Neuroblastoma

What is Neuroblastoma?

Neuroblastoma is a type of cancer that grows from immature nerve cells called neuroblasts. It is the most common solid tumor that occurs outside the brain in children.

Neuroblastoma can occur anywhere along the sympathetic nervous system (SNS). Neuroblastoma most often occurs in the abdomen and frequently develops in nerve tissue of the adrenal glands which are located on top of the kidneys. It can also occur in nerve tissue in the neck, chest, or pelvis.

Graphic of a toddler with layover of organs with adrenal glands and kidney highlighted and labeled — Neuroblastoma most often occurs in the abdomen and frequently develops in nerve tissue of the adrenal glands which are located on top of the kidneys.

Neuroblasts are cells that grow very early in fetal development as a baby begins to form inside the mother. These cells mature to become nerve cells of the sympathetic nervous system (SNS). Sometimes, neuroblasts do not develop normally and can form tumors. Neuroblastoma tumors are usually found along the main pathway of the sympathetic nervous system located on either side of spinal cord and in the adrenal glands.

Neuroblastoma is usually diagnosed in young children under 5 years of age. It is the most common tumor in infants. Neuroblastoma accounts for 50% of cancers in infants and 7-10% of all childhood cancers. About 650 children are diagnosed with neuroblastoma in the United States each year.

Symptoms of neuroblastoma depend on the location of the tumor but may include a lump or mass, pain in the abdomen, loss of appetite, and irritability. Often, neuroblastoma has spread to other parts of the body by the time it is diagnosed.

Treatment for neuroblastoma depends on the stage of disease (how much cancer has spread from the main tumor). Some children can be treated with surgery alone. Patients with more severe disease require intense treatment including surgery, chemotherapy, radiation therapy, and/or immunotherapy.

Risk Factors and Causes of Neuroblastoma

Certain factors may increase risk for neuroblastoma. Neuroblastoma is most often seen in young children and occurs slightly more often in males compared to females.

A small number of patients (1-2%) have hereditary neuroblastoma. This type of neuroblastoma can be passed down in families. Hereditary neuroblastoma is most commonly caused by a change, or mutation, in the ALK or PHOX2B gene. Children with hereditary neuroblastoma have a 50% chance of passing the disease on to their children.

Learn More About Hereditary Neuroblastoma

Signs and Symptoms of Neuroblastoma

Signs and symptoms of neuroblastoma depend on where the tumor is located and the age of the child. These may include:

Lump in the neck, chest, or abdomen
Bulging eyes or dark circles around the eyes
Stomach pain
Irritability
Decreased appetite
Constipation
Leg weakness

Other symptoms of neuroblastoma may include chronic diarrhea, change in eye movement, high blood pressure, headache, cough, difficulty breathing, fever, bruising, or Horner syndrome.

Some neuroblastoma patients may develop Horner syndrome. This disorder occurs when nerves around the eye are damaged. Features of the syndrome include eyelid drooping, constricted pupil, and loss of sweating on one side of the face. Learn more about Horner syndrome.

Tumor Location	Symptoms
Eye	Bulging eye, dark circles (“raccoon eyes”), blindness, Horner syndrome
Neck	Lump or swelling, Horner syndrome
Abdomen	Lump, loss of appetite, vomiting, constipation
Pelvis	Change in toileting behavior; bowel or bladder problems
Spinal	Weakness, paralysis

Diagnosis of Neuroblastoma

Several types of procedures and tests are used to diagnose neuroblastoma. These include:

A health history and physical exam to learn about symptoms, general health, past illnesses, family history, and other risk factors.
Lab studies to look at substances in blood and urine. These may include a complete blood count and measures of kidney and liver function.

In neuroblastoma, doctors will test the urine for vanillylmandelic acid (VMA) and homovanillic acid (HVA). These substances are produced by the breakdown of hormones of the sympathetic nervous system called catecholamines. Catecholamines are secreted by neuroblasts. Therefore, high levels of these chemicals are often seen in children with neuroblastoma. These substances may also be used to monitor response to treatment.

A neurological exam to measure different aspects of brain and nerve function including memory, vision, hearing, muscle strength, balance, coordination, and reflexes.
Imaging tests to look for tumors and help determine other tests and treatment.
- X-ray uses electromagnetic energy to take pictures of different areas of the body such as the chest and abdomen.
- Ultrasound or ultrasonography uses sound waves to create an image of body tissues.
- Computed tomography (CT or CAT scan) uses X-rays to create cross-sectional images of the organs and tissues inside the body. The machine takes many pictures to make a very detailed image. The images are taken as a series of “slices” of the body and are put together by a computer. These slices or sections can allow very small tumors to be seen.
- Magnetic resonance imaging (MRI) makes detailed pictures of the body using radio waves and magnets. The images can help doctors get a better view of the tumor and plan treatment.
- Full body imaging including a bone scan, PET scan, or MIBG scan is used to look for disease in other areas of the body.

Neuroblastoma shown in an MIBG scan image.

Whole body MIBG scan from the front, or anterior, view of a neuroblastoma patient.

The letters MIBG stand for meta-iodobenzylguanidine, a protein that is absorbed by most neuroblastoma cells. Patients receive an injection of a tracer which contains MIBG. A special camera creates images of the body and highlights where MIBG is taken up by cells. The scan can show neuroblastoma cells throughout the body.

Bone marrow aspiration and biopsy to see if there are cancer cells in the bone marrow. Doctors will obtain bone marrow samples by inserting a thin, hollow needle into the hipbone. A pathologist views the sample under a microscope.
A biopsy of the tumor is often needed to make a correct diagnosis. In a biopsy, the doctor removes a small amount of tissue from the tumor. The cells are then examined with a microscope to look for signs of cancer. An incisional biopsy or core needle biopsy may be used depending on tumor location.

The tumor will be studied to look for features that are important to the diagnosis and treatment of neuroblastoma. Some neuroblastoma tumors are more aggressive and require more intense therapy. Doctors can predict how the tumor might respond to treatment by how the cells look and whether there are certain gene changes in the tumor.

Staging of Neuroblastoma

In neuroblastoma, there are several ways the disease can be classified.

The International Neuroblastoma Staging System (INSS) stages neuroblastoma based on tumor location, spread of disease, and result of surgery.

Stage	Spread of disease
Stage I	The tumor is limited to one area and is completely removed by surgery.
Stage II	2A: The tumor is is only one area but is not completely removed by surgery. 2B: The tumor may be completely removed by surgery, but cancer cells are found in nearby lymph nodes.
Stage III	The tumor cannot be completely removed by surgery, and there is spread of disease to the other side of the body in lymph nodes or other tissue. If the tumor is along the midline (center) of the body, there is spread to lymph nodes or tissue to both sides.
Stage IV	4: The tumor has spread to distant lymph nodes, bone, bone marrow, liver, skin and/or other organs 4S: The child is under 1 year of age. The original tumor is located only where it started (Stage 1 or 2). The tumor has only spread to skin, liver, or bone marrow (small amounts). Bone marrow involvement is usually less than 10%.

The International Neuroblastoma Risk Group Staging System (INRGSS) stages cancer without using the results of surgery. This system is based on tumor location and spread of disease. Imaging tests are used to determine the stage based on image defined risk factors (a prediction of how risky it would be to remove the tumor).

Stage	Spread of disease
Stage L1 Localized	The tumor has not spread from where it began. It has not grown into vital structures. It is limited to one body compartment such as the neck, chest, abdomen, or pelvis.
Stage L2 Localized	Imaging tests show the presence of one or more image defined risk factors. The tumor may have spread to nearby structures or be found in two body compartments.
Stage M Metastatic	The tumor has spread to distant parts of the body. This includes all metastatic disease except tumors classified as MS.
Stage MS Metastatic	For children under 18 months of age: Metastic disease that is limited to the skin, liver, and/or only a small amount of bone marrow.

Neuroblastoma risk groups

Doctors also use risk groups to classify neuroblastoma and plan treatments. High risk means the tumor is more likely to come back. Patients with high risk neuroblastoma need more intense therapy.

Factors that determine risk group include:

Age of the patient
Stage of disease
Characteristics of the tumor

Learn more about Risk of Relapse Groups from the Children’s Oncology Group.

Biological and histological features of neuroblastoma tumors influence treatment outcomes. Certain genetic features of the tumor including MYCN gene amplification are associated with higher risk. Tumor histology, or the way cells look under a microscope, also influences risk.

Identified risk factors include:

Age
Stage
Tumor histology
MYCN status
Tumor chromosomes
DNA Index – a measure of DNA content in a tumor cell compared to DNA content in a normal cell

Prognosis for Neuroblastoma

The chance of recovery from neuroblastoma depends on several factors:

Child’s age at diagnosis (younger age is associated with better outcomes)
Features of the tumor including histology, gene changes, and how fast the cells grow
Risk group: Low, Intermediate, or High
Location of the tumor
Whether the cancer has spread to lymph nodes or other parts of the body (metastatic)
The ability of surgery to completely remove the tumor
How the tumor responds to treatment
If the cancer is recurrent (has come back) and how much time has passed before recurrence

Treatment of Neuroblastoma

Treatment for neuroblastoma depends on the child’s age, location of the tumor, features of the tumor (gene changes and histology), and stage of disease. These factors help determine neuroblastoma risk group (low, intermediate, or high) and treatment plans.

Treatment options for neuroblastoma include:

Observation
Surgery
Chemotherapy
High-dose chemotherapy with stem cell rescue
Immunotherapy
Radiation therapy

Very young, low risk patients may be followed with observation instead of active treatment. In certain cases, neuroblastoma may go away on its own (regression). However, this is rare, and patients will be monitored very closely to watch for tumor progression.

Surgery is used to remove the cancer when possible. A small amount of tissue around the tumor may be removed in an effort to leave little to no cancer behind. Patients with single tumors that have not spread may be treated with surgery alone. However, it may not be possible to remove the tumor completely, especially in metastatic neuroblastoma. In these cases, additional treatment is needed.
Chemotherapy (“chemo”) is a main treatment for neuroblastoma, particularly in intermediate and high risk disease. These medicines kill cancer cells or stop them from growing and making new cancer cells. More than one type of medicine will be used to treat the cancer. Most chemotherapy is given through injections but some chemotherapy may be given by mouth. In higher risk disease, chemotherapy is usually given before surgery to make the tumor smaller. Chemotherapy is often also given after surgery to remove any remaining cancer cells and to help keep the tumor from coming back.

Chemotherapy drugs often used in neuroblastoma include carboplatin, cyclophosphamide, doxorubicin, etoposide, topotecan, cisplatin, and vincristine.
High-dose chemotherapy with stem cell transplant is often used as a treatment for high-risk metastatic disease. In this treatment, stem cells are collected from patients in the beginning stages of treatment and stored for future transplant. After initial treatments (usually chemotherapy and surgery), very high doses of chemotherapy are given to kill remaining cancer cells. The patient then receives an infusion of the stem cells to rescue their bone marrow cells from this very high dose (‘myeloablative’) therapy.
Radiation therapy is often used to treat high risk neuroblastoma in combination with other treatments. Because these tumors often involve important organs, structures, and blood vessels, they often cannot be completely removed by surgery. Therefore, radiation is given to kill remaining cancer cells at the site of the main tumor and to treat metastatic disease.
Immunotherapy is being studied in the treatment of neuroblastoma. Monoclonal antibody therapy uses special proteins that attach to cancer cells. Immune cells are then able recognize and kill the cancer cell.

Children may be offered treatment for neuroblastoma as part of a clinical trial.

Neuroblastoma treatments are planned according to risk groups:

Risk Category	% of New Patients	Main Treatments	Prognosis
Low Risk	40%	Observation Surgery	>95% Survival
Intermediate Risk	15%	Surgery Chemotherapy	>90% Survival
High Risk	45-50%	Surgery Chemotherapy High-dose chemotherapy with stem cell rescue Immunotherapy Radiation therapy	<60% Survival

Life After Neuroblastoma

Monitoring for recurrence

Patients with high risk disease are at greater risk for relapse. In patients with low-risk disease, chance of recurrence is 5-15%. However, for high-risk patients, risk of relapse is as high as 50%. Recurrence in neuroblastoma is most common within the first 2 years after treatment ends. Relapse is rare when there is no evidence of cancer after 5 years of completing treatment.

Patients will receive frequent follow-up care to screen for recurrence after treatment ends. The medical team will make specific recommendations for frequency and types of tests needed.

Health after cancer

Survivors treated with systemic chemotherapy or radiation should be monitored for acute and late effects of therapy. Potential problems due to treatment may include hearing loss, heart problems, and kidney damage.

Serious chronic health conditions are present 25 years after diagnosis in approximately 25% of survivors, according to the Childhood Cancer Survivor Study. These conditions include second cancers (increased risk following exposure to radiation), congestive heart failure, infertility or complications during pregnancy, and end-stage renal disease or renal failure.

Regular physical checkups by a primary care physician are important to watch for health problems that can develop years after therapy.

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Reviewed: June 2018