p16ink4 and cytokeratin 7 immunostaining in predicting HSIL outcome for low-grade squamous intraepithelial lesions: a case series, literature review and commentary

p16ink4 and cytokeratin 7 (CK7) have been proposed to identify low-grade squamous intraepithelial lesions (LSIL) at greater or lesser risk for an outcome of high-grade squamous intraepithelial lesion (HSIL). We correlated CK7 and p16ink4 staining in LSILs with outcome on follow-up and placed this information in the context of prior reports. Cervical LSIL biopsies with at least 1-year follow-up information were immunostained for CK7 and pl6ink4. Follow-up outcomes included no SIL, LSIL (persistence) or HSIL (CIN2+). In all, 109 LSILs were studied and 18.3% stained positive for CK7. Ninety-one percent of CK7-negative LSILs regressed, 4.5% persisted, and 4.5% had an HSIL outcome, versus 60, 20, and 20% of CK7-positive LSILs, respectively (P= 0.036). p16ink4 status did not significantly associate with outcome. Review of the literature revealed a highly variable rate of both positive p16ink4 immunoreactivity in LSIL and CIN2+ outcome for p16-positive LSIL but a consistently high negative predictive value (>90%) in the case of no/low p16 expression. Inter-observer reproducibility for the diagnosis of CIN2 in the literature ranged from poor to good, with unanimous agreement on the diagnosis of CIN2 occurring in less than 25% of cases. As with high-risk human papillomavirus testing, the most clinically useful result of p16ink4 staining is a negative test, implying no lesion or CIN1 and conferring a low risk of HSIL outcome. HSIL outcomes (`progression') are highly variable and are subject to wide differences in inter-observer interpretation for CIN2. This argues against the wisdom of relying on p16ink4 to both predict CIN2+ or upgrade CIN1 to CIN2. It also begs the question of whether CIN2 should be replaced by an alternate and less pejorative term (SIL of intermediate grade) for lesions that are not reproducibly classified as LSIL or HSIL, with an appropriate management scheme.