Pancreatic NETs are uncommon with an annual incidence of 0.4-1.2 per 100,000 population. The endocrine cells give rise to pNETs which account for less than 4% of pancreatic neoplasms. The tumours can occur at any age and both sexes are affected equally.
pNETs can occur as part of 4 inherited disorders, including Multiple Endocrine Neoplasia type 1 (MEN1), von Hippel-Lindau disease (VHL), neurofibromatosis 1 (NF-1; von Recklinghausen disease) and tuberous sclerosis complex (TSC) with the most common association , up to 80%, in MEN1 patients.
Current terminology divides pNETs into:
- Non-functional tumours - often present in a manner similar to adenocarcinomas of the pancreas
- Functional tumours - excess hormone production results in clinical syndromes (e.g. sometimes in the context of a 'carcinoid syndrome', characterized by facial flushing, diarrhea, bronchial constriction caused by high levels of circulating serotonin). Other syndromes occur as a result of different hormones being produced, for example:
- Insulinomas
- Gastrinomas
- VIPomas
- Somatostatinomas
- Glucagonomas
Diagnostic and Staging Work-Up
CT scan of the chest and abdomen/pelvis is recommended to assess the extent of local involvement and to exclude distant metastases. A pancreas-protocol CT scan or MRI is indicated if the patient is thought to be an operative candidate. If a mass is not clearly identified or if there is uncertainty regarding vascular involvement, an EUS should be performed.
If there appears to be an isolated pancreatic lesion, refer to a hepatobiliary surgeon who will determine if the disease is resectable or unresectable. A biopsy is not always required but may be performed if clinically indicated.
If there are obvious metastases, then the pancreatic mass or metastases can be biopsied percutaneously with ultrasound CT guidance or by endoscopic with fine needle aspiration. In patients who have carcinoid syndrome, a potential carcinoid crisis should be prevented by prophylactic administration of octreotide, given by constant intravenous infusion at a dose of 50 mcg/h for 12 hours prior to and at least 48 hours after the procedure.
PNETs should be staged using 111In-pentetreotide scintigraphy (octreotide scan). Those with negative octreotide scans can be imaged with MIBG scintigraphy.
All patients with PNETs should have 24-hour urinary 5-HIAA and chromogranin A (CgA) measured at diagnosis.
Biliary Decompression
Patients presenting with jaundice and cholangitis should receive antibiotics and undergo biliary decompression, usually by ERCP.
Patients with jaundice only who are potentially operative candidates do not require stenting unless operative intervention will be delayed by > 1-2 weeks.
Patients without jaundice do not require stenting.
Primary Surgical Therapy
Surgical treatment of pancreatic cancer should be undertaken by surgeons having expertise and experience with these tumours.
For resectable pNETs: definitive resection of the primary tumour should always be performed whenever technically feasible. In patients who have carcinoid syndrome, a potential carcinoid crisis should be prevented by prophylactic administration of octreotide, given by constant intravenous infusion at a dose of 50 mcg/h for 12 hours prior to and at least 48 hours after the procedure.
Prophylactic cholecystectomy should be considered during any surgery for neuroendocrine tumours.
For localized, locoregional, or resectable metastatic pNETs, curative surgery should be considered if technically and clinically feasible.
For unresectable metastatic pNETs, cytoreductive surgery to achieve maximal debulking and palliation of symptoms should be considered if technically feasible and clinically appropriate.
Pathology
Recommend BC Cancer pathology review
Specimen: specify
Tumour: specify
- Site
- Size
- Histologic type
- Histologic grade
- Microscopic tumour extension
- Margins
- Treatment effect (if neo-adjuvant therapy given)
- Lymph-Vascular invasion
- Perineural invasion
- Lymph nodes: number examined, number involved
- pTNM (AJCC 7th edition)
In addition for pNETs:
- Functional type
- Mitotic rate (per 10 HPF)
- Tumour necrosis
- Ki-67labellilng index (≤ 2%, 3-20%, >20%)
- Additional pathologic findings
Treatment Options:
Treatment options are based on current evidence
Surgery
Surgery is the only curative treatment. Indications for surgery depend upon the size and location of the pNET. Surgical procedures include:
- pancreaticoduodenectomy (Whipple’s resection: classic or pylorus-preserving)
- distal pancreatectomy +/- splenectomy
- tumour enucleation
- enucleation combined with resection
- regional lymph node dissection required for 'malignant' (high grade) pNETs
Patients with “limited” metastatic disease should be considered for surgery.
Patients with liver metastases from either functioning or non-functioning tumours where greater than 90% of the tumour mass can be removed may have a delay in disease progression.
Carcinoid crisis: hormonal release can occur with manipulation of the tumour(s) during surgery. A pre-operative anesthesia consultation is recommended and a perioperative octreotide infusion is indicated.
Cholecystectomy should be done at the same time as any surgery to prevent complications from gallstone formation from any subsequent therapy with octreotide.
Cytoreductive Therapy
May be considered in symptomatic patients - selective embolization of hepatic arteries can reduce hormonal symptoms due to liver metastases. Need for MDT
Transarterial chemoembolization (TACE) involves injection of cytotoxic drugs (doxorubicin, 5FU or mitomycin C) intra-arterially with embolization material. This requires an assessment by a multidisciplinary team comprised of gastroenterologists, surgeons, radiologists and oncologists.
Transarterial radioembolization (TARE) is available at Vancouver General Hospital (VGH) and requires an assessment by the multidisciplinary team at VGH Liver Rounds. It involves injection of Yttrium-90 glass microspheres (see protocol UGIYTT).
Radiofrequency ablation (RFA) can be used to treat hepatic tumour masses of approximately 3 cm or less and, thus, reduce hormonal symptoms.
Systemic Therapy
Adjuvant - there is no established adjuvant therapy for patients with completely resected pancreatic NET.
The following systemic regimens are approved for BC Cancer funding in advanced pancreatic (GI/Lung) NET disease – refer to the specified protocols in the Chemotherapy Protocols section for details on eligibility and indications.
Pancreatic NET |
Somatostatin analogues (SSAs) if functional UGIOCTLAR or UGILAN
|
|
|
capecitabine and temozolomide (GIAVTZCAP)
streptozocin and 5FU (GIENDO2) – less commonly used
cisplatin and etoposide if high-grade
(GIPE)
|
*PRRT – Peptide radionuclide receptor therapy. Patients being considered for radionuclide therapy should be reviewed at a BC Cancer GI multidisciplinary conference.
Octreotide is the primary treatment for patients with symptomatic functioning pancreatic NET. About 80-90% of patients experience prompt improvement of their symptoms (see protocol
UGIOCTLAR).
- Caution should be taken with the use of octreotide in patients with insulinomas, since concomitant suppression of GH and glucagon can lead to a worsening of hyperglycemia.
- A significant tumour regression may be observed in <10% of patients, but stabilization of tumour growth may occur in 30-50% of patients.
- After a period of control, some patients may experience recurrence of their symptoms. The dose of octreotide should be increased or the interval between treatments reduced.
Chemotherapy with capecitabine and temozolomide can reduce normal symptoms and is effective therapy for PNETs, resulting in both improved survival and tumour shrinkage in many patients (see protocol
GIAVTZCAP).
Poorly-differentiated neuroendocrine tumours with a high proliferation index (Ki67 index greater than 20%) are treated with cisplatin and etoposide (see protocol
GIPE).
Targeted agents have shown activity in the treatment of PNETs. Patients may be treated with one of the following (but not both):
The choice and sequence of systemic therapy is determined by disease-related factors, patient factors and patient preferences as assessed by the medical oncologist.
Consider treatment on a clinical trial, if available.
Symptom management (including celiac or intrapleural block for tumour-related pain), pancreatic enzyme replacement for diarrhea, best supportive care, and involvement of palliative care services as indicated by patient’s clinical status.
PRRT - Patients with progressive and/or symptomatic metastatic pancreatic NETs whose tumours are receptor-positive as proven by an Octreoscan or Ga68 scan, and have a Ki67 less than or equal to 20% may be candidates for referral to a specialized centre for consideration of radionuclide therapy.
