What is Neuroblastoma
Neuroblastoma is a malignant tumor of the sympathetic nervous system that arises from embryonic neural crest cells, representing the most common extracranial solid tumor in childhood and the leading cause of cancer death in children aged 1-5 years. 1, 2
Origin and Pathophysiology
Neuroblastoma develops from primitive cells of the sympathetic nervous system that originate from the embryonic neural crest during development. 1, 3 These tumors arise when neural crest-derived cells undergo defective differentiation due to genomic and epigenetic impairments. 3
The tumor can develop at any anatomic site reached by migrating neural crest cells and their progeny, most commonly:
- Adrenal medulla (most frequent site) 3
- Para-spinal sympathetic ganglia 3
- Any location along the sympathetic chain 1
Classification Within Peripheral Neuroblastic Tumors
Neuroblastoma belongs to a broader category called peripheral neuroblastic tumors, which are classified by the International Neuroblastoma Pathology Classification (INPC) system into four categories based on Schwannian stroma development: 1
- Neuroblastoma (Schwannian stroma-poor) - the most common type 1
- Ganglioneuroblastoma, intermixed (Schwannian stroma-rich) 1
- Ganglioneuroma (Schwannian stroma-dominant) 1
- Ganglioneuroblastoma, nodular (composite) 1
Clinical Presentation and Epidemiology
Neuroblastoma accounts for approximately 15% of all childhood cancer deaths and is responsible for 13% of all pediatric cancer mortality. 4, 5 The disease demonstrates remarkable clinical heterogeneity:
- Approximately 50% of patients present with localized or regional disease 1
- Approximately 35% have regional lymph node involvement at diagnosis 1
- Almost half of all patients belong to the high-risk group 4
Unique Age-Related Behavior
The tumor exhibits paradoxical behavior based on patient age: 2, 6
- Infants often experience spontaneous regression, even with metastatic disease, requiring minimal or no intervention 2, 6
- Older children frequently develop aggressive metastatic disease that progresses despite intensive multimodality therapy 2, 6
Molecular and Genetic Characteristics
Neuroblastoma shows remarkable genetic heterogeneity with several key molecular features: 1
Critical Prognostic Biomarkers
MYCN amplification is the strongest independent prognostic risk factor and is associated with aggressive disease behavior. 1 This oncogene amplification should be assessed in all neuroblastomas. 1
Segmental chromosomal aberrations (SCAs) include: 1
- Loss of genetic material from chromosomes 1p and 11q (most extensively studied)
- Segmental losses involving 3p or 4p
- Segmental gains involving 17q, 1q, or 2p
Tumor cell ploidy status: DNA index >1 (hyperdiploid) is generally more favorable than DNA index =1 (diploid), particularly in infants. 1
ALK gene alterations: Amplification and sequence variants predict response to targeted agents. 1
Tumor Cell Identity and Plasticity
Single-cell RNA sequencing has revealed two distinct cell identities within neuroblastoma tumors: 3
These two states can interconvert through epigenetic reprogramming, conferring intra-tumoral heterogeneity and high plasticity to the tumor. 3 This plasticity contributes to treatment resistance and disease progression.
Diagnostic Features
Up to 90% of neuroblastoma tumors demonstrate uptake of MIBG (metaiodobenzylguanidine), a norepinephrine analogue taken up by norepinephrine transporters. 1 This characteristic forms the basis for both diagnostic imaging and therapeutic targeting.
The majority of patients have elevated urine catecholamine levels (homovanillic acid [HVA] and vanillylmandelic acid [VMA]). 1
Risk Stratification Impact
The International Neuroblastoma Risk Group (INRG) classification system stratifies patients into low-, intermediate-, and high-risk groups based on: 1
- Age at diagnosis
- INRG stage
- MYCN amplification status
- Histopathology (favorable vs. unfavorable based on INPC)
- Presence or absence of SCAs
- Ploidy status
Survival Outcomes by Risk Group
- Low-risk patients: >98% survival with observation or surgery alone 2
- Intermediate-risk patients: >90% survival with moderate chemotherapy and surgery 2
- High-risk patients: only 40% survival despite intensive multimodality therapy 3
Clinical Significance
Neuroblastoma remains a major challenge in pediatric oncology, particularly for high-risk patients who experience chemo-resistant relapse. 3 The disease's unique biology—ranging from spontaneous regression in infants to aggressive, treatment-resistant progression in older children—makes it a focus of intensive translational research efforts aimed at developing targeted therapies based on specific genetic and epigenetic alterations. 3, 5