PLASTICITY OF NEUROBLASTOMA TUMOR-CELLS TO DIFFERENTIATE ALONG A FETAL ADRENAL GANGLIONIC LINEAGE PREDICTS FOR IMPROVED PATIENT SURVIVAL

We have recently presented a model of human adrenal medullary histogenesis that incorporates all neural crest-derived lineages (chromaffin, sustentacular, and ganglionic) known to compose this tissue. To determine if neuroblastomas correspond to the arrested maturation of embryonal adrenal medullary cells, we evaluated the expression of adrenal medullary developmental markers in 81 neuroblastoma tumors. We found that patterns of chromaffin-related gene expression in these tumors correlated exactly with the patterns observed during maturation of adrenal medullary cells (P2 < 10(-5)). In a multivariate Cox proportional hazards analysis of developmental marker expression and other well-recognized prognostic variables, evidence of maturation along a fetal ganglionic lineage, as monitored by HNK-1 immunoreactivity (relative risk of 6.42, P2 = 0.0001), and age at diagnosis (relative risk of 5.05, P2 = 0.0042) were independent and significant prognostic indicators of patient survival. These studies demonstrate that neuroblastomas correspond to embryonal adrenal medullary cells arrested at recognizable stages during development, and that evidence of maturation along a fetal ganglionic lineage appears to have major importance in predicting patient survival.