What are non-functioning pancreatic NETs?

The pancreas is a leaf shaped organ that sits near the bottom of the ribs and forms part of the digestive and endocrine (hormone) systems. Pancreatic neuroendocrine tumours (NETs) are rare tumours that start in specialised neuroendocrine cells in the pancreas. They can either be functioning or non-functioning. Functioning NETs, such as insulinoma, gastrinoma, somatostatinoma or VIPomas, cause too much of a hormone to be made and cause symptoms because of this.

By comparison, non-functioning pancreatic NETs do not make hormones or produce only small (or biologically inactive) quantities of hormones such as pancreatic polypeptide, calcitonin or neurotensin, but these do not cause any symptoms.

Non-functioning pancreatic NETS still cause signs and symptoms. These are due to the size of the tumour or its spread to nearby organs such as lymph nodes or the liver. In some patients, the tumours are diagnosed by chance during radiological investigations for other conditions.

What causes non-functioning pancreatic NETs?

Non-functioning pancreatic NETs are caused by uncontrolled division and reproduction of specialised neuroendocrine cells of the pancreas. The exact trigger for this is not known. In around 1 out of 10 patients, a non-functioning pancreatic NET may be linked with a genetic condition such as multiple endocrine neoplasia type 1 syndrome or von Hippel-Lindau disease (see below).

What are the signs and symptoms of non-functioning pancreatic NETs?

The signs and symptoms of non-functioning pancreatic NETs depend on their size or spread to the nearby organs. Symptoms may include abdominal pain, an abdominal lump, nausea, weight loss and jaundice (i.e., yellowing of the skin and whites of the eyes).

As these tumours do not over-produce hormones that cause symptoms earlier, they are not usually detected until a late stage. These tumours are usually large in size (average size of 3–4 cm). In most patients with non-functioning pancreatic NETs, there is evidence of spread to nearby organs such as the liver or bone at the time of diagnosis.

How common are non-functioning pancreatic NETs?

Non-functioning pancreatic NETs are extremely rare with about 2 cases per million people per year. It is estimated that between sixty and ninety percent of all pancreatic NETs are non-functioning.

Most patients are diagnosed in their 40s to 60s. The inherited forms of non-functioning pancreatic NET are diagnosed at a much earlier age (20s to 30s).

Are non-functioning pancreatic NETs inherited?

Most of these tumours occur suddenly and are not inherited. In 1 out of 10 patients these may be inherited as part of a genetic condition. ¹This condition may be multiple neuroendocrine neoplasia type 1 (MEN1) syndrome, von Hippel-Lindau disease or tuberous sclerosis.

MEN1 syndrome can cause endocrine tumours in many glands, such as the pituitary gland, parathyroid glands and gastrointestinal-pancreatic endocrine system. Non-functioning pancreatic NETs are usually present in 50–60% of people with MEN1 syndrome. ²

Von Hippel-Lindau disease can lead to tumours in multiple organs, such as the kidneys, eyes, adrenal glands (phaeochromocytoma) or within the brain (in the cerebellum). Non-functioning pancreatic NETs are present in about 10–15% of patients.³

Lastly, tuberous sclerosis is a rare genetic condition that can lead to (mainly non-cancerous) tumours across the body. It is present from birth and mostly affects the central nervous system, skin, kidneys, heart, eyes and lungs.

How are non-functioning pancreatic NETs diagnosed?

When the care team suspect non-functioning pancreatic NETs, they first carry out radiological investigations such as computerised tomography (CT) or magnetic resonance imaging (MRI) scans. These image the size of the tumour and to look for any possible spread to other organs (such as lymph nodes or the liver).

More specific scans can also be carried out to get more information about the tumour:

• Somatostatin receptor scintigraphy/Octreotide scan assesses the extent and spread of the disease and how well the tumour responds to medical therapy. With this type of scan, a substance called octreotide will be injected into the patient’s body. NET cells often have the ability to bind to octreotide in the body and keep it in place. By scanning for octreotide, the scan can locate where in the body these cells are. 
• In a Positron emission tomography-CT (PET-CT) scan a substance called Gallium-68 labelled somatostatin analogue is injected into the patient’s body. This works in a similar way to the Octreotide scan (above). The injected substance becomes attached to the NET cells. By scanning for this substance, it can then be used to find the precise location of non-functioning pancreatic NET cells. This will also find how much they have spread to nearby or distant parts of the body.
• Blood tests check for over-production of hormones such as insulin, glucagon, somatostatin or vasoactive intestinal peptide. This helps to rule out a functioning pancreatic NET. Measurement of chromogranin A or pancreatic polypeptide levels is useful for diagnosis of the condition.
• The diagnosis of non-functioning pancreatic NETs can only be confirmed if a tissue sample is obtained (from a biopsy or post-surgery) and assessed under the microscope.

Most of these investigations can be carried out as an outpatient.

How are non-functioning pancreatic NETs treated?

There are many factors that affect which type of treatment is right for each individual patient. The exact treatment that each patient receives will be tailored to their condition. The main approaches to treatment are:

Surgical treatment

If possible, the best treatment of non-functioning pancreatic NETs is surgery. However, as most of the tumours are large in size or have spread to other organs at the time of diagnosis, surgical treatment is not possible in most patients.

Medical treatment

Medical therapy includes use of

• Somatostatin analogues such as octreotide/lanreotide to stabilise the disease; they can be given as monthly injections.
• Chemotherapy is useful to treat aggressive tumours that have spread to other organs or show poor response to medical therapy.
• Everolimus and Sunitinib, which inhibit key pathways within the body, have been shown to improve outcomes in patients with advanced non-functioning pancreatic NETs.
• Peptide receptor radionuclide therapy (PRRT) uses radioactive medicines and may be considered in cases of pancreatic NET where the disease has progressed.

Are there any side-effects to the treatment?

All treatments may have side-effects. Patients should discuss any concerns about these potential side-effects with their doctor or care team. Which side-effects occur can depend on a lot of factors, such as the exact drug used, the level of treatment, and how the individual patient responds. Examples of possible side-effects are:

• Surgery – risk of infection, feeling pain after surgery and possibly losing a lot of blood during surgery.
• Somatostatin analogue therapy – feeling sick, diarrhoea, worsening of diabetic control and gallstone formation.
• Chemotherapy – increased risk of infection, loss of hair (alopecia) and diarrhoea or constipation. 
• PRRT therapy – kidney inflammation, feeling sick, pain and a drop in blood cells (due to an effect on bone marrow).

What are the longer-term implications of non-functioning pancreatic NETs?

In cases of non-functioning pancreatic NETs where there is no evidence of spread to the liver or bone and surgery can be carried out to remove the tumour, patients have a good survival rate and can go on to lead full and active lives. Patients treated with surgery will need to attend regular hospital checks to assess if the tumour grows back using blood tests or radiological scans.

Are there patient support groups for people with non-functioning pancreatic NETs?

The NET Patient Foundation may be able to provide advice and support to patients and their families.