NUKLEARNI IZRAŽAJ RECEPTORA EPIDERMALNOG FAKTORA RASTA U SKVAMOZNIM EPITELNIM LEZIJAMA GRKLJANA

Aim of the study: The membrane EGFR (mEGFR) protein over-expression in the head and neck squamous cell carcinoma (SCC) is considered to cause increased EGFR activity which adds to tumorigenicity and therapy resistance. The mEGFR upon stimulation can translocate to the nucleus (nEGFR) where it has been associated with poor prognosis and worse survival in many cancers. The relevance of differentially located EGFR proteins in laryngeal lesions has not been studied enough and remains unclear. Aim of our study was to examine nuclear and membrane EGFR protein expression as well as EGFR gene status and cell cycle proliferation markers in the laryngeal polyps, dysplasia and SCC using immunohistochemistry and in situ hybridization. Material and Methods: We examined 37 polyps, 44 dysplasia and 42 squamous cell carcinomas (SCC) for nEGFR, mEGFR, Ki-67, p53, cyclin D1 and TGF-α protein expression using immunohistochemistry and EGFR gene status by FISH. Results: There was significantly higher frequency of strong nEGFR between SCC, dysplasia and polyps (P<0.0001), and strong mEGFR in the SCC and laryngeal dysplasia comparing to polyps (P<0.0001). Gene amplification was confirmed only in relatively small number of SCC but not in non-neoplastic lesions. The results of the mean values of Ki-67 and cyclin D1 expression differed significantly between SCC and laryngeal dysplasia as well as between SCC and polyps (P<0.001 and P=0.008, respectively), but there was no statistically significant difference in the expression between dysplasia and polyps. There was statistically significant difference in p53 expression between SCC and polyps (P=0.001) however the p53 expression was not statistically different when we compared expression between SCC and laryngeal dysplasia. Also, there was no statistically significant difference of TGF-α expression between SCC, dysplasia and benign lesions (P=0.947). In dysplasia the statistically significant positive correlations between nEGFR, and Ki-67 (P=0.029), p53 (P=0.001), and cyclin D1 (P=0.031) were found. nEGFR and mEGFR expression showed statistically significant inverse correlation in the SCC (P=0.004) as well as nEGFR and cyclin D1 (P=0.032). Univariate statistical analysis showed statistically significant correlation between strong nEGFR protein expression with worse overall survival in laryngeal SCC, alone or in co-expression with strong cyclin D1 and high Ki-67 (P=0.025, P=0.046, P=0.043, respectively). Conclusion: Our data show that nuclear EGFR cellular localization might influence biology of the laryngeal carcinogenesis and is indicator of poor survival.