p16 Positive Histologically Bland Squamous Metaplasia of the Cervix: What does It Signify?

With increasing use of p16 immunohistochemistry (IHC) in diagnosis of premalignant lesions of cervix, we occasionally encounter p16 positivity in squamous metaplasia that lacks morphologic characteristics of "atypical squamous metaplasia" or of squamous intraepithelial lesion (SIL). Our study aims to investigate if transcriptionally active human papilloma virus (HPV) can be identified in such foci and if they have any relationship with squamo-columnar junction (SCJ) cells. Twenty-two cases of cervical specimens with at least a focus of p16 positive bland squamous metaplasia, were selected. HPV E6/E7 mRNA in situ hybridization followed by IHC for CK7 (SCJ biomarker), Ki67, and HPV16 E2, were performed. Follow-up information was obtained. Four cases were excluded due to insufficient tissue. Of the final 18 cases, HPV E6/E7 mRNA in situ hybridization was positive in all. Nine cases showed positivity in >50% cells and the epithelial thickness involved was ≥lower two-thirds in 13 cases. Of the further evaluable 15 cases, CK7 was positive in 14, Ki67 was positive in 10, and HPV16 E2 was negative in all. Concomitant high-grade squamous intraepithelial lesion was identified in 10 cases. On follow-up (duration: 1 to 19 mo), 6 patients showed histologic high-grade squamous intraepithelial lesion. Our study demonstrates that p16 positivity in squamous metaplasia of cervix is associated with the presence of transcriptionally active high-risk HPV even when there are no clear morphologic features of dysplasia. Our results suggest that these lesions are early SILs or SILs that are not yet morphologically evident, most of which arise from SCJ and should be closely followed.