Search Results (167)

Background/Objectives: This study evaluated the real-world effectiveness of prophylactic Human Papillomavirus (HPV) vaccination in Korean women aged over 26 years, focusing on its impact on persistent HPV infection and disease progression. Methods: This multicenter prospective study analyzed data from the Korea HPV Cohort (2010–2021). After applying exclusion criteria, the final analytical cohort included 1,231 women aged ≥ 27 years with cytologic findings of atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesions and HPV infection. Propensity score matching was used to compare vaccinated (n = 340) and unvaccinated (n = 891) participants. After matching, 273 vaccinated and 273 unvaccinated individuals were included in the final analysis. The primary outcomes were persistent HPV infection and progression to biopsy-confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+). Logistic and Cox regression models were employed, with additional age-stratified analyses. Results: Among women aged 27–39 years, vaccination was significantly associated with a 54% reduction in the odds of persistent HPV infection (odds ratio = 0.46; 95% CI: 0.22–0.96; p = 0.040). In the full cohort, vaccinated participants had a 62% lower risk of progression to CIN2+ compared with unvaccinated participants (hazard ratio = 0.38; 95% CI: 0.18–0.81; p = 0.011). Body mass index had a notable impact on HPV persistence in HPV 16/18 genotype groups. Conclusions: HPV vaccination effectively reduced persistent infection and progression to CIN2+ in Korean women, particularly those vaccinated before age 40. These findings support the age-extended HPV vaccination policies in South Korea. Full article

Introduction: Following up on treated high-grade cervical intraepithelial neoplasia (HSIL/CIN) lesions poses a challenge. Cervical cytology often has a high false-negative rate, while high-risk human papillomavirus (HR-HPV) DNA testing, though sensitive, lacks specificity. The detection of messenger RNA of the HR-HPV E6 and E7 oncoproteins (E6/E7 mRNA) is proposed as an indicator of viral integration, which is crucial for identifying severe lesions. Additionally, HPV vaccination could reduce recurrence rates in patients treated for high-grade cervical intraepithelial neoplasia. Objective: Our study aimed to assess the clinical utility of E6/E7 mRNA determination in the follow-up of HPV-immunized patients who were treated for HSIL/CIN. Methods: We conducted a retrospective observational study including 407 patients treated for HSIL/CIN. The recurrence rate and the validity parameters of E6/E7 mRNA testing were analyzed. Results: The recurrence rate for high-grade lesions was 1.7%. This low percentage might be related to the vaccination of patients who were not immunized before treatment. The sensitivity of the E6/E7 mRNA test was 88% at the first clinical visit, reaching 100% in the second and third reviews. Specificity was 91% at the first visit, 92% at the second, and 85% at the third. Regarding predictive values, the positive predictive value was 18% at the first visit, 10% at the second, and 14% at the third, while the negative predictive value was 100% across all follow-up visits. Conclusions: The E6/E7 mRNA test appears to be an effective tool for ruling out recurrence after treatment for HSIL/CIN lesions in HPV-immunized patients. Full article

Background: Effective triage of women testing positive for high-risk HPV DNA is essential to reduce unnecessary colposcopies while preserving cancer prevention. Cytology, the current standard, has limited specificity and reproducibility. The genotype-specific 7-type HPV E6/E7 mRNA test (PreTect HPV-Proofer’7), targeting HPV types 16, 18, 31, 33, 45, 52, and 58, detects transcriptionally active infections and may enhance risk stratification. Methods: Between 2019 and 2023, 34,721 women aged 25–69 underwent primary HPV DNA screening with the Cobas 4800 assay at the University Hospital of North Norway, within the national screening program. Of these, 1896 HPV DNA-positive women were triaged with liquid-based cytology with atypical squamous cells of undetermined significance or worse (≥ASC-US) and the 7-type HPV mRNA test. Histological outcomes were followed through October 2024. Diagnostic performance for CIN2+ was evaluated overall and by genotype. Results: CIN2+ prevalence was 13.3%. The mRNA test reduced test positivity from 50.3% to 33.4% while maintaining comparable sensitivity (70.6% vs. 72.2%) and improving specificity (72.3% vs. 53.0%) and PPV (28.1% vs. 19.1%). Genotype-specific PPVs were highest for HPV16 mRNA (47.7%), followed by HPV33 (39.2%) and HPV31 (32.2%), all exceeding corresponding DNA-based estimates. Conclusion: Genotype-specific HPV mRNA triage offers superior risk discrimination compared to cytology, supporting more targeted, efficient, and accessible cervical cancer screening. Full article

Persistent high-risk human papillomavirus (HR-HPV) infection is closely associated with the development of cervical intraepithelial neoplasia (CIN) and cervical cancer. In recent years, the potential impact of viral co-infections on this process has also been investigated. This study investigated the presence of HR-HPV, HSV-1/2, and HHV-8 DNA in formalin-fixed paraffin-embedded (FFPE) cervical biopsy samples, as well as their association with lesion severity. A total of 276 FFPE cervical tissue samples were evaluated. Viral DNA was detected by real-time PCR. The samples were histopathologically classified as normal/non-dysplastic, low-grade (LSIL), and high-grade (HSIL) lesions. HR-HPV DNA was detected in 112 samples (40.6%), with the highest prevalence observed in the 30–39 age group (51.2%). Among the HPV-positive cases, 46.5% (52/112) had single-type infections, 32.1% (36/112) had multiple-type infections, and 21.4% (24/112) were untypable. Together, these categories accounted for all HPV-positive samples. The most common genotype was HPV-16 (16.7%). HHV-8 and HSV-2 DNA were not detected. HSV-1 DNA was detected in only three non-dysplastic, HPV-negative cervical samples. In conclusion, HR-HPV DNA was detected in 40.6% of cervical biopsy samples and showed a significant association with increasing histological severity, highlighting its critical role in the progression of cervical lesions. Although the absence of HHV-8 and HSV-2 suggests a limited contribution of these viruses to cervical disease, the use of a single real-time PCR assay limits the ability to draw generalized conclusions regarding their clinical relevance. Further large-scale, multicenter studies employing both tissue-based and serological approaches are needed to validate these findings and to better understand the dynamics of viral co-infections in cervical disease. Full article

In postmenopausal women with high-grade cervical intraepithelial neoplasia (CIN3), hysterectomy is frequently performed after loop electrosurgical excision procedure (LEEP) due to the concern for residual disease or occult carcinoma. However, the decision to proceed with hysterectomy is often made without validated predictive criteria, increasing the risk of overtreatment or underdiagnosis. The aim of this study is to identify independent predictors of residual CIN2+ (CIN2, CIN3, adenocarcinoma in situ, invasive carcinoma) or invasive disease in hysterectomy specimens following LEEP in this high-risk population. Methods: We conducted a multicenter retrospective study including 154 postmenopausal women (aged 50–75) who underwent total hysterectomy within 12 months after LEEP for histologically confirmed CIN3. Data collected included human papillomavirus (HPV) genotyping (pre- and post-LEEP), endocervical curettage (ECC), cone margin status, transformation zone type, and histopathological outcomes of the hysterectomy specimen. Logistic regression and ROC curve analysis were used to assess predictive factors. Results: Residual disease (CIN2+, AIS, or carcinoma) was found in 38 patients (24.7%), including 7 cases (4.5%) of occult carcinoma. Persistent high-risk HPV post-LEEP was the strongest independent predictor (adjusted OR for HPV 16/18: 74.0; p < 0.001), followed by positive ECC (OR: 3.64; p = 0.028). Cone margin status was not independently associated. The multivariate model showed good discriminative performance (AUC = 0.860; sensitivity 67.2%, specificity 72.8%). Conclusions: Our findings suggest that persistent high-risk HPV infection and positive ECC are reliable predictors of residual or occult disease. These markers should be integrated into post-LEEP follow-up protocols to better identify candidates for hysterectomy and minimize unnecessary surgeries. Full article

Background/Objectives: Cervical Intraepithelial Neoplasia (CIN) is a significant risk factor for the development of invasive cancer, and the histological detection of High-Grade CIN (CIN2+) during screening generally indicates the need for surgical removal of the lesion; cervical conization is the current gold standard of treatment. The recurrence risk for disease is reported to be up to 30%, based on data in the literature. Follow-up protocols mainly rely on High-Risk Human Papillomavirus (hrHPV) detection at six months post-treatment; if negative, this is considered the test of cure. This approach assumes that all patients have an equal risk of disease recurrence, regardless of individual characteristics. The objective of this study was to evaluate the individual recurrence risk using a mathematical model, analyzing the weight of various parameters and their associations in terms of recurrence development. Methods: We retrospectively examined 428 patients treated for CIN2+ at San Raffaele Hospital in Milan between January 2010 and April 2019. Clinical and pathological data were recorded and correlated with disease recurrence; three different variables, known to behave as significant prognostic factors, were analyzed: hrHPV persistence, the surgical margin status, Neutrophil–Lymphocyte Ratio (NLR), along with their relative associations. Data were used to engineer a mathematical model for the identification of different risk classes, allowing for the risk stratification of cases. Results: Surgical margins status, hrHPV persistence, and a high NLR index were demonstrated to act as independent and significant risk factors for disease recurrence, and their different associations significantly correlated with different recurrence rates. The mathematical model identified eight classes of recurrence probability, with Odds Ratios (ORs) ranging from 7.48% to 69.4%. Conclusions: The developed mathematical model may allow risk stratification for recurrence in a hierarchical fashion, potentially supporting the tailored management of follow-up, and improving the current protocols. This study represents the first attempt to integrate these factors into a mathematical model for post-treatment risk stratification. Full article

Objectives: To evaluate the prognostic value of systemic inflammatory response (SIR) parameters in predicting the recurrence of cervical intraepithelial neoplasia (CIN2+) in women undergoing a loop electrosurgical excision procedure (LEEP). Methods: This retrospective study included women aged ≥18 years who underwent an LEEP at a tertiary center between 2013 and 2023. Patients who were pregnant and those who had malignancies, immune disorders, or prior cervical surgery were excluded. The data collected included age, parity, cervical cytology, HPV DNA status, histology, LEEP specimen size, and preoperative blood count parameters. Follow-up was performed every six months using cytology, colposcopy, and histology to assess recurrence. The SIR markers evaluated included the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), and lymphocyte count. Statistical analyses included ROC curves and Cox regression. Results: Of the 1068 patients included, 726 had follow-up data, and 32 (4.4%) experienced a recurrence after a mean interval of 24 ± 20 months. Recurrence-negative patients had higher median lymphocyte counts (2.40 vs. 2.15, p = 0.031) and LMRs (4.57 vs. 3.86, p = 0.011). The disease-free survival period was longer in patients with high lymphocyte counts, a low NLR and PLR, and a high LMR. However, the discriminatory power of these markers was limited. In the multivariate analysis, only a PLR > 118.4 remained independently associated with an increased recurrence risk (HR 3.06, p = 0.011). Due to the small number of cases of recurrences and the small amount of HPV DNA results, the findings should be interpreted with caution. Conclusions: Preoperative SIR markers such as the PLR, NLR, LMR, and lymphocyte count showed statistical associations with CIN2+ recurrence after an LEEP, but their clinical utility appears to be limited. Further prospective studies are needed to validate these findings. Full article

Cervical intraepithelial neoplasia (CIN) is caused by human papillomavirus (HPV); however, factors such as HPV genotype and individual immune response may also contribute to its development. The loop electrosurgical excision procedure (LEEP) is a treatment for high-grade cervical intraepithelial neoplasia (CIN), as approximately 30% of these cases may progress to cancer. However, 20–40% of cases will regress spontaneously. HPV16 infection constitutes the highest risk for progression to cervical cancer and a lower probability of regression. Knowledge regarding the regression of lesions caused by other high-risk genotypes alone or in association with biomarker expression and lesion length has been limited. In the present study, the regression rates of high-grade squamous intraepithelial lesions were calculated. Twenty-one percent of the 161 women diagnosed with CIN2-3 on colposcopy-directed biopsies exhibited regression (defined as CIN1 or less) in the subsequent cone excisions. The mean interval between biopsy and treatment was 113 days (range of 71–171). High-grade lesions of the squamous epithelium caused by HPV16, together with lesions caused by HPV31, 52 and 58, showed significantly lower regression rates (HR 0.54, 0.22–0.75; low-regression group) than lesions caused by HPV18, 33, 35, 39, and 45 (HR 2.85, 1.54–5.28; high-regression group). A multivariate analysis of HPV genotypes, epithelial expressions of pRb and p53, immune cell proportions in the stroma (CD4/CD25 and CD4/CD8), and lesion lengths correctly predicted regression in 78% (Harrell’s C). A Harrell’s C value of 82% for the low-regression group indicates that different HPV genotypes or groups, together with divergent patterns of tumor suppressors, immune cells, and lesion size, can give prognostic information regarding the outcome of CIN2-3. Full article

Background/Objectives: Cervical cancer (CC) is a significant global health challenge, particularly in low- and middle-income countries (LMICs), where limited access to human papillomavirus (HPV) vaccination and effective CC screening results in a majority of cases and fatalities among women. Moreover, existing vaccines do not target HPV-independent cancers. Current screening methods are expensive and time-consuming, with a limited emphasis on CC protein biomarkers. Therefore, we aimed to validate critical markers that allow the development of affordable point-of-care screening tests for resource-limited settings. Methods: This study first optimized a cell lysis and protein extraction protocol for CC cell lines and clinical cervical swabs. Subsequently, four proteins—topoisomerase II alpha (TOP2A), minichromosome maintenance complex component 2 (MCM2), valosin-containing protein (VCP), and cyclin-dependent kinase inhibitor 2A (p16INK4a)—were quantified in the resulting lysates using enzyme-linked immunosorbent assays, as well as in cervical tumors and squamous intraepithelial lesions (SILs) using immunohistochemistry for further validation. Results: Acetone precipitation allowed for efficient cell isolation, and radioimmunoprecipitation assay buffer yielded the highest protein recovery. VCP and p16INK4a were overexpressed across all cancer cell lines compared to primary cells. All four biomarkers were overexpressed in high-grade SIL (HSIL) swab specimens and tumor samples, including CC subtypes, G1–G3 tumor grades, and HSILs. Lastly, we showed that the proteins could accurately classify swabs and tissue specimens into clinically relevant groups. Conclusions: The quantitative analysis of these biomarkers, along with the subsequent sensitive and specific clinical classification, highlights their potential application in SIL early detection and CC prevention, particularly in LMICs. Full article

Cervical cancer ranks third among malignant diseases of the female reproductive system and progressively develops through a series of pathological changes known as cervical intraepithelial neoplasia (CIN). Despite being extremely aggressive and causing increased mortality, the main treatment options include surgery or a combination of chemotherapy and radiotherapy, often based on cisplatin-based chemotherapy and external beam radiotherapy or brachytherapy. Cervical dysplasia is an abnormal growth of cells on the surface of the cervix that could lead to cervical cancer. CIN most commonly occurs at the squamocolumnar junction of the cervix, a transitional zone between the squamous epithelium of the vagina and the columnar epithelium of the endocervix. The primary cause of CIN is chronic infection of the cervix with Human Papillomavirus (HPV). Oxidative stress (OS) and chronic inflammation are associated with HPV-induced cervical dysplasia. Reactive oxygen species (ROS) facilitate the progression of CIN through DNA damage, immune evasion, and cellular mutations. Thus, the inflammatory environment, characterized by increased expression of proinflammatory cytokines, contributes to epithelial transformation. Given these mechanisms, antioxidants, including vitamins A, C, D, E, polyphenols, and carotenoids, are being investigated for their potential as adjunctive therapies in CIN management. This review aims to provide a comprehensive analysis of the influence of oxidative stress, antioxidants, and inflammation on cervical cancer. Full article

Background/Objectives: Molecular triage strategies for cervical lesions based on miR-124-2 and FAM19A4 are poorly studied in various populations. The aim of this prospective study was to evaluate the individual and combined predictive performance of these two markers for the prediction of various histological categories of cervical lesions. Methods: An FAM19A4 and miR124-2 methylation analysis was performed on 70 samples from patients negative for intraepithelial lesion or malignancy (NILM), cervical intraepithelial neoplasia (CIN)1-3 and squamous cervical carcinoma (SCC), along with human papillomavirus (HPV) genotyping and cytological and histopathological assessment. Descriptive statistics examined clinical associations, while sensitivity analysis evaluated the predictive performance of these markers individually and combined. Results: The sensitivity of miR-124-2 was 28.1%, while its specificity was 86.8% for SCC. The ROC values ranged between 0.25 and 0.62 for the evaluated histological categories, suggesting a poor to moderate predictive performance. FAM19A4 had a sensitivity of 36% for predicting CIN3 and SCC, as well as a high specificity for CIN3 and SCC (88.9%), with ROC values between 0.35 and 0.73 for the evaluated histological categories. The combined tests improved the PPV for higher-risk lesions (CIN3, SCC), but did not significantly improve the ROC values. FAM19A4 achieved the best performance for the prediction of CIN2+ (ROC: 0.64) and CIN3+ lesions (ROC: 0.73). Conclusions: We hypothesize that while not suitable as stand-alone diagnostic tools, such biomarkers may aid in stratifying patients and optimizing referral decisions, pending further validation in larger, population-based cohorts. Full article

Human papillomavirus (HPV) infection is a major risk factor for cervical cancer, demanding improved diagnostic strategies to distinguish between transient infections and those requiring intervention. Background: This systematic review and meta-analysis evaluated the diagnostic accuracy of HPV L1 immunocytochemistry (ICC) in detecting high-grade cervical intraepithelial neoplasia (CIN2+). Methods: We systematically analyzed data from 15 studies (PROSPERO 2022 CRD42022375916) comprising 3804 cervical smears with varying cytological findings (NILM to ≥ASC-US). Results: The pooled sensitivity for detecting CIN2+ was 80.7% (95% CI: 76.2–84.4%); however, substantial heterogeneity was present (I² = 65.97%, p < 0.001). Similarly, the pooled specificity was 56.9% (95% CI: 49.6–64%), with even higher heterogeneity (I² = 90.46%, p < 0.001). This considerable heterogeneity, which may be attributable to methodological variations or regional differences in HPV prevalence and genotyping, limits the generalizability of these findings. Furthermore, the moderate specificity suggests a high rate of false positives, limiting the clinical utility of HPV L1 ICC as a standalone diagnostic test. Conclusions: In conclusion, although HPV L1 ICC exhibits acceptable sensitivity for detecting CIN2+, its limitations, including low specificity and substantial heterogeneity, necessitate its use as an adjunct to other established diagnostic methods, alongside further research to enhance its diagnostic performance, and necessitate its use as a supplementary test alongside established diagnostic methods, pending further research to refine its clinical utility. Full article

To investigate the changes of ERα and PRs in the epithelium and stroma of normal and neoplastic uterine cervix. Two pathologists independently scored the expression levels of ERα, PR(A+B), and PRB in the stroma and epithelium of normal, cervical intraepithelial neoplasia grade 2 and 3 (CIN2/3), carcinoma in situ (CIS), and invasive cervical carcinoma (ICC) specimens. Sex hormone receptors were abundantly expressed in the stroma compared to the epithelium or carcinoma of the cervix. Stromal ERα was progressively upregulated during cervical carcinogenesis, with an immunoreactive score (IRS) of 1.3 ± 1.5, 2.1 ± 1.9, and 3.6 ± 3.3 in the CIN2/3, CIS, and ICC groups, respectively (p < 0.001). By contrast, epithelial PR(A+B) and PRB were downregulated, with IRS of 0.4 ± 0.7 and 0.5 ± 0.8, 0.1 ± 0.4 and 0.2 ± 0.6, and 0.1 ± 0.6 and 0.1 ± 0.4 in the CIN2/3, CIS, and ICC groups, respectively (p < 0.001). During the CIN2/3 transition, the coexpression relationship between ERα and PRs began to break down. Although epithelial PR(A+B) was downregulated, stromal PR(A+B) and PRB were upregulated with IRS of 2.0 ± 2.0 and 2.0 ± 1.9 as well as 2.1 ± 2.3 and 3.2 ± 3.2 in the CIS (p = 0.009) and ICC groups (p < 0.001), respectively. After complete transformation, the stromal PRB was significantly upregulated, and its loss was related to more distant metastasis and poorer prognosis. The results of this study highlight the carcinogenic role of stromal ERα, the tumor suppressor role of epithelial PRs, and the importance of stromal PRB in the development of cervical cancer; they can be used as a basis for developing prevention and treatment strategies for this disease. Full article

Background: HPV vaccination reduces the risk of anogenital warts, high-grade cervical intraepithelial neoplasia (CIN2+), and cervical cancer. To enhance immunogenicity, HPV vaccines include adjuvants such as toll-like receptor agonists, which may theoretically trigger autoimmune responses. However, existing data on this risk remain conflicting. This systematic review and meta-analysis assess the association between HPV vaccination and autoimmune disease onset in post-licensure controlled studies. Methods: A comprehensive literature search was conducted in Scopus, PubMed/MEDLINE, ScienceDirect, and the Cochrane Library from inception to June 2024, following PRISMA guidelines. The study protocol was registered in PROSPERO (CRD42024606834). Results: A total of 356 studies were identified, including cross-reference reviews. Fourteen met inclusion criteria for qualitative and quantitative analysis, encompassing 8,088,838 patients, of whom 2,041,865 received the HPV vaccine. Conclusions: This meta-analysis found no significant association between HPV vaccination and autoimmune disease development. However, further large-scale observational studies are needed, particularly among male recipients, as current evidence is predominantly based on female populations. Future research should also evaluate risks for specific autoimmune disorders to refine the vaccine’s safety profile. Full article

Background/Objectives: Up to 30% of cervical dysplastic lesions are missed by colposcopy alone. We performed a comparative evaluation of the diagnostic capacity for identifying cervical dysplastic lesions between shear wave elastography (SWE) of the endocervix and exocervix, defined as SonoElastoColposcopy (SEC), and colposcopy. Methods: A prospective observational study was conducted in 84 patients indicated for cervical conization surgery (presence of cervical intraepithelial neoplasia 2 or 3 (CIN-2 or 3), adenocarcinoma in situ (AIS), or high-grade suspicious lesions). All patients underwent colposcopy with lesion identification and biopsy, and SEC and SWE evaluation of the endocervix and exocervix with measurement of lesion stiffness (KPa). Cervical lesions identified by colposcopy or SEC were localized in quadrants, and a comparative evaluation of the diagnostic capacity of both techniques was performed in relation to the anatomical pathology of the cone biopsy. Results: A total of 82 women were evaluated (two cases were lost). The mean age was 38.84 ± 8.44 years. Colposcopy was adequate in 95.12% of cases. In SEC, we observed an elasticity in the lesion area of 105.42 ± 36.32 KPa compared to 19.98 ± 9.29 KPa (p < 0.0001) in the healthy area of the exocervix. In the endocervix, the results were 109.8 ± 40.86 KPa versus 18.5 ± 9.07 KPa (p < 0.0001), respectively. The concordance for colposcopy was 0.456 compared to 0.815 (p < 0.05) for SEC. Conclusions: SEC demonstrates a better ability to identify the area of cervical dysplastic lesions than colposcopy. Full article