Neuroblastoma

Clinical Background

Neuroblastoma is a common childhood neoplasm and is the most common extracranial solid tumor in children.

Epidemiology

• Incidence – 10.5/1,000,000 children <15 years old worldwide
• Age – 2 years (median)
• Sex – M<F (minimal)
• Occurrence – mostly sporadic, 1-2% are familial

Associated Conditions with Increased Risk of Neuroblastoma 

• Neurofibromatosis
• Type I congenital central hypoventilation syndrome
• Hirschsprung disease
• Neurocristopathy syndrome

Pathophysiology

• Malignant tumor consisting of poorly differentiated neuroectodermal cells derived from the neural crest

Clinical Presentation

• Determined by tumor location and stage
• Localized tumors often asymptomatic (25-40% of patients)
• Metastatic tumors frequently associated with fever, bone pain and weight loss
  • Orbital metastases – periorbital ecchymoses (“raccoon eyes”) and proptosis
    • May be confused with trauma
  • Paraspinal disease – paresis and cord compression
  • Cervical, apical thoracic disease – Horner syndrome
• Syndromes associated with neuroblastoma
  • • Horner syndrome – ptosis, miosis and anhidrosis
    • Hutchinson syndrome – limping and irritability associated with bone and bone marrow metastases
    • Neurocristopathy syndrome – neuroblastoma associated with other neural crest disorders
    • Paraneoplastic syndromes
      • Opsoclonus-myoclonus syndrome (dancing eyes, dancing feet)
        • Involuntary eye fluttering
        • Muscle jerking
        • Ataxia
    • Pepper syndrome – massive involvement of liver with metastatic disease
      • Vasoactive intestinal polypeptide secretion – refractory diarrhea, failure to thrive

Diagnosis

Indications for Testing

• Clinical presentation of disease (mass identified with imaging; associated syndrome)

Laboratory Testing

• Initial testing – increased urinary excretion of vanillylmandelic acid (VMA) and homovanillic acid (HVA)
  • VMA/creatinine and HVA/creatinine ratios are used for the diagnosis of pediatric patients
  • Neuroendocrine tumors are typically present with elevations >10 times the reference limit
• Paraneoplastic opsoclonus-myoclonus syndrome frequently associated with anti-Hu (ANNA1)

Histology

• Characteristic pathologic appearance of tissue specimens using Shimada system
  • Protocol for examination of neuroblastoma specimens (College of American Pathologists [CAP])
  • Bone marrow biopsy – required for staging of disease

Imaging Studies

• CT scan
• Metaiodobenzylguanidine scan – if CT scan is not revealing

Prognosis

• Markers
  • N-myc amplification – amplification associated with advanced stage disease, rapid tumor progression and poor prognosis
  • DNA index – aneuploidy associated with poor prognosis
  • Others – not used in initial risk staging
    • Neuron-specific enolase
    • Ferritin
    • Chromosome additions/deletions – 17a, 1p36
    • TrKA and B

Differential Diagnosis

• Nephroblastoma (Wilms tumor)
• Clear-cell sarcoma of the kidney
• Rhabdoid tumor of the kidney
• Renal or adrenal cyst/hemorrhage
• Renal-cell carcinoma
• Adrenocortical neoplasm
• Non-Hodgkin lymphoma (especially Burkitt lymphoma)
• Ewing sarcoma/primary neuroendocrine tumor
• Desmoplastic small round-cell tumor

Screening

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Vanillylmandelic Acid (VMA), Urine 0080421 Method: High Performance Liquid Chromatography
Homovanillic Acid (HVA), Urine 0080422 Method: High Performance Liquid Chromatography
Neuron Specific Enolase 0098198 Method: Enzyme-Linked Immunosorbent Assay
Ferritin 0070065 Method: Chemiluminescent Immunoassay
Achondroplasia (FGFR3) 2 Mutations 0051266 Method: Polymerase Chain Reaction/Fluorescence Resonance Energy Transfer