Neuroblastoma: Definition, Causes, Stages, Symptoms, Diagnosis, Treatment and Care

It is a very rare type of childhood cancer that develops in immature nerve cells (neuroblasts) of the sympathetic nervous system.

The term “neuro” refers to the nerves, while “blastoma” refers to a cancer that affects immature cells.

This type of cancer occurs most often in babies and young children. It is rarely found in children older than 10 years.

It develops in nervous tissue outside the central nervous system . These immature nerve cells normally grow into functional nerve cells; But in neuroblastoma, they turn into solid tumors made up of cancer cells.

Most scientists believe that neuroblastoma is an accidental growth that occurs during the development of the sympathetic nervous system.

The nervous system and how it works

The nervous system is divided into the central nervous system (which consists of the brain and spinal cord ) and the peripheral nervous system .

The nerves emanate from the latter, fan and cover the entire body like cables. These nerves carry information from one side to the other from all parts of the body.

The peripheral nervous system is divided into:

Somatic nervous system consisting of voluntary nerves : As the name suggests, it is associated with the voluntary control of body movements through the muscles of the upper and lower extremities and other areas.

Autonomic nervous system (ANS) consisting of involuntary nerves: this division controls the functioning of all our internal organs (such as heart rate, respiration and digestion) that occur below the level of our consciousness.

The autonomic nervous system can be subdivided into:

• The parasympathetic nervous system (PSNS).
• The sympathetic nervous system (SNS).

The sympathetic nervous system is often considered the “fight or flight” system and has evolved over time to protect the body from danger.

In contrast, the parasympathetic nervous system is often considered the “rest and digest” or “feed and feed” system and functions as an inhibitory or buffer system to counteract the impulse of the sympathetic nervous system.

Understanding autonomic nervous system tumors

There are three tumors that arise from this system. These are collectively called neuroblastic tumors and are called:

• Neuroblastoma.
• Ganglioneuroblastoma.
• Ganglioneuroma.

All of them arise from immature or primitive nervous tissue called sympathogonia and commonly manifest in:

• The neck.
• The chest behind the heart (posterior mediastinum).
• The adrenal gland (the small triangular glands at the top of the kidneys).
• Behind the abdominal organs (retroperitoneum).
• Pelvis.

The three tumors differ in their degree of cellular and extracellular maturation of nerve cells.

Immature tumor cells are more aggressive and malignant and generally occur in younger age groups (mean age, just under 2 years).

Mature tumor cells appear in older children (mean age, approximately 7 years) and tend to behave benignly.

The most benign neuroblastic tumor is the ganglioneuroma and is composed of ganglion cells and mature stroma. Ganglioneuroblastoma has intermediate malignant potential, as it is composed of mature ganglion cells and immature neuroblasts.

Neuroblastoma, on the other hand, is the most immature, undifferentiated, and malignant tumor of the three.

Neuroblastoma most often begins in the adrenal glands (the small triangular glands at the top of the kidneys), but it can also begin in the neural tissue that runs through the spinal cord in the neck, chest, abdomen, or pelvis.

Interestingly, neuroblastoma can also have a relatively benign course, even when it has a tendency to spread and become metastatic.

The biological behavior of these neuroblastic tumors determines their prognosis to treatment and varies widely and depends on their DNA content, chromosomal changes, and the expression of certain master genes and the synthesis of catecholamine.

It is these elements that divide neuroblastoma into high, intermediate, or low risk categories.

When they are cancerous, neuroblastoma can spread to different parts of the body, such as the lymph nodes, bones, skin, and liver.

Unfortunately, in about 70% of cases, the cancer has already spread to other parts of the body by the time it is diagnosed.

Today, even with the use of high-dose therapy or stem cell transplant therapy, more than half of children cannot be cured.

Neuroblastoma can sometimes be caused by a genetic mutation that is passed from parent to child. In such cases, the cancer occurs at a younger age and there is a greater chance that multiple tumors will form in the adrenal glands.

Key facts about neuroblastoma

• Neuroblastoma is not a brain tumor.
• Neuroblastoma is the most common extra solid cranial tumor that affects children.
• Neuroblastoma is responsible for 7 to 10 percent of childhood cancers.
• Neuroblastoma accounts for 50 percent of all cancers in babies, making it the most common tumor in babies younger than 12 months.
• The occurrence of neuroblastoma is the same worldwide (7-10 children / million).
• The appearance of neuroblastoma in different locations is: adrenal glands (60-65%), abdomen (30%), neck (1%), chest (19%) and pelvis (1%).
• Most children with neuroblastoma are diagnosed before the age of 5.
• It occurs a little more often in boys than in girls.
• Despite advances in therapy, about half of children with aggressive neuroblastoma succumb to the disease.

What Causes Neuroblastoma?

The cause of most neuroblastomas (98-99%) is not known. Neuroblastomas develop when normal fetal neuroblasts do not develop into mature nerve cells. Instead, they continue to grow and divide uncontrollably.

In 1% to 2% of cases, neuroblastoma appears to occur due to inherited genetic changes in the ALK oncogene and PHOX2B, a gene that normally helps nerve cells mature.

Also, as of today there are no lifestyle or environmental related causes of neuroblastomas. Therefore, no preventive measures can be taken to prevent these cancers.

What are the different stages of neuroblastoma?

Neuroblastoma is classified into different stages based on its location and how far it has spread. A staging system is a standard way for the cancer care team to summarize the extent of the cancer.

The stage of the neuroblastoma along with the child’s age and the results of other tests will help decide the course of treatment.

Imaging tests are done to determine the stage of the tumor, including X-rays, computed tomography (CT), magnetic resonance imaging (MRI), and bone scans.

Since the 1990s, the International Neuroblastoma Staging System (INSS) has been used to stage neuroblastoma.

• Stage 1: The cancer is still in the same area where it started. The visible tumor can be completely removed by surgery.
• Stage 2A : The cancer is still in the same area where it started and on one side of the body, but the entire tumor cannot be removed by surgery.
• Stage 2B: The cancer is on one side of the body; however, cancer cells are found in lymph nodes near the tumor.
• Stage 3 : This is considered an advanced stage and cannot be completely removed by surgery. The tumor may have reached a large size; Nearby lymph nodes may or may not be involved. The cancer, however, has not spread to distant sites.
• Stage 4: Cancer cells have spread to distant parts of the body, such as bones, liver, skin, distant lymph nodes, or other organs. It is divided into stages 4 and 4S.
• Stage 4S : This is known as a “special” neuroblastoma since this stage of cancer does not fit into the other stages defined above. In this case, the child is less than 12 months old, the cancer is on one side of the body, the neuroblastoma has spread to the liver, skin, or bone marrow, only 10% of the marrow cells are cancerous, and Imaging tests do not show that the cancer has spread to the bones or bone marrow.

Recently, the International Neuroblastoma Risk Group Staging System (INRGSS) has been introduced. The INRGSS uses Image Defined Risk Factors (IDRF) seen on imaging tests.

What are the symptoms of neuroblastoma?

About 75-80% of tumors have already spread to other parts of the body by the time they are diagnosed.

The signs and symptoms of neuroblastoma vary depending on the part of the body affected and the result of excess hormones secreted by the tumor (paraneoplastic syndrome).

Because many of the symptoms are similar to those of other common childhood diseases, many children are not diagnosed with neuroblastoma until after the cancer has already spread to other parts of the body.

• A lump in the abdomen is one of the most common signs of a neuroblastoma. It is generally painless and can cause loss of appetite resulting in weight loss. If it presses against the lymphatic vessels in the abdomen or pelvis, it can cause swelling in the legs and scrotum.
• In some cases, the pressure of a growing tumor can affect a child’s bladder or bowel, causing problems urinating and changes in bowel habits.
• A lump in the neck or chest feels like a hard, painless lump. If the tumor is in the chest, it can press on the superior vena cava (the large vein in the chest that returns blood from the head and neck to the heart) causing swelling of the face, neck, arms, and upper part of the chest. , dizziness and loss of consciousness.
• Pressure on the windpipe can cause difficulties in coughing, breathing, and swallowing.
• Pain in the bones can cause the child to limp or refuse to walk.
• If neuroblastoma spreads to the spine, pressure on the spinal cord can cause weakness, numbness, or paralysis in the arms or legs.
• The syndrome of ataxia myoclonus opsoclonus (dancing eyes, dancing feet) is characterized by a shaky and unsteady gait, myoclonus (brief, bump-like muscle spasms), and opsoclonus (rapid and irregular eye movements).
• Bruising around the eyes, dark circles under the eyes, or puffy eyes may appear if the cancer has spread to the bones around the eyes.
• Drooping eyelids are evident due to pressure on certain nerves in the neck (Horner syndrome).
• Frequent infections, excessive bruising or bleeding from small cuts or scratches, tiredness, irritability, and weakness if the cancer spreads to the bone marrow and causes a shortage of blood cells.
• Painless, bluish swellings under the skin that look like blueberries. This occurs only during the first months of life and indicates liver involvement.

How is neuroblastoma diagnosed?

• Medical history and physical exam: to rule out other health problems, such as common childhood infections or to find out if there is a family history of cancer. If the history and exam raise the suspicion that a child might have a neuroblastoma, other tests will be done to confirm the diagnosis.
• Neurological exam – to check the brain, spinal cord, and nerve function. The test is done to check the child’s ability to walk normally, muscle tone, sensation, reflexes, mental status, and coordination.
• Urine and blood tests : to detect the levels of hormones called catecholamines in the blood and urine. Sympathetic nerve cells normally release hormones called catecholamines, such as epinephrine and norepinephrine, which enter the blood. These are broken down into metabolites that pass out of the body in urine.
• Neuroblastoma cells also produce these hormones that can be detected by blood or urine tests. The 2 most commonly measured catecholamine metabolites are homovanillic acid (HVA) and vanillylmandelic acid (VMA).
• Additional blood tests – to check cell counts, liver and kidney function.

Various imaging tests are performed to determine the location and extent of the tumor, the involvement of distant sites, and the stage of the disease and the treatment plan.

• Ultrasound – to create images of organs or masses within the body. Occasionally, neuroblastoma can be detected by ultrasound before birth.
• X-rays – May be done as an early test if symptoms are unclear and the diagnosis of neuroblastoma is doubtful.
• Computed tomography (CT) scan: This is done to look for a neuroblastoma in the abdomen, pelvis, and chest. A CT scan creates detailed images of the soft tissues in the body. CT scans can also be used to guide a biopsy needle into a tumor.
• Magnetic Resonance Imaging (MRI) : Magnetic resonance imaging provides detailed images of soft tissues in the body. These scans are very helpful in looking at the brain and spinal cord.
• MIBG scan: This scan uses meta-iodobenzylguanidine (MIBG) that contains a small amount of radioactive iodine. MIBG is similar to norepinephrine, a hormone produced by sympathetic nerve cells. It is injected into a vein and attaches to neuroblastoma cells in the body. This helps to know the location of the neuroblastoma and if it has spread to other parts of the body.
• Positron emission tomography (PET) scan: uses a type of radioactive sugar known as FDG that is injected into the blood. Cancer cells in the body absorb large amounts of radioactive sugar and can be detected.
• Bone scan: uses a small amount of low-level radioactive material (technetium-99) to detect areas of active bone changes or “hot spots” in the skeleton. Other bone diseases such as Paget’s disease (a disease of abnormal bone metabolism), arthritis, and bone infection can also cause the same pattern.
• Biopsy : of the tumor and microscopic examination of the tissue to confirm the diagnosis.
• Bone marrow aspiration and biopsy : This is done to help determine the extent of the disease.

How is neuroblastoma treated?

Biological and genetic characteristics are used in conjunction with classical clinical classification to assign patients to risk groups to plan the intensity of treatment.

The following criteria are used to determine risk:

• Age of the patient.
• Extent of the spread of the disease.
• Tumor histology or microscopic appearance.
• Tumor biology (genetic characteristics).

Therapies also vary for the different risk categories:

• Low-risk neuroblastoma accounts for 37% of cases and requires only observation without any treatment or cured with surgery alone. They have an excellent prognosis with cure rates greater than 90%.
• Intermediate-risk neuroblastoma accounts for 18% of cases and is treated with surgery and chemotherapy. The prognosis is good with this group also with cure rates of 70 to 90%.
• High-risk neuroblastoma accounts for 45% of cases and can be difficult to cure. It is treated with intensive chemotherapy, surgery, radiation therapy, stem cell transplantation, 13-cis-retinoic acid bio-based therapy, and antibody therapy. Cure rates for this group were around 30% over the past two decades.

Recently, it was observed in a clinical trial that this number increased to approximately 66% two years after stem cell transplantation in patients who received antibodies with GM-CSF and IL-2.

In fact, these patients were alive and disease-free compared to 46% of the group that did not receive the antibody.

Children with neuroblastoma should have their treatment planned by a team of doctors made up of the child’s pediatrician and other experts in the treatment of childhood cancer, especially neuroblastoma.

The various treatment regimens include:

Surgery is the first treatment option when the tumor is localized. Much of the tumor can be safely removed depending on the location. If it cannot be removed, a biopsy may be done instead.

The role of surgery in advanced-stage neuroblastoma is controversial. In tumors that cannot be completely removed, the residual mass of cells is removed after surgery by chemotherapy or radiation.

Chemotherapy is when anticancer drugs are used to kill cancer cells. Systemic chemotherapy is when drugs are taken by mouth or injected into a vein and enter the bloodstream and reach cancer throughout the body.

In regional chemotherapy, the drugs inflict cancer cells belonging to a particular region, such as when administered into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen.

Chemotherapy drugs help treat neuroblastoma by killing cancer cells.

Combination therapy using two or more anticancer drugs is found to be effective.

• Alkylating agents such as cyclophosphamide or ifosfamide.
• Platinum compounds such as cisplatin or carboplatin.
• Vinca alkaloids such as vincristine.
• Anthracycline antibiotics such as doxorubicin.
• Topoisomerase 2 inhibitor such as etoposide.
• Topisomerase 1 inhibitor such as topotecan and irinotecan.
• Busulfan and melphalan (sometimes used during stem cell transplantation).

The most common combination of medications includes carboplatin (or cisplatin), cyclophosphamide, doxorubicin, and etoposide, although others may be used.

For children in the high-risk group, the combinations are usually larger and of higher doses, which can be followed by a stem cell transplant.

Radiation therapy uses high-energy rays to kill cancer cells. External radiation therapy uses a machine outside the body to send radiation toward cancer and is used to treat neuroblastoma.

Internal radiation therapy uses needles or wires that contain a radioactive substance that are placed directly into or near the cancer.

Targeted therapy uses drugs or other substances to identify and attack cancer cells without trying to harm normal cells. Two types of targeted therapies are

Tyrosine kinase inhibitors are small molecule drugs that enter cancer cells to block the signals that they need to grow and divide. An example is crizotinib which is used to treat recurrent neuroblastoma.

Antibody-drug conjugates are made up of a monoclonal antibody bound to a drug.

The monoclonal antibody binds to specific proteins or receptors found on cancer cells, while the drug enters these cells and kills them without harming other cells.

Lorvotuzumab mertansine is one of the antibody-drug conjugates being studied to treat recurrent neuroblastoma.

Iodine-131 mibg therapy treats the condition with radioactive iodine. Radioactive iodine is given intravenously and carries the radiation directly to tumor cells, where it collects and kills cancer cells.

Iodine 131-MIBG therapy is sometimes used to treat high-risk neuroblastoma that comes back after initial treatment.

Stem cell rescue along with high-dose chemotherapy and radiation therapy

Stem cells are immature blood cells that can mature into blood cells at a later date. This method removes them from the patient’s blood or bone marrow and freezes and stores them as an initial step.

High doses of chemotherapy and radiation therapy are then administered to the patient, after which the stored stem cells are thawed and infused back into the patient.

These reinjected stem cells turn into healthy blood cells. This therapy is used for high-risk neuroblastomas.

Another way to use stem cells is to use them as maintenance therapy for 6 months after high-dose chemotherapy and radiation therapy to kill any cancer cells that may recur.

Isotretinoin or a retinoid called 13-cis-retinoic acid is a vitamin-like medicine that is taken by mouth to slow the cancer’s ability to make more cancer cells and change the appearance and behavior of these cells.

It is used in high-risk patients and is given to prevent cancer from recurring after treatment with high-dose chemotherapy and stem cell transplantation.

Immunotherapy is when the child’s immune system is stimulated to fight disease. It is also known as biological therapy.

Substances made by the body or synthesized in a laboratory stimulate, direct, or restore the body’s defenses against cancer. Vaccines are a type of immunotherapy that is being studied to treat recurrent neuroblastomas.

Dinutuximab is a type of targeted monoclonal antibody therapy given by infusion that uses an antibody that identifies and binds to a substance, called GD2, on the surface of neuroblastoma cells.

The cells are exchanged, sending signals to the immune system that dinutuximab is a foreign substance and needs to be removed. Then the body’s immune system destroys the neuroblastoma cell. Dinutuximab can be given together with cytokines such as:

Granulocyte Macrophage Colony Stimulating Factor (GM-CSF), a cytokine that helps make more cells of the immune system, especially granulocytes and macrophages (white blood cells), which can attack and kill cancer cells.

Interleukin-2 (IL-2), a type of immunotherapy that mainly increases the growth and activity of lymphocytes (a type of white blood cell) that can attack and kill cancer cells.

Many of the standard cancer treatments today are based on previous clinical trials. If possible, patients may want to consider participating in a clinical trial, as it might offer them the best treatment option.

Children who are treated for neuroblastoma may be at increased risk for late effects, such as physical, psychological, or secondary cancers, which can sometimes be treated or controlled.

Follow-up tests or check-ups are repeated diagnostic tests to determine the staging of the cancer, and are done during treatment to see if it is working well and whether to continue or change it, or taken after treatment to see the benefits of treatment. .

What happens after treatment for neuroblastoma?

During treatment for neuroblastoma, the main concerns for most families are the day-to-day aspects of getting through treatment and beating cancer.

After treatment, concerns tend to shift toward the long-term effects of neuroblastoma and its treatment, and concerns about the recurrence (recurrence) of neuroblastoma.

Certainly, it is normal to want to leave neuroblastoma and its treatment behind and return to a life that does not revolve around cancer.

But it’s important to realize that follow-up care is a central part of this process, offering your child the best chance of recovery and long-term survival.

Late effects

Late effects are health problems that neuroblastoma patients can develop after treatments have finished.

Common late effects of neuroblastoma include learning disabilities, vision problems, delayed growth and development, developmental problems, seizures, headaches, and loss of function in certain organs.

The risk of developing late effects depends on several factors, such as the specific medications used during treatment, the dose of those medications, and the age of the child during treatment.

It is important to discuss possible late effects with your child’s doctor at each stage of neuroblastoma treatment.

While this is not intended to be an exhaustive list, the following provides a high-level overview of the most common late effects associated with neuroblastoma:

Neuroblastoma Learning Challenges

Learn late effects, also classified as cognitive impairments, most often manifest as:

• Lower scores on academic exams.
• Memory and attention problems.
• Poor hand-eye coordination.
• Slow development over time.
• Behavior problems
• The IQ drops 10 to 20 points.
• More apparent in diagnosed children under 5 years of age.

Vision problems

Common late effects on vision include:

• Dry Eye.
• Eye irritation (feels like something is in the eye).
• Discolored sclera (the white of the eye may be a different color, often yellow).
• Damage to the optic nerve and retina.
• Bad vision.
• Sensitivity to light.
• Poor night vision
• Tumors on the eyelid.
• Fallen eyelid.

Growth and development problems

Decreased growth rates during neuroblastoma treatment is a common occurrence. Many children will experience recovery growth after treatment, but in some children, short stature (stature) is permanent.

Chemotherapy can contribute to a slowdown in growth. But when chemotherapy is given alone, without radiation, the change in growth rate is usually short-term.

Over time, many patients achieve a normal growth pattern after treatment.

However, certain chemotherapy drugs, when given in high doses, can have long-lasting effects on a child’s growth rate, and many of the long-term effects of intensive chemotherapy are still unclear.

Many of the late effects on growth and development are related to radiation. Radiation has a direct effect on the growth of bones located in the area being treated. Radiation to the head also contributes to slower growth.

Complications of muscle and bone

Radiation treatment can have serious effects on proper bone and muscle growth in infants and children. Bones, soft tissues, muscles, and blood vessels are very sensitive to radiation during times of rapid growth.

This means that children younger than 6 years old, and those who go through a growth spurt at puberty, are at higher risk for late-effect problems.

Along with stunted bone growth, other bone and muscle-related late effects include:

• Uneven growth of body parts (the treated side does not grow in the same way as the untreated side).
• Bone-ache.
• Joint stiffness
• Changes in gait (changes in the way the child walks).
• Weak bones that can break easily ( osteoporosis ).
• Decreased calcium in the bones.

Follow-up care

Follow-up care is important after treatment ends. The follow-up routine will depend on your child’s cancer and its treatments. Visits are usually every 3 to 6 months for 5 years.

Taking care of your child

Being told that your child has neuroblastoma can be overwhelming, and cancer treatment can come at a huge cost to your child and your family. Sometimes you may feel helpless.

But you play a vital role in treating your child. During this difficult time, it is important to learn all you can about neuroblastoma and its treatment.

Being informed will help you make informed decisions and better help your child cope with tests and treatments. Don’t be afraid to ask your doctors questions.

Summary

Neuroblastoma survivors face lifelong medical and psychosocial risks related to their previous cancer therapies.

The most common complications include conditions related to hearing, the endocrine system, and SMN, although survivors are also at risk for disorders in other systems, as described above.

In order to promote early identification and treatment of these problems, lifetime surveillance and risk-based follow-up care should be provided for all survivors, particularly those treated with intensive multimodality therapy.

Research is conducted every day whose goals are focused on reducing morbidity and mortality, educating and empowering survivors and their families, and improving the quality of life among all neuroblastoma survivors.