p16INK4A and p14ARF expression pattern by immunohistochemistry in human papillomavirus-related cervical neoplasia.

Human papillomavirus is known to play an important etiological role in the genesis of cervical cancer, but only a very small proportion of infected women develop invasive cervical cancer. The purpose of cervical cancer prevention is early diagnosis of its precursors. The molecular detection of human papillomavirus DNA as a diagnostic test to cervical carcinogenesis gave a low positive predictive value as compared to the use of biomarkers. p16INK4A and possibly p14ARF have been proposed as putative surrogate biomarkers that would allow identification of dysplastic cervical epithelia. Serial consecutive biopsies representing normal cervical epithelium to cervical intraepithelial neoplasia and/or invasive cervical cancer were stained with immunohistochemistry for p16INK4A, p14ARF and proliferating cell nuclear antigen. The positive rates of these markers were significantly higher in cervical intraepithelial neoplasia and in squamous cell carcinoma than in normal cervix (P<0.01). No significant difference was noted between lesions progressing from cervical intraepithelial neoplasia to squamous cell carcinoma for both p16INK4A and p14ARF expression (P>0.05). For both biomarkers, nuclear staining was predominantly seen. However, the cytoplasmic stain of p16INK4A increased with disease progression and the pattern of expression varied between different tumors and its location within the lesion. Both nuclear and cytoplasmic staining with p16INK4A and p14ARF of affected epithelial cells were considered positive. In the adjacent normal tissue to cervical neoplasia, the positive rates of p16INK4A, p14ARF and proliferating cell nuclear antigen expression were higher than those found distant to these lesions but the findings did not reach statistical significance. No correlation was seen between the human papillomavirus types detected and the expression of p16INK4a and p14ARF. In conclusion, overexpression of p16INK4A and p14ARF act as potential biomarkers for cervical cancer progression from premalignant lesions.