Neuroblastoma In Children: Symptoms, Causes, Stages

Neuroblastoma is a cancer of neuroblasts (immature nerve cells) of the sympathetic nervous system on the neck, chest, pelvis, spinal cord, and adrenal glands. The prognosis and survival rate of neuroblastoma in children may vary depending on individual factors. Some neuroblastomas may grow and spread rapidly, while some may have slow tumor growth or may not grow at all. It is advised to seek early diagnosis and medical care for better outcomes.

Read on to know the causes, symptoms, diagnosis, treatment, survival rate, and prognosis of neuroblastoma in children.

Causes Of Neuroblastoma In Children

Abnormal growth and division of neuroblasts result in neuroblastoma. The exact cause of it is not known in all cases. Genetic mutations inherited from parents may be a cause of familial neuroblastomas in many children. However, some children may have neuroblastoma without familial inheritance (1).

The young-onset of neuroblastoma with multiple growths on adrenal glands or nerve tissues of the abdomen, pelvis, chest, or neck are seen in hereditary (familial) neuroblastoma. Abdominal X-ray, catecholamine levels, and ultrasounds are done regularly until ten years in children with positive family history.

Signs And Symptoms Of Neuroblastoma In Children

Clinical symptoms are diverse and vary depending on the anatomic location of the tumor. The spread of a tumor to nearby bones or the growth pressing against organs causes most neuroblastoma signs and symptoms. Majority of the neuroblastomas occur in the abdomen, specifically the adrenal glands.

The following symptoms and signs are commonly seen in children with neuroblastoma (2).

• Lump on neck, chest, or abdomen
• Ostalgia (bone pain)
• Swollen stomach
• Bulging eyes and dark circles around the eyes
• Bluish, painless lumps under the skin {blueberry muffin rash)
• Paralysis or weakness of limbs

Less common neuroblastoma signs and symptoms may include:

• Breathing problems such as shortness of breath
• Fever
• Tiredness
• Petechiae, red or brown spots on the skin
• Increased blood pressure
• Watery diarrhea
• Muscle jerks
• Uncontrolled eye movements
• Racoon eyes due to obstruction of the veins of the eyes and face
• Horner syndrome due to interruption of the sympathetic nervous system in the eye and face, causing droopy eyelids, reduced pupil size, and decreased sweating on the face

These signs and symptoms may also occur in other conditions. You may seek medical care for an exact diagnosis.

Diagnosis Of Neuroblastoma

Tests and procedures on various body tissues and fluids can diagnose neuroblastoma and its stage (3).

• Health history and physical examination at the doctor’s office may help assess general health status, lumps, and other signs of neuroblastoma.

• A neurological exam is also done to analyze mental status, muscle functions, reflexes, senses, and other bodily functions.

• High-frequency ultrasound may also be used to locate neuroblastomas in the abdominal cavity.

• Blood tests help determine blood count, catecholamine levels, serum creatine, liver enzymes, thyroid hormones, electrolytes, and immunoglobulin levels in the blood. Neuroblastoma and its spread may cause changes in these factors.

• Urinalysis involves the measurement of VMA (vanillylmandelic acid) and HVA (homovanillic acid) in the urine. These substances are excreted into urine after the breakdown of catecholamines (neurotransmitters). High VMA or HVA in the urinalysis is a common finding in neuroblastomas.

• X-ray imaging of the bones and chest also helps to visualize neuroblastomas in children.

• Computed tomography (CAT or CT scan) helps visualize neuroblastoma. In a CT scan, images are captured with an X-ray machine with oral or intravenous dye administration to enhance visibility.

• Magnetic resonance imaging or MRI scan with gadolinium injection also helps visualize neuroblastomas in various parts of the body. The gadolinium element collects around the growths and enhances visibility.

• Positron emission tomography or PET scan uses radioactive glucose to locate neuroblastomas.

• MIBG scan is a procedure to identify neuroendocrine tumors using a radioactive substance called MIBG. The scan is done within one to three days after intravenous injection of MIBG. Neuroendocrine tumors, such as neuroblastoma, absorb this substance, so it becomes visible on the scan. Iodine solution is also given during or before this test to reduce the absorption of MIBG by thyroid glands.

Doctors may also collect samples from the tumor with imaging techniques to identify the type of cancer. A biopsy may be done during the diagnostic procedure.

Biopsy and laboratory analysis are usually done for children older than six months since the tumor may disappear without treatment in some children younger than six months. If the tumor does not disappear after six months of age, doctors may order a biopsy.

The sample tissue undergoes the following tests in the laboratory (3).

• Light microscopy is a method of viewing the sample under the high-power microscope to identify the cell changes.

• The cytogenetic analysis helps to determine any chromosomal abnormalities in the sample cells. This may also help to choose the right treatment plans.

• Genetic studies: MYCN amplification study involves the assessment of the MYCN gene in the tumor cells. If there are more than ten copies of the MYCN gene, the condition is called MYCN amplification. It may indicate an increased risk of metastasis (tumor spread in the body) and less likelihood to respond to treatments.

• Immunochemistry uses antibodies to identify antigens or tumor markers in the sample. This test is also useful to determine one type of cancer from another.

Stages Of Neuroblastoma

Staging helps to understand how extensively the cancer is spread in the body. After the diagnosis is confirmed, doctors may order the following tests and procedures to stage the neuroblastoma.

• Bone marrow aspiration and biopsy to identify and analyze the cancer further.

• Lymph node biopsy is done to identify the presence of cancer cells in the lymph nodes. This may often be done after removing the entire node (excisional biopsy) or a part (incisional biopsy) during the cancer removal surgery. Before the surgery, lymph nodes are usually examined by core biopsy (sample collected with a wide needle) or fine-needle aspiration using a thin needle.

Cancer usually spreads through the tissue to nearby locations or through blood or lymph to other parts of the body. Neuroblastomas are of four stages based on the diagnostic evaluation of the primary growth and the spread (4).

• Stage 1: Cancer is only seen in one area, and it can be removed entirely with surgery.

• Stage 2: There is stage 2A and 2B. In stage 2A the cancer is confined to one area and visible, but complete surgical removal is not possible. A similar characteristic is seen in the 2B stage, and in addition to that, the cancer cells are also found in nearby lymph nodes.

• Stage 3: Surgical removal of the entire growth may not be possible, and the tumor may spread from one side to the other side of the body and nearby lymph nodes. Sometimes, cancer of one side may spread to the other side’s lymph nodes. Cancers located in the middle of the body may spread to both side tissues and lymph nodes.

• Stage 4: There is stage 4 and 4S. In stage 4, cancer usually spreads to distant lymph nodes and body parts (metastasis). Surgical removal may or may not be possible in this stage. Stage 4S is considered in infants, and in this stage, the cancer spreads to other parts of the body, such as the liver, bone marrow, and skin.

Neuroblastoma is also classified by International Neuroblastoma Risk Group Staging System (INRGSS). Treatments and outcomes may vary depending on the risk group. The new classification is developed based on the risks. The INRG classification system classification includes (5):

• Stage L1: Localized growth without risk factors defined on imaging

• Stage L2: Localized tumor with risk factors on imaging

• Stage M: Metastatic disease (cancer spread to other body parts)

• Stage MS: Metastatic disease in infants

Cancer staging helps to assess the risk and plan the appropriate treatment. Tumor biology, histology, and age are other factors used to evaluate risk. These factors help to predict the prognosis of the treatment.

Treatment For Neuroblastoma

There are various types of treatments for neuroblastoma in children. These methods can also be combined and used based on the risk factors. Depending on the availability and risk, doctors may offer standard (currently used) treatments or clinical trials of new options.

Neuroblastoma treatment may include the following (3).

• Monitoring (observation) of the growth can be done in some cases if there is no risk until the sign and symptoms of neuroblastoma appear.

• Surgical removal of the tumor is done if it is not spread to other parts of the body. Affected lymph nodes may also be removed in some cases.

• Chemotherapy or systemic chemotherapy involves the use of drugs to kill or stop the growth of cancer cells. This can be done with a single drug or combination of drugs (combination chemotherapy).

• Targeted therapy uses drugs or substances that specifically attack neuroblastoma. This can be used alone or combined with other treatment modalities.

• Radiation therapy involves cancer treatment with high-energy X-rays and other radiation to destroy or cease cancer cells’ growth. If the radiation is given using an external device, it’s called external radiation therapy.

• Iodine 131-MIBG therapy uses intravenous administration of radioactive iodine, which reaches the neuroblastoma through the bloodstream and destroys the cancer cells. This method is often recommended for neuroblastomas appearing after the initial treatment.

• Stem cell rescue followed by high-dose chemotherapy and radiation therapy involves the storage of stem cells followed by radiation or chemotherapy of the cancer cells. Usually, radiation or chemotherapy may also destroy healthy cells, such as immature blood cells (blood-forming cells). Therefore, stem cells are reinfused after completing the treatment.

• Immunotherapy enhances the immune system to fight cancer. At present, neuroblastoma immunotherapies are in the clinical trial phase and may require more evidence of improvement to include in the standard neuroblastoma treatment.

Cancer treatment may cause immediate side effects or late effects that begin after treatment and may stay for a long time. These side effects may include the following (3).

• Problems in hearing
• Cartilage and bone growth
• Tooth development
• Intestinal obstruction
• Metabolic syndromes, such as increased cholesterol or increased blood pressure
• Learning or memory problems
• Mood changes and other behavioral problems
• New cancers (secondary cancers)

Some of the immediate side effects and late effects can be controlled and treated. You may talk to the pediatric oncologist to have individualized options. Children may require regular follow-ups after treatment to assess the effectiveness of treatment and side effects.

Prognosis Of Neuroblastoma

Low-risk and intermediate neuroblastoma have better outcomes than high-risk neuroblastoma. In children younger than six months, neuroblastoma may disappear without any treatment known as spontaneous regression.

Some neuroblastoma cases, especially high-risk groups, may have an increased risk for refractory neuroblastoma (tumor not responding to treatment) and recurrent neuroblastoma (tumor recur after the treatment). Recurrent tumors may occur in the same location or anywhere in the central nervous system (brain and spinal cord).

The chance of recovery may depend on the following factors (6).

• Age at onset of diagnosis
• Tumor histology and biology, such as the tumor cell structure and function
• Gene changes such as MYCN amplification
• Affected area
• Stage of neuroblastoma
• Response to treatment
• Time elapsed between initial diagnosis and recurrent cancer
• Ferritin and LDH (lactate dehydrogenase) levels

Survival Rates For Pediatric Neuroblastoma

The average five-year survival rate for pediatric neuroblastoma is 81%. This means that 81% of children diagnosed with neuroblastoma survived for five years (7).

The five-year survival rate is more than 95% for children with low-risk neuroblastoma and 90% to 95% survival for intermediate-risk neuroblastoma. Children with high-risk neuroblastoma may have lower survival rates ranging from around 40% to 50% (7).

Child survival rates may vary based on individual factors and tumor characteristics. The survival rate is estimated based on the current statistics, which does not include better treatment outcomes.

References

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Reviewer

Dr. Miguel Angel Razo OsorioMD

 

Dr. Miguel Razio Osorio began his career in 2004 and has 19 years of experience in various fields of gynecology. After two years of internship and social service, he decided to specialize in G&O. Since 2013, Dr. Razo has dedicated his training and practice to improving his patients' obstetric and gynecological health, getting his degree as a certified specialist in 2017.

Read full bio of Dr. Miguel Angel Razo Osorio