Neuroblastoma

Clinical Background

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

Epidemiology

Prevalence - 600 new tumors yearly in the U.S.
Age - median is 2 years
Sex - slightly higher female predominance
Occurrence - mostly sporadic, 1-2% are familial

Risk Factors

Neurofibromatosis
Nesidioblastosis
Hirschsprung disease

Pathophysiology

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

Clinical Presentation

Determined by tumor location and stage
Localized tumors are often asymptomatic (25-40% of patients)
Metastatic tumors frequently associated with fever, bone pain and weight loss
- Orbital metastases - ecchymoses called raccoon eyes
- Paraspinal disease - paresis and cord compression
- Cervical, apical thoracic disease - Horner syndrome
Paraneoplastic syndromes
- Opsoclonus-myoclonus syndrome (dancing eyes, dancing feet)
  - Involuntary eye fluttering
  - Muscle jerking
  - Ataxia
- Vasoactive intestinal polypeptide - refractory diarrhea, failure to thrive

See Also

Sarcomas

Diagnosis

Laboratory testing
- Urinary vanillylmandelic acid and homovanillic acid - increased levels
Histology on tissue specimens - characteristic pathologic appearance using Shimada criteria
- Bone marrow biopsy - assists in staging of disease
Imaging studies
- CT scan
- Metaiodobenzylguanidine scan (MIBG) -if CT scan is not revealing

Disease Monitoring

Markers
- N-myc amplification - amplification associated with 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

Disease Screening

Urinary testing is not recommended for the general population

Prognosis

Risk Group Classification
Risk Group	INSS	Age	N-myc	DNA index	Shimada histopathology
Low	1 2A, 2B 2A, 2B 2A, 2B 4S	Any <1 greater than or equal to 1 greater than or equal to 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 greater than or equal to 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	greater than or equal to 1 <1 greater than or equal to 1 greater than or equal to 1 <1 greater than or equal to 1 <1	Amplified Amplified Nonamplified Amplified Amplified Any Amplified	Any Any Any Any Any Any Any	Unfavorable Any Unfavorable Any Any Any Any
(Adapted with permission from Weinstein, et al., 2003, 282)

Tests

Tests generally appear in the order most useful for common clinical situations

Test name: Vanillylmandelic Acid (VMA) & Homovanillic Acid (HVA), Urine

ARUP #: 0080470

Methodology: High Performance Liquid Chromatography

Use:

Initial screen for the detection of neuroblastoma

Limitations:

Moderately elevated concentrations may be caused by essential hypertension, intense anxiety, intense physical exercise, and drug interactions (including some over-the-counter medications and herbal products)

The effects of some drugs on catecholamine metabolite results may not be predictable

Follow-up:

Test name: N-myc by FISH

ARUP #: 0049235

Methodology: Fluorescence in situ Hybridization

Use:

Prognostic marker for neuroblastoma

Limitations:

Follow-up:

Test name: Immunohistochemistry Stain Offering

ARUP #: arup005

Methodology: Immunohistochemistry

Use:

For fixed tissue samples, consultative services as well as immunohistochemical staining for N-myc, CD56 (NCAM), CAM5.2 (LMW), PGP9.5, synaptophysin, GFAP, Chromogranin A, Neurofilament (68kDa) and Desmin are available

Additional Tests Available

Test name: Vanillylmandelic Acid (VMA), Urine

ARUP #: 0080421

Methodology: High Performance Liquid Chromatography

Comments:

Test name: Homovanillic Acid (HVA), Urine

ARUP #: 0080422

Methodology: High Performance Liquid Chromatography

Comments:

Additional Information

VMA/creatinine and HVA/creatinine ratios are used for the diagnosis of pediatric patients
Neuroendocrine tumors typically present with elevations greater than 10 times the reference limit

References

Cited References

Weinstein JL, Katzenstein HM, Cohn SL. Advances in the diagnosis and treatment of neuroblastoma. Oncologist. 2003;8(3):278-292.

General References

Maris JM, Hogarty MD, Bagatell R, Cohn SL. Neuroblastoma. Lancet. 2007;369(9579):2106-2120.

McHugh K. Renal and adrenal tumours in children. Cancer Imaging. 2007;7:41-51.

Papaioannou G, McHugh K. Neuroblastoma in childhood: review and radiological findings. Cancer Imaging. 2005;5:116-127.

Qualman SJ, Bowen J, Fitzgibbons PL, Cohn SL, Shimada H. Protocol for the examination of specimens from patients with neuroblastoma and related neuroblastic tumors. Arch Pathol Lab Med. 2005;129(7):874-883.

References from the ARUP Institute for Clinical and Experimental Pathology Research®

Emerson LL, Layfield LJ, Frame R. Pleomorphic olfactory neuroblastoma (esthesioneuroblastoma): histopathological findings and clinical course. Histopathology. 2007;51(3):430-432.

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.

Medical Reviewers

Frank, Elizabeth L. , Ph.D. Medical Director, Analytic Biochemistry and Calculi at ARUP Laboratories; Associate Professor, Clinical Pathology, University of Utah

Layfield, Lester , M.D. Fine-Needle Aspiration Services and Molecular Diagnostics at ARUP Laboratories; Professor and Division Head, Anatomic Pathology, University of Utah

Perkins, Sherrie L. , M.D., Ph.D. Medical Director, Hematopathology at ARUP Laboratories; Professor, Anatomic Pathology, University of Utah

Comprehensive Review: March 2008
Last Update: September 2008