Neuroblastoma

Neuroblastoma is a rare cancer that develops in developing nerve cells and primarily affects young children, with most cases diagnosed before age 5. While this cancer presents unique challenges, advances in treatment have significantly improved outcomes, and some forms may even resolve without intervention.

Table of contents

• What is neuroblastoma?
• Causes and risk factors
• Signs and symptoms
• How is neuroblastoma diagnosed?
• Stages and risk groups
• Treatment approaches
• Outlook and survival
• Life after treatment

What is neuroblastoma?

Neuroblastoma is a type of cancer that starts in cells called neuroblasts, which are immature nerve cells found in several areas of the body^[1]. These cells are present during early development and are supposed to mature into functioning nerve cells. When they grow out of control instead of developing normally, they form tumors.

This cancer most often begins in the adrenal glands, which are small organs that sit on top of each kidney and produce important hormones that control heart rate, blood pressure, blood sugar, and how the body responds to stress^[1]. However, neuroblastoma can also develop in nerve tissue in other parts of the body, including the neck, chest, belly, or along the spine^[2].

Neuroblastoma is the most common cancer in infants and the third most common type of childhood cancer overall, behind leukemia and brain tumors^[2]. About 650 to 800 cases are diagnosed in the United States each year^[2][7]. Most children are diagnosed before they turn 5 years old, and about one-third are diagnosed by their first birthday^[2]. The median age at diagnosis is 17 months^[7].

• Adrenal glands
• Nerve tissue along the spine
• Neck
• Chest
• Abdomen
• Pelvis

Causes and risk factors

Doctors do not yet fully understand why most children develop neuroblastoma. The cancer happens when changes occur in the way neuroblast cells function, particularly in how they grow and divide^[11]. These changes are caused by genetic mutations, which are alterations in the cell’s DNA that cause the cells to multiply uncontrollably.

In most cases, these genetic changes happen spontaneously and are not inherited from parents. However, about 1 to 2 percent of children may have a family history of neuroblastoma, which is known as familial or inherited neuroblastoma^[2]. Genetic mutations in specific genes, particularly the ALK gene and PHOX2B gene, are associated with inherited forms of the disease^[2][11].

Certain genetic conditions and syndromes increase the risk of developing neuroblastoma. Children with cancer predisposition syndromes such as Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, Noonan syndrome, Costello syndrome, and neurofibromatosis type 1 have an increased risk^[2][11]. In families with these conditions, children may benefit from regular screening for neuroblastoma until they are 10 years old^[4].

Studies have shown that non-Hispanic White children have a higher risk of developing neuroblastoma compared to other racial and ethnic groups^[7]. There is also a slight tendency for the disease to occur more often in boys than girls^[9].

Signs and symptoms

The symptoms of neuroblastoma vary greatly depending on where the tumor is located in the body, how large it is, and whether it has spread to other areas^[2]. Often, symptoms appear when the tumor begins to grow and press on nearby tissues or when cancer cells spread to other parts of the body.

Common signs and symptoms include a lump or swollen area in the abdomen, chest, or neck. Many children experience bone pain if the cancer has spread to the bones. A swollen stomach, difficulty breathing, and fever are also frequently reported^[2][4].

Some children may show signs related to the eyes, including bulging eyes, dark circles or bruising around the eyes that look like “black eyes,” and drooping upper eyelids^[2][4]. Other symptoms can include limping, weakness or paralysis if the tumor presses on the spinal cord, easy bruising or bleeding, unexplained weight loss, anemia, and uncontrolled eye movements or “jerky” movements^[2][4].

In some cases, children may develop high blood pressure due to the tumor compressing the kidney or producing certain substances. Some tumors produce chemicals that can cause diarrhea^[4]. In infants, painless bluish lumps may appear beneath the skin^[2].

It is important to note that these symptoms can also be caused by other, more common conditions. Parents should always consult their child’s doctor if their child experiences any of these signs^[1].

How is neuroblastoma diagnosed?

Diagnosing neuroblastoma typically begins with a physical examination. A doctor will check for any lumps or swelling and ask questions about the child’s symptoms and health history^[17]. Sometimes a pediatrician or parent discovers a mass in a baby or child’s abdomen during a routine well visit^[2].

Blood and urine tests are important diagnostic tools. Urine tests can measure the levels of certain chemicals called catecholamines, which are produced by neuroblastoma cells. When these chemicals break down in the body, they can be detected in urine as substances called vanillylmandelic acid (VMA) and homovanillic acid (HVA). Higher than normal amounts of these substances can indicate neuroblastoma^[4][17].

Imaging tests help doctors see the tumor and determine its location and size. An ultrasound, which uses sound waves to create pictures of the inside of the body, is often the first imaging test used^[17]. Other imaging tests include CT scans (computerized tomography), which use X-ray techniques and computers to create detailed cross-sectional images of the body^[17], and MRI scans (magnetic resonance imaging), which use magnets and radio waves to create pictures of soft tissues^[17].

To confirm the diagnosis, doctors perform a biopsy, which means removing a small sample of the tumor tissue to examine under a microscope^[1][17]. A pathologist looks at the cells to determine if they are neuroblastoma cells and to understand their characteristics.

Additional tests may be done to see if the cancer has spread to other parts of the body. These can include bone marrow tests, where a sample of bone marrow is removed and examined for cancer cells, and nuclear medicine scans that use small amounts of radioactive material to detect cancer cells throughout the body^[17].

Stages and risk groups

After diagnosis, doctors determine the stage of the neuroblastoma, which describes how far the cancer has spread in the body. This information, along with other factors, helps doctors decide on the best treatment plan and predict the outcome.

The International Neuroblastoma Risk Group Staging System (INRGSS) classifies neuroblastoma based on imaging studies done before any treatment or surgery^[7]. Stage L1 tumors are confined to one area of the body and do not involve vital structures. Stage L2 tumors are also confined to one area but may have spread to nearby lymph nodes or involve important structures like blood vessels. Stage M indicates that cancer has spread to distant parts of the body. Stage MS is a special category for children younger than 18 months where cancer has spread only to the skin, liver, or bone marrow, and these children generally have an excellent outlook^[7].

Doctors also classify neuroblastoma into risk groups—low-risk, intermediate-risk, or high-risk—based on several factors^[2]. These factors include the child’s age at diagnosis, the stage of the disease, how the tumor cells look under the microscope (tumor histology), and certain biological features of the cancer cells.

One important biological feature is whether the tumor has an amplification of a gene called MYCN. About 25 percent of neuroblastomas have too many copies of this gene, which is associated with more aggressive disease and poorer outcomes^[3].

By the time many children are diagnosed, the cancer has already spread to other parts of the body. In 70 to 80 percent of children, neuroblastoma has metastasized at diagnosis^[2]. When it spreads, it most commonly goes to the lymph nodes, bone marrow, bones, liver, or skin^[2].

Treatment approaches

Treatment for neuroblastoma depends on the risk group assigned to each child’s disease. The goal is to cure the cancer while minimizing side effects and long-term health problems. The main types of treatment include surgery, chemotherapy, radiation therapy, stem cell transplantation, and newer therapies such as immunotherapy.

For some very young babies with low-risk neuroblastoma, doctors may choose a period of careful observation without immediate treatment. This is because some neuroblastomas in infants can disappear on their own without any therapy, a process called spontaneous regression^[1][2]. During this time, the child has regular check-ups to make sure the tumor is shrinking.

Surgery is used to remove as much of the tumor as possible. In some cases, especially for low-risk tumors that have not spread, surgery alone may be the only treatment needed^[14]. For larger tumors, doctors may give chemotherapy first to shrink the tumor before attempting surgery, making the operation safer and easier^[14].

Chemotherapy uses powerful medicines to stop cancer cells from growing by killing them or preventing them from dividing^[15]. For children with high-risk neuroblastoma, treatment typically involves multiple cycles of intensive chemotherapy. These medicines are usually given through a vein using a device called a central line. Most chemotherapy for high-risk disease requires the child to stay in the hospital^[15].

Radiation therapy uses high-energy beams to kill cancer cells. It may be used before surgery to shrink tumors, after surgery to destroy any remaining cancer cells, or to treat areas where the cancer has spread^[14].

For high-risk neuroblastoma, treatment may include high-dose chemotherapy with stem cell transplantation. Before this treatment, doctors collect the child’s own stem cells from their blood or bone marrow. Then the child receives very high doses of chemotherapy, sometimes along with radiation. These high doses are more effective at killing cancer cells but also damage the bone marrow. After the intensive treatment, the stored stem cells are returned to the child’s body to help restore the bone marrow’s ability to make blood cells^[15][16].

Immunotherapy is a newer type of treatment that helps the body’s own immune system recognize and attack cancer cells. One immunotherapy medicine used for high-risk neuroblastoma is given after other treatments are completed to help prevent the cancer from coming back^[2][14].

Some children may also receive retinoid therapy, which uses substances related to vitamin A to help any remaining cancer cells mature into normal nerve cells or die^[14].

The treatment for high-risk neuroblastoma typically lasts about 18 months and is divided into three phases: induction (which includes chemotherapy and surgery), consolidation (which includes high-dose chemotherapy with stem cell transplant), and post-consolidation (which includes immunotherapy and retinoid therapy)^[15].

Outlook and survival

The outlook for children with neuroblastoma has improved significantly over the past several decades. Between 1975 and 2020, five-year survival rates increased from 86 percent to 93 percent for children younger than 1 year, and from 34 percent to 83 percent for children aged 1 to 14 years^[7].

Several factors affect a child’s prognosis, which is the likely course and outcome of the disease. Age at diagnosis is one of the most important factors. Children diagnosed before they are 18 months old tend to have better outcomes^[2]. The stage of the disease and the risk group also play major roles in determining survival.

Children with low-risk neuroblastoma have cure rates of up to 92 percent or higher^[9]. The prognosis is also generally good for intermediate-risk tumors. However, high-risk neuroblastoma remains challenging to treat, and survival rates are lower for this group despite intensive therapy^[2]. It is estimated that 50 to 60 percent of patients with high-risk disease experience a relapse despite aggressive treatment^[9].

When neuroblastoma comes back after initial treatment (called relapse or recurrence), it becomes much more difficult to cure. Research is focused on developing new treatments to improve outcomes for children with high-risk and relapsed disease.

The biological features of the tumor also affect prognosis. Tumors with MYCN amplification are associated with poorer outcomes^[3]. Other factors that influence prognosis include how the tumor cells look under the microscope, where the primary tumor is located, and how well the cancer responds to treatment.

Life after treatment

Children who have been treated for neuroblastoma require close monitoring for many years after treatment ends. Cancer therapy can cause side effects that may appear months or even years later, known as late effects^[7]. The type and severity of late effects depend on the treatments the child received, the doses used, and the child’s age during treatment.

Common late effects can include hearing loss, especially after certain chemotherapy medicines, changes in growth and development, heart problems, kidney problems, learning difficulties, and an increased risk of developing second cancers later in life^[21]. Regular follow-up appointments help doctors detect and manage these issues early.

Emotional and psychological support is important for both children and their families after neuroblastoma treatment. The experience of having cancer and undergoing intensive treatment can have lasting effects on mental health and emotional well-being^[27]. Counseling and support groups can help families cope with these challenges.

Many children who survive neuroblastoma go on to live full and meaningful lives. As they grow, they may need ongoing support to help them reach their full potential. Physical therapy can help children regain strength and overcome developmental delays^[20]. Good nutrition, regular medical care, and attention to both physical and emotional health are important parts of survivorship care.

Parents and caregivers also need support during and after their child’s treatment. Taking care of a child with cancer is physically and emotionally demanding. It is important for caregivers to practice self-care, accept help from others, and connect with support networks^[27]. Many hospitals and advocacy organizations offer resources specifically designed to support families affected by neuroblastoma.