What is Neuroblastoma?

Neuroblastoma: Definition and Characteristics

Neuroblastoma is a malignant tumor of the sympathetic nervous system that arises from embryonic neural crest cells, representing the most common extracranial solid tumor of infancy and the second most common extracranial malignant tumor of childhood. 1

Origin and Classification

Neuroblastoma belongs to a group known as peripheral neuroblastic tumors, which develop from the sympathetic nervous system originating from the embryonic neural crest. The International Neuroblastoma Pathology Classification (INPC) distinguishes four categories based on Schwannian stroma development:

1. Neuroblastoma (Schwannian stroma-poor) - most common type
2. Ganglioneuroblastoma, intermixed (Schwannian stroma-rich)
3. Ganglioneuroma (Schwannian stroma-dominant)
4. Ganglioneuroblastoma, nodular (composite) 1

Histopathology and Molecular Characteristics

Neuroblastoma diagnosis should be determined according to the INPC system, which classifies tumors into favorable or unfavorable histology groups based on:

• Grade of neuroblastic differentiation (undifferentiated, poorly differentiated, or differentiating)
• Mitosis-Karyorrhexis Index (MKI)
• Age at diagnosis 1

Key molecular features include:

• MYCN amplification: The strongest independent prognostic risk factor, associated with aggressive disease 1
• Segmental chromosomal aberrations (SCAs): Particularly losses in 1p and 11q, and gains in 17q, 1q, or 2p
• Ploidy status: DNA index = 1 (less favorable) vs. DNA index > 1 (more favorable)
• ALK mutations: Present in 10-15% of primary tumors and most familial cases 2

Staging and Risk Classification

The International Neuroblastoma Risk Group (INRG) Staging System is recommended:

• L1: Localized tumor without image-defined risk factors (IDRFs), confined to one body compartment
• L2: Locoregional tumor with one or more IDRFs
• M: Distant metastatic disease
• MS: Metastatic disease in children <18 months with metastases confined to skin, liver, and/or bone marrow (limited marrow disease) 1

Risk classification (low, intermediate, or high) is based on:

• Age at diagnosis
• INRG stage
• MYCN status
• Histopathology (favorable vs. unfavorable)
• Presence/absence of SCAs
• Ploidy status 1

Clinical Presentation

Neuroblastoma has diverse clinical presentations depending on:

1. Primary tumor location: Most commonly in adrenal medulla or paraspinal ganglia
2. Extent of disease: Local mass effect or metastatic spread
3. Presence of paraneoplastic syndromes 3

Common findings include:

• Abdominal mass
• Hepatomegaly
• Bone pain (from metastases)
• Periorbital ecchymosis ("raccoon eyes")
• Respiratory distress (thoracic tumors)
• Neurological symptoms (paraspinal tumors) 1

Diagnostic Approach

Diagnosis requires:

1. Imaging:

   • Cross-sectional imaging (MRI or CT) for primary tumor evaluation
   • 123I-MIBG scanning (high sensitivity and specificity for neuroblastoma)
   • 18F-FDG-PET for MIBG-nonavid disease 1

2. Laboratory studies:

   • CBC with differential
   • Comprehensive metabolic panel
   • Urine catecholamines (HVA and VMA) 1

3. Pathology:

   • Adequate tissue sampling for histologic classification
   • Molecular genetic testing for MYCN, SCAs, and ploidy 1

Prognosis

Prognosis varies dramatically based on risk stratification:

• Low-risk: Excellent prognosis with minimal intervention
• Intermediate-risk: Good prognosis with moderate therapy
• High-risk: Poor prognosis despite intensive multimodal therapy, with 5-year overall survival around 50% 2, 3

Treatment Approaches

Treatment is risk-stratified:

1. Low-risk: Observation or surgery alone
2. Intermediate-risk: Moderate-intensity chemotherapy and surgery
3. High-risk: Intensive multimodal approach including:
   • Intensive induction chemotherapy
   • Surgery
   • Myeloablative chemotherapy with stem cell rescue
   • Radiation therapy
   • Immunotherapy with dinutuximab (anti-GD2 antibody) 4
   • Differentiation therapy with 13-cis-retinoic acid 1, 4

Recent Advances

Emerging approaches include:

• Targeted therapies for ALK-mutated tumors
• Novel immunotherapeutic techniques
• Therapies targeting the tumor microenvironment
• Approaches addressing the epigenetic landscape of neuroblastoma 2, 5

Important Considerations

• Adult neuroblastoma is extremely rare and typically has a poor prognosis 6
• Spontaneous regression can occur, particularly in infants with certain biological features 2
• Long-term survivors require monitoring for late effects of therapy

Neuroblastoma remains a challenging pediatric malignancy with remarkable heterogeneity in presentation and outcomes, requiring a sophisticated risk-stratified approach to diagnosis and management.