Studies On Risk Factors Of Cervical Cancer And Its Prevention And Control

ObjectivesThe primary objective is to assess the risk ratio (RR) of future cervical intraepithelial neoplasia grade 2 or worse (CIN 2+) associated with baseline high-risk human papillomavirus (HR-HPV) and other cofactors. The secondary objectives are to determine the most appropriate sampling method for cervical cancer screening in Chinese women, particularly in low-resource settings; to juxtapose two gold standards for evaluating the accuracies of cervical cancer screening methods; and to estimate the HR-HPV infection rate and the prevalence of CIN in Chinese women aged 18-25 years, while learning about their knowledge of and attitudes towards HPV vaccination.Materials and methods1. Study on HR-HPV and other cofactors for cervical cancer and its precancerous lesions: The study population for this prospective study was from a population-based cervical cancer screening cohort established in 1999. During the 11-year follow-up, each woman was interviewed on smoking history, sexual behaviors, marital and reproductive history and other cofactors before being examined by visual inspection of acetic acid (VIA), liquid-based cytology (LBC) and HPV DNA testing (hybrid capture 2, hc2). Those with any positive screening test received colposcopic examination with directed or 4-quadrant biopsies. These biopsies not only served as a diagnostic gold standard, but allowed for the classification of progression, persistence, and regression of CIN lesions, stratified by baseline pathology. Cox proportional hazards models were used to evaluate the risk of CIN 2+incidence related with HR-HPV at baseline and to explore the cofactors that may have impacted multiple HR-HPV positive tests or the progress from HPV infection to CIN 2+lesions.2. Studies related with cervical cancer prevention and control, which included the three parts as follows:(1) Study on the most appropriate sampling method for cervical cancer screening:This study was based on the existing data from a population-based cross-sectional study on cervical cancer. In addition to receiving physician-conducted methods for cervical cancer screening, five additional specimens (physician-collected endocervix, upper and lower vagina and perineum specimens and vaginal self-collected specimen) were also collected from each woman. A percentage of these samples were tested for HPV genotypes (Linear Array(?)). The accuracies of vaginal self-collected hc2 and physician-collected hc2 for screening CIN 2+ were compared using histology results as the diagnostic gold standard. To try to determine why self-collected hc2 had lower sensitivity and specificity compare to physician-collected hc2, results of the HPV genotyping of all five specimens were analyzed for women who were false positives or false negatives. (2) Study on gold standards for evaluating cervical cancer screening methods:In the population-based cervical cancer screening study in Xiangyuan County, Shanxi Province in 2003, every woman was examined by VIA, LBC and hc2. Women with any positive test received directed or 4-quardant biopsies or endocervical curettage (ECC). The disease status of each woman was generated by two biopsy principles. One was based on colposcopy and directed biopsy, and the other was based on 4-quadrant biopsy and/or ECC. The accuracies of screening methods were evaluated separately by using each of these principles as gold standard to determine which "gold standard" is more accurate. (3) Prevalence of HPV and CIN and attitudes towards HPV vaccination among young Chinese women:316 women aged 18-25 in Jiangsu Province received VIA. LBC and hc2. A survey about their knowledge of and attitudes towards HPV vaccination was conducted.Results1. Study on HR-HPV and other cofactors for cervical cancer and its precancerous lesions: (1) A toal of 1657 women received the 11-years visit. The cumulative incidence of CIN 2+ at 11-year follow-up was 3.6%. In normal pathology group at baseline, the progression rate to cervical intraepithelial neoplasia grade 1 (CIN 1) and CIN 2+ was 2.2% and 2.7%, respectively, with the vast majority of women (95.2%) maintaining normal during the 11-year study period. For women with baseline CIN 1 lesions,17.2% progressed to CIN2+,2.0% persisted at CIN1. and 80.8% regressed to normal. Comparatively, in the non-treatment CIN 2 group (55.8% in baseline CIN 2).33.3%) progressed to CIN 3,12.5%) maintained CIN 2 lesions and 54.2% regressed to normal. (2) After adjusting other cofactors, the risk of CIN 2+ incidence in baseline HR-HPV positive women was significantly higher than that in women with negative HR-HPV at baseline (adjusted RR=13.5,95% CI:7.2-25.2). The risk ratio ascended with the number of HR-HPV positive tests. The CIN 2+ incidence was highest among those with positive HR-HPV results at baseline and two follow-up visits (54.3%). and the risk ratio was 343.6 (95%CI:76.0-1554.3) compared to women with negative HR-HPV in all three visits. (3) In addition to having HR-HPV infection at baseline. other risk factors for CIN2+ included parity, menopause, the history of cervical erosion, chronic cervicitis and polyp. Risk factors for HR-HPV infection or having multiple HR-HPV positive tests included smoking history of women or their relatives, multiple sexual partner numbers, the history of cervical erosion, chronic cervicitis and polyp, and taking baths in the tub. However, women or their sexual partners washing their genitals before sexual behavior were protective factors of CIN 2+ incidence.2. Studies related with cervical cancer prevention and controlL(1) Study on the most appropriate sampling method for cervical cancer screening indicated the sensitivity and specificity of physician-collected hc2 were higher than those of self-collected hc2 (Sensitivity:97.9% v.s.80.9%; Specificity:90.2% v.s.88.6%). Seven of 9 women with CIN 2+ and negative self-collected hc2 were positive for HR-HPV by linear Array. Of the 41 more women without CIN 2+ who tested hc2 positive on self-collection but hc2 negative on physician-collection, Linear Array tested positive for HR-HPV in 24, negative for HPV in 11 and negative for HR-HPV but positive for low-risk HPV in 6. (2) Study on gold standards for evaluating cervical cancer screening methods showed that using 4-quadrant biopsy and ECC increased the prevalence of histology confirmed CIN 2+from 3.2% to 4.2% and decreased the sensitivity of VIA for CIN 2+ from 69.5% to 58.4% with little change in specificity. (3) Study on prevalence of HPV and CIN and attitudes towards HPV vaccination among young Chinese women indicated within a study population of 316 women, the rate of HR-HPV infection was 17.1%, while 3.4% of women were diagnosed with CIN 2+. In this study population, extra-marital sexual behavior of them or their husbands were associated with an increased risk of HPV positivity. Although overall HPV awareness was low, after a brief education intervention, 98.4% of them stated they would receive HPV vaccination and would also recommend their daughters be vaccinated. However, the cost of HPV vaccination will be the main obstacle for HPV campaign in China.Conclusion and suggestions1. The prospective study confirmed the extremely strong association between HR-HPV and CIN 2+ incidence. Smoking, sexual partner number, parity, menopause and hygiene habit were associated with multiple HR-HPV positive tests or the progression to CIN 2+. It is suggested that Chinese women must be educated to learn appropriate preventative measures to decrease HPV persistence and its related disease burden. Meanwhile, women with both HPV infection and other risk factors (high-risk sexual behavior, parity and smoking) and postmenopausal women should be followed up for cervical cancer screening more frequently than other women.2. Data on progression, persistence and regression for each CIN group not only provide scientific evidence to guide clinical follow-up and treatment guidelines for CIN lesions, but also serve as the basis for calculating the probability of progression, regression, and maintenance of CIN lesions to establish the nature history model of HPV infection and cercical cancer.3. Low sensitivity of self-collected specimens is secondary to either a lower number of exfoliated cells in vaginal self-collected specimens or lower viral load of vaginal HR-HPV, compared with the physician-collected specimens. The principal cause of the lower specificity of self-collected specimens is that women may collect vaginal cells infected with HR-HPV, which is not associated with CIN 2+ but is categorized as HR-HPV positive on hc2. Although self-collection is likely to increase the compliance for cervical cancer screening, more research should be conducted to improve its sensitivity and specificity before it could be employed as a primary sampling method.4.4-quadrant biopsy can correct the bias on colposcopy diagnosis associated by VIA. decrease the verification bias, and improve the ability to confirm the diseases. Comparatively,4-quadrant biopsy and ECC yield more conservative estimates of the accuracies of screening methods. The association between VIA and colposcopy diagnosis should be considered in the future research, which should also emphasize that the accuracy of VIA may be overestimated.5. HPV infection rate and prevalence of cervical cancer are relatively high among the sampled women aged 18-25 years. Appropriate educational interventions for female adolescents and strategies to subsidize vaccine costs are urgently needed to promote the future vaccination campaigns in China.