Neuroblastoma

Diagnosis

Indications for Testing

  • Clinical presentation of disease – mass identified with imaging; presence of an associated syndrome

Laboratory Testing

  • Initial testing
    • Vanillylmandelic acid (VMA) and homovanillic acid (HVA) urine tests
      • VMA/creatinine and HVA/creatinine ratios are used for diagnosis 
      • Elevations >10 times the reference limit are highly predictive of a neuroendocrine tumor
  • Anti-Hu (ANNA1) – use if opsoclonus-myoclonus syndrome is present
  • PHOX2B, ALK genetic mutation testing
    • Patients with sporadic or familial neuroblastoma in conjunction with congenital central hypoventilation syndrome or Hirschsprung syndrome

Histology

  • Characteristic pathologic appearance of tissue specimens using the International Neuroblastoma Staging System (also called the Shimada system)
  • Recent use of flow cytometry for bone marrow studies
    • Positive for CD44, CD56, CD81, CD9
    • Negative for CD45

Imaging Studies

  • CT or MRI
  • MIBG (metaiodobenzylguanidine) scintigraphy – if CT scan is not revealing
  • Technetium bone scan – if bone disease suspected and MIBG scan is negative

Prognosis

  • Markers
    • N-MYC – 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 – >100 ng/mL indicates worse prognosis
      • Ferritin – >142 ng/mL indicates worse prognosis
      • Lactate dehydrogenase – 1,500 u/L indicates worse prognosis
      • Chromosome additions/deletions – 17q, 1p;11q
        • Commonly associated with MYC amplification
      • TrKA, B, C
        • TrKA tends to have a favorable prognosis; TrKB does not
  • Children's Oncology Group risk group classification

    Risk Group Classification

    Risk Group

    INSS*

    Age

    N-MYC

    DNA index

    Shimada histopathology

    Low

    1
    2A, 2B
    2A, 2B
    2A, 2B
    4S

    Any
    <1
    ≥1
    ≥1
    <1

    Any
    Any
    Nonamplified
    Amplified
    Nonamplified

    Any
    Any
    Any
    Any
    >1.0

    Any
    Any
    Any
    Favorable
    Favorable

    Intermediate

    3
    3
    4
    4S
    4S

    <1
    ≥1
    <1
    <1
    <1

    Nonamplified
    Nonamplified
    Nonamplified
    Nonamplified
    Nonamplified

    Any
    Any
    Any
    1.0
    Any

    Any
    Favorable
    Any
    Favorable
    Unfavorable

    High

    2A, 2B
    3
    3
    3
    4
    4
    4S

    ≥1
    <1
    ≥1
    ≥1
    <1
    ≥1
    <1

    Amplified
    Amplified
    Nonamplified
    Amplified
    Amplified
    Any
    Amplified

    Any
    Any
    Any
    Any
    Any
    Any
    Any

    Unfavorable
    Any
    Unfavorable
    Any
    Any
    Any
    Any

    * International Neuroblastoma Staging System

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

  • VMA and HVA urinary screening not recommended for general population
  • No screening studies demonstrate better survival in high-risk groups
    • Study recommendations include Japanese Neuroblastoma Screening Study, Quebec Neuroblastoma Screening Project, German Neuroblastoma Screening Study

Clinical Background

Neuroblastomas are solid tumors of the autonomic nervous system and the most common extracranial solid tumor in infants and children.

Epidemiology

  • Incidence – 10.5/1,000,000 children <15 years worldwide
  • Age – <5 years; median is 2 years
  • Sex – M<F (1:2.1)
  • Occurrence – mostly sporadic; 1-2% are familial

Conditions Associated with Increased Risk of Neuroblastoma 

  • Neurofibromatosis
  • Congenital central hypoventilation syndrome
  • Hirschsprung disease
  • Neurocristopathy syndrome

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 include abdominal pain
  • Localized tumors often asymptomatic 
  • 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 
  • 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
    • Kerner-Morrison syndrome – vasoactive intestinal polypeptide secretion causing refractory diarrhea, hypokalemia, hypovolemia, failure to thrive

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
Test Name and Number Recommended Use Limitations Follow Up
Vanillylmandelic Acid (VMA) and Homovanillic Acid (HVA), Urine 0080470
Method: Quantitative High Performance Liquid Chromatography

Initial screen for neuroblastoma

Ratios useful in pediatric diagnoses

   
MYCN (N-MYC) Gene Amplification by FISH 2007227
Method: Fluorescence in situ Hybridization

Prognostic determination in individuals with neuroblastoma or medulloblastoma

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

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Vanillylmandelic Acid (VMA), Urine 0080421
Method: Quantitative High Performance Liquid Chromatography
Homovanillic Acid (HVA), Urine 0080422
Method: Quantitative High Performance Liquid Chromatography
Neuron Specific Enolase 0098198
Method: Quantitative Enzyme-Linked Immunosorbent Assay
Ferritin 0070065
Method: Quantitative Chemiluminescent Immunoassay
Neuronal Nuclear (Hu, Ri, and Yo) Antibodies IgG by Western Blot 2007963
Method: Qualitative Western Blot

Consider in presence of opsoclonus-myoclonus syndrome in child with neuroblastoma

Lactate Dehydrogenase, Serum or Plasma 0020006
Method: Quantitative Enzymatic