Overview of Neuroblastoma

As one of the most common types of cancer in infancy, neuroblastoma is a cancer which is found in young children. The tumor begins in neuroblasts (immature nerve cells) of the central nervous system.

In particular, neuroblastoma involves nerve cells that are part of the sympathetic nervous system. The sympathetic and parasympathetic nervous systems are both parts of the autonomic nervous system, a system which controls processes in the body that we don't ordinarily need to think about such as breathing and digestion. The sympathetic nervous system is responsible for the "fight or flight" reaction which occurs when we are stressed or frightened.

The sympathetic nervous system has areas referred to as ganglia, that are located at different levels of the body. Depending on where in this system a neuroblastoma begins, it may start in the adrenal glands (roughly a third of cases), the abdomen, the pelvis, the chest, or the neck.

Statistics

Neuroblastoma is a common childhood cancer, accounting for 7% of cancers under the age of 15, and 25% of cancers that develop during the first year of life. As such, it is the most common type of cancer in infants. It is slightly more common in males than females. Around 65% of neuroblastomas are diagnosed before the age of 6 months, and this type of cancer is rare after the age of 10. Neuroblastoma is responsible for roughly 15% of cancer-related deaths in children.

Signs and Symptoms

The signs and symptoms of a neuroblastoma can vary depending on where in the body they arise as well as whether or not the cancer has spread to other regions.

The most common presenting sign is of a large abdominal mass. A mass may also occur in other regions where ganglia are present such as the chest, pelvis, or neck. A fever may be present and children may have suffered from weight loss or "failure to thrive."

When the cancer has spread (most commonly to the bone marrow, liver, or bones) other symptoms may be present. Metastases behind and around the eyes (periorbital metastases) may cause an infant's eyes to bulge out (proptosis) with dark circles under her eyes. Metastases to the skin can cause bluish black patches (ecchymoses) which has given rise to the term "blueberry muffin baby." Pressure on the spine from bone metastases can result in bowel or bladder symptoms. Metastases to long bones often cause pain and can result in pathological fractures (fracture of a bone that is weakened due to the presence of cancer in the bone).

Where Neuroblastomas Spread (Metastasize)

Neuroblastomas can spread from the primary site via either the bloodstream or the lymphatic system. The areas of the body to which it spreads most commonly include:

• Bones (causing bone pain and limping)
• Liver
• Lungs (causing shortness of breath or breathing difficulty)
• Bone marrow (resulting in pallor and weakness due to anemia)
• Periorbital region (around the eyes causing bulging)
• Skin (causing the blueberry muffin appearance)

Diagnosis

The diagnosis of neuroblastoma usually includes both blood tests looking for markers (substances that the cancer cells secrete) and imaging studies.

As part of the sympathetic nervous system, neuroblastoma cells secrete hormones known as catecholamines. These include hormones such as epinephrine, norepinephrine, and dopamine. The substances most often measured in making a diagnosis of neuroblastoma include homovanillic acid (HVA) and vanillylmandelic acid (VMA). HVA and VMA are metabolites (breakdown products) of norepinephrine and dopamine.

Imaging tests done to evaluate a tumor (and to look for metastases) may include CT scans, MRIs and PET scan. Unlike CT and MRI which are "structural" studies, PET scans are "functional" studies. In this test, a small amount of radioactive sugar is injected into the bloodstream. Rapidly growing cells, such as tumor cells, take up more of this sugar and can be detected with imaging.

A bone marrow biopsy is usually done as well since these tumors commonly spread to bone marrow.

A test unique for neuroblastomas is the MIBG scan. MIBG stands for meta-iodobenzylguanidine. Neuroblastoma cells absorb MIBG which is combined with radioactive iodine. These studies are helpful in evaluating bone metastases as well as bone marrow involvement.

Another test which is often done is an MYCN amplification study. MYCN is a gene important for cell growth. Some neuroblastomas have excess copies of this gene (more than 10 copies), a finding referred to as "MYCN amplification." Neuroblastomas with MYCN amplification are less likely to respond to treatments for neuroblastoma and are more likely to metastasize to other regions of the body.

Neuroblastoma Screening

Since levels of urine vanillylmandelic acid and homovanillic acid are fairly easy to obtain and abnormal levels are present in 75 to 90 percent of neuroblastomas, the possibility of screening all children for the disease has been debated.

Studies have looked at screening with these tests, usually at 6 months of age. While screening does pick up more children with early stage neuroblastoma, it does not appear to have any effect on the mortality rate for the disease and is not currently recommended.

Staging

As with many other cancers, neuroblastoma is divided between stages I and IV depending on the degree of spread of the cancer. The International Neuroblastoma Staging System Committee (INSS) system developed in 1988 contains the following stages:

• Stage I – In stage I disease the tumor is localized, though it may have spread to nearby lymph nodes. In this stage, the tumor may be removed in full during surgery.
• Stage II – The tumor is confined to the area in which it began and nearby lymph nodes may be affected, but the tumor can’t be removed entirely with surgery.
• Stage III – The tumor cannot be removed surgically (is unresectable). It may have spread to nearby or to regional lymph nodes, but not to other regions of the body.
• Stage IV – Stage IV includes any tumor of any size with or without lymph nodes which has spread to the bone, bone marrow, liver, or skin.
• Stage IV-S – A special classification of stage IV-S is made for tumors which are localized, but despite this have spread to the bone marrow, skin or liver in infants less than one year of age. The bone marrow may be involved, but the tumor is present in less than 10 percent of the bone marrow.

Roughly 60% to 80% of children are diagnosed when the cancer is stage IV.

The International Neuroblastoma Risk Group Staging System (INRGSS)

The International Neuroblastoma Risk Group Staging System (INRGSS )was designed specifically by the International Neuroblastoma Risk Group (INRG) in order to assess, pre-treatment, the "risk" of the cancer, in other words, how likely the tumor is to be cured.

Using this system, tumors are classified as high risk or low risk, which helps to guide treatment.

Causes and Risk Factors

Most children with neuroblastoma do not have a family history of the disease. That said, genetic mutations are thought to be responsible for around 10% of neuroblastomas.

Mutations in the ALK (anaplastic lymphoma kinase) gene are a major cause of familial neuroblastoma. Germline mutations in PHOX2B have been identified in a subset of familial neuroblastoma.

Other possible risk factors which have been proposed include parental smoking, alcohol use, some medications during pregnancy and exposure to certain chemicals, but at this time it is uncertain whether these play a role or not.

Treatments

There are several treatment options for neuroblastoma. The choice of these will depend on whether surgery is possible and other factors. Whether or not the tumor is "high risk" according to INCRSS also plays a role in the choice of treatments, and choices are usually made based on whether the tumor is high risk or low risk. Options include:

• Surgery – Unless a neuroblastoma has spread (stage IV), surgery is usually done to remove as much of the tumor as possible. If surgery is unable to remove all of the tumor, additional treatment with chemotherapy and radiation is usually recommended.
• Chemotherapy – Chemotherapy involves the use of drugs that kill off rapidly dividing cells. As such, it can result in side effects due to its effects on normal cells in the body which divide rapidly such as those in the bone marrow, hair follicles, and digestive tract. Chemotherapy drugs commonly used to treat neuroblastoma include Cytoxan (cyclophosphamide), Adriamycin (doxorubicin), Platinol (cisplatin), and etoposide. Additional drugs are usually used if the tumor is considered high risk.
• Stem cell transplant - High-dose chemotherapy and radiation therapy followed by stem cell transplant is another option for treatment. These transplants may be either autologous (using the child's own cells that are withdrawn prior to chemotherapy) or allogeneic (using cells from a donor such as a parent or an unrelated donor).
• Other treatments – For tumors which recur, other categories of treatments which may be considered include retinoid therapy, immunotherapy, and targeted therapy with ALK inhibitors and other treatments, such as using compounds taken up by neuroblastoma cells attached to radioactive particles.

Spontaneous Remission

A phenomenon referred to as spontaneous remission may occur, especially for those children who have tumors that are less than 5 cm (2 1/2 inches in size,) are stage I or stage II, and are less than a year of age.

Spontaneous remission occurs when the tumors "disappear" on their own without any treatment. While this phenomenon is rare with many other cancers, it isn't uncommon with neuroblastoma, either for primary tumors or metastases. We aren't certain what causes some of these tumors to just go away, but it is likely related to the immune system in some way.

Prognosis

The prognosis of neuroblastoma can vary tremendously among different children. Age at diagnosis is the number one factor that affects prognosis. Children that are diagnosed before the age of one have a very good prognosis, even with the advanced stages of neuroblastoma.

Factors which are associated with the prognosis of neuroblastoma include:

• Age at diagnosis
• Stage of the disease
• Genetic findings such as ploidy and amplification
• The expression by the tumor of certain proteins

Finding Support

Someone once said that the only thing worse than having cancer yourself is to have your child face cancer, and there is much truth to that statement. As parents, we want to spare our children pain. Fortunately, the needs of parents of children with cancer have received a lot of attention in recent years. There are many organizations designed to support parents who have children with cancer, and there are many in-person and online support groups and communities. These groups allow you to talk with other parents who are facing similar challenges and get the support that comes from knowing you aren't alone. Take a moment to check out some of the organizations which support parents who have a child with cancer.

It's important to mention siblings as well—kids who are coping with the emotions of having a sibling with cancer while often having much less time with their parents. There are support organizations and even camps designed to meet the needs of children facing what most of their friends would be unable to understand. CancerCare has resources for helping the siblings of a child with cancer. SuperSibs is dedicated to comforting and empowering children who have a sibling with cancer and has several different programs to meet the needs of these children. You may also wish to check out the camps and retreats for families and children affected by cancer.

A Word From Verywell

Neuroblastoma is the most common type of cancer in children during their first year of life but is rare later in childhood or adulthood. Symptoms often include finding a mass in the abdomen, or symptoms such as a "blueberry muffin" rash.

A number of treatment options are available both for neuroblastomas that have just been diagnosed or those that have recurred. The prognosis depends on many factors, but survival is highest when the disease is diagnosed in the first year of life, even if it has spread widely. In fact, some neuroblastomas, especially those in young infants, spontaneously disappear without treatment.

Even when the prognosis is good, a neuroblastoma is a devastating diagnosis for parents, who would much rather have the diagnosis themselves than to have their children face cancer. Fortunately, there has been tremendous research and advances in the treatment of childhood cancers in recent years, and new treatment approaches are being developed every year.