Prognostic significance of biochemical heterogeneity of catecholaminergic clones in neuroblastoma

Abstract

Background/Purpose Genetic heterogeneity of neuroblastic tumors leads to biochemical changes that manifest themselves in different symptoms and clinical courses, which may vary from spontaneous regression and remission to progression with fatal outcome. Methods To test the hypothesis that ratios of dopamine (DA) to noradrenaline and of DA to vanillylmandelic acid reflect the composition of adrenergic clones and tumor heterogeneity, we determined urinary DA/noradrenaline and DA/vanillylmandelic acid ratios that presumably reflect DA- β-hydroxylase (DBH) activity and the prognostic values thereof. Results Based on catecholamine metabolism, 4 model situations were defined: ( a) complete block of DBH in all cells; ( b) block of DBH in some cells; ( c) a different enzymatic block; and ( d) normal DBH activity in the population of tumor-forming cells. Normal DBH activity was encountered most frequently in children younger than 2 years and in tumors representing favorable prognostic stages (I, II, and IVS). Surviving children with stage IV neuroblastoma presented with tumors composed primarily of cells without the DBH block. Further stratification of 2 prognostically poor groups (stages IV and III + IV) was possible with respect to DBH activity. Conclusions Differential production of neurotransmitters in a population of tumor cells may be explained in terms of tumor heterogeneity.