Ki-67 immunoquantitation in cervical intraepithelial neoplasia (CIN): a sensitive marker for grading

Abstract

The aim of this study was to assess the value of Ki-67 immunoquantitation with a computerized image analysis system for grading support in cervical intraepithelial neoplasia (CIN). Sixty-five 'blind' consensus biopsies (23 CIN 1, 22 CIN 2, and 20 CIN 3) were used as a learning set. Measurements were done in the carefully selected most severely dysplastic part of the epithelium of each CIN case. The resulting discriminating combination of quantitative features was then prospectively applied on 121 new biopsies (test set) and compared with the classical CIN grade assessed routinely by six different pathologists and with the blind review grades assessed by two experienced pathologists. In the learning set of 65 cases, a jack-knifed stepwise discriminant analysis showed that the 90th percentile of the stratification index and the number of positive nuclei per 100 microm basal membrane are the best discriminating set of features to distinguish the three CIN grades at the same time. With these features, two CIN 1 cases were 'misclassified' as CIN 2 and nine CIN 2 cases as CIN 3. Overall agreement, therefore, was only 83%. However, recut of the paraffin blocks in the two 'misclassified' CIN 1 cases revealed CIN 2 in the first and CIN 3 in the other, while the other CIN 1 cases that were correctly classified with Ki-67 quantitation remained CIN 1. Likewise, nine CIN 2 cases were misclassified as CIN 3, but in two of these nine cases histological follow-up clearly indicated CIN 3. Agreement may thus be higher than the 83% in the learning set suggests. In the subsequent prospective evaluation on 121 routine CIN cases (test set), agreement between routine CIN grades (by six independent different pathologists) and quantitative Ki-67 classification was 78%. However, when compared with the blind review CIN grades of two expert pathologists, agreement was 97% and sensitivity, specificity, and positive and negative predictive value were very high. It is concluded that Ki-67 immunoquantitation is a useful diagnostic adjunct to distinguish different CIN grades and may also be a sensitive biological indicator of progression of seemingly low-grade CIN.

Ki-67 Quantitative Evaluation as a Marker of Cervical Intraepithelial Neoplasia and Human Papillomavirus Infection

“…A significant gradual increase of the total number of Ki-67Ypositive nuclei in accordance with the severity of the dysplasia, showing an increase in the cell proliferation rate, has also been previously demonstrated. 9,15 These results suggest excellent reproducibility of the Ki-67 immunohistochemistry, which offers the possibility of its use for diagnostic purposes. Although Kruse et al revealed even better results using a computerized image analysis system and calculating the stratification index (the ratio between the distance from the nucleus to the basal membrane and the thickness of the epithelium), we think that a simple analysis system, which correctly divides the epithelium into three thirds, is sufficient to assess the pattern of Ki-67 positivity within the epithelium.…”

Functional biomarkers in cervical precancer: An overview

“…Immunoquantitation of Ki-67 is an important diagnostic adjunct for grading of CIN [53][54][55] and also in distinguishing CIN from normal or benign reactive cervical squamoepithelial lesions. The combination of the Stratification Index (SI, which indicates, how high Ki-67-positive nuclei are located in the epithelium; the higher the SI, the higher the CIN grade) and the number of Ki-67 positive nuclei located in the middle third layer of the epithelium per 100 lm basal membrane (the more Ki-67-positive nuclei, the higher the grade) is the best discriminating set of features that distinguishes the three CIN grades at the same time.…”

Dynamic behavioural interpretation of cervical intraepithelial neoplasia with molecular biomarkers

“…Immunoquantitative parameters for Ki-67 are also correlated with the presence of hrHPV in CIN lesions (fig 8). 20 …”

“…[12][13][14][15][16][17][18][19][20] Without doubt, p16 and Ki-67 are the most widely available, robust, stable and strong predictive biomarkers currently available for handling CIN lesions. (The antibody MIB-1 is often used in paraffin wax sections to assess Ki-67 expression.…”