Predictive Role of the p16 Immunostaining Pattern in Atypical Cervical Biopsies with Less Common High Risk HPV Genotypes

Abstract

P16 immunostaining is considered a useful surrogate of transcriptionally active high-risk (hr) HPV infection. Only strong and widespread "block-like" immunoreactivity is considered specific, whereas weak/focal p16 positive immunostaining is considered not specific, and follow-up and HPV molecular detection is not indicated. The aim of the study was to evaluate the presence of HPV DNA and Ki67 immunostaining in 40 cervical atypical biopsies (CALs) with mild and focal histological features suggestive of HPV infection-20 cases with weak/focal p16 positive immunoreactivity and 20 cases negative for p16 expression. In 16/20 weak/focal p16 positive CALs (80%), the INNO-LiPA HPV genotyping detected hrHPV genotypes (HPV 31, 51, 56, 59, 26, 53, 66, 73, and 82). Co-infection of two or more hrHPV genotypes was often evidenced. HPV16 and 18 genotypes were never detected. Ki67 immunostaining was increased in 10/20 cases (50%). In 19/20 p16 negative CALs, hrHPV infection was absent and Ki67 was not increased. These results suggest that weak/focal p16 immunostaining represents the early stage of transcriptionally active infection, strongly related to the presence of less common hrHPV genotypes, probably with a slower transforming power, but with a potential risk of progression if the infection persists. HPV DNA genotyping and follow-up could be useful in these cases to verify if they are able to evolve into overt dysplastic changes and to improve knowledge of less common hrHPV genotypes.

Keywords: Ki67; high-risk HPV; immunohistochemistry; p16.

Figure 1

w/f p16+ CAL case showing koilocytic changes and mild epithelial atypia (A) with a focal positivity for p16 in few epithelial cells (B) and high proliferation rate with Ki67 positive immunostaining in all the squamous epithelium (C). A: Ematoxylin and eosin, 200×; B: p16 immunohistochemical stain, 100×; C: Ki67 immunohistochemical stain, 100×.

Figure 2

w/f p16+ CAL case with mild epithelial atypia (A) characterized by weak and patchy p16+ immunostaining in contiguity to a circumscribed “block like” p16 positive area (B), the latter with full thickness Ki67 immunostaining (C). A: Ematoxylin and eosin, 100×; B: p16 immunohistochemical stain, 100×; C: Ki67 immunohistochemical stain, 100×.