Search Results (373)

Human papillomavirus (HPV)-associated cervical lesions remain a significant disease burden and minimally invasive blood-based biomarkers could complement cytology and HPV testing. This study aimed to characterize the proteomic composition of plasma-derived CD9⁺ small extracellular vesicles (sEVs) across the morphological spectrum of HPV-associated cervical disease, from histologically normal (NILM) through low-grade (LSIL) and high-grade (HSIL) lesions to invasive squamous cell carcinoma (SCC). Plasma samples from 34 women (NILM, LSIL, HSIL, SCC) were pooled per group, and CD9⁺ sEVs were isolated using an electrochemically controlled immunoaffinity capture method, followed by nanoparticle tracking analysis, transmission electron microscopy, Western blotting, and label-free LC–MS/MS proteomic profiling. The core sEV proteome comprised 258 shared proteins. LSIL showed the most pronounced changes with broad enrichment of complement and coagulation components and acute-phase reactants alongside depletion of immunoglobulin chains and complement C1r-like protein (C1RL). HSIL exhibited few differential proteins, dominated by neutrophil degranulation and retinoid metabolism pathways. SCC demonstrated extensive cargo depletion (22 downregulated proteins) and a nearly sevenfold upregulation of C1RL. Five proteins (including immunoglobulin chains and GPLD1) correlated positively with lesion severity. Pathway analysis consistently implicated platelet activation, lipoprotein remodeling, and insulin-like growth factor signaling. We conclude that plasma CD9⁺ sEVs carry stage-specific proteomic signatures distinguishing HPV-associated cervical lesions, with C1RL emerging as a candidate biphasic marker warranting further validation. Full article

Background: Colposcopy is a widely used clinical and diagnostic tool for detecting cervical intraepithelial neoplasia grade 2 or higher (CIN2+). This paper aims to analyze the diagnostic accuracy, pooled sensitivity, specificity, likelihood ratios, and overall diagnostic performance of colposcopy. Methods: A systematic review of papers on diagnostic accuracy, preregistered in PROSPERO (CRD420251028776), was conducted following PRISMA-DTA guidelines. Statistical analyses were performed using SPSS 29 and METADISC 2.0. Study quality and risk of bias were assessed using QUADAS-2. Results: A total of 49 studies, including 141,355 colposcopic examinations, were included in the final analysis. The overall sensitivity was 0.745 (95% CI: 0.684–0.797) and specificity was 0.831 (95% CI: 0.770–0.879). The diagnostic odds ratio was 14.388 (95% CI: 9.673–21.400). The positive likelihood ratio was 4.419 (95% CI: 3.260–5.991). Conversely, the negative likelihood ratio was 0.307 (95% CI: 0.249–0.378). The area under the curve was 0.8569. Significant heterogeneity was observed across studies (I² > 93.2%). Conclusions: Colposcopy demonstrates moderate-to-high diagnostic accuracy in detecting CIN2+ lesions, with a good balance between sensitivity and specificity. However, significant variability exists among studies, highlighting the need for the implementation of standardized colposcopic criteria, improved examiner training, and adjunctive diagnostic methods such as HPV testing and ancillary techniques to enhance accuracy and reduce false positives and false negatives. Future research should focus on minimizing interobserver variability and refining diagnostic algorithms to optimize colposcopic performance. Full article

Background and Objectives: Persistent human papillomavirus (HPV) infection is associated with the development of cervical intraepithelial neoplasia and cervical cancer. In women with low-grade cervical lesions, a conservative management approach is commonly recommended. However, a subset of patients may experience lesion progression, which can also be accompanied by psychological distress. Adjuvant therapies during the surveillance period have gained increasing clinical interest. This consensus aims to provide multidisciplinary, expert-based recommendations on the use of a Coriolus versicolor-based vaginal gel in HPV-positive women with low-grade cervical lesions. Materials and Methods: A rapid systematic review was conducted in accordance with PRISMA guidelines, and the level of evidence was assessed using SIGN criteria. Subsequently, a multidisciplinary panel of experts formulated and evaluated consensus statements and recommendations using the nominal group technique and a voting process. Results: All statements reached consensus, with agreement levels exceeding 80%. Experts concluded that available evidence reports potential benefits of a Coriolus versicolor-based vaginal gel in HPV-positive women with low-grade cervical lesions, since it has demonstrated increased lesion regression and viral clearance rates. These benefits may be more pronounced in specific subgroups, particularly women over 40 years of age. Limited studies also suggest a positive effect on vaginal microbiota, which may contribute to both vaginal health and HPV clearance, as well as a reduction in perceived stress. The experts emphasized the importance of patient education, shared decision-making, and addressing psychosocial aspects, including emotional well-being and sexual health. Conclusions: This consensus provides a multidisciplinary perspective on the management of HPV-positive women with low-grade cervical lesions, highlighting the adjuvant role of a Coriolus versicolor-based vaginal gel during surveillance. Although current evidence suggests potential clinical benefits, further high-quality, independent studies are needed to corroborate these findings. Full article

Background/Objectives: Cervical intraepithelial neoplasia (CIN) exhibits heterogeneous clinical behavior, with some lesions regressing spontaneously, whereas others persist or progress to higher-grade disease. Identifying biomarkers that reflect lesion dynamics remains a major clinical challenge. This study aimed to evaluate the clinical significance of CD86 expression in cervical lesions by examining longitudinal changes and determining whether temporal alterations in CD86 expression are associated with lesion regression and epithelial-associated immune dynamics. Methods: Cervical samples were collected from patients with CIN, and gene expression was analyzed using reverse transcription–quantitative PCR. Longitudinal analyses were performed using paired samples to evaluate the temporal changes in CD86 expression. Regression status and time to regression were assessed, and associations with CD86 changes were evaluated using receiver operating characteristic analysis, logistic regression, and Cox proportional hazards models. Longitudinal patterns were further characterized using a spaghetti plot and slope analyses. Results: Baseline CD86 expression did not associate with regression status or CIN grade. However, longitudinal changes in CD86 expression differed significantly between the regression and non-regression group. CD86 change demonstrated moderate predictive performance for regression and was significantly associated with both regression and shorter time to regression. Longitudinal analyses revealed distinct temporal patterns between the regression and progression groups. Baseline CD86 expression was strongly correlated with FOXP3 expression, whereas CD86 dynamics were not independently associated with lymphocyte-related markers. Conclusions: Longitudinal changes in CD86 expression are significantly associated with lesion regression in CIN and may reflect lesion-associated immune dynamics during follow-up, particularly within epithelial-derived cervical cytology specimens. Full article

Background/Objective: Cervical intraepithelial neoplasia grade 2 (CIN2) shows heterogeneous clinical behavior, with substantial rates of spontaneous regression under active surveillance. Reliable molecular biomarkers are needed to distinguish regressive from transforming lesions and reduce overtreatment. We evaluated the prognostic role of host and viral DNA methylation, alone and combined with HPV genotyping, in predicting CIN2 regression. Methods: This subanalysis derives from a prospective, multicenter Italian cohort of women with histologically confirmed CIN2 managed conservatively. Among 319 enrolled women, 134 with single HPV infections and valid host (FAM19A4/miR124-2) and viral (HPV L1 region) methylation results were included. HPV genotyping was performed with partial stratification (HPV16/18 vs. non-16/18). Clinical outcomes at 24 months were classified as regression versus persistence/progression. Logistic regression models assessed associations between biomarkers and regression. Results: At 24 months, 50% of women showed regression. Host and viral methylation positivity rates were more frequent in non-regressive lesions (40.3% vs. 19.4%, p = 0.01, and 52.2% vs. 32.8%, p = 0.02, respectively). Negative host methylation was significantly associated with regression (Odds Ratio OR = 0.37, 95% CI 0.17–0.81, p = 0.02), as was negative viral methylation (OR = 0.47, 95% CI 0.23–0.96, p = 0.04). Conclusions: Both host and viral methylation are inversely associated with CIN2 regression. Combining methylation markers did not substantially improve predictive accuracy; however, methylation negativity emerged as a potential molecular reassurance marker. When integrated with HPV genotyping, the highest probability of regression was observed among women with non-HPV16/18 infections and negative methylation results. These results endorse DNA methylation testing as a molecular tool for the conservative management of CIN2. Full article

Human papillomavirus type 53 (HPV53) is one of the most prevalent HPV genotypes in China, frequently detected in cervical intraepithelial neoplasia and cervical cancer, yet remains outside the coverage of all currently available prophylactic vaccines and is relatively understudied. This study performed a comprehensive analysis of HPV53 clinical infection profiles, genomic diversity, and T-cell epitopes to inform therapeutic vaccine development. Clinical analysis of 158 HPV53-positive patients showed that infections were most prevalent in women aged 40–59 years, with persistent infection identified in 13.3% participants and a subset of cases associated with cervical lesions. Genomic analysis of 134 HPV53 isolates identified four lineages (A-D, with lineage D further subdivided into four sublineages, and an overall nucleotide variability of 4.4%. E2 was the most variable protein while E7 was the most conserved. Immunoinformatic prediction identified 176 HLA class I-restricted T-cell epitopes across E6, E7, E1, and E2, from which 20 candidates were selected for experimental validation. Ten demonstrated strong HLA binding affinity in vitro, and murine immunization identified a E6 peptide VYNFAYTDL as an immunodominant epitope. Three validated epitopes exhibited sequence overlap with 12 to 13 of other 13 high-risk HPV genotypes, suggesting their potential as broadly cross-reactive targets. These findings clarify the genomic diversity and immunogenic epitope landscape of HPV53, providing a foundation for the rational design of therapeutic vaccines. Full article

Cervical intraepithelial neoplasia grade 1 (CIN1) is usually managed conservatively, but uncertainty remains about the subsequent risk of clinically significant high-grade disease, particularly after repeated CIN1. We conducted a retrospective population-based cohort study using anonymized cervical cytology, HPV, and histopathology records from Northern Norway from 2011 to 2025. We described temporal trends in screening-related outcomes and estimated the 5-year risk of CIN3+ after histologically confirmed CIN1 diagnosed in a single calendar year or in two consecutive calendar years. Across 2011–2025, the annual datasets comprised 334,471 screening records; 35,796 had ASC-US+ cytology (10.7%), 29,723 had a positive HPV test (8.9%), 35,416 underwent biopsy (10.6%), and 7870 were diagnosed with CIN2+ (2.4%). HPV positivity increased from 0.9% in 2011 to 15.7% in 2025, whereas CIN2+ detection peaked at 3.1% in 2018 and declined to 1.8% in 2025. In person-based analyses, the 5-year risks after CIN1 diagnosed in a single calendar year versus two consecutive calendar years were 4.3% versus 3.4% for CIN3+, 0.2% versus 0.1% for cervical cancer, and 15.4% versus 14.3% for CIN2+. Repeated CIN1 was not associated with higher subsequent CIN3+ risk, supporting conservative, risk-based follow-up after CIN1 biopsy. Full article

Human papillomavirus (HPV) infection remains the principal etiological factor in cervical cancer development worldwide, with Eastern Europe continuing to demonstrate disproportionately high cervical cancer incidence and mortality rates. Regional disparities in screening implementation, vaccination coverage, and HPV genotype distribution contribute substantially to the persistent burden of HPV-related disease. In recent years, increasing attention has focused on molecular biomarkers and the vaginal microbiome as complementary approaches for improving cervical cancer prevention strategies. This systematic review aimed to evaluate recent evidence regarding HPV genotype distribution, molecular biomarkers, vaginal microbiome composition, and their implications for cervical cancer prevention in Eastern Europe. A systematic literature search was conducted in PubMed/MEDLINE, Scopus, Web of Science, Embase, and the Cochrane Library for studies published between January 2020 and May 2026. This systematic review was conducted in accordance with the PRISMA 2020 guidelines and prospectively registered in PROSPERO (CRD420261391136). Studies from Eastern European populations reporting data on HPV genotype distribution, screening strategies, vaccination, molecular biomarkers, or vaginal microbiome composition were included. HPV prevalence in screening populations ranged from approximately 12% to over 20%, with HPV16 consistently identified as the predominant genotype across all included studies. However, non-16/18 high-risk genotypes, particularly HPV31, HPV51, HPV52, HPV66, and HPV68, represented a substantial proportion of infections in several Eastern European cohorts. Studies evaluating CINtec PLUS cytology and HPV E6/E7 mRNA testing demonstrated improved specificity for identifying clinically significant cervical lesions compared with HPV DNA testing alone. Emerging evidence also suggested associations between vaginal dysbiosis, increased microbial diversity, persistent high-risk HPV infection, and progression to cervical intraepithelial neoplasia. Although the 9-valent HPV vaccine provides coverage for most circulating high-risk genotypes identified in the region, vaccination uptake remains inconsistent throughout Eastern Europe. The findings of this systematic review support the growing importance of extended HPV genotyping, molecular biomarkers, and microbiome-related approaches in cervical cancer prevention strategies in Eastern Europe. Strengthening organized screening programs, expanding vaccination coverage, and improving access to molecular diagnostic technologies remain essential priorities for reducing the regional burden of HPV-related disease. Full article

Persistent high-risk human papillomavirus infection is a critical prerequisite for cervical intraepithelial neoplasia and cervical cancer, yet viral factors alone do not fully explain why most infections clear while a subset persists and progresses. Emerging longitudinal, multi-omics, and mechanistic evidence supports a plausible model in which the cervicovaginal microbiota is not a passive bystander but a functional determinant of mucosal immunity, epithelial barrier integrity, and local metabolic tone. Lactobacillus-dominant community states, particularly those enriched in Lactobacillus crispatus, are generally associated with lower pH, regulated inflammatory signaling, stronger barrier function, and a higher likelihood of HPV clearance. In contrast, anaerobe-enriched dysbiosis is linked to elevated pro-inflammatory cytokines, altered antigen presentation, immune checkpoint signatures consistent with T-cell dysfunction, and metabolic shifts involving lactate depletion and accumulation of short-chain fatty acids and other metabolites that can influence epithelial and immune-cell programs. Importantly, the interaction is bidirectional: hrHPV can remodel the microenvironment by suppressing host defense peptides and perturbing mucosal barriers, thereby reducing Lactobacillus fitness and reinforcing dysbiosis in a feed-forward loop that favors persistence and oncogenic progression. This review integrates functional ecology, longitudinal clinical evidence, immunological and metabolic mechanisms, and translational implications, highlighting opportunities for microbiome-informed risk stratification and adjunctive interventions, as well as key gaps requiring standardized longitudinal multi-omics and rigorously designed clinical trials. Full article

Human papillomavirus (HPV) infection is a major driver of anogenital disease and virus-related carcinogenesis. Although most infections resolve spontaneously, persistent infection with high-risk genotypes may progress to high-grade squamous intraepithelial lesions (HSILs) and cancer, particularly in the setting of impaired immune surveillance. Unlike previous HPV-related reviews focused primarily on cervical disease, vaccination, or isolated immunosuppressed populations, this narrative review comparatively examines the clinical expression, colposcopic findings, screening strategies, and therapeutic implications of HPV-related disease across the immunological spectrum. This narrative review provides an integrative synthesis of HPV-related disease in the female lower genital tract across the immunological spectrum. A structured, non-systematic search of PubMed/MEDLINE, Scopus, and Web of Science was conducted using terms related to “human papillomavirus”, “HPV”, “cervical intraepithelial neoplasia”, “colposcopy”, “immunosuppression”, “HIV”, and “vaccination”. Immunosuppressed populations, including individuals living with HIV, transplant recipients, and patients receiving immunosuppressive therapy, exhibit higher rates of persistent infection, multifocal disease, recurrence, and progression to HSIL and invasive malignancy. These patients also present greater diagnostic complexity, broader anatomical involvement, and reduced response to conventional treatment. Rather than representing a uniform condition, HPV-related disease reflects a biologically dynamic spectrum shaped by host immune competence. This review highlights the distinct clinical, colposcopic, and therapeutic challenges observed in immunosuppressed populations and reinforces the need for individualized, risk-adapted strategies integrating contemporary advances in screening, vaccination, and HPV-related disease management. Full article

Background: Persistent high-risk human papillomavirus (hrHPV) infection causes over 99% of cervical precancers and cancers worldwide, with HPV genotype 16 (HPV16) responsible for 50% of the cases. Latvia ranks among the top EU countries for cervical cancer incidence and mortality. In the general Latvian population, 4.2% of women are hrHPV-infected, mostly with HPV16. However, information on the circulating HPV16 isolates is missing. Objectives: To study the genomic variability of the Latvian HPV16 isolates, compare them with HPV16 in Europe and across the globe, reveal features associated with the severity of cervical disease and uncover eventual sequence changes due to the national HPV vaccination. Methods: DNA was extracted from the formalin-fixed paraffin-embedded cervical tissues of women diagnosed with cervical intraepithelial neoplasia (CIN) stages I-III and squamous cell carcinoma (SCC) grades 1–3, collected between 2012 and 2024. Samples positive for HPV16 were subjected to whole genome sequencing (WGS) on the Illumina platform (n = 16) or Sanger sequencing of the E6/E7 coding region (n = 31). A consensus HPV16 sequence was generated, and single nucleotide polymorphisms (SNPs) and eventual amino acid substitutions (AAS) were analysed. Results: Complete genomes of 16 HPV16 variants were reconstructed, with 13 related to the European sublineage A1 and 3 to the sublineage A2 references. Sequences showed high conservation; still 93 non-redundant variants were identified. The highest variability was observed for the capsid protein L2, and the lowest, for oncoprotein E7. The prevalence of SNPs and AAS in the Latvian HPV16 variants, specifically in capsid protein L1, did not increase with time, showing no effect of HPV vaccination. Associations between HPV16 sequence features and severity of cervical disease were limited to AAS E6:L90V, which was significantly more common in SCC grade 2/3 than in CINII/III cases (p = 0.015). Conclusions: Highly conserved HPV16 genomes circulating in Latvia harbour a series of unique as well as common nonsynonymous SNPs with respective AAS, with one, AAS E6:L90V, associating with disease severity. No HPV vaccine escape variants were detected. Deciphering complete genomes of HPV16 from CIN and SCC cases in Latvia informs public authorities performing HPV vaccination and is useful for the management of HPV-associated cervical diseases. Full article

Background/Objectives: Large loop excision of the transformation zone (LLETZ) is used as a standard treatment for cervical dysplasia. Although obesity is associated with reduced cervical screening participation and may complicate gynecologic procedures, evidence on the impact of body mass index (BMI) on LLETZ outcomes remains limited. This study aimed to evaluate the association between BMI and clinical outcomes after LLETZ, with a particular focus on margin status. Methods: This retrospective single-center cohort study included 1397 patients who underwent LLETZ for cervical dysplasia between January 2010 and December 2024 at the Medical University of Vienna. Patients were categorized as normal-weight (BMI < 25 kg/m²) or overweight/obese (BMI ≥ 25 kg/m²). The primary outcome was margin status. Secondary outcomes included postoperative bleeding, lesion localization, histological findings, HPV status, cone depth, and surgeon status. Results: Overall, 949 patients had a BMI < 25 kg/m² and 448 had a BMI ≥ 25 kg/m². Negative margins were achieved in 984 patients (70.4%), with no significant difference between BMI groups. Postoperative bleeding occurred in 53 patients (3.8%) and was significantly less frequent in patients with BMI ≥ 25 kg/m². Each 5-unit increase in BMI was associated with a 38% reduction in the odds of postoperative bleeding. BMI was not significantly associated with HPV status or histological findings. Conclusions: BMI was not associated with overall margin status after LLETZ, suggesting that overweight and obesity do not adversely affect short-term surgical outcomes in general. Further prospective studies are needed to evaluate long-term outcomes. Full article

Persistent challenges in cervical cancer (CC) control highlight the need for stage-specific cost estimates to refine prevention strategies. Structural integration of National Health Insurance (NHI) administrative claims, the Taiwan Cancer Registry (TCR), and the National Cause of Death Registry (NCDR) provided the empirical basis for this population-based research. The final analytical sample encompassed 6055 women with cervical intraepithelial neoplasia (CIN) identified in 2016 as well as 9318 patients diagnosed with stage I to IV invasive CC during the 2008 to 2015 period. Reimbursed direct medical costs were estimated for CIN within 6 months after diagnosis and for CC over 5 years after diagnosis. Across CIN grades, no consistent cost gradient was observed, although inpatient utilization was highest in CIN3. Among women with CC, healthcare utilization and expenditures were concentrated in the first year after diagnosis, accounting for 52–65% of the total 5-year costs. After age adjustment, the mean first-year costs increased from NT$256,095 (US$8413) in stage I to NT$474,724 (US$15,595) in stage IV, while 5-year survival declined from 85.3% to 19.5%. These findings show that cervical disease imposes substantial direct medical costs on Taiwan’s healthcare system and provide updated evidence to inform human papillomavirus (HPV) vaccination and CC screening policy. Full article

Background: Effective triage of HPV DNA-positive women is needed to reduce unnecessary colposcopies while maintaining cervical cancer prevention. We evaluated genotype-specific 7-type HPV E6/E7 mRNA triage in a real-world screening cohort. Methods: In this population-based single-centre study at the University Hospital of North Norway, 42,791 women underwent primary screening with the cobas HPV DNA assay during the period 2019–2024. Among 2370 HPV DNA-positive women, reflex cytology, 7-type HPV mRNA testing, and an ATHENA-derived triage strategy were compared using histologically confirmed CIN3+ through 31 December 2025 as the endpoint. Results: CIN3+ was detected in 60/2370 women (2.5%). Test positivity was 47.0% for cytology, 54.7% for ATHENA-derived triage, and 33.4% for HPV mRNA. Sensitivity was 78.3%, 86.7%, and 73.3%; specificity was 53.8%, 46.1%, and 67.7%; and PPV was 4.2%, 4.0%, and 5.6%, respectively. Colposcopies per CIN3+ detected were 23.7, 24.9, and 18.0. Conclusions: HPV mRNA triage improved referral precision and colposcopy efficiency, but with lower sensitivity than ATHENA-derived triage. These findings support 7-type HPV mRNA testing as a potentially useful molecular triage option where structured follow-up is feasible. Full article

Background: Immunosuppressed women are at increased risk of residual or recurrent high-grade cervical intraepithelial neoplasia (CIN 2–3) after excisional treatment, yet long-term comparative data remain limited. Previous studies are often small and heterogeneous, and they rarely compare outcomes directly with immunocompetent populations. This study evaluated the long-term incidence, timing and associated factors of CIN 2–3 recurrence after large loop excision of the transformation zone (LLETZ), stratified by immune status. Methods: We conducted a retrospective cohort study including 283 women treated with LLETZ for CIN 2–3 between 1996 and 2016 at Bellvitge University Hospital in Barcelona, Spain. Of these, 41 were immunosuppressed and 242 immunocompetent. Clinical, histopathological, virological, and immunological variables were extracted from hospital and pathology registries. Kaplan–Meier estimates and Cox proportional hazards models adjusted for immunosuppression status were used to evaluate time-to-recurrence and factors associated with recurrence. Results: At 36 months post-treatment, the probability of residual/recurrent CIN 2–3 was 44% in immunosuppressed women versus 5% in immunocompetent women (HR = 10.42, 95% CI 4.70–23.08, p < 0.001). Recurrence appeared earlier in immunosuppressed women (median 7 vs. 13 months). Persistent high-risk HPV infection at first follow-up (HR = 23.6, 95% CI 5.44–102, p < 0.001) and positive surgical margins (HR = 3.88, 95% CI 1.45–10.3, p = 0.007) were among the factors most strongly associated with recurrence, and advanced immunodeficiency (CD4+ < 200 cells/mm³ or detectable HIV viral load) was associated with earlier recurrences, though this association was not maintained after accounting for immunosuppression status in Cox models. Conclusions: Immunosuppressed women are at significantly higher and earlier risk of residual/recurrent CIN 2–3 after LLETZ. These findings support a risk-adapted, multidisciplinary follow-up integrating gynecologic, infectious disease, and immunologic care. Tailored surveillance and perioperative HPV vaccination may enhance secondary prevention in this high-risk population. Full article