Pancreatic NETs

Pancreatic NETs are rare and they occur in approximately 10 per million population per year (prevalence 1-2% of all pancreatic neoplasms), but have a higher survival than exocrine pancreatic tumors. An overview of diagnosis and treatment follows.

Epidemiology of pancreatic NETs
There is no gender predilection and the tumor can affect all age groups with a peak incidence between 30 and 60 years. Fifteen to thirty percent of tumors are part of a hereditary syndrome, mainly multiple endocrine neoplasia type 1 (MEN 1) or von Hippel-Lindau’s (vHL) disease, and then present at an earlier age.

Classification and pathology of pancreatic NETs
It’s not fully known why these tumors develop but recent evidence suggest that they evolve from pluripotent stem cells in the ductal epithelium.

Pancreatic NETs are classified on the basis of their clinical manifestations into functioning and non-functioning tumors. “Functioning” tumors are associated with a clinical syndrome caused by inappropriate secretion of hormones. Within this group are the five “classical” syndromes: Insulinoma, Gastrinoma,
Glucagonoma, Somatostatinoma Rarely also other syndromes can occur due to a pancreatic NET, such as Ectopic cushing (producing ACTH), Acromegaly (producing IGF-1) and the Carcinoid syndrome (producing serotonin).
The ratio of the different types of pancreatic NETs is:

  • Insulinoma 17%
  • Gastrinoma 15%
  • VIPoma 2%
  • Glucagonoma 1%
  • Remaining functional <10%
  • Non-functioning 50%


Malignant endocrine pancreatic tumors are pluripotent and may cause mixed syndromes, e.g. insulinoma/gastrinoma or insulinoma/glucagonoma can be seen. The tumors can also change the hormonal profile and type of syndrome during the course. Hence, it’s important to determine peptides/hormones in serum/plasma at the primary investigation and during follow-up. A tumor biological property that can be exploited for diagnostic and therapeutic purposes is the presence of somatostatin receptor in about 80-90% of the tumors. The expression can vary between different tumors.
Another important classification is the WHO system, based on presence of metastases and the Ki67 proliferation index:

  • Well-differentiated neuroendocrine tumor: Ki67 < 2%, no metastases
  • Well-differentiatied neuroendocrine carcinoma: Ki67 3-20%, metastases
  • Poorly-differentiated neuroendocrine carcinoma: Ki67 > 20%, metastases


Treatment of pancreatic NETs
Surgery is the only treatment that can be curative in pancreatic NETs, especially in insulinomas. Currently, attempts to perform curative surgery is also made in locally advanced pancreatic NETs of other types. Recently, the surgical approach in metastatic disease has become more aggressive aiming at cure also in case with limited metastatic disease in the liver. “Debulking” surgery to reduce the tumor burden in the liver can facilitate medical treatment.

Familial pancreatic NETs occur with MEN1 or the von Hippel-Lindau syndrome, and require special management. Patients with MEN1 can have all entities of functioning and non-functioning pancreatic NETs, and require early surgery for malignancy prevention. The von Hippel-Lindau syndrome is rare and associated with non-functioning pancreatic NETs. The endocrine surgical group in Uppsala has had the aim to develop surgery for endocrine tumors with minimal morbidity and mortality. Also, the indications and techniques are different from those employed in exocrine pancreatic cancer. Surgery has been of benefit mainly for low proliferating tumors, whereas highly malignant, poorly differentiated neuroendocrine carcinomas (PDEC) have been more efficiently managed with chemotherapy.

Medical treatment
should be considered in all cases. Alternatives are different chemotherapeutic regimens, somatostatin analogues, interferon-alpha and various types of symptomatic treatment, e.g. proton pump inhibitors. The therapeutic decision should be based on a number of different factors, e.g. presence of hormonal symptoms, proliferation rate, presence of somatostatin receptor and stage of disease.

Chemotherapy for pancreatic NETs
Several different combinations can be used depending on proliferation rate. In low-to-moderate proliferative tumors combinations with streptozotocin and 5-fluorouracil or doxorubicin can be used. In highly proliferative tumors combinations with cisplatin/paraplatin plus etoposide should be used. Recently, temozolomide as monotherapy or in combination with capecitabine has been introduced in low/moderately proliferative tumors.

Side-effects differ between the combinations. Renal toxicity and bone marrow toxicity should be monitored.

Somatostatin analogs in pancreatic NETs
Somatostatin is a naturally occurring hormone, which inhibits the release of other hormones. Somatostatin analogues have been shown to be very effective in controlling hormonal symptoms, such as diarrhea, flush and skin rash. Octreotid (Sandostatin®) has been available since the 1980’s and another analogue, Lanreotide is presently available. Octreotide can be given subcutaneously (2-3 times daily) or intramuscularly (once per month). Somatostatin analogues should be given prophylactically to avoid hormonal crises at invasive procedures (surgery, embolization, chemotherapy) in patients with hormonal symptoms.

Side-effects are few, usually flatulence and diarrhoea, which subside with time.

Interferon (IFN-α) in pancreatic NETs
Interferon-alpha is a naturally occurring substance, which has been shown to have effect in malignant pancreatic NETs. There are short-acting (Introna®, Roceron®) and long-acting (PegIntron®, Pegasys®) variants. IFN-α is administrated subcutaneously and can be given in cases with a low proliferation rate, possibly in combination with somatostatin analogues. Doses should be individually titrated. Side-effects include flu-like symptoms, fatigue, bone marrow depression and elevation of liver enzymes. Treatment with interferon is contraindicated in mano-depressive and autoimmune disease.

Liver metastases of pancreatic NETs
Liver metastases in patients with NETs should generally be treated aggressively. Several methods are available.

Liver embolization can be performed to selectively deprive the blood supply.

Liver surgery may be performed by hepatic lobectomy or segmental resections. The latter are used liberally for removal of solitary or large liver metastases, and often combined with wedge resection or enucleation of additional, smaller lesions. Two-stage liver resection combined with portal embolization for triggering liver regeneration may reduce the risk for liver insufficiency.

Radiofrequency ablation of liver metastases at Uppsala Centre of Excellence
Figure 1. Radiofrequency ablation of liver metastases.

Radiofrequency ablation (RFA) can be used for treatment of liver metastases and can be done at open surgery or as a percutaneous ultrasound-guided procedure (Fig .1, Fig 2). RFA has widened indications for surgery of bilateral liver tumors. Only a limited number of metastases can be treated with combinations of surgery and RFA. The RFA has had low complication rate, but with a risk that especially central bile ducts may be damaged by RFA therapy close to the hepatic hilum.
Sustained symptom palliation and reduction of tumor markers can be achieved after removal of liver metastases if appr. 90% of the tumor volume can be excised or ablated.

Ablation cavity after RFA treatment of metastasis in the right liver lobe, remaining tumour in the left liver lobe was removed by resection.
Figure 2. Ablation cavity after RFA treatment of metastasis in the right liver lobe, remaining tumour in the left liver lobe was removed by resection.

Targeted radiotherapy with 90Y- and 177-Lu-labelled somatostatin analogues is the most recent and promising therapeutic option. The exact timing and role for this option is not yet established.