Trk A gene expression in neuroblastoma. The clinical significance of an immunohistochemical study.

Abstract

Neuroblastomas display a spectrum of morphologic and cytologic features of neural cells, and the prognosis of patients with these tumors varies widely. Expression of trk A in these tumors, as documented by Northern blot analysis, is associated with a favorable prognosis. To examine the expression of trk A at the cellular level in individual tumors and apply the results to routine clinical use, the authors designed this immunohistochemical study using an antibody with a predetermined specificity on formalin fixed, paraffin embedded tumor sections. Expression of trk A and Ha-ras genes in 105 neuroblastomas was examined by avidin-biotin-complex immunoperoxidase staining. N-myc gene amplification was examined in 81 of the tumors by Southern blot analysis. Immunohistochemical expression in tumors correlated strongly with a favorable prognosis for trk A expression (P < 0.0001) and for Ha-ras expression (P < 0.0001). N-myc amplification was found in neuroblastomas with low expression of trk A and of Ha-ras genes. Kaplan-Meier analysis resulted in a favorable outcome associated with high trk A expression and no N-myc amplification, and a poor outcome associated with low trk A expression and demonstrable N-myc amplification (P < 0.0001). Univariate analysis showed that immunohistochemical expression of trk A at the time of diagnosis was a powerful predictor of the patient's prognosis, as were N-myc amplification and Ha-ras expression. trk A expression even correlated significantly with prognosis when the analysis was restricted to Stages III and IV tumors. Immunohistochemical detection of the trk A gene product in tumor cells is strongly predictive of a favorable prognosis for patients with neuroblastomas. The coexpression of trk A and Ha-ras genes with clinical behavior of the tumor may indicate close linkage of these genes in the nerve growth factor signal transduction system. Prognostic evaluation at diagnosis based on such molecular and genetic information should be important clinically.