Neuroblastoma Stages and Prognostic Markers

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?)

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Last Medical Review: March 19, 2018 Last Revised: March 19, 2018

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