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We present the findings of assessing the expression levels of extracellular TLR2 and TLR4 and intracellular TLR3 and TLR8 correlating with the severity of clinical manifestations of HPV infection. A total of 199 women took part in a single-center prospective comparative research study on TLR2, TLR3, TLR4 and TLR8 expression in HPV-related cervical lesions. TLRs' mRNA expression was analyzed using real-time reverse transcription polymerase chain reaction (RT-PCR). Our results indicate the potential significance of TLR3, TLR4 and TLR8 in responding to HPV infection and its progression to SILs and CC, highlighting the importance of HPV polyinfection in relation to TLR4 and TLR8. [ABSTRACT FROM AUTHOR]

Objective In this study, we established a Sprague-Dawley rat model of vulvar squamous intraepithelial lesions and investigated the impact of focused ultrasound on the expression of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and mutant type p53 (mtp53) in the vulvar skin of rats with low-grade squamous intraepithelial lesions (LSIL).Materials and methods The vulvar skin of 60 rats was treated with dimethylbenzanthracene (DMBA) and mechanical irritation three times a week for 14 weeks. Rats with LSIL were randomly allocated into the experimental group or the control group. The experimental group was treated with focused ultrasound, while the control group received sham treatment.Results After 14 weeks treatment of DMBA combined with mechanical irritation, LSIL were observed in 44 (73.33%) rats, and high-grade squamous intraepithelial lesions (HSIL) were observed in 14 (23.33%) rats. 90.91% (20/22) of rats showed normal pathology and 9.09% (2/22) of rats exhibited LSIL in the experimental group at four weeks after focused ultrasound treatment. 22.73% (5/22) of rats exhibited LSIL, 77.27% (17/22) of rats progressed to HSIL in the control group. Compared with the control-group rats, the levels of HIF-1α, VEGF and mtp53 were significantly decreased in experimental-group rats (p

The lack of human‐derived in vitro models that recapitulate cervical pre‐cancerous lesions has been the bottleneck in researching human papillomavirus (HPV) infection‐associated pre‐cancerous lesions and cancers for a long time. Here, a long‐term 3D organoid culture protocol for high‐grade squamous intraepithelial lesions and cervical squamous cell carcinoma that stably recapitulates the two tissues of origin is described. Originating from human‐derived samples, a small biobank of cervical pre‐tumoroids and tumoroids that faithfully retains genomic and transcriptomic characteristics as well as the causative HPV genome is established. Cervical pre‐tumoroids and tumoroids show differential responses to common chemotherapeutic agents and grow differently as xenografts in mice. By coculture organoid models with peripheral blood immune cells (PBMCs) stimulated by HPV antigenic peptides, it is illustrated that both organoid models respond differently to immunized PBMCs, supporting organoids as reliable and powerful tools for studying virus‐specific T‐cell responses and screening therapeutic HPV vaccines. In this study, a model of cervical pre‐cancerous lesions containing HPV is established for the first time, overcoming the bottleneck of the current model of human cervical pre‐cancerous lesions. This study establishes an experimental platform and biobanks for in vitro mechanistic research, therapeutic vaccine screening, and personalized treatment for HPV‐related cervical diseases. [ABSTRACT FROM AUTHOR]

Introduction: Human papilloma virus (HPV) is the most common sexually transmitted infection worldwide. Cervicovaginal microbiota plays an important role in HPV infection and is associated with the development of squamous intraepithelial lesions (SIL). The natural history of cervical cancer involves reversible changes in the cervical tissue from a normal state, in which no neoplastic changes are detected in the squamous epithelium, to varying states of cellular abnormalities that ultimately lead to cervical cancer. Lowgrade SIL (LSIL), like another cytological category - atypical squamous cells of undetermined significance (ASCUS), may progress to high-grade SIL (HSIL) and invasive cervical cancer or may regress to a normal state. Methods: In this work, we studied cervical canal microbiome in 165 HPVpositive and HPV-negative women of a reproductive age with ASCUS [HPV(+) n = 29; HPV(-) n = 11], LSIL [HPV(+) n = 32; HPV(-) n = 25], HSIL [HPV(+) n = 46], and the control group with negative for intraepithelial lesion malignancy (NILM) [HPV(-) n = 22]. Results and Discussion: HPV16 is the most prevalent HPV type. We have not found any differences between diversity in studied groups, but several genus [like Prevotella (p-value = 0.026), Gardnerella (p-value = 0.003), Fannyhessea (p-value = 0.024)] more often occurred in HSIL group compared by NILM or LSIL regardless of HPV. We have found statistically significant difference in occurrence or proportion of bacterial genus in studied groups. We also identified that increasing of the ratio of Lactobacillus iners or age of patient lead to higher chance to HSIL, while increasing of the ratio of Lactobacillus crispatus lead to higher chance to LSIL. Patients with a moderate dysbiosis equally often had either of three types of vaginal microbial communities (CST, Community State Type) with the prevalence of Lactobacillus crispatus (CST I), Lactobacillus gasseri (CST II), and Lactobacillus iners (CST III); whereas severe dysbiosis is linked with CST IV involving the microorganisms genera associated with bacterial vaginosis and aerobic vaginitis: Gardnerella, Fannyhessea, Dialister, Sneathia, Anaerococcus, Megasphaera, Prevotella, Finegoldia, Peptoniphilus, Porphyromonas, Parvimonas, and Streptococcus. [ABSTRACT FROM AUTHOR]

Programmed death-ligand 1 (PD-L1) is overexpressed in cervical carcinoma, hindering tumor destruction. The aim of this study was to assess PD-L1 expression by immunohistochemistry in cervical squamous cell carcinoma (SCC) and squamous intraepithelial lesions (SILs) from human immunodeficiency virus–positive (HIV+) and human immunodeficiency virus-negative (HIV-) patients. A total of 166 SCC and SIL samples of HIV+ and HIV- patients were included and analyzed for PD-L1 expression through tumor proportion score (TPS), and results were stratified in five TPS groups using SP263 antibody and, combined positive score (CPS) using 22C3 antibody. In cohort 1 (SP263 clone), all HIV+ patients were negative for intraepithelial lesion or malignancy (NILM), and low-grade squamous intraepithelial lesions (LSILs) scored < 1; and 87.5% of high-grade squamous intraepithelial lesions (HSILs) adjacent to SCC, 19% of HSILs non-adjacent to SCC, and 69% of SCCs scored ≥ 1 (15.4% scored 5). In HIV- patients, all NILM, LSILs, HSILs adjacent to SCC, and two HSILs non-adjacent to SCC scored < 1. SCC: 88.2% scored ≥ 1 and 5.9% scored 5. In cohort 2 (SP263 and 22C3 clones), 16.7% of HIV+ patients with SCC were positive with both clones, CPS ≥ 1 (22C3) or score 5 (≥ 50%) (SP263), showing no significant differences in positivity between both clones. These results indicate that a relatively low percentage of SCCs (16.7%; both in HIV+ and in HIV- patients) express PD-L1 (TPS ≥ 50% and CPS > 1), which may be due to some samples being archival material, sample characteristics, or use of different methodologies, highlighting the need for standardization of PD-L1 assessment in SCC of the cervix. The fact that PD-L1 is overexpressed in SILs of HIV+ patients suggests potential additional applications for immunotherapy in this disease. [ABSTRACT FROM AUTHOR]

Cervical cytology has been an integral part of cervical cancer screening since the mid‐20th century with the implementation of screening protocols utilising Pap testing. During that time, cervical cancer has gone from the leading cause of cancer deaths in women to not even appearing in the top 10 causes of US cancer deaths. However, despite its long and widespread use, cervical cytology remains a diagnostically challenging area in the practice of cytopathology. Of particular importance for diagnosticians is the accurate diagnosis of high‐grade squamous intraepithelial lesions (HSILs), given the significant risk of progression to invasive cervical cancer and the importance to patient management. Therefore, this review is presented in order to highlight the diagnostic features of HSIL, its various appearances, and important benign and neoplastic differential considerations with an emphasis on morphological clues that can aid in distinguishing between these different processes. [ABSTRACT FROM AUTHOR]

Abstract The lack of human‐derived in vitro models that recapitulate cervical pre‐cancerous lesions has been the bottleneck in researching human papillomavirus (HPV) infection‐associated pre‐cancerous lesions and cancers for a long time. Here, a long‐term 3D organoid culture protocol for high‐grade squamous intraepithelial lesions and cervical squamous cell carcinoma that stably recapitulates the two tissues of origin is described. Originating from human‐derived samples, a small biobank of cervical pre‐tumoroids and tumoroids that faithfully retains genomic and transcriptomic characteristics as well as the causative HPV genome is established. Cervical pre‐tumoroids and tumoroids show differential responses to common chemotherapeutic agents and grow differently as xenografts in mice. By coculture organoid models with peripheral blood immune cells (PBMCs) stimulated by HPV antigenic peptides, it is illustrated that both organoid models respond differently to immunized PBMCs, supporting organoids as reliable and powerful tools for studying virus‐specific T‐cell responses and screening therapeutic HPV vaccines. In this study, a model of cervical pre‐cancerous lesions containing HPV is established for the first time, overcoming the bottleneck of the current model of human cervical pre‐cancerous lesions. This study establishes an experimental platform and biobanks for in vitro mechanistic research, therapeutic vaccine screening, and personalized treatment for HPV‐related cervical diseases.

IntroductionHuman papilloma virus (HPV) is the most common sexually transmitted infection worldwide. Cervicovaginal microbiota plays an important role in HPV infection and is associated with the development of squamous intraepithelial lesions (SIL). The natural history of cervical cancer involves reversible changes in the cervical tissue from a normal state, in which no neoplastic changes are detected in the squamous epithelium, to varying states of cellular abnormalities that ultimately lead to cervical cancer. Low-grade SIL (LSIL), like another cytological category - atypical squamous cells of undetermined significance (ASCUS), may progress to high-grade SIL (HSIL) and invasive cervical cancer or may regress to a normal state.MethodsIn this work, we studied cervical canal microbiome in 165 HPV-positive and HPV-negative women of a reproductive age with ASCUS [HPV(+) n = 29; HPV(−) n = 11], LSIL [HPV(+) n = 32; HPV(−) n = 25], HSIL [HPV(+) n = 46], and the control group with negative for intraepithelial lesion malignancy (NILM) [HPV(−) n = 22].Results and DiscussionHPV16 is the most prevalent HPV type. We have not found any differences between diversity in studied groups, but several genus [like Prevotella (p-value = 0.026), Gardnerella (p-value = 0.003), Fannyhessea (p-value = 0.024)] more often occurred in HSIL group compared by NILM or LSIL regardless of HPV. We have found statistically significant difference in occurrence or proportion of bacterial genus in studied groups. We also identified that increasing of the ratio of Lactobacillus iners or age of patient lead to higher chance to HSIL, while increasing of the ratio of Lactobacillus crispatus lead to higher chance to LSIL. Patients with a moderate dysbiosis equally often had either of three types of vaginal microbial communities (CST, Community State Type) with the prevalence of Lactobacillus crispatus (CST I), Lactobacillus gasseri (CST II), and Lactobacillus iners (CST III); whereas severe dysbiosis is linked with CST IV involving the microorganisms genera associated with bacterial vaginosis and aerobic vaginitis: Gardnerella, Fannyhessea, Dialister, Sneathia, Anaerococcus, Megasphaera, Prevotella, Finegoldia, Peptoniphilus, Porphyromonas, Parvimonas, and Streptococcus.

Introduction: A large-sample study focusing on VIN lesions of a more precise thickness is needed to help guide clinical treatment. This study aimed to investigate the depth of vulvar intraepithelial neoplasia (VIN) and involved skin appendages to provide evidence for laser surgery. Methods: The study retrospectively enrolled and analyzed the clinical characteristics of VIN patients in the obstetrics and gynecology department of a university hospital between January 1, 2019 and December 30, 2021. The study further explored the thickness of epithelium and skin appendages of 285 women with low-grade VIN (VIN1) and 285 women with high-grade VIN (VIN2/3). Results: The study included 1,139 (80%) VIN1 and 335 (20%) VIN2/3 cases. The VIN1 and VIN2/3 groups showed a significant difference in human papillomavirus infection (P<0.01) but not in cytology (P = 0.499). Most (89.90%, 1,325) cases occurred in one area of the vulva, whereas 10.11% were multifocal. VIN commonly occurred on the posterior fourchette (76.85%), labia majora (11.61%), and labia minora (9.92%). The VIN2/3 group reported a significantly higher positive rate for concurrent cervical and vaginal intraepithelial neoplasia (160 of 285) than the VIN1 group (321 of 953) (P=0.000). The involved epithelial thicknesses in VIN2/3 and VIN1 were 0.69 ± 0.44 and 0.49 ± 0.23 mm, respectively, both of which were greater than the corresponding noninvolved epithelial thickness (0.31 ± 0.19 and 0.32 ± 0.10 mm, P<0.001 and P<0.001, respectively). In cases of appendage involvement, the VIN thickness was 1.98 ± 0.64 mm. Conclusions: VIN thickness was generally ≤1mm for the superficial lesions in non-hairy areas. However, for lesions extending onto hairy areas, the thickness was approximately 3 mm, leading to the destruction of involved skin appendages. [ABSTRACT FROM AUTHOR]

Objectives The 2019 American Society of Colposcopy and Cervical Pathology management guidelines recommend that patients with an unsatisfactory Papanicolaou (Pap) test (UPT) and negative human papillomavirus (HPV) cotest undergo repeat age-based screening in 2 to 4 months. The rationale is that a negative HPV test in the setting of an UPT may reflect an inadequate sample and therefore should not be interpreted as truly "negative." For patients 25 years and older who are cotested, if HPV is positive for the 16 or 18 genotypes, direct referral for colposcopy is recommended. Our study aimed to determine if a negative HPV cotest result is predictive of the absence of a high-grade squamous intraepithelial lesion (HSIL) and whether these patients may be called back for repeat testing at an interval longer than 2 to 4 months. Methods Follow-up cervical cytology and biopsy results in women with UPT and HPV cotests from January 2017 to December 2021 were collected. Original UPT and HPV cotest results were correlated with the follow-up Pap and biopsy results. Results There were 1,496 (2.28%) UPT cases out of 65,641 total Pap tests. Among the 1,496 UPT cases, 1,010 (67.5%) had HPV cotesting; 676 (45.1%) were followed by repeat Pap or biopsy within 4 months and 850 (56.8%) within 12 months. The total follow-up rate was 81%, with a range of 3 days to 36 months. The HSIL rate in HPV-positive cases was 5.7% (3/53) vs 0.4% (2/539) (P =.006) in HPV-negative cases. In UPT, HPV cotesting showed negative predictive values for low-grade and high-grade squamous intraepithelial lesion detection of 98.5% and 99.6%, respectively, while positive predictive values were 19% and 5.7%. Conclusions A negative HPV cotest in individuals with UPT predicted the lack of HSIL in our study. Compliance with the recommended follow-up time of 2 to 4 months for women with UPT was low (45.1%). Our study suggests that women with UPT and negative HPV cotest may be safely called back at an interval longer than 4 months. [ABSTRACT FROM AUTHOR]

Background and Aim: The natural history of cervical cancer is unique that it is preceded by a precancerous condition for a long time. Morphometry as a tool can be used in early and accurate diagnosis of these precancerous and cancerous lesions. The present study aims at assessing the utility of cellular and nuclear morphometry in differentiating squamous cell abnormality from benign conditions and also differentiating the categories of squamous cell abnormalities. Materials and Methods: Forty-eight diagnosed cases of squamous epithelial cell abnormality, that is, 10 cases each of atypical squamous cell of undetermined significance ( ASC-US), low-grade squamous intraepithelial lesion (LSIL), high-grade SIL (HSIL), and squamous cell carcinoma (SCC) and eight cases of ASC-H (ASC cannot exclude HSIL), were made the sample population and compared with a control population of 10 cases of negative for intraepithelial lesion or malignancy (NILM). Parameters like nuclear area (NA), nuclear perimeter (NP), nuclear diameter (ND), nuclear compactness (NC), cellular area (CA), cellular diameter (CD), cellular perimeter (CP), and nucleocytoplasmic (N/C) ratio were used. Results: There was a significant difference in the six groups of squamous cell abnormality based on NA, NP, ND, CA, CP, and CD (P < 0.05) using one-way analysis of variance. Nuclear morphometry parameters like NA, NP, and ND were found to be the maximum for HSIL, followed by LSIL, ASC-H, ASC-US, SCC, and NILM groups in decreasing order. The mean CA, CP, and CD were found to be the maximum for NILM, followed by LSIL, ASC-US, HSIL, ASC-H, and SCC in decreasing order. On post hoc analysis, the lesions can be divided into three groups: NILM/normal; ASC-US and LSIL; and ASC-H, HSIL, and SCC, based on N/C ratio. Conclusion: In cervical lesions, holistic parameter of cytonucleomorphometry should be taken rather than taking nuclear morphometry only. N/C ratio is a highly statistically significant parameter that can differentiate between low-grade lesions and high-grade lesions.

Introduction: Cervical cancer is the second most malignant cancer that affects women globally. The most common cause for cervical cancer is persistent infection of high risk Human Papillomavirus (HPV) subtypes 16,18. Over-expression of p16 may serve as a surrogate biomarker to confirm HPV infection. Aim: The present study aimed to study high risk HPV in cervical biopsies using p16 immunostaining for detecting high grade lesions. Material and method: This cross-sectional study was conducted in the Department of Pathology, Sree Mookambika Institute of Medical Sciences, Tamil Nadu from January 2019 to February 2021 involving all women with cervical biopsies and excluding HPV vaccinated women. Samples were collected in 10% formalin. Specimens were processed and paraffin embedded. The section were stained with Haematoxylin and Eosin (H&E) and immunohistochemical staining p16 and analysed using Statistical Package for the Social Sciences (SPSS) software trial version 20.0 by qualitative analysis test i.e Chi-square test. Results: The study included 53 cases. Age distribution was between 32-78 years, with majority in 4th to 5th decades. In the study 26 (49.1%) cases were non neoplastic lesions, 16 (30.19%) were premaliganant lesions and the remaining 11 (20.75%) were malignant lesions. The difference in the proportion of HPV diagnosis between age group was statistically significant (p-value 0.003). All the non-neoplastic lesions of cervix showed negative p16 staining. Out of 16 (30.19%)premalignant lesions, 15 (93.75%) had Low grade Squamous Intraepithelial Lesion (LSIL) and only 1 (6.25%) had High grade Squamous Intraepithelial Lesion (HSIL). Few low grade lesions 7 (100%) had negative staining and all the cervical carcinoma patients showed p16 positivity. Conclusions: p16 expression was progressively increased with increasing grades of cervical neoplasm. So p16 may be useful as an adjunct in histological sections to detect HPV in those lesions which can help us to predict the progression of disease

Inflammation is a key factor in cancer promotion. Tumor-associated macrophages (TAMs), as part of the tumor microenvironment, are often associated with the progression of tumors and a worse prognosis in many cancers, namely on cervical cancer. This work exhaustively summarizes the conclusions of the different studies published concerning TAMs function in cervical cancer, from in vitro studies using cancer cell lines to the clinical perspective (histological samples-based studies). Most studies have led to the conclusion that TAMs increased density is directly related to increased severity of a malignant cervical lesion. Additionally, TAMs are normally polarized into an M2 phenotype, benefiting and promoting tumor progression, resulting in a worse disease outcome. The tumor microenvironment is also a highly critical contributor that not only influences tumor natural history but also modulates the specific immune response.

Background: P16INK4A is a surrogate signature compensating for the specificity and/or sensitivity deficiencies of the human papillomavirus (HPV) DNA and Papanicolaou smear (Pap) co‐test for detecting high‐grade cervical squamous intraepithelial lesions or worse (HSIL+). However, traditional p16INK4A immunostaining is labour intensive and skill demanding, and subjective biases cannot be avoided. Herein, we created a high‐throughput, quantitative diagnostic device, p16INK4A flow cytometry (FCM) and assessed its performances in cervical cancer screening and prevention. Methods: P16INK4A FCM was built upon a novel antibody clone and a series of positive and negative (p16INK4A‐knockout) standards. Since 2018, 24 100‐women (HPV‐positive/‐negative, Pap‐normal/‐abnormal) have been enrolled nationwide for two‐tier validation work. In cross‐sectional studies, age‐ and viral genotype‐dependent expression of p16INK4A was investigated, and optimal diagnostic parameter cut‐offs (using colposcopy and biopsy as a gold standard) were obtained. In cohort studies, the 2‐year prognostic values of p16INK4A were investigated with other risk factors by multivariate regression analyses in three cervicopathological conditions: HPV‐positive Pap‐normal, Pap‐abnormal biopsy‐negative and biopsy‐confirmed LSIL. Results: P16INK4A FCM detected a minimal ratio of 0.01% positive cells. The p16INK4A‐positive ratio was 13.9 ± 1.8% among HPV‐negative NILM women and peaked at the ages of 40–49 years; after HPV infection, the ratio increased to 15.1 ± 1.6%, varying with the carcinogenesis of the viral genotype. Further increments were found in women with neoplastic lesions (HPV‐negative: 17.7 ± 5.0–21.4 ± 7.2%; HPV‐positive: 18.0 ± 5.2–20.0 ± 9.9%). Extremely low expression of p16INK4A was observed in women with HSILs. As the HPV‐combined double‐cut‐off‐ratio criterion was adopted, a Youden's index of 0.78 was obtained, which was significantly higher than that (0.72) of the HPV and Pap co‐test. The p16INK4A‐abnormal situation was an independent HSIL+ risk factor for 2‐year outcomes in all three cervicopathological conditions investigated (hazard ratios: 4.3–7.2). Conclusions: FCM‐based p16INK4A quantification offers a better choice for conveniently and precisely monitoring the occurrence of HSIL+ and directing risk‐stratification‐based interventions. [ABSTRACT FROM AUTHOR]

Background and Aim: The natural history of cervical cancer is unique that it is preceded by a precancerous condition for a long time. Morphometry as a tool can be used in early and accurate diagnosis of these precancerous and cancerous lesions. The present study aims at assessing the utility of cellular and nuclear morphometry in differentiating squamous cell abnormality from benign conditions and also differentiating the categories of squamous cell abnormalities. Materials and Methods: Forty-eight diagnosed cases of squamous epithelial cell abnormality, that is, 10 cases each of atypical squamous cell of undetermined significance (ASC-US), low-grade squamous intraepithelial lesion (LSIL), high-grade SIL (HSIL), and squamous cell carcinoma (SCC) and eight cases of ASC-H (ASC cannot exclude HSIL), were made the sample population and compared with a control population of 10 cases of negative for intraepithelial lesion or malignancy (NILM). Parameters like nuclear area (NA), nuclear perimeter (NP), nuclear diameter (ND), nuclear compactness (NC), cellular area (CA), cellular diameter (CD), cellular perimeter (CP), and nucleocytoplasmic (N/C) ratio were used. Results: There was a significant difference in the six groups of squamous cell abnormality based on NA, NP, ND, CA, CP, and CD (P < 0.05) using one-way analysis of variance. Nuclear morphometry parameters like NA, NP, and ND were found to be the maximum for HSIL, followed by LSIL, ASC-H, ASC-US, SCC, and NILM groups in decreasing order. The mean CA, CP, and CD were found to be the maximum for NILM, followed by LSIL, ASC-US, HSIL, ASC-H, and SCC in decreasing order. On post hoc analysis, the lesions can be divided into three groups: NILM/normal; ASC-US and LSIL; and ASC-H, HSIL, and SCC, based on N/C ratio. Conclusion: In cervical lesions, holistic parameter of cytonucleomorphometry should be taken rather than taking nuclear morphometry only. N/C ratio is a highly statistically significant parameter that can differentiate between low-grade lesions and high-grade lesions. [ABSTRACT FROM AUTHOR]

Cellular Retinoic Acid Binding Protein-1 (CRABP1) facilitates retinoid metabolism; however, an abnormal expression might influence cancers developed. Biopsy samples were evaluated from patients with cervical cancer (CC), high-grade (HSIL), and lowgrade squamous intraepithelial lesions (LSIL) (n= 66) Clinic/pathological information was obtained from patients. CRABP1 gene expression was examined by RT-PCR and CRABP1 protein by immunohistochemistry (IHC) techniques. The expression of the CRABP1 gene is shown to be significantly lower in the HSIL group (p= 0.008). CRABP1 protein was expressed in 90.3% of tissues, and only in CC was presented absence of protein (9.7%). Overweight/obesity might increase the gene (p= 0.019) but not the protein expression (p= 0.053). Also, a gene expression increase was shown in high serum retinol concentration (p= 0.047) and the presence of HVP-16 (p= 0.011) (gene expression but not the protein, p > 0.05). Menopause patients were associated with an absent/weak CRABP1 immunostaining (p= 0.008). Finally, CRABP1 and associated factors might be used as biomarkers to track the progression and persistence of cervical cancer on tissue. [ABSTRACT FROM AUTHOR]

Objectives: Long-term exposure to the human papillomavirus (HPV) is a known cause of squamous intraepithelial lesions that lead to cervical cancer. The loop electrosurgical excision procedure (LEEP) conization is an established treatment method. According to the latest recommendations, we present a paper to evaluate the effectiveness of various diagnostic methods of squamous intraepithelial lesions. Material and methods: We analyzed 229 patients who reported to District Public Hospital in Poznan to undergo LEEP conization in 2019-2021 during the SARS-CoV-2 Pandemic. The analysis included Pap smear/liquid-based cytology, HPV genotyping, colposcopy with targeted biopsy and LEEP-conization. We offered post-treatment HPV vaccination and, as a follow-up, performed HPV re-genotyping after six months. Results: In total, 89.1% of patients were HPV-positive. The coloscopy-directed biopsy (CDB) results show that almost 70% of the patients had high-grade intraepithelial lesions (HSIL). The diagnosis obtained by LEEP-conization showed that half of the women were diagnosed with HSIL and one-third with the low-grade squamous intraepithelial lesion (LSIL). The sensitivity of Pap smear/LBC accounted for 93.7% and was lower than for CDB, which reached 95.1%. Both diagnostic methods tend to underestimate the final diagnosis. Conclusions: The inclusion of a colposcopic examination in an in-depth diagnostic process in women with abnormal Pap smear results facilitates the identification of patients requiring therapeutic intervention. LEEP-conization may be used without the primary biopsy. It applies to multiparous women in the perimenopausal period, extensive abnormalities, discrepancies in test results, extensive visible abnormalities, and suspicion of invasive cervical cancer in the colposcopic examination. [ABSTRACT FROM AUTHOR]

Background: High-grade anal intraepithelial squamous lesion is significantly prevalent among men who have sex with men and are infected with the human immunodeficiency virus (HIV). This condition-the precursor to anal cancer-significantly increases the risk of developing it. Conversely, low-grade anal intraepithelial squamous typically follow a benign course and usually regress spontaneously., Materials and Methods: To describe a population of men who have sex with men living with HIV followed in a specialized anal cancer screening unit we conducted an observational, retrospective, and single-center study., Results: Ninety-four patients were analyzed, with a mean age of 39±9 years, and a 87% positivity rate for high-risk human papillomavirus (HR-HPV). At the initial visit, 47% presented with low-grade squamous intraepithelial lesions. The progression rate to high-grade squamous intraepithelial lesion was 37.2 per 100,000 patients/year. None of the patients developed anal cancer. Tobacco and alcohol consumption were associated with this progression., Discussion: In this series, longer duration of HIV infection, tobacco and alcohol use and the presence of HR-HPV were significantly associated with the occurrence of high-grade intraepithelial lesions. A lower risk of progression was seen in patients with higher education., Conclusion: In men who have sex with men living with HIV, the association of factors such as smoking, alcohol, the presence of HR-HPV and an increased burden of human papillomavirus disease makes these patients more susceptible to develop high-grade anal squamous lesions., (Copyright © 2024. Publicado por Elsevier España, S.L.U.)

Background: Cervical cancer is still a public health problem in many developing countries, like Nigeria. HIV infection makes HPV infections last longer, progress to squamous intraepithelial lesion of the cervix, and eventually lead to invasive cervical cancer. Objective. Find out how often squamous intraepithelial lesions (SIL) happen and what causes them in HIV-positive women in Sagamu, southwest Nigeria. Methods. A cross-sectional study was done with 165 women with HIV and 165 women without HIV. Pap smears were done on all of the people in the study. The data was looked at with IBM-SPSS Windows v. 23. Results: Both groups were about the same age and had the same number of children (P=0.194 and P=0.388, respectively). The participants' average age (SD) was 36.8 (5.6), and the median number of children they had was 3. HIV-positive women were much more likely to have an abnormal cytology smear (24.8%) than HIV-negative women (7.3%) (2 = 18.904, P 0.001). There wasn't a link between having HIV and the severity of cervical lesions (2 = 3.66, P = 0.162). A CD4 cell count of less than 350 cells/mm³ was found to be a strong predictor of an abnormal cervical cytological smear in HIV-positive women (AOR: 25.5; CI: 8.8-73.5; P 0.001). Conclusion. In Sagamu, Nigeria, the number of HIV-positive women with SIL of the cervix was much higher than the number of HIV-negative women with SIL of the cervix. HIV-positive women, especially those with a low number of CD4 cells, need cervical smear tests more often. This will make sure that pre-invasive lesions are found and treated as soon as possible. [ABSTRACT FROM AUTHOR]

Classification of oral cytology remains controversial under the Papanicolaou system. A uniform classification system would reduce inter-observer variability and also establish well-defined thresholds for management. This study evaluated the diagnostic accuracy of Bethesda (2014) system for dysplasia and malignancy in comparison to the Pap classification system and histopathological gold standard. 806 patients presenting with oral lesions were subjected to cytological diagnosis at our institution from 2017 to 2019. 100 of these patients underwent simultaneous biopsy for these lesions (subjects of this study). PAP-stained cytological smears from these patients were classified according to PAP and Bethesda 2014 systems and compared with their histopathological diagnosis. Bethesda classification showed 52.9% sensitivity, 86.7% specificity, PPV of 90.2% and NPV of 44.1% for detecting malignant/pre-malignant oral lesions. Sensitivity, specificity, PPV and NPV of the PAP system was 70%, 80%, 89.1% and 46.6% respectively. Statistically significant association was found between histopathological diagnosis and Bethesda classification: Spearman's correlation coefficient being 0.537 (p<0.001). The Bethesda classification system uses well-defined criteria. Our study suggests that it renders cytopathological diagnosis of oral lesions more rigorous and reproducible. Oral scrape cytology reported under the Bethesda system can present clinicians with more interpretable, objective and actionable reports [ABSTRACT FROM AUTHOR]

Background: Cervical cancer is still a public health problem in many developing countries, like Nigeria. HIV infection makes HPV infections last longer, progress to squamous intraepithelial lesion of the cervix, and eventually lead to invasive cervical cancer. Objective: Find out how often squamous intraepithelial lesions (SIL) happen and what causes them in HIV-positive women in Sagamu, southwest Nigeria. Methods. A cross-sectional study was done with 165 women with HIV and 165 women without HIV. Pap smears were done on all of the people in the study. The data was looked at with IBM-SPSS Windows v. 23. Results: Both groups were about the same age and had the same number of children (P=0.194 and P=0.388, respectively). The participants’ average age (SD) was 36.8 (5.6), and the median number of children they had was 3. HIV-positive women were much more likely to have an abnormal cytology smear (24.8%) than HIV-negative women (7.3%) (2 = 18.904, P 0.001). There wasn’t a link between having HIV and the severity of cervical lesions (2 = 3.66, P = 0.162). A CD4 cell count of less than 350 cells/mm3was found to be a strong predictor of an abnormal cervical cytological smear in HIV-positive women (AOR: 25.5; CI: 8.8-73.5; P 0.001). Conclusion: In Sagamu, Nigeria, the number of HIV-positive women with SIL of the cervix was much higher than the number of HIVnegative women with SIL of the cervix. HIV-positive women, especially those with a low number of CD4 cells, need cervical smear tests more often. This will make sure that pre-invasive lesions are found and treated as soon as possible.

The anal canal is comprised of heterogenous elements, including colorectal epithelium in the upper portion, transitional epithelium in the middle portion, and squamous epithelium in the lower portion. This gives rise to a wide range of entities. The benign tumor/tumor-like conditions include hemorrhoids, hidradenoma papilliferum, and fibroepithelial polyps. The anal canal is also susceptible to dysplastic lesions associated with human papillomavirus (HPV) ranging from low-grade squamous intraepithelial lesions/condyloma acuminatum to high-grade squamous intraepithelial lesions. The latter being more commonly associated with high-risk HPV (HPV-16 and HPV-18). Buschke-Lowenstein tumors (BLT), a unique locally aggressive HPV associated neoplasm, are characterized by a pushing endophytic border with morphologic similarities to condylomas. These precursor HPV lesions can give rise to squamous cell carcinoma, the most common malignant neoplasm in the anus. Squamous cell carcinomas of the anal region have a wide morphologic spectrum including keratinization and basaloid appearance. A well-differentiated variant of squamous cell carcinoma, verrucous carcinoma, is locally aggressive and has a pushing border, similar to BLT. However, verrucous carcinomas are not associated with HPV. Other malignant neoplasms of the anus include adenocarcinoma, either primary to the anal glands, colorectal epithelium of the upper anus, or HPV-associated anogenital-type adenocarcinoma. A small subset of primary adenocarcinomas of the anus can give rise to Paget’s disease, although Paget’s disease can also arise as a primary neoplasm in the anal canal or spread from carcinoma of nearby anatomic sites. Overall, the morphologic pattern and immunohistochemical pattern of these entities can help distinguish between them.

Purpose: This study aimed to determine the potential clinical use of dynamic thiol–disulfide balance in cases with preinvasive lesions of the cervix. Methods: One hundred and sixteen patients with high-grade squamous intraepithelial lesion, 100 patients with low-grade squamous intraepithelial lesion, and 110 healthy controls were enrolled in the study. A fully automated colorimetric system was used to determine the levels of thiol–disulfide parameters. The ischemia-modified albumin, total oxidant–antioxidant capacity, and oxidative stress index of the retrieved cases were further analyzed. Results: Native thiol and total thiol levels are significantly lower in the high-grade squamous intraepithelial lesion group according to control group (p: 0.004 and 0.015, respectively). Disulfide level is significantly increased in the high-grade squamous intraepithelial lesion group compared to control group (p: 0.004). Oxidative stress index levels in high-grade squamous intraepithelial lesion group were observed as significantly higher according to the control group (p: 0.014). Ischemia-modified albumin levels in the high-grade squamous intraepithelial lesion group were observed as significantly higher compared to the control group (p: 0.020). Disulfide levels are positively correlated with risk type of Human papillomavirus (r: 0.420, p < 0.001). Conclusion: The analysis of dynamic thiol–disulfide balance revealed considerable oxidative damage in patients with Human papillomavirus-related cervical precursor lesions compared to women with ordinary cytology specimens. Therefore, investigation of thiol–disulfide balance with presented method represents a new promising test for early diagnosis and management of women at high risk for cervical cancer. [ABSTRACT FROM AUTHOR]

Background: High-risk human papillomavirus (HR-HPV) infection is the main cause of cervical cancer, but additional alterations are necessary for its development. Abnormal DNA methylation has an important role in the origin and dissemination of cervical cancer and other human tumors. In this work, we analyzed the methylation of eight genes (AJAP1, CDH1, CDH13, MAGI2, MGMT, MYOD1, RASSF1A and SOX17) that participate in several biological processes for the maintenance of cell normality. We analyzed DNA methylation by methylation-specific PCR (MSP) and HPV infection using the INNO‑LiPA genotyping kit in 59 samples diagnostic of normal cervical tissue (non-SIL), 107 low-grade squamous intraepithelial lesions (LSILs), 29 high-grade squamous intraepithelial lesions (HSILs) and 51 cervical cancers (CCs). Results: We found that all samples of LSIL, HSIL, and CC were HPV-positive, and the genotypes with higher frequencies were 16, 18, 51 and 56. In general, the genes analyzed displayed a significant tendency toward an increase in methylation levels according to increasing cervical lesion severity, except for the CDH13 gene. High CpG island methylator phenotype (CIMP) was associated with a 50.6-fold (95% CI 4.72–2267.3)-increased risk of HSIL and a 122-fold risk of CC (95% CI 10.04–5349.7). Conclusions: We found that CIMP high was significantly associated with HSIL and CC risk. These results could indicate that CIMP together with HR-HPV infection and other factors participates in the development of HSIL and CC. [ABSTRACT FROM AUTHOR]

Background & Objective: Cervical cancer is the most common cancer in women worldwide with high mortality, necessitating quicker diagnostic methods. We wish to enhance the existing cervical biopsies of Squamous Intraepithelial Lesions (SIL) using p16 and Ki67 as surrogate markers to assess correlation between its positivity and histological grade of the lesion. Methods: Analysis of p16 and Ki67 expression was done on 31 histopathologically diagnosed cases of SILs. Positive expression of p16 was assessed based on a scoring system and compared with histology and cytology. Ki67 expression was studied and the correlation was observed with degree of dysplasia. Twenty cases of chronic cervicitis was assigned to the control group for comparison. Result: Cases of HSIL showed greater expression of p16 as compared to LSIL. Sensitivity of p16 for HSIL was higher than that for LSIL. The specificity for HSIL and LSIL was 100%. Ki67 expression correlated well with the degree and level of dysplasia with a significant P-value of 0.002. Conclusion: p16 and Ki67 positivity of SILs should point towards further evaluation. The expressions of p16 and Ki67 are useful markers for confirmation of SILs and in predicting HPV infection which can be further confirmed by HPV DNA testing.

The purpose of this study was to investigate the relation between the presence of cervical dysplasia and HPV infection in women of the Republic of Sakha (Yakutia) (RS(Y)), to analyze cytological samples for detecting the presence of pathology and the degree of cervical dysplasia, and to detect the level of HPV infection, and establish the dependence of HPV-test positivity on the presence of dysplasia and the woman’s age. Methods and Results: Cytological material was taken from cervix uteri and cervical canal scraping from 100 patients aged between 22 and 60 years (mean age of 38.9±9.2 years). The sample from every patient was obtained by traditional cytology and liquid-based cytology (LBC) on the automated system CellPrep Plus (Korea). The results of LBC were interpreted under the terminology system of the Bethesda System (2015). HPV detection and typing (types 6, 11, 44, 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, 82) were performed by real-time PCR using commercial test systems according to their instructions. The analysis of cytological samples by the LBC method in women of RS(Y) revealed a high prevalence of NILM in the samples to compare with intraepithelial lesions of the cervix. Among intraepithelial lesions, LSIL was significantly more common. Positive HPV tests were observed in less than half of the cases. The vast majority of positive HPV tests were high–risk HPV types, and 16 and 51 types marked the most frequent. The positive tests for high–risk HPV types in women with NILM and intraepithelial lesions (LSIL, HSIL, ASCUS) were approximately equal. The frequency of positive tests for high–risk HPV types in women under 45 was higher than in women 46 years and older. Conclusion: The combined use of LBC and HPV testing for high–risk HPV infection improves the effectiveness of diagnostics by reducing the amount of uninformative material and allows detecting pathological changes at an earlier stage.

Abstract Background The first HPV vaccines licensed targeted two HPV types responsible for most cervical cancers. A 9-valent vaccine (9vHPV), targeting 5 additional types, was introduced in 2016 and is currently the only HPV vaccine available in the United States. Previous studies demonstrated high rates of HPV infection in Alaska Native (AN) women. We sought to measure prevalence of high risk HPV types in AN women undergoing colposcopy and to determine those preventable by vaccination. Methods For this cross-sectional study, we recruited women who were undergoing colposcopy for clinical indications at Alaska Native Medical Center to obtain cervical brush biopsy samples. Specimens were shipped to Atlanta, Georgia for DNA extraction, HPV detection, and typing using L1 PCR with type-specific hybridization to detect 37 HPV types. Results Four hundred eighty eight specimens from 489 women were tested. At least one HPV type was found in 458 (94%) specimens. Of 458 participants who were HPV positive, 332 (72%) had two or more types. At least one type targeted by 9vHPV was detected in 95% of participants with CIN 3 (21/22), 82% with CIN 2 (37/45), and 65% with CIN 1 (119/184). (p

Introduction: Dual immunostaining for p16/Ki67 is FDA-approved for use on liquid-based cervical cytology specimens; however, the utility of dual staining in anal cytology especially for ASCUS risk stratification is not well established., Methods: We investigated dual staining performance on anal cytology specimens and correlated with subsequent cytologic interpretation, high-risk HPV status, and anal biopsy results. Dual staining for p16/Ki-67 was performed on all liquid-based anal cytology specimens from December 2021 to June 2022 (n = 43)., Results: Three patients had high grade squamous intraepithelial lesion (HSIL/AIN2-3) on biopsy; dual staining was positive in all three cases. All HR-HPV negative cases were negative for dual staining. Among the 12 ASCUS samples with subsequent anal biopsy results all also had HR-HPV testing. Due to small sample size of cases with squamous intraepithelial lesion (SIL) diagnosed on biopsy, the sensitivity and positive predictive value was not calculated. However, the specificity and negative predictive value of p16/Ki-67 dual staining for SIL of any grade on biopsy were 1 (95% CI: 0.66-1) and 0.9 (95% CI: 0.65-0.97) respectively, whereas the specificity and negative predictive value of HR-HPV testing for SIL of any grade on biopsy were 0.44 (95% CI: 0.14-0.79) and 0.8 (95% CI: 0.41-0.96) respectively., Conclusion: Dual p16/Ki-67 staining indicates transforming HPV infection and could help serve as an ancillary test for risk stratification for atypical anal cytology specimens. Among ASCUS samples, dual staining was specific for SIL of any grade with a high negative predictive value and therefore could be useful in clinical practices with limited availability for follow-up care., (© 2024 Wiley Periodicals LLC.)

Background: High-grade anal intraepithelial squamous lesion is significantly prevalent among men who have sex with men and are infected with the human immunodeficiency virus (HIV). This condition-the precursor to anal cancer-significantly increases the risk of developing it. Conversely, low-grade anal intraepithelial squamous typically follow a benign course and usually regress spontaneously., Materials and Methods: To describe a population of men who have sex with men living with HIV followed in a specialized anal cancer screening unit we conducted an observational, retrospective, and single-center study., Results: Ninety-four patients were analyzed, with a mean age of 39±9 years, and a 87% positivity rate for high-risk human papillomavirus (HR-HPV). At the initial visit, 47% presented with low-grade squamous intraepithelial lesions. The progression rate to high-grade squamous intraepithelial lesion was 37.2 per 100,000 patients/year. None of the patients developed anal cancer. Tobacco and alcohol consumption were associated with this progression., Discussion: In this series, longer duration of HIV infection, tobacco and alcohol use and the presence of HR-HPV were significantly associated with the occurrence of high-grade intraepithelial lesions. A lower risk of progression was seen in patients with higher education., Conclusion: In men who have sex with men living with HIV, the association of factors such as smoking, alcohol, the presence of HR-HPV and an increased burden of human papillomavirus disease makes these patients more susceptible to develop high-grade anal squamous lesions., (Copyright © 2024. Publicado por Elsevier España, S.L.U.)

Aim: To compare the presence of Human Papilloma Virus (HPV) and Squamous Intraepithelial Lesion (SIL) in pregnant and non-pregnant adolescents treated at the “Maternidad Dr. Armando Castillo Plaza” in Maracaibo, Venezuela. Patients and Methods: A comparative research with non-experimental transectional and field design was performed; where 46 pregnant adolescents (cases) and 46 non-pregnant adolescents (controls) was included, chosen by random probability sampling, who underwent identification of factors associated with the pathology, evaluation by pap-smear and HPV genotyping by chain reaction of polymerase (PCR). Results: It was found that 32.6% of pregnant women had low grade SIL ( HPV or CIN 1) compared to 21.7% in non-pregnant women, with a risk twice higher (OR [95% CI] = 2.44 [1.05 -5.65]). The molecular diagnosis was positive in half of the total sample, being higher in pregnant women (52.1 vs. 47.9p

Vaginal microbiome may have a role in HPV infection and cervical neoplasm. To explore potential vaginal microbiome biomarkers for high-grade squamous intraepithelial lesion (HSIL), and to find the best scheme to facilitate the current cervical cancer screening strategy. This study enrolled 272 women, including 83 confirmed with HSIL, 86 with HPV infection but without cervical neoplasm, and 103 without HPV infection as controls. Vaginal microbiome composition was determined by sequencing of barcoded 16S rDNA gene fragments (V4) on Illumina HiSeq2500. The relative increasing abundance of Stenotrophomonas, Streptococcus, and Pseudomonas, and a concomitant paucity of Dialister, unidentified Prevotellaceae, Faecalibacterium, Bifidobacterium, and Bacteroides, were related with HSIL, which can be used to predict the development of HISL in high-risk HPV infected patients. The relative abundance of Stenotrophomonas being over 0.0090387%, or Faecalibacterium being under 0.01420015%, or Bifidobacterium being under 0.0116183% maybe a good predictor for HSIL for those infected with HPV 16 and/or 18. The relative abundance of Stenotrophomonas being over 0.01549105%, or Streptococcus being over 0.48409585%, or Bacteroides being under 0.0296912% maybe a good predictor for HSIL for those infected with the 12 other high-risk types of HPV with concurrent abnormal TCT results. This study revealed that potential vaginal microbiome biomarkers may relate to HSIL, and can facilitate the cervical cancer screening.

Introduction: Persistent inflammatory smear is a benign finding on pap test but is associated with premalignant lesion of the cervix. Further evaluation is therefore necessary. This study was done to determine the prevalence of cervical intraepithelial lesions in women with persistent inflammatory smear. Methods: This is descriptive observational study conducted in Department of Obstetrics and Gynaecology of tertiary care centre of Nepal from 15th May 2020 to 14th May 2021 after obtaining ethical clearance from Institutional Review Board (Reference no MEMG/IRC/338/GA). Women with two consecutive pap smear reports showing inflammatory findings were enrolled. Colposcopy was performed and Modified Reid’s colposcopic index was used to grade the lesions. Colposcopic guided biopsy was taken and tissue sent for histopathology for abnormal colposcopic lesions. Data analysis was done using Statistical Package for Social Sciences version 21 and frequency and percentages were used to present data. Point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data. Results: Among 115 women, 57 (49.5%) at 95% Confidence Interval (40.37-58.63) had Cervical Intraepithelial lesions. Among them 48 (41.7%) had low grade intraepithelial lesions and 9 (7.8%) had high grade lesions on colposcopy. Conclusions: The prevalence of cervical intraepithelial lesions in women with persistent inflammatory smear on pap was higher in our study compared to other studies.

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Objective: This research was conducted to evaluate if colposcopy and cervical biopsy could predict the extent of premalignant uterine cervix lesions and if there is still a place for hysterectomy for treating recurrent lesions in patients who underwent previous cervical surgical procedures. Materials and Methods: This was a retrospective analysis of patients after large loop excision of the transformation zone (LLETZ) in whom hysterectomy was performed in the authors' institution between 2010 and 2018 due to recurrent low-grade squamous intraepithelial lesions (LSIL) or high-grade squamous intraepithelial lesions (HSIL). A comparison between preoperative and postoperative histopathologic diagnoses (HPD) was made. The modes of hysterectomy and complication rates were analyzed. Results: Of 50 patients, preoperative and postoperative HPD matched in 46%. HPD was upgraded to HSIL in 2% and downgraded to LSIL in 16%. In 20% (all with HSIL), no lesions were found postoperatively. One patient had a microinvasive carcinoma. In 12%, the procedure indication was a pathologic Papanicolaou smear excluding HSIL; LSIL was found in only 1 of these patients. Laparoscopy was performed in 49%, vaginal in 33%, abdominal in 8%, and laparoscopically assisted vaginal approach in 12%. Postoperative complications occurred in 12%, and treatment was successful in 98%. Conclusions: Hysterectomy should be performed with care in recurrent SIL—only after exclusion of invasive cancer. With more than 50% of mismatches between pre- and postoperative diagnoses in the current study, it is vital to improve preoperative diagnostics. If hysterectomy is indicated, patient safety and postoperative complications should be taken into account and a minimally invasive approach should be taken if possible. [ABSTRACT FROM AUTHOR]

Aim: The value of top‐hat procedure during loop electrosurgical excision procedure (LEEP) for squamous intraepithelial lesions had remained controversial. This study aimed to evaluate whether top‐hat specimens positive for cervical intraepithelial neoplasia (CIN) on histopathology can serve as an independent risk factor to predict treatment failure. Methods: We reviewed the medical records of patients who underwent LEEP and top‐hat procedures in Peking University First Hospital between 2011 and 2016 and collected their follow‐up data until January 2019. We compared the pathological risk factor of treatment failure. Multivariate analysis was carried out to clarify the independent determinant of treatment failure. A Cox model was used to assess the influence of different variables on cumulative treatment failure rates. Results: This study included 295 cases for short‐term treatment failure, and among them, 178 cases were used to study the long‐term. The presence of CIN in top‐hat was relevant to short‐term treatment failure (OR = 9.64, 95% CI 2.55–36.4) despite a clear margin. On multivariate analysis, top‐hat result (OR = 3.58, 95% CI 1.30–9.89), age ≥ 50 (OR = 10.2, 95%CI 3.64–28.3) and post‐treatment HPV 16/18 infection (OR = 2.35, 95%CI 1.19–4.63) were independent risk factors in predicting short‐term failure. In the Cox model, these factors were also associated with higher cumulative failure rates. Conclusion: The current study supported the predictive value of top‐hat procedure in short‐term failure after LEEP. Typically, women with positive top‐hat need closer follow‐up despite their negative margin status. Older women with positive top‐hat findings and HPV 16/18 infections after the treatment suffer a higher risk of short‐term failure. [ABSTRACT FROM AUTHOR]

Background: In the life of a woman, after 40 years of age, onset of menopause occurs during which hormonal imbalances take place. The present study is aimed at finding out cytopathological changes in the cervical epithelium associated with this hormonal disturbance. Materials and Methods: Cervical cancer screening program is in progress under auspices of Era's Lucknow Medical College and Hospital, Lucknow, since May 2013, in the villages of Lucknow West through camp approach. Till September 2017, 140 camps have been organized and 2440 women attending the camp have been cytologically examined. Out of these, 1534 women were perimenopausal, 165 premenopausal, and 441 postmenopausal. The cytopathological changes have been studied in these three categories of women in relation to different predisposing factors to the cervical carcinogenesis. Results: The squamous intraepithelial lesion (SIL) rate was higher with onset of menopause in the premenopausal women. The SIL rate was higher with nulliparity in these women as well as in the postmenopausal women and also with different gynecological symptoms and clinical lesions of the cervix. The SIL changes associated with HPV and HSV were also higher in them. Conclusion: A high SIL rate found with onset of menopause may be the outcome of gradual estrogen withdrawal in the premenopausal women. Hence, cytological evaluation is mandatory in women between 41 and 45 years of age to rule out any occurrence of cervical cytopathology.

Aim: The incidence of anal squamous cell carcinoma (SCC) has increased dramatically in the USA. The squamous intraepithelial lesion has been identified as a precursor lesion to SCC, stratifying the abnormality into low grade or high grade. There have been studies on the prevalence of incidentally found SCC in haemorrhoidectomy specimens, but there are no studies to date on the incidence of dysplasia. The purpose of this study was to establish a baseline incidence of dysplasia that provides helpful information for future epidemiological studies. Methods: This is a retrospective review of patients who underwent haemorrhoidectomy from 2005 to 2019. Pathology regarding the type of dysplasia, medications, and diagnoses that may predispose to immunosuppression were collected. Results: In all, 810 patients with a mean age of 51.7 (range 20–91) years underwent haemorrhoidectomy. Eighteen (2.2%) of the patients had abnormal pathology (low‐grade squamous intraepithelial lesion, 3; high‐grade squamous intraepithelial lesion, 12; SCC, 2; adenocarcinoma, 1). Thirty‐seven (4.5%) of the entire cohort had some risk factors for immunosuppression: chronic steroid use (nine), human immunodeficiency virus (HIV) (13), biologic medications (six), transplant recipients (two) and immunocompromising diseases (four). Only 4/18 patients had an immunosuppression risk in that all four of these patients were HIV‐positive. Surveillance following excision was undertaken for an average of 6 (range 1–12) months, during which time four patients underwent a repeat biopsy. Discussion: Anal dysplasia found in an otherwise asymptomatic population has a prevalence of 2.2%. This finding supports the routine examination of benign anorectal specimens undergoing microscopic examination. Interestingly, the majority of the patients identified had no immunosuppressant risk factors. [ABSTRACT FROM AUTHOR]

Papanicolaou testing is effective in identifying squamous intraepithelial lesions of the cervix. Endocervical adenocarcinoma (EAC) and adenocarcinoma in situ (AIS) are far less commonly identified. Endocervical curettings (ECCs) are usually obtained after colposcopic biopsy, sample the endocervical canal, and aid in the detection of endocervical glandular lesions. Here, we examine the utility of Papanicolaou testing and endocervical curetting for detecting AIS and EAC. Cases from 2007 to 2019 with a histologically confirmed diagnosis of AIS and EAC were identified and the clinical data and diagnostic material, including the cytology and surgical specimens, obtained. A total of 108 cases of AIS and EAC were identified, Papanicolaou tests were performed in 97 of these cases, and ECC in 87. AIS or EAC were detected in 46.4% of Papanicolaou tests; 41.4% of ECC showed AIS or EAC. A total of 92.7% of cases were positive for high-risk human papillomavirus (HPV) and concurrent squamous intraepithelial lesion was present in 53.3% of cases. AIS or EAC were more commonly identified in cases without concurrent squamous intraepithelial lesions. Papanicolaou testing and endocervical curettings have a low detection rate for AIS and EAC. The majority of AIS and EAC cases test positive for high-risk HPV. Papanicolaou test and ECC show different detection rates and are complementary tools in patients with AIS and EAC. In some settings, an ECC can increase the diagnostic sensitivity and specificity of the pathologic diagnosis. • Papanicolaou testing and endocervical curettings have a low detection rate for AIS and EAC. • The majority of AIS and EAC test positive for high-risk HPV. • Papanicolaou testing and ECC show different detection rates and are complementary tools in patients with AIS and EAC. • ECC can increase the diagnostic sensitivity and specificity of the pathologic diagnosis. [ABSTRACT FROM AUTHOR]

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Background & Objective: Cervical cancer is the most common cancer in women worldwide with high mortality, necessitating quicker diagnostic methods. We wish to enhance the existing cervical biopsies of Squamous Intraepithelial Lesions (SIL) using p16 and Ki67 as surrogate markers to assess correlation between its positivity and histological grade of the lesion. Methods: Analysis of p16 and Ki67 expression was done on 31 histopathologically diagnosed cases of SILs. Positive expression of p16 was assessed based on a scoring system and compared with histology and cytology. Ki67 expression was studied and the correlation was observed with degree of dysplasia. Twenty cases of chronic cervicitis was assigned to the control group for comparison. Results: Cases of HSIL showed greater expression of p16 as compared to LSIL. Sensitivity of p16 for HSIL was higher than that for LSIL. The specificity for HSIL and LSIL was 100%. Ki67 expression correlated well with the degree and level of dysplasia with a significant P-value of 0.002. Conclusion: p16 and Ki67 positivity of SILs should point towards further evaluation. The expressions of p16 and Ki67 are useful markers for confirmation of SILs and in predicting HPV infection which can be further confirmed by HPV DNA testing. [ABSTRACT FROM AUTHOR]

It is crucial to classify cervical lesions into high-grade squamous intraepithelial lesions (HSILs) and low-grade SILs (LSILs), as LSILs are conservatively treated by observation, based on an expectation of natural regression, whereas HSILs usually require electrosurgical excision. In the present study, peripheral blood gene expression profiles were analyzed to identify transcriptomic biomarkers distinguishing HSILs from LSILs. A total of 102 blood samples were collected from women with cervical SILs (66 HSIL and 36 LSIL) for microarray hybridization. Candidate gene signatures were identified using AdaBoost algorithms, and a predictive model was constructed using logistic regression to differentiate HSILs from LSILs. To correct for possible bias as a result of the limited sample size and to verify the stability of the predictive model, a two-fold cross validation and null set analysis was conducted over 1,000 iterations. The functions of the transcriptomic biomarkers were then analyzed to elucidate the pathogenesis of cervical SIL. A total of 10 transcriptomic genes (STMN3, TRPC4AP, DYRK2, AGK, KIAA0319L, GRPEL1, ZFC3H1, LYL1, ITGB1 and ARHGAP18) were identified. The predictive model based on the 10-gene panel exhibited well-discriminated power. A cross validation process using known disease status exhibited almost the same performance as that of the predictive model, whereas null-set analysis with randomly reassigned disease status exhibited much lower predictive performance for distinguishing HSILs from LSILs. These biomarkers were involved in the 'Rho GTPase cycle', 'mitochondrial protein import', 'oncogenic MAPK signaling', 'integrin cell surface interaction' and 'signaling by BRAF and RAF fusions'. In conclusion, peripheral blood gene expression analysis is a promising method for distinguishing HSILs from LSILs. The present study proposes 10 candidate genes that could be used in the future as diagnostic biomarkers and potential therapeutic targets for cervical SILs. A simple, non-invasive blood test would be clinically useful in the diagnosis and classification of patients with cervical SILs. [ABSTRACT FROM AUTHOR]

Background: The first HPV vaccines licensed targeted two HPV types responsible for most cervical cancers. A 9-valent vaccine (9vHPV), targeting 5 additional types, was introduced in 2016 and is currently the only HPV vaccine available in the United States. Previous studies demonstrated high rates of HPV infection in Alaska Native (AN) women. We sought to measure prevalence of high risk HPV types in AN women undergoing colposcopy and to determine those preventable by vaccination. Methods: For this cross-sectional study, we recruited women who were undergoing colposcopy for clinical indications at Alaska Native Medical Center to obtain cervical brush biopsy samples. Specimens were shipped to Atlanta, Georgia for DNA extraction, HPV detection, and typing using L1 PCR with type-specific hybridization to detect 37 HPV types. Results: Four hundred eighty eight specimens from 489 women were tested. At least one HPV type was found in 458 (94%) specimens. Of 458 participants who were HPV positive, 332 (72%) had two or more types. At least one type targeted by 9vHPV was detected in 95% of participants with CIN 3 (21/22), 82% with CIN 2 (37/45), and 65% with CIN 1 (119/184). (p < 0.001) HPV 16 or 18 were detected in 77% (17/22) with CIN 3, 53% (24/45) with CIN 2, and 36% (67/184) with CIN 1. (p < 0.001). Conclusions: A substantial proportion of AN women attending colposcopy clinic had evidence of HPV 16/18 infection, as well as other high risk types targeted by 9vHPV. At least one 9vHPV type was detected in 62% of the participants overall, and 95% of participants with CIN3. AN women are expected to benefit from vaccination against HPV 16/18, and will have greater benefit from 9vHPV. Information from this study could be used to develop public health strategies to increase vaccine uptake, or to track HPV genotype prevalence over time. [ABSTRACT FROM AUTHOR]

Objective: To evaluate if the intraoperative human papillomavirus (IOP-HPV) test has the same prognostic value as the HPV test performed at 6 months after treatment of high-grade squamous intraepithelial lesion (HSIL) to predict treatment failure.Design: Prospective cohort study.Setting: Barcelona, Spain.Population: A cohort of 216 women diagnosed with HSIL and treated with loop electrosurgical excision procedure (LEEP).Methods: After LEEP, an HPV test was performed using the Hybrid Capture 2 system. If this was positive, genotyping was performed with the CLART HPV2 technique. The IOP-HPV test was compared with HPV test at 6 months and with surgical margins.Main Outcome Measure: Treatment failure.Results: Recurrence rate of HSIL was 6%. There was a strong association between a positive IOP-HPV test, a positive 6-month HPV test, positive HPV 16 genotype, positive surgical margins and HSIL recurrence. Sensitivity, specificity, and positive and negative predictive values of the IOP-HPV test were 85.7, 80.8,24.0 and 98.8% and of the HPV test at 6 months were 76.9, 75.8, 17.2 and 98.0%.Conclusion: Intraoperative HPV test accurately predicts treatment failure in women with cervical intraepithelial neoplasia grade 2/3. This new approach may allow early identification of patients with recurrent disease, which will not delay the treatment. Genotyping could be useful in detecting high-risk patients.Tweetable Abstract: IOP-HPV test accurately predicts treatment failure in women with CIN 2/3. [ABSTRACT FROM AUTHOR]

Introduction: Bcl-2-associated athanogene 3 (BAG3) is a protein involved in apoptosis and stress response, which is overexpressed in invasive cervical cancer. However, nothing is known about BAG3 expression in precancerous lesions of the uterine cervix. We aimed to evaluate the expression of BAG3 in cervical intraepithelial neoplasia/squamous intraepithelial lesions (CIN/SIL).Material and Methods: Forty patients (16 CIN1/L-SIL, 11 CIN2/H-SIL and 13 CIN3/H-SIL) were assessed by immunohistochemistry for BAG3. The intensity of BAG3 expression was categorized as null, minimal, weak, moderate or strong. The association of BAG2 intensity of expression with the grade of dysplasia was assessed using Chi-square test (significant P value <0.05).Results: In all normal controls, BAG3 expression was negative. In L-SIL specimens, BAG3 expression was confined to the basal third of the epithelium, with an intensity minimal in nine cases (56.3%), weak in six (37.5%) and strong in one (6.3%). In H-SIL specimens, BAG3 expression involved also the two upper thirds of the epithelium, with an intensity moderate in 13 cases (54.2%; 8 CIN2 and 5 CIN3) and strong in 11 cases (45.8%; 3 CIN2 and 8 CIN3). The distribution of BAG3 expression correlated perfectly with the grade of dysplasia (P = 0.0); a moderate/strong expression of BAG3 was significantly associated with H-SIL (P < 0.0001), with no significant difference between CIN2 and CIN3 (P = 0.1228).Conclusions: In CIN/SIL, both distribution and intensity of BAG3 expression correlate directly with the grade of dysplasia, supporting the involvement of BAG3 in all phases of cervical carcinogenesis and its possible diagnostic and prognostic role in cervical premalignant lesions. [ABSTRACT FROM AUTHOR]

Cervical squamous intraepithelial lesions (SILs) may present a diagnostic challenge due to their morphological similarity to benign conditions and variability in interpretation, necessitating the exploration of objective biomarkers to aid in their identification and grading. This study evaluates the immunohistochemical markers Carbonic Anhydrase IX (CAIX) and ProEx-C to assess their diagnostic potential in cervical SILs. We retrospectively identified 56 SIL cases, including 20 low-grade SILs (LSIL) and 36 high-grade SILs (HSIL), alongside a control group of nine chronic cervicitis cases. Immunohistochemical staining was performed on formalin-fixed, paraffin-embedded tissue blocks, and the sensitivity and specificity of CAIX and ProEx-C were evaluated for detecting and grading SILs. CAIX exhibited a sensitivity of 64.3 % and a specificity of 100 % for detecting SILs. ProEx-C staining displayed a sensitivity of 66.1 % and a specificity of 100 % for detecting SILs. The combination of CAIX and ProEx-C staining increased the sensitivity for detecting SILs to 80.4 % without compromising the specificity. These markers alone or in combination were not found to be significant in distinguishing LSIL from HSIL. Both markers showed positivity in benign endocervical and squamous epithelium in high rates. In conclusion, CAIX and ProEx-C are valuable immunohistochemical markers for detecting SILs in cervical specimens, with high sensitivity and specificity. Further research is needed to elucidate their roles in cervical carcinogenesis and their relationship with HPV infection. • CAIX and ProEx-C show high sensitivity and specificity for detecting squamous intraepithelial lesions (SILs). • CAIX and ProEx-C do not reliably differentiate between LSILs and HSILs. • Benign cells are often positive for CAIX and ProEx-C, hence, correlating staining with cytomorphology remains essential. [ABSTRACT FROM AUTHOR]

Ellagic acid (EA) and Annona Muricata (AM) have antioxidant, anticarcinogenic and antiviral activity demonstrated by in vitro models. This pilot study investigated the in vivo potential anti-viral activity in women affected by Low squamous intraepithelial lesion (L-SIL) related to high risk human papilloma virus (HR-HPV), and the ability to modify the oncoproteins expression in the cervical lesion thickness. Sixty women affected by HR-HPV related L-SIL, were randomly divided into two groups: group A (n = 30) supplemented with EA (16 mg) + AM (100 mg) 2 times daily for 6 months and group B (n = 30) administered with placebo. HR-HPV clearance was obtained in 74% of cases in group A compared to 25% of cases in group B (p = 0.001) and p21 expression in LSIL thickness increased in 63.2% of cases in group A compared to 20% in group B (p = 0.03). AE/AM supplementation significantly induces HR-HPV elimination and stimulates p21 expression in LSIL thickness.

Programmed death-ligand 1 (PD-L1) is overexpressed in cervical carcinoma, hindering tumor destruction. The aim of this study was to assess PD-L1 expression by immunohistochemistry in cervical squamous cell carcinoma (SCC) and squamous intraepithelial lesions (SILs) from human immunodeficiency virus-positive (HIV+) and human immunodeficiency virus-negative (HIV-) patients. A total of 166 SCC and SIL samples of HIV+ and HIV- patients were included and analyzed for PD-L1 expression through tumor proportion score (TPS), and results were stratified in five TPS groups using SP263 antibody and, combined positive score (CPS) using 22C3 antibody. In cohort 1 (SP263 clone), all HIV+ patients were negative for intraepithelial lesion or malignancy (NILM), and low-grade squamous intraepithelial lesions (LSILs) scored < 1; and 87.5% of high-grade squamous intraepithelial lesions (HSILs) adjacent to SCC, 19% of HSILs non-adjacent to SCC, and 69% of SCCs scored ≥ 1 (15.4% scored 5). In HIV- patients, all NILM, LSILs, HSILs adjacent to SCC, and two HSILs non-adjacent to SCC scored < 1. SCC: 88.2% scored ≥ 1 and 5.9% scored 5. In cohort 2 (SP263 and 22C3 clones), 16.7% of HIV+ patients with SCC were positive with both clones, CPS ≥ 1 (22C3) or score 5 (≥ 50%) (SP263), showing no significant differences in positivity between both clones. These results indicate that a relatively low percentage of SCCs (16.7%; both in HIV+ and in HIV- patients) express PD-L1 (TPS ≥ 50% and CPS > 1), which may be due to some samples being archival material, sample characteristics, or use of different methodologies, highlighting the need for standardization of PD-L1 assessment in SCC of the cervix. The fact that PD-L1 is overexpressed in SILs of HIV+ patients suggests potential additional applications for immunotherapy in this disease., (© 2023. The Author(s).)

Objective: In this study, we established a Sprague-Dawley rat model of vulvar squamous intraepithelial lesions and investigated the impact of focused ultrasound on the expression of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and mutant type p53 (mtp53) in the vulvar skin of rats with low-grade squamous intraepithelial lesions (LSIL)., Materials and Methods: The vulvar skin of 60 rats was treated with dimethylbenzanthracene (DMBA) and mechanical irritation three times a week for 14 weeks. Rats with LSIL were randomly allocated into the experimental group or the control group. The experimental group was treated with focused ultrasound, while the control group received sham treatment., Results: After 14 weeks treatment of DMBA combined with mechanical irritation, LSIL were observed in 44 (73.33%) rats, and high-grade squamous intraepithelial lesions (HSIL) were observed in 14 (23.33%) rats. 90.91% (20/22) of rats showed normal pathology and 9.09% (2/22) of rats exhibited LSIL in the experimental group at four weeks after focused ultrasound treatment. 22.73% (5/22) of rats exhibited LSIL, 77.27% (17/22) of rats progressed to HSIL in the control group. Compared with the control-group rats, the levels of HIF-1α, VEGF and mtp53 were significantly decreased in experimental-group rats ( p  < 0.05)., Conclusions: These results indicate that DMBA combined with mechanical irritation can induce vulvar squamous intraepithelial lesion in SD rats. Focused ultrasound can treat LSIL safely and effectively, prevent the progression of vulvar lesions, and improve the microenvironment of vulvar tissues by decreasing the localized expression of HIF-1α, VEGF, and mtp53 in rats.

Persistent infection with the human papillomavirus 16 (HPV 16) is the cause of half of all cervical carcinomas (CC) cases. Moreover, mutations in the oncoproteins E6 and E7 are associated with CC development. In this study, E6/E7 variants circulating in southern Mexico and their association with CC and its precursor lesions were evaluated. In total, 190 DNA samples were obtained from scrapes and cervical biopsies of women with HPV 16 out of which 61 are from patients with CC, 6 from patients with high-grade squamous intraepithelial lesions (HSIL), 68 from patients with low-grade squamous intraepithelial lesions (LSIL), and 55 from patients without intraepithelial lesions. For all E7 variants found, the E7-C732/C789/G795 variant (with three silent mutations) was associated with the highest risk of CC (odd ratio (OR) = 3.79, 95% confidence interval (CI) = 1.46–9.85). The analysis of E6/E7 bicistron conferred to AA-a*E7-C732/C789/G795 variants revealed the greatest increased risk of CC (OR = 110, 95% CI = 6.04–2001.3), followed by AA-c*E7-C732/C789/G795 and A176/G350*E7-p. These results highlight the importance of analyzing the combinations of E6/E7 variants in HPV 16 infection and suggest that AA-a*E7-C732/C789/G795, AA-c*E7-C732/C789/G795, and A176/G350*E7-p can be useful markers for predicting CC development.

Purpose: FOXP3 is a marker of the T regulatory (Treg) cell subset and drives its function and homeostasis. Its expression maintains the host immunosuppressive state that favors persistence of human papillomavirus (HPV) infection and squamous intraepithelial lesion (SIL) appearance. The present study evaluated the effects of the rs3761548 and rs2232365 intronic single-nucleotide variants (SNVs) and their haplotypes on HPV infection and SIL diagnosis in HPV-infected and -uninfected women. Methods: HPV DNA-based detection in cervical specimens was performed by PCR. FOXP3 variants were genotyped by PCR-restriction fragment length polymorphism and haplotype recombination sites were inferred for 208 HPV-infected and 218 HPV-uninfected women diagnosed or not with low- or high-grade intraepithelial lesions of cervix. Case–control analyses were carried out by logistic regression adjusted for several socio-demographic, sexual lifestyle, and clinical data. Results: The homozygous genotype of the rs3761548 variants (A/A) (related to decreased FOXP3 expression) may exert a protective role against HPV infection in women (ORAj: 0.60; 95% CI 0.36–0.99; p = 0.049) and was an independent predictor of protection against HSIL development (ORAdj: 0.28; 95% CI 0.11–0.68; p = 0.006). In addition, the homozygous genotype (G/G) of the rs2232365 variants (related to increased FOXP3 expression) was independently associated with the HPV infection (ORAdj: 2.10; 95% CI 1.06–4.15; p = 0.033). Haplotype analysis revealed no significant associations in our study. Conclusions: Our results reveal the significant and independent associations between FOXP3 genetic variants and susceptibility to HPV infection and SIL diagnosis and their role as biomarkers of HPV infection and cervical lesion management. [ABSTRACT FROM AUTHOR]