Neuroblastoma in Children Under 5 Years: Diagnosis and Treatment

Diagnostic Workup

All children with suspected neuroblastoma require comprehensive staging that includes cross-sectional imaging (CT or MRI) of the primary site, 123I-MIBG scintigraphy (or FDG-PET if MIBG-nonavid), bilateral bone marrow aspirates and core biopsies, and urinary catecholamine measurements (HVA and VMA). 1, 2

Essential Molecular Testing Before Treatment Initiation

Complete molecular profiling is mandatory before starting any therapy and must include: 1, 2, 3

MYCN amplification status (the strongest independent prognostic factor) 1, 2
Segmental chromosomal aberrations (SCAs) 1, 2
Tumor cell ploidy (DNA index) 1, 2
ALK gene amplification/mutations 2, 3
Histologic classification per International Neuroblastoma Pathology Classification (INPC) 1, 2

Histopathology Classification

Tissue diagnosis should distinguish between: 1

Neuroblastoma (Schwannian stroma-poor) - most common type
Ganglioneuroblastoma, intermixed (Schwannian stroma-rich) - favorable prognosis
Ganglioneuroma (Schwannian stroma-dominant) - favorable prognosis
Ganglioneuroblastoma, nodular (composite) - prognosis depends on neuroblastoma component

Immunohistochemical staining for PHOX2B (strongly recommended), chromogranin, synaptophysin, and tyrosine hydroxylase should be performed for small samples, unusual locations, or undifferentiated subtypes. 1

Critical Staging Details

Bone marrow involvement ≥10% tumor cells distinguishes Stage M from Stage MS (4S) disease 2, 4
Stage 4S is diagnosed exclusively in infants <18 months with metastases limited to skin, liver, and/or bone marrow (<10% infiltration) 4
MIBG imaging uses the modified Curie score for semiquantitative assessment in North America 1

Risk Stratification and Treatment Algorithm

Low-Risk Disease (5-year survival >95%)

Treatment approach: 2, 3

Stage L1 (localized, completely resectable): Surgical resection alone when it can be performed safely with minimal morbidity 2, 3
Observation without biopsy is appropriate for isolated adrenal masses ≤3.1 cm if solid or ≤5 cm if ≥25% cystic in neonates and infants <6 months 2
Favorable histology tumors in infants typically require minimal intervention 2

Intermediate-Risk Disease (5-year survival 90-95%)

Treatment approach: 2, 3

2-8 cycles of cyclophosphamide-based chemotherapy followed by surgical resection 2, 5
Preservation of organ function takes precedence over complete resection 3
Treatment intensity varies based on age, stage, and biologic features 2

High-Risk Disease (5-year survival <50%)

MYCN amplification overrides all other prognostic factors and mandates high-risk treatment, except for completely resected L1 tumors. 2, 3

Intensive multimodality therapy includes: 2, 3

Induction chemotherapy: Multiple cycles of intensive chemotherapy 2, 4
Surgical resection of primary tumor 2
Consolidation: Myeloablative chemotherapy with autologous stem cell transplant 2, 4
Radiation therapy to primary site and residual metastatic sites 1, 2
Immunotherapy with dinutuximab 2, 4
Maintenance therapy 2

Stage 4S Special Considerations

Asymptomatic infants <18 months with Stage 4S disease and favorable biology (no MYCN amplification, no SCAs, favorable histology) can be observed without treatment. 4

Unfavorable histology or presence of SCAs requires active treatment 4
Hyperdiploid status (DNA index >1) is favorable in infants 4

Response Assessment and Monitoring

Timing of Disease Evaluation

Full disease evaluation is required at: 1, 2

End of induction therapy
Start of post-consolidation therapy
End of therapy

Response Criteria

Response assessment uses revised International Neuroblastoma Response Criteria (INRC) based on: 1

RECIST criteria for primary tumor and metastatic soft tissue lesions
Modified Curie score for MIBG uptake in metastatic bone or soft tissue
FDG-PET imaging is mandatory for MIBG-nonavid disease or when MIBG and anatomic imaging do not correlate 1, 2
Urinary catecholamines are no longer used for response assessment 1

Organ Function Monitoring During High-Risk Therapy

Serial monitoring is essential for: 1, 4

Cardiac function: Electrocardiograms and echocardiograms (platinum-based chemotherapy cardiotoxicity) 1, 4
Hearing: Audiograms or brainstem auditory evoked response (critical for language development) 1, 4
Renal function: Nuclear medicine measurements of glomerular filtration rate before consolidation 1
Blood counts, chemistry panels, and urinalyses 1

Critical Management Pitfalls to Avoid

Hydration Requirements

During or immediately after cyclophosphamide administration, force diuresis with adequate fluid intake/infusion to reduce urinary tract toxicity. Cyclophosphamide should be taken in the morning. 5

Age-Specific Considerations

Infants <1 year with localized disease (Stages I-III) have 90% survival and require minimal intervention 6, 7
Infants <1 year with Stage IV disease have significantly better prognosis (18% survival) than older children with Stage IV disease 6
Treatment protocols are based on data from children <5 years; adolescents and adults may require individualized approaches due to different toxicity profiles 1, 8

Fertility Preservation

Discuss fertility preservation before initiating chemotherapy when possible, particularly for high-risk patients requiring intensive therapy. 2 Treatment beyond 90 days with cyclophosphamide increases sterility risk in males. 5

Long-Term Surveillance

Survivors of high-risk neuroblastoma face significantly elevated risks of: 2

Grade 3-5 chronic health conditions
Second malignant neoplasms
Treatment-related organ dysfunction (cardiac, renal, hearing loss)

Clinical Trial Enrollment

Enrollment in molecular classification-based clinical trials is strongly encouraged for all patients, as trials continue to refine treatment strategies and identify new therapeutic approaches. 3

What is the diagnosis and treatment approach for a child under 5 years old with suspected neuroblastoma?

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