Dysregulation of Epidermal Growth Factor Receptor Expression in Premalignant Lesions during Head and Neck Tumorigenesis

Abstract

The development of head and neck cancer, believed to result from field cancerization and a multistep process of tumorigenesis, is often associated with an accumulation of genotypic and phenotypic alterations. The phenotypic changes could be the result of dysregulation of growth control genes such as epidermal growth factor receptor (EGFR). With the goal of identifying a potential biomarker of the multistep process of tumorigenesis, we studied specimens of 36 head and neck squamous cell carcinomas from 5 different sites that contained normal epithelia and/or premalignant lesions adjacent to the tumors. Almost all of the individuals from whom these specimens were obtained had been exposed to first-hand smoking and/or alcohol consumption. Using a monoclonal anti-EGFR antibody for immunohistochemical analysis on paraffin-embedded sections with attached 886 cells for internal control, the levels of EGFR expression were assessed by image analysis. The relative staining intensity of EGFR in normal epithelia adjacent to tumors was 2-fold higher than that in normal control epithelium (P = 0.021), suggesting that, even in histologically normal epithelium, EGFR was already up-regulated in tissues surrounding tumors. These findings supported the theory of field cancerization in head and neck tumorigenesis. As tissue progressed from normal tissue adjacent to tumor to hyperplasia and to dysplasia, EGFR expression remained elevated. However, in the step from dysplasia to squamous cell carcinoma, EGFR expression was further and dramatically up-regulated (P = 0.01). Therefore, these results indicate that EGFR dysregulation happens in two steps, the moderate up-regulation of EGFR expression in normal epithelium adjacent to tumor and the further up-regulation of EGFR expression in the change from dysplasia to squamous cell carcinoma. In summary, the studies presented here indicate that EGFR dysregulation might be a useful marker for identifying individuals at risk of tumor development and an intermediate end point in chemoprevention trials.