Cervical Intraepithelial Neoplasia Grade Research Articles

Associations of Obesity with Post-Treatment Risks of Cervical Precancer and Cancer.

Individuals with obesity have an increased risk of cervical cancer, in part related to challenges associated with cervical sampling and visualization that result in missed detection of cervical precancers. The influence of obesity on the effectiveness of excisional treatment of detected cervical precancers and post-treatment disease risk is unknown. The aim of this study was to evaluate post-treatment risks of cervical precancer and cancer by body mass index (BMI). This retrospective cohort study included individuals aged 25 years and older undergoing excisional treatment for cervical precancer, either cervical intraepithelial neoplasia (CIN) grade 2 or 3 or adenocarcinoma in situ (AIS) as of January 2017 with follow-up through February 2023. Patients were excluded if they were missing BMI, had cancer upon excision or had hysterectomy in lieu of excision, or were missing a valid referral screening visit. We categorized BMI as: Underweight/Normal (<25 kg/m2), overweight (25 to <30 kg/m2), and obesity (≥30kg/m2), as well as by class (I-III) of obesity. We calculated two-year risks of CIN3 and cancer (combined as CIN3+) using Kaplan Meier methods and evaluated multivariable adjusted associations of BMI with CIN3+ using Cox Proportional Hazards regression analyses, accounting for age at treatment, race and ethnicity, and treatment type. Among 10,614 patients, a total of 680 (6.4%) developed post-treatment CIN3+; most (91%) within two years of treatment. Two-year CIN3+ and cancer risks were highest in those with obesity (8.65%, 95% CI, 7.6-9.9% and 0.79%, 95% CI, 0.5-1.2%, respectively) and lowest in those with normal weight (5.57%, 95% CI, 4.9-6.3% and 0.29%, 95% CI, 0.2-0.5%, respectively). Hazard ratios measuring associations of BMI with risk of post-treatment CIN3+ ranged from 1.19 (95% CI, 1.0-1.4) among those with overweight to 1.89 (95% CI, 1.4-2.6) among those with class III obesity (p-trend <0.0001). A similar trend was observed for cancer, from 1.62 (95% CI, 0.8-3.3) for overweight and 3.50 (95% CI, 1.3-9.3) for class III obesity (p-trend =0.016). Patients with obesity undergoing excisional treatment for cervical precancer have a higher risk of residual or recurrent disease, likely due to incomplete excision.

Declining Prevalence of Human Papillomavirus Co-Infections Among Young Japanese Women With Cervical Cancer and Its Precursors.

Co-infections with human papillomavirus (HPV) of multiple genotypes mainly occur due to increased sexual activity. To address the prevalence and trend of HPV co-infections in Japan, HPV-type-specific data from Japanese women (n = 8128) aged < 40 years and newly diagnosed with cervical abnormalities at 24 hospitals between 2012 and 2023 were analyzed. These included cervical intraepithelial neoplasia grade 1/2 (CIN1/2, n = 2745), CIN3/adenocarcinoma in situ (AIS) (n = 3953), and invasive cervical cancer (ICC, n = 1430). For women enrolled in this study since 2019, information on sexual behaviors was collected via a self-administered questionnaire. Time-trend analyses by disease category showed significant declines in the prevalence of multiple HPV infections in CIN1/2 (49.1%-38.3%, ptrend = 0.0004), CIN3/AIS (44.7%-31.5%, ptrend = 0.0002), and ICC (26.7%-10.5%, ptrend < 0.0001) during the last decade. When these data were analyzed separately for women aged 20-29 and 30-39 years, similar declining trends were observed in each disease category. Using data from 2111 women for whom information on sexual history was available, the number of sexual partners was strongly associated with increased multiple HPV infections (p < 0.0001). In conclusion, the declining prevalence of HPV co-infections in cervical cancer and its precursors may reflect a decrease in sexual activity among Japanese women of reproductive age.

Triage performance of DNA methylation for women with high-risk human papillomavirus infection.

DNA methylation is a promising biomarker for cervical cancer screening. This study aimed to validate the triage performance of cytological DNA methylation for detecting cervical intraepithelial neoplasia of grade 3 or worse (CIN3+) in women with high-risk human papillomavirus (hrHPV) infection from a large prospective cohort undergoing opportunistic screening in China (METHY3). The triage performance for detecting CIN3+ lesions was compared between HPV16/18 genotyping, a liquid-based cytology (LBC) test, and the PAX1 and JAM3 methylation (PAX1m/JAM3m) test according to cervical pathologic outcomes. Among the 4394 women infected with hrHPV, 1105 had definitive cervical histological findings that were analyzed. For detecting CIN3+, the specificity of HPV16/18(+), the LBC result of ≥atypical squamous cells of undetermined significance (ASCUS), and PAX1m/JAM3m(+) was 66.4%, 23.9%, and 89.6%, respectively, with odds ratios of 4.24 (95% confidence interval [CI], 2.85-6.40), 4.44 (2.27-10.1), and 18.5 (12.1-28.7) (P < .001), respectively. PAX1m/JAM3m(+) had the highest area under the receiver operating characteristic curve (0.790, 95% CI, 0.747-0.832) in the whole cohort and in women of various ages. PAX1m/JAM3m (+) was detected in all patients with cancer (n = 28). Compared with HPV16/18 genotyping and the LBC test, PAX1m/JAM3m testing reduced referrals to colposcopy by 20.64 percentage points and 61.18 percentage points, respectively. PAX1 m /JAM3 m testing is highly specific for detecting CIN3+. As a triage biomarker, it is superior to HPV 16/18 genotyping and LBC testing for women with hrHPV infection.

Prediction of high-grade cervical precancerous abnormalities: The role of personal factors, vaginal microflora, sexually transmitted infections, and high-risk human papillomavirus.

High-risk human papillomavirus infection (HR-HPV) is necessary but not the only factor needed to develop cervical cancer. It is essential to estimate cervical cancer development risk in the population of high-risk HPV-positive women and to avoid unnecessary examinations and treatment in low-risk individuals. The study aimed to identify associations between different personal factors, vaginal microflora, sexually transmitted, high-risk HPV infection, and various degrees of cervical precancerous lesions. A study was performed in 2016-2020. The study group consisted of 112 patients with abnormal cervical cytology results referred for colposcopic examination. 120 women who came for a routine gynecological check-up were included in the control group. Material from the cervix and upper vaginal fornix was taken for pH measurement, wet mount microscopy, testing the six most common high-risk HPV DNA types (16/18, 31, 33, 45, 58), HPV E6/E7 mRNA, and 7 genital infections-C. trachomatis, N. gonorrhea, T. vaginalis, M. hominis, M. genitalium, U. urealyticum, U. parvum. Results showed that women with all grades of cervical intraepithelial neoplasia (CIN) more often were smokers, had increased vaginal pH levels, and had positive HR-HPV DNA and HR HPV E6/E7 mRNA expression. Abnormal vaginal microflora, especially types associated with aerobic vaginitis, and M. hominis were significantly more often found in women with CIN2+. The presence of C.trachomatis, U. parvum, and U.urealyticum did not differ between the groups. The most important factors independently associated with CIN2+ were positive high-risk HPV E6/E7 mRNA expression (OR 59.4, 95% CI 14.84-237.51), and positive high-risk HPV DNA (OR 3.9, 95% CI 1.16-13.23). Higher education level was associated with reduced risk of CIN2+ (OR 0.2, 95% CI 0.07-0.71). In conclusion, this study reports HR-HPV DNA of the most common six types and E6/E7 mRNA positivity as the most significant factors associated with CIN2+ lesions and higher education related to lower risk of high-grade cervical lesions.

Nationwide cohort study on the risk of high-grade cervical dysplasia and carcinoma after conservative treatment or hysterectomy for adenocarcinoma in situ.

Internationally, little consensus exists about the best treatment for cervical adenocarcinoma in situ (AIS). This study aimed to determine the incidence of recurrent high-grade cervical dysplasia and development of local cervical cancer after treatment for AIS. This nationwide, retrospective cohort study included patients with AIS, who were treated by a large loop excision of the transformation zone (LLETZ), cold-knife conization (CKC), or hysterectomy between January 1, 1990 and December 31, 2021 in the Netherlands. Pathology reports were retrieved from the Dutch Nationwide Pathology Databank (Palga). Primary outcomes were the cumulative incidences of high-grade cervical dysplasia (cervical intraepithelial neoplasia grade 2 or 3, and AIS) and local cervical cancer up to 20 years after primary treatment. In total, 4243 patients with AIS were included. The primary treatment was a LLETZ, CKC, or hysterectomy in 1593, 2118, and 532 patients, respectively. The incidence of recurrent high-grade cervical dysplasia after LLETZ (10.5%; 95%CI: 8.6-12.3) was higher than after CKC (5.5%; 95%CI: 4.4-6.6, p <.0001). When a radical excision, that is, surgical margins free of dysplasia at end of treatment, was achieved, the incidence of recurrent high-grade dysplasia and local cervical cancer did not differ between LLETZ (5.6% [95%CI: 3.3-7.9] and 1.9% [95%CI: 0-4.4]) and CKC (4.7% [95%CI: 3.5-5.8], p = .631 and 1.5% [95%CI: 0.7-2.3], p = .918). After hysterectomy, none of the patients developed cervical dysplasia or local cervical cancer. Conservative treatment for AIS can be considered a safe and final treatment modality when a radical excision is achieved.

Risk assessment of careHPV testing for the detection of cervical precancerous lesions: 5-year follow-up of a screening program in China

BackgroundCareHPV is a highly promising screening HPV assay that functions as a simplified and rapid point-of-care test, making it particularly well-suited for low-resource areas. It exhibits high sensitivity for detecting cervical precancerous lesions in cross-sectional study design. However, there is still limited evidence on the long-term protection of careHPV testing in the practical setting. MethodsA government-led cervical cancer screening program was implemented in Ordos City, China, specifically targeting female residents aged 35-64 years since 2016. CareHPV specimens were collected and visual inspection with acetic acid and Lugol iodine (VIA/VILI) was performed in the baseline screening. Women who were HPV-positive at baseline were invited for a one-year follow-up screening. At the same time, those who were HPV-negative were scheduled for a 5-year rescreening. Women diagnosed with cervical intra-epithelial neoplasia grade 2 or worse (CIN2+) would be referred to clinical treatment as per the clinical guidelines. The current study includes participants who had valid baseline screening results and attended follow-ups with valid careHPV results conducted between January 2017 and December 2021, aiming to assess the long-term risk stratification for careHPV. Cumulative incidence rate (CIRs) and hazard ratio (HRs) for CIN2+ were calculated, using survival analysis. ResultsAmong the 179,306 women enrolled in the baseline screening between 2016 and 2020, 12.60% tested positive for careHPV, with 657 cases of CIN2+ identified. The final analysis included 18,562 women in our study, of whom 58.54% were careHPV-positive at baseline. The final analysis consisted of 17,905 women who underwent screening between 2016 and 2020 and attended follow-ups from 2017 to 2021, with valid HPV results, and 657 women who identified as CIN2+ at the baseline. The 5-year CIRs were 0.003 and 0.101 among women who tested negative and positive for baseline careHPV, respectively. The 5-year CIRs for developing CIN2+ during follow-ups were 0.009, 0.009, and 0.11 for the groups of women who transitioned from careHPV-negative to positive (831, 4.64%), careHPV-positive to negative (6688, 37.35%), and maintained a stable positive careHPV status (3535, 19.74%), respectively. ConclusionsOur findings support the long-term safety and protection of careHPV testing in 5-year follow-ups of screening programs. CareHPV represents a viable option for regions with limited healthcare resources.

Clinical Performance of OncoPredict HPV Screening Assay on Self-Collected Vaginal and Urine Specimens Within the VALHUDES Framework.

The introduction of self-sampling in cervical cancer screening has raised the importance of HPV test validation on self-collected samples. This study aimed to evaluate the clinical accuracy of the OncoPredict HPV Screening (SCR) assay on self-collected vaginal and first-void urine (FVU) samples, relative to cervical specimens, using the VALHUDES Framework. FVU and vaginal self-samples followed by a clinician-collected cervical brushing were collected from 500 women referred to colposcopy and tested using OncoPredict HPV SCR assay. The assay demonstrated clinical sensitivity to detect cervical intraepithelial neoplasia grade 2 or worse (≥ CIN2) similar to cervical samples in FVU (ratio: 0.95, [95% CI: 0.88-1.02]) and vaginal self-samples (ratio: 0.96 [95% CI: 0.90-1.02]). The clinical specificity for < CIN2 was lower in vaginal (ratio: 0.90 [95% CI: 0.84-0.96]) but not in FVU samples (ratio: 1.03 [95% CI: 0.96-1.12) when compared to cervical samples. However, the relative specificity improved following cut-off optimization (ratio: 0.94, 95% CI: [0.88-1.01]). Moderate to excellent agreement in HPV detection between self-collected and cervical samples was demonstrated (Kappa values: 0.53-1.00). To conclude, OncoPredict HPV SCR assay demonstrated similar accuracy on FVU and cervical samples. On vaginal compared to cervical samples sensitivity was similar with a lower specificity, which improved with cut-off optimization.

Post-marketing study design to evaluate the effectiveness of the 9-valent and 4-valent HPV vaccines on serious HPV-related cervical disease in China

ABSTRACT The 4-valent (4 v) and 9-valent (9 v) human papillomavirus (HPV) vaccines are approved in China for females aged 9–45 years. However, the real-world impact of 4vHPV or 9vHPV vaccination for the prevention of high-grade cervical disease in Chinese women is lacking. Two post-marketing surveillance studies will be conducted to measure the occurrence of high-grade cervical lesions in Chinese women who had received ≥1 dose of the 4vHPV (aged 20–45 years) or 9vHPV (aged 16–26 years) vaccine in Ningbo, China. Vaccination data will be extracted from the Ningbo Regional Health Information Platform (NRHIP) from the date of the first 4vHPV (January 9, 2018) or the first 9vHPV (January 25, 2019) vaccination to March 31, 2021. The primary 4vHPV and 9vHPV vaccinated cohorts will include women vaccinated per protocol. The 4vHPV/9vHPV vaccinated test-negative (cervical HPV negative; ThinPrep cytology test negative) and corresponding matched unvaccinated HPV test-negative sub-cohorts will also be assessed. Outcomes will be the occurrence of new-onset cervical intraepithelial neoplasia grade 2/3, adenocarcinoma in situ, and invasive cervical cancer. This study aims to demonstrate that such a methodological approach is feasible and can be used to assess the impact of HPV vaccination in other regions across China.

Nationwide study on development and validation of a risk prediction model for CIN3+ and cervical cancer in Estonia

Transitioning to an individualized risk-based approach can significantly enhance cervical cancer screening programs. We aimed to derive and internally validate a prediction model for assessing the risk of cervical intraepithelial neoplasia grade 3 or higher (CIN3+) and cancer in women eligible for screening. This retrospective study utilized data from the Estonian electronic health records, including 517,884 women from the health insurance database and linked health registries. We employed Cox proportional hazard regression, incorporating reproductive and medical history variables (14 covariates), and utilized the least absolute shrinkage and selection operator (LASSO) for variable selection. A 10-fold cross-validation for internal validation of the model was used. The main outcomes were the performance of discrimination and calibration. Over the 8-year follow-up, we identified 1326 women with cervical cancer and 5929 with CIN3+, with absolute risks of 0.3% and 1.1%, respectively. The prediction model for CIN3 + and cervical cancer had good discriminative power and was well calibrated Harrell’s C of 0.74 (0.73–0.74) (calibration slope 1.00 (0.97–1.02) and 0.67 (0.66–0.69) (calibration slope 0.92 (0.84–1.00) respectively. A developed model based on nationwide electronic health data showed potential utility for risk stratification to supplement screening efforts. This work was supported through grants number PRG2218 from the Estonian Research Council, and EMP416 from the EEA (European Economic Area) and Norway Grants.

The Level of Serum Selenium in Patients with Cervical Intraepithelial Neoplasia in Medical City/ Baghdad Teaching Hospital

Introduction: Selenium is an essential trace element involved in different physiological functions of the human body. An inverse relationship between serum selenium levels and cervical intraepithelial neoplasia has been reported. cervical intraepithelial neoplasia is regarded as a potentially premalignant transformation of squamous cells of the cervix. Objectives: To evaluate the relationship between the serum level of selenium and cervical intraepithelial neoplasia. Methods: A case-control study was conducted at Baghdad Teaching Hospital and Iraqi National Cancer Research Center in the University of Baghdad during the period from July 2021 to July 2022. A convenient sample of 100 women was enrolled in the current study and included case group which consisted of 50 women who were diagnosed with cervical intraepithelial neoplasia and control group which consisted of 50 women who did not have cervical intraepithelial neoplasia as confirmed through histological examination after punch biopsy by colposcopy. Results: The serum level of the selenium was significantly lower in the case groups compared to the control groups (P-value=0.001). In addition, the proportion of the participant with abnormal levels of selenium was significantly higher in the case group compared to the control group (P-value=0.001). In the case group, there was a significant difference between the cervical intraepithelial neoplasia grade regarding the serum level of selenium, the level of selenium significantly decreased with the progression of the disease (P-value=0.001). Conclusions: Selenium deficiency may significantly increase the incidence of cervical intraepithelial neoplasia. In addition, it significantly impacts the transformation to a higher degree as there was a significant difference between cervical intraepithelial neoplasia I, II, and III regarding the level of serum selenium.

Age-specific 3-year risk of cervical precancer among HPV-positive women attending screening: a post hoc analysis from a retrospective cohort

This post hoc analysis explored the age-specific risk of cervical precancer in women infected with human papillomavirus (HPV), using data from a cohort of 7263 participants aged 21-71years undergoing cervical screening. We found a slightly varied prevalence of high-risk HPV (hrHPV) in different age, with highest in women under 30 years old (9.28% for 13 hrHPVs tested by HC2-HPV, 10.82% for 14 hrHPVs tested by DH3-HPV). However, the prevalence of cytology abnormalities peaked in age 30–39 years (~ 3.6%). A total of 5840 women completed 3-year follow-up. Among them, 558 were positive for HC2 assay and 583 were positive for DH3-HPV at baseline. Of note, the 3-year cumulative risks for cervical intraepithelial neoplasia grade 2+ (CIN2+) or grade 3+ (CIN3+) in women infected with high-risk HPV did not increase with age but declined (e.g., 41.67%, 27.78%, 26.42%, 15.98%, and 18% for CIN2 + risk in HC2-positive women at year 25–29, year 30–39, year 40–49, year 50–59, and year 60–71, respectively). If stratified by the median age, younger women (25–48 years) positive with HC2-HPV at baseline had a higher 3-year CIN2+/CIN3 + risk than older women (49–71 years) [26.55% (95%CI = 21.8-31.92%) vs. 18.28% (95%CI = 14.11-23.34%), P = 0.019; 15.52% (95%CI = 11.81-20.14%) vs. 9.7% (95%CI = 6.71-13.83%), P = 0.039]. Similarly, for women positive with DH3-HPV at baseline, younger group had a higher 3-year CIN2+/CIN3 + risk than older group [26.44% (95%CI = 21.73-31.75%) vs. 17.01% (95%CI = 13.11-21.78%), P = 0.006; 15.25% (95%CI = 11.6-19.8%) vs. 9.03% (95%CI = 6.24-12.9%), P = 0.021]. These findings indicate the potential value of age-specific risk assessment in cervical cancer screening.

Comparative study of triage strategies for women with atypical squamous cells of undetermined significance in the post-vaccine era.

The research focused on a comparative analysis of triage strategies for women with Atypical Squamous Cells of Undetermined Significance (ASC-US) before and after receiving the HPV vaccine, aiming to optimize cervical cancer prevention strategies, especially in resource-limited healthcare settings. Between September 2018 and December 2023, 7,511 women aged 21 years or older who underwent liquid-based cytology for cervical cancer screening were recruited. Women diagnosed with ASC-US were included in the study. All participants underwent HPV testing and liquid-based cytology examination, and those with abnormal results were referred for colposcopy. Women with abnormal colposcopy findings underwent further histopathological examination. The gold standard for diagnosis was pathological, with cervical intraepithelial neoplasia grade 2 or higher (CIN2+) on histology as the endpoints. In the final analysis, 933 women with ASC-US were enrolled as the unvaccinated group, with 179 of them testing positive for HPV 16/18. Assuming that all women would receive the bivalent vaccine targeting HPV 16/18 in the post-vaccine era, and given that the vaccine protection rate is 100% against HPV 16/18, then 754 women excluding those of HPV 16/18 positive would comprise the vaccinated group. In the unvaccinated group, the overall HPV positivity rate was 59.27% among ASC-US women, with a 100% HPV prevalence rate among those with CIN2+ lesions. The combination genotyping model of HPV16/18 showed the highest specificity (81.77%) and the lowest referral rate (32.37%). In the vaccinated group, the HPV positivity rate was 49.61% among ASC-US women, with a 100% HPV prevalence rate among those with CIN2+ lesions. The specificity of HPV33/58 was the highest (86.99%), and the colposcopy referral rate was lowest (27.54%), with statistical significance. Sensitivity, positive predictive value, and negative predictive value were not statistically significant. HPV16/18 demonstrated a more efficacious triaging effect in the unvaccinated group. HPV33/58 will potentially replace HPV16/18 as the priority screening genotyping among vaccinated populations.

Cost-Effectiveness of Computer-Assisted Cytology in a Primary hrHPV-Based Cervical Cancer Screening Programme.

Computer-assisted screening (CAS) shows equal performance compared to manual screening, although results are heterogeneous. Furthermore, using CAS may save costs through a potentially increased screening productivity of technicians, therefore also offering a solution for temporary and structural capacity shortage. We evaluated the circumstances under which CAS will be cost-effective compared to manual cytology triage in a primary HPV-based cervical screening programme. Microsimulation model MISCAN-Cervix was used to evaluate 198 different CAS scenarios with varying probabilities to detect cervical intraepithelial neoplasia grade 1 (CIN1) and CIN3 and cost reductions per test, compared to manual cytology triage. Cost-effectiveness was evaluated by costs per (quality-adjusted) life year ((QA)LY) gained. CAS will be cost-effective in all scenarios, except for the following combinations: (1) no cost reduction and an increased probability of detecting CIN1, (2) a cost reduction of €2 per test and an increased probability of detecting CIN1 from 4% onwards or (3) a cost reduction of €4 per test and an increased probability of detecting CIN1 from 6% onwards, compared to manual cytology triage. All CAS scenarios with any reduction in the probability of detecting CIN1 (i.e., increased CIN2+ specificity), or a reduction in costs from €6 per test onwards suggested a more cost-effective strategy compared to manual cytology triage. As we based our analysis on a realistic range in costs and test performance, the implementation of CAS is likely to be cost-effective. Our results can be used as a guideline to advise when to choose CAS instead of manual cytology triage.

Human papillomavirus self-sampling and urine-sampling tests and the management and short-term outcomes of cervical intraepithelial neoplasia: A prospective observational study.

The importance of human papillomavirus (HPV) co-testing using physician-, self-, and urine-collected samples to predict cervical intraepithelial neoplasia (CIN) grade 1-2 prognoses has not been previously reported. Therefore, this study aimed to investigate outcomes of patients with CIN 1-2 who simultaneously underwent physician-, self-, and urine-collection sampling tests. This study was conducted in Japan between October 2019 and November 2022 and examined the proportion of cases with CIN 1-2 progressions, the percentage of cases with persistent CIN 1-2, and the outcome differences according to the results of physician-, self-, and urine-sampling tests. There were 105 and 59 CIN 1 and 2 cases, respectively, with progression or persistence in 27 (29.3%) and 21 (50.0%) cases, respectively. The median follow-up was 20 and 12 months, respectively. Progression and persistence of CIN 1 were significantly associated with HPV-positive physician- and self-collected samples. No significant difference was observed between cases with CIN 2 who had HPV-positive and HPV-negative results using any sampling method. Physician- and self-testing for HPV are crucial for predicting disease progression risk in CIN 1 cases. Future research with an extended observation period and consideration of the progression risks is warranted.

Ranking the attribution of high-risk genotypes among women with cervical precancers and cancers: a cross-sectional study in Ningbo, China

BackgroundThe region-specific importance of carcinogenic HPV genotypes is required for optimizing HPV-based screening and promoting appropriate multivalent HPV prophylactic vaccines. This information is lacking for Ningbo, one of the first cities of China’s Healthy City Innovation Pilot Program for Cervical Cancer Elimination. Here, we investigated high-risk HPV (HR-HPV) genotype-specific distribution and attribution to biopsy-confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+) before mass vaccination in Ningbo, China.MethodsA total of 1393 eligible CIN2+ archived blocks (including 161 CIN2, 1107 CIN3, and 125 invasive cervical cancers [ICC]) were collected from 2017 to 2020 in Ningbo. HR-HPV DNA was genotyped using the SPF10-DEIA-LiPA25 version 1 detection system and the SureX HPV 25X Genotyping Kit. Genotype-specific attribution to CIN2+ was estimated using a fractional contribution approach.ResultsRanking by the attributable proportions, HPV16 remained the most important genotype in both cervical precancers and cancers, accounting for 36.8% of CIN2, 53.2% of CIN3, and 73.3% of ICC cases. Among cervical precancers, HPV52 (17.3% in CIN2, 12.7% in CIN3) and HPV58 (13.9%, 14.9%) ranked second and third, while HPV33 (8.3%, 7.9%) and HPV31 (6.5%, 4.1%) ranked fourth and fifth, respectively. However, among ICCs, HPV18 (5.7%) accounted for the second highest proportion, followed by HPV33 (5.4%), HPV58 (4.0%), and HPV45 (3.2%). HPV18/45 together accounted for 46.8% of adenocarcinomas, which was slightly lower than that of HPV16 (47.7%). The remaining HR-HPV genotypes (HPV35/39/51/56/59/66/68) combined accounted for only 6.7% of CIN2, 2.9% of CIN3, and 4.2% of ICC.ConclusionsWith Ningbo’s strong medical resources, it will be important to continue HPV16/18 control efforts, and could broaden to HPV31/33/45/52/58 for maximum health benefits. However, different strategies should be proposed for other HR-HPV genotypes based on their lower carcinogenic risks.

Head-to-head comparison of two human papillomavirus vaccines for efficacy against cervical intraepithelial neoplasia grade 3 and adenocarcinoma in situ-population-based follow-up of two cluster-randomized trials.

We report head-to-head comparison of the bivalent and quadrivalent HPV vaccine efficacies against immediate precursors of cervical cancer from 15 years' country-wide cancer registry follow-up of phase III trial cohorts and an age-aligned cohort of unvaccinated women. These individually and/or clusterrandomized cohorts of HPV6/11/16/18- and HPV16/18-vaccinated and unvaccinated women were enrolled, respectively, in 2002, 2004, and 2003/2005. The trial cohorts comprised initially 16- to 17-year-old HPV6/11/16/18-vaccinated FUTURE II (NCT00092534) participants (866) and HPV16/18-vaccinated PATRICIA (NCT00122681) and 012 trial (NCT00169494) participants (2,465), and 16,526 initially 16- to 19-year-old unvaccinated controls. After active 4-year clinical follow-up, passive, country-wide Finnish Cancer Registry (FCR) follow-up for cervical intraepithelial neoplasia grade 3 (CIN3) and adenocarcinoma in situ (AIS) was based on consented use of unique personal identifiers and started 6 months after the end of the FUTURE II and PATRICIA trials in 2007 and 2009, and ended at the end of 2019. The follow-up with altogether 229,020 follow-up years was age-aligned to ensure that similarly aged cohorts were passively followed up for 15 years post=vaccination for the intention-to-treat analyses of vaccine efficacy. Overall, we identified 5 and 16 CIN3 (no AIS) cases in the HPV6/11/16/18 and HPV16/18 cohorts, respectively, during the FCR-based follow-up. In the unvaccinated cohort, we identified 281 CIN3 cases, 20 AIS cases, and 13 cases with invasive cervical cancer. Vaccine efficacies against CIN3+ were 68.4% and 64.5% for the quadrivalent and the bivalent vaccines, respectively, with overlapping confidence intervals. Long-term follow-up of randomized, initially adolescent HPV-vaccinated and unvaccinated cohorts shows, in this head-to-head setting, that the bivalent and quadrivalent HPV vaccines are equally effective against immediate precursors of cervical cancer.

Time trends in the clinical management of cervical intraepithelial neoplasia grade 2: A Danish register-based study.

Active surveillance for cervical intraepithelial neoplasia grade 2 (CIN2) has been implemented recently in many countries, including the Nordic countries. In Denmark, the only eligibility criterion for active surveillance for CIN2 is that the woman should be of reproductive age. With this study, we aimed to evaluate clinical and socioeconomic characteristics in women with CIN2 managed by active surveillance or large loop excision of the transformation zone (LLETZ) and to evaluate temporal changes in the clinical management of CIN2. We conducted a Danish nationwide study using data from healthcare registries. All female residents aged 18-40 years, diagnosed with incident CIN2 from January 1, 1998, to February 29, 2020, were included. We collected data on age, index cytology result, year of CIN2 diagnosis, region of residence, civil status, HPV vaccination status, and socioeconomic position indicators. The variables were tabulated overall and by management group (active surveillance vs. LLETZ). To evaluate time trends, we used joinpoint regression to calculate the annual percentage change (APC), including 95% confidence intervals (CI). Of the 27 536 women with CIN2 included, 12 500 (45.4%) underwent active surveillance, and 15 036 (54.6%) underwent a LLETZ. Women undergoing active surveillance were younger, more often HPV-vaccinated, and more likely to have a normal/low-grade index cytology result than women undergoing LLETZ. Socioeconomic position indicators did not differ. Over time, the proportion of women undergoing active surveillance increased from 21.7% in 2004 to 73.6% in 2019 (APC 9.7, 95% CI 8.1-11.4). The proportion of women undergoing active surveillance aged <30 declined over time (APC -2.2, 95% CI -2.9 to -1.5). The proportion of women with normal/low-grade index cytology increased slightly to 51.6% in 2019 (APC 0.8, 95% CI 0.4-1.3). The use of active surveillance for CIN2 has increased over the past two decades in Denmark. Observed differences in characteristics between women undergoing active surveillance vs LLETZ are likely related to indications for clinical management.

Multiscale Optical Imaging Fusion for Cervical Precancer Diagnosis: Integrating Widefield Colposcopy and High-Resolution Endomicroscopy.

Early detection and treatment of cervical precancers can prevent disease progression. However, in low-resource communities with a high incidence of cervical cancer, high equipment costs and a shortage of specialists hinder preventative strategies. This manuscript presents a low-cost multiscale in vivo optical imaging system coupled with a computer-aided diagnostic system that could enable accurate, real-time diagnosis of high-grade cervical precancers. The system combines portable colposcopy and high-resolution endomicroscopy (HRME) to acquire spatially registered widefield and microscopy videos. A multiscale imaging fusion network (MSFN) was developed to identify cervical intraepithelial neoplasia grade 2 or more severe (CIN 2+). The MSFN automatically identifies and segments the ectocervix and lesions from colposcopy images, extracts nuclear morphology features from HRME videos, and integrates the colposcopy and HRME information. With a threshold value set to achieve sensitivity equal to clinical impression (0.98 [p = 1.0]), the MSFN achieved a significantly higher specificity than clinical impression (0.75 vs. 0.43, p = 0.000006). Our findings show that multiscale optical imaging of the cervix allows the highly sensitive and specific detection of high-grade precancers. The multiscale imaging system and MSFN could facilitate the accurate, real-time diagnosis of cervical precancers in low-resource settings.

Triage performance of PAX1m/JAM3m in opportunistic cervical cancer screening of non‒16/18 human papillomavirus-positive women: a multicenter prospective study in China

ObjectivesIn this study, we aimed to validate the performance of the PAX1 and JAM3 methylation (PAX1m/JAM3m) test as a triage tool for detecting cervical intraepithelial neoplasia grade 3 or worse (CIN3 +) in non-16/18 high-risk human papillomavirus-positive patients (non-16/18 hrHPV +).MethodsThe triage performance of liquid-based cytology (LBC) and the PAX1m/JAM3m test for detecting CIN3 + were compared.ResultsIn total, 1851 participants had cervical histological outcomes and were included in the analysis. The sensitivity/specificity of the LBC test results with atypical squamous cells of undetermined significance or worse (LBC ≥ ASCUS) and the PAX1m/JAM3m test were 90.1%/26.7% and 84.8%/88.5%, respectively. PAX1m/JAM3m( +) had the highest diagnostic AUC (0.866, 95% confidence interval (CI) 0.837–0.896) in the whole cohort. All cancers (n = 20) were detected by PAX1m/JAM3m(+). Compared with LBC ≥ ASCUS, PAX1m/JAM3m(+) reduced the number of patients who needed referral for colposcopy by 57.21% (74.66% vs. 17.45%). The odds ratios for detecting CIN3 + by LBC ≥ ASCUS and PAX1m/JAM3m(+) were 3.3 (95% CI 2.0–5.9) and 42.6 (27.1–69.6), respectively (p < 0.001). The combination of LBC ≥ ASCUS or PAX1m/JAM3m(+) slightly increased the diagnostic sensitivity (98.0%, 95% CI: 95.8–100%) and referral rate (77.09%) but reduced the diagnostic specificity (24.8%, 22.7–26.8%).ConclusionsIn non-16/18 hrHPV(+) women, PAX1m/JAM3m was superior to cytology for detecting CIN3 + . Compared with LBC ≥ ASCUS, PAX1m/JAM3m(+) reduced the number of significant referrals to colposcopy without compromising diagnostic sensitivity.

Association between folate level and cervical intraepithelial neoplasia risk: a systematic review and meta-analysis.

There were several studies about the association between folate level and the risk of cervical intraepithelial neoplasia (CIN). This meta-analysis was conducted to evaluate whether folate deficiency is related to a high risk of CIN and cervical cancer. Odds ratios (ORs)/relative risks and 95% confidence intervals (CIs) were summarized regarding the association between folate level and risk of CIN or cervical cancer. The meta-analysis indicated that higher serum folate levels (the second, third, and fourth quartiles of serum folate) were associated with a lower risk of CIN, as demonstrated by a random-effects model (OR = 0.42, 95% CI: 0.28-0.62). Conversely, no significant association was found between erythrocyte folate levels and the risk of CIN, as indicated by a random-effects model (OR = 0.69, 95% CI: 0.43-1.12). In addition, random-effects models demonstrated that higher serum folate levels (the second, third, and fourth quartiles of serum folate) were associated with lower risks of CIN grade 1 and CIN grades 2 or 3, compared with the lowest quartile of serum folate (CIN grade 1: OR = 0.52, 95% CI: 0.29-0.93; CIN grades 2 or 3: OR = 0.33, 95% CI: 0.19-0.58). Higher serum folate levels (the second, third, and fourth quartiles of serum folate) were associated with a lower risk of cervical cancer, compared with the lowest quartile of serum folate (OR = 0.53, 95% CI: 0.36-0.79). Serum low folate levels could increase the risk of CIN and cervical cancer, while erythrocyte folate concentration was not associated with the risk of CIN.