Cancer starts when cells in the body begin to grow out of control and crowd out normal cells. Cells in nearly any part of the body can become cancer, and can spread to other areas of the body. To learn more about how cancers start and spread, see What Is Cancer?

The types of cancers that develop in children are often different from the types that develop in adults. To learn more about , see What Are the Differences Between Cancers in Adults and Children?

Neuroblastoma starts in certain very early forms of nerve cells, most often found in an embryo or fetus. (The term neuro refers to nerves, while blastoma refers to a cancer that affects immature or developing cells). This type of cancer occurs most often in infants and young children. It is rare in children older than 10 years.

To understand neuroblastoma, it helps to know about the sympathetic nervous system, which is where these tumors start.

The sympathetic nervous system

The brain, spinal cord, and the nerves that reach out from them to all areas of the body are all part of the nervous system. The nervous system is needed for thinking, sensation, and movement, among other things.

Part of the nervous system also controls body functions we are rarely aware of, such as heart rate, breathing, blood pressure, digestion, and other functions. This part of the nervous system is known as the autonomic nervous system.

The sympathetic nervous system is part of the autonomic nervous system. It includes:

• Nerve fibers that run along either side the spinal cord.
• Clusters of nerve cells called ganglia (plural of ganglion) at certain points along the path of the nerve fibers.
• Nerve-like cells found in the medulla (center) of the adrenal glands. The adrenals are small glands that sit on top of each kidney. These glands make hormones (such as adrenaline [epinephrine]) that help control heart rate, blood pressure, blood sugar, and how the body reacts to stress.

The main cells that make up the nervous system are called nerve cells or neurons. These cells interact with other types of cells in the body by releasing tiny amounts of chemicals (hormones). This is important, because neuroblastoma cells often release certain chemicals that can cause symptoms (see Signs and Symptoms of Neuroblastoma).

Neuroblastomas

Neuroblastomas are cancers that start in early nerve cells (called neuroblasts) of the sympathetic nervous system, so they can be found anywhere along this system.

• Most neuroblastomas begin in sympathetic nerve ganglia in the abdomen, about half of these start in the adrenal gland.
• Most of the rest start in sympathetic ganglia near the spine in the chest or neck, or in the pelvis.
• Rarely, a neuroblastoma has spread so widely by the time it is found that doctors can’t tell exactly where it started.

Some neuroblastomas grow and spread quickly, while others grow slowly. Sometimes, in very young children, the cancer cells die for no reason and the tumor goes away on its own. In other cases, the cells sometimes mature on their own into normal ganglion cells and stop dividing (this makes the tumor a benign ganglioneuroma).

Other autonomic nervous system tumors in children

Not all childhood autonomic nervous system tumors are malignant (cancerous). However, there may be tumors that have both non-cancerous and cancerous cells within the same tumor.

• Ganglioneuroma is a benign (non-cancerous) tumor made up of mature ganglion and nerve sheath cells.
• Ganglioneuroblastoma is a tumor that has both malignant and benign parts. It contains neuroblasts (immature nerve cells) that can grow and spread abnormally, similar to neuroblastoma, as well as areas of more mature tissue that are similar to ganglioneuroma.

Ganglioneuromas are usually removed by surgery and looked at carefully with a microscope to be sure they don’t have areas of malignant cells (which would make the tumor a ganglioneuroblastoma). If the final diagnosis is ganglioneuroma, no other treatment is needed. If it’s found to be a ganglioneuroblastoma, it’s treated the same as a neuroblastoma.

Survival rates are a way to get an idea of the outlook for children with a certain type of cancer. Some parents might want to know the statistics for children in similar situations, but others might not find the numbers helpful, or may even not want to know them.

The 5-year survival rate refers to the percentage of children who live at least 5 years after their cancer is diagnosed. Of course, many children live much longer than 5 years (and many are cured).

In order to get 5-year survival rates, doctors have to look at children who were treated at least 5 years ago. Improvements in treatment since then may result in a better outlook for children now being diagnosed with neuroblastoma.

Survival rates are based on previous outcomes of large numbers of people who had the disease, but they cannot predict what will happen in any particular child’s case. The risk group of a child’s cancer is important in estimating their outlook. But many other factors can also affect a child’s outlook, such as their age, the location of the tumor, and how well the cancer responds to treatment. Your child’s doctor can tell you how the numbers below might apply to your child, as he or she knows your situation best.

Survival by Children’s Oncology Group (COG) risk group

Low-risk group: Children in the low-risk group have a 5-year survival rate that is higher than 95%.

Intermediate-risk group: Children in the intermediate-risk group have a 5-year survival rate of around 90% to 95%.

High-risk group: Children in the high-risk group have a 5-year survival rate around 40% to 50%.

Important research into neuroblastoma is being done right now in many university hospitals, medical centers, and other research institutions around the world. Each year, scientists find out more about what causes the disease and how to improve treatment.

Genetics of neuroblastomas

Researchers now have better tests to look for changes in the genes of neuroblastoma cells. Researchers might know that a change has happened on a certain chromosome (a strand of DNA inside the cell, which contains its genes), but they still need to know more about that gene or what part of a gene has been affected. There are a few different ways that genes change in neuroblastoma:

• Sometimes there are extra copies of the same gene (called amplification) on a chromosome.
• Sometimes a chromosome can have missing pieces of DNA (called deletions) or extra pieces of DNA (called gains or additions), which can affect which genes the chromosome has.

Understanding the gene changes in neuroblastoma helps researchers understand which neuroblastomas are likely to be cured with less intense treatment, and which will need more aggressive treatment. More aggressive neuroblastoma tumors are often called high-risk neuroblastomas, while tumors that tend to be easier to treat are called low- or intermediate-risk neuroblastomas.  Some of these gene changes are being used now to help cancer care teams determine a child's neuroblastoma stage and risk group. Other gene changes might help researchers find new treatments that work on certain types of neuroblastoma cells.

Here are some specific DNA and gene changes currently being studied:

• DNA changes on the short arm of chromosome 6 (6p22) are more likely to be seen in neuroblastomas that grow more aggressively.
• Neuroblastoma cells in older children are more likely to have changes in the ATRX tumor suppressor gene. Tumors with this gene change tend to grow more slowly, but they are also harder to cure. This may help explain why older children tend to have high-risk neuroblastoma while younger children tend to have low- or intermediate-risk neuroblastoma and do better.
• Changes in or having more than one copy (amplification) of the ALK and MYCN genes are features used to help decide a child's risk group. Some drugs might work well against neuroblastomas with ALK gene changes. Some scientists also are studying how ALK gene changes might be related to extra copies of the MYCN gene in neuroblastoma cells.

Treatment

Survival rates for neuroblastoma have gotten better as doctors have found ways to improve on current treatments, but survival rates for children with high-risk neuroblastoma are not as good as they are for children with low- or intermediate-risk disease. Most research studies about high-risk neuroblastoma (more aggressive and hard to treat tumors) focus on finding the best combinations of chemotherapy drugs, stem cell transplant regimens, immunotherapies and other new treatments to try to cure more children. Current studies of low- and intermediate-risk neuroblastoma are trying to figure out if children can get less treatment and still do as well.

Chemotherapy

The search continues for the best combinations of chemotherapy drugs to treat neuroblastoma.

Several chemotherapy drugs that are already used to treat other cancers, such as topotecan, irinotecan, and temozolomide, are now being studied in combination with other kinds of therapies for use against high-risk neuroblastoma or neuroblastoma that has come back.

Other studies are looking to see if children with low- or intermediate-risk neuroblastoma can be treated with less (or even no) chemotherapy. The goal is to still have the same good results, but with fewer side effects from treatment.

Stem cell transplants

Doctors are also trying to improve the success rate for children with aggressive neuroblastoma with high-dose chemotherapy and stem cell transplants, using different combinations of chemotherapy, radiation therapy, retinoids, and other treatments. A recent clinical trial looked at whether giving two stem cell transplants to children with high-risk neuroblastoma works better than giving just one stem cell transplant. The long-term improvement in survival for children who received two transplants is not yet clear, but early results show that two stem cell transplants, followed by certain kinds of immunotherapy works better than one stem cell transplant . Other studies are looking to see if using stem cells donated from another person (an allogeneic stem cell transplant) might help some children with hard-to-treat tumors. More research will be done to confirm these results.  If you have questions about this, talk with your doctor.

Retinoids

Retinoids such as 13-cis-retinoic acid (isotretinoin) have reduced the risk of recurrence after treatment in children with high-risk neuroblastoma, especially when they are given with certain immunotherapy treatments. Giving 13-cis-retinoic acid in combination with different types of chemotherapy drugs, immunotherapies called monoclonal antibodies, and targeted drugs is being studied in a number of clinical trials to help determine the combinations that might work the best.

Targeted drugs

Knowing what makes neuroblastoma cells different from normal cells could lead to new approaches to treating this disease. Newer drugs that target neuroblastoma cells more specifically than standard chemo drugs are now being studied in clinical trials. For example, doctors are now studying medicines that target the pathways inside neuroblastoma cells that help them grow, such as crizotinib (Xalkori) for the ALK pathway and alisertib (MLN8237) for the aurora A pathway.

Crizotinib is a drug that targets cells with changes in the ALK gene. Up to 15% of neuroblastomas have changes in this gene. In an early study, crizotinib was found to cause some neuroblastomas to shrink, although it’s not clear how long this might last, or if giving this drug with certain chemotherapy drugs might work better. Other drugs that target cells with ALK changes are being developed. Some of these are approved for treating other cancers and are being studied to see if they work in neuroblastoma.

Some other drugs that work differently from standard chemo drugs are being studied in clinical trials against neuroblastoma as well. Examples include bortezomib, vorinostat,, temsirolimus, bevacizumab, nifurtimox, and DMFO.

Immunotherapy

Immunotherapy is the use of medicines to help a patient’s own immune system fight cancer. A few different kinds of immunotherapy are being used in neuroblastoma.

Anti-GD2 monoclonal antibodies

The monoclonal antibody dinutuximab (Unituxin®), which targets GD2 on neuroblastoma cells, is now used routinely for children with high-risk neuroblastoma, to help immune system cells find and destroy the cancer cells.

Clinical trials are now testing the effectiveness of several other antibodies that target GD2:

• Hu14.18-IL2 is an antibody that is linked to interleukin-2 (an immune-boosting cytokine). Early results have found that this antibody/cytokine combination may help some children for whom other treatments are no longer working.
• Hu14.18K322A is a modified antibody that might work as well as other GD2 antibodies without some of the side effects.
• Hu3F8 is another modified antibody that targets GD2. It is being studied in combination with other treatments.

Vaccines

Several cancer vaccines are also being studied for use against neuroblastoma. For these vaccines, injections of modified neuroblastoma cells or other substances are given to try to get the child’s own immune system to attack cancer cells. These treatments are still in the early stages of clinical trials.

CAR T-cell therapies

CAR T-cell therapy is a promising new way to get a patient's own immune cells called T cells (a type of white blood cell) to fight cancer by changing them in the lab so they can find and destroy cancer cells. The T cells used in CAR T-cell therapies get changed in the lab to spot specific cancer cells by adding a man-made receptor (called a chimeric antigen receptor or CAR). One early trial created CAR T-cells to target GD2 on neuroblastoma cells. Other clinical trials are studying using CAR T-cells that target other proteins on the outside of neuroblastoma cells. These are very new clinical trials and are ongoing or in the planning phase. Talk to your doctor about these trials if you have questions.

 

Neuroblastomas are usually found when a child is brought to the doctor because of signs or symptoms he or she is having. If a tumor is suspected, tests will be needed to confirm the diagnosis.

Medical history and physical exam

If your child has signs or symptoms that might be caused by a neuroblastoma (or another tumor), the doctor will ask about the symptoms and how long they have been present. The doctor might also ask if there is any history of possible risk factors, such as a family history of neuroblastoma.

The doctor will examine your child for possible signs of a neuroblastoma and other health problems. For example, the doctor may be able to see or feel an abnormal mass or swelling. The doctor might feel to see if the child has lumps or bumps under the skin and examine your child's eyes closely. They might also look at your child's blood pressure because sometimes neuroblastoma cells can make hormones that cause high blood pressure. Neuroblastomas can sometimes grow close to the spinal cord, which can affect movement and strength in the child’s arms and legs, so the doctor will pay close attention to these.

Some signs that could be caused by neuroblastoma, such as fever and enlarged lymph nodes, are much more likely to be caused by an infection, so the doctor might look for other signs of infection at first.

Lab and imaging tests

If the history and exam suggest a child might have a neuroblastoma (or another type of tumor), more tests will be done. These could include blood and urine tests, imaging tests, and biopsies. These tests are important because many of the symptoms and signs of neuroblastoma can also be caused by other diseases, such as infections, or even other types of cancer.

Blood and urine catecholamine tests

The body makes many different types of hormones. Sympathetic nerve cells normally release hormones called catecholamines, such as epinephrine (adrenaline) and norepinephrine, which enter the blood and eventually break down into smaller pieces, called metabolites. The metabolites normally pass out of the body in urine. When epinephrine and norepinephrine are broken down by the body, the two most common metabolites made are:

• Homovanillic acid (HVA)
• Vanillylmandelic acid (VMA)

Neuroblastoma cells can also make these catecholamines. These 2 catecholamine metabolites can be measured in blood and urine. In most cases, neuroblastoma cells make enough catecholamines to be detected by blood or urine tests. If neuroblastoma cells are making catecholamines, the amount of HVA and VMA in urine or blood will be higher than expected.

If neuroblastoma is suspected or has been found, your child’s doctor will probably order blood tests to check blood cell counts, liver and kidney function, and the balance of salts (electrolytes) in the body. A urinalysis (urine test) may also be done to further check kidney function.

Imaging tests

Imaging tests use x-rays, magnetic fields, sound waves, or radioactive substances to create pictures of the inside of the body. Imaging tests can be done for a number of reasons, including:

• To help find out if a suspicious area might be cancerous
• To learn how far cancer has spread
• To help determine if treatment has been effective

If neuroblastoma is highly suspected, the most common imaging test to have first is usually an MRI or CT scan.  If your child is diagnosed with neuroblastoma, they will have an MIBG scan as well. Most children who have or might have neuroblastoma will have one or more of these tests, but might not need all of these tests.

Children with neuroblastoma are often very young, so it can be hard to do some of these tests because the child might need to hold very still. Depending on your child's age and the imaging test that they will have, they might get medicines that are a kind of anesthesia or sedation to help them keep still.

Ultrasound (sonogram)

Ultrasound might be one of the first tests done in very young children if a tumor is suspected, because it is fairly quick and easy, it does not use radiation, and it can often give the doctor a good view inside the body, especially in the abdomen (belly). Ultrasounds are usually not done if the child has already had an MRI or CT scan.

For this test, your child lies on a table (or sits on your lap) while a small wand called a transducer is placed on the skin over the belly (which is first lubricated with gel). The wand gives off sound waves and picks up the echoes as they bounce off organs. The echoes are converted by a computer into a black and white image on a screen. The test is not usually painful, but it might cause some discomfort if the transducer is pressed down hard on the belly.

Ultrasound is used most often to look for tumors in the abdomen. (It’s not used to look in the chest because the ribs block the sound waves.)

Magnetic resonance imaging (MRI) scan

MRI scans provide detailed images of soft tissues in the body. These scans are very helpful in looking at the brain and spinal cord. They may be slightly better than CT scans for seeing the extent of a neuroblastoma tumor, especially around the spine.

MRI scans use radio waves and strong magnets to create the images instead of x-rays, so there is no radiation. A contrast material called gadolinium may be injected into a vein before the scan to better see details.

MRI scans can take up to an hour. For most MRI machines, your child has to lie inside a narrow tube, which is confining and can be distressing. Newer, more open MRI machines may be an option in some cases, but they still require the child to stay still for long periods of time. The MRI machine also makes loud buzzing and clicking noises that may be disturbing. Younger children and children who will not be able to be still for a long period of time are often given medicine to help keep them calm or even asleep during the test.

Computed tomography (CT or CAT) scan

CT scans are often used to look for neuroblastoma in the abdomen, pelvis, and chest.

Before the test, your child may be asked to drink a contrast solution and/or get an IV (intravenous) injection of a contrast dye. This helps better outline structures in the body.

Younger children or children that might not be able to hold still may be sedated (given medicine to make them sleepy) before the test to reduce movement and help make sure the pictures come out well.

CT-guided needle biopsy: CT scans can also be used to help guide a biopsy needle into a tumor. It is not as common for children to have a needle biopsy if neuroblastoma is suspected because the amount of the sample collected might not be enough for all of the tumor tests that are needed.

MIBG scan

This test is often an important part of finding out how far a child's neuroblastoma has spread. It is often done after a CT scan or MRI has already been done. This scan uses a form of the chemical meta-iodobenzylguanidine (MIBG) that contains a small amount of radioactive iodine. MIBG is similar to norepinephrine, a hormone made by sympathetic nerve cells. It is injected into a vein and travels through the blood, and in most patients it will attach to neuroblastoma cells anywhere in the body. Between 1 and 3 days later, the body is scanned with a special camera to look for areas that picked up the radioactivity. This helps doctors know where the neuroblastoma is and if it has spread to the bones and/or other parts of the body.

MIBG scans can be repeated after treatment to see if the tumors are responding well. It is also good to know if the tumor takes up the MIBG because in some cases, this radioactive molecule can be used at higher doses to treat the neuroblastoma (see Radiation Therapy for Neuroblastoma). The thyroid gland can also absorb MIBG, so a medicine containing iodine is sometimes given before and during the test to protect the thyroid.

Bone scan

A bone scan can help show if a cancer has spread to the bones, and can provide a picture of the entire skeleton at once. Neuroblastoma often causes bone damage, which a bone scan can find. This test used to be done routinely, but in many centers it has been replaced by use of MIBG or PET scans.  This test might be done after an MIBG scan, depending on those results.

For this test, a small amount of low-level radioactive material (technetium-99) is injected into a vein. (The amount of radioactivity used is very low and will pass out of the body within a day or so.) The substance settles in areas of damaged bone throughout the skeleton over the course of a couple of hours. Your child then lies on a table for about 30 minutes while a special camera detects the radioactivity and creates a picture of the skeleton. Younger children may be given medicine to help keep them calm or even asleep during the test.

Areas of active bone changes attract the radioactivity and appear as “hot spots” on the skeleton. These areas may suggest cancer, but other bone diseases can also cause the same pattern. To help tell these apart, other imaging tests such as plain x-rays or MRI scans, or even a bone biopsy might be needed.

Positron emission tomography (PET) scan

For a PET scan, a radioactive substance (usually a type of sugar related to glucose, known as FDG) is injected into the blood. The amount of radioactivity used is very low and will pass out of the body within a day or so. Because cancer cells in the body are growing quickly, they absorb large amounts of the radioactive sugar. After about an hour, your child will be moved onto a table in the PET scanner. He or she will lie on the table for about 30 minutes while a special camera creates a picture of areas of radioactivity in the body. Younger children may be given medicine to help keep them calm or even asleep during the test. The picture from a PET scan is not as detailed as a CT or MRI scan, but it can provide helpful information about the whole body.

Some newer machines can do a PET and CT scan at the same time (PET/CT scan). This lets the doctor compare areas of higher radioactivity on the PET scan with the more detailed appearance of that area on the CT scan.

X-rays

The doctor may order an x-ray of the chest or another part of the body as an early test if a child is having symptoms but it’s not clear what might be causing them. But the pictures might not be good enough to spot tumors.

An MIBG scan or a bone scan is usually better for looking at the bones in the rest of the body and to see if neuroblastoma has spread to the bones.

A standard chest x-ray may be done if a child is having trouble breathing, but a CT or MRI scan of the chest can show more about the tumor size and location.

Biopsies

Exams and imaging tests might strongly suggest a child has neuroblastoma, but a biopsy (removing some of the tumor for viewing under a microscope and other lab testing) is usually needed to be sure. During a biopsy, the doctor removes a piece of the tumor. The biopsy samples are sent to a lab, where they are viewed under a microscope by a pathologist (a doctor with special training in identifying cancer cells). Some neuroblastomas are easily recognized when looked at by experienced doctors. But some may be hard to tell apart from other types of children’s cancers. In these cases, special lab tests must be done to show the tumor is a neuroblastoma.

In adults, biopsies are sometimes done using local anesthetic (numbing medicine), but in children they are more often done while the child is under general anesthesia (asleep). There are 2 main types of biopsies:

• Incisional (open or surgical) biopsy: This type of biopsy is done by removing a piece of the tumor through an incision (cut) in the skin. For tumors deep in the body this may be done laparoscopically using long, thin surgical tools inserted through small cuts in the skin.
• Needle (closed) biopsy: For this type of biopsy, a thin, hollow needle is placed through the skin and into the tumor to remove a small sample. If the tumor is deep within the body, CT scans or ultrasound can be used to help guide the needle into the tumor. Needle biopsies are not usually helpful when a child might have neuroblastoma because the amount of tumor in the sample is often not large enough to have all the special tests that are needed.

Other lab tests on neuroblastoma samples can help determine how quickly the tumor might grow or spread in the body. What doctors learn about a child's neuroblastoma from these tests can help determine what treatments might work the best. Some of these tests are described in Neuroblastoma Stages and Prognostic Markers.

Bone marrow aspiration and biopsy

Neuroblastoma often spreads to the bone marrow (the soft inner parts of certain bones). If blood or urine levels of catecholamines are increased, then finding cancer cells in a bone marrow sample is enough to diagnose neuroblastoma (without getting a biopsy of the main tumor). If neuroblastoma has already been diagnosed by a biopsy done elsewhere in the body, bone marrow tests are done to help determine the extent of the disease.

A bone marrow aspiration and biopsy are usually done at the same time. In most cases the samples are taken from the back of both of the pelvic (hip) bones.

Even when the area is numbed with local anesthetic, these tests can be painful, so in most cases the child is also given other medicines to reduce pain or even be asleep during the procedure.

For a bone marrow aspiration, a thin, hollow needle is inserted into the bone and a syringe is used to suck out a small amount of liquid bone marrow.

A bone marrow biopsy is also done. A small piece of bone and marrow is removed with a slightly larger needle that is pushed down into the bone. Once the biopsy is done, pressure is applied to the site to help stop any bleeding.

Samples from the bone marrow are sent to a lab, where they are looked at and tested for the presence of cancer cells. You can read more about testing tissue samples in Testing Biopsy and Cytology Specimens for Cancer.

After someone is diagnosed with neuroblastoma, doctors will try to figure out if it has spread, and if so, how far. This process is called staging. The stage of a child's neuroblastoma describes how much cancer is in the body. Stage is used to help determine how serious the cancer is and how best to treat it.

For neuroblastoma, several other factors are looked at along with a child's stage to decide what risk group a child falls into. A risk group is an overall picture of how a child's neuroblastoma will respond to treatment and helps doctors select the treatments that might work the best. Doctors also use neuroblastoma risk groups when talking about survival statistics. For more information, see Neuroblastoma Risk Groups

There are two systems used for neuroblastoma staging today. The main difference between the two systems is whether the staging system can be used to help determine a child's risk group before treatment has started.

• The International Neuroblastoma Risk Group Staging System (INRGSS) uses results from imaging tests (such as CT or MRI and MIBG scan) to help decide a stage. The INRGSS can be determined before treatment has started.
• The International Neuroblastoma Staging System (INSS) uses results from the surgery to remove a child's tumor instead of imaging tests.

Since many children with neuroblastoma will have surgery as part of their treatment plan, the INSS does not work as well for assigning a risk group before some treatment has started. INRGSS is now being used to determine staging for most Children's Oncology Group studies, but some studies have results that will be published over the next few years that used INSS.

These staging systems can both be used to help make sure children with neuroblastoma get the treatments that are best for them. If your child has neuroblastoma and has not had surgery, you are most likely to hear about your child's stage based on INRGSS. If your child has had a surgery, you may hear doctors talk about your child's stage using either system.

For more information about the physical exams, imaging tests, and biopsies used to help determine neuroblastoma stages, see Tests for Neuroblastoma.

The stages and risk groups for neuroblastoma are complex and can be confusing. If you are unsure about what these mean for your child, ask your child’s doctor to explain them to you in a way you can understand.

International Neuroblastoma Risk Group Staging System (INRGSS)

The INRGSS was developed to help determine a child's stage and risk group before treatment has started. It has also helped researchers around the world compare results of studies to help figure out which treatments are the best. Before it was developed, researchers in different countries couldn't easily compare study results because of different staging systems. INRGSS uses imaging tests (usually a CT or MRI scan, and an MIBG scan), as well as exams and biopsies to help define the stage. The stage can then be used to help predict how resectable the tumor is – that is, how much of it can be removed with surgery.

The INRGSS uses image-defined risk factors (IDRFs), which are factors seen on imaging tests that might mean the tumor will be harder to remove. This includes things like the tumor growing into a nearby vital organ or growing around important blood vessels.

The INRGSS has 4 stages:

L1: A tumor that has not spread from where it started and has not grown into vital structures as defined by the list of IDRFs. It is confined to one area of the body, such as the neck, chest, or abdomen.

L2: A tumor that has not spread far from where it started (for example, it may have grown from the left side of the abdomen into the left side of the chest), but that has at least one IDRF.

M: A tumor that has spread (metastasized) to a distant part of the body (except tumors that are stage MS).

MS: Metastatic disease in children younger than 18 months with cancer spread only to skin, liver, and/or bone marrow. No more than 10% of marrow cells are cancerous, and an MIBG scan does not show spread to the bones and/or the bone marrow.

International Neuroblastoma Staging System (INSS)

Since the mid-1990s, most cancer centers have used the INSS to stage neuroblastoma. This system takes into account the results of surgery to remove the tumor. It cannot help doctors determine a stage before any treatment has started, so it doesn't work as well for children who don't need or cannot have surgery. In simplified form, the stages are:

Stage 1: The cancer is still in the area where it started. It is on one side of the body (right or left). All visible tumor has been removed completely by surgery (although looking at the tumor’s edges under the microscope after surgery may show some cancer cells). Lymph nodes outside the tumor are free of cancer (although nodes enclosed within the tumor may contain neuroblastoma cells).

Stage 2A: The cancer is still in the area where it started and on one side of the body, but not all of the visible tumor could be removed by surgery. Lymph nodes outside the tumor are free of cancer (although nodes enclosed within the tumor may contain neuroblastoma cells).

Stage 2B: The cancer is on one side of the body, and may or may not have been removed completely by surgery. Nearby lymph nodes outside the tumor contain neuroblastoma cells, but the cancer has not spread to lymph nodes on the other side of the body or elsewhere.

Stage 3: The cancer has not spread to distant parts of the body, but one of the following is true:

• The cancer cannot be removed completely by surgery and it has crossed the midline (defined as the spine) to the other side of the body. It may or may not have spread to nearby lymph nodes.
• The cancer is still in the area where it started and is on one side of the body. It has spread to lymph nodes that are relatively nearby but on the other side of the body.
• The cancer is in the middle of the body and is growing toward both sides (either directly or by spreading to nearby lymph nodes) and cannot be removed completely by surgery.

Stage 4: The cancer has spread to distant sites such as distant lymph nodes, bone, liver, skin, bone marrow, or other organs (but the child does not meet the criteria for stage 4S).

Stage 4S (also called “special” neuroblastoma): The child is younger than 1 year old. The cancer is on one side of the body. It might have spread to lymph nodes on the same side of the body but not to nodes on the other side. The neuroblastoma has spread to the liver, skin, and/or the bone marrow. However, no more than 10% of marrow cells are cancerous, and imaging tests such as an MIBG scan do not show cancer in the bones or the bone marrow.

Recurrent: While not formally part of the staging system, this term is used to describe cancer that has come back (recurred) after it has been treated. The cancer might come back in the area where it first started or in another part of the body.

Prognostic markers

Prognostic markers are features that help predict whether the child’s outlook for cure is better or worse than would be predicted by the stage alone. Many of these prognostic markers are used along with a child's stage to assign their risk group. The following markers are used to help determine a child’s prognosis:

• Age: Younger children (under 12-18 months) are more likely to be cured than older children.

• Tumor histology: Tumor histology is based on how the neuroblastoma cells look under the microscope. Tumors that contain more normal-looking cells and tissues tend to have a better prognosis and are said to have a favorable histology. Tumors whose cells and tissues look more abnormal under a microscope tend to have a poorer prognosis and are said to have an unfavorable histology.

• DNA ploidy: The amount of DNA in each cell, known as ploidy or the DNA index, can be measured using special lab tests, such as flow cytometry or imaging cytometry. Neuroblastoma cells with about the same amount of DNA as normal cells (a DNA index of 1) are classified as diploid. Cells with increased amounts of DNA (a DNA index higher than 1) are termed hyperdiploid.  Neuroblastoma cells with more DNA are associated with a better prognosis, particularly for children under 2 years of age.  DNA ploidy is not as useful for understanding a prognosis in older children.

• MYCN gene amplifications: MYCN is an oncogene, a gene that helps regulate cell growth. Changes in oncogenes can make cells grow and divide too quickly, as with cancer cells. Neuroblastomas with too many copies (amplification) of the MYCN oncogene tend to grow quickly and and can be harder to treat.

• Chromosome changes: Tumor cells that are missing certain parts of chromosomes 1 or 11 (known as 1p deletions or 11q deletions) may predict a less favorable prognosis. Having an extra part of chromosome 17 (17q gain) is also linked with a worse prognosis. Understanding the importance of chromosome deletions/gains is an active area of neuroblastoma research, for more information see What's New In Neuroblastoma Research?
• Neurotrophin (nerve growth factor) receptors: These are substances on the surface of normal nerve cells and on some neuroblastoma cells. They normally allow the cells to recognize neurotrophins – hormone-like chemicals that help the nerve cells mature. Neuroblastomas that have more of certain neurotrophin receptors, especially the nerve growth factor receptor called TrkA, may have a better prognosis.

Serum (blood) levels of certain substances can be used to help predict prognosis.

• Neuroblastoma cells release ferritin, a chemical that is an important part of the body's normal iron metabolism, into the blood. Patients with high ferritin levels tend to have a worse prognosis.
• Neuron-specific enolase (NSE) and lactate dehydrogenase (LDH) are made by some types of normal cells as well as by neuroblastoma cells. Increased levels of NSE and LDH in the blood are often linked with a worse outlook in children with neuroblastoma.
• A substance on the surface of many nerve cells known as ganglioside GD2 is often increased in the blood of neuroblastoma patients. Although the usefulness of GD2 in predicting prognosis is unknown, it may turn out to be more important in treating neuroblastoma. (See What’s New in Neuroblastoma Research?)

Neuroblastoma can cause many different signs and symptoms. Common symptoms include:

• Lump or swelling in the child's abdomen or neck that doesn't seem to hurt
• Swelling of the legs or upper chest, neck and face
• Enlarged belly
• Problems breathing or swallowing
• Weight loss
• Not eating or complaining about feeling full
• Problems with bowel movements or urinating
• Pain in bones
• Lumps or bumps in the skin that may appear blue
• Drooping eyelid and small pupil (the black area in the center of the eye) in one eye
• Problems being able to feel or move move parts of the body
• Eyes that appear to bulge and/or bruising around the eyes

The signs and symptoms that a child has might be different depending on where the tumor is, how large it is, how far it has spread, and if the tumor makes chemicals called hormones.

Many of the signs and symptoms above are more likely to be caused by something other than neuroblastoma. Still, if your child has any of these symptoms, check with your doctor so the cause can be found and treated, if needed.

Signs or symptoms caused by the main tumor

Tumors in the abdomen (belly) or pelvis: One of the most common signs of a neuroblastoma is a large lump or swelling in the child’s abdomen. The child might not want to eat (which can lead to weight loss). If the child is old enough, he or she may complain of feeling full or having belly pain. But the lump itself is usually not painful to the touch.

Sometimes, a tumor in the abdomen or pelvis can affect other parts of the body. For example, tumors that press against or grow into the blood and lymph vessels in the abdomen or pelvis can stop fluids from getting back to the heart. This can sometimes lead to swelling in the legs and, in boys, the scrotum.

In some cases the pressure from a growing tumor can affect the child’s bladder or bowel, which can cause problems urinating or having bowel movements.

Tumors in the chest or neck: Tumors in the neck can often be seen or felt as a hard, painless lump.

If the tumor is in the chest, it might press on the superior vena cava (the large vein in the chest that returns blood from the head and neck to the heart). This can cause swelling in the face, neck, arms, and upper chest (sometimes with a bluish-red skin color). It can also cause headaches, dizziness, and a change in consciousness if it affects the brain. The tumor might also press on the throat or windpipe, which can cause coughing and trouble breathing or swallowing.

Neuroblastomas that press on certain nerves in the chest or neck can sometimes cause other symptoms, such as a drooping eyelid and a small pupil (the black area in the center of the eye). Pressure on other nerves near the spine might affect the child’s ability to feel or move their arms or legs.

Signs or symptoms caused by cancer spread to other parts of the body

About 2 out of 3 neuroblastomas have already spread to the lymph nodes or other parts of the body by the time they are found.

Lymph nodes are bean-sized collections of immune cells found throughout the body. Cancer that has spread to the lymph nodes can cause them to swell. These nodes can sometimes be felt as lumps under the skin, especially in the neck, above the collarbone, under the arm, or in the groin. Enlarged lymph nodes in children are much more likely to be a sign of infection than cancer, but they should be checked by a doctor.

Neuroblastoma often spreads to bones. A child who can talk may complain of bone pain. The pain may be so bad that the child limps or refuses to walk. If it spreads to the bones in the spine, tumors can press on the spinal cord and cause weakness, numbness, or paralysis in the arms or legs. Spread to the bones around the eyes is common and can lead to bruising around the eyes or cause an eyeball to stick out slightly. The cancer can also spread to other bones in the skull, causing bumps under the scalp.

If the cancer spreads to the bone marrow (the inner part of certain bones that makes blood cells), the child may not have enough red blood cells, white blood cells, or blood platelets. These shortages of blood cells can result in tiredness, irritability, weakness, frequent infections, and excess bruising or bleeding from small cuts or scrapes.

Rarely, large tumors can start to break down, leading to a loss of clotting factors in the blood. This can result in a high risk of serious bleeding, which is known as a consumption coagulopathy and can be life threatening.

A special widespread form of neuroblastoma (known as stage 4S) occurs, but only during the first few months of life. In this special form, the neuroblastoma has spread to the liver, to the skin, and/or to the bone marrow (in small amounts). Blue or purple bumps that look like small blueberries may be a sign of spread to the skin. The liver can become very large and can be felt as a mass on the right side of the belly. Sometimes it can grow large enough to push up on the lungs, which can make it hard for the child to breathe. Despite the fact that the cancer is already widespread when it is found, stage 4S neuroblastoma is very treatable, and often shrinks or goes away on its own. Almost all children with this form of neuroblastoma can be cured.

Signs or symptoms caused by hormones from the tumor

Neuroblastomas sometimes release hormones (chemicals) that can cause problems with tissues and organs in other parts of the body, even though the cancer has not spread to those tissues or organs. These problems are called paraneoplastic syndromes.

Symptoms of paraneoplastic syndromes can include:

• Constant watery diarrhea
• Fever
• High blood pressure (causing irritability)
• Rapid heartbeat
• Reddening (flushing) of the skin
• Sweating

An uncommon set of symptoms is called the opsoclonus-myoclonus-ataxia syndrome or “dancing eyes, dancing feet.” The child has irregular, rapid eye movements (opsoclonus), twitch-like muscle spasms (myoclonus), and appears uncoordinated when standing or walking (ataxia). He or she might also have trouble speaking. For reasons that are not clear, neuroblastomas that cause this syndrome tend to be less life-threatening than other forms of the disease.

 

Neuroblastoma is by far the most common cancer in infants (less than 1 year old). It accounts for about 6% of all cancers in children. There are about 800 new cases of neuroblastoma each year in the United States. This number has remained about the same for many years.

The average age of children when they are diagnosed is about 1 to 2 years. In rare cases, neuroblastoma is detected by ultrasound even before birth. Nearly 90% of cases are diagnosed by age 5. Neuroblastoma is rare in people over the age of 10 years.

In about 2 of 3 cases, the disease has already spread to the lymph nodes or to other parts of the body when it is diagnosed.

Statistics related to survival are discussed in Survival Rates for Neuroblastoma Based on Risk Groups.

Visit the American Cancer Society’s Cancer Statistics Center for more key statistics.

A risk factor is anything that affects your chance of getting a disease such as cancer. Different cancers have different risk factors.

Lifestyle-related risk factors such as body weight, physical activity, diet, and tobacco use play a major role in many adult cancers. But these factors usually take many years to influence cancer risk, and they are not thought to play much of a role in childhood cancers, including neuroblastomas.

No environmental factors (such as being exposed during the mother’s pregnancy or in early childhood) are known to increase the chance of getting neuroblastoma.

Age

Neuroblastoma is most common in very young children, but it is still rare even in this age group. It is very rare in people over the age of 10 years.

Heredity

In about 1% to 2% of all neuroblastomas, children inherit an increased risk of developing neuroblastoma from a parent. But most neuroblastomas do not seem to be inherited.

Children with the familial form of neuroblastoma (those with an inherited tendency to develop this cancer) usually come from families with one or more members who had neuroblastoma as infants. The average age at diagnosis of familial cases is younger than the age for sporadic (not inherited) cases.

Children with familial neuroblastoma sometimes develop 2 or more of these cancers in different organs (for example, in both adrenal glands or in more than one sympathetic ganglion). It’s important to distinguish neuroblastomas that start in more than one organ from neuroblastomas that have started in one organ and then spread to others (metastatic neuroblastomas). When tumors develop in several places at once it suggests a familial form. This might mean that family members should consider genetic counseling and testing (see Genetic Testing: What You Need to Know). Both familial and neuroblastoma that is not inherited can spread to other organs.

Having birth defects (congenital anomalies)

Some studies have shown that children with birth defects might have an increased risk of developing neuroblastoma. Some of the link between birth defects and neuroblastoma might be related to changes in genes that happen during fetal development.

Genes are made of DNA, which is a chemical inside our cells. Genes are instructions that tell our body cells what to do. Fetal development, which happens in a mother's uterus, is also directed by genes that tell the cells how to grow and divide. If cell growth and development doesn't happen normally in the fetus, it can cause a birth defect. Changes in genes that happen during fetal development might contribute to a birth defect and increase the risk of some kinds of childhood cancers, like neuroblastoma. That doesn't mean all children with birth defects will get neuroblastoma. More research is needed to understand the relationship between birth defects and risk of childhood cancer. For more information about genes and causes of neuroblastoma, see What Causes Neuroblastoma?

 

The causes of most neuroblastomas are not known. But researchers have found important differences between neuroblastoma cells and the normal neuroblasts (early forms of nerve cells) from which they develop. They have also found differences between neuroblastomas that are likely to respond to treatment and those that have a poor prognosis (outlook). These differences (known as prognostic markers) are sometimes helpful in choosing the best treatment.

How normal cells become neuroblastoma

Nerve cells and cells of the medulla (center) of the adrenal gland develop from neuroblasts in the fetus. These neuroblasts usually grow and change into mature nerve cells. Neuroblastomas develop when normal fetal neuroblasts do not become mature nerve cells or adrenal medulla cells. Instead, they continue to grow and divide.

Neuroblasts might not have matured completely in babies by the time they are born. Most of these eventually mature into nerve cells or simply die off and do not form neuroblastomas. Sometimes, neuroblasts remaining in very young infants continue to grow and then form tumors. Some can even spread to other parts of the body. But many of these tumors will still eventually mature into nerve tissue or go away on their own.

However, as children get older, it becomes less likely that these cells will mature and more likely that they will grow into a cancer. By the time neuroblastomas are large enough to be felt or cause symptoms, most can no longer mature on their own and will grow and spread unless treated.

The failure of some neuroblasts to mature and to stop growing is due to abnormal DNA inside the cells. DNA is the chemical in each of our cells that makes up our genes, which control how our cells function. The DNA inside our cells is in long string-like structures called chromosomes.

Some genes contain instructions for controlling when our cells grow, divide into new cells, and die:

• Certain genes that help cells grow, divide, or stay alive are called oncogenes.
• Genes that help keep cell division under control or cause cells to die at the right time are called tumor suppressor genes.

Cancers can be caused by DNA changes that turn on oncogenes or turn off tumor suppressor genes. These gene changes can be inherited from a parent (as is rarely the case with childhood cancers), or they may happen during a person’s lifetime as cells in the body divide to make new cells.

In most cases, neuroblastoma cells have chromosome changes (such as having too many or too few chromosomes or missing part of a chromosome) that are likely to affect certain genes. Scientists are still trying to determine which genes are affected by these chromosome changes, as well as how these changes affect the growth of neuroblastoma cells.

Gene changes in neuroblastoma

In rare cases, neuroblastoma seems to occur because of gene changes inherited from a parent. Inherited changes in certain genes account for most cases of hereditary neuroblastoma:

• ALK oncogene changes account for most cases of inherited neuroblastoma.
• Changes in PHOX2B, a gene that normally helps nerve cells mature, account for a small number of inherited neuroblastomas.

Still, most neuroblastomas are not caused by inherited DNA changes. They are the result of gene changes that happen at some point during the child’s development, sometimes before birth. What causes these gene changes is not known. These changes are found only in the child’s cancer cells, so they will not be passed on to his or her children. For example, about 10% to 15% of sporadic (not inherited) neuroblastomas also have changes in the ALK gene. In many neuroblastomas the exact genes affected are not known.

Other gene changes seem to affect how quickly a neuroblastoma can grow. Here are some examples of gene changes in neuroblastoma cells and what they can mean about a child's neuroblastoma:

•  Neuroblastoma cells sometimes have extra copies of an oncogene called MYCN amplification, which is often a sign that the tumor will grow quickly and be harder to treat.
• When the NTRK1 gene (which makes the TrkA protein) is overactive in the cells of neuroblastomas, it can be sign that a child's neuroblastoma might have a better outlook.
• Neuroblastoma cells in older children are more likely to have changes in the ATRX tumor suppressor gene. Tumors with this gene change tend to grow more slowly, but they are also harder to cure. This may help explain why younger children with neuroblastoma tend to do better long term than children who are older when they are diagnosed.

Researchers have found some of the gene changes that may lead to neuroblastoma, but it’s still not clear what causes these changes. Some gene changes may be inherited. Some might have unknown outside causes, but others could just be random events that sometimes happen inside a cell, without having an outside cause. There are no known lifestyle-related or environmental causes of neuroblastomas at this time, so it’s important to remember that there is nothing these children or their parents could have done to prevent these cancers.

Researchers have studied whether screening infants for neuroblastoma might find these tumors earlier and lead to better treatment results. Screening is testing for a disease, such as cancer, in people who don’t have any symptoms. One way to screen for neuroblastoma is to test children’s urine for certain substances made by neuroblastoma tumors. (For more information on this urine test, see Tests for Neuroblastoma.)

Studies have not found neuroblastoma screening to be helpful. Testing infants when they were 6 months old did find many tumors that wouldn’t have normally been diagnosed. But most of these tumors were of a type that probably would have gone away or matured into benign (non-cancerous) tumors on their own. These tumors probably would never have caused any problems. The screening didn’t lower the number of cancers found at advanced stages or save lives.

What’s more, finding tumors that would never cause serious problems may needlessly frighten parents and can lead to unnecessary tests and surgery in children whose tumors would have gone away or matured on their own if left alone.

For these reasons, most experts do not recommend screening for neuroblastoma in infants who are not at increased risk of the disease.

In rare instances, neuroblastoma is found before birth during an ultrasound, a test that uses sound waves to create an image of the internal organs of a fetus. Ultrasounds are usually done to estimate the age of a fetus, predict the date of birth, and look for certain common birth defects. Improvements in ultrasound technology or other tests may lead to more accurate prenatal (before birth) testing for this disease.

Neuroblastoma is sometimes found incidentally in young children without any symptoms during tests done to find other childhood diseases. These children will usually have a good outcome, and some may not even need treatment.

But most often, neuroblastoma is first detected because of signs or symptoms the child is having.

Neuroblastoma can cause long-lasting side effects. Most of the long-term side effects depend on exactly what kind of treatment a child had, where the tumor was located, and how old the child was when treated. Children who received 3 or more kinds of treatment (surgery, radiation, chemotherapy, etc.) are more likely to have serious long-term side effects of treatment. For more information see Late Effects of Childhood Cancer Treatment.

Because of major advances in treatment, most children treated for neuroblastoma are now surviving into adulthood. Doctors have learned that the treatment can affect children’s health later in life, so watching for health effects as they get older has become more of a concern in recent years.

Neuroblastoma survivors are at risk for several possible late effects of their treatment. It’s important to discuss what these possible effects might be with your child’s medical team.

After treatment, the cancer care team will create a Survivorship Care Plan describing the treatments given and what that tells you about your child's risk of late effects. The plan will also describe how the child should be monitored for these problems. Most children do not experience all the problems they might be at risk for, but it's important to find any problems that do come up early, so they can be treated effectively.

  Late effects after neuroblastoma treatment can include:

• Hearing loss
• Problems with bones and muscles, like scoliosis (curving of the spine)
• Thyroid problems
• Problems with growth and development
• Fertility problems
• Neurological problems
• Second cancers, including leukemia
• Emotional or psychological issues

In very rare instances and for unknown reasons, in some children with neuroblastoma the body’s immune system attacks the child’s normal nerve tissue. This can lead to problems such as learning disabilities, delays in muscle development, language problems, and behavioral problems. This is called opsoclonus myoclonus syndrome.

Children whose tumors are in the neck or chest and who have problems with the eyes or with muscle twitches may need further treatment with corticosteroids, intravenous immunogloblulin (IVIG), or other drugs.

Long-term follow-up guidelines

To help increase awareness of late effects and improve follow-up care of childhood cancer survivors throughout their lives, the Children’s Oncology Group (COG) has developed long-term follow-up guidelines for survivors of childhood cancers. These guidelines are used to create a child's Survivorship Care Plan.

To learn more, ask your child’s doctors about the COG survivor guidelines. You can also download them for free at the COG website: www.survivorshipguidelines.org. The guidelines are written for health care professionals. Patient versions of some of the guidelines are available (as “Health Links”) on the site as well.

Emotional and social Issues in children with neuroblastoma

When a child is diagnosed with cancer, it is a crisis for the whole family. Younger children might not remember much about their experience after treatment completes, but getting through it and helping them cope can be a challenge. Older children might have difficulty being away from school, friends, and activities that they enjoy, in addition to dealing with treatment stresses. Most pediatric cancer centers have special support programs and services to help children with cancer during treatment and for many years after treatment ends.  

Parents and other family members, especially siblings, can also be affected, both emotionally and in other ways. The family’s situation should be evaluated by the treatment center as soon as possible. Some common family concerns include financial stresses, traveling to and staying near the cancer center, the need for family members to take time off from work, the possible loss of a job, and the need for home schooling. Social workers and other professionals at cancer centers can help families sort through these issues.  

To learn more about helping children with neuroblastoma and their loved ones cope during and after treatment, see Finding Help and Support When Your Child Has Cancer.