The neuroendocrine system is made up of neuroendocrine cells which are cells that are similar to nerve cells and produce hormones. These hormones are released into the blood and have effects on many areas in the body. Neuroendocrine cells are present in many parts of the body, commonly including the intestine, stomach, oesophagus, lung, pancreas and liver.
Tumours that develop in the neuroendocrine system are known as neuroendocrine tumours. About half of all tumours of this type occur in the digestive tract and about a quarter of them occur in the lung. The rest occur in other parts of the body. Neuroendocrine tumours are uncommon tumours and the average age at which they occur is around 50-60 years.
Risk factors for developing neuroendocrine tumours include those affected with hereditary conditions such as MEN syndrome, Von Hippel-Lindau syndrome, Neurofibromatosis type 1 and Tuberous sclerosis. Other potential risk factors are smoking, diabetes and chronic gastritis which is an inflammation of the stomach.
Neuroendocrine tumours can be either benign or malignant tumours. Which type they are is dependent on the type of tumour and its rate of increase, that is how actively the cells are dividing. Some tumours can be very slow growing and behave like benign tumours, whereas other grow quickly and are like malignant tumours or cancers.
These tumours are given a grade of 1 to 3 depending on the appearance of the cells of the tumour when seen under the microscope. A Ki-67 index is given and this determines the grade. Ki-67 looks at the proportion of cells in the tumour that are actively dividing. The more the cells divide, the higher the Ki-67 and grade. The cells of a grade 1 tumour appear very similar to normal cells and tend to grow slowly, whereas cells of a grade 3 tumour look very different to a normal cell and tend to grow more quickly.
Neuroendocrine tumours may not produce any symptoms at all when they are small and may be found incidentally while tests are done for other reasons. Symptoms when produced depend on the location of the tumour and the degree of spread of the tumour to other parts of the body, particularly the liver. The symptoms of these tumours are given in the respective sections below.
Carcinoid syndrome occurs when a neuroendocrine tumour from the intestine mainly, spreads into the liver and produces chemicals (serotonin) that cause various symptoms in the patient such as loose motions, pain in the abdomen, redness and flushing of the skin, palpitations and difficulty with breathing.
When neuroendocrine tumours are suspected, many tests can be done to make a diagnosis, know about the specific type of tumour, its spread to different parts of the body and its potential response to treatment. The important tests are listed below.
Neuroendocrine tumours produce chemicals such as serotonin which may be detected in the urine, helping to make a diagnosis or assess a response to treatment. The substance tested for in the urine is 5-HIAA or 5 hyroxy indole acetic acid. The total urine produced by the patient over 24 hours is collected in a bottle and sent to the lab for assessment. Prior to collection of this urine, the patient is advised to follow certain precautions such as not eating foods that contain small amounts of serotonin including tomatoes, brinjals, bananas, alcohol, tea, coffee, pineapple and nuts. The container to collect urine is given by the lab.
Blood tests are commonly done to help in diagnosis of these tumours and to assess response to treatment. Common blood tests done include CBP, liver function, kidney function tests along with other tests such as Chromogranin A and B. This is a protein produced by these tumours and helps in the diagnosis when it is increased in the blood. The test is also used to see if the patient is responding to treatment or if the tumour is coming back after initial treatment.
Other blood tests that can be done are to look at the levels of Insulin, glucagon, Serotonin, Gastrin and VEP. These chemicals can be elevated in certain types of neuroendocrine tumours.
Ultrasound scans use sound waves to make images and are used commonly in diagnosis of breast and other cancers. These scans are cheap and harmless but may not be as good in detecting some cancers as other scans do.
A CT scan is a scan that uses x-rays to give a three-dimensional image of the part of the body that is scanned. It is more accurate than an x-ray in identifying and staging cancer. A contrast enhanced scan is one where an injection is given into the vein prior to the scan and this gives better images. Oral contrast is given to the patient to drink when the abdomen is being scanned. CT scan takes only a few minutes to do. CT scan is also used to help guide the doctor when certain biopsies are done.
An MRI scan uses magnetic fields to generate images and is used very often to diagnose and stage cancer. This scan is done for some types of cancer. MRI produces better images than CT in areas such as brain, spine and pelvis (lower part of abdomen). Some patients find it difficult to have an MRI scan as they can feel claustrophobic while the scan is being done. The time taken for MRI scans is longer ranging from 20 mins to up to an hour. Contrast agent is injected during the scan to get better images. The scan is done as sequences and usually many sequences are done in one scan in cancer patients.
This type of scan differs from standard CT scan by having a functional element to the scan. The PET component of the scan is able to detect areas in the body where cells rapidly divide such as cancers, infection, inflammation etc. PET-CT is better than CT scan in staging certain cancers. The PET part of the scan is done by injecting a radiolabelled substance into the body first and then a scan is done. This substance is taken up by the dividing cells and shows up on the scan.
There are different types of PET-CT scan and the difference lies in the type of radiolabelled tracer used to detect the rapidly dividing cells. The standard PET-CT scan is an FDG PET which uses 18Fluorine. The other tracers used include Choline C-11, 11 C Methionine, 18F labelled Choline, Gallium 68 labelled somatostatin analogue scans used for neuroendocrine tumours. A PET-CT scan is commonly used these days to make a diagnosis of cancer and to help in accurately staging the disease. It has to be noted that not all cancers show up on PET-CT. Some cancers do not take up the radioactive tracer as other cancers do and hence PET-CT is recommended as a definitive investigation in only some cancers.
Scans coupled with the use of radioactive tracers are used in the diagnosis and treatment of neuroendocrine tumours. Some of these tumours absorb these radioactive substances, which can then be seen on the scans. It helps in identifying small tumours that cannot be seen on normal scans. Common radioactive tracers used include Octreotide, mIBG(metaiodobenzylguanidine), gallium dotatate (PET). The radioactive substances are normally injected into the vein and after some time, images are taken of the body with a scanning machine called a gamma camera.
A biopsy is done to confirm a diagnosis of neuroendocrine tumour. A biopsy can be of different types from being an FNAC, where a small needle is passed into the tumour and a few cells are taken to a core biopsy, where a small part of the tumour is sampled with a large needle. Excision biopsy, where the tumour is completely removed is also used. The biopsy is done with the help of an ultrasound scan, CT scan or depending on the location of the tumour, an endoscopy, colonoscopy or bronchoscopy are done to enable a biopsy to be taken.
The treatment of neuroendocrine tumours is dependent on the location of the primary tumour, the type of tumour and the presence of spread of tumour to different parts of the body. The main options of treatment include
- Drug therapy
- Radiation therapy
- Radionuclide therapy
- Local therapy
This is the treatment of choice in tumours that are small and amenable to surgery. In most neuroendocrine tumours that are slow growing and confined to one area, surgery is all that is needed as treatment. Complete removal of the tumour with an area of normal tissue around it is aimed at the operation. Depending on the location of the tumour, surgery can be of different types.
In tumours of the lung, surgery may involve removal a part of the lung (lobe removed) or the entire lung. For tumours of the stomach, a part of the stomach or all the stomach is removed. A part of the intestine is removed for tumours of the small or large intestine. A type of operation called Whipple’s procedure is done for tumours of the pancreas or biliary tract such as gall bladder and bile duct. The same surgery may be done for those in the duodenum or part of the stomach. A part of the liver is removed in tumours that involve only the liver. The thyroid gland is removed in case of tumours present in it.
Surgery for removal of neuroendocrine tumours also includes removal of surrounding lymph nodes to look for presence of tumour into them. This will help in more accurately staging the tumour and will aid in better predicting the outcome after treatment.
Surgery may also be done to reduce the bulk of disease when all of it cannot be removed. This helps to increase the effectiveness of other treatments such as drugs or radiotherapy. In some patients where the tumour has spread to different parts of the body, surgery may be done to help improve symptoms related to the cancer.
Drugs are used to treatment neuroendocrine tumours or cancers to limit the symptoms produced by the tumour and to keep it in control.
Somatostatin analogues are a group of drugs that are very commonly used in the treatment in carcinoid syndrome. This syndrome occurs when a neuroendocrine tumour from the intestine mainly, spreads into the liver and produces chemicals (serotonin) that cause various symptoms in the patient such as loose motions, pain in the abdomen, redness and flushing of the skin, palpitations and difficulty with breathing.
Commonly used somatostatin analogues are Octreotide and Lanreotide. Both drugs are given as injections under the skin. Octreotide has short acting form which needs to be given daily and long acting form which is given once every 4 weeks. Lanreotide is a long acting form only and given every 4 weeks.
Chemotherapy is used less commonly in neuroendocrine tumours. It is effective mainly in high grade tumours which tend to grow faster and behave like cancers. The purpose of chemotherapy is to control the tumour and improve symptoms and survival.
Biological drugs or targeted therapy includes use of drugs that target specific areas in the cancer cells and can be used in certain types of neuroendocrine tumours. Drugs such as Everolimus and Sunitinib are used in this setting to help control the disease and improve symptoms and survival of the patient.
Radiotherapy in the form of external beam radiotherapy delivered using a linear accelerator is used to treat some neuroendocrine tumours particularly those that have spread to the bones. Treatment helps in reducing pain arising from the bones.
This is targeted radiotherapy using a radioisotope that is attached or combined to a molecule that attaches to the tumour or cancer cell. When such drugs are given, they are taken up by the tumour and the radionuclide delivers a dose of radiation in the area around the tumour cell, killing or damaging it. Such treatment is also called as peptide receptor radioligand therapy (PRRT).
Before such treatment is contemplated, a radionuclide scan with somatostatin is done to see if the tumour takes up somatostatin. If there is take up of this substance, these treatments can work.
Commonly used treatments are Lutetium Lu-177 dotatate and Yttrium-90 Dotatoc. Which drug to use depends on availability of the compound at the centre. Repeat treatments with these drugs can be given if found to be useful in the patient.
Treatment that is directed locally to the area of maximum disease is an option of treatment in neuroendocrine tumours. This option is used mainly when the majority of disease is present in the liver.
Hepatic artery embolization is a process where drugs are injected into the artery providing blood supply to the part of the liver where the bulk of tumour is located. This injection will block the artery and reduce blood and nutrient supply to the tumour and by that reducing its size. Chemotherapy drugs can also be injected into the hepatic artery to deliver chemotherapy locally to the tumour. This is called as chemoembolization.
Radioembloization is a similar process where a radioactive nuclide is injected locally into the hepatic artery to deliver radiotherapy to the tumour.
Radiofrequency ablation involves applying a radiofrequency probe to the area of disease in the liver and heat is delivered to the tumour to kill it.
Which of these treatments to select will depend on the local expertise and availability.