Alternative names for glucagonoma

Glucagon-secreting pancreatic neuroendocrine tumour; glucagon-secreting pancreatic islet cell tumour; pancreatic islet alpha cell tumour; glucagonoma syndrome; 4D syndrome

What are glucagonomas?

Glucagon is a hormone, which is normally released from alpha cells in the pancreas in response to low levels of blood sugar. After glucagon is released, it acts on the liver to turn glycogen into glucose, which is then released into the bloodstream, increasing blood glucose levels and returning blood sugar levels back to normal.

A glucagonoma belongs to a family of tumours called neuroendocrine tumours (NETs), which are tumours that occur in parts of the body that release hormones in response to stimulation by nerves. A glucagonoma is a tumour in the alpha cells of the pancreas that results in too much of the hormone glucagon being produced. Unfortunately, at the point of diagnosis, the majority (~80%) of glucagonomas have already spread and caused secondary (metastatic) tumours in other parts of the body, most commonly the liver. These are termed malignant glucagonomas.  

What causes glucagonomas?

In the majority of cases there is no known reason why a glucagonoma occurs. However, in a small number of cases, the glucagonoma is linked to an inherited condition called multiple endocrine neoplasia type 1 syndrome.

What are the signs and symptoms of glucagonomas?

Glucagonomas do not usually present with clear or specific symptoms because the tumour is known to grow slowly. As the tumour grows, the amount of glucagon released by the tumour will continue to increase. As this happens a number of key symptoms may start to become noticeable:

• skin rash (present in 80% of patients with glucagonoma) – the characteristic rash found in glucagonomas is known as necrolytic migratory erythema. This refers to a rash that initially starts at the groin and spreads to other parts of the body, in particular, the chest, lower legs and buttocks. The rash appears blistered and crusty and after a period of time, the skin around the rash may change in colour
• decreased appetite leading to weight loss
• feeling thirsty, having to pass urine frequently and blurred vision – these are all the initial symptoms of type 2 diabetes mellitus present in 60–80% of patients with a glucagonoma
• diarrhoea
• depression
• deep vein thrombosis(present in ~50% of patients with a glucagonoma)
• cracked surface of the tongue
• thickened nails
• chapped lips
• tiredness
• reddening and swelling around the inside surface of the cheeks and on the tongue
• women who develop glucagonomas often experience reddening and swelling around the vagina or vulva. This is called vulvovaginitis
• some hair loss.

It is also important to think about any previous hospital admissions associated with blood clots such as a pulmonary embolism or a deep vein thrombosis. This may point towards an increased risk of developing blood clots, which is also one of the signs of a glucagonoma.

How common are glucagonomas?

Glucagonomas are extremely rare. In the UK, it has been estimated that each year one case of glucagonoma is diagnosed per million people.  

Are glucagonomas inherited?

The majority of glucagonomas are not inherited. However, a minority of cases are linked to a genetic disorder known as multiple endocrine neoplasia type 1. If the patient has a parent with multiple endocrine neoplasia type 1, then there is a 50% chance that he/she will also inherit the condition. However, even among patients with MEN1, only a very small proportion will develop a glucagonoma.

How are glucagonomas diagnosed?

The first test carried out in a suspected case of glucagonoma is a fasting blood sugar test. This is normally done in an outpatient setting. This test measures the amount of sugar in the blood. Before doing the test, the patient should not eat anything for eight hours (usually overnight). If a glucagonoma is present, then the result of the fasting blood sugar test will be much higher than normal. The results from this blood test can also be used as evidence for diabetes associated with glucagonoma.

A test called a fasting gut hormone profile is taken from patients suspected of having a glucagonoma to measure the levels of chemicals such as glucagon and chromogranin A. Normally levels of chromogranin A in the blood are low, but if a glucagonoma (or any other neuroendocrine tumour) is present, levels of chromogranin A in the blood will be increased. A patient with a glucagonoma may also produce other hormones such as pancreatic polypeptide, which may be detected as part of the fasting gut hormone screen.

Imaging tests are then used to localise the glucagonoma. These might include:

• an abdominal ultrasound scan
• a computerised tomography (CT) scan
• a magnetic resonance imagining (MRI) scan
• an octreotide scan – with this type of scan, the doctor will inject a substance known as octreotide (which has been made mildly radioactive) into your body. The octreotide sticks to the glucagonoma cells so the doctor can then use a scanner to identify where the octreotide is and therefore where the glucagonoma cells are. This will help identify whether the glucagonoma has spread or whether it is confined to one place
• special ultrasound machines may be used, either attached to a telescope passed, under gentle sedation, through the mouth (endoscopic ultrasound) or during the time of surgery (intra-operative ultrasound).

Typically, glucagonomas are not difficult to find and an abdominal ultrasound and/or CT/MRI are often sufficient.

If it is suspected that the glucagonoma is due to the inherited condition multiple endocrine neoplasia type 1, blood samples can be taken to look for other abnormalities typically found in this condition. If the results show that the patient has multiple endocrine neoplasia type 1, the patient will be seen by a genetic specialist at an outpatient clinic to discuss what this means for them. See the article on multiple endocrine neoplasia type 1 for further information.

How are glucagonomas treated?

The first part of treating a glucagonoma is to manage the symptoms. This usually involves having to take anti-diabetic tablets or insulin injections to manage the high blood sugar levels. For the rash, this is often managed by taking supplements of amino acids and zinc whilst also applying skin cream over the rash.

The main treatment for removing the glucagonoma is surgery, which is usually done as an inpatient at a specialist hospital. Here the tumour is removed by a specialist pancreatic surgeon in conjunction with the endocrine (hormone specialist) team. In some situations the spleen may also have to be removed but this depends on the exact location of the glucagonoma.

In cases of malignant glucagonoma, there are several treatment options still available. The treatment you have depends on:

• where the tumour is and its size
• whether it has spread
• your general health
• whether you have a rare inherited syndrome called multiple endocrine neoplasia 1 (MEN1)

Surgery is the only treatment that can cure a glucagonoma. Types of surgery include:

• Two way surgery – here the surgeon initially removes the glucagonoma in the pancreas and then any glucagonoma that has spread to the other part of the body. This is not always possible.
• Debulking surgery – during this procedure the surgeon will remove part of the glucagonoma to help increase the effectiveness of removing the remaining glucagonoma with other therapies and to reduce symptoms caused by the excess hormone secretion.
• Somatostatin analogue medication may be used both to reduce symptoms and to control tumour growth.
• Interferon treatment – this drug works by encouraging the immune system to combat and fight off the tumour cells.
• This needs to be discussed with a specialised oncologist
• The drugs Sunitinib and Everolimus, which stop the tumour from growing.
• Transarterial chemoembolisation, which is a procedure done with an X-ray machine to block the blood vessels supplying tumours in the liver. This is done in case tumours spread to the liver.
• Radioactive nuclear medicine therapies such as radiolabelled octreotide.
• Radio-frequency ablation: uses heat made by radio waves to kill tumour cells. You might have this if the NET has spread to the liver.
• Blood thinning tablets to reduce the risk of blood clots arising in the legs and the lungs.

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. Patients should discuss any concerns about these treatment options with their doctor or specialist.

Are there any side-effects to the treatment?

The main possible side-effects of surgery include risk of an infection, feeling pain after surgery and possibly losing a lot of blood during surgery.

Other side-effects are specific to the individual drug. For example, with the somatostatin analogues, the side-effects that patients could experience include diarrhoea, headaches, nausea and vomiting, pain or swelling at the site of the injection and possible stomach pain or discomfort.

What are the longer-term implications of glucagonoma?

If the glucagonoma is confined to the pancreas then, in the majority of cases, it can be successfully removed by surgery. Most of the patients who have their glucagonoma removed no longer report any of their symptoms and have a good outcome. Patients treated with surgery will need to attend regular hospital checks to assess for recurrence of the tumour using blood tests or radiological investigations. However, in the majority of patients where the glucagonoma has already spread to other parts of the body, long-term management involves controlling their symptoms using the treatments detailed above.

Suggested reading: https://www.cancerresearchuk.org/about-cancer/neuroendocrine-tumours-nets/pancreatic-nets/glucagonoma