Neuroblastoma in Children – Stages, Symptoms, Causes, and Treatment by Dr. Stalin Ramprakash

Neuroblastoma is majorly seen in children less than five years old. It occurs in the adrenal nerve tissue. Adrenal glands are the triangular organs placed above the kidneys. There are two adrenal glands that are very important in regulating vital hormones that control stress, blood pressure, and blood sugar.

Other than adrenal glands, neuroblastoma can also occur in the neck nerve tissues, chest nerve tissues, and spine nerve tissues close to the vertebrae alongside the part of the sympathetic nervous system we call the sympathetic chain. These solid tumors are often detectable with lumps in the neck, chest, and abdomen. Neuroblastoma is very rare in older children, yet not unknown.

The Human Nervous System

The nervous system of the human body is a complex one that controls and commands all its functions. The two vital divisions include Central Nervous System (CNS) and Peripheral Nervous System (PNS).

1. The brain and the spinal cord cumulatively form the Central Nervous System. The neurons or the nerve cells conduct the stimuli to these organs.

2. The peripheral nervous system is a branching of the CNS which carries the impulses to the other parts of the body. The peripheral nervous system is further subdivided into two types

• The somatic Nervous System conducts voluntary actions of the human body.
• The autonomic nervous system conducts the involuntary or reflex actions of the human body.

The autonomic nervous system is further divided into two types in which the neurons of the sympathetic nervous system conduct fight or flight reactions and the neurons of the parasympathetic nervous system work in the opposite direction by conducting calming impulses.

Neuroblastoma can also occur in adults in extremely rare cases. The mutated gene that can lead to abnormal cell division starts at the fetal stage.

Stages of Neuroblastoma in Children

There are stages in neuroblastoma that are staged based on metastasis and advancement. They are

1. Stage L1

In this stage, the tumor is completely localized to one body compartment and has not spread to any other part of the body and does not involve vital structures by imaging (i.e. Image defined risk factors). This stage is the low-risk stage. The tumor diagnosed at this stage can be surgically removed without any remains.

2. Stage L2

It is a stage in which the tumor has spread locally or to regional lymph nodes with one or more image-defined risk factors but has not spread to distant locations. s

3. Stage M

It is an advanced stage where the tumor has spread to distant locations which we call distant metastasis, and these are very high-risk patients. This stage excludes the special category stage MS which is defined below.

4. Stage MS

Metastatic disease in children younger than 18 months with the distant spread confined to skin, liver and/or bone marrow. This is considered a special category as these patients behave differently compared to stage M patients and have relatively good outcomes.

Signs and Symptoms of Neuroblastoma in Children

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Children with neuroblastoma may show different symptoms like

• Painless lump in abdomen, neck and head
• Swollen abdomen with constipation and pain
• Shortness of breath and difficulty in swallowing
• Protrusion of the eyes
• Bluish lumps under the skin of infants
• Droopy eyelids, and dark circles or bruising around the eyes.
• Pain in bone
• Limping while walking
• Localized back pain
• Bladder symptoms – difficulty in voiding urine
• Tiredness and fatigue
• Loss of appetite
• Weight loss
• Fever (a less common symptom)

Very rarely, neuroblastoma can lead to opsoclonus-myoclonus-ataxia syndrome (a neurological disorder) in children, the symptoms include

• Rapid eye movement (dancing eyes)
• Coordination troubles

Causes of Neuroblastoma in Children

There are no particular causes associated with neuroblastoma in children. Most research studies show that not even a single environmental factor is responsible for most childhood cancers. Neuroblastomas are rarely associated with children born with congenital disorders. However, there are possibilities that children with congenital disorders may stand at the risk of contracting neuroblastoma in very rare cases.

It is important to note there is no known cause except for mutated genes for such childhood cancers. Only a small percentage of neuroblastomas are associated with heredity. The major cause behind the occurrence of neuroblastoma is a gene mutation and that can happen without any particular cause.

Top 10 Tests For Diagnosis of Neuroblastoma in Children

If you take your child with the symptoms of neuroblastoma, doctors might conduct some physical examinations and may also enquire about the child’s clinical history. Then the doctors may request some investigations to establish the diagnosis.

There are various tests that the doctor will use to diagnose the condition and its severity in kids. Here is the list of tests.

1. Blood Tests and Blood Chemistry

These tests provide information about the number of red blood cells, white blood cells, and blood platelets. These three types of blood cells hold an important place in regulating body functions.

Blood chemistry tests reveal the functioning of kidneys and liver by showing the normal and abnormal levels of certain chemicals like creatinine.

2. Urine Catecholamine Tests

Pathologists check the urine sample to identify if there is an abnormal amount of VMA (Vanillylmandelic Acid) and HVA (HomoVanillic Acid). Neuroblastoma cells take up and metabolize catecholamines and release VMA and HVA which are released in the urine. Higher than usual levels of these two secretions indicate the presence of neuroblastoma.

3. Biopsy of the Tumour

A biopsy of the affected tissue is necessary for children with neuroblastoma for the final confirmation of the diagnosis.

Before planning a biopsy, it is essential that a discussion takes place between the pediatric oncologist, pediatric or onco-surgeon familiar with neuroblastoma surgeries and radiologist to decide on the best mode of obtaining the biopsy specimen.

The biopsy can be obtained by open incision by a surgeon or image-guided by an interventional radiologist. Care should be taken to avoid seeding the needle tract which goes through uninvolved areas with tumor cells.

Pathologists will be able to look at the biopsy specimen under a microscope and with the use of special stains will be able to confirm the diagnosis of Neuroblastoma.

A special test on the biopsy sample called MYC-N amplification study (a type of gene which is often amplified in the neuroblastoma cancer cells) helps in identifying certain types of neuroblastomas that are stubborn and do not respond well to treatment. Such patients are considered high-risk patients and treated more aggressively.

Pathologists will also conduct several other tests to check for certain chromosomal abnormalities (cytogenetic analysis) which may affect the prognosis.

4. Bone Marrow Biopsy

When neuroblastoma is suspected, bone marrow tests are performed as part of the staging or at times may confirm the diagnosis initially if the marrow is involved (especially if there are abnormalities in standard blood tests like complete blood counts). The bone marrow test is far easier to perform than a biopsy of the primary tumor.

5. Staging Studies

The aim of these studies is to define the extent of the disease. It is mandatory to complete the staging investigations prior to proceeding with the treatment. These studies along with clinical features, histopathological findings and myc-n status decide the treatment. These studies are best performed in a pediatric cancer center which routinely deals with neuroblastomas.

6. CT Scan

A CT scan or a Computed Tomography gives clear images of the organs and tissues inside the body. Any abnormal growths or tumors can be easily detected using a CT or CAT scan.

7. MRI

Magnetic Resonance Imaging is a process in which doctors get clear pictures of the areas inside the body. Radiologists may inject a substance called gadolinium, which collects around the tissues of cancer cells and shows up more clearly. Both CT and MRI scans should be planned along with the paediatric oncologist and the surgeons who may be operating on the patient later.

8. MIBG Scan (Methyl Iodo Benzyl Guanine)

MIBG scan is a special test conducted to check for the presence of cancer in nerve cells or to identify neuroendocrine tumors. A small amount of radioactive iodine is given to the child intravenously.

MIBG is swallowed by the cancerous nerve cells and is visible and can be identified through a scanner. This is more sensitive and specific to pick up metastasis, but the facility is not available in many centers in India and 10% of the tumors may not take up the MIBG dye. Hence alternative methods should be used.

9. PET-CT

In MIBG non-avid tumors or if MIBG is not available this scan will be used to pick up the metastatic lesions.

Dotatate scan is another method of radionucleotide scan where radiolabeled somatostatin analogue is used to delineate metastatic lesions. About 77-89% of the tumors express somatostatin receptors and will take up this dye and will show up on the scan.

10. Bone Scans

These are conducted using X Rays to see if bones are abnormal. Radiologists will be able to identify bone cancers through these scans.

Based on the stage, histological characteristics, genetic nature of the tumor cells and your child’s clinical features, doctors will place your child in different risk groups and may discuss the available treatment options for your child.

Treatment of Neuroblastoma in Children

The treatment options will be based on confirmation of neuroblastoma, degree of maturity of cancer cells, the stage of the disease, amplification of the MYCN gene and age at diagnosis.

Treatment may involve one or more of the following based on whether it is considered low risk, intermediate risk or high-risk disease.

1. Observation

In very low-risk patients just observation with periodic clinical examination and scan may be sufficient as some of these lesions can resolve spontaneously.

2. Chemotherapy

It is a standard treatment that is administered to stop cancer cells from dividing. Doctors administer chemotherapy in the form of oral medication or intravenous medication. Few chemotherapy medications may be used in combination repetitively which we call chemotherapy cycles.

3. Radiation Therapy

One of the standard cancer treatments is that the oncologists administer high-energy radiations or X Rays to kill the cancer cells inside the body. This is often administered to the primary tumor site after chemotherapy and or surgery.

4. Surgery

In the case of low-risk neuroblastomas, doctors will remove the tumor completely through the surgical process. This may be the only treatment needed in low-risk patients.

5. MIBG Therapy

Doctors administer this type of treatment for neuroendocrine cancers like neuroblastoma. They will insert a certain amount of radioactive iodine into the child’s veins. This will flow into the bloodstream to enter the cancer cells and kill them with a small dose of radiation.

6. High-Dose Chemotherapy And Stem Cell Rescue

Doctors consider administering high-dose chemotherapy for children with high-risk neuroblastomas or recurrent or refractory neuroblastomas. Such cases need high-energy medications to stop the multiplication of the cancer cells.

Oncologists take out the child’s stem cells to preserve them from the damage caused by the high-dose chemotherapy treatment. They will reimplant the stem cells once the child completes the high-dose chemotherapy treatment.

7. Targeted Therapy

Targeted therapy aims only at cancer cells and kills them effectively without affecting healthy cells. It has fewer side effects compared to other cancer treatments.

Certain targeted therapies like monoclonal antibody therapy and ALK inhibition therapy in selected cases of neuroblastoma are available at the moment they need to be imported for treatment in India.

8. Immunotherapy

This is a type of treatment in which the doctors prepare a child’s immunity to fight against the cancer cells. Immunotherapy treatments are still in clinical trials. A child will be taken in for clinical trials only with the complete consent of the parent.

Dinutuximab, CAR (Chimeric Antigen Receptor) T cell immunotherapy and a few other experimental treatments are areas of active research in an effort to improve outcomes in high-risk neuroblastoma patients.

When to See a Doctor?

Neuroblastoma is a cancer that occurs in children less than 5 years old. Some of the obvious symptoms include

• A lump in the abdomen or neck or head
• Bluish painless lumps under the skin
• Abnormal eye movements
• Loss of coordination
• Limping while walking
• Bone pain in children
• Swollen abdomen with constipation
• Dark circles around the eyes
• Droopy eyelids and swollen eyes

Report all the above obvious symptoms to your child’s pediatrician immediately. They may conduct a physical examination before prescribing further tests to confirm neuroblastoma.

Is Neuroblastoma Serious in All Patients?

The seriousness of the disease depends on the age and stage of the diagnosis. Doctors can remove low-risk neuroblastomas completely through the process of surgery and may not require multiple treatments.

Some types of neuroblastomas in infants may not require any treatment and will disappear on their own. It may not be the same with all, high-risk neuroblastomas may require multiple treatments and also have a high chance of recurrence in spite of multiple lines of treatment.

There is a wide spectrum in severity varying from relatively benign course to life-threatening progressive disease with a high potential for recurrence. It is important not to ignore any obvious symptoms that your child shows. Explain every symptom of your child to the doctor to get the best diagnosis and treatment options.

There is no known reason for different kinds of childhood cancers. Cancer starts with a simple gene mutation and dealing with such a situation can be mentally draining. That is why it is very important to stand by your child who might need to go through various rigorous treatments for neuroblastoma. You also need a treating team who is well versed in dealing with such situations.

It is also very important to have all the information about the diagnosis, medications, tests, and follow-ups that your child might need after the treatment. The journey might look long but listening to the stories of children with long-term remissions can be reassuring for the child and the family.

FAQ’s

1. Can Neuroblastoma Cancer be Cured?

Low-risk neuroblastomas can be surgically removed and have a very good prognosis (chance of recovery), while high-risk neuroblastomas are hard to treat. Still a decent proportion of them will achieve long-term cure. With all the advancements in science, there are many better treatment options available where your child can stay in remission for a long time. A greater proportion of them are getting cured compared to historical cohorts.

2. What Age is Neuroblastoma Diagnosed?

Neuroblastomas are common in children younger than 5 years. Most neuroblastomas are diagnosed in infancy and before 5 years. Neuroblastomas are very rare in older children and adults.

Read Also: Rhabdomyosarcoma in Children(RMS) – Symptoms, Causes, and Treatment by Dr. Stalin Ramprakash