In 2017, the Netherlands introduced primary human papillomavirus (HPV)-based screening with cytology triage, which increased colposcopy referrals and low-grade lesions detected. In 2022, HPV16/18 genotyping was added for women with borderline/low-grade cytology. Triage with HPV genotyping may better balance screening benefits, harms, and costs. Therefore, we evaluated the cost-effectiveness of 19 triage strategies based on net monetary benefit (NMB) at cost-effectiveness thresholds of €20,000 and €50,000/quality-adjusted life-year (QALY), with the highest NMB indicating the most cost-effective strategy. Triage tests included 16/18 genotyping, 7-type (16/18/31/33/45/52/58) genotyping, and cytology (high-grade squamous intraepithelial lesions [HSIL]: moderate/severe, atypical squamous cells of undetermined significance [ASC-US]/low-grade squamous intraepithelial lesions [LSIL]: borderline/low-grade, negative for intraepithelial lesion or malignancy [NILM]: normal). Effects on cancer incidence and mortality were obtained by combining POBASCAM trial data with nationwide screening and cancer registries. Time since the onset of high-grade lesion (cervical intraepithelial neoplasia [grade 2/3] [CIN2/3]) at baseline of the Population-based Screening Study Amsterdam trial cannot be estimated from the data and was varied between 0 and 10 years. At a €20,000/QALY threshold, immediate referral for HSIL and 16/18-positive ASC-US/LSIL, and repeat cytology for 16/18-negative ASC-US/LSIL and 7-types positive NILM had the highest NMB (€214.1 to €309.3/woman gained compared to referring all HPV-positive women). At a €50,000/QALY threshold, immediate referral for all 16/18-positives and/or HSIL, and repeat cytology for 16/18-negative ASC-US/LSIL and 7-types positive NILM had the highest NMB if time since onset of CIN2/3 was greater than 2 years. Cytology combined with HPV16/18 and extended genotyping is cost-effective for triage of HPV-positives. Immediate colposcopy referral of all HPV16/18-positives is cost-effective at a €50,000/QALY threshold.

A meta-analysis of photodynamic therapy in the treatment of cervical intraepithelial neoplasia: Based on randomized controlled trials.

Human papillomavirus (HPV) molecular testing is central to cervical cancer screening. Commercial assays commonly target either the L1 gene or the E6/E7 oncogenes, yet comparative performance data under standardized conditions remain limited. We developed two HPV genotyping assays targeting L1 and E6/E7 regions, respectively, using the same MeltArray platform to minimize technical variability. Both assays detect 18 high-risk and potential high-risk HPV types. A total of 2,477 clinical samples (2,034 liquid-based cytology [LBC] and 413 formalin-fixed paraffin-embedded [FFPE] specimens) were analyzed. Concordance in HPV detection and genotyping was assessed using Cohen's kappa statistics. The assays showed 98.8% overall agreement in HPV detection (Cohen's kappa [κ] = 0.976), with high concordance across LBC and FFPE samples, including high-grade squamous intraepithelial lesion, cervical intraepithelial neoplasia (CIN) 2/CIN 3, and cervical cancer. Discordant genotyping results were rare and concentrated in types with differing limits of detection (e.g., HPV39, HPV52, and HPV66). No substantial detection bias favoring either target gene was observed in cancer cases. When performed under matched analytical conditions, L1 and E6/E7-based assays provide equivalent performance in HPV detection and genotyping. These findings support their interchangeable use in cervical cancer screening, with both targets demonstrating high reliability across the full spectrum of cervical lesions.IMPORTANCEHuman papillomavirus (HPV) testing is the principal strategy for cervical cancer screening, with most commercially available assays targeting either the L1 gene or the E6/E7 oncogenes. However, the comparisons of L1 and E6/E7 targets under standardized technical conditions remain limited. In this study, we developed and evaluated two parallel HPV genotyping assays targeting the L1 gene and E6/E7 genes, respectively, using the same MeltArray platform and unified reaction conditions. Analysis of a clinical cohort comprising 2,477 patients demonstrated equivalent performance between L1 and E6/E7 assays in both cervical swab and tissue samples, supporting their interchangeable use in cervical cancer screening.

Introduction While the conventional Papanicolaou (Pap) smear has long been the cornerstone of cervical cancer (CC) screening, it presents well-documented limitations in sample collection, processing, and interpretation. Liquid-based cytology (LBC) was introduced to address these drawbacks by offering more uniform cell samples and enabling standardized evaluation. However, due to ongoing debate and conflicting study results regarding their comparative diagnostic accuracy, a rigorous evidence-based assessment is needed. The objective of this systematic review and meta-analysis was to systematically assess the diagnostic accuracy of LBC compared to conventional Pap cytology in the detection of cervical precancerous and cancerous lesions. Methods PubMed and Cochrane library were systematically searched. Comparative studies LBC and conventional Pap cytology in primary CC screening were included. Outcomes included unsatisfactory sample rate, abnormal histology-confirmed cytology detection rate (ADR) CIN2+ lesions (cervical intraepithelial neoplasia), SCC (squamous cell carcinoma), and glandular abnormalities. Random-effects models were used to estimate risk ratios (RR). A two-sided p-value of 0.05 was used to determine statistical significance. Results 97 studies were included. LBC had a lower unsatisfactory sample rate than conventional Pap cytology (RR 0.63, 95% CI: 0.47-0.85, p = .003). The detection rate of SCC was similar (RR 1.77, 95% CI: 0.96-3.26, p = .07). The glandular abnormality detection rate showed no overall difference (RR 1.23, 95% CI: 0.75-2.02, p = .42), but a subgroup analysis (FDA-approved tests) showed superiority of LBC (RR 1.52, 95% CI: 1.18-1.96, p = .001). LBC had a 35% higher abnormal cytology detection rate confirmed by histology (RR 1.35, 95% CI: 1.20-1.52, p < .0001) and 27% higher detection of confirmed CIN2+ abnormalities (RR 1.27, 95% CI: 1.11-1.45, p = .0006). Conclusion LBC improves CIN2+ and histological confirmed abnormal detection rates while reducing unsatisfactory samples, supporting its use in CC screening. SCC detection rates were similar. Findings suggest that LBC, particularly when using FDA-approved tests, enhances glandular abnormality detection. Further research should evaluate its cost-effectiveness in low-resource settings.

Our aim was to explore the reasoning and experiences of women when offered a self-sampling HPV test. This study implemented a qualitative study design and content analysis using an inductive approach. Data consisted of written narratives collected through open-ended questions from a total of 173 women. Women were included if they had been offered a self-sampling device since September 2021 and were southern Sweden residents. To achieve purposive sampling with maximum variation, attenders adhering to the screening programme, nonattenders (absent for at least two screening rounds), and women with cervical dysplasia were recruited. The content analysis generated seven categories: (1) unpleasant experience with a vaginal examination; (2) gratefulness and acceptability of self-sampling; (3) varied perception of one's capacity to perform self-sampling; (4) preference for cervical sampling by healthcare professionals; (5) anxiety and fear concerning a potential or detected HPV infection; (6) different risk assessments for acquiring an HPV infection; and (7) negative impact on mental well-being due to cervical dysplasia. The overarching theme became "the HPV self-sampling reduced practical and emotional barriers to attending the cervical cancer screening programme, but test results may create anxiety." Most women valued HPV self-sampling, although their confidence in performing it varied. Self-sampling can reduce the emotional and practical barriers to participation in cervical cancer screening. However, anxiety about cervical dysplasia or following a positive HPV test was noted, highlighting the need for healthcare professionals to provide personalised information to alleviate negative emotions.

In low- and middle-income countries (LMICs), cervical cancer is a major burden. Screening is mainly based on visual inspection lacking sufficient sensitivity and specificity. For roll-out of colposcopy-based early detection sufficient qualified staff is not available. Several self-sampling device products have been proposed as alternative, but their usability in primary care needs to be proven. Implementation of an HPV-based self-sampling approach in a population-based setting in Indonesia was evaluated. Four self-sampling devices (2 urine, 2 swab) were applied in a primary care setting covering an entire district in Indonesia with Kulon Progo as pilot region. Cluster randomization was used for comparison of rural and urban areas. HPV-testing was done using standardized and validated PCR-techniques. HPV-positive women and a randomly selected HPV-negative control group underwent colposcopy, PAP smears and biopsies for cervical intraepithelial neoplasia (CIN) validation. In 21 primary care units 2056 women (30-55 y) were recruited. Three devices achieved sufficient technical validation (92.1 - 99.7% DNA detection rate). Participant's test acceptance was 99.1%. HPV-prevalence was 2.6% (urine 2.4%, swab 2.8%). In 29.4% of HPV-positive women high-risk HPV-16/18 were detected. Colposcopy and morphological examination were refused by 3.0% of HPV-positive women and were technically invalid in 5.0%. Pathology revealed Negative for Intraepithelial Lesion or Malignancy (NILM) in 55.8%, CIN I in 25.0% and CIN II + in 3.8%. In the control group CIN I was found in 2.0%. This resulted in a sensitivity of 27.4% for all CIN and 100.0% for CIN II + , with specificities of 98.5% and 97.7%, respectively. The negative predictive values (NPV) were 97.9% and 100.0%, and positive predictive values (PPV) were 34.1% and 4.5%. Regression analysis confirmed high negative predictive impact of HPV-negativity in women > 40 years. Under primary care setting self-sampling-based HPV-testing is accepted. Urine- and swab-based techniques can be applied if the test systems provide technically valid DNA-detection rates. The prevalence was very low and requires further comparison within Indonesia. High NPV of this approach supports its applicability as screening in LMICs. For high-risk lesions PPV is still low suggesting a combination with additional test that are mainly independent from the availability of qualified staff.

Monitoring human papillomavirus (HPV) types detected in cervical precancers has been one approach to evaluate HPV vaccination impact in the United States. During 2008-2014, the proportion of cervical precancers positive for HPV16/18 decreased overall and among some demographic and histologic subgroups. This updated analysis describes trends through 2019. We analyzed cervical precancers among women aged 20-39 years from a 5-site, population-based surveillance program for cervical intraepithelial neoplasia grades 2 or higher and adenocarcinoma in situ (AIS; collectively CIN2+). Available archived diagnostic tissue was tested for HPV 16, 18, and other HPV types. We evaluated the average annual percent change (AAPC) in the proportion of cervical precancers with HPV 16 or 18 detected overall and by vaccination status, age group, diagnosis, race/ethnicity, and surveillance site. During 2008-2019, 17,323 CIN2+ cases had valid typing results. The proportion of cases positive for HPV16/18 significantly decreased 3.6% per year. The largest decrease occurred among cases in vaccinated women (AAPC = -8.9), with smaller but still significant decreases among unvaccinated women (AAPC = -2.3). Significant decreases were observed among all subgroups evaluated except women aged 35-39 years, AIS, and Asian women. During 2008-2019, decreases in the proportion of CIN2+ that were HPV16/18-positive among vaccinated and unvaccinated women, and in most subgroups evaluated, suggest direct and indirect HPV vaccination impact. HPV vaccination impact on precancers is prognostic of future decreases in cervical cancer. Continued monitoring can enable evaluation of vaccination impact in population subgroups.

HighlightsWhat are the main findings?A three-miRNA panel (miR-21, miR-205, and miR-218) improves the detection of HSIL and cervical cancer compared to individual biomarkers.Circulating miRNA expression patterns are associated with HPV status, including HPV16/18 positivity and multiple HPV infections.What are the implications of the main findings?Circulating miRNA signatures represent a promising minimally invasive approach to refine risk stratification in cervical dysplasia.Integration of miRNA biomarkers with HPV-based screening may enhance early detection and clinical surveillance strategies.Persistent high-risk human papillomavirus (hr-HPV) infection drives cervical carcinogenesis, yet improved molecular biomarkers are needed to define high-risk groups. Circulating microRNAs (miRNAs), stable in blood and involved in carcinogenic pathways, represent promising liquid biopsy biomarkers. This study assessed five miRNAs for distinguishing high-grade squamous cell intraepithelial lesions (HSILs) and cervical cancer from healthy controls and for HPV stratification. Circulating miRNAs were quantified in blood samples from 80 women (38 HSIL, 10 cervical cancer, and 32 controls). Relative expression by disease and HPV status was measured by RT-qPCR and normalized to miRNA-23a. Diagnostic performance of single and combined miRNAs was evaluated by logistic regression and ROC curve analysis. Three circulating miRNAs (miR-21, miR-205, and miR-218) were found to be significantly differentially dysregulated in the patient cohorts. A combination of the three markers showed the best diagnostic value for HSIL (AUC of 0.81, sensitivity of 79%, and specificity of 71%) and cancer (AUC of 0.81, sensitivity of 90%, and specificity of 65%). Whereas miR-205 was significantly associated with HPV16/18 in HSIL patients, the combined model had the highest diagnostic performance for multiple HPV infections. Circulating miRNA signatures show promise as liquid biopsy biomarkers for detecting cervical dysplasia and stratifying for HPV status in HSIL, warranting validation in larger prospective studies.

To evaluate the diagnostic proficiency of well-established multimodal Large Language Models (LLMs)-specifically Gemini, Claude, and Copilot-in interpreting cervical cytopathology (PAP smears). This diagnostic accuracy study used 30 representative cases from the "Cytopathology of the Uterine Cervix-Digital Atlas," which represented the gold standard. The models were tested using a standardized, zero-shot prompt to distinguish between normal cells, benign modifications (infections), and cervical cell abnormalities. The models demonstrated significant variability. While Gemini and Copilot showed high proficiency (90%) in identifying normal physiological morphology, performance declined sharply for infectious pathogens and dysplastic/neoplastic lesions. Notably, all models misclassified several invasive carcinomas as benign or low-grade lesions. Claude exhibited a high rate of "diagnostic escalation," frequently misidentifying normal cells as having abnormalities. Current LLMs are inadequate for the definitive diagnosis of cervical dysplasia and malignancy due to significant rates of overdiagnosis and failure to detect invasive carcinomas. They should be viewed as emerging educational aids rather than autonomous diagnostic tools, requiring rigorous human oversight.

Cold coagulation, although less commonly used today, offers a less invasive alternative to excisional procedures for high-grade cervical intraepithelial neoplasia (CIN). This study evaluated post-treatment cytologic and virologic negativity rates among reproductive-age women with high-grade CIN. This retrospective study analyzed the medical records of 151 reproductive-age women diagnosed with CIN 2 or 3 who were treated with cold coagulation at a single tertiary referral hospital between January 2010 and April 2022. Efficacy was assessed using follow-up liquid-based cytology and human papillomavirus (HPV) tests performed 3 months to 3 years after treatment. Statistical analyses included odds ratios and a univariate Cox proportional hazards model to evaluate treatment outcomes and failure rates. At 6 months, cytologic negativity was achieved in 66.7% of patients and virologic negativity in 50.0%; these rates increased to 81.3% and 70.0%, respectively, by 3 years. Treatment failure occurred in 26.5% of patients. However, no significant differences in negative test rates were observed between CIN2 and CIN3 or between HPV16/18 and other high-risk HPV types. Persistent disease occurred in 25.8% of patients, whereas recurrence was observed in 2.6%. Minimal complications were reported, and no cases of progression to cervical cancer were identified. Cold coagulation demonstrated moderate post-treatment cytologic and virologic negativity rates with minimal immediate complications in this retrospective cohort. However, given the substantial rate of persistent disease and the nonstandard role of ablative treatment in settings where excision is available, these findings should be interpreted with caution.

Analysis of factors affecting lesion or HPV clearance rate after photodynamic therapy of persistent cervical intraepithelial neoplasia grade 1.

Diagnostic performance of pap smear for cervical intraepithelial neoplasia in women with treatment-resistant vaginal infections: A colposcopy-guided biopsy correlated study.

To evaluate the risk of cervical intraepithelial neoplasia, grade 2 or worse (≥ CIN2) in women with normal cervical cytology using extended high-risk human papillomavirus (HR-HPV) genotyping. This study is a population-based, nationwide, multi-center prospective cohort study. A subset of 6853 women with normal cytology and HPV testing results using an extended genotyping assay were included in the analysis. The odds ratio (OR) and adjusted OR (aOR) was calculated using univariate analyses and multivariate logistic regression, with HPV negative and other 9 HR-HPV-positive genotypes (HPV 31, 35, 39, 45, 51, 56, 59, 66, and 68) as reference, respectively. The 3-year cumulative absolute risk was calculated. Over the study period, 87 ≥ CIN 2 cases were identified. Most ≥ CIN 2 cases were positive for HPV 16 (50.6%) or HPV 33/52/58 (46.0%) at baseline. Compared to other 9 h-HPV, HPV 16 (aOR = 20.5, 95% CI: 8.5-49.5), HPV18 (aOR = 10.1, 95% CI: 3.2-31.8), and HPV 33/52/58 (aOR = 4.8, 95% CI: 2.0-11.8) were significantly associated with higher risk of ≥ CIN 2. HPV 16 and 33 had the highest cumulative absolute risk of ≥ CIN2 (25.9% and 22.2%), followed by HPV 18 (15.4%), HPV 58 (11.3%), and HPV 52 (8.1%). Other 9 h-HPV had a lower risk of ≥ CIN 2 (4.7%). Extended HPV genotyping beyond HPV 16/18 (e.g., HPV 33, 52, and 58) might be effective for risk stratification in women with normal cervical cytology. The management of HPV-positive women based on refined genotype-based risk estimations may be a promising strategy for cervical cancer screening. The study was registered at the Chinese Clinical Trial Registry Center of the World Health Organization International Clinical Trials Registry Platform (Registration number ChiCRT2200055287).

Emerging evidence demonstrates the benefit of adjuvant HPV vaccination at the time of loop electrosurgical excision procedure (LEEP) in reducing cervical intraepithelial neoplasia 2+ (CIN2+) recurrence. Our primary objective aimed to increase the HPV vaccination rate by 15% over 6 months among a high-risk patient population seen in colposcopy. A secondary objective surveyed patient barriers to vaccination. This interrupted time series quality improvement study followed 127 immunocompetent patients aged 24-45 undergoing their first LEEP for high-grade cervical dysplasia from January to June 2023 in a quaternary colposcopy clinic. Interventions included nurse-led education and providing Gardasil-9 prescriptions to unvaccinated patients. The primary outcome was the total vaccination rate at 6 months. Weekly rates of prescription and patient brochure distribution, and the proportion of newly vaccinated patients by follow-up, were tracked as process measures to inform Plan-Do-Study-Act cycles. Balancing measures included cost and vaccine reactions. Data was analyzed with descriptive statistics, Mann-Whitney tests, and statistical process control (p) charts. Among eligible patients, 73/127 (56.6%) were unvaccinated at the time of LEEP. Among patients seen in follow-up, 47.9% (n = 34/71) started the vaccine series. The proportion of patients who pursued vaccination by their 6-month follow-up appointment increased from 42.5% (n = 54/127) to 69.3% (n = 88/127), a 26.8% absolute increase. Among the still unvaccinated cohort seen in follow-up (n = 37/71; 52.1%), the most common barriers were cost (n = 12/37; 32.4%) and time restraints (n = 9/37; 23.3%). Collaborative interventions to identify and counsel unvaccinated patients undergoing their first LEEP increases HPV vaccination rates, presenting an effective opportunity to engage patients in cervical cancer prevention.

Human papillomavirus (HPV) assays vary regarding the minimum amount of virus they detect. We investigated analytical thresholds of HPV detection and cervical screening sensitivity and specificity. One hundred cervical intraepithelial neoplasia grade 2 or worse (CIN2+) cases and 200 matched population-based controls were obtained at the Swedish National HPV Reference Laboratory and analyzed by 10 laboratories across 10 countries. Cumulative sensitivity (weighted according to the global HPV type distribution in invasive cervical cancer (ICC)) and specificity were estimated at varying analytical detection thresholds. Consensus results found HPV in 99/100 CIN2+ cases and 52/200 controls. HPV16 prevalence declined in HPV-vaccinated birth cohorts, among both cases and controls. Line plots of 1-specificity and ICC-weighted sensitivity found optimal analytical detection thresholds as 3 International Units (IU)/µl for HPV16/18, 25 IU/µl for HPV31/33/35/45/52/58 and 100 genome equivalents (GE)/µl for HPV 39/51/56/59 resulting in 92.00% cumulative specificity and 90.08% ICC-weighted sensitivity. Thresholds defined using virus amounts per 104 human cells gave similar results. Comparator assay testing using manufacturer-defined thresholds achieved high ICC-weighted sensitivity (96.61%) but low specificity (82.50%). Thisinternational collaborative study has identified HPV analytical detection thresholds optimizing the sensitivity and specificity of cervical screening.

Current professional guidelines recommend discontinuing Papanicolaou (Pap) test screening in women aged 65 years and older who have had adequate prior negative testing. However, limited data exist on Pap test performance and histologic outcomes in this population. Searches were performed for all Pap tests from women aged 65 years and older accessioned at a women's hospital between January 2023 and December 2024. Pap tests were performed using the liquid-based cytology ThinPrep test, and high-risk HPV testing was performed using Aptima high-risk human papillomavirus (HPV) assays. Surgical pathology follow-up within 6 months was recorded. A Pearson χ2 test was performed to compare HPV positivity among patients who had abnormal Pap tests. In total, 1536 women aged 65 years and older underwent Pap testing during the study period. The overall HPV-positivity rate was 24.2%. Abnormal Pap results (atypical squamous cells of undetermined significance or worse) comprised 939 of 1536 cases (61.1%). Histologic follow-up was available for 402 cases. Lesions categorized as cervical intraepithelial neoplasia grade 2 (CIN2) or more severe disease were identified in 94 cases (23.3%), including 11 squamous cell carcinomas, three endocervical carcinomas, 40 CIN2/3 lesions, and 40 endometrial carcinomas. Notably, three of 11 squamous cell carcinomas (27.3%) and 12 of 40 CIN2/3 lesions (30%) were HPV-negative. The abnormal Pap rate in women aged 65 years and older was high (61.1%), whereas HPV positivity remained low. CIN2 or more severe disease and endometrial lesions after negative HPV testing occurred at a substantial rate (33.8%). The rate for detecting atypical glandular cells was also elevated (3.0%), correlating with a significant number of endometrial carcinoma diagnoses. These findings underscore the need for additional research and suggest that continued screening with Pap and HPV cotesting may benefit older women.

Randomized clinical trial protocol: Acceptability and feasibility of combination treatment for cervical precancer among South African women living with HIV (ACT 2).

Global research trends and evidence-based clinical efficacy of photodynamic therapy in gynecology: A bibliometric analysis (2010-2025).

Background: In this study, we evaluated the effects of the nonavalent Gardasil® vaccine in a heterogeneous cohort of women who underwent conization or LLETZ for various degrees of CIN, aiming to assess the adjuvant effect of vaccination on HPV clearance. Methods: We conducted a three-year prospective study with a two-year follow-up of 219 patients presenting to our facility for cervical dysplasia. All patients underwent HPV genotyping and were divided into HPV-vaccinated and non-vaccinated groups. Results: We detected a significant association between the final outcome and vaccination timing (p-value = 0.005). All women vaccinated before conization achieved viral clearance; 94.9% of those vaccinated at the time of conization/LLETZ and 68.6% of those vaccinated after the excisional procedure became HPV-negative. Logistic regression showed that, with increasing age, the likelihood of healing after vaccination decreased by approximately 9% per additional year, and non-16/18 HPV-positive women had a 5.5-fold higher chance of healing after vaccination compared with those HPV-positive for 16 and 18 genotypes. Conclusions: Adjuvant prophylactic HPV vaccination in the context of surgical treatment for cervical precancerous lesions is significantly associated with a reduced risk of lesion recurrence and HPV persistence/reinfection when administered prior to or at the same time as the excisional procedures.

Cervical cancer (CC) is an alarming global health problem, with predominantly higher incidence, lethal progression, and mortality among women of African ancestry (AA) than women of European ancestry (EA). Although persistent high-risk human papillomavirus (HPV) integration and infection are the key etiological factors, currently available evidence implicates epigenetic reprogramming as a prime contributor to ancestry-associated differences in CC pathogenesis. To address these disparities, we performed genome-wide DNA methylation profiling of HPV-positive cervical intraepithelial neoplasia (CIN) lesions from AA (n = 15) and EA (n = 15) women. Differential methylation analysis identified a distinct epigenomic landscape in AA-CIN lesions, with widespread hypermethylation and hypomethylation at promoter-associated and regulatory CpG sites. Pathway enrichment analyses highlighted dysregulation of ECM-receptor interaction, focal adhesion, PI3K-Akt, MAPK, Ras, Rap1, and RUNX-dependent transcriptional networks. Comparative analysis across CIN grades (CIN1–CIN3) revealed progressive epigenetic reprogramming affecting cell cycles, cytoskeletal dynamics, signaling, and metabolic pathways. Among hypermethylated tumor suppressor genes, SH3GL2 and ARHGAP25 showed significantly higher methylation in AA lesions, accompanied by concomitant loss of their protein expression. MBD1, a methylation-binding regulator, was upregulated in AA-CIN lesions, coinciding with global loss of 5-hydroxymethylcytosine (5hmC), suggesting enhanced transcriptional repression. In contrast, EA lesions retained protein expression and 5hmC levels. Collectively, these findings indicate that early, ancestry-specific epigenetic modifications target tumor suppressor pathways and converge on oncogenic signaling, cytoskeletal remodeling, and cell–cell adhesion. Our study provides mechanistic insight into CC health disparities, identifying SH3GL2 and ARHGAP25 hypermethylation as potential biomarkers, and highlighting epigenetic regulation as a contributor to disparate CC progression in AA women.