Neuroblastoma

  • Diagnosis
  • Screening
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

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

Laboratory Testing

  • Initial testing
    • Vanillylmandelic acid (VMA) and homovanillic acid (HVA) urine tests
      • Use VMA/creatinine and HVA/creatinine ratios for diagnosis
      • Elevations >10 times the reference limit are highly predictive of a neuroendocrine tumor
  • Anti-Hu (ANNA1)
    • Use if opsoclonus-myoclonus paraneoplastic syndrome is present
  • Genetic mutation testing – PHOX2B, ALK
    • Patients with sporadic or familial neuroblastoma in conjunction with congenital central hypoventilation syndrome or Hirschsprung syndrome
    • Family history of neuroblastoma
    • Condition suggestive of mutation (eg, bilateral primary adrenal tumors)

Histology

  • Diagnosis requires positive bone marrow with increased urinary catecholamines or tumor biopsy
  • Characteristic pathologic appearance of tissue specimens using the International Neuroblastoma Staging System (also called the Shimada system)
    • Protocol for examination of neuroblastoma specimens (College of American Pathologists [CAP])
    • Bilateral bone marrow aspiration and biopsy – required for staging of disease
    • Surgical specimen (eg, adrenal/periadrenal, retroperitoneal/nonadrenal, thoracic paraspinal, cervical)
  • Recent use of flow cytometry for bone marrow studies
    • Positive for CD44, CD56, CD81, CD9
    • Negative for CD45

Imaging Studies

  • CT or MRI – chest, abdomen, and pelvis
  • 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 – 1p, 11q, 17q
        • Commonly associated with MYC amplification
      • TrKA, B, C
        • TrKA tends to have a favorable prognosis; TrKB does not

Differential Diagnosis

  • Renal tumors
    • Nephroblastoma (Wilms tumor)
    • Clear-cell sarcoma of the kidney
    • Rhabdoid tumor of the kidney
    • Renal or adrenal cyst/hemorrhage
    • Renal-cell carcinoma
    • Adrenocortical neoplasm
  • Rhabdomyosarcoma
  • Germ cell tumors
  • Hepatoblastoma
  • Ewing sarcoma/desmoplastic small round-cell tumor
  • Non-Hodgkin lymphoma (especially Burkitt lymphoma)
  • Primary neuroendocrine tumor
  • Vanillylmandelic acid (VMA) and homovanillic acid (HVA) urinary screening – not recommended for general population
  • Screening studies do not demonstrate better survival in high-risk groups
    • Study recommendations include Japanese Neuroblastoma Screening Study, Quebec Neuroblastoma Screening Project, German Neuroblastoma Screening Study
  • Obstetrical ultrasound screening – detects prenatal neuroblastoma

Neuroblastomas are solid tumors of the neuroendocrine 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 type 1
  • Congenital central hypoventilation syndrome
  • Hirschsprung disease
  • Beckwith-Wiedemann syndrome
  • Li-Fraumeni
  • Noonan syndrome
  • Turner syndrome
  • DiGeorge 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 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
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.

Vanillylmandelic Acid (VMA) and Homovanillic Acid (HVA), Urine 0080470
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

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

Cancer Panel, Hereditary, Sequencing and Deletion/Duplication, 47 Genes 2012032
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Limitations 

Not determined or evaluated deep intronic and regulatory variants, breakpoints of large deletions/duplications, sequence changes in EPCAM, 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)
  • 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 

Guidelines

Protocol for the Examination of Specimens from Patients with Neuroblastoma. No AJCC/UICC TNM Staging System; The International Neuroblastoma Staging System is recommended; Protocol web posting date: Jun 2012. College of American Pathologists (CAP). Northfield, IL [Revised Aug 2016; Accessed: Apr 2017]

Shimada H, Ambros IM, Dehner LP, Hata J, Joshi VV, Roald B, Stram DO, Gerbing RB, Lukens JN, Matthay KK, Castleberry RP. The International Neuroblastoma Pathology Classification (the Shimada system). Cancer. 1999; 86(2): 364-72. PubMed

General References

Esiashvili N, Anderson C, Katzenstein HM. Neuroblastoma. Curr Probl Cancer. 2009; 33(6): 333-60. PubMed

Neuroblastoma Screening. Neuroblastoma Canada. [Posted Oct 2010; Accessed: Apr 2017]

Park JR, Eggert A, Caron H. Neuroblastoma: biology, prognosis, and treatment. Hematol Oncol Clin North Am. 2010; 24(1): 65-86. PubMed

Schneiderman J, London WB, Brodeur GM, Castleberry RP, Look T, Cohn SL. Clinical significance of MYCN amplification and ploidy in favorable-stage neuroblastoma: a report from the Children's Oncology Group. J Clin Oncol. 2008; 26(6): 913-8. PubMed

Varma N, Naseem S. Application of flow cytometry in pediatric hematology-oncology. Pediatr Blood Cancer. 2011; 57(1): 18-29. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Comstock JM, Willmore-Payne C, Holden JA, Coffin CM. Composite pheochromocytoma: a clinicopathologic and molecular comparison with ordinary pheochromocytoma and neuroblastoma. Am J Clin Pathol. 2009; 132(1): 69-73. PubMed

De Biase I. Commentary. Clin Chem. 2016; 62(8): 1064. PubMed

Layfield LJ, Willmore-Payne C, Shimada H, Holden JA. Assessment of NMYC amplification: a comparison of FISH, quantitative PCR monoplexing and traditional blotting methods used with formalin-fixed, paraffin-embedded neuroblastomas. Anal Quant Cytol Histol. 2005; 27(1): 5-14. PubMed

Medical Reviewers

Content Reviewed: 
April 2017

Last Update: July 2017