Glucagonoma

Glucagonoma is a glucagon secreting alpha cell neuroendocrine tumour of the pancreas that causes the glucagonoma syndrome: necrolytic migratory erythema, diabetes mellitus, weight loss, anaemia, venous thrombosis and mucosal lesions. Most are large and malignant, and many already have liver metastases when the syndrome is recognised.

It is rare, with an incidence of about 0.01 to 0.1 cases in 100,000 people each year. Median age at diagnosis is 50 to 60, and the sexes are affected equally. Most are sporadic, and 3% to 10% are linked with MEN1.

Tumours are mostly in the pancreatic body or tail and are over 3 cm at diagnosis. Liver metastases are present in over 50% and malignant behaviour in about 60% to 80%.

Pathophysiology. Excess glucagon increases hepatic glucose output and amino acid catabolism. Hypoaminoacidaemia, zinc deficiency and essential fatty acid deficiency are thought to drive the characteristic rash. Glucagon also causes catabolism with weight loss, and a hypercoagulable state contributes to venous thrombosis.

Prognosis. Median survival is about 4 to 5 years in metastatic disease, and 5-year survival after complete resection of localised tumours is about 50% to 70%.

• Necrolytic migratory erythema (70% to 90%): a migratory, relapsing erythematous rash with blistering, crusting and healing with hyperpigmentation, over the perineum, groin, buttocks and distal limbs.
• Diabetes or impaired glucose tolerance (80% to 90%), usually mild.
• Weight loss, normochromic normocytic anaemia, glossitis, angular stomatitis and cheilitis.
• Diarrhoea (about 30%), venous thromboembolism (up to 30%) and neuropsychiatric symptoms (depression, ataxia, dementia).
• Dilated cardiomyopathy in rare cases.

Red flags.

• Deep vein thrombosis or pulmonary embolism.
• Severe weight loss and malnutrition.
• Extensive skin erosion with sepsis.

• Fasting plasma glucagon: over 500 pg/mL (500 ng/L) is diagnostic in the right clinical setting, and over 1000 pg/mL is near certain. Mildly raised levels occur with renal failure, cirrhosis, sepsis, burns, pancreatitis, fasting and stress.
• Biopsy of the rash edge: necrolysis of the upper epidermis with pallor, vacuolation and keratinocyte necrosis (not specific).
• Low plasma amino acids, zinc, albumin and essential fatty acids. Normocytic anaemia, raised glucose and HbA1c.
• Multiphasic CT or MRI of the pancreas and liver, endoscopic ultrasound with biopsy (Ki-67, grade) and 68Ga-DOTATATE PET-CT. Calcium, PTH and genetic testing for MEN1.

Differential diagnosis.

• Zinc deficiency (acrodermatitis enteropathica), pellagra and biotin deficiency
• Psoriasis, pemphigus foliaceus and seborrhoeic dermatitis
• Other functional pancreatic neuroendocrine tumours and pancreatic adenocarcinoma
• Primary diabetes mellitus and drug induced hyperglucagonaemia

Management is surgical when possible, with symptom control, nutritional repair and thromboprophylaxis before and after.

Surgery. Distal pancreatectomy (with splenectomy and lymph node clearance) for tumours in the body and tail, or pancreatoduodenectomy for tumours in the head. Resection or ablation of liver metastases and debulking are worthwhile because glucagon excess causes the syndrome. Preoperative nutritional and thrombosis prophylaxis is given.

Control of the syndrome.

• Somatostatin analogue: 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
• Thromboprophylaxis: enoxaparin 40 mg subcutaneously once daily for thromboprophylaxis during active disease and for 4 weeks after surgery (therapeutic dosing of 1 mg/kg twice daily if thrombosis is established); maximum 40 mg daily for prophylaxis; monitoring: platelet count at baseline and every 2 to 4 weeks, creatinine, signs of bleeding, anti-Xa level in obesity or renal impairment; adjustment: 20 mg daily when creatinine clearance is under 30 mL/min, hold for platelets under 50 x 10^9/L or active bleeding, time the dose at least 12 hours before and 4 hours after a neuraxial procedure
• Zinc supplementation: zinc sulfate 220 mg (50 mg elemental zinc) orally once to three times daily with food for 4 to 8 weeks, for zinc deficiency with skin or mucosal lesions; maximum 150 mg elemental zinc daily; monitoring: serum zinc and copper every 4 to 8 weeks (prolonged zinc lowers copper), gastrointestinal upset; adjustment: reduce the dose and add copper if copper falls, reduce in renal impairment, separate from tetracyclines and quinolones by at least 2 hours
• Intravenous amino acids and fatty acid supplements are given for severe rash and malnutrition. Glucose control is managed with the diabetes team, and hypoglycaemia is uncommon.
• Skin care: gentle wound care, topical antiseptics and treatment of secondary infection.

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 (embolisation, radioembolisation, ablation).

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. Glucagon, glucose, zinc, albumin and weight every 3 months. Imaging every 3 to 6 months initially, then every 6 to 12 months. Rash and nutritional status at each visit.

Referral and escalation.

• Referral to a neuroendocrine tumour centre on suspicion.
• Emergency admission for venous thromboembolism, severe malnutrition or sepsis.

Special groups.

• MEN1: genetic counselling and surveillance for other tumours.
• Pregnancy: surgery in the second trimester when needed, and radionuclide therapy is contraindicated.
• Renal impairment: dose adjustments for enoxaparin and chemotherapy.