- Author: Byron D Joyner, MD, MPA; Chief Editor: Brian H Kopell, MD more...
General laboratory studies should be routinely obtained in children suspected of having neuroblastoma. Results are as follows:
A complete blood cell count (CBC) should be obtained to determine if the child has anemia, which typically does not occur until the tumor has become widely disseminated; in patients with overwhelming bone marrow involvement, thrombocytopenia may also be present
Once dissemination occurs, abnormalities in findings of coagulation studies (prothrombin time [PT], activated partial thromboplastin time [aPTT]) may occur secondary to liver involvement
The erythrocyte sedimentation rate, a nonspecific acute-phase reactant, is elevated in classic neuroblastoma
Elevated metabolic catecholamine by-products can be detected in the urine of patients with neuroblastoma. The presence of these by-products serves as useful inclusion criteria when the diagnosis of neuroblastoma is being considered.
Phenylalanine and tyrosine are catecholamine precursors, which are converted through a sequence of enzymatic events to dihydroxyphenylalanine (DOPA), dopamine, norepinephrine, and epinephrine. DOPA and dopamine are metabolized into their final product, homovanillic acid (HVA), while norepinephrine and epinephrine are metabolized into vanillylmandelic acid (VMA).
Ninety percent of neuroblastoma tumors secrete these by-products. This fact becomes clinically relevant because children with dedifferentiated tumors excrete higher levels of HVA than VMA. This occurs because dedifferentiated tumors have lost the final enzymatic pathway that converts HVA to VMA. A low VMA-to-HVA ratio is consistent with a poorly differentiated tumor and indicative of a poor prognosis.
Neuroblastoma cells lack the enzyme that converts norepinephrine to epinephrine. Despite this fact, elevated levels of norepinephrine are not identified in the serum of patients with neuroblastoma. This might be explained by at least two processes: (1) norepinephrine may be catabolized within the tumor; and/or (2) tyrosine hydrolase, the initial enzyme in catecholamine synthesis, is subject to a negative feedback loop by norepinephrine.
A LaBrosse VMA spot test may be used to screen patients in certain institutions. It is economical but has low sensitivity and specificity.
High-performance liquid chromatography has a much lower false-positive rate and is more sensitive than the LaBrosse VMA spot test, but it is more expensive and is therefore often used only to confirm a positive result on a spot test.
Nonspecific tumor markers can be identified in patients with neuroblastoma. Neuron-specific enolase (NSE), lactic dehydrogenase (LDH), and ferritin are markers useful in the identification of active disease, as well as in prognostication. Approximately 96% of patients with metastatic neuroblastomas demonstrate an elevated NSE level, which has been associated with a poor prognosis.
Radiographic assessment is recommended in all infants and children with an abdominal mass. The standard diagnostic imaging modalities include the following:
Plain abdominal radiography (kidneys, ureters, bladder [KUB])
Computed tomography (CT) or magnetic resonance imaging (MRI)
KUB most commonly reveals finely stippled calcifications of the abdomen or posterior mediastinum.
Renal/bladder ultrasonography improves the diagnostic evaluation and is probably the single best imaging modality to obtain. Ultrasonography is noninvasive and provides relevant information regarding the laterality, consistency, and size of the mass.
Abdominal CT scanning or MRI usually follows ultrasonography. Both of these studies are more invasive, in that they require general sedation for young children. The benefit is that they enhance the ultrasonographic findings by providing information about regional lymph nodes, vessel invasion, and distant metastatic disease. See the images below.
Bone scintigraphy and a skeletal survey to detect cortical bone disease are helpful in the diagnosis of neuroblastoma. Metaiodobenzylguanidine (MIBG) is a compound taken up by catecholaminergic cells that competes for uptake even in neuroblastoma cells. In this way, MIBG is quite sensitive and specific in the detection of metastasis to bones and soft tissue, with highest sensitivity (91-97%) in the detection of bone deposits.
Bone scintigraphy using 99Tc diphosphonate and a skeletal bone survey to detect cortical bone disease are essential if MIBG scintigraphy results are negative in the bone. MIBG is recommended for re-assessment both during and after therapy in high-risk patients with MIBG-avid disease at diagnosis.
Expression of somatostatin (SS) receptors has been described in neuroblastoma cell lines and tumors. Studies have shown that these tumors can be successfully targeted with radioactive SS analogs as a method of detection. Currently, the indication for scanning with radio-labeled SS analog in children with neuroblastoma is not well-defined because this method is less sensitive than MIBG scanning (64% vs 94%). However, because the presence of neuroblastoma SS receptors is associated with favorable clinical and biological prognostic factors, radio-labeled SS analog could provide valuable information. In fact, improved survival has been found in patients with SS receptor–positive neuroblastoma. However, more studies need to be performed to confirm the benefits of SS receptor scanning.
Biopsy is the sine qua non in the diagnostic evaluation of neuroblastoma. To confirm the diagnosis of neuroblastoma, histologic evidence of neural origin or differentiation is required. Samples of tumor tissue can be viewed via light or electron microscopy or via immunohistochemistry. Although open surgical biopsy has traditionally been advocated, Mullassery and colleagues reported that image-guided needle biopsy can also yield adequate tissue samples.
Another option is to sample bone marrow, a frequent metastatic site for neuroblastoma. The literature is confusing in terms of the number of bone marrow aspirates or biopsies needed to diagnose neuroblastoma. An international committee on neuroblastoma staging has recommended obtaining two bone marrow aspirates and two biopsies, one from each posterior iliac crest.
The issue of biopsies might become obsolete because immunocytology of marrow aspirates may offer the single best source of diagnostic information. Recently, a large body of published work has addressed the use of immunocytochemical and polymerase chain reaction (PCR)–based technologies to detect neuroblastoma cells and neuroblastoma-specific transcripts such as tyrosine hydroxylase and disialoganglioside (GD2) synthase in marrow or blood samples. This method is used to assess minimal disease during the course of treatment. Although these techniques can greatly increase sensitivity, whether this increased sensitivity provides prognostic information about the likelihood of relapse is still unclear.
The three distinct histologic patterns of the neurocristopathies include neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. They represent a spectrum of maturation and dedifferentiation. The typical neuroblastoma is characterized by small uniform cells that contain dense hyperchromatic nuclei and scant cytoplasm. A neuritic process called neuropil is pathognomonic of all except the most primitive neuroblastoma. Homer-Wright pseudorosettes are clusters of neuroblasts surrounding areas of eosinophilic neuropil and are observed in 15-50% of patients. If identified, they are diagnostic of neuroblastoma.
The minimal diagnostic criteria for diagnosing neuroblastoma have been established by an international group of conferees and corresponding participants. These criteria include (1) unequivocal pathologic diagnosis or (2) unequivocal bone marrow (syncytia) and elevated levels of urinary catecholamine metabolic by-products. Both of these diagnostic criteria require a histopathologic diagnosis.
The cancer genes most commonly altered in adult carcinogenesis (eg, TP53, CDKN2A, ras) are rarely aberrant in neuroblastoma. TP53 -inactivating mutations are uncommon in primary tumors due to neuroblastoma, although they have been documented in cell lines among patients with relapsing neuroblastoma. Thus, with the exception of N-myc, major pathways of human neoplasia do not seem to be deregulated. Indeed, the only reliable genetically engineered murine model of neuroblastoma results from targeted overexpression of human N-myc cDNA to the murine neural crest.
Activating mutations in the tyrosine kinase domain of the anaplastic lymphoma kinase (ALK) gene occur in the majority of hereditary neuroblastoma cases, and also in some sporadic cases of advanced neuroblastoma. Subclonal ALK mutations can be present at diagnosis, with subsequent clonal expansion at relapse
At least six different staging systems for neuroblastoma exist. Historically, each staging system represents a temporal improvement in the understanding of the tumor. However, the presence of so many systems has not only confounded the literature but also complicated the comparison of studies between institutions. Twenty years ago, the International Neuroblastoma Staging System (INSS) was established to provide a uniform staging system.
The INSS is a clinical, radiographic, and surgical appraisal of children with neuroblastoma. The system combines many of the most important diagnostic criteria from each of the staging systems and includes initial distribution and surgical resectability of the tumor.
Specific requirements to stage neuroblastoma include the following:
Bone marrow aspirates and biopsy samples
Body CT scan (excluding head, if not clinically indicated)
Arabic numerals are used to distinguish INSS staging from other systems. INSS stages are as follows:
Stage 1 is characterized by a localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes that test negative for tumor are present microscopically (nodes attached to and removed with the primary tumor may test positive)
Stage 2A is characterized by a localized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph nodes that test negative for tumor are present microscopically
Stage 2B is characterized by a localized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes that test positive for tumor; enlarged contralateral lymph nodes must test negative microscopically
Stage 3 is an unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node involvement; a localized unilateral tumor with contralateral regional lymph node involvement; or a midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement (the midline is defined as the vertebral column; tumors that originate on one side and cross the midline must infiltrate to or beyond the opposite side of the vertebral column)
Stage 4 is any primary tumor disseminated to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs (except as defined for stage 4S)
Stage 4S (S = special) occurs in infants younger than 12 months and is characterized by a localized primary tumor (as defined for stage 1, 2A, or 2B), with dissemination limited to skin, liver, and/or bone marrow
Other features of stage 4S include the following:
Marrow involvement should be minimal (ie, < 10% of total nucleated cells identified as malignant via bone biopsy or bone marrow aspirate); more extensive bone marrow involvement is considered stage 4 disease
The results of the MIBG scan (if performed) should be negative for disease in the bone marrow.
Stage 4S is the most unusual group, comprising approximately 5% of patients with neuroblastoma. All else being equal, these children would normally be classified as having stage 1 or 2 disease; however, disease in this special group of infants almost always spontaneously regresses. Nonetheless, infants younger than 2 months frequently develop extensive and rapidly progressive intrahepatic expansion of neuroblastoma that can result in respiratory compromise. The 5-year survival rate in patients with stage 4S disease is 75%.
Stage for stage, infants with neuroblastoma have a better prognosis than older children. In fact, statistically, age is the most significant clinical prognosticator for neuroblastoma. Forty percent of infants (< 1 y) have localized neuroblastoma, compared with 20% of children older than 1 year. Additionally, nearly 70% of children older than 1 year have disseminated neuroblastoma, compared with less than 25% of infants.
The Children’s Oncology Group (COG) uses the major prognostic factors to place children into three risk groups: low, intermediate, and high. These risk groups are used to guide treatment selection. Five-year survival rates by risk group are as follows:
Low risk: > 95%
Intermediate risk: Approximately 90-95%
High risk: Approximately 40-50%
Low-risk group criteria are as follows:
Stage 1 disease
Stage 2A or 2B disease, patient age younger than 12 months
Stage 2A or 2B disease, patient age older than 12 months, no extra copies of the MYCN gene
Stage 4S disease, favorable histology, hyperdiploid, no extra copies of MYCN
Intermediate-risk group criteria are as follows:
Stage 3 disease, patient age younger than 12 months; no extra copies of MYCN
Stage 3 disease, patient age older than 12 months, no extra copies of MYCN, favorable histology
Stage 4 disease, patient age younger than 12 months, no extra copies of MYCN
Stage 4S disease, no extra copies of MYCN, normal DNA ploidy, and/or unfavorable histology
High-risk group criteria are as follows:
Stage 2A or 2B disease, patient age older than 12 months, extra copies of MYCN
Stage 3 disease, patient age younger than 12 months, extra copies of MYCN
Stage 3 disease, patient age older than 12 months, extra copies of MYCN
Stage 3 disease, patient age older than 18 months, unfavorable histology
Stage 4 disease, extra copies of MYCN
Stage 4 disease, patient age older than 18 months
Stage 4 disease, patient age between 12 and 18 months, extra copies of MYCN, unfavorable histology, and/or normal DNA ploidy (DNA index of 1)
Stage 4S disease, extra copies of MYCN
Cancer Facts & Figures 2014. American Cancer Society. Available at http://www.cancer.org/acs/groups/content/@research/documents/webcontent/acspc-041787.pdf. Accessed: January 2, 2015.
Lacayo NJ. Pediatric Neuroblastoma. Medscape Reference. Available at http://p://emedicine.medscape.com/article/988284. Accessed: January 6, 2015.
Irwin MS, Park JR. Neuroblastoma: Paradigm for Precision Medicine. Pediatr Clin North Am. 2015 Feb. 62(1):225-256. [Medline].
Virchow R. Hyperplasie der Zirbel und der Nebennieren. Die Krankhaften Geschwulste. Vol 2: 1864-65.
Marchand F. Beitrage zur Kenntniss der normalen und pathologischen Anatomie der Glandula carotica und der Nebennieren. Festschrift fur Ruduloph. Vichows Arch. 1891. 5:578.
Herxheimer G. Ueber Turmoren des Nebennierenmarkes, insbesondere das Neuroblastoma sympaticum. Beitr Pathol Anat. 1914. 57:112.
Cushing H, Wolback SB. The transformation of a malignant paravertebral sympathicoblastoma into a benign ganglioneuoma. Am J Pathol. 1927. 3:203.
Everson TC, Cole WH. Spontaneous regression of neuroblastoma. Everson TC, Cole WH, eds. Spontaneous Regression of Cancer. Philadelphia, Pa: WB Saunders; 1966. 88.
Mason GA, Hart-Mercer J, Millar EJ, Strang LB, Wynne NA. Adrenaline-secreting neuroblastoma in an infant. Lancet. 1957 Aug 17. 273(6990):322-5. [Medline].
Beckwith JB, Perrin EV. In situ neuroblastomas: A contribution to the natural history of neural crest tumors. Am J Pathol. 1963 Dec. 43:1089-104. [Medline].
Knudson AG Jr, Strong LC. Mutation and cancer: neuroblastoma and pheochromocytoma. Am J Hum Genet. 1972 Sep. 24(5):514-32. [Medline].
Nitschke R, Smith EI, Shochat S, et al. Localized neuroblastoma treated by surgery: a Pediatric Oncology Group Study. J Clin Oncol. 1988 Aug. 6(8):1271-9. [Medline].
Stigliani S, Coco S, Moretti S, Oberthuer A, Fischer M, Theissen J, et al. High genomic instability predicts survival in metastatic high-risk neuroblastoma. Neoplasia. 2012 Sep. 14(9):823-32. [Medline]. [Full Text].
Mullassery D, Sharma V, Salim A, Jawaid WB, Pizer BL, Abernethy LJ, et al. Open versus needle biopsy in diagnosing neuroblastoma. J Pediatr Surg. 2014 Oct. 49(10):1505-7. [Medline].
Schleiermacher G, Javanmardi N, Bernard V, Leroy Q, Cappo J, Rio Frio T, et al. Emergence of new ALK mutations at relapse of neuroblastoma. J Clin Oncol. 2014 Sep 1. 32(25):2727-34. [Medline].
Neuroblastoma risk groups. American Cancer Society. Available at http://www.cancer.org/cancer/neuroblastoma/detailedguide/neuroblastoma-risk-groups. Accessed: January 2, 2014.
Gains J, Mandeville H, Cork N, Brock P, Gaze M. Ten challenges in the management of neuroblastoma. Future Oncol. 2012 Jul. 8(7):839-58. [Medline].
Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010 Sep 30. 363(14):1324-34. [Medline].
Pai Panandiker AS, Beltran C, Billups CA, McGregor LM, Furman WL, Davidoff AM. Intensity modulated radiation therapy provides excellent local control in high-risk abdominal neuroblastoma. Pediatr Blood Cancer. 2012 Sep 28. [Medline].
Molenaar JJ, Domingo-Fernández R, Ebus ME, Lindner S, Koster J, Drabek K, et al. LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression. Nat Genet. 2012 Oct 7. [Medline].
Shimada H, Chatten J, Newton WA Jr, et al. Histopathologic prognostic factors in neuroblastic tumors: definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastomas. J Natl Cancer Inst. 1984 Aug. 73(2):405-16. [Medline].
Bostrom B, Nesbit ME Jr, Brunning RD. The value of bone marrow trephine biopsy in the diagnosis of metastatic neuroblastoma. Am J Pediatr Hematol Oncol. 1985 Fall. 7(3):303-5. [Medline].
Brodeur GM, Castleberry RP. Neuroblastoma. Pizzo PA, Poplack DG, eds. Principles and Practice of Pediatric Oncology. Philadelphia, Pa: Lippincott, Williams & Wilkins; 1993. Vol 1: 739-67.
Brodeur GM, Green AA, Hayes FA. Cytogenetic studies of primary human neuroblastomas. Prog Cancer Res Ther. 1980. 12:73.
Brodeur GM, Pritchard J, Berthold F, et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993 Aug. 11(8):1466-77. [Medline].
Brodeur GM, Seeger RC, Barrett A, et al. International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma. J Clin Oncol. 1988 Dec. 6(12):1874-81. [Medline].
Buckley SE, Chittenden SJ, Saran FH, Meller ST, Flux GD. Whole-body dosimetry for individualized treatment planning of 131I-MIBG radionuclide therapy for neuroblastoma. J Nucl Med. 2009 Sep. 50(9):1518-24. [Medline].
Connolly AM, Pestronk A, Mehta S, et al. Serum autoantibodies in childhood opsoclonus-myoclonus syndrome: an analysis of antigenic targets in neural tissues. J Pediatr. 1997 Jun. 130(6):878-84. [Medline].
Evageliou NF, Hogarty MD. Disrupting polyamine homeostasis as a therapeutic strategy for neuroblastoma. Clin Cancer Res. 2009 Oct 1. 15(19):5956-61. [Medline].
Fulda S. The PI3K/Akt/mTOR pathway as therapeutic target in neuroblastoma. Curr Cancer Drug Targets. 2009 Sep. 9(6):729-37. [Medline].
Grosfeld JL. Neuroblastoma. Pediatric Surgery. 1998. Vol 1: 405-19.
Homsy YL, Austin PF. Neuroblastoma. Graham SD Jr, ed. Glenn's Urologic Surgery. 5th ed. Philadelphia, Pa: Lippincott-Raven; 1998. 687-90.
Howman-Giles R, Shaw PJ, Uren RF, Chung DK. Neuroblastoma and other neuroendocrine tumors. Semin Nucl Med. 2007 Jul. 37(4):286-302. [Medline].
Kim S, Chung DH. Pediatric solid malignancies: neuroblastoma and Wilms' tumor. Surg Clin North Am. 2006 Apr. 86(2):469-87, xi. [Medline].
Kushner BH, Helson L. Coordinated use of sequentially escalated cyclophosphamide and cell- cycle-specific chemotherapy (N4SE protocol) for advanced neuroblastoma: experience with 100 patients. J Clin Oncol. 1987 Nov. 5(11):1746-51. [Medline].
Lessig MK. The role of 131I-MIBG in high-risk neuroblastoma treatment. J Pediatr Oncol Nurs. 2009 Jul-Aug. 26(4):208-16. [Medline].
Look AT, Hayes FA, Shuster JJ, et al. Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol. 1991 Apr. 9(4):581-91. [Medline].
Maris JM, Hogarty MD, Bagatell R, Cohn SL. Neuroblastoma. Lancet. 2007 Jun 23. 369(9579):2106-20. [Medline].
Matthay KK, Sather HN, Seeger RC, et al. Excellent outcome of stage II neuroblastoma is independent of residual disease and radiation therapy. J Clin Oncol. 1989 Feb. 7(2):236-44. [Medline].
Meany HJ, Sackett DL, Maris JM, Ward Y, Krivoshik A, Cohn SL, et al. Clinical outcome in children with recurrent neuroblastoma treated with ABT-751 and effect of ABT-751 on proliferation of neuroblastoma cell lines and on tubulin polymerization in vitro. Pediatr Blood Cancer. 2010 Jan. 54(1):47-54. [Medline]. [Full Text].
Mora J, Cheung NK, Kushner BH, et al. Clinical categories of neuroblastoma are associated with different patterns of loss of heterozygosity on chromosome arm 1p. J Mol Diagn. 2000 Feb. 2(1):37-46. [Medline].
Mueller S, Matthay KK. Neuroblastoma: biology and staging. Curr Oncol Rep. 2009 Nov. 11(6):431-8. [Medline].
Mullassery D, Dominici C, Jesudason EC, McDowell HP, Losty PD. Neuroblastoma: contemporary management. Arch Dis Child Educ Pract Ed. 2009 Dec. 94(6):177-85. [Medline].
Nyalendo C, Sartelet H, Barrette S, Ohta S, Gingras D, Béliveau R. Identification of membrane-type 1 matrix metalloproteinase tyrosine phosphorylation in association with neuroblastoma progression. BMC Cancer. 2009 Dec 4. 9:422. [Medline]. [Full Text].
Reid GS, Shan X, Coughlin CM, Lassoued W, Pawel BR, Wexler LH, et al. Interferon-gamma-dependent infiltration of human T cells into neuroblastoma tumors in vivo. Clin Cancer Res. 2009 Nov 1. 15(21):6602-8. [Medline]. [Full Text].
Roberts S, Creamer K, Shoupe B, et al. Unique management of stage 4S neuroblastoma complicated by massive hepatomegaly: case report and review of the literature. J Pediatr Hematol Oncol. 2002 Feb. 24(2):142-4. [Medline].
Ross JA, Davies SM. Screening for neuroblastoma: progress and pitfalls. Cancer Epidemiol Biomarkers Prev. 1999 Feb. 8(2):189-94. [Medline].
Rufini V, Calcagni ML, Baum RP. Imaging of neuroendocrine tumors. Semin Nucl Med. 2006 Jul. 36(3):228-47. [Medline].
Russo C, Cohn SL, Petruzzi MJ, de Alarcon PA. Long-term neurologic outcome in children with opsoclonus-myoclonus associated with neuroblastoma: a report from the Pediatric Oncology Group. Med Pediatr Oncol. 1997 Apr. 28(4):284-8. [Medline].
Tonini GP, Boni L, Pession A, et al. MYCN oncogene amplification in neuroblastoma is associated with worse prognosis, except in stage 4s: the Italian experience with 295 children. J Clin Oncol. 1997 Jan. 15(1):85-93. [Medline].
Van Maerken T, Vandesompele J, Rihani A, De Paepe A, Speleman F. Escape from p53-mediated tumor surveillance in neuroblastoma: switching off the p14(ARF)-MDM2-p53 axis. Cell Death Differ. 2009 Dec. 16(12):1563-72. [Medline].
Weinstein JL, Katzenstein HM, Cohn SL. Advances in the diagnosis and treatment of neuroblastoma. Oncologist. 2003. 8(3):278-92. [Medline].