Cervical intraepithelial neoplasia grade 3 (CIN 3)-like squamous cell carcinoma (SCC) is a recently identified subtype of cervical cancer with a deceptive growth pattern. It mimics the phenotype of CIN 3, involving endocervical crypts, presenting significant challenges and potential for diagnostic confusion. This study aims to clarify the differences in epigenetic profiles and HPV viral load(VL) among CIN 3, CIN 3-like SCC, early invasive SCC, and invasive SCC. A retrospective analysis was conducted on 138 cases of cervical high-grade lesions and SCC diagnosed at Peking University People's Hospital from March 2022 to June 2024. The cases included 65 high-grade squamous intraepithelial lesions (HSIL) [23 CIN 2 and 42 CIN 3] and 73 SCC [27 CIN 3-like SCC, 21 early invasive SCC, and 25 invasive SCC]. Histological samples were analyzed for methylation levels of the epigenetic factors PAX1 and JAM3, as well as HPV VL. Methylation levels of PAX1 and JAM3, as well as total HPV VL, were significantly higher in cervical cancer than in HSIL(< 0.001). The PAX1 methylation level of CIN3 was significantly lower than that of invasive SCC, but there was no significant difference compared with CIN3 and CIN 3-like SCC; For the PAX1/JAM3 methylation levels in CIN 3-like SCC, no statistically significant differences were observed when compared with those in early invasive SCC and invasive SCC. The HPV VL in CIN 3-like SCC was significantly higher than that in CIN 3 and early invasive SCC, but no significant difference was found compared with invasive SCC. In the same stage of FIGO, although PAX1/JAM3 methylation and HPV VL (especially HPV16/18 VL) showed a tendency to increase in CIN3-like SCC compared with early invasive SCC, the difference was not significant, further expansion of sample size is needed to confirm this. PAX1 and JAM3 methylation levels are significantly higher in SCC than HSIL, but no difference in methylation levels was observed between CIN 3-like SCC, early invasive SCC, and invasive SCC. Total HPV VL (especially HPV16/18 VL) in CIN3-like SCC is significantly higher than that in CIN3 and early invasive SCC, suggesting potential shared and distinct features in epigenetics and HPV VL between CIN3-like SCC and early invasive SCC, which need more molecular biology research to explore the difference.

BACKGROUND:Human Papillomavirus (HPV) E6/E7 mRNA testing has been proposed as a potential improvement over HPV DNA testing for predicting cervical lesion progression. This systematic review and meta-analysis evaluated the diagnostic performance of HPV E6/E7 mRNA testing across various clinical scenarios. METHODS:A comprehensive search was conducted in Medline, Embase, Cochrane, Web of Science, and other databases. Two clinical scenarios were analyzed: triage of atypical squamous cells of undetermined significance (ASCUS), prediction of post-conization recurrence.. Diagnostic accuracy was assessed using standardized quality appraisal tools, with results synthesized through forest plots and Summary Receiver Operating Characteristic (SROC) curves. RESULTS:In ASCUS triage, all mRNA methods, including PreTect, APTIMA, and QuantiVirus, achieved comparable sensitivity but significantly higher specificity than DNA testing, with PreTect showing the strongest performance. For post-conization recurrence prediction, QuantiVirus and PreTect assays provided similar sensitivity but greater specificity compared to HPV DNA testing. CONCLUSION:HPV E6/E7 mRNA testing offers higher specificity while maintaining comparable sensitivity to HPV DNA testing across multiple clinical scenarios. For ASCUS triage, PreTect demonstrates superior performance with the highest specificity and should be prioritized for clinical implementation in this setting. For post-conization recurrence prediction, QuantiVirus provides optimal diagnostic accuracy and represents the preferred choice for surveillance following cervical conization. SYSTEMATIC REVIEW REGISTRATION:PROSPERO: CRD42023473415.

This chapter reviews the global and Chinese landscapes of human papillomavirus (HPV) vaccination and its implications for cervical cancer prevention. We summarized the epidemiology and disease burden of HPV infection, the development of prophylactic vaccines, and evidence from pre-licensure trials and real-world studies on immunogenicity, efficacy/effectiveness, durability, and safety. Drawing on clinical data from multiple regions, including China, we confirmed that prophylactic HPV vaccines are safe and effective in preventing cervical cancer and other HPV-related diseases. We also further outlined the vaccination strategies currently adopted in China and highlighted an emerging pipeline for therapeutic HPV vaccines. As a cornerstone of primary prevention, HPV vaccination is essential for achieving the World Health Organization (WHO) initiative to eliminate cervical cancer as a public health problem. These efforts, coupled with screening and timely treatment, are expected to yield substantial and durable health benefits.

Background:A safe and highly efficacious Escherichia coli-produced HPV-16/18 bivalent vaccine (Cecolin®) offers a cost-effective cervical cancer prevention measure. Here, we report data on the long-term efficacy and immunopersistence up to 10 years post-vaccination. Methods:In the Phase III clinical trial (NCT01735006), 7372 women were enrolled and randomly assigned to receive the HPV or control vaccine (hepatitis E vaccine). Women from 2 sites (Xinmi City and Fengning County; N = 1986) were invited to participate in the extension study. Cervical samples were collected for ThinPrep Pap tests and HPV DNA testing. Serum samples from participants in the immune persistent subcohort (N = 300) were collected for neutralising antibody testing. The co-primary outcomes were high-grade cervical, vulvar or vaginal lesions and persistent infection (over 6 months) associated with HPV 16/18 in the per-protocol population. Findings:A total of 1648 women participated in the extension study (806 from the vaccine group and 842 from the control group). Over a median 10.2-year follow-up, vaccine efficacy was 87.5% (95% CI 6.4-99.7) against high-grade cervical, vulvar or vaginal lesions (1 case in the vaccine group and 8 cases in the control group, P = 0.0391), and 97.0% (95% CI 78.9-100.0) against persistent infection (over 6 months, 1 case in the vaccine group and 32 cases in the control group, P < 0.0001) in the per-protocol population. The GMCs of neutralising antibodies peaked by month 7, declined through month 42, with HPV-16 plateauing and HPV-18 continuing to decline thereafter. At 114 months, 98.9% (93/94) of baseline seronegative participants remained seropositive for HPV-16 with the GMC of 61.84 IU/mL and 97.0% (98/101) remained seropositive for HPV-18 with the GMC of 18.73 IU/mL. Interpretation:The E. coli-produced HPV 16/18 bivalent vaccine elicits sustained antibody responses and confers durable protection against HPV 16/18 associated high-grade cervical, vulvar or vaginal lesions and persistent infections for a minimum of 10 years post-vaccination. Funding:National Key Research and Development Program of China (2023YFC2307602), National Natural Science Foundation of China (823B2086, 82273640), Beijing Natural Science Foundation (L244091), and Fundamental Research Funds for the Central Universities (20720220005).

NECESSITY AND SIGNIFICANCE OF ESTABLISHING GUIDELINES FOR CERVICAL CANCER PREVENTION AND TREATMENT IN CHINA Cervical cancer remains a significant threat to the health and lives of Chinese women.In 2022 alone,national cancer registry data reported 150700 new cervical cancer cases and 55 700 deaths,with a global age-standardised incidence rate of 13.83/100 000 and a mortality rate of 4.54/100 000,repre-senting 6.58％and 5.89％of all female cancer cases and deaths,respectively.

BACKGROUND AND AIMS:Human papillomavirus (HPV) vaccines have been available in China for only 8 years, and routine HPV testing is not recommended prior to vaccination. Therefore, evaluation of HPV vaccine effectiveness and the impact of pre-vaccination HPV infection status on vaccine protective effect in Chinese women is warranted. METHODS:From June 2022 to June 2023, women aged 18 to 50 years without a history of cervical or uterine excision were recruited from three medical institutions. Baseline characteristics were compared between vaccinated and unvaccinated participants, with inverse probability treatment weighting (IPTW) applied to adjust for confounding factors. HPV infection rates and vaccine effectiveness (VE) were calculated. Additionally, a sub-group analysis was conducted among vaccinated women to explore the impact of pre-vaccination HPV infection status. RESULTS:After adjusting for group differences, the vaccine effectiveness against new HPV16/18 infections was 76.1% (95% CI: 58.7%-86.2%) among 2285 participants. Older age and possession of a master's degree or higher were identified as protective factors, whereas increased parity and exclusive use of oral contraceptives were determined to be risk factors for HPV16/18 infection. Women with unknown pre-vaccination HPV status exhibited significantly higher post-vaccination rates of high-risk HPV infections (RR 4.278, 95% CI: 2.537-7.215) compared to those who were HPV-negative prior to vaccination. However, no significant difference in new high-risk HPV infection rates was observed between pre-vaccination HPV-negative and HPV-positive women. CONCLUSION:In addition to HPV vaccination, factors such as age, parity, exclusive use of oral contraceptives, and higher education attainment were independently associated with HPV16/18 infection rates. Pre-vaccination HPV infection status did not significantly influence the protective efficacy of the HPV vaccine against previously unencountered HPV types.

OBJECTIVE:Assessment of whether contrast-enhanced ultrasound (CEUS) can be used to differentiate diverse cervical lesions. METHODS:A retrospective analysis of ultrasonographic reports was conducted for patients with different cervical lesions, including 18 cases of chronic cervicitis, 28 cases of cervical intraepithelial neoplasia grade I (CIN1), 46 cases of cervical intraepithelial neoplasia grade II (CIN2), 100 cases of cervical intraepithelial neoplasia grade III (CIN3), 7 cases of carcinoma in situ (CIS), and 26 cases of cervical cancer (CC). Timing began with the contrast agent injection via the elbow vein, recorded separately when the myometrium and cervix began to be enhanced. The intensity of enhancement of the cervix was observed and recorded as hyper-enhancement, iso-enhancement, or hypo-enhancement with respect to the myometrium. The rate of regression of the cervix enhancement was also analyzed and classified as fast, synchronous, or slow relative to the myometrium. Quantitative data were analyzed using either one-way ANOVA or the Kruskal-Wallis H test, while qualitative data were analyzed using Fisher's exact test. Significant differences were further analyzed using post-hoc tests, logistic regression models, and ROC curves. RESULTS:Menopausal status affected longitudinal, anteroposterior, and transverse diameters of the cervix, in addition to cervical volume. Moreover, the time when the myometrium and cervix began to image was also different between the menopause group and the pre-menopause group (P < 0.05), whereas there was no significant variance of pulsatility index (PI), resistance index (RI), enhancement intensity of the cervix, or rate of the cervix fading. The study population was grouped according to their menopausal status, and then we discovered that in the pre-menopausal group, the cervical anteroposterior diameter (APD) differed in the six cervical lesion groups (P = 0.006), especially in CIN1 & CIN2, CIN1 & CIN3, and CIN1 & CC (P = 0.014, 0.045, 0.021, respectively). The enhancement start time (EST) of the cervix differed among the cervical lesion groups (P = 0.02). In particular, there was a significant difference in CC & CIN2 and CC & CIN3 (P = 0.04, 0.03, respectively). The subjects of the study were divided into two groups: those with cervical cancer and those with precancerous lesions. The discrepancy of cervical EST was still significant along with the sensitivity of 0.62, the specificity of 0.76 using a cutoff of 14.895 s, and the accuracy was 0.74. CONCLUSION:The cervical EST can serve as an indicator of malignancy, and CEUS can be a complementary tool for cervical cancer screening. However, it should be noted that qualitative CEUS analysis alone was unable to differentiate among various precancerous lesions.

Background:To investigate the overall and type-specific prevalence of high-risk human papillomavirus (HR-HPV) infection in China across different age groups and regions and to evaluate the triage of HPV-positive cases. Methods:A prospective cross-sectional study recruited a total of 20 103 women aged 30-59 years from 13 provinces in China. Self-collected vaginal samples were tested for 14 HR-HPV types using next-generation sequencing or multiplex real-time PCR assays. Results:The five most common types were HPV52, 58, 16, 39 and 51. The prevalence of single-type HR-HPV was 10.70%. The overall proportion of HPV16/18 was 20.67%, with a significant difference observed among provinces (p<0.05). The age-specific prevalence curve of HR-HPV followed a U-shaped pattern from 30 to 59 years, with a lower prevalence observed in women aged 40-44 years (12.35%), which subsequently changed with age. The proportion of women aged 30-34 years with HPV16 (21.59%) was significantly higher than that in other age groups, showing two peaks in young and older women. There was a significantly higher prevalence of HPV16 single-type infection in the youngest group, whereas HPV16 multi-type infection was higher in older women. Among cervical intraepithelial neoplasia grade 2 or higher (CIN)2+ cases, HPV16 infection accounted for 43.98%, HPV18 infection for 7.84%, and other 12 infections for 48.20%. HPV16 had the highest sensitivity for detecting CIN2+, reaching 42.7% among single HPV types, followed by HPV52 and HPV58. When HPV16/18/33 were combined for detection, the sensitivity for detecting CIN2+ increased to 66.67%. Conclusions:The prevalence and genotype distribution of HR-HPV based on vaginal self-sampling varied across different regions and ages in China. HPV16 was more prevalent in both younger and older age groups. Different HPV subtypes have different detection rates for CIN2+, and combining HPV16/18/33 significantly improved the sensitivity for detecting CIN2+.

Significance To compare the efficacy and safety of ALA-PDT and CO2 Laser in the treatment of high-grade VaIN. Approach A retrospective review was conducted on 59 patients with high grade VaIN who were treated by ALA-PDT (n=21) or CO2 Laser (n=28) in Peking University People's Hospital from January 2023 to September 2024. After treatment patients were followed up at 3 and 6 months afterwards. Results (1) The clinical characteristics of patients in the two groups were similar.(2) At 3 and 6 months after treatment in ALA-PDT group, the overall complete remission (CR) rates were similar to that in CO2 Laser group and The total HPV clearance rates were significantly high in ALA-PDT group.(2) The incidence of the adverse events(AE) in ALA-PDT group was lower than that in CO2 laser group. Conclusions ALA-PDT has equivalent lesion reversal rates and superior HPV clearance compared with CO2 laser in the treatment of high-grade VaIN.

Therapeutic HPV vaccines that induce potent HPV-specific cellular immunity and eliminate pre-existing infections remain elusive. Among various candidates under development, those based on DNA constructs are considered promising because of their safety profile, stability, and efficacy. However, the use of electroporation (EP) as a main delivery method for such vaccines is notorious for adverse effects like pain and potentially irreversible muscle damage. Moreover, the requirement for specialized equipment adds to the complexity and cost of clinical applications. As an alternative to EP, lipid nanoparticles (LNPs) that are already commercially available for delivering mRNA and siRNA vaccines are likely to be feasible. Here, we have compared three intramuscular delivery systems in a preclinical setting. In terms of HPV-specific cellular immune responses, mice receiving therapeutic HPV DNA vaccines encapsulated with LNP demonstrated superior outcomes when compared to EP administration, while the naked plasmid vaccine showed negligible responses, as expected. In addition, SM-102 LNP M exhibited the most promising results in delivering candidate DNA vaccines. Thus, LNP proves to be a feasible delivery method in vivo, offering improved immunogenicity over traditional approaches.

Current estimates of the HPV infection rate in China vary by geographic region (9.6-23.6%), with two age peaks in prevalence in women <= 20-25 years of age and 50-60 years of age. HPV-16, 52 and 58 are the most commonly-detected HPV genotypes in the Chinese population. In China, five HPV vaccines are licensed and several others are undergoing clinical trials. Multiple RCTs have shown the efficacy and safety of the bvHPV (Cervarix), Escherichia coli-produced bvHPV (Cecolin), Pichia pastoris-produced bvHPV (Walrinvax), qvHPV (Gardasil) and 9vHPV (Gardasil-9) vaccines in Chinese populations, including two studies showing long-term efficacy (>= 8 years) for the bvHPV and qvHPV vaccines. Real-world data from China are scarce. Although modeling studies in China show HPV vaccination is cost-effective, uptake and population coverage are relatively low. Various policies have been implemented to raise awareness and increase vaccine coverage, with the long-term aim of eliminating cervical cancer in China.

The relationship of PAX1/JAM3 methylation as well as HPV viral load (VL) with cervical lesions has been reported, but their role in persistent HPV infection without cervical high-grade lesions has not been fully elucidated. A total of 231 females diagnosed with persistent HPV infection and pathologically confirmed absence of high-grade cervical lesions were selected from the Colposcopy Outpatient Clinic of Peking University People’s Hospital, from March 2023 to December 2023. They were categorized into two groups based on the duration of HPV infection: the HPV persistent less than 3 years group and the more than 3 years group. PAX1/JAM3 methylation and HPV VL were determined by real-time PCR and BioPerfectus Multiplex Real-Time (BMRT)-HPV reports type-specific VL/10,000 cells, respectively. The average age of individuals with HPV infection lasting more than 3 years was higher compared to those with less than 3 years (48.9 vs. 45.1 years), with a statistically significant difference. Among the participants, 81.8% (189/231) had no previous screening. The methylation levels of JAM3 and PAX1 were significantly higher in individuals with HPV infection persisting for more than 3 years compared to those with less than 3 years, with a statistically significant difference (p < 0.05). There was a significant correlation between PAX1 and JAM3 methylation (p < 0.001), which could be used as cumulative evidence of HPV infection duration before the occurrence of precancerous lesions. The incidence of vaginal intraepithelial lesions was higher in individuals with HPV infection persisting for more than 3 years compared to those with less than 3 years, and HPV VL can be used as an indicative biomarker for concurrent cervical–vaginal lesions, especially for HPV other than 16/18 genotypes.

Background: Both cervical cancer and cervical intraepithelial neoplasia (CIN) are associated with human papillomavirus (HPV) infection at different anogenital sites, but the infection features of high-risk (HR) HPVs at these sites and their association with cervical lesions have not been well characterized. Given the limitation of cervical HPV 16/18 test in screening patients with high-grade CIN (CIN 2+), studies on whether non-16/18 HR-HPV subtype(s) have potential as additional indicator(s) to improve CIN 2+ screening are needed. Methods: The infection of 15 HR-HPVs in vulva, anus, vagina, and cervix of 499 Chinese women was analyzed, and CIN lesion-associated HR-HPV subtypes were revealed. Results: In addition to the well-known cervical-cancer-associated HPV 16, 52, and 58, HPV 51, 53, and 56 were also identified as high-frequency detected subtypes prevalently and consistently present at the anogenital sites studied, preferentially in multi-infection patterns. HPV 16, 52, 58, 56, and 53 were the top five prevalent subtypes in patients with CIN 2+. In addition, we found that cervical HPV 33/35/52/53/56/58 co-testing with HPV 16/18 might improve CIN 2+ screening performance. Conclusion: This study provided a new insight into HR-HPV screening strategy based on different subtype combinations, which might be used in risk stratification clinically.

Cervical cancer is the most common malig-nant tumour of the female lower reproduc-tive tract,1 which seriously threatens the health of Chinese women.According to data released by China's National Cancer Center in 2023,new incident cases of cervical cancer amounted to 155 700,with 55 700 deaths.Among women aged 15-44,both the inci-dence and mortality rates of cervical cancer rank third highest among female malignan-cies in China.

Objective:To explore the ability of PAX1 methylation (PAX1m) to predict the pathological upgrade of cervical intraepithelial neoplasia (CIN) before cold knife conization (CKC).Methods:A total of 218 women that underwent colposcopy-directed biopsy (CDB) pathology for the confirmation of CIN2 and CIN3 between December 2020 to September 2021 were enrolled in this study. The methylation levels of PAX1 (ΔCpPAX1) were determined by quantitative methylation-specific polymerase chain reaction (qMSP). Receiver operating characteristic curve was used to identify the optimal cut-off value of ΔCpPAX1 for predicting the pathological upgrade of disease.Results:In the CDB-confirmed CIN2 group, 36% of CIN2 was found to have pathologically upgraded to CIN3 and 30% regressed to low-grade squamous intraepithelial lesion (LSIL) and below, and none of CIN2 upgraded to early-stage cervical cancer (ESCC) after CKC. In the CDB-confirmed CIN3 group, 19.5% (23/118) of CDB-confirmed CIN3 were pathologically upgraded to ESCC after CKC. Regardless of CIN2 or CIN3, the ΔCpPAX1 level of women with upgraded pathology after CKC was significantly lower than that of women with degraded pathology. The optimal △CpPAX1 cut-off value in predicting CIN3 to be upgraded to ESCC after CKC was 6.360 and the area under the curve (AUC) was 0.814, with similar sensitivity (78.3%) and higher specificity (84.2%) than cytology≥LSIL (Se:78.3%;Sp:58.9%) and HPV16/18 positive (Se:73.9%;Sp:46.3%) patients.Conclusions:PAX1m could be a promising auxiliary marker in predicting the pathological upgrade of CIN before CKC. We found that if the △Cp PAX1 cut-off value is lower than 6.360, it is highly suggestive of invasive cervical cancer.

世界卫生组织(WHO)在2020年向世界发出加速消除子宫颈癌的全球战略,实现该目标,需要在2030年达到"90-70-90"的目标[1].其中提出对90％确诊为癌前病变的女性要做到规范治疗.因此,不仅要推动人乳头瘤病毒(HPV)疫苗的接种和积极扩大子宫颈癌筛查的覆盖面,更重要的是如何实现对子宫颈上皮内病变进行规范的精细化管理.现提出子宫颈上皮内病变管理中需要注意的难点.

The relationship between the thickness of the epithelium and the colposcopic diagnosis is controversial. The present study was conducted to determine whether colposcopic underdiagnosis of cervical intraepithelial neoplasia (CIN) is associated with thin high-grade squamous intraepithelial lesions (HSILs) of the cervix. A total of 136 cases of HSIL verified by pathological biopsy at Peking University People's Hospital between June and October 2021 were retrospectively analyzed; 79 cases were CIN2 and 57 cases were CIN3. The number and thickness of epithelial layers were analyzed using colposcopic impressions. In the low-grade colposcopic impression group, the number of epithelial layers (12.8±4.2 vs. 17.8±4.2) and epithelial thickness (105.2±41.9 µm vs. 150.3±50.0 µm) of CIN2 lesions were significantly lower compared with the high-grade colposcopic impression group; however, the differences for CIN3 were not statistically significant. CIN2 lesions had significantly fewer (12.8±4.2 vs. 17.2±5.4) and thinner (105.2±41.9 µm vs. 140.4±48.6 µm) epithelial layers than CIN3 lesions in the low-grade colposcopic impression groups. In the high-grade colposcopic impression group, however, there were no significant differences in the number or thickness of epithelial layers between CIN2 and CIN3. In 12 cases of thin HSILs, 91.6% of the colposcopic impressions were low-grade. Thin HSILs are likely associated with underdiagnosed colposcopic findings, particularly for CIN2. Thin HSILs usually present with small to minute lesions and lack the typical colposcopic appearance of classic HSIL, which may help to explain why thin HSILs are easily underestimated under colposcopy.

The incidence rate and mortality rate of cervical cancer have steadily increased in young women in China. Therefore, it is critical to improve HPV vaccination rates, particularly for the younger population. There are currently five types of prophylactic vaccines in China: bivalent HPV vaccine (AS04-HPV-16/18), quadrivalent HPV vaccine, 9-valent HPV vaccine, homemade Escherichia coli-produced HPV bivalent vaccine, and Pichia pastoris produced HPV bivalent vaccine. All these five HPV vaccines have completed relevant clinical trials in China, and have been proven to be generally well-tolerated and immunogenic, efficacious against persistent HPV-related infections and genital precancerous lesions (data for 9-valent HPV vaccine is absent), and have demonstrated acceptable safety profiles, as previously shown in global studies. Given that the HPV vaccination rate in China is still very low, additional HPV vaccine coverage is needed to reduce the incidence and mortality rates of cervical cancer.

Cervical cancer is still a serious threat to the health of women in China. The current strategy is a three-level prevention strategy, among which the diversion of screening and screening abnormalities in the secondary prevention is an important link in preventing cervical cancer. For more than 20 years, China has implemented diversified screening methods such as cytological examination, high-risk human papillomavirus (HPV) testing, and naked eye screening. With the discovery that high-risk HPV infection is closely related to the occurrence of cervical cancer, the screening method for cervical cancer has shifted from cytological examination to HPV testing as the preferred screening method. This article introduces the advantages and disadvantages of high-risk HPV testing and cytological examination as screening methods, and proposes the issues that need to be paid attention to in screening; The principle of diverting screening abnormalities was proposed, and it was proposed that in the process of diverting, individualized and refined management principles should be implemented for screening abnormality projects based on the patient′s age and fertility requirements.