Neuroblastoma

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Early Detection, Diagnosis, and Staging TOPICS

How is neuroblastoma staged?

The stage of a cancer describes how far it has spread. Your child’s treatment and prognosis (outlook) depend, to a large extent, on the cancer’s stage.

The stage of the neuroblastoma is based on results of physical exams, imaging tests, and biopsies of the main tumor and other tissues (which were described in the section, “How is neuroblastoma diagnosed?”). The results of surgery are sometimes used in staging as well.

For neuroblastoma, several other factors also affect prognosis, including a child’s age and certain tests of blood and tumor specimens. These prognostic factors are not used to determine the stage of the cancer, but they are used along with the stage to determine which risk group a child falls into, which in turn affects treatment options. These prognostic factors and risk groups are also described below and in the “Risk groups” section.

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 Staging System

A staging system is a standard way for the cancer care team to sum up the extent of the cancer. Since the mid-1990s, most cancer centers have used the International Neuroblastoma Staging System (INSS) to stage neuroblastoma. This system takes into account the results of surgery to remove the tumor. 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 that the cancer has spread to 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.

International Neuroblastoma Risk Group Staging System

A risk-group staging system now coming into use is known as the International Neuroblastoma Risk Group Staging System (INRGSS). It is similar to the INSS, but it does not use the results of surgery to help define the stage. This lets doctors determine a stage before surgery, based on the results of imaging tests (usually a CT or MRI scan, and an MIBG scan), as well as exams and biopsies. 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: 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 body compartment, 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.

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. 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.

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. Ploidy is not as useful a factor 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 are less likely to mature. Children whose neuroblastomas have this feature tend to have a worse prognosis than other children with neuroblastoma.

Other markers

These markers are not used to help determine risk groups at this time, but they are still important and may influence the treatment of a child with neuroblastoma.

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. It is thought that these chromosome parts, which are missing in many neuroblastomas, may contain important tumor suppressor genes, but more studies are needed to verify this.

Having an extra part of chromosome 17 (17q gain) is also linked with a worse prognosis. This probably means that there is an oncogene in this part of chromosome 17.

Understanding the importance of chromosome deletions/gains is an active area of 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 markers: 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 the section, “What’s new in neuroblastoma research and treatment?”).


Last Medical Review: 03/14/2014
Last Revised: 03/17/2014