Neuroblastoma in Children: Symptoms, Treatment & Prognosis

What Is Neuroblastoma?

Neuroblastoma is a cancer that develops from immature nerve cells called neuroblasts in the sympathetic nervous system. It is the most common cancer in infants and the most common extracranial solid tumor in children, accounting for approximately 6-8% of all childhood cancers. The disease most commonly arises in the adrenal glands but can occur anywhere along the sympathetic nervous chain.

Neuroblastoma originates in the sympathetic nervous system, which is part of the autonomic nervous system responsible for the body's "fight or flight" response. This network of nerves extends from the base of the skull through the neck, along the spine, into the chest and abdomen, and down into the pelvis. Because neuroblasts are distributed throughout this system during fetal development, neuroblastoma can arise at multiple locations.

The most common primary site is the adrenal glands, which sit atop each kidney. These small, triangular organs produce hormones including adrenaline and are a frequent location for neuroblastoma because they develop from the same embryonic tissue as the sympathetic nervous system. Approximately 40% of neuroblastomas originate in the adrenal glands, while others develop in nerve tissue along the spine in the abdomen, chest, neck, or pelvis.

What makes neuroblastoma particularly interesting from a biological standpoint is its remarkable heterogeneity. The disease exhibits a spectrum of clinical behaviors that ranges from tumors that spontaneously regress without any treatment to highly aggressive cancers that resist intensive therapy. This variability is largely determined by the tumor's genetic and molecular characteristics, particularly the presence or absence of certain genetic abnormalities.

Epidemiology and Incidence

Neuroblastoma primarily affects young children, with approximately 90% of cases diagnosed in children under 5 years of age. The median age at diagnosis is between 17 and 19 months, making it the most common cancer diagnosed during infancy. In the United States, approximately 700-800 new cases are diagnosed annually, while smaller countries may see 15-20 cases per year.

The incidence of neuroblastoma is relatively consistent across populations worldwide, with slight variations that may reflect differences in screening practices and diagnostic capabilities. There is no significant difference in incidence between males and females, though some studies suggest a slightly higher rate in males. The disease occurs across all ethnic and racial groups.

Causes and Risk Factors

The exact cause of neuroblastoma remains unknown. Unlike many adult cancers, neuroblastoma is not associated with environmental exposures, lifestyle factors, or parental behaviors during pregnancy. The disease is believed to result from genetic changes that occur during fetal development, specifically in the cells destined to become the sympathetic nervous system.

Most cases of neuroblastoma are sporadic, meaning they occur without any family history of the disease. However, approximately 1-2% of cases are familial, occurring in families with a history of neuroblastoma. Familial neuroblastoma is associated with germline mutations in genes such as ALK (anaplastic lymphoma kinase) and PHOX2B. Children with these inherited mutations may develop neuroblastoma at an earlier age and may have multiple primary tumors.

Certain genetic syndromes are associated with an increased risk of neuroblastoma, including neurofibromatosis type 1, Beckwith-Wiedemann syndrome, and Hirschsprung disease. However, these conditions account for only a small minority of neuroblastoma cases.

What Are the Symptoms of Neuroblastoma?

Neuroblastoma symptoms depend on tumor location and whether the cancer has spread. Common signs include an abdominal mass or swelling, unexplained fever, bone pain, fatigue, weight loss, and changes in bowel or bladder function. Some children may have proptosis (bulging eyes), dark circles around the eyes ("raccoon eyes"), or high blood pressure due to hormone secretion by the tumor.

The symptoms of neuroblastoma are often subtle and nonspecific, which can lead to delays in diagnosis. Many symptoms overlap with common childhood illnesses, making it challenging for parents and healthcare providers to recognize the disease early. The clinical presentation depends primarily on the location of the primary tumor, the extent of disease spread, and whether the tumor is producing hormones.

Abdominal neuroblastomas, which account for the majority of cases, often present as a firm, painless mass that parents may notice during bathing or dressing. As the tumor grows, it may cause abdominal pain, constipation, or changes in urinary patterns due to pressure on surrounding organs. Some children experience nausea, vomiting, or decreased appetite, leading to weight loss.

Thoracic (chest) neuroblastomas may cause respiratory symptoms such as coughing, wheezing, or difficulty breathing. These tumors can also cause Horner syndrome, characterized by a drooping eyelid, constricted pupil, and decreased sweating on one side of the face. Neck tumors may present as visible or palpable masses.

Paraneoplastic Syndromes

Some children with neuroblastoma develop paraneoplastic syndromes, which are symptoms caused by substances produced by the tumor rather than by direct tumor invasion. These syndromes can sometimes be the first sign of the disease.

Opsoclonus-myoclonus syndrome (OMS), also known as "dancing eyes, dancing feet," is characterized by rapid, chaotic eye movements (opsoclonus), jerking movements of the limbs and trunk (myoclonus), and ataxia (difficulty with coordination). This syndrome occurs in approximately 2-3% of children with neuroblastoma and, paradoxically, is often associated with favorable tumor biology and better outcomes for the cancer itself, though the neurological symptoms may persist.

Chronic diarrhea can occur when the tumor secretes vasoactive intestinal peptide (VIP), causing watery diarrhea that does not respond to standard treatments. This symptom typically resolves once the tumor is removed or treated.

Signs of Metastatic Disease

When neuroblastoma has spread to other parts of the body, additional symptoms may occur. Bone metastases can cause significant pain, particularly in the legs, pelvis, or spine. Children may limp, refuse to walk, or become irritable due to pain they cannot articulate. Bone marrow involvement may lead to anemia, causing fatigue and pallor, or thrombocytopenia, increasing the risk of bruising and bleeding.

A distinctive presentation in infants is periorbital ecchymosis, often called "raccoon eyes," which results from tumor spread to the bones around the eyes. This can be accompanied by proptosis (protrusion of the eyeballs). These signs, while alarming in appearance, are important diagnostic clues.

How Is Neuroblastoma Diagnosed?

Neuroblastoma diagnosis involves urine tests for catecholamine metabolites (VMA and HVA), imaging studies including ultrasound, CT, MRI, and MIBG scans, bone marrow biopsies to check for metastatic spread, and tumor tissue biopsy for histological confirmation and genetic testing. MYCN amplification status and other molecular markers are essential for risk stratification and treatment planning.

The diagnosis of neuroblastoma requires a systematic approach that combines clinical evaluation, laboratory tests, imaging studies, and tissue analysis. Because neuroblastoma is a complex disease with significant biological heterogeneity, accurate diagnosis and risk stratification are essential for determining the appropriate treatment approach.

Initial evaluation typically begins when a child presents with symptoms or when a mass is discovered incidentally during imaging for another reason. The healthcare provider will perform a thorough physical examination, looking for palpable masses, lymphadenopathy (enlarged lymph nodes), signs of metastatic disease, and neurological abnormalities.

Laboratory Tests

Urine catecholamine metabolites are elevated in approximately 90% of children with neuroblastoma. The tumor cells produce catecholamines (adrenaline-like hormones), which are broken down into metabolites called vanillylmandelic acid (VMA) and homovanillic acid (HVA). Measuring these metabolites in urine or blood provides a highly sensitive screening test for neuroblastoma.

Blood tests may reveal anemia, elevated lactate dehydrogenase (LDH), or abnormalities in liver function if the disease has spread. Serum ferritin and neuron-specific enolase (NSE) levels are sometimes measured as they can provide prognostic information.

Imaging Studies

Multiple imaging modalities are used to evaluate the extent of disease:

• Ultrasound is often the first imaging test, particularly for abdominal masses. It is noninvasive, does not involve radiation, and can help characterize the tumor and its relationship to surrounding structures.
• Computed tomography (CT) provides detailed cross-sectional images and is useful for evaluating tumor size, extent, and involvement of adjacent organs or blood vessels.
• Magnetic resonance imaging (MRI) offers excellent soft tissue detail without radiation exposure and is particularly valuable for assessing intraspinal extension or tumors in the neck and pelvis.
• MIBG (metaiodobenzylguanidine) scintigraphy is a nuclear medicine scan that uses a radioactive tracer specifically taken up by neuroblastoma cells. This scan can detect the primary tumor and metastatic sites throughout the body with high specificity.

Tissue Diagnosis and Molecular Testing

A definitive diagnosis of neuroblastoma requires tissue confirmation, typically obtained through biopsy or surgical resection of the primary tumor. The tissue is examined microscopically to confirm the diagnosis and classify the tumor according to the International Neuroblastoma Pathology Classification (INPC).

Molecular and genetic testing of tumor tissue is essential for risk stratification. The most important genetic marker is MYCN amplification, which occurs in approximately 20-25% of neuroblastomas and is associated with aggressive disease and poorer outcomes. Other important markers include chromosomal abnormalities such as 1p deletion and 11q deletion, DNA ploidy, and segmental chromosomal aberrations.

What Are the Stages of Neuroblastoma?

Neuroblastoma is staged using the International Neuroblastoma Risk Group Staging System (INRGSS), which categorizes tumors as L1 (localized without image-defined risk factors), L2 (localized with risk factors), M (metastatic), or MS (metastatic special, limited to liver, skin, and bone marrow in infants). Risk stratification combines stage, age, MYCN status, and tumor histology to determine treatment intensity.

Accurate staging is critical for neuroblastoma because treatment intensity varies dramatically based on risk category. The current international standard is the International Neuroblastoma Risk Group Staging System (INRGSS), which replaced the older International Neuroblastoma Staging System (INSS) for newly diagnosed patients.

The INRGSS focuses on imaging findings at diagnosis and uses the presence or absence of "image-defined risk factors" (IDRFs) to classify localized tumors. IDRFs are anatomical features that indicate involvement of critical structures and predict surgical risk.

Stage Definitions

• Stage L1: Localized tumor that does not involve vital structures as defined by image-defined risk factors. These tumors are generally amenable to complete surgical resection.
• Stage L2: Localized tumor with one or more image-defined risk factors, indicating involvement of critical structures such as major blood vessels or airways that may complicate surgery.
• Stage M: Metastatic disease with distant spread to lymph nodes, bone, bone marrow, liver, skin, or other organs. This stage corresponds to the older Stage 4 classification.
• Stage MS: Metastatic special - a unique category for infants (typically under 18 months) with metastatic disease limited to liver, skin, and/or bone marrow (<10% involvement). These patients often have favorable outcomes despite metastatic spread.

Risk Stratification

Beyond staging, neuroblastoma is classified into risk groups that guide treatment intensity. The International Neuroblastoma Risk Group (INRG) classification system integrates multiple factors:

• Stage at diagnosis
• Age at diagnosis (particularly the 18-month threshold)
• MYCN amplification status
• Histopathological classification
• DNA ploidy (hyperdiploid vs. diploid)
• Segmental chromosomal abnormalities (11q aberration, 1p deletion)

Based on these factors, patients are classified as very low risk, low risk, intermediate risk, or high risk. This classification has profound implications for treatment: very low-risk patients may require only observation, while high-risk patients need intensive multimodal therapy including stem cell transplantation.

How Is Neuroblastoma Treated?

Treatment for neuroblastoma depends on risk category. Low-risk disease may require only observation or surgery alone. Intermediate-risk treatment includes surgery and chemotherapy. High-risk neuroblastoma requires intensive multimodal therapy: induction chemotherapy, surgery, high-dose chemotherapy with autologous stem cell rescue, radiation therapy, anti-GD2 immunotherapy, and isotretinoin maintenance therapy.

The treatment of neuroblastoma exemplifies risk-adapted therapy in pediatric oncology. The intensity of treatment is carefully calibrated to match the aggressiveness of the disease, minimizing treatment-related toxicity for children with favorable tumors while providing intensive therapy for those with high-risk disease.

Low-Risk Neuroblastoma

Children with low-risk neuroblastoma have excellent outcomes with minimal treatment. Many infants with stage MS disease and older children with localized tumors that can be completely resected may be observed without chemotherapy. In some cases, particularly in very young infants, the tumor may spontaneously regress - a remarkable phenomenon unique to neuroblastoma among childhood cancers.

When surgery is performed for low-risk disease, the goal is complete or near-complete tumor removal. Even if some tumor remains, the prognosis is generally excellent, with survival rates exceeding 95%.

Intermediate-Risk Neuroblastoma

Intermediate-risk neuroblastoma typically requires a combination of surgery and chemotherapy. The chemotherapy regimen is less intensive than that used for high-risk disease and may consist of 4-8 cycles of agents such as carboplatin, etoposide, cyclophosphamide, and doxorubicin.

The sequence of surgery and chemotherapy depends on the specific clinical situation. In some cases, chemotherapy is given first to shrink the tumor and facilitate safer surgical resection (neoadjuvant therapy). In other cases, surgery is performed initially, followed by chemotherapy to treat residual disease.

High-Risk Neuroblastoma Treatment

High-risk neuroblastoma requires intensive, prolonged treatment over approximately 18 months. Treatment is divided into three phases: induction, consolidation, and maintenance.

Induction Phase: The initial treatment phase consists of 5-8 cycles of intensive chemotherapy using agents such as cisplatin, etoposide, cyclophosphamide, doxorubicin, and vincristine. The goal is to achieve maximal tumor response and facilitate surgical resection of the primary tumor. Surgery to remove the primary tumor is typically performed after several cycles of chemotherapy.

Consolidation Phase: Following induction, children receive high-dose chemotherapy (typically with carboplatin, etoposide, and melphalan or busulfan-melphalan) followed by autologous stem cell transplantation (using the child's own previously collected stem cells). This intensive approach aims to eliminate any remaining tumor cells. Radiation therapy to the primary tumor site is also administered during or after transplant.

Maintenance Phase: Even after intensive consolidation, microscopic residual disease often remains, leading to relapse. Maintenance therapy aims to prevent or delay relapse. Current standard maintenance includes isotretinoin (13-cis-retinoic acid), a vitamin A derivative that can induce differentiation of neuroblastoma cells, making them less malignant. Anti-GD2 immunotherapy using monoclonal antibodies (such as dinutuximab or naxitamab) has significantly improved outcomes for high-risk patients by targeting a sugar molecule (GD2) abundant on neuroblastoma cells.

MIBG Therapy

For patients whose tumors take up MIBG on diagnostic scans, therapeutic MIBG (using higher doses of radioactive iodine-131 or iodine-123) can deliver targeted radiation directly to tumor cells. This approach is particularly valuable for relapsed or refractory disease but is also being studied in upfront treatment protocols.

What Is the Prognosis for Neuroblastoma?

Neuroblastoma prognosis varies dramatically by risk group. Low-risk disease has >95% survival rate, intermediate-risk approximately 90-95%, while high-risk neuroblastoma has 50-60% survival with current intensive treatments. Key prognostic factors include age at diagnosis (younger is better), stage, MYCN amplification status, and tumor histology. Ongoing research continues to improve outcomes.

The prognosis for neuroblastoma spans an exceptionally wide range, reflecting the biological heterogeneity of this disease. Understanding the factors that influence prognosis helps families prepare for what to expect and allows clinicians to tailor treatment intensity appropriately.

The most important prognostic factors include age at diagnosis, stage of disease, and tumor biology. Children diagnosed before 18 months of age generally have significantly better outcomes than older children, even when the disease has spread. This observation reflects fundamental biological differences between tumors arising at different ages.

Survival by Risk Group

The risk stratification system directly correlates with expected outcomes:

• Very low-risk and low-risk: Survival rates exceed 95%. Many of these children are cured with surgery alone or minimal chemotherapy. Some infants with favorable biology may be observed without treatment as their tumors spontaneously regress.
• Intermediate-risk: Survival rates range from 90-95%. These children require surgery and moderate chemotherapy but generally have excellent outcomes.
• High-risk: Despite aggressive multimodal therapy, survival rates have historically been approximately 30-40%. Recent advances, particularly the addition of anti-GD2 immunotherapy, have improved outcomes to approximately 50-60%, with ongoing research aiming to improve this further.

Specific Prognostic Factors

MYCN amplification: The presence of extra copies of the MYCN oncogene is the single most powerful adverse prognostic factor. MYCN-amplified tumors tend to be more aggressive, resistant to chemotherapy, and more likely to relapse. MYCN amplification occurs in approximately 20-25% of all neuroblastomas but is present in nearly 50% of high-risk cases.

Tumor histology: The International Neuroblastoma Pathology Classification categorizes tumors as favorable or unfavorable based on microscopic features including degree of differentiation and mitotic activity. Favorable histology is associated with better outcomes.

DNA ploidy: Tumors with hyperdiploid DNA content (more than the normal amount of DNA per cell) generally have better outcomes than those with diploid DNA content, particularly in infants.

Long-Term Considerations

Survivors of neuroblastoma, particularly those who received intensive treatment, require lifelong follow-up for potential late effects. These may include hearing loss from platinum-based chemotherapy, growth and hormone deficiencies, cardiac effects from anthracycline chemotherapy, and secondary cancers from radiation or chemotherapy exposure. With appropriate monitoring and intervention, most survivors lead healthy, productive lives.

What Research Is Being Done on Neuroblastoma?

Active research includes new immunotherapy approaches (CAR-T cells, checkpoint inhibitors), targeted therapies against ALK mutations and other genetic alterations, radioimmunotherapy combining antibodies with radiation, and improved risk stratification using liquid biopsies and advanced genomics. International collaborative trials continuously refine treatment protocols.

Neuroblastoma research is a highly active field, with ongoing efforts to improve outcomes for high-risk patients while reducing treatment toxicity for those with favorable disease. International collaboration through groups such as the International Society of Paediatric Oncology (SIOP), the Children's Oncology Group (COG), and SIOPEN has accelerated progress.

Immunotherapy Advances

Building on the success of anti-GD2 antibodies, researchers are exploring enhanced immunotherapy approaches. Chimeric antigen receptor T-cell (CAR-T) therapy, which has revolutionized treatment for certain leukemias and lymphomas, is being adapted for neuroblastoma. CAR-T cells engineered to target GD2 or other neuroblastoma markers are in clinical trials.

Checkpoint inhibitor immunotherapy, successful in many adult cancers, is also being evaluated in neuroblastoma, though the relatively low mutational burden of pediatric cancers presents challenges.

Targeted Therapies

Approximately 10-15% of neuroblastomas have mutations or amplifications of the ALK gene, making ALK inhibitors (such as crizotinib, lorlatinib) promising targeted agents. Clinical trials are incorporating these drugs into treatment regimens for patients with ALK-altered tumors.

Other targeted approaches under investigation include drugs targeting the Aurora kinase family, MDM2 inhibitors, and agents affecting cellular metabolism or epigenetic regulation.

Improved Risk Stratification

Advances in genomic technology are enabling more precise risk stratification. Whole-genome sequencing can identify additional genetic abnormalities that influence prognosis and may identify targets for therapy. Liquid biopsies that detect circulating tumor DNA in blood samples are being developed to monitor disease response and detect relapse earlier.