Utility of CK7 Versus p16 as a Prognostic Biomarker in CIN 2

Abstract

Cervical intraepithelial neoplasia (CIN) 2 is an equivocal diagnosis, with p16 immunohistochemical positivity currently recommended for diagnostic confirmation. Biomarkers characteristic of squamocolumnar junction cells were recently found to be positive in almost all CIN 2 and CIN 3. CIN 1 lesions which express squamocolumnar junction markers (in particular cytokeratin 7 [CK7]) are associated with a higher rate of subsequent high-grade squamous intraepithelial lesion, suggesting that CK7 may be a useful prognostic biomarker for CIN 1. We sought to determine the utility of CK7 as a prognostic biomarker in the setting of morphologic CIN 2, and to compare this to the utility of p16 in this setting. We performed CK7 immunohistochemical on 116 cases originally diagnosed as CIN 2. Of these, 68.1% were p16 and 90.5% were CK7. A total of 19.5% of patients had a subsequent diagnosis of CIN 3 on biopsy or excision; the index CIN 2 lesion was CK7 in all of these cases (sensitivity 100%) and p16 in all but 1 (21/22; sensitivity 95.5%). The specificity of p16 (37.4%) and CK7 (8.0%) for predicting subsequent CIN 3 were significantly different (P<0.001). While p16 expression was significantly associated with subsequent CIN 3 (P=0.002), CK7 expression was not (P=0.202). We conclude that CK7, unlike p16, is not useful as a prognostic biomarker in CIN 2. While it is still promising as a prognostic marker in CIN 1, additional studies are needed to determine optimal staining/interpretation criteria.

Expression of CK7 and CDKN2 in Cervical Intraepithelial Neoplasia and Correlation with Clinical Outcome

“…Considering the previously cited studies, CDKN2A is a relevant biomarker to detect patients who unlikely to have progression of an intraepithelial lesion but will not indicate an unfavorable prognosis regardless of the previous histological diagnosis of CIN1 or CIN2. Umphress et al pointed out a high sensitivity for CDKN2A in predicting progression to CIN3 or worse (23) , similarly to our study.…”

“…A profile analysis of CDKN2A and CK7 markers showed that expression was positive for both in 64.7% of cases and was negative for 28.3%. It has also been found that positive expression of CDKN2A and CK7 increases the chance of progression from CIN2 to CIN3 or worse (23). In addition, this investigation indicated that CDKN2A specificity is greater than CK7, as observed in the present study.…”

“…Two other studies presented positive expression in all high-risk lesions, indicating that high-grade lesions have a greater expression of CK7 (5,19). In addition, a recent evaluation of 116 cervical biopsies with CIN2 histological diagnosis showed that 90.5% of cases were positive for CK7 (23). In CIN2, we observed that all patients with unfavorable clinical outcome were CK7-positive, with a sensitivity of 100% for the marker in identifying an unfavorable outcome.…”

“…In CIN2, we observed that all patients with unfavorable clinical outcome were CK7-positive, with a sensitivity of 100% for the marker in identifying an unfavorable outcome. Umphress et al obtained similar results (23). A few studies have evaluated the prognosis of patients with CIN2 using CK7, but no one presented the same criteria, making this work unheard of.…”

A Study of Cytokeratin-7 Expression and Clinicopathological Correlation in Dysplasia and Squamous Cell Carcinoma of the Cervix

“…CK-7 is described as a marker for SCJ progenitor cells and is expressed in mostly in case of CIN II and CIN III. Higher the grade of CIN, higher the CK-7 expression (van der Marel et al, 2014;Umphress et al, 2018;Lima et al 2018). The site of origin of LSIL (CIN I) plays an important role in its progression.…”