All About Neuroblastoma

What is neuroblastoma?

Neuroblastoma is a tumor that usually involves nerve tissue. Neuroblastoma starts in very early forms of nerve cells, often in an unborn child. “Neuro” means nerves, and “blastoma” is a cancer that affects early forms of cells.

Neuroblastoma often starts in the abdomen (from the adrenal glands, which sit on top of the kidneys), but can also start in the neck, chest, or pelvis. Neuroblastoma does have the ability to spread, usually to the lymph nodes, liver, lungs, bones, or bone marrow.

What causes neuroblastoma and who is at risk?

Neuroblastoma is the most common non-brain solid pediatric tumor. It makes up about 6% of all cancers in children. There are about 800 new cases of neuroblastoma each year in the United States.

At this time, there are no known risk factors linked to lifestyle choices or environmental factors of mom or baby. Two risk factors of neuroblastoma are:

• Age: Neuroblastoma most often affects infants and young children. Most neuroblastoma cases are diagnosed in children younger than 5 years of age. It is rarely found in children older than 10 years. Sometimes the tumor is present at birth but not found until later, when it has grown bigger and/or starts to cause symptoms.
• Heredity/Genetics: About 1-2% of neuroblastoma cases are thought to come from a gene that is passed down from a parent to the baby. If this is the case, there are probably other family members who had neuroblastoma when they were young.

How can neuroblastoma be prevented in a child?

Children who are diagnosed with neuroblastoma often do not have any risk factors. Sometimes, neuroblastoma starts even before the child is born. Because of this there is no way to prevent neuroblastoma.

What screening tests are used?

There are no recommended screening tests for childhood cancer. A child won't be tested for neuroblastoma unless they are showing signs or symptoms of the disease.

What are the signs and symptoms?

Signs and symptoms of neuroblastoma depend on the location of the tumor. Symptoms occur when the tumor grows and puts pressure on nearby organs or within bone.

• An abdominal (belly) tumor may cause belly pain, nausea, vomiting, and/or constipation.
• Tumors in or around bones and bone marrow can cause diffuse (all over) bony pain or pain in a specific bone or joint. Parents of young children who cannot yet speak may note that a child with neuroblastoma has started refusing to walk. This may be due to pain with walking.
• If the tumor is near the orbit of the eyes, the child may have bulging eyes and dark circles under the eyes ("raccoon eyes").
• General signs or symptoms may include fever, weight loss, and anemia.
• Occasionally, neuroblastoma tumors may release hormones and neurotransmitters that can cause high blood pressure, severe watery diarrhea, jerky muscle spasms, and/or uncontrollable eye movement (a syndrome called "opsoclonus/myoclonus" or "dancing eyes/dancing feet”).

How is neuroblastoma diagnosed?

Although rare, there are a few reports of neuroblastoma cases that are found incidentally (by chance) before birth by fetal ultrasound. More commonly, neuroblastoma is diagnosed after symptoms such as the above are noted. If a provider thinks that a child could have neuroblastoma, the first step is for the provider to perform a thorough physical. The provider may ask the child about how they are feeling and what symptoms they have been having. Along with a physical exam and history, the provider will order other tests which may include:

• Urine test- 90% of neuroblastomas make hormones called catecholamines (which are normally only made by the adrenal gland). These can be found in the urine.
• Computed tomographic (CT) scan.
• Magnetic resonance imaging (MRI).
• Biopsy- a definitive diagnosis of neuroblastoma requires a tissue sample. A tissue biopsy from the tumor and/or bone marrow is obtained. A biopsy is a small sample of the tumor tissue that is surgically removed and looked at under a microscope. It can sometimes be done by making a small hole and using a needle to remove a sample of the tissue.

Once the diagnosis of neuroblastoma is made, a bone marrow biopsy and other scans will be done to see if the tumor has spread. The I-123 MIBG scan is a nuclear medicine study that is used to stage and evaluate neuroblastoma. It uses a radioactive tracer (metaiodobenzylguanidine, or MIBG) that is specifically taken up by neuroblastoma cells. It may help find hidden pieces of tumor using a special type of camera that can detect the MIBG.

How is neuroblastoma staged?

Staging refers to where the neuroblastoma tumor is and if it has spread to anywhere else in the body. Knowing the stage of neuroblastoma can help the provider choose which treatment will work best. There are two main staging systems the provider may use: The International Neuroblastoma Staging System Committee (INSS) system, and the International Neuroblastoma Risk Group Staging System (INRGSS).

Which staging system your provider uses will depend on if your child has had surgery or not. The INSS, developed in 1988, uses results from surgery to stage neuroblastoma. The INRGSS, developed in 2009, is based on pre-surgery imaging results, like CT scans and MRIs.

Staging for neuroblastoma is complex. Be sure to talk with the care team about your child’s staging and treatment plan.

The two different staging systems are below:

International Neuroblastoma Staging System Committee (INSS) system (1988)

Stage 1: The tumor can be removed completely during surgery. Lymph nodes attached to the tumor removed during surgery may or may not contain cancer, but other lymph nodes near the tumor do not.

Stage 2A: The tumor is located only in the area it started and cannot be completely removed during surgery. Nearby lymph nodes do not contain cancer.

Stage 2B: The tumor is located only in the area where it started and may or may not be completely removed during surgery, but nearby lymph nodes do contain cancer.

Stage 3: The tumor cannot be removed with surgery. It has spread to regional lymph nodes (lymph nodes near the tumor) or other areas near the tumor, but not to other parts of the body.

Stage 4: The original tumor has spread to distant lymph nodes (lymph nodes in other parts of the body), bones, bone marrow, liver, skin, and/or other organs, except for those listed in stage 4S, below.

Stage 4S: The original tumor is located only where it started (as in stage 1, 2A, or 2B), and it has spread only to the skin, liver, and/or bone marrow, in infants younger than one. The spread to the bone marrow is minimal, usually less than 10% of cells examined show cancer.

The International Neuroblastoma Risk Group Staging System (INRGSS)

Stage L1: The tumor is located only in the area where it started; no IDRFs (image defined risk factors) are found on imaging scans, such as CT or MRI.

Stage L2: The tumor has not spread beyond the area where it started and the nearby tissue; IDRFs are found on imaging scans, such as CT or MRI.

Stage M: The tumor has spread to other parts of the body (except stage MS, see below)

Stage MS: The tumor has spread to only the skin, liver, and/or bone marrow (less than 10% bone marrow involvement) in patients younger than 18 months.

The INRGSS also uses certain risk factors to make a treatment plan and predict how a child might respond to the treatment. These risk factors are broken down into risk groups. The results of the risk groups will define how your child is likely to respond to treatment. These risk groups are defined as very low-risk, low-risk, intermediate-risk, or high-risk. Talk with your child’s care team about the risk factors of your child.

How is neuroblastoma treated?

Because neuroblastoma is relatively rare, it is best treated at a facility by providers who have experience.

Treatment for neuroblastoma will depend on many factors, including the age of the child, where the tumor is, the symptoms the child is having, the risk classification, and the goals of treatment. More than one treatment may be used.

Observation

There have been studies of infants less than 6 months of age who have neuroblastoma that is localized to one part of the body. By observing them closely with imaging, physical exams, and lab tests, the majority of the tumors disappeared without treatment. If the tumor was still there, the infants then had surgery, with or without chemotherapy.

Surgery

Surgery may be done to remove the tumor and some surrounding healthy tissue. If the cancer has not spread, the whole tumor may be able to be removed (resected). Most neuroblastomas, however, are not found until after they have already spread. Even if the tumor cannot be removed because of its location, surgery may be done to remove a piece of the tissue for biopsy.

If the tumor cannot be completely removed, radiation therapy and/or chemotherapy may be used.

Chemotherapy

Most children with neuroblastoma will need to have chemotherapy. Chemotherapy may be used as the main treatment for neuroblastoma. It can also be given before surgery to shrink the tumor or after surgery to kill any remaining cancer cells.

These are some of the chemotherapy medications used to treat neuroblastoma: Carboplatin (Paraplatin), Cyclophosphamide (Neosar), Doxorubicin (Adriamycin), Etoposide (Toposar, VePesid, Etopophos, VP-16), Busulfan (Busulfex, Myleran), Carboplatin (Paraplatin), Cisplatin (Platinol), Cyclophosphamide (Neosar), Cytokines (GM-CSF and IL2), Dinutuximab (Unituxin), and Ifosfamide (Ifex).

Radiation Therapy

Radiation is the use of high energy x-rays to kill cancer cells. Most children with neuroblastoma will not need radiation therapy. It may be used when there are life-threatening side effects of neuroblastoma that would be relieved with radiation to shrink the tumor. It is also sometimes used after stem cell transplant, discussed below. The most common radiation therapy used is photon therapy, but some children may benefit from proton therapy. Proton therapy has been used for neuroblastoma at some specialized centers. Talk with the care team about your child’s treatment options.

Stem Cell Transplant

A stem cell transplant, also called a bone marrow transplant, is used to treat some cases of neuroblastoma. Very high doses of chemotherapy are given, which kills off the body’s own blood cells. Then the body is "rescued" with new stem cells which will begin to form new blood cells. The stem cells can either come from blood, bone marrow, or a baby's umbilical cord blood.

There are two different types of stem cell transplants. An allogenic stem cell transplant (“allo”) uses cells from a donor. The donor's tissue type is tested to make sure it is a match for the patient. An autologous transplant (“auto”) uses the patient's own healthy stem cells. An autologous transplant is most often used for children with high-risk neuroblastoma.

The process starts when a child is given very high doses of chemotherapy and sometimes whole body radiation. The goal is to get rid of any cancer cells in the body but it also severely weakens the immune system. Stem cells are then infused into the child's body to help rebuild the immune system with the hopes of stopping cancer cells from growing. There are a number of possibly severe side effects. This treatment requires a long hospital stay in a facility equipped to take care of patients who have had transplants.

Retinoid Therapy

Retinoids are chemicals that are similar to Vitamin A. They are thought to help neuroblastoma cells mature into normal cells. Some retinoids are still being studied, but one that is currently being used is 13-cis-retinoic acid (isotretinoin). In children with high risk neuroblastoma, isotretinoin has lowered the chances of neuroblastoma coming back after a stem cell transplant.

Immunotherapy

Immunotherapy medications use the body's own immune system to kill cancer cells. There are studies ongoing looking at how immunotherapy can be used in treatment of neuroblastoma. One medication that has shown promise in children with high risk neuroblastoma, often after a stem cell transplant, is dinutuximab. Dinutuximab is a type of immunotherapy called a monoclonal antibody. It attaches to GD2, a compound found on many neuroblastoma cells. Sometimes dinutuximab is given in combination with cytokines, which are hormones released by the immune system. Together, this mix targets neuroblastoma cells and kills them.

Talk with your child's care team about possible treatment options. Ask about any possible late or longterm side effects of each type of treatment. Read through a list of possible longterm side effects caused by pediatric cancer treatments at OncoLink.

Clinical Trials

There are clinical research trials for most types of cancer, and every stage of the disease. Clinical trials are designed to determine the value of specific treatments. Trials are often designed to treat a certain stage of cancer, either as the first form of treatment offered, or as an option for treatment after other treatments have failed to work. They can be used to evaluate medications or treatments to prevent cancer, detect it earlier, or help manage side effects. Clinical trials are extremely important in furthering our knowledge of disease. It is through clinical trials that we know what we do today, and many exciting new therapies are currently being tested. Talk to your provider about participating in clinical trials in your area. You can also explore currently open clinical trials using the OncoLink Clinical Trials Matching Service

Follow-up Care and Survivorship

After treatment for childhood cancer, the patient will be followed closely to monitor for the cancer coming back, to help them heal from ongoing side effects, and to help them to transition to survivorship. Initially they will be seen often and have ongoing tests to monitor their health. As time goes on, these visits and testing will become less frequent. The oncology team will discuss each patient’s individual follow up plan with them.

Survivors often wonder what steps they can take to live healthier after cancer. There is no supplement or specific food you can eat to assure good health, but there are things you can do to live healthier, prevent other diseases, detect any subsequent cancers early and work with the social and emotional issues, including insurance, employment, relationships, sexual functioning, and fertility, that a prior cancer diagnosis sometimes brings with it. Your oncology team is there to support you and can help you find support resources.

It is important to have a plan for who will provide your cancer-focused follow up care (an oncologist, survivorship doctor or primary care doctor). Talk with your oncology team about developing a survivorship care plan. If you would like to find a survivorship doctor to review your history and provide recommendations, you can contact cancer centers in your area to see if they have a survivor's clinic or search for a clinic on OncoLink's survivorship clinic list.

References for Further Reading

Neuroblastoma – from the American Cancer Society

Neuroblastoma in Children – from CureSearch

Neuroblastoma – from the National Cancer Institute