Insulinoma

Insulinoma is a pancreatic neuroendocrine tumour that secretes insulin autonomously, causing recurrent fasting hypoglycaemia. It is the commonest functional pancreatic neuroendocrine tumour and most are benign, solitary, small and cured by surgery.

Incidence is about 1 to 4 cases in 1,000,000 people each year. Median age is 45 to 55 (younger in MEN1, around 30), and women are affected slightly more often. About 90% are benign and under 2 cm, and about 5% to 10% are malignant.

About 5% to 10% occur in multiple endocrine neoplasia type 1 and are often multiple. Tumours are distributed evenly across the head, body and tail of the pancreas, and ectopic tumours are very rare.

Pathophysiology. Tumour beta cells secrete insulin independently of glucose, suppressing hepatic glucose output and ketogenesis. Inappropriate insulin secretion at low glucose causes neuroglycopenia. YY1 T372R mutations occur in many sporadic tumours, and MEN1 loss in familial cases.

Malignant insulinoma. Defined by metastasis (liver and nodes). Features of malignancy are size over 2 cm, Ki-67 over 2%, and necrosis. Five year survival is about 30% to 60% in metastatic disease and about 95% after resection of benign tumours.

• Whipple triad: symptoms of hypoglycaemia, low plasma glucose at the time, and relief when glucose is raised.
• Neuroglycopenic symptoms: confusion, visual blurring, behavioural change, seizures, loss of consciousness (often fasting, early morning or after exercise).
• Adrenergic symptoms: sweating, tremor, palpitations, hunger, anxiety.
• Weight gain from frequent eating, and misdiagnosis as epilepsy or psychiatric illness.

Red flags.

• Seizure, coma or persistent neurological deficit during a hypoglycaemic episode.
• Hypoglycaemia that does not respond to oral glucose.

• Supervised fast (up to 72 hours) with glucose, insulin, C-peptide, proinsulin and beta hydroxybutyrate measured when plasma glucose falls under 3.0 mmol/L (55 mg/dL), or when symptoms occur. Diagnostic pattern: glucose under 3.0 mmol/L with insulin 3 microunits/mL or more, C-peptide 0.6 ng/mL (0.2 nmol/L) or more, proinsulin 5 pmol/L or more, beta hydroxybutyrate 2.7 mmol/L or less, and a glucose rise of 1.4 mmol/L or more after glucagon 1 mg IV.
• Sulfonylurea and meglitinide screen in plasma or urine, and insulin antibodies, to exclude factitious or drug induced hypoglycaemia and insulin autoimmune hypoglycaemia.
• Localisation: multiphasic CT or MRI, endoscopic ultrasound (sensitivity over 80%), and glucagon like peptide-1 receptor imaging (exendin PET-CT), which is more sensitive than DOTATATE PET because many insulinomas express few somatostatin receptors. Intra-arterial calcium stimulation with hepatic venous sampling in occult tumours.
• MEN1 screening: calcium, PTH, prolactin, IGF-1, and genetic testing.

Differential diagnosis.

• Factitious hypoglycaemia (insulin or sulfonylurea use) and insulin autoimmune hypoglycaemia
• Non-insulinoma pancreatogenous hypoglycaemia (nesidioblastosis, post-gastric bypass hypoglycaemia)
• Adrenal insufficiency, hypopituitarism, severe liver disease and alcohol
• Non-islet cell tumour hypoglycaemia (IGF-2)

Acute hypoglycaemia.

• Oral glucose and glucagon: glucose 15 to 20 g orally for conscious hypoglycaemia, repeated after 15 minutes if the glucose remains under 3.9 mmol/L, and glucagon 1 mg IM or subcutaneously once for severe hypoglycaemia when oral intake is impossible (a second dose after 15 minutes if no response), followed by a carbohydrate meal; maximum 2 doses of glucagon in an episode before IV dextrose; monitoring: capillary glucose every 15 minutes until above 3.9 mmol/L; adjustment: glucagon works poorly in fasting induced hypoglycaemia with depleted liver glycogen, so give IV dextrose (10% or 50% solution) if no response, and in insulinoma recurrent hypoglycaemia is expected until the tumour is removed

Definitive treatment. Surgery is curative in over 90% for benign tumours. Enucleation for solitary tumours away from the main duct (open or laparoscopic), and distal pancreatectomy or pancreatoduodenectomy for tumours near the duct or large tumours. Intraoperative ultrasound and glucose monitoring guide surgery. Lymphadenectomy is added for larger or suspicious tumours.

Medical therapy while awaiting surgery or when surgery is not possible.

• Diazoxide: diazoxide 150 to 200 mg orally daily in 2 to 3 divided doses, increased every few days to 3 to 8 mg/kg daily as needed for fasting glucose; maximum 600 mg daily in adults (up to 1200 mg in rare cases); monitoring: fasting and postprandial glucose, fluid retention and weight, blood pressure, hirsutism, FBC, uric acid; adjustment: add a thiazide diuretic for fluid retention, reduce in renal impairment, avoid in heart failure or pulmonary hypertension, stop if no glucose benefit after 1 to 2 weeks
• Frequent small carbohydrate meals and slow release carbohydrate at night.
• Somatostatin analogues can worsen hypoglycaemia by suppressing counter regulatory glucagon and growth hormone when tumours lack receptors, so they are started under glucose monitoring. Lanreotide 120 mg deep subcutaneously every 28 days is used when imaging shows receptor expression (maximum 120 mg every 28 days; monitoring: capillary glucose, gallbladder ultrasound, thyroid function; adjustment: start at 60 mg in moderate to severe renal or hepatic impairment).
• 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

Metastatic malignant insulinoma. Liver directed therapy, lutetium dotatate for receptor positive disease, systemic chemotherapy, and continuous glucose control.

• 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)

Post-operative care. Transient hyperglycaemia is common after resection and resolves. Check for pancreatic fistula and diabetes.

Monitoring. Glucose monitoring after surgery, with fasting glucose at follow up. Imaging every 6 to 12 months for 5 years when there is a malignant or MEN1 tumour. Annual MEN1 screening.

Referral and escalation.

• Referral to an endocrine and pancreatic surgery team for confirmed insulinoma.
• Emergency admission for severe hypoglycaemia, seizure or coma.

Special groups.

• MEN1: multiple tumours, parenchyma sparing surgery and lifelong surveillance.
• Pregnancy: diazoxide crosses the placenta and can cause neonatal hyperbilirubinaemia and hypoglycaemia, so surgery in the second trimester is preferred, with fetal and neonatal glucose monitoring.
• Renal and hepatic impairment: lower diazoxide doses and close monitoring.
• Older adults: more falls and cognitive effects, so tolerate fewer hypoglycaemic episodes.