High-grade Cervical Intraepithelial Neoplasia Research Articles

Distribution and Severity of Cervical Intraepithelial Neoplasia in Women With Different Human Papillomavirus: An Analysis From Liaoning Province of Northeastern China.

Persistent infection with high-risk human papillomavirus (HPV) is a key contributor to cervical intraepithelial neoplasia (CIN), but the relation between high-risk HPV genotypes and the location of CIN lesions remains unclear. The aims of this study were to investigate the most frequent biopsy site of CIN lesions in women with different HPV infection and to analyze the biopsy times, CIN frequency, and the clustering of CIN frequency based on 12-o'clock sites and cervical quadrant locations. We conducted a retrospective study of HPV detection and genotyping at the virology department of our hospital. Colposcopy exams were performed by specialists according to a standardized protocol, and all visually abnormal areas were further biopsied. Pearson chi-squared tests and cluster analyses were implemented to analyze the data. Among 1,381 women enrolled in this study, 933 cases infected with HPV. HPV16, HPV58, and HPV18 were the most common genotypes. The most frequent biopsy site was the 6 o'clock position. The highest frequency of high-grade CIN findings in single-genotype HPV groups was the 6 o'clock position and that for multiple-genotype HPV group was the 12 o'clock location. All CIN clusters were found in the 6 and 12 o'clock biopsy sites, except in the HPV18 group. Quadrant 2 and 4 were clustered in most groups. The 6 and 12 o'clock sites in cervical quadrant 2 and 4 should be targeted during cervical biopsy procedures. These findings can provide clinicians with specific recommendations on the optimal site for CIN biopsy when considering the HPV genotype.

The Incidence of Cervical Intraepithelial Neoplasia or Cervical Cancer in Women Referred With Postcoital Bleeding.

The incidence of cervical cancer among patients with postcoital bleeding (PCB) was the primary objective of this study. Furthermore, the proportion of cervical intraepithelial neoplasia requiring treatment and the correlation between PCB and the presence of high-risk human papillomavirus (HPV) was determined. Lastly, the study aimed to identify risk factors among the referred women. A retrospective cohort study was conducted at a university hospital in Denmark between January 1, 2017 and December 31, 2019. Women referred with PCB were identified with the ICD diagnosis codes "DN930 Postcoital and contact bleeding" and "DN930B Contact bleeding." Demographic and paraclinical data were extracted from the journals and the supportive systems: Patoweb and the Danish Microbiology Database. A total of 789 women were included in this study, with only 0.25% (n = 2) diagnosed with cervical cancer and 2.5% (n = 20) diagnosed with cervical intraepithelial neoplasia II-III and adenocarcinoma in situ. Human papillomavirus testing was only conducted in a minority of cases, and a low incidence of high-risk human papilloma virus was detected in the 22 cases, n = 5. A very low incidence of cervical cancer and high-grade cervical intraepithelial neoplasia reported among women referred with PCB. Prognostic factors as body mass index, smoking, and HPV vaccination status may predict the risk of cervical cancer. Selection criteria like primary testing for hrHPV and cytology as cotests before referral to colposcopy may reduce the number of unnecessary colposcopies.

Imiquimod Is Effective in Reducing Cervical Intraepithelial Neoplasia: A Systematic Review and Meta-Analysis.

Topical Imiquimod is an immune response modifier approved for the off-label use of vulvar intraepithelial neoplasia. We conducted this systematic review and meta-analysis to investigate the efficacy and safety of Imiquimod in treating cervical intraepithelial neoplasia (CIN) and human papillomavirus (HPV)-positive patients. The study was prospectively registered (CRD420222870) and involved a comprehensive systematic search of five medical databases on 10 October 2022. We included articles that assessed the use of Imiquimod in cervical dysplasia and HPV-positive patients. Pooled proportions, risk ratios (RRs), and corresponding 95% confidence intervals (CIs) were calculated using a random effects model to generate summary estimates. Statistical heterogeneity was assessed using I2 tested by the Cochran Q tests. Eight articles reported on 398 patients who received Imiquimod out of 672 patients. Among CIN-2-3 patients, we observed a pooled regression rate of 61% (CI: 0.46-0.75; I2: 77%). When compared, Imiquimod was inferior to conization (RR: 0.62; CI: 0.42-0.92; I2: 64%). The HPV clearance rate in women who completed Imiquimod treatment was 60% (CI: 0.31-0.81; I2: 57%). The majority of side effects reported were mild to moderate in severity. Our findings indicate that topical Imiquimod is safe and effective in reducing cervical intraepithelial neoplasia and promoting HPV clearance. However, it was found to be inferior compared to conization. Imiquimod could be considered a potential medication for high-grade CIN patients and should be incorporated into guidelines for treating cervical dysplasia.

Impact of HPV Vaccination on the Incidence of High-Grade Cervical Intraepithelial Neoplasia (CIN2+) in Women Aged 20-25 in the Northern Part of Norway: A 15-Year Study.

Human papillomavirus (HPV), the most prevalent sexually transmitted infection globally, is a key risk factor for high-grade cervical lesions and cervical cancer. Since 2009, HPV vaccination has been part of the national immunization program for girls in 7th grade in Norway (women born 1997 and later). This study aimed to assess the impact of HPV vaccination on the incidence of high-grade cervical precursors (CIN2+) among women aged 20-25 in Troms and Finnmark over a 15-year period. In this time series study, we analyzed cervical screening data from 15,328 women aged 20-25 in Troms and Finnmark, collected between 2008 and 2022. Statistical methods, including linear and logistic regression, were employed to evaluate changes in cervical intraepithelial neoplasia grade 2 and worse (CIN2+) incidence and compare risks between vaccine-offered cohorts and pre-vaccine cohorts. The incidence of CIN2+ initially increased from 31 cases per year in 2008 to 110 cases in 2018, then significantly decreased to 44 cases per year by 2022 (p < 0.01). Women in pre-vaccine cohorts had a substantially higher risk of CIN2+ (OR 9.02, 95% CI 5.9-13.8) and CIN3+ (OR 19.6, 95% CI 7.3-52.6). Notably, no vaccinated women with CIN2+ tested positive for HPV types 16 or 18. Furthermore, none of the 13 cervical cancer cases recorded during the study were from the vaccinated cohorts. The findings suggest a significant reduction in the incidence of high-grade cervical precursors following the introduction of the HPV vaccine in Norway's national immunization program, highlighting its effectiveness in cervical cancer prevention among young women in Northern Norway.

Aerobic vaginitis is associated with carbonic anhydrase IX in cervical intraepithelial neoplasia

The aim of this study was to analyze the association between vaginal microbiota, carbonic anhydrase IX (CAIX) and histological findings of cervical intraepithelial neoplasia (CIN). The study included 132 females, among them 66 were diagnosed with high-grade intraepithelial lesion (CIN2, CIN3, and cancer), 14 with low-grade disease, and 52 assigned to the control group. An interview focused on the behavior risk factors, together with vaginal fluid pH measurement, wet mount microscopy, detection of Chlamydia trachomatis, and Trichomonas vaginalis were performed. After colposcopy, high-grade abnormalities were detected via direct biopsies and treated with conization procedure. Conuses were immuno-stained with CAIX antibody. The histological findings were CIN1 (n = 14), and CIN2+ (included CIN2 (n = 10), CIN3 (n = 49), and cancer (n = 7; squamous cell carcinomas)). Prevalence of bacterial vaginosis (BV) was similar between the groups. Moderate or severe aerobic vaginitis (msAV) was diagnosed more often among CIN2+ (53.0%) than CIN1 (21.4%). Moderate or strong immunostaining of CAIX (msCAIX) was not detected among CIN1 cases. Thus, msAV was prevalent in CAIX non-stained group (p = 0.049) among CIN2 patients. Co-location of msAV and msCAIX was found in CIN3. Regression model revealed that msAV associated with high-grade cervical intraepithelial neoplasia independently from smoking and the number of partners.

Long-term prediction by DNA methylation of high-grade cervical intraepithelial neoplasia: Results of the ARTISTIC cohort.

Methylation markers have shown potential for triaging high-risk HPV-positive (hrHPV+) women to identify those at increased risk of invasive cervical cancer (ICC). Our aim was to assess the performance of the S5 DNA methylation classifier for predicting incident high-grade cervical intraepithelial neoplasia (CIN) and ICC among hrHPV+ women in the ARTISTIC screening trial cohort. The S5 classifier, comprising target regions of tumour suppressor gene EPB41L3 and L1 and L2 regions of HPV16, HPV18, HPV31, and HPV33, was assayed by pyrosequencing in archived hrHPV+ liquid-based samples from 343 women with high-grade disease (139 CIN2, 186 CIN3, and 18 ICC) compared to 800 hrHPV+ controls. S5 DNA methylation correlated directly with increasing severity of disease and inversely with lead time to diagnosis. S5 could discriminate between hrHPV+ women who developed CIN3 or ICC and hrHPV+ controls (p <.0001) using samples taken on average 5 years before diagnosis. This relationship was independent of cytology at baseline. The S5 test showed much higher sensitivity than HPV16/18 genotyping for identifying prevalent CIN3 (93% vs. 61%, p = .01) but lower specificity (50% vs. 66%, p <.0001). The S5 classifier identified most women at high risk of developing precancer and missed very few prevalent advanced lesions thus appearing to be an objective test for triage of hrHPV+ women. The combination of methylation of host and HPV genes enables S5 to combine the predictive power of methylation with HPV genotyping to identify hrHPV-positive women who are at highest risk of developing CIN3 and ICC in the future.

Human Papilloma Virus Typing as a Triage Tool for Women with Postcoital Bleeding: A Retrospective Cohort Study.

Objective: To investigate the performance of human papilloma virus (HPV) typing as a triage tool in the management of patients with postcoital bleeding (PCB). Methods: All patients referred for colposcopy at a cervical pathology clinic of a nationwide health insurance organization, due to PCB and had a preceding high-risk HPV (hrHPV) test between 2018 and 2020, were retrospectively located. Demographic and pathologic data were collected from electronic medical files. Sensitivity, specificity, and negative and positive predictive value of hrHPV test according to final pathology were calculated. Results: Three hundred ninety patients referred for colposcopy due to PCB with a preceding hrHPV test were located. HrHPV-positive patients were significantly younger (33.7 ± 10 vs. 37.2 ± 9, p < 0.006) with a higher proportion of nulliparous, nonmarried, and smokers compared with hrHPV-negative patients (75% vs. 47%, p < 0.001; 75.4% vs. 45.1%, p < 0.001; and 24.6% vs. 12.8%, p < 0.028, respectively). No case of high-grade cervical intraepithelial neoplasia (CIN2/3) was identified among hrHPV-negative patients. The sensitivity and NPV of the hrHPV test for high-grade cervical lesions were both 100%, decreasing to 36% and 95%, respectively, for any cervical dysplasia (CIN1/CIN2/CIN3). Adding cytology to HPV typing had a negligible effect on test performance. At univariate analysis, age, HPV vaccine status, nulliparity, and positive HPV typing were independently associated with cervical dysplasia. At multivariate analysis, only positive HPV typing remained significantly associated with cervical dysplasia (hazard ratio 2.75, confidence interval 1.1-6.5, p = 0.023). Conclusion: A negative HPV test even in the presence of PCB may rule out cervical dysplasia with extremely high accuracy and may save unnecessary colposcopies.

Multiple high-risk HPV infections probably associated with a higher risk of low-grade cytological abnormalities but not with high-grade intraepithelial lesions of the cervix

BackgroundFor women diagnosed with HR-HPV DNA positivity in community hospitals, the necessity of investigating the potential presence of multiple HR-HPV infections upon referral to tertiary medical institutions remains unclear.MethodsIn our cohort, women tested positive for HR-HPV DNA during examinations in community hospitals, were subsequently referred to tertiary medical facilities, reevaluated HR-HPV genotype and categorized based on cytological and histopathological results. The risk of cytologic/histopathology abnormalities and ≧ high grade squamous intraepithelial lesion(HSIL) or Cervical Intraepithelial Neoplasia (CIN) 2 associated with individual genotypes and related multiple HPV infections are calculated.ResultsA total of 1677 women aged between 21 and 77 were finally included in the present study. The cytology group included 1202 women and the histopathological group included 475 women with at least one HR-HPV infection of any genotype. We only observed a higher risk of low grade cytological abnormalities in women with multiple infections than those in corresponding single infections (for all population with an OR of 1.85[1.39–2.46]; p < 0.05). However, this phenomenon was not observed in histopathology abnormalities (CIN1). The risk of developing of ≥ HSIL/CIN2 in women who were infected with multiple HR-HPV also showed a similar profile to those with a single HR-HPV genotype.ConclusionMultiple HR-HPV infections is only associated with a higher associated risk of low grade cytological abnormalities. There is no evidence of clinical benefit to identify the possible presence of multiple HR-HPV infection frequently in a short period of time for women with HR-HPV-DNA positive.

PAD-mediated citrullination is a novel candidate diagnostic marker and druggable target for HPV-associated cervical cancer.

Citrullination is an emerging post-translational modification catalyzed by peptidyl-arginine deiminases (PADs) that convert peptidyl-arginine into peptidyl-citrulline. In humans, the PAD family consists of five isozymes (PADs 1-4, 6) involved in multiple diseases, including cancer. Given that high-risk (hr) human papillomaviruses (HPVs) are the etiological agents of cervical cancer, in this study, we sought to determine whether PAD-mediated protein citrullination would play a functional role in the HPV-driven transformation of epithelial cells. Here we show that both total protein citrullination and PAD4 expression levels are significantly associated with cervical cancer progression. Specifically, epithelial immunostaining for PAD4 revealed an increasingly higher histoscore from low-grade (CIN1) to high-grade (CIN2, CIN3) cervical intraepithelial neoplasia, and invasive squamous cell carcinoma (SCC) lesions, raising the attractive possibility that PAD4 may be used as tumor staging markers. Furthermore, taking advantage of the epidermoid cervical cancer cell line CaSki, which harbors multiple copies of the integrated HPV16 genome, we show that the expression of E6 and E7 HPV oncoproteins is impaired by treatment with the pharmacological pan-PAD inhibitor BB-Cl-amidine. Consistently, p53 and p21, two targets of HPV oncoproteins, are upregulated by the PAD inhibitor, which undergoes cell growth arrest and apoptosis. Altogether, these findings highlight a novel mechanism by which hrHPVs alter host regulatory pathways involved in cell cycle and survival to gain viral fitness, raising the possibility that PADs may represent an attractive target for developing novel host-targeting antivirals effective in preventing cervical cancer progression.

Comparison of 5-ALA-PDT and LEEP of cervical squamous intraepithelial neoplasia (CIN2) with high-risk human papillomavirus infection in childbearing age women: A non-randomized controlled polit study

Background5-Aminolevulinic acid-mediated photodynamic therapy (5-ALA-PDT) is a possible minimally-invasive treatment for high-grade cervical intraepithelial neoplasia (HSIL). The present study was carried out to assess the effect of 5-ALA-PDT and loop electrosurgical excision procedure (LEEP) in cervical squamous intraepithelial neoplasia (CIN2) combined with high-risk human papillomavirus (HR-HPV) infection. MethodsIn this study, 190 patients with CIN2 and HR-HPV infection were finally included. They were divided into the LEEP Group (n = 116) and PDT Group (n = 74) according to gynecologist's recommendation and patient's willingness. All patients were followed up at 4–6 months and 12 months after treatment, including HPV testing, cytology, and colposcopy examination. Results(1) 4–6 months after treatment, the pathological regression rate was 97.30 % (72/74) in the PDT group and 98.28 % (114/116) in the LEEP group (P = 0.952). The HPV clearance rate was 81.08 % (60/74) in the PDT group and 80.17 % (93/116)in the LEEP group (P = 0.877). (2) 12 months after treatment, the pathological regression rate was 93.24 % (69/74) in the PDT group and 96.55 % (112/116) in the LEEP group (P = 0.486). The recurrence rate of CIN2 was 4.05 % (3/74) in the PDT group and 1.72 % (2/116) in the LEEP group (P = 0.608). The HPV clearance rate was 90.54 % (67/74) in the PDT group and 89.66 % (104/116)in the LEEP group (P = 0.843). The reinfection rate of HR-HPV was 5.41 % (4/74) in the PDT group and 1.72 % (2/116) in the LEEP group (P = 0.322). (3) The adverse reactions in the PDT Group were slightly lower than that in the LEEP Group (P = 0.4956), but the incidence of vaginal bleeding in the PDT group was lower than that in the LEEP group during follow-up. ConclusionsThe effectiveness of 5-ALA-PDT is similar to LEEP for CIN2 with less side effects. Therefore, 5-ALA-PDT, a non-invasive treatment, may be an effective method for CIN2 patients of childbearing age.

Performance of BD Onclarity HPV assay on FLOQSwabs vaginal self-samples.

Human papillomavirus (HPV) testing on self-collected vaginal samples has been shown to improve women's participation to cervical cancer screening programs, particularly in regions with limited access to health care. Nevertheless, the introduction of self-sampling in cervical cancer screening programs requires prior clinical validation of the HPV assay in combination with a self-sample collection device, including also the laboratory workflow and automation required for high-throughput testing in screening. In this study, the performance of BD Onclarity HPV on FLOQSwab-collected vaginal self-samples has been compared to clinician-taken liquid-based cytology samples, to detect high-grade cervical intraepithelial neoplasia using two high-throughput platforms, BD Viper LT and BD COR. The study findings have shown a similar performance of BD Onclarity on testing self-collected samples, confirming the validation of the proposed pre-analytical and analytical protocols for their use in cervical cancer screening programs based on self-collected vaginal samples.

Safety, Efficacy, and Immunogenicity of Therapeutic Vaccines for Patients with High-Grade Cervical Intraepithelial Neoplasia (CIN 2/3) Associated with Human Papillomavirus: A Systematic Review

Despite the knowledge that HPV is responsible for high-grade CIN and cervical cancer, little is known about the use of therapeutic vaccines as a treatment. We aimed to synthesize and critically evaluate the evidence from clinical trials on the safety, efficacy, and immunogenicity of therapeutic vaccines in the treatment of patients with high-grade CIN associated with HPV. A systematic review of clinical trials adhering to the PRISMA 2020 statement in MEDLINE/PubMed, Embase, CENTRAL Cochrane, Web of Science, Scopus, and LILACS was undertaken, with no data or language restrictions. Primary endpoints related to the safety, efficacy, and immunogenicity of these vaccines were assessed by reviewing the adverse/toxic effects associated with the therapeutic vaccine administration via histopathological regression of the lesion and/or regression of the lesion size and via viral clearance and through the immunological response of individuals who received treatment compared to those who did not or before and after receiving the vaccine, respectively. A total of 1184 studies were identified, and 16 met all the criteria. Overall, the therapeutic vaccines were heterogeneous regarding their formulation, dose, intervention protocol, and routes of administration, making a meta-analysis unfeasible. In most studies (n = 15), the vaccines were safe and well tolerated, with clinical efficacy regarding the lesions and histopathological regression or viral clearance. In addition, eleven studies showed favorable immunological responses against HPV, and seven studies showed a positive correlation between immunogenicity and the clinical response, indicating promising results that should be further investigated. In summary, therapeutic vaccines, although urgently needed to avoid progression of CIN 2/3 patients, still present sparse data, requiring greater investments in a well-designed phase III RCT.

A prospective clinical trial of diathermy ablation for patients with high-grade cervical intraepithelial neoplasia from a single institution in Japan

Approximately 500,000 women are diagnosed with cervical cancer annually, with high-grade cervical intraepithelial neoplasia (CIN) estimated to be 20 times higher. The diathermy ablation is an inexpensive minimally invasive surgeries for CIN. However, little is known about the treatment outcomes. A prospective clinical trial was therefore conducted to evaluate ablation outcomes based on detailed colposcopy findings, cytology, and biopsy results over a two-year period. We enrolled CIN2 (n = 32) and CIN3 (n = 7) patients. Eligibility criteria included: aged between 29 and 49 (median: 36, mean: 36.3), visible transformation zone with high-grade lesions not entirely occupying the cervix, and histologically diagnosed with CIN2 or CIN3. Cytology and HPV genotyping were performed, and colposcopic findings were evaluated. Colposcopy-guided diathermy ablation was conducted by a certified gynecologic oncologist. The incidence of recurrent or residual disease was 5.1% (2/39, 95% confidence interval: − 0.02 to 0.12). The prevalence of HPV infection at 12 months decreased after surgery, as 67.6% (23/34, 0.52–0.83) of patients were HPV-negative. No severe adverse events were reported, while there were five pregnancies with full-term deliveries. The promising outcome was possibly due to selection of rigorous surgical indication and skilled surgical techniques. The study highlights the importance of experienced and skilled colposcopists.TrialRegistry This study was registered in the clinical trial registration system of the University hospital Medical Information Network Clinical Trials Registry (UMIN-CTR ID: UMIN000024483). Open for the trial to the public through the website: 01/11/2016. First registration of the patient: 30/01/2017.

Logistic regression analysis of mRNA expression changes and prognosis after cervical surgery

Objective: The aim of this study was to investigate the diagnostic value of HPV (human papillomavirus) E6/E7 mRNA combined with thin-layer liquid-based cytology test (TCT) detection in patients with cervical intraepithelial neoplasia (CIN) in the residual and recurrence of lesions after cervical conization. Methods: A total of 154 patients who had undergone cervical conization and were diagnosed with high-grade cervical intraepithelial neoplasia (CIN 1 and CIN 3) by histopathology and had complete follow-up data were enrolled. TCT, HPV-DNA detection, and HPV E6/E7 mRNA detection combined with TCT detection in 12 months can be used to detect abnormal cytology (&amp;gt;atypical squamous epithelium of undetermined significance). Patients with atypical squamous cell of undetermined significance or high-risk HPV-DNA (+) or HPV E6/E7 mRNA combined with TCT (+) underwent colposcopy and cervical biopsy again for pathological diagnosis. Results: There were 9 cases of residual lesions and 22 cases of recurrence. Thirty of the 57 cases with positive HPV-DNA after surgery were still there or came back. Of the 26 cases with positive HPV E6/E7 mRNA combined with TCT, 24 were still there or came back. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy rate of HPV-DNA detection were 96.8%, 78.0%, 52.6%, 99.0%, and 81.8%, respectively; the sensitivity and specificity of HPV E6/E7 mRNA were combined with TCT detection of sex. Conclusion: HPV E6/E7 mRNA combined with TCT detection can be included in follow-up examinations, which can timely and effectively predict the risk of CIN residual or recurrence after cervical conization and reduce excessive examination and treatment.

Retracted: Expression of GMFB in High-Grade Cervical Intraepithelial Neoplasia and Its Role in Cervical Cancer.

[This retracts the article DOI: 10.1155/2022/7784921.].

Immediate histologic correlation in patients with different HPV genotypes and ages: a single center analysis in China

BackgroundHuman papillomavirus (HPV) has been confirmed as a major causative factor for malignant transformation of cervical epithelial cells and for the development of cervical intraepithelial neoplasia (CIN) and invasive cervical cancer. We carried out this study to investigate the association of different HPV genotypes and ages with immediate histological cervical lesions in opportunistic screening patients in a single center.MethodsA total of 1,661 samples with biopsy-confirmed histologic findings were collected from the gynecological clinic of our hospital between October 2017 and May 2020 for analysis. The distribution of single-type HPV genotypes in CIN of different severities and the age-dependent prevalence for single-type HPV infection were analyzed.ResultsIn both CIN2 and CIN3 group, HPV16, 58, 52, 33 and 31/18 were detected as top 5 high-risk human papillomavirus (hrHPV) types, which accounts for 89.25% and 88.54% of single HPV infection incidence respectively. Besides, not a single case of HPV45 was found in CIN2 and CIN3. HPV16 was the dominant genotype in both CIN2 and CIN3, accounted for 46.24% and 55.21%, respectively. The prevalence of HPV16 was the most frequent in all the age groups, except ≥ 65 years group in CIN3, and almost one in three HPV16-positive patients were diagnosed with high grade CIN. The peak of the incidence of CIN3 was observed at 25 ~ 34 years (33.68%), followed by 35 ~ 44 years (31.58%).ConclusionHigh grade CIN peak at 25 ~ 44 years, women of this age are recommended for normative screening if conditions permit. HPV16-positive patients should be given high priority in opportunistic screening, while the single-center data suggesting a low risk of CIN2/3 in HPV45-positive patients. For women ≥ 65 years old, patients infected with other HPV types should be also taken seriously. In general, HPV16, 58, 52, 33, 31 and 18 were the most common genotypes in CIN2/3, and a vaccine including these predominant genotypes might be of great significance for cervical cancer prevention in China.

Staged design recommendations for validating relative sensitivity of self-sample human papillomavirus tests for cervical screening

ObjectivesTo ensure that the emerging methods for human papillomavirus (HPV) testing on self-collected samples in cervical screening are evaluated robustly. Study Design and SettingWe assess paired study designs for relative sensitivity of self-collected vs. traditional clinician-collected samples in detection of high-grade cervical intraepithelial neoplasia. ResultsDesigns considered are (D1) both samples at screening, with clinical actions triggered by HPV positivity; (D2) offering a self-sample test to clinician-collected HPV-positive women; (D3) as D2 but using a repeat clinician-sample as comparator; (D4) offering a choice of self- vs. clinician-sampling, and the alternative test in HPV-positive women; (D5) paired samples at referral appointment. D1 is simple to analyze but requires the largest sample size and referral of self-sample positive, clinician-sample negative women. D2 requires a much smaller sample size, and no change to clinical practice, and could be used to rule-in a test because estimates are conservative (against self-sampling). D3 mitigates this bias but requires a second clinician sample. D4 is only manageable where self-sampling already occurs. The liberal D5 might be used to rule-out a self-sampling test. ConclusionA universal recommendation for an optimal study design is challenging. Staged validation might be useful with D5 as a gatekeeper for D1-D4.

Margin status after loop electrosurgical excision procedure (LEEP) and laser excision in patients with high-grade cervical neoplasia

IntroductionEarly management of high-grade cervical intraepithelial neoplasia is one of the key steps in cervical cancer prevention after vaccination and screening. It relies on lesion removal by surgical excision, and the French National Cancer Institute (INCa) in 2016 recommend using a loop electro excision procedure (LEEP). However, the laser excision method seems to be as effective with similar rates of negative excision margins and postoperative clearance of HPV. ObjectiveThe main objective of our study was to compare the laser excision method to LEEP by evaluating the quality of the surgical margins. We also studied factors associated with the status of the margins and the depth of cones. MethodsWe conducted a retrospective unicentric study between 2009 and 2017. ResultsTwo hundred and thirty-one patients were included: 154 laser excisions and 77 LEEP. Negative surgical margin was achieved in 69.5 % of laser excisions and 72.7 % of LEEP (p = 0.649). Concerning factors predicting margin status, only a greater cone depth was associated with negative margins (OR: 0.91 (95 %CI: 0.84, 0.89); p = 0.02). The surgical technique was not found to be associated with the status of the margins (OR: 0.85 (95 %CI: 0.46,1.56); p = 0.61). Concerning factors predicting cone depth, only the LEEP was associated with a shorter cone depth (OR: 0.24 (95 %CI: 0.08, 0.69); p 0.008). Significant results are based on univariate analysis. ConclusionNo difference was found between the two technics concerning the rate of negative margins. However, LEEP seems to be associated with shorter cone depth in this study.

Performance of DNA methylation analysis in the detection of high-grade cervical intraepithelial neoplasia or worse (CIN3+): a cross-sectional study

It is commonly accepted that host genes show high methylation in cervical intraepithelial neoplasia 3 (CIN3) or worse (CIN3+). However, study quality varies, as does the clinical performance of markers in different populations. We aimed to validate candidate gene DNA methylation with standardized testing methods in the same batch of samples. We first compared the performance of 16 DNA methylation markers for detecting CIN3+ in the 82-sample training set, including 24 subjects with ≤ CIN1, 10 subjects with CIN2, 23 subjects with CIN3, and 25 subjects with cervical cancer (CC). Then five methylation markers were selected and subsequently validated among an independent set of 74 subjects, including 47 subjects with ≤ CIN1, 13 subjects with CIN2, 6 subjects with CIN3, and 8 subjects with CC. The results in the validation set revealed that methylation analysis of the SOX1 (SOX1m) showed a superior level of clinical performance (AUC = 0.879; sensitivity = 85.7%; specificity = 90.0%). SOX1m had better accuracy than cytology, with a reduced referral rate (23.0% vs. 31.4%) and a lower number of overtreatment (5 vs. 13) cases among high-risk human papillomavirus (hrHPV)-positive women. Importantly, among hrHPV-positive and SOX1m-negative women, only 1 CIN3 patient was at risk for follow-up after 1 year, whereas 1 CIN3 patient and 1 CC patient were at risk among hrHPV-positive and cytology-negative women. In this investigation, we screened 16 reported methylation markers to provide a basis for future studies related to potential precancerous lesion/cancer methylation markers in the Chinese population. The study also revealed that SOX1m has optimal CIN3+ detection performance, suggesting that it may be a promising biomarker for detecting CIN3+ in the Chinese population.

HPV-related lesions after hysterectomy for high-grade cervical intraepithelial neoplasia and early-stage cervical cancer: A focus on the potential role of vaccination.

To date, no data supports the execution of vaccination after hysterectomy for high-grade cervical intraepithelial neoplasia (CIN2+) and early-stage cervical cancer. We aim to evaluate the potential effect of vaccination after hysterectomy for high-grade cervical intraepithelial neoplasia and early-stage cervical cancer. This is a multi-center retrospective study evaluating data of women who develop lower genital tract dysplasia (including anal, vulvar and vaginal intra-epithelial neoplasia) after having hysterectomy for CIN2+ and FIGO stage IA1- IB1 cervical cancer. Overall, charts for 77 patients who developed lower genital tract dysplasia were collected. The study population included 62 (80.5%) and 15 (19.5%) patients with CIN2+ and early-stage cervical cancer, respectively. The median (range) time between hysterectomy and diagnosis of develop lower genital tract dysplasia was 38 (range, 14-62) months. HPV types covered by the nonavalent HPV vaccination would potentially cover 94.8% of the development of lower genital tract dysplasia. Restricting the analysis to the 18 patients with available HPV data at the time of hysterectomy, the beneficial effect of nonvalent vaccination was 89%. However, considering that patients with persistent HPV types (with the same HPV types at the time of hysterectomy and who developed lower genital tract dysplasia) would not benefit from vaccination, we estimated the potential protective effect of vaccination to be 67% (12 out of 18 patients; four patients had a persistent infection for the same HPV type(s)). Our retrospective analysis supported the adoption of HPV vaccination in patients having treatment for HPV-related disease. Even in the absence of the uterine cervix, HPV vaccination would protect against develop lower genital tract dysplasia. Further prospective studies have to confirm our preliminary research.