Laminin receptor 1 expression in premalignant and malignant squamous lesions of the cervix.

Laminin receptor 1 (LAMR) may have a role in the progression of premalignant squamous epithelial lesions to cervical cancer. Therefore, we aimed to investigate the expression of laminin receptor 1 (LAMR) in normal, premalignant, and malignant tissues of the uterine cervix. Paraffin blocks of 129 specimens with the diagnoses of normal cervical tissue (n = 33), cervical intraepithelial neoplasia (CIN) 1 (n = 30), CIN 2 (n = 14), CIN 3 (n = 28), and squamous cell carcinoma (n = 24) were immunohistochemically stained with LAMR antibody and its expression percentage, pattern, and intensity in these tissues were assessed. Compared to the other groups, the nonstaining with LAMR was highest in low grade squamous intraepithelial lesion (LSIL) (p < 0.0001). LAMR expression, which was positive in less than 50% of cells with weak staining, increased significantly between normal cervical epithelium and high-grade squamous intraepithelial lesion (HSIL) or invasive carcinoma, as well as between LSIL and HSIL (p < 0.0001). Between LSIL and invasive carcinoma, a significant increment was also observed for weak staining in less than 50% of cells (p < 0.001). LAMR expression, which was positive in more than 50% of cells with strong staining, was significantly higher in normal cervical tissue compared to the other groups (p < 0.0001). Disease progression related gradual increment of LAMR expression from normal cervical epithelium or LSIL towards HSIL or cervical cancer reveals that LAMR may play an important role in the transition from premalignant to malignant state in cervical lesions.

Retrospective analysis of negative cytology results correlated with a positive high-risk in the human papillomavirus result and subsequent results of patients over a period of three years.

This research paper evaluates the efficacy of co-testing in precluding cervical cancer, with a particular focus on distinguishable outcomes of the human papillomavirus (HPV) vs. cytology tests. A retrospective review of 5948 patients, who tested positive for high-risk HPV but showed negative cytologic findings, revealed that 15.006% tested positive in subsequent screenings. A comparative analysis of various commercial HPV tests highlighted the precision of mRNA-based HPV testing by Aptima (Hologic) in reducing the likelihood of false-negative cytology. The paper challenges the conviction that a negative cytology alone suffices advocating for a condensed testing interval in instances of positive HPV outcomes, thereby facilitating earlier intervention and optimal preventive care. These findings unveil an exigency for reconsidering preventive strategies based on test outcomes.

TPP1 is associated with risk of advanced precursors and cervical cancer survival.

It is unclear how telomere-binding protein TPP1 interacts with human telomerase reverse transcriptase (hTERT) and influences cervical cancer development and progression. This study included all eligible 156 cervical cancers diagnosed during 2003-2008 and followed up through 2014, 102 cervical intraepithelial neoplasia (CIN) patients, and 16 participants with normal cervix identified at the same period. Correlation of expression of TPP1 and hTERT in these lesions was assessed using Kappa statistics. TPP1 was knocked down by siRNA in three cervical cancer cell lines. We assessed mRNA expression using quantitative real-time polymerase chain reaction and protein expression using tissue microarray-based immunohistochemical staining. We further analyzed the impact of TPP1 expression on the overall survival of cervical cancer patients by calculating the hazard ratio (HR) with 95% confidence intervals (CIs) using the multivariable-adjusted Cox regression model. Compared to the normal cervix, high TPP1expression was significantly associated with CIN 3 and cervical cancers (P<0.001 for both). Expressions of TPP1 and hTERT were highly correlated in CIN 3 (Kappa statistics = 0.50, P = 0.005), squamous cell carcinoma (Kappa statistics = 0.22, P = 0.011), and adenocarcinoma/adenosquamous carcinoma (Kappa statistics = 0.77, P = 0.001). Mechanistically, knockdown of TPP1 inhibited the expression of hTERT in both mRNA and protein levels. High expression of TPP1 (HR = 2.61, 95% CI 1.23-5.51) and co-high expression of TPP1 and hTERT (HR = 2.38, 95% CI 1.28-4.43) were independently associated with worse survival in cervical cancer patients. TPP1 and hTERT expression was correlated and high expression of TPP1 was associated with high risk of CIN 3 and cervical cancer and could predict a worse survival in cervical cancer.

Clinical analysis of 314 patients with high-grade squamous intraepithelial lesion who underwent total hysterectomy directly: a multi-center, retrospective cohort study.

OBJECTIVE: To identify the risk factors of cervical high-grade squamous intraepithelial lesion(HSIL) complicated with occult cervical cancer and standardize the management of initial treatment for HSIL. METHOD: The clinical data of patients who underwent total hysterectomy directly due to HSIL in the obstetrics and gynecology department of two tertiary hospitals and three secondary hospitals from 2018 to 2023 were collected. Their general characteristics, pathological parameters and survival status were analyzed. Logistic regression model was used to analyze the correlation between clinical parameters and postoperative pathological upgrading. RESULT: 1. Among the 314 patients with HSIL who underwent total hysterectomy directly, 73.2% were from primary hospitals. 2. 25 patients (7.9%) were pathologically upgraded to cervical cancer, all of which were early invasive cancer. 3. Up to now, there was no recurrence or death in the 25 patients with early-stage invasive cancer, and the median follow-up period was 21 months(range 2-59 months). 4. Glandular involvement(OR 3.968; 95%CI 1.244-12.662) and lesion range ≥ 3 quadrants (OR 6.527; 95% CI 1.78-23.931), HPV 16/18 infection (OR 5.382; 95%CI 1.947-14.872), TCT ≥ ASC-H (OR 4.719; 95%CI 1.892-11.766) were independent risk factors that affected the upgrading of postoperative pathology. 5. The area under the curve (AUC) calculated by the Logistic regression model was 0.840, indicating that the predictive value was good. CONCLUSION: There is a risk of occult cervical cancer in patients with HSIL. Glandular involvement, Lesion range ≥ 3 quadrants, HPV 16/18 infection and TCT ≥ ASC-H are independent risk factors for HSIL combined with occult cervical cancer. The prognosis of biopsy-proved HSIL patients who underwent extrafascial hysterectomy and unexpected early invasive cancer was later identified on specimen may be good.

Compositional and functional differences of the vaginal microbiota of women with and without cervical dysplasia.

Alterations in the vaginal microbiota, including both species composition and functional pathways, have been associated with HPV infection and progression of dysplasia to cervical cancer. To further explore this, shotgun metagenomic sequencing was used to taxonomically and functionally characterize the vaginal microbiota of women with and without cervical dysplasia. Women with histologically verified dysplasia (n = 177; low grade dysplasia (LSIL) n = 81, high-grade dysplasia (HSIL) n = 94, cancer n = 2) were compared with healthy controls recruited from the cervical screening programme (n = 177). Women with dysplasia had a higher vaginal microbial diversity, and higher abundances of Gardnerella vaginalis, Aerococcus christensenii, Peptoniphilus lacrimalis and Fannyhessea vaginae, while healthy controls had higher relative abundance of Lactobacillus crispatus. Genes involved in e.g. nucleotide biosynthesis and peptidoglycan biosynthesis were more abundant in women with dysplasia. Healthy controls showed higher abundance of genes important for e.g. amino acid biosynthesis, (especially L-lysine) and sugar degradation. These findings suggest that the microbiota may have a role in creating a pro-oncogenic environment in women with dysplasia. Its role and potential interactions with other components in the microenvironment deserve further exploration.

Risk of progression of cervical intraepithelial neoplasia grade 2 in human papillomavirus-vaccinated and unvaccinated women: a population-based cohort study.

BACKGROUND: Many countries have implemented active surveillance (ie, leaving the lesion untreated) as an option among younger women with cervical intraepithelial neoplasia grade 2 because regression rates are high and excisional treatment increases the risk for preterm birth in subsequent pregnancies. However, early identification of women at increased risk for progression to cervical intraepithelial neoplasia grade 3 or worse is important to ensure timely treatment. Because women who have received a human papillomavirus vaccine have a lower risk for cervical cancer, they may have a lower risk for progression of untreated cervical intraepithelial neoplasia grade 2 to cervical intraepithelial neoplasia grade 3 or worse. OBJECTIVE: This study aimed to investigate if women who received a human papillomavirus vaccine and who are undergoing active surveillance for cervical intraepithelial neoplasia grade 2 are less likely to progress to cervical intraepithelial neoplasia grade 3 or worse when compared with women who did not receive the vaccine. STUDY DESIGN: We conducted a population-based cohort study in Denmark using data from national health registers. We identified all women aged 18 to 40 years who were undergoing active surveillance for cervical intraepithelial neoplasia grade 2 from January 1, 2007, to December 31, 2020. Women with a previous record of cervical intraepithelial neoplasia grade 2 or worse, hysterectomy, or a loop electrosurgical excision procedure were excluded. Exposure was defined as having received ≥1 dose of a human papillomavirus vaccine at least 1 year before the cervical intraepithelial neoplasia grade 2 diagnosis. We used cumulative incidence functions to estimate the risk for progression to cervical intraepithelial neoplasia grade 3 or worse within 28 months using hysterectomy, emigration, and death as competing events. We used modified Poisson regression to calculate crude and adjusted relative risks of progression during the 28-month surveillance period. Results were stratified by age at vaccination and adjusted for index cytology, disposable income, and educational level. RESULTS: The study population consisted of 7904 women of whom 3867 (48.9%) were vaccinated at least 1 year before a diagnosis of cervical intraepithelial neoplasia grade 2. At the time of cervical intraepithelial neoplasia grade 2 diagnosis, women who were vaccinated were younger (median age, 25 years; interquartile range, 23-27 years) than those who were not (median age, 29 years; interquartile range, 25-33 years). The 28-month cumulative risk for cervical intraepithelial neoplasia grade 3 or worse was significantly lower among women who were vaccinated before the age of 15 years (22.9%; 95% confidence interval, 19.8-26.1) and between the ages of 15 and 20 years (31.5%; 95% confidence interval, 28.8-34.3) when compared with women who were not vaccinated (37.6%; 95% confidence interval, 36.1-39.1). Thus, when compared with women who were not vaccinated, those who were vaccinated before the age of 15 years had a 35% lower risk for progression to cervical intraepithelial neoplasia grade 3 or worse (adjusted relative risk, 0.65; 95% confidence interval, 0.57-0.75), whereas women who were vaccinated between the ages of 15 and 20 years had a 14% lower risk (adjusted relative risk, 0.86; 95% confidence interval, 0.79-0.95). For women who were vaccinated after the age of 20 years, the risk was comparable with that among women who were not vaccinated (adjusted relative risk, 1.02; 95% confidence interval, 0.96-1.09). CONCLUSION: Women who were vaccinated and who were undergoing active surveillance for cervical intraepithelial neoplasia grade 2 had a lower risk for progression to cervical intraepithelial neoplasia grade 3 or worse during 28 months of follow-up when compared with women who were not vaccinated but only if the vaccine was administered by the age of 20 years. These findings may suggest that the human papillomavirus vaccination status can be used for risk stratification in clinical management of cervical intraepithelial neoplasia grade 2.

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.

Cervical precancerous and cancerous lesions screening using Pap smear test at Provincial Referral Hospital of Bukavu, Eastern DR Congo: profile and recommendations to stakeholders.

Introduction: cervical cancer is a health concern worldwide. The South Kivu Province in the Eastern DR Congo is facing many cases of this disease but poorly screened and reported. The objective of this was to determine the prevalence of cell abnormalities at cervical cytology in a tertiary teaching hospital in Bukavu and their association with common risk factors of cervical cancer. Methods: a cross-sectional study was conducted on 142 women attending the Provincial Referral Hospital of Bukavu (HPGRB) from February to December 2021. Quantitative variables were described by their median following their asymmetric distributions and the qualitative variables in absolute and relative frequencies. Then the Chi-square test was used for the comparison of proportion. Results: forty-five percent of the participants had between three and five children. Twenty-two (15.5%) of the 142 patients reported to have two or more sexual partners and 17.5% reported the use of hormonal contraception. The prevalence of cell abnormalities at cervical cytology was 17% of which Low- Grade Squamous Intraepithelial Lesion (LSIL) was the most representative (12.9%). There was no statistically significant association between the common cervical risk factors and the occurrence of cell abnormalities. Conclusion: cervical pre-cancerous lesions are frequent in South Kivu province. The Pap smear test remains an early and affordable screening method and constitutes a secondary prevention strategy in women of 18 years and older in a low-income country such as DR Congo where vaccination against HPV is still hypothetic.

Randomized Phase II Trial of Imiquimod with or without 9-Valent HPV Vaccine versus Observation in Patients with High-grade Pre-neoplastic Cervical Lesions (NCT02864147).

PURPOSE: We report the results of a randomized phase II trial of imiquimod, a topical immune-response modulator versus imiquimod plus a 9-valent human papillomavirus (HPV) vaccine (9vHPV) versus clinical surveillance in cervical intraepithelial neoplasia (CIN2/3) patients. PATIENTS AND METHODS: We randomly allocated 133 patients with untreated CIN2/3 in equal proportions to a 4-month treatment with self-applied vaginal suppositories containing imiquimod (Arm B) or imiquimod plus a 9vHPV (Arm C) versus clinical surveillance (Arm A). The main outcome was efficacy, defined as histologic regression to CIN1 or less. Secondary outcomes were HPV clearance and tolerability. Exploratory objectives included the comparison of cervical CD4/CD8 T-cell infiltration at baseline, mid-study, and posttreatment by flow cytometry among study arms. RESULTS: Of the 114 evaluable patients 77% and 23% harbored CIN2 and CIN3, respectively. Regression to CIN1 or less was observed in 95% of patients in the imiquimod group (Arm B) compared with 79% in the control/surveillance (Arm A); P = 0.043 and 84% in the imiquimod+9vHPV group (Arm C; P = 0.384 vs. Arm A). Neither of the treatment-arm differences from Arm A reached the prespecified α = 0.025 significance level. No significant differences were noted in the secondary outcome of rate of HPV clearance. The number of tissue-resident memory CD4/CD8 T cells in cytobrush samples demonstrated a >5-fold increase in Arm B/imiquimod when compared with Arm A/surveillance (P < 0.01). In contrast, there was no significant difference in T-cell responses among participants in Arm C when compared with Arm A. Imiquimod treatment was well tolerated. CONCLUSIONS: Although imiquimod induced a higher regression to CIN1 or less and significant increases in CD4/CD8 T cells infiltrating the cervix, it did not meet its prespecified statistical outcome for efficacy. A higher regression rate than expected was observed in the surveillance arm of this prospective trial. Future clinical trials with imiquimod targeting CIN3 patients are warranted.

[Application of optical coherence tomography in the evaluation of cervical lesions: a multicenter study].

Objective: To explore the value of optical coherence tomography (OCT) imaging system in evaluating cervical lesions in vivo. Methods: A total of 1 214 patients with cervical lesions were collected from January 2020 to December 2021 in the Third Affiliated Hospital of Zhengzhou University, Maternal and Chlid Heaith Hospital of Gushi County, Xinyang City, Henan Province, and Maternal and Chlid Heaith Hospital of Sui County, Shangqiu City, Henan Province. The age of the patients was (38.9±10.5) years (range: 16-77 years). All patients underwent in vivo cervical OCT examination and cervical biopsy pathology examination, and summarized the OCT image features of in vivo cervical lesions. Using the pathological diagnosis as the "gold standard", the accuracy, specificity, sensitivity, positive predictive value (PPV) and negative predictive value (NPV) of OCT image interpretation results were evaluated, as well as the consistency of OCT image diagnosis and pathological diagnosis. At the same time, the in vivo cervical OCT imaging system, as a newly developed screening tool, was compared with the traditional combined screening of human papillomavirus (HPV) and Thinprep cytologic test (TCT), to assess the screening effect. Results: By comparing the OCT images of the cervix in vivo with the corresponding HE images, the OCT image characteristics of the normal cervix and various types of cervical lesions in vivo were summarized. The accuracy, sensitivity, specificity, PPV and NPV of OCT image in the diagnosis of high-grade squamous intraepithelial lesion (HSIL) and above (HSIL+) were 93.4%, 88.5%, 95.0%, 85.0% and 96.2%, respectively. The accuracy, sensitivity, specificity, PPV and NPV of OCT for low-grade squamous intraepithelial lesion (LSIL) were 84.7%, 61.7%, 96.3%, 89.3% and 83.2%, respectively. The consistency between OCT image diagnosis and pathological diagnosis was strong (Kappa value was 0.701).The accuracy, sensitivity and specificity of OCT screening, HPV and TCT combined screening were 83.7% vs 64.9% (χ²=128.82, P<0.001), 77.8% vs 64.5% (χ²=39.01, P<0.001), 91.8% vs 65.4% (χ²=98.12, P<0.001), respectively. The differences were statistically significant. Conclusions: OCT imaging system has high sensitivity and specificity in the evaluation of cervical lesions in vivo, and has the characteristics of non-invasive, real-time and high efficiency. OCT examination is expected to become an effective method for the diagnosis of cervical lesions and cervical cancer screening.

Reevaluation of negative cervical conizations: Frequency, diagnostic errors, risk factors and management.

OBJECTIVE: Cervical conization is an effective treatment for precancerous lesions. However, in cases where no high-grade lesion is identified in the surgical specimen, managing these patients may be challenging due to the absence of established follow-up protocols for negative conizations. This study aimed to assess the negative conization rates at our institution by histopathological review, identify diagnostic errors, possible risk and recurrence factors and propose follow-up strategies for this group of patients. METHODS: A retrospective study from January-2010 to December-2020 analyzed patients with negative conization including all surgical techniques and procedure indications. Biopsy and cervical conizations slides were reviewed and patients who kept a negative result underwent deeper levels sectioning of the paraffin blocks with immunohistochemical stains application: p16, Ki-67 and geminin. Data were compared with a control group composed by 29 women with CIN3. RESULTS: Out of 1022 conizations, 186 were negative (18.1%), with 151 cases selected for the study after excluding 35 patients. Following pathology review, 4 patients were excluded due to false-positive cervical biopsy results, 16 for false-negative conization results and 9 for hidden dysplasia identified after deeper sectioning. The remaining 122 patients were considered truly negative cones (11.9%) and exhibited IHC staining with p16 positive in 20.4% of cases, low Ki-67 expression, and low geminin score in most cases. Specimens with CIN 1 had higher prevalence of p16 staining, Ki-67 expression and geminin score when compared to absence of neoplasia, nevertheless geminin had no statistical difference. Older age, higher parity and IHC pattern with negative p16, low Ki-67 and geminin expressions were identified as risk factors for negative cones (p<0.05). Only 10 patients recurred for high-grade lesions, with no statistically significant risk factors identified. CONCLUSIONS: The negative conization rate was 11.9%, with diagnostic errors identified across pre-surgical biopsy, cone specimen, and deeper levels. Risk factors included older age, higher parity, low expression of p16, Ki-67 and geminin (p<0.05). Recurrence represented 8.1% of the negative cones, without identification of statistically significant risk factors. Pathological review with deeper level sections and 2-year follow-up are recommended for patients with negative conizations.

Correlation between P16/Ki67 in cervical cytology and diagnosis of cervical intraepithelial neoplasia 2-3 in Thai women infected with high-risk types of human papillomavirus.

OBJECTIVES: The addition of p16/Ki-67 dual immunostaining to human papilloma virus (HPV) screening tests has been shown to increase the detection rate of high-grade cervical intraepithelial neoplasia. Thus, the aim of this study was to evaluate the accuracy of p16/Ki67 dual staining in the detection of cervical intraepithelial neoplasia 2 (CIN2+) in women with high-risk HPV infection. MATERIALS AND METHODS: A cross-sectional study was conducted between August 2017 and August 2019 at the Chulabhorn Hospital in Bangkok, Thailand. Women aged 20-70 years who underwent co-testing and tested positive for high-risk (HR) HPV (N = 215) were invited to participate in the study. P16/Ki67 testing was performed on residual cytological materials. Colposcopic biopsies were performed on all patients, and the results were correlated with positive or negative p16/Ki-67 test results. RESULTS: The sensitivity and specificity of p16/Ki-67 dual staining in the detection of CIN2+ in the women with HR HPV infection were 74.4 % and 63.4 %, respectively. Compared with liquid-based cytology (LBC), p16/Ki67 cytology had similar sensitivity (p = 1.000) and specificity (p = 0.561) to LBC for detecting CIN2+. CONCLUSION: In this study, p16/Ki67 dual staining in HPV triage demonstrated a test performance similar to that of LBC.

The importance of combined HPV and CINtec® PLUS genotyping testing for p16 in women with cervical squamous cell carcinoma.

INTRODUCTION: Immunohistochemistry (IHC) for p16INK4A (p16) is a reliable surrogate test for the presence of a high-risk, potentially transformative human papillomavirus (HPV) infection in precursor and malignant lesions of the cervix. The purpose of this study was to evaluate changes in cervical cells caused by persistent HPV infection, by IHC (p16 protein) by comparison with HPV genotyping. PATIENTS, MATERIALS AND METHODS: The study included female patients aged between 26 and 57 years who presented to a public hospital, with complaints related to the genital area, namely vaginal bleeding and dyspareunia. After selecting the patients, samples were subjected to cytological testing and IHC for p16 and for the determination of HPV types. RESULTS: The relationship between HPV status and p16 status was statistically significant (p=0.0001), of the 41 patients, 53.7% were HPV positive, respectively 56.1% were p16 positive, the agreement relationship between the two indicators was very high (weighted kappa: 0.951). The clinical performance of CINtec® PLUS triage for p16 shows a high positive predictive value (PPV) and a high negative predictive value (NPV) of 95.7% and 100%, respectively, as regards HPV. CONCLUSIONS: The p16 marker (CINtec® PLUS) can be used as a prognostic biomarker and provides clinical usefulness through increased sensitivity (Se) and specificity (Sp) in the triage of women at risk of developing precancerous lesions, compared to cytology that is based on morphology, but has a rather low Se and high Sp, while HPV testing is very sensitive but slightly more specific.

Cervical Cancer Screening via Visual Inspection With Acetic Acid and Lugol Iodine for Triage of HPV-Positive Women.

Importance: Limited evidence supports the performance of human papillomavirus (HPV) DNA testing as a primary screening method, followed by triage with visual inspection with acetic acid, in areas with limited health care resources, as suggested by the 2021 World Health Organization guidelines. Objective: To evaluate the performance of visual inspection with acetic acid and Lugol iodine as a triage method for detecting cervical precancerous lesions among HPV-positive women in 1 visit. Design, Setting, and Participants: This cohort study examined the implementation of a government-led cervical cancer screening program conducted from January 1, 2016, to December 31, 2020, in Ordos City, China. Female residents, aged 35 to 64 years, who understood the screening procedures and voluntarily participated were included in the study. Women were excluded if they reported never having had sexual intercourse, were pregnant, had a hysterectomy, or had ever undergone treatment for cervical lesions. Statistical analysis was conducted from December 2022 to December 2023. Exposures: The program used the careHPV DNA assay as the primary screening method, and immediate triage was performed by visual inspection if HPV screening results were positive, with a 5-year screening interval. A colposcopy was performed for the women who had suspected cancer on visual inspection results or who were HPV positive and had abnormal visual inspection results, all in 1 visit. Main Outcomes and Measures: The rate of compliance with colposcopy and the detection rate of cervical intraepithelial neoplasia grade 2 or higher (CIN2+). Results: The study included 187 863 women (median age, 46 years [IQR, 40-52 years]) who participated in the program and had valid HPV test results. The overall prevalence of HPV positivity was 12.8% (24 070 of 187 863), and the adherence to triage with visual inspection among HPV-positive women was 93.9% (22 592 of 24 070). Among HPV-positive women, the rate of compliance with colposcopy was 65.6% (2714 of 4137), and the CIN2+ detection rate was 2.8% (643 of 22 592). Conclusions and Relevance: The findings of this cohort study suggest that the implementation of HPV testing, visual inspection, and colposcopy within 1 visit may mitigate losses to follow-up, detect precancerous lesions, and hold significant implications for screening in comparable areas with limited health care resources.

Topical delivery of drugs in the treatment of high-grade cervical squamous intraepithelial lesions: A meta-analysis.

OBJECTIVE: The present study aims to evaluate the efficacy and effect of localized delivery of drugs in the treatment of high-grade squamous intraepithelial lesion (HSIL) based on a meta-analysis. STUDY DESIGN: Databases including Cochrane Library, PubMed, Embase, Scopus, CNKI, and Wanfang were searched from their inception till August 2022. Randomized controlled trials (RCTs) that compared the efficacy of drugs and surgery in the treatment of HSIL were collected. A meta-analysis was performed using the software of Review Manager (version 5.4.1). RESULTS: Eight RCTs involving 523 patients were included in the meta-analysis. For HSIL, the rate of cervical lesions histological regression was 69.85 % in the surgery group and 59.88 % in the drug group, there was no significant difference between the two groups [OR = 0.45, 95 % CI (0.07, 3.03), P = 0.41]. The histological regression rate of cervical lesions in the placebo group was 37.76 %, and the difference between the drug group and the placebo group was statistically significant [OR = 4.94, 95 % CI (2.65, 9.20), P < 0.00001]. CONCLUSION: A total of four drugs were involved in the eight RCTS included in this study, which were imiquimod, 5-fluorouracil (5-FU), cidofovir and interferon. The results showed that although drug administration was effective in the histological regression of HSIL, the efficacy was less than about 10% of surgical treatment. Considering the recurrence of the disease after surgery and the problems of abortion, premature delivery and premature rupture of membranes after cervical conization in reproductive women, drug therapy can be used as a supplement to surgery or conservative treatment to promote the histological regression of cervical lesions in patients with HSIL.

Recommendations for Use of p16/Ki67 Dual Stain for Management of Individuals Testing Positive for Human Papillomavirus.

OBJECTIVES: The Enduring Consensus Cervical Cancer Screening and Management Guidelines Committee developed recommendations for dual stain (DS) testing with CINtec PLUS Cytology for use of DS to triage high-risk human papillomavirus (HPV)-positive results. METHODS: Risks of cervical intraepithelial neoplasia grade 3 or worse were calculated according to DS results among individuals testing HPV-positive using data from the Kaiser Permanente Northern California cohort and the STudying Risk to Improve DisparitiES study in Mississippi. Management recommendations were based on clinical action thresholds developed for the 2019 American Society for Colposcopy and Cervical Pathology Risk-Based Management Consensus Guidelines. Resource usage metrics were calculated to support decision-making. Risk estimates in relation to clinical action thresholds were reviewed and used as the basis for draft recommendations. After an open comment period, recommendations were finalized and ratified through a vote by the Consensus Stakeholder Group. RESULTS: For triage of positive HPV results from screening with primary HPV testing (with or without genotyping) or with cytology cotesting, colposcopy is recommended for individuals testing DS-positive. One-year follow-up with HPV-based testing is recommended for individuals testing DS-negative, except for HPV16- and HPV18-positive results, or high-grade cytology in cotesting, where immediate colposcopy referral is recommended. Risk estimates were similar between the Kaiser Permanente Northern California and STudying Risk to Improve DisparitiES populations. In general, resource usage metrics suggest that compared with cytology, DS requires fewer colposcopies and detects cervical intraepithelial neoplasia grade 3 or worse earlier. CONCLUSIONS: Dual stain testing with CINtec PLUS Cytology is acceptable for triage of HPV-positive test results. Risk estimates are portable across different populations.

The role of multiple high-risk human papillomavirus infection on the persistence recurrence of high-grade cervical lesions after standard treatment: A systematic review and a meta-analysis.

INTRODUCTION: The role of multiple high-risk human papillomavirus (HR-HPV) infections on the occurrence of persistence/recurrence of high-grade squamous intraepithelial lesion (HSIL) after conization/surgery for cervical intraepithelial neoplasia was evaluated. MATERIAL AND METHODS: A systematic search of Pubmed/Medine, Scopus, Cochrane databases from inception to June 30, 2023 was performed. Three reviewers independently screened the abstracts of the selected studies and extracted data from full-text articles. The data were subsequently tabulated and compared for consistency. The bias associated with each included study was evaluated according to the OSQE method. PROSPERO registration number CRD42023433022. RESULTS: Out of 1606 records screened, 22 full text articles met the inclusion criteria. A total of 8321 subjects treated (loop electrosurgical excision, laser or surgery) because of HSIL were followed-up and included in the meta-analysis. The pooled prevalence of overall persistence and/or recurrence was 17.6 (95% CI: 12.3-23.5) in multiple and 14.3 (95% CI: 10.1-19.2) in single HR-HPV infections detected shortly before or at surgery. The pooled rate of multiple HR-HPV infections was 25% (95% CI: 20.4-30). The odds ratio of histologically confirmed HSIL persistence and/or recurrence was significantly higher (OR: 1.38, 95% CI:1.08-1.75, p = 0.01, heterogeneity = 39%) among multiple than single HR-HPV infections. Increased risk of HSIL persistence/recurrence was more marked among studies with multiple HR-HPVs prevalence ≥25% (12 studies, N = 3476) (OR: 1.47, 95% CI: 1.18-1.84, heterogeneity = 0%) and in those evaluating true histologically confirmed recurrence after at least 6 months of negative follow-up (9 studies, N = 5073) (OR: 1.67, 95% CI: 1.17-2.37, heterogeneity = 37%). Multiple HR-HPVs infection detected during follow-up visits had no effect on the risk of recurrence although the number of included studies was small (4 studies, N = 1248) (OR: 0.98, 95% CI: 0.68-1.39, heterogeneity = 0%). The risk of bias was rated as high in 10 and low-moderate in 12 studies, respectively. In subgroup analysis, the risk of bias of the included studies (low/moderate vs. high), had a small, although not significant effect on the odds ratios of persistence/recurrence of HSIL (OR: 1.57, 95% CI: 1.23-2 for low-moderate risk of bias and OR: 1.06, 95% CI: 0.65-1.75 for high risk of bias; p-value for subgroup differences = 0.17). CONCLUSIONS: Multiple HR-HPVs infections at the time of standard treatment of HSIL entail a small but significant increased risk of persistence/recurrence of HSIL and should be taken into account in the follow-up plan.

PAX1 and SOX1 Gene Methylation as a Detection and Triage Method for Cervical Intraepithelial Neoplasia Diagnosis.

INTRODUCTION: Methylation assays have demonstrated potential as dependable and high-precision approaches for identifying or triaging individuals with cervical cancer (CA) or cervical intraepithelial neoplasia (CIN). Our investigation aimed to assess the efficacy of the diagnosis and triage of the PAX1/SOX1 methylation panel in detecting CIN or CA. METHODS: A total of 461 patients with abnormal high-risk human papillomavirus (hrHPV) or cytology test results were recruited for this study. Each patient underwent an assortment of assessments, comprising a cytology test, hrHPV test, colposcopy examination, and PAX1 and SOX1 methylation tests. RESULTS: The extent of methylation of both genes demonstrates a positive correlation with the severity of CIN lesions and CA. To determine the correlation for patients with CIN2 or worse (CIN2+), the area under curve was 0.821 (95% CI: 0.782-0.853) for PAX1 and 0.800 (95% CI: 0.766-0.838) for SOX1, while for CIN3 or worse (CIN3+), 0.881 (95% CI: 0.839-0.908) for PAX1 and 0.867 (95% CI: 0.830-0.901) for SOX1. The PAX1/SOX1 methylation marker panel performed sensitivity and specificity of 77.16% and 91.67% for CIN2+, 84.76% and 90.50% for CIN3+, respectively. Regarding triaging hrHPV+ patients, the PAX1/SOX1 methylation test only referred 11.83% of the patients who are unnecessary for colonoscopy examination, which is comparatively lower than cytology, thereby signifying a promising triage strategy for hrHPV-positive women. Furthermore, we observed that the positive PAX1/SOX1 methylation test result for untreated CIN1 or fewer patients would result in a higher likelihood of progression upon a 24-month follow-up visit. CONCLUSION: The present investigation demonstrates that the PAX1/SOX1 methylation marker panel exhibits favorable diagnostic performance in CIN detection and holds the potential to be employed for individual CIN tests or hrHPV-positive triage.

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.

Performance of Different Follow-Up Strategies and Genotype-Based Recurrence Risk After Treatment of Cervical High-Grade Squamous Intraepithelial Lesion.

OBJECTIVE: Our aim was to evaluate the performance of different follow-up strategies after treatment for cervical intraepithelial neoplasia (CIN) 2 or 3, including human papillomavirus (HPV) detection, cytology, or colposcopy, as well as their combinations. Additionally, we compared the influence of the persistence of HPV 16/18 versus that of other high-risk HPV genotypes (HR-HPV) in the recurrence risk. METHODS: Retrospective register-based study, including women who had an excision of the transformation zone for CIN2 or CIN3 at our institution, between January 2011 and December 2022. The outcome assessed was histopathological recurrence/persistence of CIN2 or worse. RESULTS: Of the 721 women included, 6.8% (49/721) had recurrence/persistence. The sensitivity, specificity, and positive and negative predictive values of the HPV test were 97.4%, 80%, 22.3%, and 99.8%, respectively, whereas for cotesting (HR-HPV and cytology), 86.8%, 90.1%, 34.4%, and 99.1%, respectively. The referral rates for colposcopy were 24.3% and 14.2%, respectively. The sensitivity of colposcopy was low (40.0%).Women who were initially positive for non-16/18 genotypes at baseline who became HPV16/18 positive during follow-up, had a statistically significant increased risk of CIN2 or worse, compared with those who tested positive only for other HR-HPV genotypes during both stages (hazard ratio = 4.98; 95% CI = 1.66-14.91). CONCLUSIONS: Human papillomavirus testing is the best strategy for follow-up after treatment of cervical HSIL. The addition of cytology triage decreases by more than 40% the referrals for colposcopy, without significantly missing cases of recurrence/persistence. Human papillomavirus 16/18 in the follow-up, regardless of being previously positive, is associated with higher risk of recurrence/persistence of HSIL.