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.


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


  • 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


  • 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


  • VMA and HVA urinary screening – not recommended for general population
  • Screening studies (including a Japanese neuroblastoma screening study, the Quebec Neuroblastoma Screening Project, and a German neuroblastoma screening study) do not demonstrate better survival in high-risk groups
  • Obstetrical ultrasound screening – detects prenatal neuroblastoma



  • 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


  • 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

Initial test for the diagnosis and monitoring of neuroblastoma

Prognostic determination in individuals with neuroblastoma or medulloblastoma

Results may be compromised if recommended fixation procedures have not been followed

Confirm diagnosis of a hereditary cancer syndrome with personal or family history consistent with features of more than one cancer syndrome

Refer to Additional Testing Information document for more information

Not determined or evaluated: deep intronic and regulatory variants, breakpoints of large deletions/duplications, sequence changes in EPCAM, and deletions/duplications in ATM (exon 12), BAP1 (exon 1), BMPR1A (exon 9), CDH1 (exon 1), CHEK2 (exons 11-15) with the exception of the c.1100delC variant, FH (exons 1, 9), FLCN (exon 8), MSH2 (exon 1), NF2 (exons 7, 13), PTEN (exon 8), RET (exon 1), RAD51D (exon 1), SMARCB1 (exon 5), STK11 (exons 4, 6, 7), and TSC2 (exons 7,17, 23, 25, 29, 32, 41)

Small deletions or insertions may not be detected

Diagnostic errors can occur due to rare sequence variations

Genes tested by sequencing: ALK, APC, ATM, BAP1, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN1B, CDKN2A, CHEK2 common mutations, FH, FLCN, MAX, MEN1, MET, MLH1, MSH2, MSH6, MUTYH, NBN, NF2, PALB2, PHOX2B, PMS2, PTEN, RAD51C, RAD51D, RB1, RET, SDHAF2, SDHB, SDHC, SDHD, SMAD4, SMARCB1,STK11, SUFU, TMEM127, TSC1, TSC2, TP53, VHL

Genes tested by deletion/duplication: ALK, APC, ATM, BAP1, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN1B, CDKN2A, CHEK2 common mutations, EPCAM deletion only, FH, FLCN, MAX, MEN1, MET, MLH1, MSH2, MSH6, MUTYH, NBN, NF2, PALB2, PHOX2B, PMS2, PTEN, RAD51C, RAD51D, RB1, RET, SDHAF2, SDHB, SDHC, SDHD, SMAD4, SMARCB1,STK11, SUFU, TMEM127, TSC1, TSC2, TP53, VHL

Related Tests

Initial test for the diagnosis and monitoring of neuroblastoma

Order concurrently with urine HVA test

Useful for evaluation of classic paraneoplastic neurologic syndrome

Use as a tumor marker for evaluation of neuroendocrine tumors

Aid in the diagnosis of iron deficiency anemia and iron overload

Monitor treatment of hemochromatosis

Medical Experts



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


Additional Resources