Neuroendocrine tumours or NETs, is the umbrella term for a group of relatively uncommon cancers, often called the ‘quiet cancers’. This is because NETs are often slow growing and so the symptoms can take time to develop, may be vague, or attributed to more common and less serious problems such as irritable bowel syndrome (IBS), Crohn’s disease, peptic ulcer disease or gastritis.
Neuroendocrine cancer is formed in the diffuse neuroendocrine system, which is made up of neuroendocrine cells found in the respiratory and digestive tracts. The respiratory tract includes the bronchial tubes and lungs. The digestive tract starts at the mouth and ends at the rectum.
Neuroendocrine cells are also found in the endocrine glands, such as the adrenal glands, pancreas, thyroid and pituitary. These cells are also found in the ovaries and the testes.
How NETs are formed is still not fully understood. As with all forms of cancer, NETs arise when cells multiply rapidly in the body. Normal cells in our body divide in a controlled manner, but in cancer the control signals go wrong. This causes abnormal cells to form, which divide quickly resulting in tumour growth.
Terminology of NETs
The terminology for NETs can be very confusing. The name for NETs has changed somewhat over the last few years. Carcinoid is sometimes still used, but the more accurate description is NET or Gastroenteropancreatic (GEP) NET. The term GEP came about because the tumours often arise in the cells of the stomach (gastro), intestines (entero) and the pancreas:
- “G” – gastro (stomach)
- “E” – entero (intestines)
- “P” – pancreatic (pancreas)
Types of Neuroendocrine Tumours
There are a number of different types of NET. Although they all arise from neuroendocrine cells and share certain similar biological features, they each have a slightly different way of presenting themselves, both in terms of symptoms and how they look under a microscope.
- Carcinoids: lung, thymic, gastric, duodenal, pancreatic, small intestine, appendiceal, colon, rectal, ovarian and carcinoid tumours of unknown origin (unknown primary)
- Functioning and Non-Functioning Pancreatic Tumours
- Multiple Endocrine Neoplasias (MEN)
- Goblet Cell Carcinoids
The place where the NET first appears is called the ‘primary’ site. However, the NET may spread and be found in other parts of the body e.g. the liver, and if this occurs your doctor may refer to these as a ‘secondary’ tumour or metastases.
Carcinoid NETs are the most common and typically account
for about 55% of all NETs diagnosed
Some NETs produce abnormally large amounts of hormones, which are chemicals made by the body to trigger its various functions. For example most carcinoid tumours produce excess serotonin and gastrinomas produce an excess of gastrin. These NETs have a related syndrome which means that the hormones secreted cause noticeable symptoms like flushing, diarrhoea, cramps, wheezing, heart valve damage and skin changes.
Most NETs occur without any genetic link, but there are cases where they are present as part of a familial endocrine cancer syndrome such as MEN1, MEN 2, neurofibromatosis type 1 or Von Hippel Lindau.
Classification of NETs
NETs are still mainly classified according to the area in which they are found.
Foregut tumours: found in the lungs, stomach, pancreas, gall bladder and duodenum
Midgut tumours: found in the jejunum, ileum, appendix and right colon
Hindgut tumours: found in the left colon and rectum
The group of tumours that arise in the pancreas can be classified into two different groups; functioning and non-functioning. The functioning group will produce a number of clinical syndromes that are related to where they originate, for example, an insulinoma will over-secrete insulin and gastrinomas are gastrin-secreting tumours. The non-functioning group which accounts for around 30-40% of pancreatic tumours, may secrete certain hormones and peptides like other NETs, but the release of these chemicals does not cause an identifiable ‘syndrome’ or collection of symptoms. This can make diagnosis difficult and explains why so many cases are picked up incidentally.
Although we do not have a figure for Ireland, in the UK it is believed that approx 3-5 people per 100,000 are diagnosed with new cases of NETs each year. However it is also believed that there are likely to be many more people around the country with NETs who remain undiagnosed and unaware of their condition because the disease is so slow growing and often produces none or very minor symptoms. As with all cancers, the sooner the disease is found and correctly diagnosed, then the better is the outcome and prognosis. It is often said that “if you are going to get cancer then this is the best one to get”. Many NET patients live long and healthy lives benefitting from the excellent medical knowledge of combinative surgery, diagnostics and prescribed drug regimens.
Typical Paths to Diagnosis
NET cancers are difficult to diagnose. The onset of symptoms takes an average of five to seven years, and even then symptoms are often non-specific and vague. If NET cancers are detected early in their development, they can often be cured with surgery. At present however, most NET cancers are diagnosed at a later stage, when they have already spread to other parts of the body. In these cases, they can rarely be cured, although the symptoms can often be managed successfully for a number of years.
NET cancers can give rise to a wide variety of symptoms depending on where they are in the body and the type of cells they originate from. The symptoms may be mild or non-specific, and are often similar to those of other, more common conditions. For example, many of the symptoms associated with carcinoid tumors are similar to those of IBS, Crohn’s disease, peptic ulcer disease, gastritis or other digestive disorders.
Many doctors are unfamiliar with NET cancers and are therefore less likely to suspect a NET cancer in their initial investigations. NET cancers are difficult to detect for a number of reasons:
- Size: they are often small; some NET cancers can be less than a centimetre in size
- Location: NET cancers can occur almost anywhere in the body
- Symptoms: these can vary enormously, and some patients have no symptoms at all
- Testing: there are many different types of NET cancer, and a series of specialised tests is necessary for a definitive diagnosis
There are many tests and scans available that your healthcare team will use to gather information about the NET, its spread and rate of growth.
You may be asked to have a fasting gut hormone blood test, and blood will also be collected for a range of other tests. Doctors look for certain NET markers, particularly chromogranin A and B. Other examples of hormones and peptides that the doctors look for are pancreatic polypeptides, insulin and gastrin, as well as checking how well your kidneys and liver are functioning.
If the results of this test suggest the presence of a NET, further imaging tests will be carried out to confirm the diagnosis.
5-HIAA (hydroxyindoleacetic acid) is a substance that is naturally produced and eliminated by the body. Normally, only small amounts are present in the urine. Elevated levels in a urine sample may indicate a NET, although further tests are required to confirm the diagnosis.
You will be asked to avoid certain foods 24 hours prior to, and for 24 hours during, the test. The foods include chocolate, olives, bananas, pineapple and its juice, all tomato products, plums, aubergine, avocado, kiwi fruit, walnuts, brazil nuts, cashew nuts, tea, coffee and alcohol.
For three to seven days prior to the test you will also be asked to avoid several medicines i.e. certain cough, cold and flu remedies, treatments for high blood pressure, the muscle relaxants e.g. diazepam, monoamine oxidase inhibitors and any natural herbal products purchased in health food shops that produce the same effects as these medicines. This is because all these products naturally contain substances that might artificially raise your 5-HIAA levels and give a false test result.
In this test, a flexible camera, called an endoscope, is used to examine the digestive tract. The tube can be inserted down the back of the throat (gastroscopy) or via the rectum (colonoscopy). In both cases you will be offered sedation.
If abnormal-looking tissues are found during this procedure, a sample can be collected and examined under a microscope. A tissue biopsy like this can be the only definitive test for a NET cancer.
Ultrasound scans use sound waves to build up a picture of the inside of the body. They are completely painless. These scans are usually done in the hospital X-ray department.
The ultrasound scanner has a microphone which gives off sound waves. The microphone is passed over your body and the sound waves bounce off the organs inside your body, and are picked up again by the microphone. The microphone is linked to a computer which turns the reflected sound waves into a picture.
This involves taking a piece of tissue from the suspect tumour and analysing it in the laboratory by a specialist called a histopathologist.
The specialist may review the biopsy sample and give your tumour a ‘proliferative index’ i.e. a measure of the number of cells in the tumour that are dividing (proliferating). A proliferation index of less than 2% means that the tumour is very slow growing, while a value above 10% suggests faster growth.
Being able to look at the tumour under the microscope can be the only way to determine exactly what type of NET cancer it is.
Computerised Tomography (CT) Scan
A CT scanner is a special type of X-ray machine which uses ionising radiation to provide a three dimensional picture of the inside of the body. It can be used to determine the position and size of tumours, and regular scans are useful to find out more about the rate of tumour growth and how the tumour is responding to treatment.
Before the scan, you may be asked to have an injection or drink a fluid containing a dye that shows up on the scan.
Magnetic Resonance Imaging (MRI)
An MRI scan can be used to locate a tumour. Magnetism is used instead of X-rays to produce soft tissue images that can distinguish between normal and diseased tissue.
If a tumour is identified in this way, further tests may be needed to confirm the type of tumour.
These scans use a body imaging technique. Cells that receive hormonal messages do so through receptors on the surface of the cells. For reasons that are not fully understood, many NET cells possess especially strong receptors; for example, GEP-NETs often have strong receptors for somatostatin, a very common hormone.
The OctreoScan uses a synthetic form of somatostatin, which is chemically bound to a radioactive substance. This is injected via a vein in the arm and then observed 24 hours later using a radio-sensitive scan. These scans can diagnose and locate around 80-90% of GEP-NETs, although further scans, such as PET scans may still be required.
There are a many other tests that may be employed in the diagnosis and classification of your NET:
- MIBG Scan
- PET Scan
- Bone Scan
Multidisciplinary Team Approach to Care
Different NETs affect people in different ways in terms of how the tumour grows, the symptoms produced, whether or not they spread and how they spread. Gaining the histology (what the tumours look like under a microscope) is very important in order to classify the cancer into a type, and your healthcare team can then work with you to plan the most appropriate treatment.
Although NETs share similar characteristics, the diagnosis and the way your cancer behaves may be different.
The most important aspect of caring for a person with a NET is that the care should be tailored to suit the individual and provided by a specialist in the field of NETs. Your quality of life is paramount and so team work is essential to provide a solid plan of treatment and follow-up.
There has been much research work done by specialist healthcare professionals, and progress has been made in terms of understanding these tumours. It is important to ensure that you are seen by these specialists in order to access all the knowledge available.
NET cancer care can be complex. For you the journey can encompass not only a whole host of emotions, but also a range of investigations, treatments and healthcare professionals. Often there is more than one treatment option available, and so there has to be a collaboration amongst all key healthcare professional groups who are making clinical decisions for you. This collaboration is called a multidisciplinary team or MDT. The MDT management approach is now being used across the world in the care of people with NETs.
Throughout the NET journey, you may potentially see the following healthcare professionals:
The treatment of a NET cancer depends on the size and location of the tumour, whether the cancer has spread, and your overall health.
These are a complex group of cancers to manage, and ideally, a MDT will work with you to determine the best treatment plan. The MDT will always have several goals in mind as they formulate your treatment plan.
Not all of the treatments described here are suitable for all people with NETs. Treatment plans should always be tailored to the individual.
The main treatment goals are listed below:
- Remove the tumour by surgery; however, if the tumour has spread, this may not be possible
- Alleviate symptoms
- Control the tumour growth
- Maintain a good quality of life for you
Some of the treatments that are used to reduce or stabilise tumour size and alleviate symptoms are discussed below.
If the tumour is contained in one area (localised), or if there has been only limited spread, surgery is usually the first choice of treatment. If it is possible to remove the tumour completely no other treatment may be necessary.
If the tumour has spread (metastasised), surgery may still be possible to remove the part of the tumour that is producing too many hormones. This is often referred to as tumour debulking.
If a GEP or NET is blocking an organ, such as the bowel, surgery may be helpful to relieve the blockage (obstruction). If the tumour has spread to the liver, surgery can be used to remove the parts of the liver containing the tumour. Very occasionally, a liver transplant may be considered.
Surgery may be used throughout a patient’s treatment plan for many reasons, including in combination with other therapies.
Somatostatin is a substance produced naturally in many parts of the body. It can stop the over-production of hormones that cause symptoms such as diarrhoea, flushing and wheezing. Lanreotide and octreotide are somatostatin analogues i.e. drugs that copy or mimic the action of somatostatin.
Some NETs produce hormones that can cause other symptoms, for example, patients with a carcinoid tumour may have diarrhoea, flushing, and wheezing. You may have different symptoms depending on the type of tumour that you have. These symptoms can be distressing and often affect your quality of life.
The aim of this treatment is to block the release of the extra hormones your body is producing and therefore improve your symptoms.
Lanreotide can be given as an injection every 7-14 days or as a long-acting injection every 28 days. The long-acting injection can be administered by a nurse, either in hospital or by a practice nurse. For some patients who are stabilised on their treatment with lanreotide, it may be possible for the patient, or a relative or friend, to be taught how to give the injection themselves. The injection is given in the upper, outer quadrant of the buttock or, if you are self-injecting, into the upper, outer thigh. If you are using lanreotide at home it should be kept in the refrigerator, in its original package, at a temperature between 2C and 8C; it should not be frozen.
Octreotide can be given as a short-acting injection two to three times a day, or as a long-acting injection administered by a healthcare professional every 28 days. The short-acting form is injected into the tissue under the skin, either in the upper arm, thigh or stomach. The long-acting form is injected in the large muscle in the buttock. Octreotide should be stored between 2C and 8C; it should not be frozen.
There may be some side effects, but it is important to remember that the following are only possible side effects and do not affect all patients:
- Loss of appetite and problems in the gastrointestinal tract (gut) such as nausea, vomiting, abdominal pain and bloating, wind, and upset bowels
- Occasional discomfort at the site of the injection
- After a period of time some patients may develop gallstones as a result of the treatment but your centre monitors this when you have your regular scans
- Short and longer-acting injections can affect blood sugar levels
Interferon is a naturally occurring substance that is produced by the body’s immune system during an illness such as a viral infection e.g. flu. It is sometimes referred to as biological therapy or immunotherapy and is used to treat some patients with NETs. Sometimes interferon is given on its own, but quite often it is given as a combination therapy with somatostatin analogues. It may not be a suitable therapy for all NET patients.
Some people may be given chemotherapy e.g. to treat pancreatic and bronchial NETs, and also for some NET tumours which are growing a little quicker than they might normally do.
The histology of your tumour will help determine whether chemotherapy will be appropriate for you or not. If you have chemotherapy the oncology team, who are specialists in this field, will look after you.
Researchers are constantly looking at various chemotherapy regimens for NET patients and this may be discussed with you at your hospital appointment.
Chemotherapy drugs are normally administered through a cannula inserted in your arm but there are also tablet forms. You can normally receive your treatment as an outpatient, although if it is your first time, you may be asked to stay in overnight just to check that you tolerate the treatment.
The drugs used, and any possible side effects, will be discussed in-depth prior to commencing any treatments and written information will also be given. You will be given many opportunities to ask questions.
You may be given an information and record book from the chemotherapy team. It might be helpful to note down the specific contact numbers for them.
If the tumour has spread to the liver, you may be offered hepatic artery embolisation (HAE). In this procedure, a catheter is placed in the groin, and then threaded up to the hepatic artery that supplies blood to the tumors in the liver. Tiny particles called embospheres (or microspheres) are injected through the catheter into the artery. These particles swell and block the blood supply to the tumour, which can cause the tumour to shrink or even die.
This treatment can also be combined with systemic treatments for people with liver metastases and metastases outside of the liver. It is a procedure that would be done by a specialist called an interventional radiologist. You will be sedated for the treatment.
Sometimes this embolisation process is combined with chemotherapy and called Hepatic Artery Chemoembolisation (HACE), or Transcatheter Arterial Chemoembolisation (TACE), or radiotherapy (Radioactive Microsphere Therapy [RMT] or Selective Internal Radiation Therapy [SIRT]).
Radiofrequency Ablation (RFA) is used if there are relatively few secondary tumours. A needle is inserted into the centre of the tumour and a current is applied to generate heat, which kills the tumour cells.
Radionuclide therapy is also called peptide receptor radionuclide therapy (PRRT) or hormone-delivered radiotherapy. It is sometimes referred to as the ‘magic bullet’. This treatment involves a similar strategy as that applied in an octreotide scan, but the dose of radiation is high enough to prevent further tumour growth or even kill the tumour.
This treatment is not available in Ireland but is offered by some very specialist centres around Europe. One such centre is the university hospital in Uppsalla, Sweden which has close links with several Irish hospitals. This treatment is accessible to Irish NET patients through the EU’s E112 system as part of their overall healthcare strategy.
Radioactive substances are chemically combined with hormones that are known to accumulate in a NET. This combination is injected, the hormones enter the tumour and the attached radiation will kill the tumour cells.
There are a number of different radioactive agents available:
- 90-Yttrium DOTATOC
You will be admitted to hospital for these treatments, but usually you will only need to stay in overnight. You will remain in a lead-lined room for 12-24 hours afterwards and have a scan the following day so the doctor can see if the active agent has been taken up correctly.
The therapy is commonly delivered intravenously through a cannula in the arm. In certain centres it can also be delivered transarterially if the doctor wants to particularly target tumours in the liver. This involves administering the treatment under sedation via an artery (see embolisation).