What is an insulinoma?

Normally, the beta cells within the pancreas secrete insulin in response to rises in blood glucose after a person eats a meal and absorbs the carbohydrates within the meal. The role of insulin is to help the body use the carbohydrates to release energy and to keep blood glucose at normal levels.

An insulinoma is a rare type of tumour called a neuroendocrine tumour (NET) that arises from the beta cells of the pancreas and causes problems by secreting too much insulin. Usually (>90%) these tumours are benign single lesions in the pancreas (i.e. they do not spread to other parts of the body). Occasionally, insulinomas may spread and develop secondary tumours beyond the pancreas, mostly affecting the liver. These insulinomas are known as malignant.

What causes insulinomas?

It is unclear why insulinomas occur in most cases, although some occur as part of a genetic condition called multiple endocrine neoplasia type 1.

What are the signs and symptoms of insulinomas?

The symptoms of insulinomas can often be vague and non-specific. As insulinomas secrete too much insulin, this means that the blood glucose can drop to seriously low levels. This can cause symptoms such as:

• Sweating
• A pale appearance (pallor)
• Racing of the heartbeat
• Feelings of anxiety
• Irritability or confusion
• Double vision
• Unusual behaviour
• Blackouts or seizures

These episodes can occur particularly when not eating for long periods (fasting), or first thing in the morning, but may occur at any time. Typically, eating or drinking foods that contain carbohydrate (such as bread, potatoes or pasta) relieves the symptoms.

How common are insulinomas?

Insulinomas are rare. It is estimated that one case per 250,000 people of the general population is diagnosed per year. In the UK, this translates to approximately 250 new cases a year.

Are insulinomas inherited?

The majority of patients with insulinomas have not inherited the condition. For 1 in 14 patients, the insulinoma may be part of an inherited syndrome called multiple endocrine neoplasia type 1. People with multiple endocrine neoplasia type 1 usually have other problems with high blood calcium levels, tumours in the pituitary gland and other tumours in the pancreas.

How are insulinomas diagnosed?

In order to diagnose an insulinoma, patients suspected of the disease are usually admitted to hospital to undergo a supervised 72-hour fast. During this time, patients are allowed to drink water, but not to eat food. Regular finger-prick tests for blood sugar levels are done. If the blood sugar drops below a certain level, a blood sample to test for glucose, insulin and another substance, C-peptide, is taken. A blood or urine test is also taken to test for any medications that might cause the blood sugar levels to drop. If the blood test confirms that the blood glucose is below the criteria level, the fast is stopped and the patient is allowed to eat.
Computerised tomography (CT) or magnetic resonance imaging (MRI) scans are used to look for insulinomas in the pancreas and liver and to locate their exact position.

Insulinomas may not always be straightforward to find on a CT or MRI scan and so one or more of a variety of other localisation techniques may also be used:

• Specialised nuclear medicine scans such as octreotide scan or positron emission tomography (PET) scans may be used to identify insulinomas and to look for any evidence of spread of the tumours. In an octreotide scan, the doctor will inject a substance known as octreotide (which has been made mildly radioactive) into your body. The octreotide sticks to the insulinoma cells so the doctor can then use a scanner to identify where the octreotide is and therefore where the insulinoma cells are. This will help identify whether the insulinoma has spread or whether it is limited to one place.
• Special ultrasound machines may be used, either attached to a telescope which is passed through the mouth (endoscopic ultrasound) and this is carried out under gentle sedation or during the time of surgery (intra-operative ultrasound).
• A procedure known as a calcium stimulation test can be used to confirm that the insulinoma is in the pancreas and actively secreting insulin. This is done in specialist hospitals. It involves placing thin plastic tubes (catheters), under local anaesthetic, into the groin area. Using small injections of special dye that shows up under an X-ray machine, these catheters are threaded into the blood vessels that supply the pancreas with blood. Then a small amount of calcium solution, which is harmless to patients, is injected into the blood vessels, and blood tests are taken to measure the levels of insulin secreted by the pancreas. This test usually takes about 1 hour to perform.
  
  If multiple endocrine neoplasia type 1 is suspected, a blood test to look for defects in the gene responsible for this disease can be carried out. Genetic specialists will talk through the implications of genetic testing, which is usually performed in outpatient clinics.

How are insulinomas treated?

Benign insulinomas are usually removed by surgery with the intention being to remove the tumour fully and achieve a long-term cure and normal life expectancy. The surgery takes place in specialist hospitals and is completed by a specialist pancreatic surgeon with support from the endocrine (hormone specialist) team. The extent of the surgery depends on the location and size of the tumour. Sometimes it is possible to do a smaller operation that cuts out only the insulinoma (enucleation). However, in some cases it may also be necessary to remove larger portions of the pancreas in a more complicated operation.

Medication may be used to increase blood glucose levels before the operation in order to control low blood glucose levels. Commonly used drugs include diazoxide and somatostatin analogues (e.g. lanreotide and octreotide).

Patients should also be given dietary advice to ensure a frequent supply of carbohydrates to try and prevent blood glucose levels dropping. For example, small meals can be taken more frequently, for example five to six times a day. A food additive such as guar gum can also be used to lengthen the time the body can absorb carbohydrates.

There are a range of different treatment options for malignant insulinomas. Surgery may still be utilised although the intent would not be curative but instead to try to significantly reduce the amount of tumour present to reduce the symptoms and challenges of a recurrent low blood glucose. Diazoxide and the somatostatin analogues may be used in this setting to control symptoms. The somatostatin analogues may also be used to control tumour growth. Other options that may be considered include; radiolabelled somatostatin analogue therapy, chemotherapy or relatively new drugs called Everolimus or Sunitinib.

Are there any side-effects to the treatment?

In most cases, surgery is successful and the patient does not experience any side-effects. Occasionally, surgery can cause side-effects including excessive bleeding, infections and pain. If a large part of the pancreas is removed, patient may start to have excessively high levels of blood sugar (diabetes mellitus). This is because there is insufficient insulin being secreted by the pancreas. In addition, if the part of the pancreas that makes digestive enzymes is damaged these enzymes may need to be replaced.

Other side-effects are specific to the individual drug. The commonest agent, diazoxide, has the following side effects: diabetes mellitus, nausea, vomiting, ankle swelling, dizziness and excessive growth of body hair (if taken for prolonged periods).

What are the longer-term implications of insulinomas?

If the insulinoma is benign and has been removed by surgery, the outcome is good and patients are usually cured of the condition.

If the insulinoma is malignant and has spread to the liver, the symptoms of low blood sugar may continue to be a problem, and long-term treatment with the aim of stabilising tumour growth, may be required.

Patients with frequent episodes of low blood sugar should not drive or operate heavy machinery.