Cervical cancer in Malaysia.

Cervical cancer is preventable due to effective screening to detect pre-malignant lesion, and vaccination against its causative organism namely human papillomavirus (HPV). This review article described current situation of cervical cancer in Malaysia. There is decreasing cervical cancer incidence in the country, with age-standardized rate of 10.3, versus 14.1 and 7.5 per 100 000 for worldwide and high-income countries, respectively. School-based HPV vaccination is part of national immunization since 2010, with yearly coverage rate of 83%-91%. The figure declined during coronavirus disease-19 pandemic due to scarce vaccine supply and movement-control order, resulting in about 500 000 students missing their course, with catch-up program currently onboard. Opportunistic cervical screening program started in 1960s with cervical smear cytology, which is succeeded by HPV DNA screening since 2020. Cervical cytology remains indispensable  screening method in healthcare facility without access to HPV test kit, and used to triage high-risk HPV positive with abnormal cytology that require urgent colposcopy. Computed tomography is the main imaging modality to assess local and distal extent of cervical cancer. Primary surgical treatment for early-stage cancer is performed by trained gynecologic oncologist, with long waiting list for radiation therapy in locally advanced disease due to limited available public facility. There is restricted access to targeted therapy due to high treatment cost. In conclusion, Malaysia is heading toward cervical cancer elimination through rigorous investment in primary and secondary prevention, and increase in public engagement with the support of government policy enforcement.

Telomere Length, Telomerase Activity, and Vaginal Microbiome in Patients with HPV-Related Precancerous Lesions.

Persistent high-risk human papillomaviruses (HR HPVs) infection leads to the development of squamous intraepithelial lesions in cervical cells that may lead to cancer. The telomere length, telomerase activity, and species composition of the vaginal microbiome may influence the dynamic of changes and the process of carcinogenesis. In the present study, we analyze relative telomere length (RTL), relative hTERT expression (gene for the telomerase component-reverse transcriptase) in cervical smear cells and vaginal microbiomes. Total RNA and DNA were isolated from tissue samples of 109 patients from the following groups: control, carrier, low-grade or high-grade squamous intraepithelial lesion (L SIL and H SIL, respectively), and cancer. The quantitative PCR method was used to measure telomere length and telomerase expression. Vaginal microbiome bacteria were divided into community state types using morphotype criteria. Significant differences between histopathology groups were confirmed for both relative telomere length and relative hTERT expression (p < 0.001 and p = 0.001, respectively). A significant difference in RTL was identified between carriers and H SIL (p adj < 0.001) groups, as well as between carriers and L SIL groups (p adj = 0.048). In both cases, RTL was lower among carriers. The highest relative hTERT expression level was recorded in the H SIL group, and the highest relative hTERT expression level was recorded between carriers and the H SIL group (p adj < 0.001). A correlation between genotype and biocenosis was identified for genotype 16+A (p < 0.001). The results suggest that identification of HPV infection, telomere length assessment, and hTERT expression measurement together may be more predictive than each of these analyses performed separately.

Benefit and burden in the Dutch cytology-based vs high-risk human papillomavirus-based cervical cancer screening program.

BACKGROUND: In 2017, the Dutch cervical cancer screening program had replaced the primary cytology-based screening with primary high-risk human papillomavirus-based screening, including the opportunity to participate through self-sampling. Evaluation and balancing benefit (detection of high-grade cervical intraepithelial neoplasia) and burden of screening (unnecessary referrals, invasive diagnostics, and overtreatment) is needed. OBJECTIVE: This study aimed to compare the referral rates, detection of high-grade cervical intraepithelial neoplasia, overdiagnosis, and overtreatment in the new high-risk human papillomavirus-based screening program, including physician-sampled and self-sampled material, with the previous cytology-based screening program in the Netherlands. STUDY DESIGN: A retrospective cohort study was conducted within the Dutch population-based cervical cancer screening program. Screenees with referrals for colposcopy between 2014 and 2015 (cytology-based screening) and 2017 and 2018 (high-risk human papillomavirus-based screening) were included. Data were retrieved from the Dutch Pathology Registry (PALGA) and compared between the 2 screening programs. The main outcome measures were referral rate, detection of high-grade cervical intraepithelial neoplasia or worse, overdiagnosis (cervical intraepithelial neoplasia grade 1 or less in the histologic specimen), and overtreatment (cervical intraepithelial neoplasia grade 1 or less in the treatment specimen). RESULTS: Of the women included in the study, 19,109 received cytology-based screening, and 26,171 received high-risk human papillomavirus-based screening. Referral rates increased from 2.5% in cytology-based screening to 4.2% in high-risk human papillomavirus-based screening (+70.2%). Detection rates increased to 46.2% for cervical intraepithelial neoplasia grade 2 or worse, 32.2% for cervical intraepithelial neoplasia grade 3 or worse, and 31.0% for cervical cancer, and overdiagnosis increased to 143.4% with high-risk human papillomavirus-based screening. Overtreatment rates were similar in both screening periods. The positive predictive value of referral for detection of cervical intraepithelial neoplasia grade 2 or worse in high-risk human papillomavirus-based screening was 34.6% compared with 40.2% in cytology-based screening. Women screened through self-sampling were at higher risk of cervical intraepithelial neoplasia grade 2 or worse detection (odds ratio, 1.38; 95% confidence interval, 1.20-1.59) and receiving treatment (odds ratio, 1.31; 95% confidence interval, 1.16-1.48) than those screened through physician-sampling. CONCLUSION: Compared with cytology-based screening, high-risk human papillomavirus-based screening increases detection of high-grade cervical intraepithelial neoplasia, with 462 more cervical intraepithelial neoplasia grade 2 or worse cases per 100,000 women but at the expense of 850 more cases per 100,000 women with invasive diagnostics indicating cervical intraepithelial neoplasia grade 1 or less.

Implementation of pre-captured videos for remote diagnosis of cervical cytology specimens.

OBJECTIVE: The objective of this study was to investigate the feasibility of implementing short videos captured by static telecytological applications for remote evaluation of cervical smears prepared by means of liquid-based cytology. METHODS: The study was performed on representative short videos captured from a total of 404 cervical smears (benign, 135; atypical squamous cells of undetermined significance, 92; low-grade squamous intraepithelial lesion, 62; high-grade squamous intraepithelial lesion, 87; squamous cell carcinoma, 26; adenocarcinoma, 2) that were sent via file transfer protocol to password-protected accounts for remote review by three independent cytopathologists. In addition to diagnosis, reviewers commented on the overall digital video quality. Contributors' and reviewers' diagnoses were collected, recorded, and statistically evaluated. RESULTS: Statistical evaluation detected no significant difference in diagnostic accuracy between cytological diagnoses based on short videos versus conventional slides. The overall interobserver agreement ranged from substantial to almost perfect with κ values of 0.74-0.91. CONCLUSIONS: Short videos produced by static telecytology applications can be used as an alternative method for telecytological diagnosis of cervical smears, particularly for quality control purposes. It is a prompt and valid method for quality assessment and proficiency testing and can be integrated into the daily workflow. Short pre-captured videos of cervical smears can be used for rapid and accurate diagnosis, diminishing turnaround times and improving small cytology departments' quality indices. They can also be used for archiving, teleconsultation, and second opinion purposes, improving the performance of already existing static telecytology stations.

Possible high-grade squamous intraepithelial lesion (pHSIL) in the new cervical screening paradigm: The outcomes and the role of clinicopathological review.

BACKGROUND: A renewed National Cervical Screening Program (NCSP) was introduced in Australia in December 2017. Under the renewed NCSP, there are limited data to guide the management of discordant colposcopy and biopsy results after a liquid-based cytology (LBC) finding of 'possible high-grade squamous intraepithelial lesion' (pHSIL). AIMS: This study aims to determine the proportion of women referred with pHSIL who are found to have HSIL, identify influencing factors of women most at risk, and examine the role that cytopathology review plays in management decisions. MATERIALS AND METHODS: Two-hundred and thirty-two women presenting to a tertiary women's hospital in Australia with pHSIL since December 2017 were identified. Women with HSIL following colposcopy directed biopsy were referred for treatment. When HSIL was not identified, these patients were referred for multidisciplinary clinicopathological review. Pathological outcomes and treatment recommendations are included. MAIN OUTCOME MEASURES: The primary outcome of the study was histological confirmation of HSIL. RESULTS: Primary outcome data were available for 182 women (78.5%); 62 (34.1%) had HSIL on histology, three (1.7%) had adenocarcinoma in situ (AIS) and one (1%) had cervical squamous cell carcinoma (SCC). There was no association between age and the presence of HSIL. The presence of human papillomavirus 16 and/or 18 increased the likelihood of HSIL on histology (relative risk 1.9; 95% CI 1.27-2.80, P = 0.002). Fifty-nine (25.4%) women were referred for observation who had low-grade squamous intraepithelial lesion/no dysplasia. CONCLUSIONS: Clinicopathological review optimises management and triage of patients with pHSIL on referral cytology. Understanding outcomes in these patients informs counselling and management.

Women's attitudes and understanding of cervical cancer and the new National Cervical Screening Program.

ISSUES ADDRESSED: The new National Cervical Screening Program (NCSP) has recently been implemented. Little research is available on women's attitudes towards the program. This study aims to quantitatively assess Australian women's understanding and attitudes towards the new guidelines and their barriers to screening. METHOD: Authors designed a cross-sectional survey which was piloted and distributed as a waiting room survey to eligible women who attended a private general practice in North Queensland. RESULTS: Of the respondents, 53.8% had accurate knowledge of the new NCSP. Most participants (75.8%) believed they were not provided sufficient information about the NCSP and 60.2% wished to receive this information from their general practitioner. The screening test itself remains an issue, with embarrassment and discomfort listed as the most common barriers to screening. CONCLUSION: Many women do not have accurate knowledge of the new NCSP. Further health promotion in this area is warranted, where the general practitioner may play a key role. SO WHAT?: While the new NCSP will lead to further reduction in cervical cancer mortality, it appears from the data that women did not fully understand cervical cancer and its screening. This suggests the need for further health education to women about updated screening guidelines.

Clinical practice variation and overtreatment risk in women with abnormal cervical cytology in the Netherlands: two-step versus see-and-treat approach.

BACKGROUND: Only a few small studies have compared the 2-step method (biopsy followed by treatment) with a see-and-treat (immediate treatment) approach in women both low-grade or high-grade referral cytology. The clinical practice variation in the Netherlands has not been reviewed before. OBJECTIVES: To determine overtreatment rates in the 2-step versus see-and-treat approach in women referred for colposcopy because of abnormal cytology results, and to evaluate clinical practice variation in the Netherlands. MATERIALS AND METHODS: This was a population-based retrospective cohort study including 36,581 women with a histologic result of the cervix identified from the Dutch Pathology Registry (PALGA) between 2016 and 2017. Odds ratios for overtreatment, defined primarily as cervical intraepithelial neoplasia grade 1 or less, were determined for the 2-step and see-and-treat approach in relation to age, high-risk human papillomavirus status, and referral cytology. RESULTS: Of the included women 10,713 women (29.3%) received the 2-step method; 6,851 women (18.7%) underwent see-and-treat; and 19,017 women (52.0%) received conservative management after colposcopy with histologic assessment with cytologic follow-up or another type of treatment. Despite the existence of a national guideline advising see-and-treat only in case of suspected high-grade disease in women who have completed their childbearing, there is a wide practice variation between the 2 strategies in the Netherlands, with 7.0-88.3% of the women receiving see-and-treat per laboratory. The median time between cytology and treatment was 1-2 months (range, 0-12 months) in women receiving see-and-treat and the 2-step method, respectively. A total of 4119 women (23.5%) were overtreated, with older women, high-risk human papillomavirus-negative women, and women with low-grade cytology results being more likely to be overtreated. Women with low-grade cytology results and see-and-treat were associated with a higher overtreatment rate than women receiving the 2-step method (65.0% [1414 of 2174] versus 32.1% [1161 of 3613], respectively; odds ratio, 3.34; 95% confidence interval, 2.92-3.82). However, in women with high-grade cytology results, see-and-treat was inversely associated with overtreatment (11.3% [529 of 4677] versus 14.3% [1015 of 7100], respectively; odds ratio, 0.68; 95% confidence interval, 0.58-0.81). CONCLUSION: A see-and-treat approach is justified only in women with high-grade cytology results who have completed their childbearing. There is a wide practice variation between the 2 strategies in the Netherlands, and gynecologists should adhere to the guideline to prevent overtreatment.

Cytopathological review of cervical pathology: Impact for women and follow-up results.

BACKGROUND: Cervical screening programs have had an important effect on the reduction of cervical cancer rates. Comprehensive programs require access to pathological review to improve the sensitivity of screening cytology and the specificity of diagnostic histology. AIMS: To determine the number of cases where cervical cytology or histology was amended at cytopathological review; whether amendments were 'upgrades' or 'downgrades', and how amendments aligned with follow-up results for these patients. MATERIALS AND METHODS: A retrospective cohort study was performed of all patients reviewed from January 2016 to December 2017 (n = 287 cases, from 254 patients) at colposcopy multidisciplinary meetings at Wellington Hospital, a tertiary referral hospital. Where amendments to cytology or histology were made, follow-up results were retrieved where available (85.7% and 84.2% respectively). RESULTS: Cytology or histology was amended in 24.7% of cases. Smear cytology was amended in 16.7%. Where cytology was upgraded (n = 9), 44% had subsequent results of equal or higher grade including one case of adenocarcinoma. Where cytology was downgraded (n = 19), 93.8% (81.9-100%) had follow-up studies showing equal or lower results. Cervical biopsy histology was amended in 12.2% of cases (upgraded n = 19, downgraded n = 6). Large loop excision of the transformation zone or cone biopsy histology was amended in three cases (7.9%). CONCLUSIONS: Cytopathological review appears to improve the specificity of the comprehensive cervical screening program, leading to a reduction in unnecessary treatment. Additionally, a small number of cases of malignant or premalignant disease were detected.

The Use of Static Telecytology for Quality Assessment Purposes in the Evaluation of Cervical Smears Prepared by Means of Liquid-Based Cytology.

Objective: The objective of this study was to investigate the role of telecytology as a tool with increased quality standards in the optimal evaluation of telecytological diagnoses proffered on the basis of digitized images from cervical smears prepared by means of liquid-based cytology. Materials and Methods: The study was performed on representative digital cytological images from a total of 808 cervical smears (benign, 270; atypical squamous cells of undetermined significance, 184; low-grade squamous intraepithelial lesion, 124; high-grade squamous intraepithelial lesion, 174; squamous cell carcinoma, 52; and adenocarcinoma, 4) that were transferred through file transfer protocol to password-protected accounts for remote review by three independent cytopathologists. In addition to diagnosis, reviewers also commented on overall digital image quality. Contributor's and reviewer's diagnoses were collected, recorded, and statistically evaluated. Their reports were recorded and classified. Results: Statistical evaluation of cytological diagnoses detected no significant difference in diagnostic accuracy between the diagnoses proffered on the basis of digitized images and conventional slides. The overall interobserver agreement was almost perfect with κ values of 0.79-0.97. Conclusions: Static telecytology can be used as an alternative method for the cytological diagnosis of cervical smears, particularly in quality assurance programs. It is a prompt and valid method for quality assessment and proficiency testing and can be integrated into daily workflow. Digital images of cervical smears can be used for rapid and accurate diagnosis, by diminishing turnaround times and improving small cytology departments' quality indices.

The influence of probiotics on genital high-risk human papilloma virus clearance and quality of cervical smear: a randomized placebo-controlled trial.

BACKGROUND: Probiotics has been shown to be effective in reducing vaginal colonization of pathogenic organisms. The aim of this study was to investigate the influence of probiotic strains Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 on genital high-risk human papilloma virus (HR-HPV) clearance and quality of cervical smear. METHODS: This was a randomized, double-blinded, placebo-controlled trial. Women with genital HR-HPV infection were randomized into study and control groups. A probiotic or placebo preparation was administered orally (one capsule daily) until negative HR-HPV testing. A cervical smear and HR-HPV tests were performed at the beginning of the study and every 3 months thereafter until a negative result was obtained. RESULTS: A total of 121 women with genital HR-HPV infection were enrolled (62 in the study group and 59 in the control group). There was no significant difference in HR-HPV clearance rate between the two groups (58.1% vs. 54.2%). The only factor predicting HR-HPV clearance was a lower initial viral load (HR 3.214; 95% CI: 1.398, 7.392; p = 0.006). Twenty-two women had a mildly abnormal initial cervical smear and nine had an unsatisfactory smear. At 6 months follow-up, both mildly abnormal cervical smear and unsatisfactory smear rates had decreased significantly in the study group compared to the control group (p = 0.017 and 0.027). CONCLUSIONS: The application of probiotic strains Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 did not influence genital HR-HPV clearance, but may have decreased the rates of mildly abnormal and unsatisfactory cervical smears. TRIAL REGISTRATION: Clinicaltrials.gov NCT01599416 , May, 2012. Retrospectively registered.

A Quantum Hybrid PSO Combined with Fuzzy k-NN Approach to Feature Selection and Cell Classification in Cervical Cancer Detection.

A quantum hybrid (QH) intelligent approach that blends the adaptive search capability of the quantum-behaved particle swarm optimisation (QPSO) method with the intuitionistic rationality of traditional fuzzy k-nearest neighbours (Fuzzy k-NN) algorithm (known simply as the Q-Fuzzy approach) is proposed for efficient feature selection and classification of cells in cervical smeared (CS) images. From an initial multitude of 17 features describing the geometry, colour, and texture of the CS images, the QPSO stage of our proposed technique is used to select the best subset features (i.e., global best particles) that represent a pruned down collection of seven features. Using a dataset of almost 1000 images, performance evaluation of our proposed Q-Fuzzy approach assesses the impact of our feature selection on classification accuracy by way of three experimental scenarios that are compared alongside two other approaches: the All-features (i.e., classification without prior feature selection) and another hybrid technique combining the standard PSO algorithm with the Fuzzy k-NN technique (P-Fuzzy approach). In the first and second scenarios, we further divided the assessment criteria in terms of classification accuracy based on the choice of best features and those in terms of the different categories of the cervical cells. In the third scenario, we introduced new QH hybrid techniques, i.e., QPSO combined with other supervised learning methods, and compared the classification accuracy alongside our proposed Q-Fuzzy approach. Furthermore, we employed statistical approaches to establish qualitative agreement with regards to the feature selection in the experimental scenarios 1 and 3. The synergy between the QPSO and Fuzzy k-NN in the proposed Q-Fuzzy approach improves classification accuracy as manifest in the reduction in number cell features, which is crucial for effective cervical cancer detection and diagnosis.

Prevalence and factors associated with coinfection of human papillomavirus and Chlamydia trachomatis in adolescents and young women.

BACKGROUND: Human papillomavirus and Chlamydia trachomatis share the same route of sexual transmission and possess similar risk factors, indicating that coinfection may act synergistically in the induction of epithelial cell abnormalities. OBJECTIVE: This study aimed to determine the prevalence of human papillomavirus and Chlamydia trachomatis in adolescents and young women and identify factors associated with coinfection. STUDY DESIGN: This cross-sectional study included 276 female participants, aged 15-24 years, who were sexually active. Interviews were conducted and cervical specimens were collected for cervical smears and molecular tests. All cervical specimens were tested for 27 human papillomavirus genotypes by polymerase chain reaction amplification and hybridization to a human papillomavirus linear array. Detection of Chlamydia trachomatis was performed by polymerase chain reaction using primers directed to the region encoding the cryptic plasmid. Bivariate and multivariate analyses were performed to evaluate the factors associated with coinfection with human papillomavirus and Chlamydia trachomatis. The odds ratio, the adjusted odds ratio, and the 95% confidence interval were calculated. RESULTS: The prevalence of infection by Chlamydia trachomatis and human papillomavirus was 9.1% (95% confidence interval, 5.61-12.4) and 47.1% (95% confidence interval, 41.0-53.2), respectively. The prevalence of coinfection with human papillomavirus and Chlamydia trachomatis was 5.8% (95% confidence interval, 3.3-9.2); coinfection with 1 human papillomavirus type was 3.3% (95% confidence interval, 1.5-6.1) and with multiple types was 2.5% (95% confidence interval, 1.0-5.2). The prevalence of cytological abnormalities was 12.3% (95% confidence interval, 8.6-16.79). Human papillomavirus infections of high oncogenic risk were more prevalent (85.4%). Factors independently associated with coinfection of human papillomavirus/Chlamydia trachomatis obtained by multivariate analysis were the initiation of sexual activity under 16 years of age with an an odds ratio of 4.9 (95% confidence interval, 1.0-23.63; P = .05) and cytological abnormalities with an odds ratio of 10.7 (95% confidence interval, 1.9-59.5; P = .01), which indicates there is risk for the detection of cytological abnormalities in adolescents and young women coinfected with human papillomavirus/Chlamydia trachomatis. CONCLUSION: The prevalence of coinfection among our study population was of a magnitude that warrants attention by public health services. Adolescents and young women should be monitored for Chlamydia trachomatis infection and vaccinated against human papillomavirus. The association between cytological abnormalities and coinfection with human papillomavirus and Chlamydia trachomatis indicates the potential synergistic role of these infections in carcinogenesis of the cervix.

Evidence supporting see-and-treat management of cervical intraepithelial neoplasia: a systematic review and meta-analysis.

BACKGROUND: Studies of see-and-treat management of cervical intraepithelial neoplasia (CIN) vary in their inclusion criteria, resulting in a broad range of overtreatment rates. OBJECTIVES: To determine overtreatment rates in see-and-treat management of women referred for colposcopy because of suspected CIN, in order to define circumstances supporting see-and-treat management. SEARCH STRATEGY: MEDLINE, EMBASE, and the Cochrane Library were searched from inception up to 12 May 2014. SELECTION CRITERIA: Studies of see-and-treat management in women with a reported cervical smear result, colposcopic impression, and histology result were included. DATA COLLECTION AND ANALYSIS: Methodological quality was assessed with the Newcastle-Ottawa scale. We used the inverse variance method for pooling incidences, and a random-effects model was used to account for heterogeneity between studies. Overtreatment was defined as treatment in patients with no CIN or CIN1. MAIN RESULTS: Thirteen studies (n = 4611) were included. The overall overtreatment rate in women with a high-grade cervical smear and a high-grade colposcopic impression was 11.6% (95% CI 7.8-15.3%). The overtreatment rate in women with a high-grade cervical smear and low-grade colposcopic impression was 29.3% (95% CI 16.7-41.9%), and in the case of a low-grade smear and high-grade colposcopic impression it was 46.4% (95% CI 15.7-77.1%). In women with a low-grade smear and low-grade colposcopic impression, the overtreatment rate was 72.9% (95% CI 68.1-77.7%). AUTHOR'S CONCLUSIONS: The pooled overtreatment rate in women with a high-grade smear and high-grade colposcopic impression is at least comparable with the two-step procedure, which supports the use of see-and-treat management in this subgroup of women. TWEETABLE ABSTRACT: See-and-treat management is justified in the case of a high-grade smear and a high-grade colposcopic impression.

Efficacy of modified rapid economic acetic acid-based Papanicolaou stain.

BACKGROUND: Papanicolaou (Pap) staining is used with various modifications for the staining of cervical smears. It gives a good contrast with sharp nuclear features which aid in accurate interpretation. However, it utilises ethyl alcohol, which is expensive and difficult to purchase. We have attempted to devise a rapid Pap technique which uses acetic acid instead of ethyl alcohol, and yet provides good staining for correct diagnosis. METHODS: Liquid-based cytology samples were collected from 102 patients as a part of routine screening. Two smears were prepared from each sample, which were stained with conventional as well as rapid Pap. In the rapid Pap method, the smears were fixed in methanol and dehydration was performed before and after OG6 with 0.5% acetic acid. The final dehydration was performed with methanol. Smears from both techniques were compared by two independent observers for staining quality. RESULTS: With the rapid Pap stain, nuclear staining was comparable with that of conventional Pap (P < 0.05). Cytoplasmic staining was optimal in 69.6% of cases; however, the suboptimal staining in the rest of the smears did not pose any diagnostic problem. CONCLUSION: The rapid Pap technique is a cost-effective alternative to conventional Pap which also saves time and provides good staining quality without compromising the diagnostic interpretation.

Discovery and technical validation of high-performance methylated DNA markers for the detection of cervical lesions at risk of malignant progression in low- and middle-income countries.

BACKGROUND: Cervical cancer remains a leading cause of death, particularly in developing countries. WHO screening guidelines recommend human papilloma virus (HPV) detection as a means to identify women at risk of developing cervical cancer. While HPV testing identifies those at risk, it does not specifically distinguish individuals with neoplasia. We investigated whether a quantitative molecular test that measures methylated DNA markers could identify high-risk lesions in the cervix with accuracy. RESULTS: Marker discovery was performed in TCGA-CESC Infinium Methylation 450 K Array database and verified in three other public datasets. The panel was technically validated using Quantitative Multiplex-Methylation-Specific PCR in tissue sections (N = 252) and cervical smears (N = 244) from the USA, South Africa, and Vietnam. The gene panel consisted of FMN2, EDNRB, ZNF671, TBXT, and MOS. Cervical tissue samples from all three countries showed highly significant differential methylation in squamous cell carcinoma (SCC) with a sensitivity of 100% [95% CI 74.12-100.00], and specificity of 91% [95% CI 62.26-99.53] to 96% [95% CI 79.01-99.78], and receiver operating characteristic area under the curve (ROC AUC) = 1.000 [95% CI 1.00-1.00] compared to benign cervical tissue, and cervical intraepithelial neoplasia 2/3 with sensitivity of 55% [95% CI 37.77-70.84] to 89% [95% CI 67.20-98.03], specificity of 93% [95% CI 84.07-97.38] to 96% [95% CI 79.01-99.78], and a ROC AUC ranging from 0.793 [95% CI 0.68-0.89] to 0.99 [95% CI 0.97-1.00] compared to CIN1. In cervical smears, the marker panel detected SCC with a sensitivity of 87% [95% CI 77.45-92.69], specificity 95% [95% CI 88.64-98.18], and ROC AUC = 0.925 [95% CI 0.878-0.974] compared to normal, and high-grade squamous intraepithelial lesion (HSIL) at a sensitivity of 70% (95% CI 58.11-80.44), specificity of 94% (95% CI 88.30-97.40), and ROC AUC = 0.884 (95% CI 0.822-0.945) compared to low-grade intraepithelial lesion (LSIL)/normal in an analysis of pooled data from the three countries. Similar to HPV-positive, HPV-negative cervical carcinomas were frequently hypermethylated for these markers. CONCLUSIONS: This 5-marker panel detected SCC and HSIL in cervical smears with a high level of sensitivity and specificity. Molecular tests with the ability to rapidly detect high-risk HSIL will lead to timely treatment for those in need and prevent unnecessary procedures in women with low-risk lesions throughout the world. Validation of these markers in prospectively collected cervical smear cells followed by the development of a hypermethylated marker-based cervical cancer detection test is warranted.

Detection rates and factors affecting thereof in endometrial hyperplasia, endometrial carcinoma, and cervical glandular lesions on cervical smear.

INTRODUCTION: Endometrial lesions are morphologically diverse and uncommon on cervical smears, with its detection rate and associated diagnostic categories uncharacterized. In this study, cervical smears matched to histologically proven endometrial hyperplasias and carcinomas were reviewed and compared with cervical in-situ-carcinomas/carcinomas, aiming to detail the diagnostic performance of cervical smears for upper tract and glandular lesions. METHODS: Pathology reports of cervical smears, hysterectomies, endometrial and cervical biopsies from 1995 to 2021 were retrieved. Diagnoses of cervical smears were matched to endometrial hyperplasias and carcinomas, or cervical carcinomas and reviewed. RESULTS: Totally 832 cervical smears (272 cervical carcinomas, 312 endometrial carcinomas, and 248 hyperplasias) were included. Considering all cytologic glandular diagnosis as positive, the detection rate of cervical adenocarcinoma-in-situ was the highest (64.3%), followed by cervical adenocarcinoma (63.8%), endometrial carcinoma (31.7%), and hyperplasia (with atypia-8.5%; without atypia-2.3%) (p < 0.001). Endometrial hyperplasia was most often diagnosed as atypical squamous cells of undetermined significance (ASCUS) (5.0%) or atypical glandular cells, not otherwise specified (3.6%) without indication of endometrial origin. For endometrial carcinomas, higher FIGO grading and endocervical involvement were associated with higher detection rates across all diagnostic categories (p = 0.002-0.028). High FIGO grade was associated with suspicious/favor neoplastic (C4) (31.1%vs10.3%, p < 0.001) and carcinoma (C5) (17.8% vs. 5.6%, p = 0.005) categories, but not for all glandular diagnoses combined (33.3% vs. 31.0%, p = 0.761). CONCLUSION: Detection rates for endometrial lesions are lower than cervical lesions but not insignificant. Endometrial hyperplasia should be recognized as a differential of human papilloma virus-negative ASCUS and prompt consideration of investigation of the upper genital tract.

Feasibility of implementing cytology-based cervical cancer screening national program in Lebanon: A pilot study.

OBJECTIVE: To review our national cervical cancer screening program using existing Ministry of Public Health primary healthcare centers (PHCs) and report the impact of women's knowledge, attitude, behavior, and practices on screening uptake and outcome. METHODS: A cross-sectional study on cervical cancer screening offered to sexually active Lebanese women aged 21 years and above visiting PHCs. Exclusions were history of complete hysterectomy, gynecologic cancers, and current pregnancy. Data were collected through a questionnaire and conventional cervical smear performed by trained healthcare providers and sent to one centralized cytopathology laboratory. RESULTS: Of 12 273 eligible women, 1.7% had an abnormal cervical smear test including 161 atypical squamous cells (ASC) of undetermined significance, 6 atypical glandular cells of undetermined significance, 16 low-grade squamous intraepithelial lesion (SIL), 17 ASC-cannot rule out high-grade SIL, 11 high-grade SIL, and one invasive carcinoma. Knowledge and attitudes significantly affected participation in screening; women lacking awareness had rarely undergone a cervical smear. CONCLUSION: In Lebanon, cytology-based cervical cancer screening is feasible within the PHCs. Positive screen incidence was low. Despite previous campaigns, a low level of knowledge persists, and affects women's com with the screening guidelines. Advocacy and awareness activities by key healthcare providers may help to improve participation.

Successful Preventive Treatment of Oncogenic Transforming HPV Infections in Low-Grade Cytology (ASC-US/LSIL) Patients with an Adsorptive and Antioxidant Vaginal Gel.

OBJECTIVE: This study aimed to investigate the preventive effect of a vaginal gel on p16/Ki-67-positive abnormal cytological cervical findings (ASC-US, LSIL) and hr-HPV in women. METHODS: The study included 134 women with p16/Ki-67-positive ASC-US or LSIL. Participants were selected from a randomized controlled trial that focused on women with histological diagnoses of p16-positive CIN1 lesions or CIN2. In the treatment group (TG), 57 patients applied the vaginal gel daily for three months, while 77 patients in the "watchful wait" control group (CG) received no treatment. The study's endpoints were cytological development, p16/Ki-67 and hr-HPV clearances. RESULTS: At three months, cytopathological results improved in 74% (42/57) of patients in the TG, compared with 18% (14/77) in the CG. Progression occurred in 7% (4/57) of TG patients compared with 18% (14/77) of CG patients. The p16/Ki-67 status changed statistically significantly in favor of the TG (p < 0.001), with 83% (47/57) becoming negative, compared with 18% (14/77) in the CG. The prevalence of hr-HPV decreased significantly in the TG by 51%, and by 9% in the CG (p < 0.001). CONCLUSIONS: Topical application of the gel resulted in statistically significant clearance of hr-HPV and p16/Ki-67 concomitant with amelioration of cytological findings, thus providing effective prevention and protection against oncogenic development. TRIAL REGISTRATION: ISRCTN11009040, on 10 December 2019.

The role of micronucleus scoring in cervical papanicolaou smears: A 1-year study.

Aims and Objectives: To compare the micronucleus (MN) score in all the major diagnostic categories as per "The Bethesda System for Reporting Cervical Cytology" 2014 including negative for intraepithelial lesions and malignancy (NILM), inflammatory, abnormal squamous cells of undetermined significance (ASC-US), abnormal squamous cells cannot exclude high-grade squamous intraepithelial lesion (HSIL) (ASC-H), low-grade squamous intraepithelial lesion (LSIL), HSIL, and invasive carcinoma (IC) and to assess the role of MN scoring as a biomarker for predicting risk of carcinoma. Materials and Methods: A total of 1000 conventional cervical smears stained with Papanicolaou (Pap) stain, comprising unsatisfactory for evaluation (86), NILM (140), inflammatory (696), ASC-US (23), ASC-H (16), LSIL (18), HSIL (15), and IC (6) were studied independently by two pathologists, and the number of MN cells per 1000 epithelial cells in high-power (×400) and oil immersion (×1000) was counted and expressed as MN score per 1000 cells. Results: The mean MN score ± standard deviation was found to be 0.99 ± 0.744 in NILM cases, 0.67 ± 0.782 in inflammatory cases, 1.57 ± 0.507 in ASC-US cases, 1.63 ± 0.50 in ASC-H cases, 1.56 ± 0.511 in LSIL cases, 2.47 ± 0.516 in HSIL cases, and 3.0 ± 0.00 in IC cases. A step-wise increase was observed in MN score from inflammatory to IC categories. Conclusions: MN score is a reliable and easy test that can be used in conjunction with routine cervical PAP to assess the risk of malignant transformation in the uterine cervix as a biomarker for predicting the risk of carcinoma.

Résumé Objectifs et objectifs: comparer le score du micronucléus (MN) dans toutes les principales catégories de diagnostic selon "le système Bethesda pour signaler la cytologie cervicale" 2014, y compris négatif pour les lésions intraépithéliales et la malignité (Nilm), inflammatoire et anormal des cellules squameuses de signification indéterminées (Nilm), inflammatoire et anormale des cellules squameuses de signification indéterminées (Nilm), inflammatoire et anormale des cellules pure ASC - US), les cellules squameuses anormales ne peuvent pas exclure la lésion intraépithéliale épidermoïde de haute qualité (HSIL) (ASC - H), la lésion intraépithéliale squameuse à faible teneur (LSIL), le carcinome invasif (IC) et pour évaluer le rôle de MN La notation en tant que biomarqueur pour prédire le risque de carcinome. Matériaux et méthodes: un total de 1000 frottis cervicaux conventionnels colorés avec une tache de papanicolaou (PAP), comprenant insatisfaisant l'évaluation (86), nilm (140), inflammatoire (696), ASC - US (23), ASC - H (16), LSIL (18), HSIL (15) et IC (6) ont été étudiés indépendamment par deux pathologistes, et le nombre de cellules Mn pour 1000 cellules épithéliales dans la puissance (× 400) et l'immersion à l'huile (× 1000) ont été comptées et exprimé en score MN par 1000 cellules. Résultats: Le score MN moyen ± l'écart type s'est révélé être de 0,99 ± 0,744 dans des cas nilms, 0,67 ± 0,782 dans des cas inflammatoires, 1,57 ± 0,507 dans les cas ASC - US, 1,63 ± 0,50 dans les cas ASC - H, 1,56 ± 0,511 dans LSIL cas, 2,47 ± 0,516 dans les cas HSIL et 3,0 ± 0,00 dans les cas IC. Une augmentation de pas de pas a été observée dans le score MN des catégories inflammatoires vers IC. Conclusions: Le score MN est un test fiable et facile qui peut être utilisé en conjonction avec le PAP cervical de routine pour évaluer le risque de transformation maligne dans le col utérine en tant que biomarqueur pour prédire le risque de carcinome. Mots-clés: Frottis cervical, micronucleus, dépistage.

Cervical cytology: Radiation and other therapy effects.

The different treatment options for carcinoma cervix include radiation, chemotherapy, and surgical treatments. Cytological analysis of smears is crucial for patient follow-up to determine response to therapy and to diagnose the persistence or recurrence of malignancy. Anatomical alterations and changes in cell morphology following radiation or chemotherapy make collecting and interpreting cervical cytology samples difficult. These issues can be mitigated by liquid-based cytology. Ionizing radiation is used in radiotherapy (RT) to kill cells. It is important that cytologists are aware of alterations in morphology of the cells. Radiation can cause cytoplasmic and nuclear changes. Cellular enlargement, vacuolation, granularity loss, and other changes linked with cell death are examples of cytoplasmic alterations. Nuclear enlargement and multinucleation are the most frequent nuclear alterations. These changes are determined by the amount of time that has passed since radiation. It should be emphasized that no one characteristic is pathognomonic. Post-irradiation dysplasia is a condition described as abnormal cellular changes in non-neoplastic epithelial cells after RT. Chemotherapy causes comparable alterations as radiation but impacts fewer cells. Busulfan and other chemotherapeutic treatments may produce morphological alterations, which cytologists must be aware of and able to identify. Immunosuppressive treatments, hormonal therapy, and tamoxifen are some of the other drugs that might cause changes in cervical morphology. Surgical methods used in the detection and treatment of cervical cancer may potentially cause alterations as a result of thermal damage and healing. For the treatment of cervical lesions, electrocautery and the loop electrosurgical excisional procedure are available. These procedures employ electric current ablation leading to ischemic changes in the cervical smear. Cytological analysis of smears following treatment with these modalities necessitates a comprehensive history, kind of therapy, and duration of treatment.