Pancreatic Neuroendocrine Tumours

Pancreatic neuroendocrine tumours are neoplasms of the endocrine pancreas that range from indolent well differentiated tumours to aggressive poorly differentiated carcinomas. They are functional (hormone secreting syndrome) or nonfunctioning, graded by proliferation index, and managed by surgery when localised and by systemic and local therapy for metastatic disease.

They form 1% to 2% of pancreatic tumours, with an incidence of about 5 cases in 1,000,000 people each year, rising with imaging. Median age at diagnosis is 55 to 65, and the sexes are equal. Most cases are sporadic, and 10% are hereditary.

Hereditary syndromes: multiple endocrine neoplasia type 1 (MEN1), von Hippel-Lindau disease, neurofibromatosis type 1 and tuberous sclerosis. Risk factors in sporadic disease are smoking, diabetes and family history.

Pathophysiology. Commonly altered genes in sporadic tumours are MEN1, DAXX, ATRX and mTOR signalling genes (PTEN, TSC2). Tumours express somatostatin receptors in most cases, which allows imaging and receptor targeted therapy.

Classification. Grade 1 (Ki-67 under 3%), grade 2 (3% to 20%) and grade 3 (over 20%) well differentiated tumours are separated from poorly differentiated neuroendocrine carcinoma (small cell or large cell type, Ki-67 usually over 55%). Stage is by tumour size, nodal and distant spread.

Prognosis. Localised grade 1 to 2 tumours are curable, with a 5-year survival of over 90%. Metastatic grade 1 to 2 tumours have median survival of about 3 to 5 years or longer, and neuroendocrine carcinomas under 1 year.

• Nonfunctioning tumours (60% to 90%): incidental finding, abdominal pain, weight loss, jaundice, pancreatitis, or symptoms of liver metastasis.
• Functional syndromes: hypoglycaemia (insulinoma), peptic ulcer disease and diarrhoea (gastrinoma), watery diarrhoea with hypokalaemia (VIPoma), diabetes with necrolytic migratory erythema (glucagonoma), gallstones and steatorrhoea (somatostatinoma).
• Hereditary syndromes: hypercalcaemia from primary hyperparathyroidism and pituitary tumour (MEN1), retinal and cerebellar haemangioblastoma (von Hippel-Lindau disease).

Red flags.

• Severe hypoglycaemia with neuroglycopenia.
• Severe diarrhoea with hypokalaemia (VIPoma).
• Upper gastrointestinal bleeding or perforation (gastrinoma).

• Multiphasic CT or MRI of the pancreas and liver (hypervascular, enhancing mass). Endoscopic ultrasound with fine needle biopsy for tissue and Ki-67.
• 68Ga-DOTATATE PET-CT for staging and receptor status, with FDG-PET for grade 3 disease.
• Chromogranin A (not specific), and hormone testing chosen by symptoms: fasting glucose with insulin, C-peptide and proinsulin; fasting gastrin with gastric pH; VIP; glucagon; and calcium and parathyroid hormone for MEN1.
• Histology: synaptophysin and chromogranin A positive, with Ki-67 and mitotic count for grade, plus DAXX and ATRX.
• Genetic testing (MEN1, VHL) for young patients, multifocal tumours or family history.

Differential diagnosis.

• Pancreatic adenocarcinoma and solid pseudopapillary neoplasm
• Metastatic neuroendocrine tumour from small bowel or lung
• Acinar cell carcinoma and pancreatic metastasis from renal cell carcinoma
• Pancreatic cystic neoplasm

Treatment depends on grade, stage, hormone syndrome and genetics, in a neuroendocrine multidisciplinary team.

Surgery. Resection with lymphadenectomy (enucleation for small benign behaving tumours such as insulinoma, distal pancreatectomy, or pancreatoduodenectomy). Liver metastases are resected or ablated when feasible, and liver transplantation is considered in selected young patients.

Control of hormone symptoms.

• 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

Progressive or metastatic grade 1 to 2 tumours.

• 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. After resection, CT or MRI every 3 to 6 months for 2 years, then every 6 to 12 months for at least 10 years. Chromogranin A and hormone markers where relevant. Surveillance for syndrome related tumours.

Referral and escalation.

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

Special groups.

• MEN1 and von Hippel-Lindau disease: genetic counselling, surveillance, and size thresholds for surgery.
• Pregnancy: surgery in the second trimester when needed, with radionuclide therapy contraindicated.
• Diabetes and renal impairment: adjust drug choice and doses.