A DEVELOPMENTAL MODEL OF NEUROBLASTOMA - DIFFERENTIATING STROMA-POOR TUMORS PROGRESS ALONG AN EXTRAADRENAL CHROMAFFIN LINEAGE

The prognosis of children with neuroblastoma (NB) is dependent upon th e patient's age at diagnosis, the location of the primary tumor, and h istologic tumor cell differentiation. These characteristics, as well a s the presumption that NE results from clonal expansion of primitive c ells involved in sympathetic nervous system (SNS) development, predict that a model of tumorigenesis based upon normal fetal SNS histogenesi s might indicate tumor progenitor status and define biologic and clini cal behavior. Immunohistochemistry and in situ hybridization were used to examine a panel of marker gene products predicted or shown to be e xpressed during SNS development in the normal human fetal SNS from 8 t o 24 weeks' gestational age. A similar analysis was performed in a sel ection of clinical NE tumors, and the results were compared. In a subs et of differentiating, often extra-adrenal NE tumors in patients who f requently had a favorable outcome, advancing morphologic tumor cell di fferentiation spatially paralleled an advancing fetal extra-adrenal ch romaffin marker gene expression phenotype tie, increasing TrkA, TrkC, TH, IGF-2, and neuron-specific enolase expression but a lack of phenyl ethanolamine N-methyltransferase expression). In these tumors, express ion of gene products associated with normal fetal sympathetic ganglion ic differentiation tie, Bcl-2, HNK-1, and neuropeptide Y) was lost wit h morphologic tumor cell differentiation. In contrast, undifferentiate d tumors, the majority of which were high stage, adrenal in origin, an d prognostically unfavorable, displayed marker expression characterist ics mirroring that of an early fetal ganglionic lineage. Thus, we show that morphologic differentiation in stroma-poor NE tumors, long held as an important prognostic feature in tumor grading systems, often cor responds to an extra-adrenal chromaffin rather than a ganglion cell or adrenal medullary chromaffin phenotype. Understanding the biology of extra-adrenal chromaffin tissues may provide an explanation for the cl inically less aggressive nature of differentiating NE tumors and sugge st potential mechanisms for spontaneous regression and/or treatment re sponse.