P21 Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis

Human papillomavirus is involved in the carcinogenesis of tonsillar squamous cell carcinomas. Here, we investigated the expression and the prognostic value of key cell cycle proteins in the pRb and p53 pathways in both human papillomavirus type 16-positive and -negative tonsillar squamous cell carcinomas. Using immunohistochemistry, 77 tonsillar squamous cell carcinomas with known human papillomavirus type 16 status and clinical outcome were analyzed for expression of Ki67, p16 INK4A, cyclin D1, pRb, p14 ARF , MDM2, p53, p21 Cip1/WAF1 , and p27 KIP1 . Results were correlated with each other and with clinical and demographic patient data. A total of 35% of tonsillar carcinomas harbored integrated human papillomavirus type 16 DNA and p16 INK4A overexpression, both being considered essential features for human papillomavirus association. These tumors also showed the overexpression of p14 ARF ( P <0.0001) and p21 Cip1/WAF1 ( P =0.001), and downregulation of pRb ( P <0.0001) and cyclin D1 ( P =0.027) compared with the human papillomavirus-negative cases. Univariate Cox regression analyses revealed a favorable survival rate for non-smokers ( P =0.006), as well as for patients with T1-2 tumors ( P <0.0001) or tumors showing low expression of cyclin D1 ( P =0.028), presence of human papillomavirus and overexpression of p16 INK4A ( P =0.01), p14 ARF ( P =0.02) or p21 Cip1/WAF1 ( P =0.004). In multivariate regression analyses, smoking and tumor size, as well as expression of cyclin D1 and p21 Cip1/WAF1 , were found to be independent prognostic markers. We conclude that human papillomavirus positivity in tonsillar squamous cell carcinomas strongly correlates with p21 Cip1/WAF1 and p14 ARF overexpression and downregulation of pRb and cyclin D1. In particular p21 Cip1/WAF1 overexpression is an excellent favorable prognosticator in tonsillar squamous cell carcinomas.