Search Results (183)

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: Vaginal intraepithelial neoplasia (VaIN) is a rare but potentially precancerous condition strongly associated with human papillomavirus (HPV) infection. Despite increased detection rates due to HPV screening and colposcopy, diagnosis and management remain challenging. This study aimed to evaluate the epidemiological characteristics, risk factors, and outcomes of VaIN in patients referred to a tertiary academic center. Methods: We conducted a retrospective analysis of 48 patients who underwent colposcopy-directed vaginal biopsies between January 2019 and June 2024 at the Medical University of Warsaw. Data collected included patient demographics, HPV status, cytology, histopathology, and treatment outcomes. Patients were grouped based on the presence and grade of VaIN (VaIN 1 vs. VaIN 2/3). Statistical analyses were performed using SPSS software. Results: VaIN was diagnosed in 24 patients (50%), VaIN was confirmed in half of the cohort, VaIN 2 in 30%, and VaIN 3 in 18% of cases. HPV infection and prior cervical pathology were significantly associated with VaIN diagnosis (P = 0.03 and P = 0.05, respectively), and high-risk HPV infection correlated with higher-grade lesions (P = 0.04). Among VaIN 2+ cases, most patients required laser ablation or surgical excision, while VaIN 1 often regressed spontaneously. Regression occurred in 11 cases, and high-risk HPV infection was inversely associated with spontaneous regression (P = 0.04). Conclusions: This study confirms the central role of HPV, particularly high-risk subtypes, in VaIN pathogenesis. Conservative management may be appropriate for VaIN 1, while VaIN 2+ requires active intervention. HPV genotyping should be integrated into diagnostic workups, and long-term follow-up is essential due to the risks of persistence and recurrence. Full article

Human papillomavirus 18 (HPV18) is the second most oncogenic high-risk HPV genotype, after HPV16, and is responsible for about 15% of cervical cancer cases worldwide. The integration of high-risk HPV DNA into the host genome leads to the disruption of the E1 and/or E2 genes, which is considered a risk factor for viral-induced carcinogenesis. This study examined the disruption events of HPV18 E1 and E2 genes in precancerous cervical lesions to investigate the rates and sites of gene disruption in the Greek population. The complete E1 and E2 genes were amplified using three and four overlapping primer sets, respectively. Extensive analysis revealed that the disruption/deletion events of the E1 and E2 genes were detected in all grades of cytology-determined lesions, with high frequency. E2 gene disruption was significantly related to LSIL+ cases (Fisher’s exact test, p = 0.022). No significant association was found in the analysis of the E1 gene. Additionally, no preferential sites of E1/E2 gene disruption were detected. This is the first study to provide evidence of disruption events of the HPV18 E1 gene. The data from the current analysis suggest that disruption of the E2 gene could be a significant marker for the progression of cytology-determined cervical dysplasia. However, future studies are required to evaluate whether different geographic populations have particular profiles regarding the rates and sites of gene disruption to further determine population-specific biomarkers. Full article

Background/Objectives: Cervical cancer remains a significant global health issue, with high incidence and mortality rates, particularly in Eastern Europe. Despite the availability of vaccines against human papillomavirus (HPV), regular screening remains crucial for prevention. Testing for HPV, alone or combined with cytology, has become an alternative to traditional methods. However, since many HPV infections are transient, additional tests are needed to identify high-risk cases. Methods: This study aims to generate detailed statistical data specific to the Bulgarian population, reinforcing the necessity of incorporating updated European methodologies and algorithms for the prophylaxis and prevention of cervical carcinoma. Results: By evaluating epidemiological trends, risk factors, and the effectiveness of current preventive measures, this research seeks to provide a strong foundation for enhancing cervical cancer screening and early detection programs. This method improves triage by identifying women who require further evaluation, ensuring timely referrals for colposcopy or biopsy. Conclusions: While liquid-based cytology (LBC) and HPV genotyping improve detection, the introduction of p16/Ki-67 dual staining has enhanced risk stratification, offering higher sensitivity and specificity for detecting high-grade lesions. These advancements are improving cervical cancer screening and patient outcomes. 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

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

Background: Cervical cancer continues to pose a significant global health challenge, particularly in low-resource regions with limited access to advanced diagnostics. Cervical conization can occasionally uncover invasive carcinoma in patients initially suspected of having only pre-invasive lesions. This study assessed the platelet-to-lymphocyte ratio (PLR) as a potential predictive biomarker for identifying invasive disease in patients undergoing a loop electrosurgical excision procedure (LEEP). Methods: A retrospective study was conducted on 371 patients who underwent LEEP conization for cervical dysplasia. Preoperative PLR values were collected and compared across final histopathological categories (negative, low-grade, high-grade, invasive carcinoma) using the Kruskal–Wallis test, followed by Mann–Whitney U tests for pairwise comparisons. Receiver operating characteristic (ROC) analysis was used to evaluate diagnostic accuracy. Results: PLR values above 7.7 were significantly associated with HPV positivity, increasing with histopathological severity. There were significant PLR differences across the outcome groups (p = 0.005), with notably higher values in cases of invasive carcinoma (p < 0.01). ROC analysis showed moderate diagnostic utility (AUC ≈ 0.72); at a PLR cutoff of ~11.9, sensitivity was 65% and specificity 81%. Conclusions: The PLR cutoff of 7.7 was associated with HPV positivity, while a higher cutoff of 11.93 was identified for predicting invasive cervical cancer. These findings support that preoperative PLR is a non-invasive, clinically relevant marker correlated with lesion severity, offering potential for preoperative risk stratification, particularly where advanced diagnostics are limited. Full article

Background/Objectives: Since 2020, Germany has replaced its annual cytological screening for cervical cancer in women aged 35 and older with a combination screening program. This updated protocol, conducted every three years, includes both a cervical Pap smear and an HPV (human papillomavirus) test. In addition, the 2020 update of the German Cervical Cancer Screening Program mandates a more timely follow-up for certain abnormal findings compared to the previous approach. Methods: Results of cytologic, colposcopic, and histologic examinations between 2018 and 2021 were retrospectively retrieved from the electronic patient records of the Institute of Pathology Saarbrücken Rastpfuhl in order to present relevant findings within the years 2018–2019 and 2020–2021. The present study included all women who received appropriate follow-up based on the corresponding underlying screening modality. Results: Our reporting considered data from 30,715 women in 2018/19 (prior screening modality group) and 25,924 women in 2020/21 (updated screening modality group). In 2018/19, a total of 93 histological examinations were performed, compared to 237 in 2020/21. In 2018/19, 52 cases of CIN III and 12 cases of CIN II were identified, while in 2020/21, 78 cases of CIN III and 31 cases of CIN II were detected. In contrast, while women with negative cytological findings in 2018/19 were typically not referred for further colposcopic or histological evaluation, the updated program enabled earlier detection and treatment of cases with diagnosed high-grade dysplasia based solely on a positive HPV test. Notably, 31 women who were diagnosed at an earlier stage based solely on a positive HPV test initially presented with a cytological Pap I result (negative for intraepithelial lesion or malignancy; NILM). Conclusions: Additional HPV co-testing within the updated German cervical cancer screening program resulted not only in high rates of high-grade dysplasia detection but also a rise in the number of colposcopic procedures. While negative follow-up HPV findings regularly showed remission of the original finding, incidence of high-grade dysplasia was usually linked to a positive HPV test. Full article

Background/Objectives: Understanding the regional distribution of human papillomavirus (HPV) genotypes is essential for guiding effective vaccination and screening strategies. This study aimed to assess the prevalence and distribution of HPV genotypes among unvaccinated women aged 30 years and older undergoing routine screening in Ankara. It also aimed to compare the frequencies of genotypes included and not included in current vaccines and to investigate their association with cervical smear cytology. Methods: This descriptive, cross-sectional, single-center study was conducted at Ankara Etlik City Hospital between 15 November 2024 and 15 February 2025. A total of 500 sexually active, unvaccinated women aged 30 years or older were enrolled. Cervical swab samples were analyzed for HPV DNA and genotypes using real-time PCR (28-type panel), and cytology results were retrospectively obtained from medical records. Results: HPV infection was detected in 18.2% of participants. Among HPV-positive women, 71.4% had single-type and 28.6% had multiple-type infections. The most common high-risk genotypes among HPV-positive individuals were HPV 16 (13.2%), HPV 18 (13.2%), and HPV 59 (13.2%). While 35.2% of HPV-positive cases included genotypes covered by the nonavalent vaccine, 64.8% involved at least one genotype not covered, mainly HPV 59, 44, and 51. HPV was detected in 17% of individuals with normal cytology, 19% of those with atypical squamous cells of undetermined significance (ASC-US), and 100% of cases with low-grade squamous intraepithelial lesion (LSIL) (p < 0.001). Conclusions: The findings emphasize the persistence of high-risk and non-vaccine-covered HPV types in the population, highlighting the need for updated vaccination policies and the development of broader-spectrum vaccines aligned with local genotype profiles. Full article

The aberrant DNA methylation of tumour suppressor genes, including CADM1, MAL, and PAX1, is implicated in cervical carcinogenesis. Objectives: This pilot study aimed to evaluate the methylation levels of these genes in HPV-positive women and assess their diagnostic performance for detecting histologic high-grade squamous intraepithelial lesions (HSILs) and carcinoma. Methods: Cervical samples from 73 HPV-positive women were analyzed using droplet digital PCR (ddPCR) to quantify methylation levels of CADM1, MAL, and PAX1. The methylation levels were further compared across cytological and histological classifications. A control group of 26 HPV-negative women with negative cytology was also included. The diagnostic performance was assessed through receiver operating characteristic (ROC) analysis, as well as sensitivity and specificity calculations for individual genes and gene panels. Results: MAL methylation was absent in NILM, LSIL, and HSIL samples but was significantly elevated in carcinoma. PAX1 methylation was observed in both high-grade and some low-grade lesions. CADM1 methylation remained low or undetectable in the NILM, LSIL, and HSIL groups, with a significant increase observed in carcinoma cases. The CADM1/MAL panel demonstrated the highest diagnostic accuracy, with an area under the curve (AUC) of 0.912, 70% sensitivity, and 100% specificity. ddPCR exhibited superior analytical sensitivity compared to real-time PCR. Conclusions: The CADM1/MAL methylation panel, assessed by ddPCR, may serve as a specific biomarker for the triage of HPV-positive women at risk of HSIL and carcinoma. However, this study’s limited sample size and single-centre design necessitate cautious interpretation. Further validation in larger, population-based cohorts is necessary to confirm its clinical utility. Full article

Background: Cervical dysplasia is a pre-malignant condition of the uterine cervix and is highly prevalent in Sub-Saharan Africa; especially affecting HIV-infected Black women. The anti-dysplastic effect of vitamin D hormones in cervical dysplasia is poorly understood. Therefore, we conducted a cross-sectional case–control observational study to assess the relationship between serum 25-hydroxycholecalciferol (25(OH)D) and cervical dysplasia, amongst Black women with and without HIV infection. Methods: The study participants attended a gynaecologic oncology clinic at an academic hospital in Pretoria, South Africa (n = 109). Patient clinical data were obtained during consultation. Cervical dysplasia was identified by cytology (PAP smear) which classified the case group as high-grade squamous epithelial lesions (HSILs), and the control group as <HSIL. Serum biochemistry measured 25(OH)D and its covariate biochemical variables. The data were statistically modelled to adjust for clinical and biochemical covariates, identify a significant relationship (p ≤ 0.05) between 25(OH)D and cervical dysplasia, and analyse subgroup interaction between HIV status and cervical dysplasia. Results: The data showed high levels of vitamin D insufficiency and deficiency in Black women with and without HIV infection. After covariate adjustment, 25(OH)D demonstrated an inverse relationship with HSIL in HIV-uninfected Black women. Furthermore, an interaction effect between women with and without HIV infection was observed. Conclusions: The role of 25(OH)D in the primary prevention of cervical dysplasia in Black women without HIV infection is promising, and dosing strategies require investigation. Also, future studies exploring the immunomodulatory role of 25(OH)D in cervical dysplasia in HIV-infected women is warranted. 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

The incidence of malignancies diagnosed during pregnancy is estimated at 1 in 1000 pregnancies, with cervical cancer being the most common gynecological malignancy in this population. The increasing maternal age and widespread use of prenatal screening contribute to the rising detection rates. Early symptoms of cervical cancer, such as vaginal bleeding or discharge, often mimic normal pregnancy changes, leading to potential delays in diagnosis. Cervical dysplasia, a known precursor of cervical cancer, is closely associated with high-risk HPV infection, which affects approximately 25% of women of reproductive age. Screening using cytology and HPV testing is considered safe and effective during pregnancy in early detection. Colposcopy remains the gold standard in further diagnostics, with targeted biopsy indicated in selected cases. In cases of high-grade lesions (CIN II/III), conservative management is often preferred, as more than 60% of lesions regress postpartum. Invasive cervical cancer diagnosed during pregnancy is rare, with an estimated incidence of 1.4–4.6 per 100,000 pregnancies. Management decisions depend on gestational age, cancer stage, and the patient’s reproductive preference. Chemotherapy can be administered after the first trimester with acceptable maternal and fetal safety profiles. This review presents current evidence on screening, diagnostic pathways, and treatment strategies. It emphasizes the importance of individualized care, multidisciplinary collaboration, and shared decision-making to optimize outcomes for both mother and fetus. 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 screening is crucial for early detection and prevention. In Japan, women with negative intraepithelial lesion or malignancy (NILM) and high-risk human papillomavirus (HR-HPV) positivity are recommended retest for 12 months, rather than immediate colposcopy. International guidelines differ, and often prioritize early colposcopy for persistent HPV16/18 infections. This study evaluates Japan’s current screening approach, and identifies areas for improvement. A retrospective cohort study analyzed cervical cancer screening data from Saga Prefecture (2019–2021), assessing follow-up adherence, colposcopy referral rates, and CIN2+ and CIN3+ detection among NILM/HR-HPV+ cases. Among 27,789 individuals screened, 2248 (8.1%) were NILM/HR-HPV+. Follow-up adherence after 12 months was 54.4%. Of these, 132 with cytological abnormalities underwent colposcopy, revealing CIN2+ in 27.3% of cases. Additionally, 561 women with persistent NILM/HR-HPV+ underwent colposcopy, with CIN2+ in 7.6% and CIN3+ in 3.9% of cases. Japan’s current NILM/HR-HPV+ management strategy could delay the detection of high-grade cervical lesions. International guidelines favor earlier colposcopy referrals, particularly for HPV16/18+ cases. To improve cervical cancer prevention, Japan should consider a risk-based stratification model, enhance follow-up adherence, expand colposcopy access, and develop a national patient tracking system. Adopting primary HPV-based screening could attain the best global practices, facilitating earlier detection and reducing cervical cancer. Full article