Pancreatic Neuroendocrine Tumours (pNET)

What is a pancreatic neuroendocrine tumour?

Pancreatic neuroendocrine tumours (pNET) are relatively uncommon tumours arising from the neuroendocrine cells in the pancreas, which can produce hormones.

They are a different group of diseases from pancreatic ductal adenocarcinoma, the commonest cancer of the pancreas.

This distinction matters, because pNETs can differ from classical pancreatic cancer in:

• Their rate of growth,
• Their symptoms,
• Their imaging features,
• Their treatment,
• The course of the disease.

Some pNETs grow very slowly over years, while others behave more quickly and aggressively. So a diagnosis of “a neuroendocrine tumour in the pancreas” does not on its own show how the disease will run.

Are pNETs common?

No. Pancreatic neuroendocrine tumours make up a small proportion of pancreatic tumours.

But because imaging methods such as CT, MR and EUS are used more often today, small pNETs that cause no symptoms in particular are found more frequently than in the past.

Some are found by chance during imaging done for another reason.

What do functioning and non-functioning pNET mean?

pNETs can be divided clinically into two main groups.

Functioning pNET

These are tumours that secrete hormone in amounts that produce symptoms in the body.

Even a small tumour can give rise to marked symptoms because of the hormone it produces.

Non-functioning pNET

These are tumours that do not give rise to a clear syndrome of hormone excess.

A substantial proportion of pNETs are non-functioning.

Because these tumours produce no hormonal symptoms, they are sometimes found by chance, or noticed when they have grown and are pressing on the surrounding structures.

What is an insulinoma?

An insulinoma is a functioning pNET that secretes insulin in excess.

Excess insulin can cause the blood sugar to fall, that is hypoglycaemia.

The patient may have, particularly while fasting:

• Sweating,
• Shaking,
• Palpitations,
• An intense feeling of hunger,
• Dizziness,
• Difficulty concentrating,
• Changes in behaviour,
• Confusion.

That the complaints settle after eating or taking sugar can be an important clue.

A substantial proportion of insulinomas are small.

What is a gastrinoma?

A gastrinoma is a neuroendocrine tumour that secretes the hormone gastrin in excess.

Excess gastrin can markedly increase the production of acid in the stomach.

The result may be:

• Recurrent or resistant ulcers of the stomach and duodenum,
• Abdominal pain,
• Reflux,
• Diarrhoea.

This picture is called Zollinger–Ellison syndrome.

Gastrinomas can develop not only in the pancreas but in the duodenum as well.

What other hormone-producing pNETs are there?

More rarely:

Glucagonoma: secretes glucagon; diabetes, weight loss and characteristic skin lesions may be seen.

VIPoma: large volumes of watery diarrhoea and electrolyte disturbances can develop from excessive secretion of the hormone VIP.

Somatostatinoma: can lead to symptoms such as diabetes, diarrhoea, fatty stools and gallstones.

These are quite rare tumours.

What symptoms can a pNET cause?

The symptoms vary according to whether the tumour secretes hormone.

In non-functioning pNETs there may be:

• Abdominal pain,
• Pain going through to the back,
• Weight loss,
• Loss of appetite,
• Nausea.

Large tumours can press on the bile ducts or on other structures.

But a substantial proportion of small tumours may give no symptoms at all.

In functioning pNETs, the symptoms due to the hormone the tumour secretes are what stand out.

Is a pNET a cancer?

The answer to this question is rather more complicated than the classical division into benign and malignant.

The biological behaviour of pancreatic neuroendocrine tumours differs greatly from one to another.

Some grow very slowly and may stay confined for many years. Others can spread to the surrounding tissues or to other organs.

For this reason, in assessing a pNET it is not only the name of the tumour that is assessed but:

its size + its grade + its Ki-67 value + its differentiation + its extent

taken together.

What does grade mean?

Grade helps to assess how quickly the tumour cells are multiplying and how the tumour behaves biologically.

On pathological examination, the Ki-67 proliferation index and the activity of cell division in particular are taken into account.

Broadly, well-differentiated neuroendocrine tumours can be graded as G1, G2 and G3.

Higher proliferative activity is generally associated with faster biological behaviour.

Is a neuroendocrine carcinoma the same thing?

No.

This distinction is very important.

A well-differentiated pancreatic neuroendocrine tumour (pNET) and a poorly differentiated neuroendocrine carcinoma (NEC) are not the same disease.

Neuroendocrine carcinomas are generally faster-growing tumours requiring different treatment.

For this reason the differentiation and grade in the pathology report matter in planning treatment.

How is a pNET diagnosed?

Different methods may be used in making the diagnosis, according to the patient’s symptoms.

The chief investigations are:

• Blood tests,
• Hormone measurements,
• Computed tomography (CT),
• Magnetic resonance (MR),
• Endoscopic ultrasound (EUS),
• Biopsy where needed.

Where a functioning tumour is suspected, specific blood tests for the hormone in question can be done.

Why does EUS matter?

Endoscopic ultrasound (EUS) allows the pancreas to be examined at high resolution from very close to the stomach and duodenum.

It can be very useful particularly in detecting small pancreatic neuroendocrine tumours.

Where it is thought necessary, a tissue sample can be taken from the tumour with a needle during EUS.

Pathological examination can then give information about the neuroendocrine origin of the tumour and its proliferative characteristics.

Can a special PET scan be done?

Yes.

A substantial proportion of well-differentiated neuroendocrine tumours carry somatostatin receptors on their surface.

Special nuclear medicine scans showing these somatostatin receptors can be done, making use of that property.

Today, in suitable patients, somatostatin receptor PET/CT is very valuable in establishing the extent of the tumour in the body.

This investigation can also help in assessing suitability for certain specific treatments.

Is every pNET operated on?

No.

This is an important matter today in particular.

In some pNETs that are very small, do not secrete hormone and show low-risk features, the option of close follow-up may be considered instead of an immediate operation.

But the decision is not made by looking at the diameter of the tumour alone.

What is assessed together is the tumour’s:

• Size,
• Rate of growth,
• Position within the pancreas,
• Grade and Ki-67 value,
• Whether it secretes hormone,
• Relationship to the main pancreatic duct,
• The patient’s age and general condition.

How is surgical treatment carried out?

The kind of operation can vary with which part of the pancreas the tumour is in.

For some tumours in the head of the pancreas a Whipple operation may be needed, and for tumours in the body or the tail a distal pancreatectomy.

For some small and suitably placed tumours, more limited surgical methods aimed at preserving as much pancreatic tissue as possible may be used.

It matters that the surgical decision is made by a team experienced in pancreatic surgery.

Is treatment possible if the disease has spread?

Yes.

There are different treatment options even in metastatic pNETs, and some well-differentiated tumours in particular can be kept under control for a long time.

The treatment options may include:

• Somatostatin analogues,
• Targeted drugs,
• Chemotherapy,
• Treatments directed at the liver in some patients,
• Peptide receptor radionuclide therapy (PRRT),
• Surgery in selected patients.

Which treatment is chosen is decided according to the grade of the tumour, its extent, its hormone secretion, its somatostatin receptor status and the patient’s general condition.

What is PRRT?

Peptide receptor radionuclide therapy (PRRT) is a specific treatment for certain neuroendocrine tumours carrying somatostatin receptors on their surface.

Put simply:

a molecule that finds the receptor on the tumour cell + a radioactive treatment substance

are brought together.

The molecule binds to the tumour cell and helps to deliver the radiation largely to the targeted tumour tissue.

Not every patient with a pNET is suitable for PRRT.

Can a pNET spread to the liver?

Yes.

In advanced disease the liver is one of the commonest sites of metastasis.

But the spread of a pNET to the liver should not be assessed in the same way as with classical pancreatic adenocarcinoma.

According to the biological behaviour of the tumour, some metastatic pNETs can be kept under control for a long time.

In selected patients, surgical, interventional radiological or systemic treatments directed at liver metastases may be used.

Is there a connection with genetic diseases?

Most pNETs are not inherited.

But in some patients they may be associated with certain inherited syndromes, chief among them MEN1 (multiple endocrine neoplasia type 1).

Genetic assessment may come into consideration particularly where there is:

• A tumour developing at a young age,
• More than one pNET,
• Similar tumours in the family,
• Other endocrine tumours accompanying it.

What is the difference between a pNET and classical pancreatic cancer?

This distinction matters a great deal for patients.

Classical pancreatic cancer (ductal adenocarcinoma) and pancreatic neuroendocrine tumour develop from different cells.

So:

a diagnosis of pNET is not a diagnosis of classical pancreatic cancer.

Their treatments and the course of the disease differ too.

Some low-grade pNETs in particular can run a far slower course than classical pancreatic adenocarcinoma.

How is follow-up carried out?

The follow-up plan is set individually according to the characteristics of the disease.

Imaging methods such as CT or MR, somatostatin receptor imaging where necessary, and tests for the relevant hormone in hormone-secreting tumours may all be used.

Long-term follow-up may also be needed after an operation, according to the characteristics of the tumour.

Remember

Pancreatic neuroendocrine tumours are a different group of tumours from classical pancreatic cancer.

Some secrete hormone and can produce very characteristic symptoms such as hypoglycaemia, resistant ulcers or severe diarrhoea; others give no symptoms at all and are found by chance on imaging.

The behaviour of pNETs differs greatly from one to another. So the treatment decision looks not only at the size of the tumour but at whether it is functioning, at its grade, its Ki-67 value, its differentiation and its extent.

Just as not every small pNET has to be operated on straight away, so in advanced disease there are various treatment options including somatostatin analogues, targeted treatments and PRRT.

It matters that the diagnosis and treatment are assessed by a multidisciplinary team in which gastroenterology, endocrinology, pancreatic surgery, medical oncology, nuclear medicine, radiology and pathology work together.