Prognostic Value of p16^INK4A and Ki67 Co-expression in Patients with Vaginal Intraepithelial Neoplasia

Vaginal intraepithelial neoplasia (VaIN) refers to a premalignant lesion of the vagina that has the potential to progress to invasive cancer. The rate of progression to invasive carcinoma among patients treated due to VaIN was reported between 2 and 12%. High-risk (hr) HPV infection is an important factor in the development of VaIN. Consequently, overexpression of p16 protein in the cells of dysplastic epithelium is accepted as an indicator of hr HPV associated transformation. In addition, HPV infection causes increased cell proliferation and concurrent overexpression of Ki67.

The aim was to analyze the roles of p16^INK4A and Ki67 expression and HPV infection in the recurrence of VaIN. Forty-eight patients with histologically confirmed VaIN, diagnosed between 2003 and 2020 at a tertiary gynecologic oncology center, were evaluated retrospectively. p16^INK4A and Ki67 expression were evaluated by immunohistochemistry, and HPV infection was detected by Hybrid Capture II assay. Intraepithelial neoplasia was categorized into low-grade (VaIN1) and high-grade (VaIN2 and VaIN3) lesions. SPSS software v20.0 was used for data interpretation and statistical analysis.

Forty-eight cases with VaIN were eligible for analysis; ten (21%) had VaIN1, and 38 (79%) had VaIN2/3 (six for VaIN2, 32 for VaIN3). Patients with diffuse and high co-expression of p16^INK4A and Ki67 had significantly higher disease recurrence (p = 0.024). In addition, patients with diffuse and high co-expression of p16^INK4A and Ki67 had a significantly higher disease progression to invasive cancer (p = 0.016). Interestingly, HPV infection with HPV18 subtype was found very rare in patients with VaIN (2.6%).

There was a significant correlation between the expression of p16^INK4A and Ki67 together with the disease recurrence and progression to invasive cancer. In addition, the infection rate with HPV18 subtype appears to be less than expected in patients with VaIN.