Diagnostic Value Of P16/Ki67 Dual-stained Cytology In High-grade Cervical Intraepithelial Lesions

Objective:To study the performance of p16/Ki67 dual-stained cytology in the diagnosis of high-grade cervical intraepithelial lesions in thepopulation,and to evaluate the feasibility and effectiveness of p16/Ki67 dual-stained cytology in screening atypicalsquamous cells of undetermined significance(ASC-US),low-gradesquamous cell intraepithelial lesion(LSIL),high-risk HPV-positive population and colposcopic cervical transformation zone type Ⅲ patients with high-grade cervical lesions.Methods:A prospective,cross-sectional study was performed in the Department of Gynecology,Affiliated Hospital of Qingdao University over 30 months including 1915 patients.Allpatients underwent p16/Ki67 dual-stained cytology,hrHPV Cobas4800 detection and liquid-based cytology.867 patients with abnormal cervical epithelium underwent colposcopy,biopsy or conization,immunochemical staining to evaluate the performance of p16/Ki67 dual-stained cytology in the diagnosis of high-grade cervical lesions in the population,and compared with liquid based cytology(LCT)and hrHPV detection.At the same time,p16/Ki67 dual-stained cytology in ASC-US/LSIL,hrHPV positive and colposcopic cervical transformation zone type Ⅲ patients were evaluated for the sensitivity,specificity,positive predictive value(PPV),negative predictive value(NPV),area under the ROC curve(AUC),positive likelihood ratio(+LR)and negative likelihood ratio(-LR)of high-grade cervical lesions.Results:1.The positive rate of p16/Ki67 dual-stained cytology increased with the grade of cytology and histology.According to the consistency analysis with CIN2+,the consistency rate of p16/ki67 dual-stained cytology was 92.4%,and the Kappa value was 0.846,which was better than the LCT and hrHPV.The AUC value of p16/Ki67 dual-stained cytology was0.929(0.91-0.948),which was significantly higher than LCT’s 0.748 and hrHPV’s 0.575;its sensitivity was 96.5%,which was significantly higher than 85.9% of LCT,and the specificity was 89.4%,which was significantly higher than 18.2% of hrHPV and 63.7% of LCT;meanwhile,PPV was 87%.NPV was 97.2%,+LR was 9.08,both higher than LCT and hrHPV;there was a statistical difference between the two comparisons.2.The AUC value of p16/Ki67 dual-stained cytology shunt ASCUS detection CIN2+was 0.883(0.836-0.93),which was higher than 0.522 of hrHPV and 0.63 of HPV16/18genotype;its sensitivity was 95.1%,which was higher than HPV16/18 genotype 49.5%,and the specificity was 81.5%,which was significantly higher than 7.3% of hrHPV;meanwhile PPV81%,NPV95.3% and +LR5.13 were the largest;the difference was statistically significant.The maximum AUC value of p16/Ki67 dual-stained cytology shunt LSIL detection CIN2+ was 0.926(0.852-0.999),which was higher than 0.559 of hrHPV and 0.708 of HPV16/18 genotype;the sensitivity was 96.9%,which was higher than 56.3% of HPV16/18 genotype,the specificity was 88.2%,which was significantly higher than 11.8%of hrHPV,and PPV was 88.6%,+LR was 8.23,which were higher than 51.6%,1.13 of hrHPV and 78.3%,3.83 of HPV16/18 genotype;the difference was statistically significant.3.The AUC value,sensitivity,specificity,PPV and NPV of p16/Ki67 dual-stained cytology in the shunt of 225 HPV16/18 positive patients were 0.897,97.4%,82%,84.7%,96.8%,and LCT was 0.736,87.7%,59.5%,69%,82.5% respectively.The AUC value,sensitivity,specificity,PPV and NPV of p16/Ki67 dual-stained cytology in the shunt of 439 other 12hrHPV-positive patients were 0.939,97.2%,90.6%,83.1%,and 98.5%,while LCT were 0.729,85.2%,60.6%,50.8% and 89.6% respectively.Compared with each other,the difference is statistically significant.4.In colposcopy examination of cervical transformation zone type Ⅲ,the AUC value of p16/Ki67 dual-stained cytology to detect CIN2+ was 0.947(0.914-0.981),which was higher than 0.558 of hrHPV and 0.741 of LCT;its sensitivity was 98.2%,which was significantly higher than the 86% of LCT;there was statistically significant;but its specificity was 91.2%,which was significantly higher than 16.9% of hrHPV and 62.2% of LCT;it also had a high PPV of 81.2% and +LR 11.2,which was statistically significant compared with LCT and hrHPV.Conclusion:1.The p16/Ki67 dual-stained cytology had good consistency in the diagnosis of CIN2+,and the positive rate gradually increases with the increase of the degree of lesions.Compared with hrHPV,the specificity was higher,and the sensitivity was increased compared with LCT.It can be helpful for cervical cancer screening.2.In p16/Ki67 double-stained cytology shunt ASCUS and LSIL had significantly higher specificity,PPV and AUC without significantly reducing their sensitivity compared with hrHPV.It has the clinical value of shunting ASCUS and LSIL.3.In p16/Ki67 double-stained cytology shunt HPV16/18 and other 12 hrHPV-positive patients,they had good sensitivity,specificity,PPV,NPV,AUC values,and reduced colposcopy referral.It has clinical value of shunt HPV16/18 and other 12 hrHPV-positive patients.4.In colposcopic patients with cervical transformation zone type Ⅲ,the sensitivity of p16/Ki67 double-stained cytology was higher than that of LCT,its specificity was significantly higher than that of LCT and hrHPV.It is an effective screening method.