Nonfunctioning Pancreatic Neuroendocrine Tumour

Nonfunctioning pancreatic neuroendocrine tumours are pancreatic neuroendocrine neoplasms with no clinical hormone syndrome. They form most pancreatic neuroendocrine tumours, are often found by chance on imaging, and range from small indolent lesions suitable for observation to large tumours with liver metastasis.

They account for about 60% to 90% of pancreatic neuroendocrine tumours, with the incidence rising to about 5 cases in 1,000,000 people each year because of wider imaging. Median age is 55 to 65, with equal sex ratio. Tumours are present in the pancreatic head in about half.

Associations are multiple endocrine neoplasia type 1 (multiple microadenomas and tumours), von Hippel-Lindau disease, neurofibromatosis type 1 and tuberous sclerosis.

Pathophysiology. Tumour cells may secrete pancreatic polypeptide or chromogranin A without symptoms. Common alterations are MEN1, DAXX, ATRX and mTOR signalling mutations. Most express somatostatin receptors.

Risk of malignancy. Size is the main predictor: under 1 cm have very low metastatic risk, and tumours over 2 cm have a higher risk of nodal and liver spread (about 20% to 30% for 2 to 4 cm tumours and more for over 4 cm). Grade 2 or 3 histology, main duct dilatation, rising size, symptoms and raised CA 19-9 indicate more aggressive tumours.

• Most patients are asymptomatic. Incidental finding on imaging.
• Large or advanced tumours cause abdominal pain, weight loss, jaundice from bile duct compression, pancreatitis, gastric outlet obstruction, or palpable mass.
• Liver metastases: hepatomegaly and pain, with later cachexia.

Red flags.

• Jaundice with cholangitis.
• Gastrointestinal bleeding from tumour invasion.

• Multiphasic CT or MRI of the pancreas and liver, and endoscopic ultrasound with fine needle biopsy (Ki-67 and grade) for tumours over 1 cm.
• 68Ga-DOTATATE PET-CT for staging when surgery or systemic therapy is planned.
• Chromogranin A and pancreatic polypeptide levels, with hormone screening (fasting glucose and insulin, gastrin, VIP, glucagon) to exclude functioning tumours. Calcium and PTH for MEN1.
• Genetic testing (MEN1, VHL) for young patients, multiple tumours or family history.

Differential diagnosis.

• Pancreatic adenocarcinoma and solid pseudopapillary neoplasm
• Pancreatic cystic neoplasm and metastasis (renal cell carcinoma)
• Accessory spleen and lymph node

Treatment depends on size, grade, location and patient fitness.

Small tumours (under 2 cm, grade 1, incidental). Active surveillance with MRI or EUS every 6 to 12 months, since about 90% do not grow. Surgery for growth, rising grade, symptoms, main duct involvement, or patient preference.

Tumours over 2 cm, grade 2 or higher, or with nodal involvement. Resection with lymphadenectomy (distal pancreatectomy with splenectomy, or pancreatoduodenectomy), preferably in a high volume centre. Parenchyma sparing resection is used for selected small tumours.

Metastatic or unresectable disease.

• 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
• 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)
• 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. After resection, imaging every 6 months for 2 years and then yearly for at least 10 years. Surveillance tumours need imaging every 6 to 12 months for 5 years.

Referral and escalation.

• Referral to a neuroendocrine tumour centre on suspicion.
• Emergency admission for jaundice with cholangitis or bleeding.

Special groups.

• MEN1: surgery at lower size thresholds is not needed, and imaging surveillance continues, with decisions at specialist centres.
• Older adults and frail patients: observation for small tumours.
• Pregnancy: observation with imaging by MRI, and surgery in the second trimester when needed.