Neuroblastoma

Content Review: April 2018 Last Update:

Neuroblastomas are solid tumors of the neuroendocrine system and the most common extracranial solid tumor in infants and children. Initial laboratory testing includes vanillylmandelic acid (VMA) and homovanillic acid (HVA) urine tests. Diagnosis requires tumor biopsy or positive bone marrow with increased urinary catecholamines. Neuroblastomas may regress spontaneously or may progress to death, despite maximal treatment. Because of this difference in prognosis, significant investigation has been performed to define high-risk indicators, such as imaging characteristics, surgical features, histopathology, cytogenetics characteristics, and molecular genetics features.

Diagnosis

Indications for Testing

  • Abdominal swelling
  • Mass identified with imaging
  • Presence of an associated syndrome

Laboratory Testing

  • Initial testing – VMA and HVA urine tests
  • Genetic mutation testing for familial neuroblastoma (NCI PDQ, 2017)
    • 1-2% of patients with neuroblastoma have a family history of neuroblastoma
    • Germline mutations have been associated with an increased risk of developing neuroblastomas, including
      • ALK – approximately 75% of familial neuroblastoma caused by germline mutations in the ALK gene
      • PHOX2B – usually in combination with central hypoventilation syndrome or Hirschsprung disease
      • Deletion at 1p36 or 11q14-23 – both germline and somatic changes associated with neuroblastoma
    • Single nucleotide polymorphisms (SNPs) identified in several genes have been associated with variable risk of developing neuroblastomas
      • SNPs associated with susceptibility to high-risk neuroblastomas include
        • BARD1
        • LMO1
        • LIN28B
        • HACE1
        • CASC15/NBAT-1
    • Other SNPs have been linked to low-risk neuroblastomas

Histopathology

  • Diagnosis and prognosis is based on evaluation of a surgical specimen; however, in infants who present with tumor at or before 6 months, biopsy may be postponed until up to 18 months of age
  • Bone marrow aspiration and biopsy – required for staging of disease
  • Protocol for examination of neuroblastoma specimens (College of American Pathologists [CAP], 2016)

Imaging Studies

  • Computed tomography (CT) or magnetic resonance imaging (MRI) – chest, abdomen, and pelvis
  • Metaiodobenzylguanidine (MIBG) scintigraphy – if CT scan is not revealing
  • Technetium bone scan – if bone disease is suspected and MIBG scan is negative

Prognosis

  • Markers for high-risk neuroblastoma (NCI PDQ, 2017)
    • MYCN (N-MYC) – amplification associated with advanced stage disease, rapid tumor progression, and poor prognosis
    • Ploidy status
      • Hyperdiploid and near triploid – low risk
      • Near diploid and near tetraploid – high risk or intermediate risk

Differential Diagnosis

Screening

  • VMA and HVA urinary screening – not recommended for general population
  • Obstetrical ultrasound screening – detects prenatal neuroblastoma

Background

Epidemiology

  • Incidence – 10.5/million children <15 years worldwide
  • Age – <5 years; median is 2 years
  • Sex – M<F (1:2.1)
  • Occurrence – mostly sporadic; 1-2% are familial

Pathophysiology

  • Malignant tumor from undifferentiated or poorly differentiated neuroectodermal cells of the neural crest
    • Some infants born with tumors
  • Abdominal tumors in ~65% of cases, 40% of which are adrenal
  • About 50% of cases have aggressive, fast-growing tumors
    • May spread to lymph nodes and other organs before symptoms are evident

Clinical Presentation

  • Symptoms determined by tumor location and stage
    • Abdominal site
      • Most common
      • Symptoms can include abdominal pain, distension, swelling, and bowel obstruction
      • Local compression of renal vasculature may cause hypertension
    • Metastatic tumors
      • Frequently associated with crying and irritability, fever, bone pain, weight loss
      • Initially may be asymptomatic (~50% of patients)
      • Orbital metastases – periorbital ecchymoses (“raccoon eyes”) and proptosis
      • May be confused with trauma
      • Paraspinal disease – paresis and cord compression
      • Cervical, apical thoracic disease
    • Localized tumors often asymptomatic
  • Syndromes associated with neuroblastoma
    • Horner syndrome
      • Ptosis, miosis, anhidrosis (associated with thoracic or cervical [neck] primary tumor)
    • Hutchinson syndrome
      • Limping and irritability associated with bone pain and bone marrow metastases
    • Neurocristopathy syndromes
      • Congenital neuroblastoma associated with other neural crest disorders
      • Congenital central hypoventilation syndrome (also called Ondine curse)
      • Hirschsprung disease – congenital megacolon
      • Opsoclonus-myoclonus syndrome (also called dancing eyes-dancing feet syndrome, Kinsbourne syndrome, myoclonic encephalopathy of infants)
        • Involuntary eye fluttering
        • Muscle jerking
        • Ataxia
    • Pepper syndrome
      • Massive metastatic disease in infants <1 year involving skin, liver, bone marrow
    • Verner-Morrison syndrome

ARUP Laboratory Tests

Genes tested: ALK, APC, ATM, AXIN2, BAP1, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDC73, CDH1, CDK4, CDKN1B, CDKN2A, CHEK2, CTNNA1, DICER1, EGFR, EPCAM, FH, FLCN, HOXB13, HRAS, KIT, LZTR1, MAX, MC1R, MEN1, MET, MITF, MLH1, MLH3, MSH2, MSH3, MSH6, MUTYH, NBN, NF1, NF2, NTHL1, PALB2, PDGFRA, PMS2, POLD1, POLE,  POT1, PRKAR1A, PTCH1, PTEN, RAD51C, RAD51D, RB1, RECQL, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, SMAD4, SMARCA4, SMARCB1, SMARCE1, STK11, SUFU, TERT, TMEM127, TP53, TSC1, TSC2, VHL, WT1

References

Additional Resources

Medical Experts

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Frank

Elizabeth L. Frank, PhD, DABCC
Professor of Pathology (Clinical), University of Utah
Medical Director, Analytic Biochemistry, Calculi and Manual Chemistry; Co-Medical Director, Mass Spectrometry, ARUP Laboratories
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