What is neuroblastoma?

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 children and a leading cause of pediatric cancer mortality. 1, 2

Origin and Pathophysiology

Neuroblastoma develops from primitive neural crest-derived cells that undergo defective differentiation due to genomic and epigenetic impairments. 3 The tumor originates from cells of the sympathetic nervous system, most commonly arising in the adrenal medulla (primary site) or paraspinal sympathetic ganglia, though it can develop at any location reached by migrating neural crest cells during embryonic development. 1

The disease is classified as a peripheral neuroblastic tumor, specifically characterized as Schwannian stroma-poor, distinguishing it from related entities like ganglioneuroblastoma (Schwannian stroma-rich) and ganglioneuroma (Schwannian stroma-dominant). 1

Epidemiology and Clinical Significance

• Neuroblastoma accounts for 8-10% of all childhood malignancies and contributes to approximately 15% of pediatric cancer-related deaths, making it disproportionately lethal relative to its incidence. 4
• Globally in 2021, there were 5,560 new cases with 1,977 deaths and 174,186 disability-adjusted life years (DALYs) lost. 4
• The disease shows remarkable clinical heterogeneity—some tumors spontaneously regress while others aggressively metastasize and resist therapy. 5, 6

Clinical Presentation

Patients most commonly present with an abdominal mass or abdominal distension (the primary tumor being in the abdomen in most cases). 1 Additional presenting signs and symptoms include:

• Constitutional symptoms: loss of appetite, weight loss, irritability, fever 1
• Gastrointestinal: constipation 1
• Cardiovascular: hypertension 1
• Hematologic: anemia, pancytopenia 1
• Neurologic: paralysis (from spinal cord compression), bone pain (from metastases) 1
• Ophthalmologic: bruising or swelling around the eyes (periorbital ecchymoses/"raccoon eyes") 1

Opsoclonus-myoclonus-ataxia syndrome (OMAS) occurs in a small subset of patients, presenting as a paraneoplastic syndrome with rapid eye movements, ataxia, irritability, sleep disturbance, and irregular muscle movements. 1

Genetic and Molecular Features

Familial and Syndromic Associations

While most cases are sporadic, familial neuroblastoma accounts for approximately 1-2% of cases, with germline gain-of-function ALK mutations and loss-of-function PHOX2B mutations identified as causative factors. 1 Associated genetic syndromes include:

• Li-Fraumeni syndrome 1
• RAS pathway disorders: Costello syndrome, Noonan syndrome, neurofibromatosis 1

Key Prognostic Biomarkers

MYCN amplification is the strongest independent prognostic risk factor, associated with aggressive disease and poor outcomes. 1 Other critical molecular markers include:

• Segmental chromosomal aberrations (SCAs): losses of 1p, 3p, 4p, 11q or gains of 1q, 2p, 17q correlate with inferior outcomes 1
• Tumor cell ploidy: DNA index >1 generally more favorable than DNA index =1 1
• ALK alterations: predict response to targeted therapies 1

Histologic Classification

Diagnosis must be determined according to the International Neuroblastoma Pathology Classification (INPC) system, which stratifies tumors into favorable versus unfavorable histology groups based on: 1

• Grade of neuroblastic differentiation (undifferentiated, poorly differentiated, or differentiating subtypes)
• Mitosis-Karyorrhexis Index (MKI): low (<100), intermediate (100-200), or high (≥200 per 5,000 cells)
• Age at diagnosis

Immunohistochemical staining for chromogranin, synaptophysin, PHOX2B (strongly recommended), and tyrosine hydroxylase helps confirm diagnosis in challenging cases with small samples or undifferentiated subtypes. 1

Disease Extent at Presentation

• Approximately 50% of patients present with localized or regional disease 1
• Approximately 35% have regional lymph node involvement at diagnosis 1
• Local extension commonly involves vascular encasement, infiltration of kidneys and liver, and epidural space involvement when arising from paraspinal sympathetic chains 1

Prognosis and Risk Stratification

The International Neuroblastoma Risk Group (INRG) Classification System integrates age, stage, histology, MYCN status, SCAs, and ploidy to stratify patients into risk groups that guide treatment intensity. 1 Outcomes vary dramatically:

• Low and intermediate-risk patients: excellent outcomes with reduced therapy 7
• High-risk patients: only 40% survival rate despite intensive multimodal therapy including chemotherapy, surgery, radiation, and immunotherapy 3, 5
• High-risk disease with MYCN amplification carries particularly poor prognosis 1

Tumor Cell Identity and Plasticity

Recent single-cell RNA sequencing has identified two distinct cell identities within neuroblastomas: undifferentiated mesenchymal (MES) and committed adrenergic (ADRN) states, which can interconvert through epigenetic reprogramming, conferring high intra-tumoral heterogeneity and plasticity that contributes to treatment resistance. 3