Neuroblastoma in Children – Just Diagnosed

Diagnosing Neuroblastoma

Sympathetic Nervous System

Depending on the location of the tumor and other factors, doctors use different tests to diagnose neuroblastoma. Often these texts include x-rays or other imaging, like CT scans or MRIs, to determine the location and size of the neuroblastoma tumor. In about 90% of neuroblastoma cases, tumor cells produce elevated levels of hormones. The hormones are broken down by the body into acids called HVA and VMA, which are eliminated from the body in the urine. To diagnose neuroblastoma, your child may need to give a urine sample to evaluate HVA and VMA levels. High HVA to VMA ratio may indicate an undifferentiated, unfavorable tumor whereas a high VMA level may represent a more differentiated, less aggressive tumor. In addition, a complete blood count (CBC) and chemistry panel will give more information about kidney and liver function.

Once doctors have located the tumor, they take a biopsy to confirm the diagnosis and to develop the best treatment plan. Doctors will perform surgery to remove either part or the entirety of the tumor. Following surgery, a healthcare team will identify the exact type of tumor and its particular characteristics. These factors are important in determining the best treatment for your child. In some children, neuroblastoma will have spread to the bone marrow by the time of diagnosis. To evaluate your child, the healthcare team will perform a bone marrow aspirate and a bone marrow biopsy on both hips.

Determining Treatment and Risk of Relapse

After your child undergoes testing to identify the extent of tumor present and to learn about the biology or characteristics of the tumor cells, the information gathered will determine the likelihood of a recurrence of disease after treatment. Neuroblastoma is classified as low-, intermediate- or high-risk disease. The risk of relapse of neuroblastoma tumor is determined by the biology of the cancer cells, rather than when the diagnosis is made.

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Factors that Help Determine the Risk for Relapse
  • The age of the child at diagnosis: many children under 18 months have “low risk” or “intermediate risk” disease, and the cancer is less likely to recur in these children.
  • Tumor Histopathology: Histopathology refers to the evaluation of tumor cells under a microscope. A pathologist will determine the type of cells in the tumor and will decide whether the tumor is neuroblastoma or one of the related, but less aggressive related tumors called ganglioneuroblastoma or ganglioneuroma.
  • MYCN Status: MCYN is a gene that is involved in regulation of the growth of some cells, including neuroblasts. Tumor cells are examined to determine the number of copies of the gene within the tumor cell. A single copy (non-amplified) is normal. Multiple copies of the MYCN gene (amplified) are associated with a more aggressive tumor type.
  • DNA Index: The DNA content (ploidy) of a tumor cell is compared to that of a normal cell. Normal cells have a DNA index of 1. A DNA index of more than 1 is associated with a better outcome in some groups of children with neuroblastoma.
  • Chromosomes: Certain consistent changes have been identified in the chromosomes of neuroblastoma tumor cells and their presence can help to determine a risk classification.
  • The stage of the disease: staging refers to the physical location of the primary tumor and the location of any secondary tumors (metastases).

Currently, tumors are categorized by two different systems, the International Neuroblastoma Staging System (INSS) and the newer International Neuroblastoma Risk Group (INRG).

INSS Stages
  • Stage 1: Tumor is confined to one area (localized) and can be completely removed through surgery. Nearby lymph nodes do not contain cancer cells.
  • Stage 2A: Tumor is localized and confined to one side of the body but cannot be completely removed. Nearby lymph nodes do not contain cancer cells.
  • Stage 2B: Tumor is localized and may or may not be completely removed. Nearby lymph nodes show cancer cells. Enlarged lymph nodes on the opposite side of the body do not contain cancer cells.
  • Stage 3: Must meet one of these two criteria:
    • Tumor starts in or crosses the vertical midline of the body (marked by the spine) and cannot be removed surgically. Lymph nodes in the area may or may not contain cancer cells.
    • Tumor is restricted to one side of the body but there are enlarged lymph nodes on the opposite side of the body that contain cancer cells.
  • Stage 4: The primary tumor(s) has spread to distant lymph nodes, bone, bone marrow, liver, skin and/or other organs.
  • Stage 4-S: The “S” stands for “special.” These tumors are unique in that they often disappear on their own (spontaneous regression) without any treatment. Must meet special criteria:
    • Child must be less than 12 months old.
    • Localized primary tumor that has spread only to the skin, lymph nodes or liver. Very small amounts of tumor may be seen in the bone marrow, but the disease cannot involve the outer portion of the bone (cortex).
INRG Stages
  • L1: Localized tumor not involving vital structures as defined by the list of image-defined risk factors. Tumor is confined to one body compartment.
  • L2: Locoregional tumor, which has one or more image-defined risk factors.
  • M: Distant metastatic disease
  • MS: Metastatic disease in children younger than 18 months with metastases confined to skin, liver, and/or bone marrow.

Understanding the risk for relapse is important because there are large differences between the treatments for low-risk, intermediate-risk and high-risk disease. In general, high-risk neuroblastomas are more likely to come back and therefore require stronger treatment than low- or intermediate-risk disease. Stronger treatment selected for high-risk disease has been shown to benefit patients; however, it also has more side effects. Therefore, risk assessment is an essential step in determining appropriate treatment.

International teams of neuroblastoma specialists have developed current treatment plans over several decades to carefully balance the benefits and risks of treatment and the chance that treatment will not be successful. Once your doctor has completed all the necessary tests and has assigned a risk category for your child, focus your attention on that particular risk group’s treatment section.

Risk of Relapse Groups

Low-risk patients have about a 95% probability of survival. Low-risk disease has the following characteristics:

  • Any age with Stage I (completely removed) disease
  • Stage II disease with non-amplified MYCN and > 50% of the tumor is removed by the surgeon
  • Stage IV-S disease with non-amplified MYCN, DNA index >1, favorable histology and without symptoms (asymptomatic patients)

Intermediate-risk patients have a greater than 90% chance of survival. Intermediate-risk disease has the following characteristics:

  • Stage II disease with non-amplified MYCN but < 50% of the tumor was removed
  • Stage III disease in patients < 18 months and non-amplified MYCN
  • Stage III disease in patients > 18 months with non-amplified MYCN and favorable histology
  • Stage IV disease in patients < 12 months with non-amplified MYCN
  • Stage IV disease in patients 12 – 18 months with non-amplified MYCN, favorable histology and DNA index of >1
  • Stage IV-S disease, non-amplified MYCN and either unfavorable histology or a DNA index of 1
  • Stage IV-S disease, non-amplified MYCN, DNA index >1, favorable histology and with symptoms (symptomatic patients)

High-risk patients have a 40% chance of survival with current therapy. High-risk disease has the following characteristics:

  • Stage II, III, IV or IV-S disease with amplified MYCN
  • Stage III disease in patients > 18 months with unfavorable histology
  • Stage IV disease in patients 12 – 18 months with any one of the following: non-amplified MYCN, unfavorable histology or DNA index=1
  • Stage IV disease in patients >18 months

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