Advancements in the Management of Cervical Intraepithelial Neoplasia: A Comprehensive Review.

Cervical intraepithelial neoplasia (CIN) represents a significant precursor to cervical cancer, posing a considerable threat to women's health globally. This comprehensive review examines recent advancements in the management of CIN, encompassing screening, diagnosis, and treatment modalities. The etiology and pathogenesis of CIN are explored alongside an analysis of traditional and emerging screening techniques, including liquid-based cytology and molecular biomarkers. Treatment options, from minimally invasive procedures to immunotherapy approaches, are evaluated for efficacy and potential impact on patient outcomes. Furthermore, this review highlights the implications of these findings for clinical practice, emphasizing the importance of staying abreast of evolving guidelines and integrating innovative strategies into routine care. Recommendations for future research and practice are provided, emphasizing personalized approaches, disparities in access to care, and the exploration of novel therapeutic avenues. By addressing these challenges and opportunities, this review aims to contribute to the ongoing efforts to mitigate the burden of CIN and cervical cancer, ultimately improving women's health outcomes worldwide.

Impact of HPV Vaccination on the Incidence of High-Grade Cervical Intraepithelial Neoplasia (CIN2+) in Women Aged 20-25 in the Northern Part of Norway: A 15-Year Study.

BACKGROUND: Human papillomavirus (HPV), the most prevalent sexually transmitted infection globally, is a key risk factor for high-grade cervical lesions and cervical cancer. Since 2009, HPV vaccination has been part of the national immunization program for girls in 7th grade in Norway (women born 1997 and later). This study aimed to assess the impact of HPV vaccination on the incidence of high-grade cervical precursors (CIN2+) among women aged 20-25 in Troms and Finnmark over a 15-year period. MATERIALS AND METHODS: In this time series study, we analyzed cervical screening data from 15,328 women aged 20-25 in Troms and Finnmark, collected between 2008 and 2022. Statistical methods, including linear and logistic regression, were employed to evaluate changes in cervical intraepithelial neoplasia grade 2 and worse (CIN2+) incidence and compare risks between vaccine-offered cohorts and pre-vaccine cohorts. RESULTS: The incidence of CIN2+ initially increased from 31 cases per year in 2008 to 110 cases in 2018, then significantly decreased to 44 cases per year by 2022 (p < 0.01). Women in pre-vaccine cohorts had a substantially higher risk of CIN2+ (OR 9.02, 95% CI 5.9-13.8) and CIN3+ (OR 19.6, 95% CI 7.3-52.6). Notably, no vaccinated women with CIN2+ tested positive for HPV types 16 or 18. Furthermore, none of the 13 cervical cancer cases recorded during the study were from the vaccinated cohorts. INTERPRETATION: The findings suggest a significant reduction in the incidence of high-grade cervical precursors following the introduction of the HPV vaccine in Norway's national immunization program, highlighting its effectiveness in cervical cancer prevention among young women in Northern Norway.

Knowledge of cytology results affects the performance of colposcopy: a crossover study.

OBJECTIVE: To determine whether knowledge of cytology affects the colposcopist's diagnostic accuracy in the identification of cervical intraepithelial neoplasia grade 2 and worse (≥ CIN2). METHOD: In this cross-over study, healthcare professionals interpreted colposcopy images from 80 patient cases with known histological diagnoses. For each case, 2 images taken with a colposcope were provided (native and after acetic acid application). Inclusion criteria consisted of women with a transformation zone type 1 or 2, who had both a cytological and histological diagnosis. Cases were distributed across two online surveys, one including and one omitting the cytology. A wash-out period of six weeks between surveys was implemented. Colposcopists were asked to give their diagnosis for each case as < CIN2 or ≥ CIN2 on both assessments. Statistical analysis was conducted to compare the two interpretations. RESULTS: Knowledge of cytology significantly improved the sensitivity when interpreting colposcopic images, from 51.1% [95%CI: 39.3 to 62.8] to 63.7% [95%CI: 52.1 to 73.9] and improved the specificity from 63.5% [95%CI: 52.3 to 73.5] to 76.6% [95%CI: 67.2 to 84.0]. Sensitivity was higher by 38.6% when a high-grade cytology (ASC-H, HSIL, AGC) was communicated compared to a low-grade cytology (inflammation, ASC-US, LSIL). Specificity was higher by 31% when a low-grade cytology was communicated compared to a high-grade. CONCLUSIONS: Our data suggests that knowledge of cytology increases sensitivity and specificity for diagnosis of ≥ CIN2 lesions at colposcopy. Association between cytology and histology may have contributed to the findings.

YAP/TAZ-TEAD activity promotes the malignant transformation of cervical intraepithelial neoplasia through enhancing the characteristics and Warburg effect of cancer stem cells.

A number of studies have confirmed that Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ)-transcriptional enhanced associate domain (TEAD) activity is the driver of cancer development. However, the role and mechanism of the YAP/TAZ-TEAD pathway in cervical intraepithelial neoplasia (CIN) remain to be clarified. Therefore, this study was designed to observe the effect of YAP/TAZ-TEAD activity on the development of CIN and provide new ideas for the diagnosis and treatment of CIN. Firstly, cervical tissues were collected from CIN patients in different stages [CIN grade 1 (CIN1) tissue, CIN grade 2/3 (CIN 2/3) and squamous cell carcinoma (SCC)] and healthy volunteers. Next, the expression levels of YAP, TAZ and TEAD in cervical tissues and cells were observed by immunohistochemistry, qRT-PCR and western blot. Besides, Z172 and Z183 cells were transfected with siRNA-YAP/TAZ (si-YAP/TAZ) and YAP/TAZ overexpression vector (YAP-5SA). Also, Z172 cells were co-transfected with YAP-5SA and si-TEAD2/4. Subsequently, the stemness characteristics, glycolysis level and malignant transformation of cells in each group were observed by sphere-formation assay, commercial kit, MTT, Transwell, scratch experiment, xenotransplantation and western blot.The expression of YAP, TAZ and TEAD increased significantly in cervical cancer tissue and cell line at the stage of CIN2/3 and SCC. When YAP/TAZ was knocked down, the stemness characteristics, glycolysis level and malignant transformation of cancer cells were notably inhibited; while activating YAP/TAZ exhibited a completely opposite result. In addition, activating YAP/TAZ and knocking down the TEAD expression at the same time significant weakened the effect of activated YAP/TAZ signal on precancerous cells and reduced inhibitory effect of knocking down TEAD alone. YAP/TAZ-TEAD signal activates the characteristics and Warburg effect of cancer stem cells, thereby promoting the malignant transformation of CIN.

Human Papillomavirus Infections and the Role Played by Cervical and Cervico-Vaginal Microbiota-Evidence from Next-Generation Sequencing Studies.

This comprehensive review encompasses studies examining changes in the cervical and cervico-vaginal microbiota (CM and CVM) in relation to human papillomavirus (HPV) using next-generation sequencing (NGS) technology. HPV infection remains a prominent global health concern, with a spectrum of manifestations, from benign lesions to life-threatening cervical cancers. The CM and CVM, a unique collection of microorganisms inhabiting the cervix/vagina, has emerged as a critical player in cervical health. Recent research has indicated that disruptions in the CM and CVM, characterized by a decrease in Lactobacillus and the overgrowth of other bacteria, might increase the risk of HPV persistence and the progression of cervical abnormalities. This alteration in the CM or CVM has been linked to a higher likelihood of HPV infection and cervical dysplasia. NGS technology has revolutionized the study of the cervical microbiome, providing insights into microbial diversity, dynamics, and taxonomic classifications. Bacterial 16S rRNA gene sequencing, has proven invaluable in characterizing the cervical microbiome, shedding light on its role in HPV infections and paving the way for more tailored strategies to combat cervical diseases. NGS-based studies offer personalized insights into an individual's cervical microbiome. This knowledge holds promise for the development of novel diagnostic tools, targeted therapies, and preventive interventions for cervix-related conditions, including cervical cancer.

Immunotherapy that leverages HPV-specific immune responses for precancer lesions of cervical cancer.

Cervical cancer and its precursor lesion, cervical intraepithelial neoplasia (CIN), are caused by high-risk human papillomavirus (HPV) viral infection and are highly susceptible to host immunity targeting of HPV viral proteins, which include both foreign antigens and cancer antigens expressed by tumors. Immunotherapy that induces Th1 immunoreactivity against viral proteins is expected to take advantage of this immunological regression mechanism. However, although cancer immunotherapies for cervical cancer and CIN have been developed over the past several decades, none have been commercialized. Most of these immunotherapies target the viral cancer proteins E6 and E7, which are generally the same. The reasons for the underdevelopment of HPV-targeted immunotherapy differ depending on whether the target is invasive cancer or CIN. We here summarize the developmental history of cancer immunotherapy for CIN and discuss strategies for solving the problems that led to this underdevelopment. We note that CIN is a mucosal lesion and propose that inducing mucosal immunity may be the key.

Optimising cervical cancer screening during pregnancy: a study of liquid-based cytology and HPV DNA co-test.

This study assessed the efficacy of ThinPrep cytologic test and human papillomavirus (HPV) co-test in cervical cancer screening during pregnancy. A cohort of 8,712 pregnant women from Ren Ji Hospital participated in the study. Among them, 601 (6.90%) tested positive for high-risk HPV (HR-HPV) and 38 (0.44%) exhibited abnormal cytology results (ASCUS+). Following positive HR-HPV findings, 423 patients underwent colposcopy, and 114 individuals suspected of having high-grade squamous intraepithelial lesion and cervical cancer (HSIL+) underwent cervical biopsy. Histological examination revealed 60 cases of normal pathology (52.63%), 35 cases of low-grade squamous intraepithelial lesion (30.70%), 17 cases of HSIL (14.91%), and 2 cases of cervical cancer (1.75%). The incidence of HSIL+ in HPV 16/18 group was significantly higher than that in non-HPV16/18 group (10.53% vs. 6.14%, P < 0.05). Subsequent evaluation of the clinical performance of cytology alone, primary HPV screening, and co-testing for HSIL+ detection revealed that the HSIL+ detection rate was lowest with cytology alone. These findings suggest that HPV testing, either alone or combined with cytology, presents an efficient screening strategy for pregnant women, underscoring the potential for improved sensitivity in cervical cancer screening during pregnancy. The significantly higher incidence of HSIL+ in the HPV16/18 group emphasizes the importance of genotype-specific considerations.

HPV E6/E7 mRNA combined with thin-prep cytology test for the diagnosis of residual/recurrence after loop electrosurgical excision procedure in patients with cervical intraepithelial neoplasia.

To evaluate the diagnostic value of combining HPV E6/E7 mRNA testing with Thin-Prep cytology (TCT) for residual/recurrence detection, a total of 289 patients who underwent loop electrosurgical excision procedure (LEEP) for high-grade cervical lesions were included. Patients were followed up at different time points, and residual/recurrent lesions were confirmed through vaginoscopy. TCT, HPV-DNA, and HPV E6/E7 mRNA tests were conducted. Diagnostic performance, including sensitivity, specificity, positive predictive value, negative predictive value, and accuracy, was assessed. Among the patients, 76 cases showed residual lesions/recurrence, while 213 cases showed no residual/recurrence. Positive margins in the cervical-vaginal and cervical canal areas were associated with a higher risk of residual/recurrence. The combined HPV E6/E7 mRNA and TCT test showed higher diagnostic efficacy than individual tests at 6-, 12-, and 24-months follow-up. The combined test consistently demonstrated higher specificity and sensitivity, with significantly larger area under the curve (AUC) values compared to the individual tests.

The Efficiency of Cervical Pap and Comparison of Conventional Pap Smear and Liquid-Based Cytology: A Review.

Cervical cancer is one of the leading health burdens globally with a huge incidence in developing countries like India. Cervical cancer has an extended premalignant stage known as cervical dysplasia or cervical intraepithelial neoplasia (CIN). CIN can be grade 1, 2, or 3 depending on its severity. One of the most effective methods of cervical cancer screening and prevention is detecting these premalignant lesions by cervical cytology. Pioneered by Dr. George Nicholas Papanicolaou, the Papanicolaou (Pap) stain became an important advent for the microscopic evaluation of the exfoliated cervical cells. Over the years, this method of conventional Pap smear became more practiced and yielded excellent results, so much so that the incidence of cervical cancer actually started to decline in developed countries. However, few drawbacks started to become evident with conventional Pap smears like unsatisfactory samples due to obscuring materials, false negative results due to sampling error, and low sensitivity. To overcome these drawbacks of conventional Pap smear, liquid-based cytology (LBC) was introduced in 1996. Thereafter, many investigations and studies have been conducted by many authors to compare the efficacy of conventional Pap smear and LBC. This review puts forward the facts and results of various studies pertaining to efficacy of cervical cytology, comparing conventional Pap smear and LBC, and highlighting the pros and cons of each method based on various studies. For this review, relevant articles under the headings "Conventional PAP smear", "Cervical cancer screening", "Liquid-based cytology" and "Comparison" have been searched in PubMed/MEDLINE and Google Scholar. About 100 articles were studied, and all the facts have been highlighted. While many studies did support LBC over conventional Pap smear for screening of cervical abnormalities, some studies did not find any major difference between the two and preferred the practice of conventional Pap smear in our Indian scenario considering the low-resource setting and low price. This research highlights the various facts of the two types of cervical Pap smear and their comparison.

Immediate histologic correlation in patients with different HPV genotypes and ages: a single center analysis in China.

BACKGROUND: Human papillomavirus (HPV) has been confirmed as a major causative factor for malignant transformation of cervical epithelial cells and for the development of cervical intraepithelial neoplasia (CIN) and invasive cervical cancer. We carried out this study to investigate the association of different HPV genotypes and ages with immediate histological cervical lesions in opportunistic screening patients in a single center. METHODS: A total of 1,661 samples with biopsy-confirmed histologic findings were collected from the gynecological clinic of our hospital between October 2017 and May 2020 for analysis. The distribution of single-type HPV genotypes in CIN of different severities and the age-dependent prevalence for single-type HPV infection were analyzed. RESULTS: In both CIN2 and CIN3 group, HPV16, 58, 52, 33 and 31/18 were detected as top 5 high-risk human papillomavirus (hrHPV) types, which accounts for 89.25% and 88.54% of single HPV infection incidence respectively. Besides, not a single case of HPV45 was found in CIN2 and CIN3. HPV16 was the dominant genotype in both CIN2 and CIN3, accounted for 46.24% and 55.21%, respectively. The prevalence of HPV16 was the most frequent in all the age groups, except ≥ 65 years group in CIN3, and almost one in three HPV16-positive patients were diagnosed with high grade CIN. The peak of the incidence of CIN3 was observed at 25 ~ 34 years (33.68%), followed by 35 ~ 44 years (31.58%). CONCLUSION: High grade CIN peak at 25 ~ 44 years, women of this age are recommended for normative screening if conditions permit. HPV16-positive patients should be given high priority in opportunistic screening, while the single-center data suggesting a low risk of CIN2/3 in HPV45-positive patients. For women ≥ 65 years old, patients infected with other HPV types should be also taken seriously. In general, HPV16, 58, 52, 33, 31 and 18 were the most common genotypes in CIN2/3, and a vaccine including these predominant genotypes might be of great significance for cervical cancer prevention in China.

HPV genotype-specific distribution and attributable risk in cervical intraepithelial neoplasia in a referral population with a history of LSIL.

BACKGROUND AND OBJECTIVE: CINtec PLUS and cobas HPV tests (Roche) were previously ascertained for triaging an LSIL referral population [1]. As part of this study, genotype-specific distribution and attributable risk of high-risk (HR)-HPV in cervical intraepithelial neoplasia (CIN) were determined. METHODS: Archived cervical specimens in ThinPrep PreservCyt (Hologic Inc) from the LSIL referral population (n= 533) were genotyped using the Anyplex II HPV HR test (Anyplex, Seegene Inc). Since the study specimens had been in storage in ambient temperature for 31-47 months since collection, Anyplex results were compared with that of the initial cobas testing of fresh specimens to validate the suitability and stability of specimens for the present study. RESULTS: Overall, Anyplex test was positive in 63% (336/533) vs. 55.7% (297/533) for cobas test. Anyplex test performed identical to cobas test identifying 93.2% (82/88) of ⩾CIN2/adenocarcinoma in situ (AIS). Anyplex test detected genotypes 16/18 in 15.7% (36/230) ⩽CIN1 vs. 45.5% (40/88) ⩾CIN2/AIS; the corresponding figures were 13.5% (31/230) and 45.5% (40/48) for the cobas test. Genotype 16 showed increasing attribution, 13.2% in CIN1, 27.1% in CIN2 and 40% in CIN3/AIS. Of the 12 other high-risk (OHR) types collectively identified by cobas, Anyplex test specifically detected, in decreasing order, genotypes 51, 31, 35, 56, 39, and 45 as the most frequent types, often in multiple-type infections, in 64.8% ⩾CIN2. Regardless, estimated attribution was evident for each of the 12 OHR types in ⩾CIN2. Multiple-type infections were more frequent than single-type infections in all CIN grades. CONCLUSIONS: Attributable risk of all HR-HPV genotypes targeted by both Anyplex and cobas tests was evident in ⩾CIN2/AIS Testing for these genotypes in HPV primary cervical screening and cytology triage could identify those at increased risk of cervical cancer and also be beneficial in the management of LSIL referral populations.

Outcome and associated factors of high-risk human papillomavirus infection without cervical lesions.

OBJECTIVE: To study the outcome of human papillomavirus (HPV) infection in women with cervical pathology results of non-cervical intraepithelial neoplasia (CIN) or cervical cancer and positive high-risk HPV test, as well as analyze the associated risk factors affecting the outcome of infection. METHODS: To investigate the outcome of high-risk (HR)-HPV infection in the female genital tract and analyze the associated risk factors affecting their outcome, a total of 196 women with positive HR-HPV test results and non-CIN or cervical cancer cervical pathology results were selected for follow-up at the Cervical Disease Clinic of the Obstetrics and Gynecology Hospital, Zhejiang University School of Medicine from January 2017 to March 2020. The follow-up interval was every 6 months, and both cervical cytology (TCT) and HR-HPV testing were performed at each follow-up visit. If the cervical cytology results were normal upon recheck and the HR-HPV test was negative, the woman was considered to be cleared of the HPV infection and was entered into the routine cervical screening population. When the repeat HR-HPV test remained positive after 6 months, the woman was defined as having a persistent HR-HPV infection. If HR-HPV persisted but the TCT results were normal, follow-up was continued. If HR-HPV persisted and the TCT results were abnormal, a colposcopy-guided biopsy was performed immediately. In this situation, if the histological results were still non-CIN or cervical cancer, the follow-up was continued. If the histological results confirmed the development of CIN or invasive cancer, then enter another study follow-up to further track its development and outcome, and the woman commenced the treatment process. The HPV infection clearance time was analyzed by the Kaplan-Meier method, and the comparison of the HPV clearance rate and infection clearance time between each of the different groups was performed using aχ2 test or Fisher's exact test, as appropriate. After the univariate analysis, several significant factors were included in the Cox model and independent risk factors were analyzed. RESULTS: A total of 163 women were enrolled in this study. The median age was 40.0 years (22-67 years) and the median follow-up time was 11.5 months (6-31 months). The spontaneous clearance rate of HR-HPV infection was 51.5%, and the median time to viral clearance was 14.5 months. Age and the initial viral load were high risk factors affecting the spontaneous clearance of HR-HPV infection. The factors significantly associated with HPV clearance rate and time to HPV clearance consisted of menopause and full-term delivery (P < 0.05). CONCLUSIONS: In women with normal or low-grade lesions on the cell smear, the spontaneous clearance rate of HR-HPV infection was 51.5% and the time to clearance was 14.5 months. Age and the initial viral load were independent associated factors affecting the spontaneous clearance of HR-HPV infection in the female genital tract. These findings suggest that non-young women or those with high viral loads have a higher rate of persistent HR-HPV infection. Thus, intensive screening should be recommended.

Characteristics of vaginal microbiota in various cervical intraepithelial neoplasia: a cross-sectional study.

BACKGROUND: Precancerous lesions of cervical cancer exhibit characteristics indicative of natural progression. To prevent overtreatment of patients whose cervical intraepithelial neoplasia (CIN) in regression and to predict the onset of invasive cervical cancer at an early stage, we've identified the vaginal microbiome as a potential key factor, which is associated with both HPV infection and the various cervical intraepithelial neoplasia. This study aims to investigate the microbiome characteristics of patients with various cervical intraepithelial neoplasia. METHODS: Utilizing high-throughput 16S ribosomal RNA (16S rRNA) sequencing technology, a description of the characteristics and community composition of Vaginal Microbiota (VMB) was conducted among 692 Chinese women infected with the High-risk Human Papillomavirus (HR-HPV). RESULTS: As the grade of the lesions increased, the proportions of Lactobacillus and Pseudomonas demonstrated a significant declining trend, while the proportions of Gardnerella, Dialister, and Prevotella significantly increased. The diversity of the VMB was more significant in high-grade CIN. Furthermore, KEGG pathway enrichment analysis indicates that high-grade cervical intraepithelial neoplasia can inhibit various pathways, including those of phosphotransferase system, transcription factors, Fructose and mannose metabolism, amino sugar and nucleotide sugar metabolism, and galactose metabolism, which may contribute to the development of early cervical cancer symptoms. CONCLUSION: Patients with CIN exhibit a distinct vaginal microbial profile characterized by a decrease in Lactobacillus and Pseudomonas, and an increase in Gardnerella, Prevotella, and Dialister. The proliferation and diminution of these two types of microbial communities are interrelated, suggesting a mutual restraint and balance among them. Disruption of this regulatory balance could potentially lead to the onset of cervical lesions and carcinogenesis. Retrospectively registered: This study was approved by the Ethics Committee of the Beijing Chaoyang Hospital affiliated with the Capital Medical University (NO.2023-S-415).

Cervical Intraepithelial Neoplasia Grade 3 in the Third Trimester of Pregnancy: A Case Report.

The incidence of malignancies during pregnancy has been on the rise in the recent years, primarily due to an increase in older age pregnancies. This poses a significant risk to both the mother and the developing fetus. We present the case of a 29-year-old woman who experienced intermittent vaginal bleeding during her pregnancy. In the last trimester, the patient presented with abnormal vaginal bleeding and abdominal pain. The gestational age was 37.6 weeks. Notably, to our knowledge, there have been no reported cases of grade 3 cervical intraepithelial neoplasia in the third trimester.

A rare case of squamous cell carcinoma associated with a huge ovarian dermoid cyst in a postmenopausal woman.

Malignant transformation of mature cystic teratoma (MCT) is a well-known but uncommon phenomenon seen mostly in postmenopause women. We report a case of a 65-year-old postmenopausal woman with a malignant transformation of MCT and with a low-grade squamous intraepithelial lesion in her cervix. She was treated surgically by total abdominal hysterectomy with bilateral salpingo-oophorectomy with a preoperative diagnosis of right ovarian teratoma. Her postoperative period was uneventful. On follow-up, the histopathology report revealed a right ovarian dermoid cyst with well-differentiated squamous cell carcinoma; there was no evidence of malignancy elsewhere, including the cervix. Ascitic fluid was also free of malignant cells, and the disease was at stage Ia. The patient did not receive any adjuvant chemotherapy and was followed up with clinical examination postoperatively for 1 year, and there was no evidence of any relapse clinically. Preoperative diagnosis of malignant transformation of squamous cell carcinoma (SCC) is difficult, as there is no specific screening marker and no consensus or standard guidelines available regarding the optimum management of this relatively poorly known entity. Here we emphasize the need for a high index of suspicion of malignant transformation with the presence of factors such as elderly age, the huge size of the tumor, and large solid components in the tumor. Considering the scarcity of case reports and studies about SCC arising from MCT, every experience with malignant transformation of MCT should be reported for a better understanding of the disease presentation and management.

Micronutrients and prevention of cervical pre-cancer in HPV vaccinated women: a cross-sectional study.

Objectives: Prophylactic vaccines against high-risk human papillomaviruses (HR-HPVs) hold promise to prevent the development of higher grade cervical intraepithelial neoplasia (CIN 2+) and cervical cancer (CC) that develop due to HR-HPV genotypes that are included, in HPV vaccines, but women will continue to develop CIN 2+ and CC due to HR-HPV genotypes that are not included in the quadrivalent HPV vaccine (qHPV) and 9-valent HPV vaccine (9VHPV). Thus, the current vaccines are likely to decrease but not entirely prevent the development of CIN 2+ or CC. The purpose of the study was to determine the prevalence and determinants of CIN 2+ that develop due to HR-HPVs not included in vaccines. Methods: Study population consisted of 1476 women tested for 37 HPVs and known to be negative for qHPVs (6/11/16/18, group A, n = 811) or 9VHPVs (6/11/16/18/31/33/45/52/58, group B, n = 331), but positive for other HR-HPVs. Regression models were used to determine the association between plasma concentrations of micronutrients, socio-demographic, lifestyle factors and risk of CIN 2+ due to HR-HPVs that are not included in vaccines. Results: The prevalence of infections with HPV 31, 33, 35 and 58 that contributed to CIN 2+ differed by race. In group A, African American (AA) women and current smokers were more likely to have CIN 2 (OR = 1.76, P = 0.032 and 1.79, P = 0.016, respectively) while in both groups of A and B, those with higher vitamin B12 were less likely to have similar lesions (OR = 0.62, P = 0.036 and 0.45, P = 0.035, respectively). Conclusions: We identified vitamin B12 status and smoking as independent modifiable factors and ethnicity as a factor that needs attention to reduce the risk of developing CIN 2+ in the post vaccination era. Continuation of tailored screening programs combined with non-vaccine-based approaches are needed to manage the residual risk of developing HPV-related CIN 2+ and CC in vaccinated women.

The relationship of immunohistochemical SOX-2 staining with histopathological diagnosis in patients with abnormal colposcopic findings.

This study aimed to analyze immunohistochemical staining and pathological data in cervical intraepithelial neoplasia (CIN) and squamous cell cervical carcinoma (SCC) with abnormal colposcopic findings. A histopathological evaluation of 45 low-grade squamous lesions (LSILs), 177 high-grade squamous lesions (HSILs) and 16 SCC biopsy materials from existing slides was obtained from blocks obtained from the archive. In addition, SOX-2 immunohistochemical staining was evaluated. The mean age of the HSIL group was 43.20 ± 8.97 years, younger than the mean age of the LSIL group of 51.62 ± 9.64 years (p = 0.000). There was no difference between the groups regarding the method of biopsy (p > 0.05). Endocervical gland involvement was not observed in the LSIL group, but was observed in 66 (37.3%) biopsy materials in the HSIL group (p = 0.000). There was a difference between the groups in terms of the level of CIN at the surgical margin (p = 0.000). Ki-67, SOX-2 staining percentage and p16INK4a positivity were higher in the HSIL group than in the LSIL group (respectively, 67.57 ± 19.10 vs. 14.62 ± 7.11, p = 0.000; 27.72 ± 31.56 vs. 10.09 ± 15.38, p = 0.003; 66 (82.5%) vs. 8 (44.4%), p = 0.001). While there was no difference in SOX-2 intensity between the HSIL and LSIL groups (p > 0.05), it was statistically significantly higher in the SCC group (p = 0.000), as was the percentage of SOX-2 (p = 0.000). We have shown that p16INK4a and SOX-2 staining is useful, in addition to Ki-67 immunostaining, which is widely used for SCC, which is one of the preventable cancer types. In addition, SOX-2 may provide a glimmer of hope in the development of SCC treatment modalities, especially since it is aggressively elevated in SCC rather than CIN lesions.

Feasibility of 5-fluorouracil and imiquimod for the topical treatment of cervical intraepithelial neoplasias (CIN) 2/3.

OBJECTIVES: To determine the feasibility (as measured by tolerability and safety) and efficacy of topical 5-fluorouracil (5-FU) and imiquimod for the treatment of cervical intraepithelial neoplasia (CIN) 2/3. METHODS: This pilot prospective study was conducted in women aged 18-45 years with p16+ CIN 2/3. Participants underwent an 8-week alternating regimen of self-applied 5% 5-FU on weeks 1, 3, 5, and 7 and physician-applied imiquimod on weeks 2, 4, 6, and 8. Adverse events (AEs) were collected by symptom diary and clinical exam. Feasibility was measured by tolerability and safety (AEs) of the study intervention. Tolerability was assessed as the number of participants able to apply 50% or more of the treatment doses. The safety outcome was calculated as the number of participants who experienced "specified AEs" defined as possibly, probably, or definitely related grade 2 or worse AE or grade 1 genital AEs (blisters, ulcerations, or pustules) lasting more than 5 days. The efficacy of the intervention was determined by histology and high-risk human papillomavirus (hrHPV) testing was done after treatment. RESULTS: The median age of the 13 participants was 27 ± 2.9 years. Eleven (84.61%) participants applied 50% or more of the treatment. All participants reported grade 1 AEs; 6 (46.15%) reported grade 2 AEs; and 0 reported grade 3/4 AEs. Three (23.08%) participants had specified AEs. Histologic regression to normal or CIN 1 among those completing 50% or more of the treatment doses was observed in 10 (90.91%) participants, and 7 (63.63%) tested negative for hr-HPV at the end of the study. CONCLUSIONS: Topical treatment for CIN 2/3 with 5-FU/imiquimod is feasible, with preliminary evidence of efficacy. Topical therapies need further investigation as adjuncts or alternatives to surgical therapy for CIN 2/3.

Cervical Intraepithelial Neoplasia Grading from Prepared Digital Histology Images.

The paper proposes an integrated approach to the automated diagnosis of cervical intraepithelial neoplasia (CIN) in epithelial patches extracted from digital histology images. Experiments were conducted to determine the most suitable deep learning model for the dataset and fuse patch predictions to decide the final CIN grade of the histology samples. Seven candidate CNN architectures were assessed in this study. Three fusion methods were applied to the best CNN classifier. The model ensemble, combined CNN classifier and highest performing fusion method achieved an accuracy of 94.57%. This result shows significant improvement over the state-of-the-art classifiers for cervical cancer histopathology images. It is hoped that this work will contribute towards further research to automate diagnosis of CIN from digital histopathology images.

Identification of a methylation panel as an alternative triage to detect CIN3+ in hrHPV-positive self-samples from the population-based cervical cancer screening programme.

BACKGROUND: The Dutch population-based cervical cancer screening programme (PBS) consists of primary high-risk human papilloma virus (hrHPV) testing with cytology as triage test. In addition to cervical scraping by a general practitioner (GP), women are offered self-sampling to increase participation. Because cytological examination on self-sampled material is not feasible, collection of cervical samples from hrHPV-positive women by a GP is required. This study aims to design a methylation marker panel to detect CIN3 or worse (CIN3+) in hrHPV-positive self-samples from the Dutch PBS as an alternative triage test for cytology. METHODS: Fifteen individual host DNA methylation markers with high sensitivity and specificity for CIN3+ were selected from literature and analysed using quantitative methylation-specific PCR (QMSP) on DNA from hrHPV-positive self-samples from 208 women with CIN2 or less (< CIN2) and 96 women with CIN3+. Diagnostic performance was determined by area under the curve (AUC) of receiver operating characteristic (ROC) analysis. Self-samples were divided into a train and test set. Hierarchical clustering analysis to identify input methylation markers, followed by model-based recursive partitioning and robustness analysis to construct a predictive model, was applied to design the best marker panel. RESULTS: QMSP analysis of the 15 individual methylation markers showed discriminative DNA methylation levels between < CIN2 and CIN3+ for all markers (p < 0.05). The diagnostic performance analysis for CIN3+ showed an AUC of ≥ 0.7 (p < 0.001) for nine markers. Hierarchical clustering analysis resulted in seven clusters with methylation markers with similar methylation patterns (Spearman correlation> 0.5). Decision tree modeling revealed the best and most robust panel to contain ANKRD18CP, LHX8 and EPB41L3 with an AUC of 0.83 in the training set and 0.84 in the test set. Sensitivity to detect CIN3+ was 82% in the training set and 84% in the test set, with a specificity of 74% and 71%, respectively. Furthermore, all cancer cases (n = 5) were identified. CONCLUSION: The combination of ANKRD18CP, LHX8 and EPB41L3 revealed good diagnostic performance in real-life self-sampled material. This panel shows clinical applicability to replace cytology in women using self-sampling in the Dutch PBS programme and avoids the extra GP visit after a hrHPV-positive self-sampling test.