Once the neuroblastoma has been detected, the doctor combines all the tests to determine the stage of the cancer. This is the most important factor in estimating the prognosis (the outlook for survival) and choosing the most appropriate treatment. Certain tests of blood and tumor specimens, called prognostic marker tests, also help in predicting outlook and choosing treatment but are not included in determining the stage.

Staging Systems

Since the mid-1990s, many cancer care centers have started using a method known as the International Neuroblastoma Staging System (INSS). In simplified form, the stages are:

Stage 1: The cancer is localized (hasn't spread). It is on one side of the body. All visible tumor is totally removed by surgery. Examination of the tumor's edges under the microscope may show some cancer cells. Lymph nodes enclosed within the tumor may contain neuroblastoma cells, but lymph nodes outside of the tumor should be free of cancer.

Stage 2A: The cancer is localized, but because of its size, location, or relationship to other organs, most but not all of the tumor can be removed by surgery. It is on one side of the body. Lymph nodes enclosed within the tumor may contain neuroblastoma cells, but lymph nodes outside of the tumor should be free of cancer.

Stage 2B: The cancer is localized, and may or may not be able to be totally removed by surgery. It is on one side of the body. 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 cannot be completely removed by surgery or 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,

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 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 and is localized. It may 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 may be cancerous, and imaging studies do not show bone damage.

Recurrent: The cancer has come back (recurred) after it has been treated. It may come back in the area where it first started or in another part of the body.

Prognostic Markers

Prognostic markers are specific features of cancer that predict whether the child's outlook for cure is better or worse than would be predicted by the stage alone. The following 4 markers are used to calculate a child’s chance of cure.

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

Tumor grade: Tumor grade is based on the appearance of the neuroblastoma under the microscope. Most grading systems include estimates of the number of growing cells, and the proportions of very immature cells to cells that more closely resemble mature nerve tissue.

The presence of many dying cells or reproducing cells (mitosis) is a predictor of a poor prognosis. (This is an "unfavorable histology.") Fewer growing cells and more mature nerve tissue (a "favorable histology") predict a better outlook.

DNA ploidy: The amount of DNA in each cell, known as ploidy, can be measured by special lab techniques, such as flow cytometry or imaging cytometry. Cells with about the same amount of DNA as normal cells are classified as diploid. Neuroblastoma cells with increased amounts of DNA are termed hyperdiploid.

In infants, hyperdiploid cells tend to be associated with earlier stages of disease, respond better to chemotherapy, and usually predict a more favorable prognosis (outcome) than diploid cells.

MYCN gene amplifications: MYCN is an oncogene. Oncogenes are regions of DNA that are important in regulating growth of cells. Alterations of those genes can make cells grow and divide too quickly – features of cancer cells.

Researchers have found that neuroblastomas with too many copies of the MYCN oncogene (amplification) tend to grow more rapidly and mature less. Children whose neuroblastomas have this feature tend to have a worse prognosis than other children with neuroblastoma.

Other markers:

These are also important and may influence a doctor's decision on how to treat a patient with neuroblastoma.

Cytogenetics: In this test, the number of chromosomes in each cell is counted under a microscope, and the abnormalities of any chromosome are described. Normal cells have 46 chromosomes (2 sets of 23), which are made of DNA and protein. Neuroblastomas with normal chromosome numbers tend to be more aggressive than those with extra chromosomes.

Cells that are missing certain parts of chromosomes 1 or 11 (known as "1p deletions" or "11q deletions") may also predict a less favorable prognosis. It is thought that these chromosome parts – missing in many neuroblastoma patients – may contain important tumor suppressor genes, but more studies are needed to verify this. Having an extra part chromosome 17 (17 q gain) is also associated with a worse prognosis; this probably means that there is an oncogene in this part of chromosome 17.

Neurotrophin receptors: These are substances on the surface of normal nerve cells and on some neuroblastoma cells. They recognize hormone-like chemicals that help the nerve cells to mature.

Neuroblastomas with more neurotrophin receptors, especially the nerve growth factor receptor called TrkA, have a more favorable prognosis.

Serum markers: 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 also produced by several types of normal cells as well as by neuroblastoma cells. Increased levels of NSE and LDH in the blood predict a worse outlook for 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 useful in treating neuroblastoma (see "What's New in Neuroblastoma Research and Treatment?").

Risk Groups

These different prognostic factors have been combined with the age of the child and stage of the disease to form 3 different risk groups. These risk groups are used to help predict how easily a child can be cured. A child in a low-risk group would usually be cured with simple treatment, often surgery alone. With children in higher risk groups, more and often more intensive treatment is used. Yet the hope of cure is still less than for children in the low risk group.

Low Risk

• all children who are Stage 1
• any child who is Stage 2A or 2B and younger than age 1
• any child who is Stage 2A or 2B, older than age 1, whose cancer has no extra copies of the MYCN gene
• any child who is Stage 2A or 2B, older than age 1, whose cancer has extra copies of the MYCN gene but has a favorable histology (appearance under the microscope)
• any child who is Stage 4S, whose cancer has favorable histology, is hyperdiploid (excess DNA) and no MYCN amplification

Intermediate Risk

• any child who is Stage 3, younger than age 1, whose cancer has no extra copies of the MYCN gene
• any child who is Stage 3, older than age 1, whose cancer has no extra copies of the MYCN gene and has favorable histology (appearance under the microscope)
• any child who is Stage 4, younger than age 1, whose cancer has no extra copies of the MYCN gene
• any child who is Stage 4S (younger than age 1), whose cancer has no extra copies of the MYCN gene and has normal DNA ploidy (number of chromosomes) or has unfavorable histology

High Risk

• any child who is Stage 2A or 2B, older than age 1, whose cancer has extra copies of the MYCN gene and unfavorable histology (appearance under the microscope)
• any child who is Stage 3, younger than age 1, whose cancer extra copies of the MYCN gene
• any child who is Stage 3, older than age 1, whose cancer has no extra copies of the MYCN gene but has unfavorable histology (appearance under the microscope)
• any child who is Stage 3, older than age 1, whose cancer has extra copies of the MYCN gene
• any child who is Stage 4, younger than age 1, whose cancer has extra copies of the MYCN gene
• any child who is Stage 4 and older than age 1
• any child who is Stage 4s, younger than age 1, whose cancer has extra copies of the MYCN gene

5-year survival rates for these risk groups

The 5-year survival rate refers to the percentage of patients who live at least 5 years after their cancer is diagnosed. Five-year rates are used to produce a standard way of discussing prognosis (the outlook for recovery and survival). Of course, many people live much longer than 5 years.

Survival by risk group: Low-risk children have a 5-year survival of around 95%. Intermediate-risk children's 5-year survival is around 85% to 90%. The 5-year survival of high-risk children is around 30%.

Revised: 08/04/2006