Neuroblastoma Definition and Characteristics
Neuroblastoma is a malignant tumor that originates from the neural crest of the sympathetic nervous system, primarily affecting young children and commonly occurring in the adrenal glands, but can also develop in nerve tissues of the neck, chest, abdomen, and pelvis. 1, 2
Origin and Classification
Neuroblastoma belongs to a group known as peripheral neuroblastic tumors that arise from the embryonic neural crest. The International Neuroblastoma Pathologic Classification (INPC) categorizes these tumors into four main types based on Schwannian stroma development:
- Neuroblastoma (Schwannian stroma-poor) - most common type
- Ganglioneuroblastoma, intermixed (Schwannian stroma-rich)
- Ganglioneuroma (Schwannian stroma-dominant)
- Ganglioneuroblastoma, nodular (composite, Schwannian stroma-rich/stroma-dominant and stroma-poor) 1
Epidemiology and Impact
- Primary cause of death from pediatric cancer for children between ages one and five years
- Accounts for approximately 13-15% of all pediatric cancer mortality
- Most commonly diagnosed in children under five years of age 3, 4
Genetic and Molecular Characteristics
Neuroblastoma has several key genetic features:
Familial cases: Rare (1-2% of all cases), associated with:
- Germline gain-of-function ALK mutations
- Loss-of-function PHOX2B mutations
- Genetic syndromes: Li-Fraumeni syndrome, Costello syndrome, Noonan syndrome, and neurofibromatosis 1
Key prognostic molecular biomarkers:
- MYCN amplification (strongest independent prognostic risk factor)
- Segmental chromosomal aberrations (SCAs) - particularly loss of material from chromosomes 1p and 11q
- Tumor cell ploidy status (DNA index) 1
Clinical Presentation
Symptoms vary depending on tumor location but commonly include:
- Abdominal mass or distension (most common presentation)
- Loss of appetite and weight loss
- Irritability
- Constipation
- Fever
- Hypertension
- Anemia
- Paralysis
- Periorbital bruising or swelling
- Bone pain
- Pancytopenia 1
A small subgroup of patients may present with opsoclonus-myoclonus-ataxia syndrome (OMAS), a paraneoplastic syndrome characterized by rapid eye movements, ataxia, irritability, sleep disturbance, and irregular muscle movements 1.
Diagnostic Criteria
According to international consensus, a definitive diagnosis requires one of the following:
- Unequivocal pathologic diagnosis from tumor tissue by light microscopy
- Bone marrow aspirate/biopsy containing unequivocal tumor cells plus increased urinary catecholamine metabolites 1
Tumor Biology and Cellular Identities
Recent research has identified two distinct cell identities in neuroblastoma that represent different differentiation states:
- Undifferentiated mesenchymal (MES)
- Committed adrenergic (ADRN)
These states can interconvert through epigenetic reprogramming, contributing to intra-tumoral heterogeneity and high plasticity 5.
Risk Classification and Treatment Approach
Treatment is risk-stratified based on molecular and clinical features:
- Low-risk: Primarily surgical approach
- Intermediate-risk: Surgery plus chemotherapy
- High-risk: Intensive multimodal therapy including induction chemotherapy, myeloablative chemotherapy, differentiation therapy, and immunotherapy 3, 6
The prognosis varies significantly based on risk classification, with high-risk patients having only about 40% survival rate when experiencing chemo-resistant relapse 5.