Neuroendocrine Tumors

Neuroendocrine tumors are an uncommon group of cancers. This information is about neuroendocrine cancers, their symptoms, how they’re diagnosed and possible treatments. A neuroendocrine tumor is a tumor of the neuroendocrine system. The neuroendocrine system makes chemical messengers called hormones, which regulate the workings of different organs in the body. Neuroendocrine cells are spread throughout the body in organs such as the stomach, bowels and lungs.

NETs can be non-cancerous (benign) or cancerous (malignant). This information is about malignant tumors and is mainly about NETs affecting the digestive system.

NETs are classified according to where the cancer started (where the primary tumor is) in the body. For example:

• small bowel NETs
• large bowel NETs
• appendiceal NETs
• pancreatic NETs
• gastric NETs
• lung NETs

Rarely, NETs are found in other areas, including the liver, gallbladder, bile ducts, kidneys, ovaries or testicles. You may hear some NETs referred to as carcinoid tumors. NETs often grow slowly, and it may be several years before symptoms appear and the tumor is diagnosed. However, some NETs may be fast-growing and more likely to spread to surrounding tissues, and to other parts of the body.

Causes and possible risk factors of NETs

Neuroendocrine tumors are uncommon. As with many other forms of cancer, the exact cause is unknown. These tumors are most likely to affect people over the age of 60. People who have a rare condition called Multiple Endocrine Neoplasia 1 (MEN1) have an increased risk of developing a NET.

Signs and symptoms of neuroendocrine tumors

Symptoms will depend on where in the body the NET is. A NET in your digestive system may cause pain or discomfort in the tummy area (abdomen) that comes and goes. You may feel sick (nauseated) or be sick (vomit), or there may be a change in your bowel habits (how often you pass stools). If you have a NET in the lung, it may cause chest infections and shortness of breath, or you may have a cough or cough up blood. NETs sometimes make too much of certain types of hormone, which cause symptoms when they are released into the blood stream. The type of hormone that’s overproduced depends on the gland that’s affected by the tumor.

NETs that cause symptoms of carcinoid syndrome

Some NETs (more commonly NETs of the small bowel, large bowel or appendix) may overproduce a hormone-like substance called serotonin. Serotonin causes a characteristic collection of symptoms called the carcinoid syndrome.

Symptoms may include:

• diarrhea
• flushing of the skin
• wheezing (similar to asthma)
• loss of appetite
• weight loss

People with carcinoid syndrome may be advised to avoid things that may trigger flushing, such as drinking alcohol or eating spicy food. You may be able to reduce diarrhea by making changes to your diet. A specialist dietician can advise you about this.

Other NETs that cause symptoms

There are a number of other NETs that can cause specific symptoms due to the overproduction of hormones. These include insulinomas, gastrinomas, glucagonomas, VIPomas and somatostatinomoas.

Insulinomas
These can occur in any part of the pancreas. The pancreas produces insulin, which controls the level of sugar in the blood. In people with an insulinoma, the tumor produces an abnormally high level of insulin, which causes low blood-sugar levels (hypoglycaemia).

A low blood-sugar level may cause symptoms such as:

• headaches
• confusion
• trembling and palpitations
• anxiety
• eyesight changes
• fits (seizures)
• feeling weak

A low blood-sugar level is most likely to occur first thing in the morning, when exercising or after missing a meal. You can often raise your blood-sugar level again by eating or by having a sugary drink.

Gastrinomas
Gastrinomas usually start in the pancreas or the upper part of the small bowel (duodenum). They may produce too much gastrin. Gastrin is a hormone that causes gastric acid to be made. High levels of gastric acid can lead to ulcers in the stomach, the gullet (esophagus) and the small bowel. There may be several ulcers, which often don’t respond well to the usual ulcer medicines. This is often called Zollinger-Ellison syndrome.

Common symptoms include:

• bleeding into the stomach
• a hole (perforation) in the wall of the stomach or small bowel
• tummy cramps or feeling bloated (due to narrowing of part of the bowel)
• diarrhea
• pale, greasy and offensive-smelling stools (steatorrhea)
• soreness and tightness in the gullet (esophagitis).

Glucagonomas
These tumors occur most often in the pancreas. They usually produce too much glucagon, which is a hormone that helps control blood-sugar levels.

Common symptoms of a glucagonoma include:

• anemia (a low level of red blood cells)
• weight loss
• high blood-sugar (diabetes)
• a skin rash
• blood clots

VIPomas
These usually occur in the pancreas. They may produce too much of a substance called vasoactive intestinal peptide.

Common symptoms include:

• watery diarrhea
• low levels of potassium as a result of the diarrhea
• feeling weak and tired
• feeling sick (nauseated) and being sick (vomiting)

Somatostatinomas
Somatostatinomas are extremely rare tumors that usually occur in the pancreas or parts of the small bowel (the duodenum or jejunum). They produce extra somatostatin.

Common symptoms of a somatostatinoma include:

• pale, greasy and offensive-smelling stools (steatorrhea)
• weight loss
• anemia (a low level of red blood cells)
• pain in the affected area
• diarrhea
• high blood-sugar (diabetes)

NETs that don’t cause symptoms

Some tumors don’t overproduce hormones and may not cause symptoms. These are known as non-functioning NETs.  They may be discovered by chance during an operation or a test being carried out for other reasons.

How neuroendocrine tumors are diagnosed

You may have some of the following tests:

Urine tests

Some NETs cause an increase of a substance called serotonin in the body. Serotonin is broken down by the liver into a chemical called 5HIAA and then passed out of the body in the urine. This test looks for raised levels of 5HIAA in your urine. You will be asked to save all the urine you pass in a 24-hour period so that it can be tested. Certain foods, drinks and medicines can raise the levels of 5HIAA. You may be asked to avoid these for a few days before and during the urine collection.

Blood tests

The levels of some chemicals in the blood, particularly serotonin and chromograninA (CgA), may be raised if you have a NET. You will have samples of blood taken to check the levels of these chemicals. You’ll also have a blood test to count the number of healthy blood cells in your blood (called a full blood count or FBC).

Ultrasound scan

This uses soundwaves to build up a picture of the inside of your body. You’ll usually be asked not to eat or drink anything for at least six hours before the scan. Once you are lying comfortably on your back, a gel is spread on to your abdomen. A small device that produces sound waves is then rubbed over the area. The sound waves produce a picture on a computer. The test is painless and only takes a few minutes. You may also have an ultrasound of your heart, called an echocardiogram.

CT (computerized tomography) scan

A CT scan takes a series of x-rays that build up a three-dimensional picture of the inside of the body. The scan is painless and takes 10–30 minutes. CT scans use small amounts of radiation that are very unlikely to hurt you, or anyone you come in contact with. You’ll be asked not to eat or drink for at least four hours before the scan. You may be given a drink or injection of a dye that allows particular areas to be seen more clearly. This may make you feel hot all over for a few minutes. If you are allergic to iodine or have asthma you could have a more serious reaction to the injection, so it’s important to let your doctor know beforehand.

MRI (magnetic resonance imaging) scan

This test is similar to a CT scan, but uses magnetism instead of x-rays to build up detailed pictures of areas of your body. Before the scan you may be asked to complete and sign a checklist. This is to make sure it’s safe for you to have an MRI scan. Before having the scan, you’ll be asked to remove any metal belongings, including jewelry. Some people are given an injection of a dye into a vein in the arm. This is called a contrast medium and can help the images from the scan show up more clearly. During the test you will be asked to lie very still on a couch inside a long cylinder (tube) for about 30 minutes. It’s painless but can be slightly uncomfortable, and some people feel a bit claustrophobic during the scan. It’s also noisy, but you’ll be given earplugs or headphones. You’ll be able to hear and speak to the person operating the scanner.

Radioactive scans (octreotide scan or MIBG-scan)

These tests may be used to find where the cancer started (the primary tumor), or to check for any spread of the disease (secondaries or metastases). Neuroendocrine tumors often absorb a substance called octreotide. A small amount of octreotide is ‘labelled’ with a mildly radioactive tracer to make it show up on scan pictures. The octreotide is then injected into the bloodstream and taken up by NETs, wherever they are. You will have three scans: one on the day of the injection and two more over the next two days. You will have to keep still while the scanner takes pictures. Each scan takes up to about an hour and a half. You will be able to go home between scans. Sometimes a substance called MIBG, which may be absorbed by NETs, is used for the scan. It’s also made mildly radioactive, and scans are done in a similar way to the scan using octreotide. The dose of radioactivity from these scans is very low (about the same amount you get from an x-ray), and almost all of it leaves your body within a week. If you are planning to travel abroad within three months of the scan, let the doctor in the scanning department know. They can give you a letter to show to customs officials. This is because ports and airports have very sensitive radiation detectors that may pick up tiny amounts of radioactivity.

PET/CT scan

This is a combination of a CT (computerized tomography) scan, which takes a series of x-rays to build up a three-dimensional picture, and a positron emission tomography (PET) scan. A PET scan uses low-dose radiation to measure the activity of cells in different parts of the body. PET/CT scans give more detailed information about the part of the body being scanned. You may have to travel to a specialist center to have one. You can’t eat for six hours before the scan, although you may be able to drink. A mildly radioactive substance is injected into a vein, usually in your arm. The radiation dose used is very small. The scan is done after at least an hour’s wait. It usually takes 30-90 minutes. You should be able to go home after the scan.

Biopsy

A small sample of cells is taken from the tumor and examined under a microscope. You will have a local anesthetic to numb the area before the sample is taken. Sometimes a biopsy is taken under a general anesthetic, depending on where the NET is in your body.

Staging and grading of neuroendocrine tumors

Grading

Grading refers to the appearance of tumor cells under a microscope. The grade gives an idea of how quickly the tumor may develop.

• Low-grade (grade 1) means that the cells look very much like normal cells. They are usually slow-growing.
• Moderate-grade tumors (grade 2) fall somewhere in between low-grade and high-grade tumors in their appearance and behaviour.
• High-grade tumors (grade 3) have cells that look very abnormal (sometimes called anaplastic or poorly differentiated NET). They are likely to grow more quickly and are more likely to spread.

Staging

The stage of a cancer is a term used to describe its size and whether it has spread beyond its original site. Knowing the stage of the cancer helps the doctors decide on the most appropriate treatment. There isn’t a standard staging system for NETs, but doctors may divide them into three stages: localized, regional spread and distant spread (metastatic).

• Localized The cancer is contained inside the organ where it started (for example, the appendix, bowel or stomach).
• Regional spread The cancer has grown through the wall of the organ into nearby tissues. It may also have spread to nearby lymph nodes.
• Distant spread (metastatic) The cancer has spread to other parts of the body, such as the liver, bones or lungs.

Treatment for neuroendocrine tumors

The treatment you have depends on a number of factors, including:

• where the NET started
• the size of the tumor and whether it has spread (its stage)
• whether you have symptoms of carcinoid syndrome or the overproduction of other hormones
• the appearance of the cells under a microscope

The results of your tests will help your doctor discuss the best type of treatment with you. Whenever possible, the main treatment is surgery to remove the tumor. The aim of this is to cure the cancer. If the NET can’t be completely removed by surgery, treatment is generally aimed at relieving symptoms and improving quality of life. Some NETs are very slow-growing and may not change for months or years. If you have a NET that has spread but isn’t causing any symptoms, you may not need treatment straight away. Your doctor will monitor you with regular check-ups and you will be offered treatment if you develop symptoms. This approach is sometimes called ‘watchful waiting’.

Consent

Before you have any treatment, your doctor will give you full information about what it involves and explain its aims to you. They will ask you to sign a form saying that you give permission (consent) for the hospital staff to give you the treatment. No medical treatment can be given without your consent.

Surgery

If you have a localized NET and are well enough for surgery, an operation to completely remove the tumor is usually the main treatment. The aim is to cure the cancer. Sometimes this type of operation is also possible if there has been only limited spread (regional spread). An operation to remove all of the cancer may occasionally be possible for NETs that have spread to the liver. This can usually only be done if there are just one or two tumors in the same area (lobe) of the liver. Surgery can also help relieve symptoms of a NET that has spread to more distant sites (metastatic). For example, if a tumor in the small bowel is causing a blockage, an operation can be done to remove the tumor or bypass the blockage. Surgery to remove as much of the tumor as possible may also be done to relieve symptoms of carcinoid syndrome.

Somatostatin analogues

Somatostatin analogues are drugs used to treat the symptoms of carcinoid syndrome and can help reduce flushing and diarrhea. They work by stopping the body from making too many hormones. They may also control the growth of NETs. The most commonly used somatostatin analogues are octreotide (Sandostatin®, Sandostatin Lar®) and lanreotide (Somatuline® LA, Somatuline Autogel®). To begin with, you may be given an injection under the skin up to three times a day. Then, once your symptoms are well-controlled, you may be given a longer-acting injection. These are given into the muscle 7–28 days apart, depending on the drug that is used and your response.

Chemotherapy

This is the use of anti-cancer (cytotoxic) drugs to destroy cancer cells. It may sometimes be used to treat NETs that have spread. The aim is to shrink the tumor and reduce symptoms. The type of chemotherapy you are given depends on where in the body the NET started.

Targeted therapies

Drugs known as targeted therapies are also used to treat certain types of NET. These are drugs that target the differences between cancer cells and normal cells.  They include sunitinib (Sutent®) and everolimus (Afinitor®).  These drugs are taken as capsules or tablets. Your doctor can advise you on whether you might be suitable to receive a targeted therapy and what side effects you may experience.

Interferon alpha (IntronA®)

Another type of treatment for NETs uses the drug interferon. Interferon can be used to treat the symptoms of NETs and may also control the growth of the tumor. Interferon is a protein that occurs naturally in the body in small amounts. When given as a drug, it can stimulate the body’s immune system to destroy cancer cells. It is given as an injection under the skin. At first it can cause flu-like symptoms such as chills, fever, aching joints and tiredness, but these side effects usually lessen after a few weeks. Sometimes interferon is given in combination with somatostatin analogues.

Radiotherapy

Radiotherapy treats cancer by using high-energy x-rays to destroy cancer cells, while doing as little harm as possible to normal cells. It may be given externally from a radiotherapy machine (called external beam radiotherapy), or internally by placing radioactive material close to the tumor (called brachytherapy). External beam radiotherapy is most likely to be given to treat symptoms, such as pain, if the tumor has spread to the bones.

Targeted radionuclide therapy

This may be used to relieve symptoms of carcinoid syndrome and control the growth of NETs. A radioactive substance is taken as a drink or injected into the bloodstream. Almost all of the radiation is absorbed by the tumor, and very little goes to normal healthy tissues. This is why it’s called targeted radionuclide therapy. Treatments use either MIBG or octreotide as the ‘carrier’ of the radiation. The treatment only works for NETs that absorb large amounts of one of these substances. So before it’s given you’ll have a scan that measures how much octreotide or MIBG is absorbed by the tumor. If you have radionuclide therapy, you may need to be in a room by yourself for a few days, so that other people are not unnecessarily exposed to the radiation. Some people develop tummy aches or feel sick because of the treatment, but this can be relieved with medication. You may have a temporary drop in the levels of some of your blood cells. If this happens you may feel tired, be more at risk of infection, or bruise or bleed more easily. For most people, the side effects don’t last long and they recover quite quickly.

Treatments for neuroendocrine tumors in the liver

Treatments that directly target the liver are sometimes used for NETs in the liver. These treatments include hepatic artery embolization and radiofrequency ablation.
Hepatic artery embolization
This may be used to shrink NETs in the liver and relieve the symptoms of carcinoid syndrome. It works by reducing blood flow to the tumors. Tumors can’t survive without a blood supply. The doctor gently introduces a thin tube into the main blood vessel in your groin (the femoral artery). Using a scan to guide them, they slowly feed the tube up into the main blood vessel of the liver (the hepatic artery). They then inject a drug that blocks the blood supply (embolizes it). Sometimes this is combined with chemotherapy (called chemoembolization). You will probably stay in the hospital overnight. You may feel sick and have tummy (abdominal) pain and a high temperature for a few days afterwards. Your doctor or nurse can give you more information.

Radiofrequency ablation
Radiofrequency ablation may be used to treat NETs in the liver. It uses laser or radio waves to destroy the cancer cells by heating them to high temperatures. You are given a sedative to make you feel drowsy and relaxed. The doctor uses a local anesthetic to numb the skin of your tummy (abdomen). A fine needle is then inserted through the skin over the liver and into the center of the tumor. Powerful laser light or radio waves are passed through the needle and into the tumor, which heats the cancer cells and destroys them. You will probably stay in hospital overnight. You may feel sick, have tummy (abdominal) pain and have a high temperature for a few days afterwards. Your doctor or nurse can give you more information.