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Neuroblastoma, a tumor of the sympathetic
nervous system, is the most common solid tumor in childhood. Interestingly, some
infants with metastatic disease experience complete tumor regression
without therapy, and other patients may have maturation of their
tumor into a benign ganglioneuroma. Nevertheless, the majority of
patients have metastatic disease at diagnosis that progresses despite
intensive multimodality therapy.1-3 Current risk classification
schemes use biological and clinical features at diagnosis to predict
tumor behavior and to stratify patients to an appropriate treatment.
Children with tumors that have lower risk features are spared unnecessary
therapies yet still achieve excellent outcomes. However, the survival
of patients with high-risk neuroblastoma is still unacceptably low.
Advances in understanding the molecular pathogenesis of this tumor,
including how alterations in specific biological pathways impact
tumor behavior, may lead to novel therapeutics to reduce toxicity
in patients with favorable disease and improve outcomes in those
with unfavorable disease.4,5
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Epidemiology,
Genetics, and Molecular Pathogenesis
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Neuroblastoma is the most common malignancy diagnosed in infants
and accounts for 8% to 10% of childhood cancers
overall. Unfortunately, it also accounts for 15% of childhood
cancer-related deaths. The prevalence is about 1 per 7000 live births,
and there are about 650 new cases per year in the United States,
with an incidence of 10.5 per million per year in white and 8.8
per million per year in black children less than 15 years of age.1-3 This
incidence appears fairly uniform throughout the world. The tumor
is slightly more common in males than in females, with a male-to-female
ratio of 1.2:1 in most large studies. The median age at diagnosis is
22 months, and less than 5% of patients are diagnosed after
10 years of age. The rare adolescent or young adult with neuroblastoma
poses a unique treatment challenge, as their tumors appear biologically distinct
with an indolent and often progressive course.
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The etiology of neuroblastoma is unknown in most cases, but it
appears unlikely that environmental exposures play a major role,
because no prenatal or postnatal drug, chemical, or radiation exposure
has been strongly or consistently associated with an increased risk.
Neuroblastoma has been reported in patients with neurofibromatosis
type 1, as well as central congenital hypoventilation syndrome (CCHS)
and Hirschsprung disease, suggesting that disordered neural crest
development may predispose to neuroblastoma. Mutations in the PHOX2B gene,
a key regulator of autonomic neural development, have been identified
in neuroblastomas associated with these latter disorders, and in
occasional sporadic tumors.6,7 Diverse congenital anomalies
have also been reported in association with neuroblastoma, but without
a causal genetic etiology. Finally, there may be a decreased prevalence
of neuroblastoma in patients with Down or Klinefelter syndromes,
and an increase in Turner syndrome, but the reasons for this are
unclear.
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As with many embryonal tumors, a small subset of neuroblastoma
patients has a familial predisposition that follows an autosomal
dominant pattern of inheritance. Analysis of ...