopsy and 68Ga-DOTATATE PET-CT for staging. Endoscopy with biopsy for ampullary and duodenal lesions.
• Histology: synaptophysin and chromogranin A positive, somatostatin staining, Ki-67 and mitotic count for grade, and psammoma bodies in duodenal tumours.
• Glucose and HbA1c, faecal elastase and fat, B12 and fat soluble vitamins, calcium and PTH, and genetic assessment (NF1, MEN1, VHL).

Differential diagnosis.

• Pancreatic adenocarcinoma and ampullary adenocarcinoma
• Other neuroendocrine tumours (gastrinoma, glucagonoma, nonfunctioning tumours)
• Chronic pancreatitis, cholelithiasis and primary diabetes mellitus
• Duodenal gangliocytic paraganglioma

Management is mainly surgical for localised disease, with systemic therapy for metastatic disease.

Surgery. Pancreatoduodenectomy for head and ampullary tumours, and distal pancreatectomy for body and tail tumours, with lymph node dissection. Cholecystectomy is performed at the same operation, because somatostatin analogues and the tumour itself promote gallstones. Duodenal tumours may be locally excised when small and non-invasive (ampullary resection) in selected patients.

Symptom control.

• Pancreatic enzyme replacement: pancrelipase 25,000 to 40,000 lipase units orally with each main meal and 10,000 to 25,000 units with snacks, taking half at the start of the meal and half during it, increased in response to stool fat and weight; maximum 10,000 lipase units/kg daily; monitoring: stool frequency and fat content, weight, fat soluble vitamins (A, D, E, K), HbA1c, abdominal pain; adjustment: increase stepwise over 1 to 2 weeks for persistent steatorrhoea, add a proton pump inhibitor when the response is poor, review the dose if above 6,000 lipase units/kg daily is needed because of the risk of fibrosing colonopathy
• Diabetes: glucose control with the diabetes team. Fat soluble vitamins and B12 are replaced when levels are low.
• Somatostatin analogue (antiproliferative effect, used with gallbladder surveillance and caution because they may worsen steatorrhoea and diabetes): 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

Metastatic or progressive 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 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. Imaging every 3 to 6 months for 2 years and then every 6 to 12 months for at least 10 years. Glucose, nutritional status, fat soluble vitamins and gallbladder ultrasound every 6 to 12 months.

Referral and escalation.

• Referral to a neuroendocrine tumour centre on suspicion.
• Emergency admission for cholangitis, bleeding or gastric outlet obstruction.

Special groups.

• Neurofibromatosis type 1: genetic counselling and surveillance for other tumours.
• Pregnancy: surgery in the second trimester if needed, and radionuclide therapy is contraindicated.
• Elderly or frail patients: endoscopic or limited resection and symptomatic care.