Neuroblastoma: biological insights into a clinical enigma

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Abstract
Neuroblastoma is the most common extracranial tumour of childhood. This tumour originates from precursor cells of the peripheral (sympathetic) nervous system and usually arises in a paraspinal location in the abdomen or chest. The aetiology of neuroblastoma is unknown, but it seems unlikely that environmental exposures are important. A subset of patients inherits a genetic predisposition to neuroblastoma, and these patients usually have multifocal primary tumours that arise at an early age. A predisposition locus has been mapped to the short arm of chromosome 16. Neuroblastomas can be classified into subtypes that are predictive of clinical behaviour based on the patterns of genetic change. This information can be useful in the selection of therapy. Favourable tumours are characterized by near-triploid karyotypes with whole chromosome gains. These tumours rarely have structural rearrangements, and they usually express the TrkA neurotrophin receptor. Patients with these tumours are more likely to be less than 1 year of age, have localized tumours and a good prognosis. Unfavourable tumours are characterized by structural changes, including deletions of 1p or 11q, unbalanced gain of 17q and/or amplification of the MYCN protooncogene. They might also express the TrkB neurotrophin receptor and its ligand, brain-derived neurotrophic factor (BDNF). These patients are usually older than 1 year of age, have more advanced stages of disease and a much worse prognosis, even with aggressive treatment. Mass screening for neuroblastoma at 6–12 months of age led to an increased prevalence of neuroblastoma detected in the screened populations, but no decrease in mortality from this disease. The tumours detected have overwhelmingly been of the favourable genetic subtype. Novel, biologically based therapies are being developed that would specifically target the genes, proteins and pathways that are responsible for malignant transformation and progression in neuroblastomas. These approaches are likely to be more effective and less toxic than conventional therapy. In the future, it is likely that more extensive molecular profiling of the genetic changes and expression patterns of neuroblastoma will lead to an even more precise subclassification system that will be predictive of outcome, as well as therapies to which the tumour is most likely to be responsive.