Stages, Prognostic Markers, and Risk Groups for Neuroblastoma
Doctors use different stages and risk groups to help decide which treatments may be best for each child with neuroblastoma.
Neuroblastoma staging
There are two systems used for neuroblastoma staging. The main difference between them 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 scans) to help decide the stage. The INRGSS stage can be determined before treatment has started.
- The International Neuroblastoma Staging System (INSS) is based on the results from the surgery to remove a child's tumor instead of imaging tests.
These staging systems are used to help make sure children with neuroblastoma get the best treatment for them. The INRGSS staging system is most used.
The stages for neuroblastoma are complex and can be confusing. If you are unsure about what they mean for your child, ask your child’s doctor to explain them to you in a way you can understand.
The INRGSS was developed to help determine a child's stage and risk group before treatment starts. It has also helped researchers around the world compare results of studies to help figure out which treatments are best. 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 divides neuroblastomas into 4 stages:
L1: The tumor has not spread from where it started and has not grown into vital structures. It is confined to one area of the body, such as the neck, chest, or abdomen.
L2: The tumor 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 it has at least one IDRF.
M: The tumor 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.
The INSS uses the results of surgery to stage the tumor. It cannot help doctors determine a stage before any treatment has started, so it does not work as well for children who do not 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). The 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 near 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 the whole visible tumor could not be removed by surgery. Lymph nodes near 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 it 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 nearby but on the other side of the body.
- The cancer is in the middle of the body and cannot be removed. It is growing toward both sides (either directly or by spreading to nearby lymph nodes) of the body.
Stage 4: The cancer has spread to distant parts of the body such as distant lymph nodes, bones, liver, skin, bone marrow, or other organs (but the child does not meet the criteria for stage 4S).
Stage 4S (also called “special” neuroblastoma): 4S is a unique type of neuroblastoma that has spread, but only to the liver, skin and/or bone marrow in children less than 1 year of age. 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. Infants with 4S neuroblastoma do better than other children with cancer that has spread.
Recurrent: While not a formal 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 to the area where it first started or in another part of the body.
Prognostic markers
A number of prognostic clinical and biological risk factors are used to categorize patients as low-, intermediate-, or high-risk for relapse and poor outcome. The factors include:
Age: Younger children (between 2–18 months of age) are more likely to have a better outcome than older children.
Tumor stage: Children with tumors that have not spread tend to have a better outlook than children with neuroblastoma that has spread to other parts of the body.
Tumor histology: Tumor histology is 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.
MYCN gene amplifications: MYCN is a gene that normally helps regulate cell growth. Gene changes can turn MYCN into an oncogene, which can make cells grow and divide too quickly. Neuroblastomas with too many copies (amplification) of the MYCN oncogene tend to grow quickly and can be harder to treat.
Chromosome changes: Tumor cells that have lost or gained certain parts of chromosomes 1 or 11 may predict a less favorable prognosis. Having an extra part of chromosome 1, 2 or 17 (chromosome gain) or losing a part of chromosome 3 or 4 (chromosome loss) is also linked with a worse prognosis.
ALK variants: Changes in the ALK gene may drive tumor development in some neuroblastomas, making them harder to treat. In children with neuroblastoma where ALK is altered, specific drugs called ALK inhibitors can be used.
Symptoms: For infants with MS neuroblastoma, having symptoms from their tumor can change their risk group, even if other prognostic markers are good. Symptoms such as having a very large liver, trouble breathing, or failing kidneys at diagnosis are considered in this group of children.
Serum (blood) levels of certain substances can also 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.
- An increased level of lactate dehydrogenase (LDH) in the blood is also linked with a worse prognosis in children with neuroblastoma.
Risk groups
Risk groups are used to help predict how likely it is that a child with neuroblastoma can be cured (and therefore how intensive treatment might need to be). For example, a child in a low-risk group can often be cured with limited treatment, such as surgery alone. Children in higher risk groups often need more intensive treatment to have the best chance of being cured.
The risk groups are based on the stage (extent) of the cancer, as well as other prognostic factors listed above.
The risk groups included here are commonly accepted standard risk groups in the United States. Other internationally used risk groups are being tested in clinical trials.
The COG groups neuroblastoma tumors into three risk groups:
- Low risk
- Intermediate risk
- High risk
Risk group assignment includes factors such as the patient’s age, neuroblastoma stage at diagnosis, MYCN status, how tumor cells look under the microscope and gene changes in the tumor cells.
The risk groups for neuroblastoma are complex and can be confusing. If you are unsure about your child’s risk group and what it means, ask your child’s doctor to explain it to you in a way you can understand. Understanding your child’s risk group is important for choosing a treatment plan and getting a sense of your child’s outlook.
The INRG classification is another system that is being used to help researchers in different countries compare results and work together to find the best treatments.
Like the COG system, the INRG classification uses tumor stage and prognostic factors to put children into risk groupings. However, the INRG system includes 16 different pre-treatment groups (lettered A through R) and each pre-treatment group falls into 1 of 4 overall risk groups:
- Very low risk
- Low risk
- Intermediate risk
- High risk
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- References
Developed by the American Cancer Society medical and editorial content team with medical review and contribution by the American Society of Clinical Oncology (ASCO).
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Last Revised: June 26, 2025
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