The cause of neuroblastoma is unknown, and no specific environmental exposure or risk factors have been identified.
Because of young age of onset with this disease, investigators have focused on events before conception and during gestation.
According to SEER data, factors investigated for which evidence is limited or inconsistent include medications, hormones, birth characteristics, congenital anomalies, previous spontaneous abortion or fetal death, alcohol or tobacco use, and paternal occupational exposures.
The vast majority of neuroblastoma arises sporadically without family history of the disease. However, 1-2% of newly diagnosed cases do have a family history of neuroblastoma. Patients with familial neuroblastoma often present at earlier age or with several distinct primary tumors.
Neuroblastoma has been known to occur in the setting of other disorders that are linked to abnormal development of neural crest tissues, such as Hirschsprung disease or central congenital hypoventilation syndrome. Genome-wide analysis of neuroblastoma from these rare familial cases has identified a genetic defect involved in these cases. Cases of neuroblastoma that accompany other congenital abnormalities of the neural crest have been associated with a germline mutation in PHOX2B. This gene is a homeobox gene that acts as a regulator of autonomic nervous system development.
In familial neuroblastoma cases that are not associated with other congenital disorders of neural crest development, ALK mutations have been identified in the germline. [9] These mutations largely occur in the kinase domain causing activation of ALK signaling. Efforts are ongoing to investigate the incidence of ALK mutations across all subsets of neuroblastoma, but initial evidence indicates that somatic mutations of the ALK gene are also present in some cases of sporadic neuroblastoma.
A 2014 study reported that deep-sequencing techniques can identify new ALK mutations at relapse of neuroblastoma, suggesting that patients would benefit from repeated tumor sampling. [10]
De Brouwer et al illustrate the occurrence of the ALK mutation specifically in neuroblastomas. Although they studied a small proportion of cases, mutations were found in similar frequencies in favorable and unfavorable outcome cases. The F1174L mutant was found more frequently in the poor outcome subgroup. [11] This example illustrates the heterogeneity of cancer and the likely possibility that targeted therapies to the ALK gene may be of benefit in a subset of ALK cancers, which may possibly include a small subset of MYC -amplified neuroblastomas. The challenge for drug development in neuroblastoma is to identify upfront high-risk cases that may benefit from ALK -directed therapy.
Genome-wide association studies (GWAS) have been used to discover numerous genetic variations associated with neuroblastoma. Variations in LMO1, BARD1, and FLJ22536 have all been associated with aggressive forms of neuroblastoma. [12, 13, 14] Genomic variations within DUSP12, DDX4, IL21RA, and HSD17B12 are associated with low-risk forms of neuroblastoma. [15]
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Histologic subtypes of neuroblastoma. Top right panel, neuroblastoma: A monotonous population of hyperchromatic cells with scant cytoplasm. Bottom left panel, ganglioneuroblastoma: Increased schwannian stroma. Bottom right panel, ganglioneuroma: Mature ganglion cell with schwannian stroma.
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CT scan of abdomen in a patient with a retroperitoneal mass arising from the upper pole of the left kidney and elevated urine catecholamines.
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MRI of a left adrenal mass. The mass was revealed by fetal ultrasonography at 30 weeks' gestation. During infancy, the mass was found on the inferior pole of the left adrenal and was completely resected. Before surgery, the metastatic workup was negative. Surgical pathology service confirmed a diagnosis of neuroblastoma. After 3 years of follow-up care, no recurrence was observed.
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A one-week-old neonate had abdominal ultrasonography for evaluation of projectile vomiting. A right adrenal mass (100% cystic) was an incidental finding. Evaluation of the mass by CT was consistent with an adrenal bleed (3.6 x 3.1 x 2.4 cc). The infant was followed at 2 weeks (2-dimensional size diminished to 1.5 x. 2.4 cm2 on ultrasonography) and then at 6 weeks to document that the adrenal bleed continued to involute. Urine catecholamines were normal.
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Table. A Consensus Pretreatment Classification schema by the International Neuroblastoma Risk Group (INRG). This schema is based in the INRG stage, age, histologic category, tumor grade of differentiation, MYCN sastus, 11q-aberrations and DNA ploidy. A combination of these characteristics results in four risk groups noted in the last column: very low, low, intermediate and high risk, with the following 5 year EFS: >85%, >75%-85%, >50%-75%, and < 50%. These risk groups are distributed among the different stages and labeled alphabetically from A to R (without letters L and M to avoid confusion with the INRG stage notation). Notations in the table are as follow: L1, localized tumor confined to one body compartment; L2, locoregional tumor with presence of one or more risk factors defined radiologically; M, distant metastatic disease (except stage MS); MS, metastatic disease confined to skin, liver and/or bone marrow in children < 18 months of age. GN, ganglioneuroma; GNB, ganglioneuroblastoma; Amp, amplified; n/amp, not amplified. (Adapted from The International Neuroblastoma Risk Group (INRG) Classifications System: An INRG Task Force Report by Cohn, et al. Journal of Clinical Oncology 27(2):289-297, 2009).
