Neuroblastoma: Causes, Symptoms, Diagnosis & Treatment

Book An Appointment

Introduction

Neuroblastoma is a rare type of cancer that primarily affects young children, typically arising from immature nerve cells in the adrenal glands, neck, chest, or spinal cord. This malignancy can manifest with a range of symptoms, including abdominal pain, lumps, bone pain, and fatigue, depending on its location and progression.

To fully understand neuroblastoma, it is essential to delve into several key areas: the causes of neuroblastoma, which often involve genetic mutations and familial predispositions; the symptoms that can help in early detection; the diagnostic methods such as imaging and biopsy used to confirm its presence; and the variety of treatment options available, from surgery and chemotherapy to immunotherapy and stem cell transplants. Understanding these terminologies and concepts is crucial for grasping the complexity of this aggressive childhood cancer.

What is Neuroblastoma?

Neuroblastoma is a malignant neoplasm arising from neural crest cells, precursors to the sympathetic nervous system. It most commonly originates in the adrenal medulla or paraspinal sympathetic ganglia and is characterized by the proliferation of immature neuroblasts.

These cells fail to differentiate fully into mature nerve cells and instead form tumors. Neuroblastoma is the most common extracranial solid tumor in childhood and exhibits a wide range of clinical behavior, from spontaneous regression to aggressive metastasis. The disease is associated with various genetic abnormalities, including amplifications of the MYCN oncogene, deletions of chromosome 1p, and alterations in the ALK gene.

Symptoms of Neuroblastoma

The symptoms of neuroblastoma vary depending on the location of the tumor, its size, and whether it has spread to other parts of the body. Common symptoms include:

Abdominal swelling or a mass: This is often the most noticeable sign, especially if the tumor is located in the abdomen.
Pain: Neuroblastoma can cause bone pain if it has spread to the bones or localized pain near the tumor.
Unexplained weight loss: A child may experience significant weight loss without changes in diet.
Fatigue and weakness: Affected children may become unusually tired or weak.
Fever: Persistent, low-grade fevers can occur without an apparent cause.
Loss of appetite: Reduced interest in eating may accompany other symptoms.
Lumps in the neck, chest, or pelvis: Depending on where the tumor arises, visible or palpable lumps may develop.
Bone marrow involvement: This can lead to anemia (fatigue, pale skin), easy bruising or bleeding, and frequent infections.
Difficulty breathing or swallowing: Tumors in the chest may compress nearby structures.
Horner’s syndrome: Tumors in the neck can cause drooping eyelids, constricted pupils, and reduced sweating on one side of the face.
Paralysis or weakness: If the tumor compresses the spinal cord, it may lead to weakness or paralysis in the lower limbs.
High blood pressure: Neuroblastoma in the adrenal glands may affect hormone production, leading to hypertension.
Proptosis and periorbital ecchymosis: Spread to the orbit can cause bulging eyes and dark circles around the eyes (often referred to as “raccoon eyes”).

What are the causes of Neuroblastoma?

The exact causes of neuroblastoma are not fully understood, but it is believed to result from a combination of genetic and environmental factors. The primary causes include:

Genetic mutations: Neuroblastoma is thought to develop when immature nerve cells, known as neuroblasts, undergo abnormal growth due to genetic changes. These mutations often occur sporadically, meaning they are not inherited but arise during a child’s development. Some common genetic alterations in neuroblastoma include:
- MYCN gene amplification: This is found in about 20-25% of cases and is associated with a more aggressive form of the disease.
- Chromosome 1p deletions and 17q gains: These are often found in tumors and may play a role in tumor progression.
- ALK gene mutations: Mutations in the ALK (anaplastic lymphoma kinase) gene are associated with some familial cases of neuroblastoma and are also seen in sporadic forms of the disease.
Familial neuroblastoma: Although most neuroblastoma cases are sporadic, around 1-2% of cases are hereditary. In these familial cases, children inherit a predisposition to develop neuroblastoma due to mutations in genes like ALK or PHOX2B. Children with familial neuroblastoma often develop the disease at a younger age and may have multiple tumors.
Embryonal origin: Neuroblastoma arises from neural crest cells, which are involved in developing the sympathetic nervous system. During fetal development, these cells migrate and differentiate into various tissues. In neuroblastoma, some of these cells fail to mature properly, leading to the formation of tumors.
Environmental factors: While no direct environmental causes of neuroblastoma have been identified, researchers have investigated potential links with prenatal or postnatal exposures, such as parental smoking or ecological toxins, but no conclusive evidence has been found.
Developmental factors: The majority of neuroblastomas are diagnosed in children under 5 years of age, indicating that the disease may be related to developmental abnormalities occurring early in life. Some cases may regress spontaneously, suggesting that the disease may be triggered by factors influencing cell growth and differentiation during early childhood.

Risk Factors of Neuroblastoma

The risk factors for neuroblastoma are not fully understood but include several genetic and environmental influences:

Age: Most commonly diagnosed in children under 5, particularly in infants and toddlers; rarely seen in older children and adults.
Genetic predisposition:
- Familial neuroblastoma: Rare (1-2% of cases), associated with inherited mutations in genes like ALK or PHOX2B, often leading to multiple tumors at an earlier age.
- Hereditary mutations: Genetic changes, even in non-familial cases, can increase risk.
- Neurocristopathy syndromes: Conditions like Hirschsprung disease and congenital central hypoventilation syndrome (CCHS) that affect neural crest cell development are linked to higher risk.
- Genetic abnormalities: Amplification of the MYCN oncogene in tumors is associated with aggressive behavior.
Family history: A family history of neuroblastoma increases risk, with inherited cases often linked to ALK gene mutations.
Congenital syndromes: Certain congenital disorders involving nerve tissue development or genetic predispositions may elevate risk.
Environmental factors: Prenatal exposure to substances like alcohol or pesticides may increase risk, though evidence is inconclusive.
Ethnicity and gender: More common in children of European descent and slightly more prevalent in boys than girls.

Complications of Neuroblastoma

Neuroblastoma can lead to several serious complications, especially if the cancer spreads or as a result of treatment. These include:

Metastasis: Spread to bones, liver, skin, and occasionally the brain, causing pain, fractures, anemia, and neurological issues.
Spinal cord compression: This can result in pain, weakness, or paralysis if the tumor presses on the spinal cord.
Paraneoplastic syndromes: Conditions like opsoclonus-myoclonus-ataxia (OMAS) and hypertension due to adrenal gland involvement.
Horner’s syndrome: Tumor compression in the neck or chest can cause drooping eyelids and other facial symptoms.
Organ dysfunction: Large tumors may impair organ function, causing gastrointestinal or urinary issues.
Infections: Weakened immunity from treatments increases the risk of severe infections.
Growth and developmental delays: Treatments can lead to developmental delays and cognitive impairments.
Hearing loss: Certain chemotherapy drugs can cause permanent hearing damage.
Secondary cancers: Increased risk of other cancers later in life due to radiation or chemotherapy.
Emotional impact: The disease and its treatment can cause emotional distress, anxiety, and PTSD in children and their families.

Diagnosis of Neuroblastoma

Diagnosing neuroblastoma involves several steps and a variety of tests to confirm the presence of the tumor, determine its location, and assess its stage. Common diagnostic methods include:

Physical Examination: The doctor checks for any lumps, swelling, or signs of the disease, such as abdominal mass or high blood pressure.
Imaging Tests:
- Ultrasound: Often used initially to detect masses in the abdomen.
- X-ray: May help identify bone involvement or large tumors.
- Computed Tomography (CT) scan: Provides detailed cross-sectional images of the body to determine tumor size and location.
- Magnetic Resonance Imaging (MRI): Useful for detailed images of soft tissues, such as spinal cord involvement.
- Metaiodobenzylguanidine (MIBG) scan: A specialized scan that uses radioactive iodine to detect neuroblastoma cells throughout the body.
Biopsy: A sample of the tumor is taken and examined under a microscope to confirm neuroblastoma and identify specific genetic mutations, like MYCN amplification, that can guide treatment.
Bone Marrow Aspiration and Biopsy: To check if neuroblastoma has spread to the bone marrow, samples are taken from the pelvic bone and analyzed for cancer cells.
Urine and Blood Tests:
- Urine catecholamines: Neuroblastoma cells often produce catecholamines (hormones) that are detectable in urine, specifically elevated levels of vanillylmandelic acid (VMA) and homovanillic acid (HVA).
- Blood tests: These may assess overall health and help detect specific markers or abnormalities associated with neuroblastoma.
Genetic Testing: To identify mutations such as MYCN amplification or ALK gene mutations, which can affect prognosis and treatment options.
Staging: After diagnosis, further tests are done to stage the cancer, determining how far it has spread. Staging typically uses the International Neuroblastoma Staging System (INSS) or International Neuroblastoma Risk Group (INRG) staging system.

Treatment of Neuroblastoma

The treatment of neuroblastoma depends on the child’s age, the stage of the cancer, and the tumor’s genetic characteristics. Treatment options are tailored based on risk groups (low, intermediate, and high) and often involve a combination of therapies:

Surgery
- Primary treatment for localized neuroblastoma. The goal is to remove as much of the tumor as possible. In low-risk cases, surgery alone may be curative. In more advanced cases, surgery is combined with other treatments.
Chemotherapy
- Systemic treatment that uses drugs to kill cancer cells throughout the body. Chemotherapy is often used:
  - Before surgery (neoadjuvant chemotherapy) to shrink the tumor.
  - After surgery (adjuvant chemotherapy) to eliminate any remaining cancer cells.
  - As the main treatment for advanced or high-risk neuroblastoma, often combined with other therapies.
- Radiation Therapy
  - High-energy radiation targets cancer cells, typically used for:
    - High-risk or advanced neuroblastoma when surgery or chemotherapy isn’t enough.
    - Treating tumors that can’t be fully removed or have spread to other areas, such as bones.
  - Immunotherapy
    - Monoclonal antibodies (such as dinutuximab) are used to target and destroy neuroblastoma cells. This therapy boosts the body’s immune response against the cancer.
    - Cytokines (like IL-2 and GM-CSF) may be used to enhance the immune system’s ability to fight cancer.
  - Stem Cell Transplant (Bone Marrow Transplant)
    - High-dose chemotherapy is followed by a stem cell transplant to replace damaged bone marrow. This is often used in high-risk cases where aggressive treatment is needed.
    - The patient’s stem cells (autologous transplant) are typically harvested before chemotherapy and then reintroduced to the body after high-dose treatment.
  - Retinoid Therapy
    - 13-cis-retinoic acid (isotretinoin) is used after chemotherapy to help cancer cells mature into normal nerve cells. This therapy helps reduce the risk of relapse in high-risk neuroblastoma.
  - Targeted Therapy
    - ALK inhibitors (e.g., crizotinib) are used in cases where neuroblastoma is linked to specific mutations in the ALK gene. Targeted therapies focus on molecular abnormalities in cancer cells and are often used when other treatments are less effective.
  - Clinical Trials
    - Many children with high-risk neuroblastoma may be enrolled in clinical trials that test new therapies, combinations of treatments, or cutting-edge approaches like CAR T-cell therapy.
  - Palliative Care
    - For advanced or recurrent neuroblastoma, palliative care focuses on relieving symptoms, managing pain, and improving the child’s quality of life.

Conclusion

In conclusion, neuroblastoma presents a significant challenge in pediatric oncology, necessitating early diagnosis and effective management.

Rungta Hospital excels in diagnosing and treating neuroblastoma under its Pediatric Oncology department, utilizing advanced technology and a specialized team to ensure comprehensive care. While the exact causes remain unclear, awareness of risk factors and continued research into genetic predispositions are crucial for prevention. Promoting routine health check-ups and educating parents on the signs and symptoms can facilitate early detection.

Collaborative efforts in research, education, and clinical practice are essential to improving outcomes and ultimately finding ways to prevent this devastating disease in young children.