What are non-functioning pancreatic NETs?

Non-functioning pancreatic neuroendocrine tumours (NETs) originate from specialised neuroendocrine cells of the pancreas. Functioning neuroendocrine tumours, such as insulinoma, gastrinoma or somatostatinoma show symptoms of too much hormone production. By comparison, non-functioning NETs do not show any symptoms relating to overproduction of hormones.

Non-functioning pancreatic NETs do produce small (or biologically inactive) quantities of hormones such as pancreatic polypeptide, calcitonin or neurotensin, which also do not cause any symptoms.

Signs and symptoms of non-functioning pancreatic NETS do exist. These are due to the size of the tumour or its spread to adjacent organs such as lymph nodes or 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 their uncontrolled division is not known. Most of these tumours arise sporadically although, in around 1 out of 10 patients, a non-functioning pancreatic NET may be associated with a genetic condition such as multiple endocrine neoplasia type 1 syndrome or von Hippel-Lindau disease.

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

The signs and symptoms associated with non-functioning pancreatic NETs depend on their size or spread to the adjacent organs. Symptoms may include abdominal pain, an abdominal lump, nausea, weight loss and jaundice.

As these tumours are not associated with hormone over-production, they are not usually detected until a late stage. These tumours are usually large in size (average size of 3–4 cm). In up to 80% of 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 3–4 cases per million people per year. It is estimated that between sixty and ninety percent of all pancreatic endocrine tumours are non-functioning.

Most patients are diagnosed in their 40s to 60s. The inherited forms of non-functioning pancreatic NET (as in multiple neuroendocrine neoplasia type 1 syndrome) are diagnosed at a much earlier age (20s to 30s).

Are non-functioning pancreatic NETs inherited?

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

MEN1 syndrome is characterised by endocrine tumours in multiple glands such as the pituitary gland, parathyroid glands and gastrointestinal-pancreatic endocrine system. Non-functioning pancreatic NETs are usually present in 50–60% of individuals with multiple endocrine neoplasia type 1 syndrome.  

Von Hippel-Lindau disease is characterised by 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 these patients.

How are non-functioning pancreatic NETs diagnosed?

In a patient suspected of having non-functioning pancreatic NETs, radiological investigations such as computerised tomography (CT) or magnetic resonance imaging (MRI) scans are carried out initially to evaluate the size of the tumour and to look for any possible spread to other organs such as lymph nodes or the liver.

Additional, more specialised, scans can also be undertaken:

• Somatostatin receptor scintigraphy/Octreotide scan may be carried out to assess the extent and spread of the disease and responsiveness of the tumour to medical therapy. With this type of scan, a substance known as octreotide will be injected into the patient’s body. Cells within a neuroendocrine tumour typically have the ability to bind octreotide and the scan will be able to confirm the location of these cells.
• Positron emission tomography-CT (PET-CT) where a substance called Gallium-68 labelled somatostatin analogue is injected into the patient’s body is another scan that works in a similar way to the Octreoscan. The injected substance becomes attached to the neuroendocrine tumour cells. It can then be used for identifying the precise location of non-functioning pancreatic NETs and the extent to which they have spread to nearby or distant parts of the body.
• Blood tests are also carried out to check for over-production of hormones such as insulin, glucagon, somatostatin or vasoactive intestinal peptide to rule out a functional pancreatic NET. Measurement of chromogranin A or pancreatic polypeptide levels is useful for diagnosis of the condition. Most of these investigations can be carried out as an outpatient.
• The diagnosis of non-functioning pancreatic NETs can only be confirmed if a tissue sample from a patient suspected of having this condition is obtained (from a biopsy or post-surgery) and assessed under the microscope.

How are non-functioning pancreatic NETs treated?

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

Surgical treatment

Wherever possible, the definitive 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 the majority of 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 (with streptozotocin/doxorubicin/etoposide) 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 radionucleotide therapy (PRRT) is a specialised therapy that may be considered in cases of pancreatic neuroendocrine tumour where there is progression of the disease.

Are there any side-effects to the treatment?

• Surgery is associated with potential side-effects including risk of an infection, feeling pain after surgery and possibly losing a lot of blood during surgery.
• Somatostatin analogue therapy is associated with side-effects such as nausea, diarrhoea, worsening of diabetic control and gallstone formation.
• Chemotherapy is associated with side-effects such as reduced immunity to infection, loss of hair (alopecia) and gastrointestinal  Patients should discuss any concerns about these potential side-effects with their doctor or specialist.
• PRRT therapy can affect bone marrow and kidneys

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 should go on to lead full and active lives. Patients treated with surgery will need to attend regular hospital checks to assess for recurrence of the tumour using blood tests or radiological investigations.

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.