Low‐ and high‐risk CIN 1 and 2 lesions: prospective predictive value of grade, HPV, and Ki‐67 immuno‐quantitative variables

Abstract

The aim of this study was to evaluate in small cervical biopsies (non-cone, non-large loop excision of the transformation zone, LLETZ) the prognostic value of both routinely assessed and reviewed cervical intraepithelial neoplasia (CIN) grades 1 and 2, oncogenic human papillomavirus (onco-HPV) DNA (HPV status) and Ki-67 immuno-quantitative features for the prediction of progression. In biopsies from 44 CIN patients (the learning set), subjective CIN grade, onco-HPV by PCR, and Ki-67 immuno-quantitative features were assessed. We followed development of the lesions by colposcopy and cytology, but the final endpoint was the histological grade (again in small biopsies). The outcome was defined as progression (histological (CIN 1 to (CIN 2 or 3)) or CIN 2 to CIN 3) or not (all other cases). Single and multivariate (Cox regression) and survival analyses were applied. The resulting predictive combination of quantitative features was then applied to a new test set of 35 consecutive CIN 2 (small) biopsies followed by large (cone or LLETZ) biopsies. In the learning set, mean follow-up of non-progression cases was 18.8 months (range 4.7-35.9), and of progression cases 13.1 months (range 6.4-32.9) (p = 0.18). Five cases progressed (11%). Of the 16 CIN 1 and 28 CIN 2 lesions, 31 cases (70%) were onco-HPV positive (5 of the CIN 1 and 26 of the CIN 2). The age of women with progression or not did not differ (p = 0.68). All 5 progression cases were CIN 2 (on review, one of these was reclassified as CIN 1), and positive for onco-HPV. Cox regression analysis showed that the percentage of Ki-67-positive cells located in the middle third layer of the epithelium (MIDTHIRD) and the 90th percentile of the stratification index (SI90) was the best combination to predict progression (log rank = 5.1, p = 0.02). Furthermore, sensitivity (100%), specificity (56%), positive predictive value (23%), negative predictive value (100%), and overall percentage correctly classified cases (61%) of this Ki-67 combination were higher than that of subjective CIN grade or HPV status, either single or combined (both for routine and review CIN grades). Adding CIN grade or HPV status did not improve the Ki-67 prognostic results. Application of the prognostic Ki-67 combination to the test set of 35 small biopsies followed by large (cone or LLETZ biopsies) gave comparable results. Analyses on homogeneous subgroups (CIN 2 only, onco-HPV+ only, or CIN2/onco-HPV+ only) gave similar results. In conclusion, Ki-67 immuno-quantitation of small biopsies showing CIN 1 or CIN 2 has strong independent prognostic value for progression.

Usefulness of liquid-based cytology specimens for the immunocytochemical study of p16 expression and human papillomavirus testing

“…All HPV subtypes detected in the current study belonged to the high-risk group and these results were found to be in keeping with previous findings showing that HPV-16 was the most frequent HPV subtype detected in cervical lesions, followed by the HPV-52 subtype. 24 Because the advantages of HPV testing have been established in cervical carcinoma screening, known biomarkers such as Ki-67 25 and MN 26 antigen have been found to be unsatisfactory in terms of their specificity and sensitivity in primary screening for cervical carcinoma. In 1998, Sano et al clearly demonstrated the overexpression of p16 in CIN lesions and nearly all cervical carcinomas.…”

An Armamentarium of Wart Treatments

“…290 The co-application of vidarabine and podophyllin over six treatments resulted in the cytological and histological regression of lesions and the disappearance of HPV 16 and 18 DNA in 17 of 21 (81%) of women with CIN I-II. 291 Vidarabine is a DNA polymerase inhibitor that suppresses HPV gene expression in immortalized human cervical keratinocytes and cervical cancer cell lines in vitro.…”

Diagnostic role of p16/INK4A protein in Human Papillomavirus (HPV) induced cervical dysplasia

“…The decreased availability of the functioning Rb protein due to the over-expression of E7 polypeptide, not only leads to p16 overexpression, but also explains the higher expression Ki-67 protein [56]. To achieve precise grading of LSIL versus HSIL lesions following Ki-67 antigen staining, Kruse et al [57] suggested to count the number of positive nuclei per 100 μm epithelium thickness starting from the parabasal zone (stratification index). The authors in question found a positive correlation (of 83%) with the original histological classification based on H.E.…”