Amplification of the MYCN oncogene has profound impact on prognosis. MYCN is located on the distal short arm of chromosome 2. MYCN amplification is present in about 25% to 30% of primary tumors, most in advanced-stage disease; the greater the number of copies, the worse the prognosis. Amplification of MYCN does not karyotypically manifest at the resident 2p23p24 site, but rather as extrachromosomal double minute chromosomes or homogeneously staining regions on http://ebooksmedicine.net
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Fig. 7.34 ). MYCN amplification is currently the most important genetic abnormality used in risk stratification of neuroblastic tumors and automatically renders a tumor as “high” risk, irrespective of stage or age.
DNA ploidy is another prognostic factor, with tumors that are hyperdiploid (with whole chromosome gains) having more favorable prognosis than tumors that are near-diploid. The latter subset, although closer to diploidy on absolute number, tends to have multiple structural rearrangements between, and within, chromosomes that can result in adverse molecular events, such as MYCN amplification.
Although age, stage, MYCN status, and ploidy are used clinically for assigning prognostication, many other “experimental” molecular aberrations have been identified that might also have prognostic bearings, or be potential candidates for targeted therapy. For example, expression of TrkA, a high-affinity receptor for nerve growth factor that is indicative of differentiation toward sympathetic ganglia lineage, is associated with favorable prognosis. Overall, besides MYCN amplification and ALK mutations (latter in ~10%), de novo neuroblastomas have few recurrent “hotspot” mutations. However, a very high frequency of relapsed neuroblastomas (>75%) have mutations in the RAS-MAP kinase signaling pathway, suggesting that relapsed tumors might be targeted with therapies against these oncogenic pathways.
Children younger than 2 years with neuroblastomas generally present with a protuberant abdomen resulting