Human papillomavirus genotyping and p16INK4a expression in cervical intraepithelial neoplasia of adolescents

Abstract

Adolescents have high rates of human papillomavirus (HPV) infection, and persistent high-risk HPV infection can lead to the development of cervical cancer. The cyclin-dependent kinase inhibitor, p16INK4a is overexpressed in cervical intraepithelial neoplasia (CIN), probably due to a persistent and integrated HPV infection. This study investigated p16INK4a expression, grades of CIN, and high-risk HPV infection in adolescent cervical biopsies. Biopsies were immunohistochemically stained for p16INK4a. The presence of wide-spectrum, low-risk, or high-risk HPV was determined by amplifying DNA extracted from the cervical biopsies. Biopsies were classified as cervicitis, 15 cases; CIN 1, 48 cases; CIN 2, 46 cases, and CIN 3, 52 cases. The distribution of p16INK4a staining was graded as patchy, diffuse basal, and diffuse full thickness. Pearson's χ2 tests analyzed the relationships between p16INK4a staining, HPV infection, and CIN. Biopsies of cervicitis were negative for HPV and for p16INK4a expression. High-risk HPV 16, 18, and 31 increased from 18% in CIN 1 to 66% in CIN 2/3 (P<0.001). In CIN 1, p16INK4a was positive in 44% of biopsies with 35% showing patchy, 7% diffuse basal, and one case (2%) showing diffuse full thickness staining. In CIN 2/3, p16INK4a was positive in 97% of biopsies with 23% showing patchy, 21% diffuse basal, and 53% diffuse full thickness staining. The difference in the proportions of biopsies showing patchy p16INK4a staining in CIN 1 and diffuse full thickness staining in CIN 2/3 was significant (P<0.001). In CIN 1, 61% of high-risk HPV-positive biopsies were p16INK4a negative, while all high-risk HPV-positive CIN 2/3 biopsies were p16INK4a positive. Diffuse, full thickness p16INK4a expression discriminated low-grade from high-grade CIN and appears to be a marker of persistent high-risk HPV infection.