Relationship between the presence of oncogenic HPV DNA assessed by polymerase chain reaction and Ki-67 immunoquantitative features in cervical intraepithelial neoplasia

• Published in: The Journal of pathology 2001-12, Vol.195 (5), p.557-562
• Main Authors: Kruse, Arnold-Jan, Baak, Jan P. A., de Bruin, Peter C., van de Goot, Frank R. W., Kurten, Nicolette
• Format: Article
• Language: English
• Subjects: Adult; Biological and medical sciences; Biomarkers, Tumor - analysis; Cervical Intraepithelial Neoplasia - pathology; Cervical Intraepithelial Neoplasia - virology; cervix; CIN; DNA, Viral - analysis; dysplasia; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; HPV; Human papillomavirus; Humans; Image Processing, Computer-Assisted - methods; Ki-67; Ki-67 Antigen - analysis; Medical sciences; Multivariate Analysis; Papillomaviridae - isolation & purification; Polymerase Chain Reaction; Prospective Studies; quantitation; Tumors; Uterine Cervical Neoplasms - pathology; Uterine Cervical Neoplasms - virology
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.998

The aims of this study were firstly to determine which Ki‐67 immunoquantitative parameters correlate with the presence of oncogenic human papillomavirus (HPV) in cervical intraepithelial neoplasia (CIN) lesions; and secondly to compare prospectively the routinely assessed CIN grades with the Ki‐67 quantitative pathological CIN grade, the expert revised grade, and the presence of oncogenic HPV DNA. HPV polymerase chain reaction (PCR) and Ki‐67 immunoquantitation were performed on 90 consecutive biopsies (16 CIN 1, 35 CIN 2, and 39 CIN 3). CIN grade was assessed routinely by six different pathologists. The presence of the lesion was confirmed in a histological section following the material used for PCR and Ki‐67 analysis. In a second prospective routine test set analysis, 66 more CIN lesions (14 CIN 1, 15 CIN 2, and 37 CIN 3) were routinely graded (also by six different pathologists, routine CIN grade=CINROUT), studied for oncogenic HPV DNA, and graded by quantitative Ki‐67 features (quantitative pathological CIN grade=CINQP). These latter cases were blindly revised by one of the authors (reference CIN grade=CINREF). Eight of the nine Ki‐67 immunoquantitative features showed a significant difference between the oncogenic HPV‐positive and ‐negative cases. The best single discriminator was the 90th percentile of the stratification index (SI90). All 61 cases with Ki‐67 SI90>0.60 were HPV‐positive (68% of the total group studied). Of the 29 cases with SI90≤0.60, 16 were negative and 13 positive for oncogenic HPV and none of the Ki‐67 features (either single or combined) could distinguish them. Using stepwise multivariate analysis, the best discriminating combination of features was SI90 and the percentage of Ki‐67‐positive nuclei in the deep third layer of the epithelium (PERC DL). The combination of SI90 and the percentage of Ki‐67‐positive nuclei per 100 µm basal membrane was nearly as strong as that of SI90 and PERC DL. With these two features, 86% of the cases were correctly classified. The subjective estimate of SI90 (>0.60 or ≤0.60) by two independent observers was not accurate and not reproducible. In the prospective routine test set analysis of 66 cases, the 37 CINROUT=3 all had CINQP and CINREF=3 and all these cases were oncogenic HPV‐positive. Eight of the 14 original CINROUT=1 grades were oncogenic HPV (=HPV)‐positive and five of these eight were upgraded by CINQP to CIN 2 and CIN 3. These upgrades were in agreement with the blind reference revisions