| Cervical cancer is the most common gynecological malignant tumor in the world,which not only seriously endangers women's physical and mental health,but also brings serious burden to individuals,families and society.Although the incidence of cervical cancer varies in different countries and regions.However,according to IRAC GLOBOCAN statistics in 2018,there were 569,847 new cases and 311,365 deaths of cervical cancer worldwide in 2018,accounting for 13.1%and 6.9%of new cancer cases and deaths respectively,ranking fourth among female malignant tumors.The Chinese cancer statistics report published in 2015 showed that the incidence and mortality of cervical cancer increased year by year from 2000 to 2011;Moreover,it is the second most common malignancy among women aged 34 to 44.Cervical cancer is the only malignant tumor whose etiology is known,which can be detected by early screening and whose morbidity and mortality are reduced by medical intervention.A large amount of evidence shows persistent infection with high-risk human papillomaviruses(HR-HPV)is the pathogenic factor of cervical cancer,among which HPV-16 and HPV-18 are the two most carcinogenic types of cervical cancer in the world.Currently,cervical exfoliation cytology and HPV DNA detection are the most commonly used methods for cervical cancer screening in clinical practice,but both methods have their own advantages and disadvantages.Although the sensitivity of HPV DNA test has been improved,but the specificity is low,which can neither distinguish between temporary and persistent infection,nor timely determine whether there is a risk of further progress of cervical lesions in HPV infected people.The specificity of cytological examination was good,but the sensitivity was low,and some false negative results were produced.Therefore,it is urgent to seek new early molecular indicators that can predict the development trend of cervical lesions or auxiliary diagnostic indicators of the main screening methods for cervical cancer,so that potential cervical cancer patients can be precisely screened from high-risk groups with persistent HPV infection to achieve the goal of accurate prevention and early treatment of cervical cancer.Through in-depth research on the pathogenesis of cervical cancer,it was found that the expression of p16INK4a was up-regulated during the formation of cervical cancer,and the overexpression of p16IN4a protein was closely related to cervical cancer and its precancerous lesions.In 2014 the WHO(World Health Organization)and in 2012 the LAST(lower anogenital squamous terminology standardization)are proposed to excessive expression of p16 as one of the important indices for high-grade squamous intraepithelial lesion or cervical cancer.For cases of CIN2 that are difficult to be diagnosed by morphology,p16IK4a immunocytochemical staining should be introduced to assist in the evaluation of HSIL and LSIL,rather than the identification by morphology alone.Therefore,p16INK4a staining is common in the diagnosis of cervical histology,while p16INK4a staining's role in cytological screening and diagnosis is rarely reported,and most of them are hand-dyed.There are no fixed standards for the operation techniques and the interpretation of staining results,resulting in large differences in reported results.The purpose of this study was to verify that p16INK4a staining was beneficial to improve the accuracy of diagnosis of high-grade cervical intraepithelial lesions,reduce the rate of missed diagnosis and misdiagnosis,and improve the accuracy and specificity of cervical cancer screening by using automatic immune cells independent temperature control and separate drip staining instrument through large sample clinical trials.Objective:To investigate the value of automated and standardized staining of p16INK4a immunocytochemistry in clinical specimens during the cervical cancer screening.Materials and Methods:In this study,a total of 1100 women(aged 20-65 years,median age 44 years)who participated in cervical cancer screening and underwent HR-HPV test and thinprep cytologic test(TCT)in the gynecology ward and clinic of Maternal and Child Health Hospital of Henan Province from September 2017 to November 2018 were selected as the observation subjects.HR-HPV types were detected by polymerase chain reaction(PCR)?diversion hybridization.Cytology were classified using the 2014 Bethesda Reporting System(TBS)by three professional cytopathologists in the cell room of our hospital.Cytology(ASC-US and above)and HR-HPV(at least one positive of 14 high-risk types)were included in the study and histological results were tracked.As 130 pathological findings were not tracked,970 women were finally included in the study.540 patients with at least one abnormality of cytology(ASC-US and above)and HR-HPV(at least one positive of 14 high-risk types)were used as the experimental group,and then divided into A?B and C group according to the cytology and HR-HPV test results.There were 239 cases of cervical cytology and HR-HPV both positive in group A,106 cases of cervical cytology positive and HR-HPV negative in group B,and 195 cases of cervical cytology negative and HR-HPV positive in group C.Cytology and HR-HPV were both negative,and 430 women who underwent hysterectomy due to other benign gynecological uterine diseases(such as uterine fibroids,endometriosis,adenomyosis and other severe symptoms without fertility requirements)served as the control group.After cytological diagnosis,the remaining samples were further examined by automated immunocytochemical staining of p16INK4a and slides were remade.The immunocytochemical staining results of p16INK4awere evaluated and confirmed by three senior cytopathologists,and only when the diagnosis results were consistent could they be included in the statistical analysis.The interval between the two examinations of cytology and histology was within 30-40.With the histopathological results as the gold standard,statistical methods were used to analyze the test results.This study has been approved by the hospital ethics committee,and all participants have given informed consent and signed the consent form.Results:1.The positive rate of p16INK4a staining in the experimental group was significantly higher than the control group(?2=175.28,P<0.01);In the experimental group,the positive rates of p16INK4a staining among group A(TCT+,HR-HPV+)?group B(TCT+,HR-HPV-)and group C(TCT-,HR-HPV+)were 63.18%,26.42%,and 22.05%,respectively.Group A was significantly higher than group B and C(both P<0.01).However,there was no significant difference was observed between the group B and C(P>0.05).The expression risk of p16INK4a staining in HPV16/18 group and 12 other HR-HPV groups was higher than HR-HPV negative group,with OR values of 16.67(95%CI:10.88-25.56)and 5.36(95%CI:3.60-7.98).2.The positive rates of p16INK4a staining in NILM,ASC-US,ASC-HH+LSIL and HSIL+(HSIL+SCC)group were 9.76%,33.3 3%,48.57%,and 83.53%,respectively.The p16INK4a staining gradually increased with the increase of the cytological diagnosis level(?2=275.55,P<0.01),and the staining intensity gradually increased.3.In histology,the positive rates of p16INK4a staining in cervical benign group,LSIL(CIN1 and p16 negative CIN2)group,HSIL(CIN3 and p16 positive CIN2)group and SCC group were 11.38%,54.05%,96.90%,100%,respectively.The positive rate of p16INK4a staining increased with the severity of cervical lesioms,and the difference was statistically significant(Fisher's exact test ?2=428.20,P<0.01).In 4 cases of SCC,1 case cytological diagnosis as ASC-H which p16INK4a stained positive;in 129 cases of HSIL,60 cases of cytological diagnosis were consistent with histological diagnosis,however,there were 125 cases of p16INK4a staining were positive.The accuracy of p16INK4a staining and cytology in diagnosing cervical SCC and HSIL was statistically significant(P<0.05).4.The sensitivity and specificity of p16INK4a staining for the diagnosis of cervical histology HSIL+were 96.99%and 86.74%,respectively,which were better than HR-HPV test(90.98%and 62.60%)and cytology(86.47%and 72.52%).Conclusions:1.The expression of p16INK4a is related to the type of HR-HPV infection and the degree of cytological and histological lesions.2.p16INK4a automatic immunocytochemical staining has higher sensitivity and specificity in the diagnosis of high-grade and above cervical lesions,and can be used as an important auxiliary method for HR-HPV and cytological detection in cervical cancer screening. |
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