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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

Epidemiology, Genetics, and Molecular Pathogenesis

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.

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.

As with many embryonal tumors, a small subset of neuroblastoma patients has a familial predisposition that follows an autosomal dominant pattern of inheritance. Analysis ...

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