| Background and ObjectiveCervical cancer is the only cancer whose cause is clearly preventable and controllable.After decades of prevention and control in China,it still poses a serious threat to women's health.In 2018,there were 106,000 new cases in China,with an incidence rate of about 15.5/100,000,which is the country with the highest incidence of cervical cancer in 2018.The current primary screening measures for cervical cancer in China still rely on HPV testing,liquid-based cytology testing(TCT),or a combination of both.The latest version of the World Health Organization(WHO)in 2012 changed the three-level classification of cervical precancerous lesions to a two-level classification and suggested that SIL should be used with the CIN designation during the transition period of the new nomenclature,that is,low-level squamous Intraepithelial lesions(LSIL,CIN?)and high-grade squamous intraepithelial lesions(HSIL,CIN?),(HSIL,CIN?).Among them,HSIL(CIN?+)is defined as a disease that has a high risk of progressing to cervical cancer,which needs to be detected and screened for timely intervention.However,the sensitivity of the cytology test and the low specificity of the HPV test have caused the deficiency of the two in cervical cancer screening.In our country,reports of different levels of cytopathologists have low repeatability and coincidence rate.For atypical squamous cells of unknown significance(ASCUS)and atypical squamous cells that do not exclude high-grade intraepithelial lesions(ASC-H)even worse.As a specific biomolecular marker of cervical cancer,p16 and Ki-67 proteins,a large number of studies have confirmed that p16 and Ki-67 proteins in the same cell are antagonistic to each other in regulating the cell growth cycle.The simultaneous expression of the two in the same cell indicates the abnormal proliferation and cancerous tendency of the cell.Some scholars have proposed that the detection of these two markers can be used as a method to detect cervical precancerous lesions in advance.This study investigated p16/Ki67 combined dual staining detection,that is,the detection of cervical exfoliated cell smears based on the principle of immunocytochemical staining to evaluate its application value in the screening and shunt management of cervical cancer.MethodsFrom September 2018 to October 2019,381 women with abnormal cytology(screening?ASCUS)in cervical cancer screening at the gynecology clinic of the Second Affiliated Hospital of Zhengzhou University were selected,and had HR-HPV test results and pathological results.The remaining effective cervical exfoliated cell preservation solution was detected by p16/Ki-67 double staining.Using pathological results as the gold standard,the detection of CIN?+in p16/Ki-67 immunocy-tochemical double staining and HR-HPV DNA detection in ASC,LSIL,and cytological results?ASCUS,respectively,was analyzed,Compare the sensitivity(SE),specificity(SP),positive predictive value(PPT),negative predictive value(NPT),positive likelihood ratio(+LR),negative likelihood ratio(-LR),etc.of the two groups.The results were analyzed by ?2,and the coincidence rate and Kappa index were used to analyze the consistency with the gold standard.The effects of the two methods in cervical cancer screening were compared.Results1.Cytology?ASCUS population pathological distribution characteristics and expression levels of two different detection methodsAmong the 381 specimens with cytology? ASCUS,there were 159 ASC(ASCUS&ASC-H),including 117 ASCUS,42 ASC-H,162 LSIL,52 HSIL,and 8 SCC.Among the 159 specimens of patients with cytological results of ASC,the pathological diagnosis was 57 cases of inflammation/normal,44 cases of CINI,30 cases of CINII,19 cases of CINIII,and 9 cases of SCC.Among the 162 specimens of patients with cytological results of LSIL,the pathological diagnosis was 59 cases of inflammation/normal,60 cases of CINI,39 cases of CINII,3 cases of CINIII,and 1 case of SCC.Among the 60 patients with cytological results?HSIL,the pathological diagnosis was 25 for CINII,23 for CINIII,and 12 for SCC.Crowd pathological findings showed a total of 116 cases of normal or chronic inflammation,90 cases of CINI,108 cases of CINII,45 cases of CINIII,and 22 cases of cervical cancer.The positive rate of p16/Ki-67 double staining immunochemical cell test in chronic inflammation,CINI,CINII,CINIII and cervical cancer was 12.07%,21.15%,85.10%,77.78%,86.36%,HR-HPV DNA test The positive rates of expression in different levels of cervical lesions were:74.14%,76.92%,94.68%,100%and 100%.2.Detection of CIN?+in p16/Ki-67 dual staining and HR-HPV detection in cytology ASCThe sensitivity of p16/Ki-67 dual staining detection for CIN?+was 82.75%(95%CI,70.12%-90.99%),specificity was 89.10%(95%CI,80.96%-94.17%),and positive predictive value was 81.35%(95%CI,68.67%-89.89%),negative predictive value of 90.00%(95%CI,81.96%-94.84%),positive likelihood ratio of 7.591(95%CI,4.297-13.438),and negative likehood ratio of 0.194(95%CI,0.110-0.341).The sensitivity of HR-HPV DNA test for CIN?+detection was 96.55%(95%CI,87.05%-99.40%),specificity was 36.63%(95%CI,27.44%-46.86%),and positive predictive value was 46.67%(95%CI,37.58%-55.97%),negative predictive value 94.87%(95%CI,81.37%-99.11%),positive likelihood ratio 1.523(95%CI,1.303-1.781),negative likelihood ratio 0.094(95%CI,0.023-0.380).3.Detection results of p16/Ki-67 double staining,HR-HPV detection and combined screening for CINII+in cytology LSILThe sensitivity of p16/Ki-67 dual staining detection to CINII+is 67.77%(95%CI,53.70%-82.33%),specificity is 83.19%(95%CI,74.99%-89.19%),and positive predictive value is 60.00%(95%CI,45.20%-73.27%),negative predictive value 88.3%(95%CI,80.60%-93.43%),positive likelihood ratio 4.151(95%CI,2.659-6.481),negative release ratio 0.363(95%CI,0.230-0.574).The sensitivity of HR-HPV DNA test for CIN?+detection is 100%(95%CI,89.79%-100%),specificity is 31.93%(95%CI,23.86%-41.20%),and positive predictive value is 34.68%(95%CI,26.51%-43.81%),negative predictive value 100%(95%CI,88.57%-100%),positive likelihood ratio 1.469(95%CI,1.299-1.662).The diagnostic efficacy of p16/Ki-67 dual staining combined with HR-HPV DNA test on CIN?+in the LSIL population is as follows,with a sensitivity of 90.70%(95%CI,76.95%-96.98%)and specificity of 92.44%(95%CI,85.73%-96.26%),positive predictive value of 81.25%(95%CI,66.90%-90.56%),negative predictive value of 96.49%(95%CI,90.73%-98.87%),positive likelihood ratio of 11.992(95%CI,6.353-22.638),negative likelihood ratio of 0.100(95%CI,0.039-0.256).4.Detection of CIN?+in p16/Ki-67 double staining and HR-HPV detection in cytology?ASCUS populationThe sensitivity of p16/Ki-67 dual staining detection for CIN?+was 83.83%(95%CI,77.17%-88.90%),specificity was 85.98%(95%CI,80.43%-90.92%),and positive predictive value was 82.35.%(95%CI,75.60%-87.60%),negative predictive value 87.20%(95%CI,81.76%-91.25%),positive likelihood ratio 5.980(95%CI,4.263-8.388%),negative release ratio 0.188(95%CI,0.133-0.266).The sensitivity of HR-HPV DNA test for CINII+detection was 95.81%(95%CI,91.22%-98.15%),specificity was 32.71%(95%CI,26.56%-39.49%),and positive predictive value was 52.63%(95%CI,46.86%-58.34%),negative predictive value 90.90%(95%CI,81.61%-95.96%),positive likelihood ratio 1.424(95%CI,1.290-1.571),negative likelihood ratio 0.128(95%CI,0.061-0.270).5.Consistency analysis results of p16/Ki-67 double staining,HR-HPV detection and gold standard for pathological resultsThe coincidence rate of p16/Ki-67 detection for CIN?+detection in cytology ASC was 0.696,and the Kappa value was 0.716;HR-HPV DNA detection was detected for CINII+detection in cytology ASC.The coincidence rate was 0.427,and the Kappa value was 0.270.The coincidence rate of CINII+detected in cytology LSIL by p16/Ki-67 double staining was 0.431,and the Kappa value was 0.503.HR-HPV DNA detection was detected by CINII+in cytology LSIL.The coincidence rate was 0.323,and the Kappa value was 0.199.The coincidence rate of CINII+detected by p16/Ki-67 double staining in cytology?ASCUS was 0.696,and the Kappa value was 0.696;HR-HPV DNA detection in cytology? ASCUS The coincidence rate detected by CIN?+was 0.471,and the Kappa value was 0.465.Conclusions1.Compared with HR-HPV DNA detection,p16/Ki-67 immunocytochemical double staining detection can have higher specificity on the basis of high sensitivity,and has higher consistency with the gold standard of pathology.2.In the cytology LSIL population,even though the sensitivity of the p16/Ki-67 immunocytochemical double staining test is lower than that of the HR-HPV DNA test,the p16/Ki-67 double staining test as an independent screening method is not ideal,however,In combination with HR-HPV DNA testing,screening accuracy can be greatly improved. |
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