Folkman and colleagues were among the first to suggest that the intensity of intratumoral angiogenesis correlates with tumor grade and aggressiveness (Brem et al. 1972). Although the majority of published studies have shown a positive correlation between intratumoral microvessel density and prognosis in solid tumors (Hasan et al. 2002), the prognostic role of angiogenesis in neuroblastoma is unclear. Meitar et al. initially reported in a study of 50 primary tumors that high tumor vascularity strongly correlated with widely disseminated disease, MYCN amplification, unfavorable histology, and poor survival (Meitar et al. 1996). Ribatti et al. found similar results in a smaller series of patients, with increased microvessel density associated with advanced-stage tumors (Ribatti et al. 2001). In further support, Erdreich-Epstein and co-workers (2000) have recently demonstrated a significant association between high-risk neuroblastoma and high levels of expression of the integrins avb3 and avb5, which are markers of active angiogenesis. In contrast, Canete et al. (2000) in a study of 69 neuroblastoma patients found no correlation of vascular parameters with the prognostic factors of age, stage, histology, TrkA, or MYCN amplification or with overall survival. The conflicting results most likely reflect differences in techniques used to measure vessel number, a difficulty encountered in reconciling the results of studies of other solid tumors such as breast cancer (Hasan et al. 2002). Interestingly, all three studies are in concordance, i.e., infants with stage-4S disease have higher levels of vascularity than any of the other stages. The increased vascularity in stage 4S is consistent with the rapid rate of tumor growth in a subset of these patients with widely disseminated disease.
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