Copy Number Profiling Implicates Thin High-Grade Squamous Intraepithelial Lesions as a True Precursor of Cervical Human Papillomavirus-Induced Squamous Cell Cancer.

Full-thickness high-grade squamous intraepithelial lesions (HSIL) are precursors of invasive cervical squamous cell carcinoma (SCC). The World Health Organization and Lower Anogenital Squamous Terminology Standardization Project for human papilloma virus (HPV)-associated lesions divide full-thickness HSIL of the cervix into thin HSIL with thickness of 1 to 9 cell layers and the typical full-thickness HSIL of >10 cell layers. Although HPV oncogene transcripts and p16ink4a overexpression, as markers of transforming HPV infection, are detectable in thin HSIL, the biological significance of thin HSIL in cervical carcinogenesis remains poorly understood. To further characterize thin HSIL, we performed a comparative study of chromosomal copy number variations (CNV), an analysis of dysregulated genes present in the segments with CNV, and a generalized genetic complexity calculation for 31 thin HSIL, 31 thick HSIL, 24 microinvasive SCC (pT1a SCC), and 22 highly invasive SCC samples. Thin HSIL share various CNV and specific dysregulated gene pathways with thick HSIL and invasive SCC. Thin HSIL exhibited an average CNV of 11.6% compared with 14.1% for thick HSIL, 15.5% for pT1a SCC, and 26.6% for highly invasive SCC. The CNV included gains at 1q and 3q (40% and 43%, respectively), partial loss of 3p, and loss of chromosomes 11 (18%), 16 (50%), 20 (35%), and 22 (40%). Pathways affected solely in thin HSIL were those enhancing immune evasion and primarily involved the (interleukin) IL6, IL21, and IL23 genes. ILs are transiently upregulated in response to infection and play a crucial role in mounting antitumor T-cell activity. Deregulation reflects an attempt by the HPV to evade the initial immune response of the host. The primary pathways shared by thick HSIL and invasive SCC were interactions between lymphoid and nonlymphoid cells, NOTCH2 signaling, tight junction interactions (primarily of the claudin family), and FGR2 alternative splicing. Our results show that thin HSIL carry similar genetic changes as thick HSIL and SCC, indicating that thin HSIL are true precursor lesions that can progress to thick HSIL and SCC.

Low methylation marker levels among human papillomavirus-vaccinated women with cervical high-grade squamous intraepithelial lesions.

Cervical cancer screening programs, including triage tests, need redesigning as human papillomavirus (HPV)-vaccinated women are entering the programs. Methylation markers offer a potential solution to reduce false-positive rates by identifying clinically relevant cervical lesions with progressive potential. In a nested case-control study, 9242 women who received the three-dose HPV16/18-vaccine at ages 12-15 or 18 in a community-randomized trial were included. Subsequently, they were re-randomized for either frequent or infrequent cervical cancer screening trials. Over a 15-year post-vaccination follow-up until 2022, 17 high-grade squamous intraepithelial lesion (HSIL) and 15 low-grade (LSIL) cases were identified at the 25-year screening round, alongside 371 age and community-matched HPV16/18-vaccinated controls. Methylation analyses were performed on cervical samples collected at age 25, preceding histologically confirmed LSIL or HSIL diagnoses. DNA methylation of viral (HPV16/18/31/33) and host-cell genes (EPB41L3, FAM19A4, and miR124-2) was measured, along with HPV-genotyping. No HPV16/18 HSIL cases were observed. The predominant HPV-genotypes were HPV52 (29.4%), HPV59/HPV51/HPV58 (each 23.5%), and HPV33 (17.7%). Methylation levels were generally low, with no significant differences in mean methylation levels of viral or host-cell genes between the LSIL/HSIL and controls. However, a significant difference in methylation levels was found between HSIL cases and controls when considering a combination of viral genes and EPB41L3 (p value = .0001). HPV-vaccinated women with HSIL had HPV infections with uncommon HPV types that very rarely cause cancer and displayed low methylation levels. Further investigation is warranted to understand the likely regressive nature of HSIL among HPV-vaccinated women and its implications for management.

Methylation markers for anal cancer screening: A repeated cross-sectional analysis of people living with HIV, 2015-2016.

People living with HIV (PLWH) are at highest risk of anal cancer and will benefit from optimized screening for early disease detection. We compared host DNA methylation markers in high-grade squamous intraepithelial lesions (HSIL) versus samples negative for intraepithelial lesions (NILM) or low-grade intraepithelial lesions (LSIL) in PLWH. We recruited PLWH identifying as male aged ≥18 years undergoing high-resolution anoscopy (HRA) in Seattle, Washington, 2015-2016. Anal brush samples were collected for HPV detection, genotyping, and pyrosequencing methylation (host genes ASCL1, PAX1, FMN2, and ATP10A); clinical data were abstracted from medical records. We assessed associations between methylation and presence and extent of HSIL using generalized estimating equation logistic regression, adjusting for age, CD4 count and HIV viral load. Marker panels using HPV DNA and methylation were also evaluated to predict prevalent HSIL. We analyzed 125 samples from 85 participants (mean age 50.1; standard deviation 11.0 years). ASCL1 (adjusted odds ratio [aOR] per 1 unit increase mean percent methylation: 1.07, 95% CI: 1.01-1.13) and FMN2 (aOR per 1 unit increase mean percent methylation: 1.14, 95% CI: 1.08-1.20) methylation were significantly associated with HSIL versus NILM/LSIL. ASCL1 (aOR: 1.06, 95% CI: 1.01-1.11) and FMN2 (aOR: 1.13, 95% CI: 1.08-1.17) methylation were positively associated with increasing HSIL extent. A panel combining methylation (ASCL1 and FMN2) and HPV DNA (HPV16, HPV18, and HPV31) demonstrated best balance of sensitivity (78.2%) and specificity (73.9%) for HSIL detection compared with methylation or HPV alone. Increasing levels of DNA methylation of ASCL1 and FMN2 were positively associated with HSIL detection in PLWH. Host gene methylation testing shows promise for HSIL screening and triage.

Clinical evaluation of an artificial intelligence-assisted cytological system among screening strategies for a cervical cancer high-risk population.

BACKGROUND: Primary cervical cancer screening and treating precancerous lesions are effective ways to prevent cervical cancer. However, the coverage rates of human papillomavirus (HPV) vaccines and routine screening are low in most developing countries and even some developed countries. This study aimed to explore the benefit of an artificial intelligence-assisted cytology (AI) system in a screening program for a cervical cancer high-risk population in China. METHODS: A total of 1231 liquid-based cytology (LBC) slides from women who underwent colposcopy at the Chinese PLA General Hospital from 2018 to 2020 were collected. All women had received a histological diagnosis based on the results of colposcopy and biopsy. The sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), false-positive rate (FPR), false-negative rate (FNR), overall accuracy (OA), positive likelihood ratio (PLR), negative likelihood ratio (NLR) and Youden index (YI) of the AI, LBC, HPV, LBC + HPV, AI + LBC, AI + HPV and HPV Seq LBC screening strategies at low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL) thresholds were calculated to assess their effectiveness. Receiver operating characteristic (ROC) curve analysis was conducted to assess the diagnostic values of the different screening strategies. RESULTS: The Se and Sp of the primary AI-alone strategy at the LSIL and HSIL thresholds were superior to those of the LBC + HPV cotesting strategy. Among the screening strategies, the YIs of the AI strategy at the LSIL + threshold and HSIL + threshold were the highest. At the HSIL + threshold, the AI strategy achieved the best result, with an AUC value of 0.621 (95% CI, 0.587-0.654), whereas HPV testing achieved the worst result, with an AUC value of 0.521 (95% CI, 0.484-0.559). Similarly, at the LSIL + threshold, the LBC-based strategy achieved the best result, with an AUC of 0.637 (95% CI, 0.606-0.668), whereas HPV testing achieved the worst result, with an AUC of 0.524 (95% CI, 0.491-0.557). Moreover, the AUCs of the AI and LBC strategies at this threshold were similar (0.631 and 0.637, respectively). CONCLUSIONS: These results confirmed that AI-only screening was the most authoritative method for diagnosing HSILs and LSILs, improving the accuracy of colposcopy diagnosis, and was more beneficial for patients than traditional LBC + HPV cotesting.

Endoscopic underwater detection and resection of anal squamous intraepithelial lesions in non-anesthetized patients - a feasibility study and comparison with standard surgical treatment.

BACKGROUND: Anal squamous intraepithelial lesions (ASILs) correspond to premalignant changes preceding the development of anal squamous cell carcinoma. OBJECTIVE: To describe a new endoscopic technique to detect and remove ASILs in non-anesthetized patients and compare it with standard surgical treatment. METHODS: For endoscopic treatment, high resolution (HR) flexible endoscopes with a distal attachment were used. Underwater inspection of the anal canal was performed in near-focus mode with white light and narrow-band imaging. Detected lesions were resected with a diathermia snare after local injection of xylocaine/adrenaline. We did a retrospective comparison of all patients who underwent endoscopic or standard surgical treatment for ASILs at Ersta hospital in Stockholm between 2018 and 2020. Patient files were reviewed for number of lesions, treatments until macroscopic radicality, degree of dysplasia, bleeding, pain and other complications. RESULTS: Endoscopic (n = 37) and surgical (n = 43) treatment displayed comparable number of lesions per patient (p = .37). The number of procedures until macroscopic radicality was higher for endoscopy than surgery (p = .04). However, in endoscopic follow up of 12 of the surgically treated patients, residual ASIL was found in 10 cases. Post-procedural bleeding requiring healthcare occurred in two endoscopy patients and one surgically treated patient. CONCLUSIONS: Underwater resection using a HR flexible endoscope in non-anesthetized is a new, feasible and well tolerated method for ASILs treatment. Its efficacy and risk of complications seem comparable to standard surgical treatment while avoiding general anesthesia. However, minor lesions might be overlooked at surgery.

Topical imiquimod treatment of residual or recurrent cervical intraepithelial neoplasia lesions (TOPIC-2): A randomised controlled trial.

OBJECTIVE: To investigate the efficacy of imiquimod in women with residual or recurrent cervical intraepithelial neoplasia (rrCIN), compared with large loop excision of the transformation zone (LLETZ). DESIGN: Randomised controlled non-inferiority trial. SETTING: One academic and one regional hospital in the Netherlands. POPULATION: Thirty-five women with rrCIN were included in the study between May 2016 and May 2021. METHODS: Women were randomised to receive treatment with 5% imiquimod cream (12.5 mg) intravaginally (three times a week for a duration of 16 weeks) or a LLETZ procedure (standard treatment). MAIN OUTCOME MEASURES: The primary outcome was reduction to normal cytology at 6 months after starting treatment. Secondary outcomes were clearance of high-risk human papilloma virus (hr-HPV) in both groups and reduction to ≤CIN1 in the imiquimod group. Side effects were monitored. RESULTS: Treatment success was 33% (6/18) in the imiquimod group versus 100% (16/16) in the LLETZ group (P < 0.001), whereas HPV clearance was 22% (4/18) in the imiquimod group versus 88% (14/16) in the LLETZ group (P < 0.001). After the randomisation of 35 women, the futility of treatment with imiquimod was proven and the trial was prematurely finished. In the follow-up period, three patients remained without additional treatment, whereas all other patients underwent LLETZ, conisation or hysterectomy. In the LLETZ group none of the patients received additional treatment during 2 years of follow-up. CONCLUSIONS: This is the first randomised controlled trial to show that topical imiquimod has a significantly lower success rate in terms of reduction to normal cytology and hr-HPV clearance, compared with LLETZ, in women with rrCIN. Additionally, imiquimod has numerous side effects and after using imiquimod most women with rrCIN still required additional surgical treatment.

Evaluation of human papillomavirus type 16 viral load and genome physical status in Iranian women with cervical disease.

BACKGROUND: This study examined the viral load and physical status of the human papillomavirus 16 (HPV-16) genome in non-cancerous, precancerous and cancerous cervical lesions. METHODS: Quantitative real-time PCR was performed to determine HPV-16 E2 and E6 viral load in 132 cervical specimens. E2/E6 viral load ratio was used to determine the physical status of HPV-16 genome. RESULTS: E2 gene viral load was a significant (P < 0.001) predicting biomarker in differentiating non-cancerous from precancerous and cancerous samples. E6 gene viral load was significantly different between the groups (P < 0.001). The specificity and sensitivity of E2 and E6 in distinguishing SCC samples were 100% and 95% respectively. CONCLUSION: HPV-16 viral load measured through E2 and E6 genes is a reliable indicator of lesion type.

Association between HIV Serostatus and premalignant cervical lesions among women attending a cervical cancer screening clinic at a tertiary care facility in southwestern Uganda: a comparative cross-sectional study.

BACKGROUND: Uganda has approximately 1.2 million people aged 15-64 years living with human immunodeficiency virus (HIV). Previous studies have shown a higher prevalence of premalignant cervical lesions among HIV-positive women than among HIV-negative women. Additionally, HIV-infected women are more likely to have human papilloma virus (HPV) infection progress to cancer than women not infected with HIV. We determined the prevalence of premalignant cervical lesions and their association with HIV infection among women attending a cervical cancer screening clinic at Mbarara Regional Referral Hospital (MRRH) in southwestern Uganda. METHODS: We conducted a comparative cross-sectional study of 210 women aged 22-65 years living with HIV and 210 women not living with HIV who were systematically enrolled from March 2022 to May 2022. Participants were subjected to a structured interviewer-administered questionnaire to obtain their demographic and clinical data. Additionally, Papanicolaou smears were obtained for microscopy to observe premalignant cervical lesions. Multivariate logistic regression was performed to determine the association between HIV status and premalignant cervical lesions. RESULTS: The overall prevalence of premalignant cervical lesions in the study population was 17% (n = 72; 95% C.I: 14.1-21.4), with 23% (n = 47; 95% C.I: 17.8-29.5) in women living with HIV and 12% (n = 25; 95% C.I: 8.2-17.1) in women not living with HIV (p < 0.003). The most common premalignant cervical lesions identified were low-grade squamous intraepithelial lesions (LSIL) in both women living with HIV (74.5%; n = 35) and women not living with HIV (80%; n = 20). HIV infection was significantly associated with premalignant lesions (aOR: 2.37, 95% CI: 1.27-4.42; p = 0.007). CONCLUSION: Premalignant cervical lesions, particularly LSILs, were more common in HIV-positive women than in HIV-negative women, highlighting the need to strengthen the integration of cervical cancer prevention strategies into HIV care programs.

Reconnoitering correlation between human papillomavirus infection-induced vaginal microecological abnormality and squamous intraepithelial lesion (SIL) progression.

OBJECTIVE: This study aims to investigate the relationship between abnormal vaginal microecology and human papillomavirus (HPV) infection, as well as the squamous intraepithelial lesions (SIL) progression. METHODS: A total of 383 patients diagnosed with HPV infection in our hospital between March 2017 and February 2022 were selected as the experimental group. In addition, several volunteers (n = 898) who underwent physical examination during the same period were randomly selected as the control group. Subsequently, we conducted several investigations, such as HPV detection and gene typing, examined vaginal microecological imbalances, and performed cytological examinations to analyze the correlation between microecological changes, different types of HPV infection, and SIL progression. RESULTS: HPV detection primarily included single and high-risk types of HPV infections. Moreover, significant disparities in the vaginal microecological environment between patients with persistent HPV infection and the control group, as well as patients with low-grade and high-grade SIL (LSIL and HSIL), were observed. The regression analysis revealed a correlation between LSIL and microflora density, diversity, bacteriological vaginosis (BV), vulvovaginal candidiasis (VVC), trichomonas vaginalis (TV), sialidase, as well as Lactobacillus. In addition, we identified an association between HSIL and pH, flora density, diversity, BV, VVC, candida vaginitis (CV), leukocyte esterase, catalase, and Lactobacillus levels. CONCLUSION: These findings revealed a significant association between abnormal vaginal microecology and both HPV infection and the SIL progression.

HiPorfin photodynamic therapy for vaginal high-grade squamous intraepithelial lesion.

PURPOSE: We aimed to evaluate the efficacy and safety of HiPorfin-photodynamic therapy (PDT) in women with vaginal high-grade squamous intraepithelial Lesion (HSIL). METHODS: Retrospective analysis of eighteen patients with vaginal HSIL received HiPorfin-PDT between June 2019 and May 2023. Illumination with a 630-nm laser light was applied to the lesions 48-72 h after intravenous injection of 2 mg/kg HiPorfin®. The light dose to the lesions was 150 J/cm2. RESULTS: The mean age of the 18 patients was 45.8 years (range, 24 to 63). The complete response (CR) rate was 66.7% (12/18), 83.3% (15/18) and 83.3% (15/18) at 3, 6 and 12 months after PDT, respectively. Patients who achieved CR showed no signs of recurrence during long-term follow-up. There were three cases of persistent disease showing partial response (PR) and the lesion area was significantly reduced more than 50%. One patient with persistent disease then underwent thermocoagulation one time and subsequently showed no evidence of HSIL. Pre-treatment, 100% (18/18) patients were high-risk human papilloma virus (HR-HPV)-positive. HPV eradication rate was 16.7% (3/18), 22.2% (4/18) and 44.4% (8/18) after PDT at 3, 6 and 12 months, respectively. Before treatment, liquid-based cytology test ≥ atypical squamous cells of undetermined significance (ASCUS) was 94.4% (17/18). Negative conversion ratio of cytology was 47.1% (8/17), 52.9% (9/17) and 76.5% (13/17) at 3, 6 and 12 months, respectively. There were no serious adverse effects during and after PDT. CONCLUSIONS: HiPorfin-PDT may be an effective alternative treatment for vaginal HSIL for organ-saving and sexual function protection.

Clinical application of endoscopic submucosal dissection for superficially invasive squamous cell carcinoma/high-grade squamous intraepithelial lesion involving the canal anal.

BACKGROUND: Superficially invasive squamous cell carcinoma (SISCC) and high-grade squamous intraepithelial lesions (HSIL) involving the anal canal are rare, and their surgical management involves local excision. Endoscopic submucosal dissection (ESD) has recently emerged as a promising treatment. This study aimed to evaluate the feasibility and safety of ESD for SISCC and HSIL in the anal canal. METHODS: All patients diagnosed with SISCC or HSIL in the anal canal who underwent ESD between November 2018 and May 2023 were included. Patient age, sex, pathology, human immunodeficiency virus (HIV) status, human papillomavirus (HPV) status, T stage, en bloc rate, and R0 resection rate were analyzed. RESULTS: Ten patients, including two men and eight women, with a median age of 61 (51-68) years were enrolled. All patients were HIV-negative, but five (50%) were HPV-positive. Pathological examination showed tumor stage of two patients as T2, one as T0 of SISCC, and seven as Tis of HSIL. The median specimen and tumor sizes were 24 (6-65) mm and 18 (6-55) mm, respectively. The en bloc and R0 resection rates were 100% and 80%, respectively. No severe complications occurred and no recurrence was observed at the follow-up (median follow-up period, 9 (1-35) months). CONCLUSIONS: ESD is a reliable and minimally invasive procedure that enables more individualized treatment options for specific groups. As we were limited by the length of the observation period, the long-term performance of ESD for SISCC and HSIL involving the anal canal requires further investigation.

Performance of Human Papillomavirus Attribution Algorithms to Predict Causative Genotypes in Anal High-Grade Lesions.

BACKGROUND: Gay and bisexual men (GBM) are at increased risk of human papillomavirus (HPV)-associated anal high-grade squamous intraepithelial lesions (HSILs). Understanding the fractions of HSILs attributable to HPV genotypes is important to inform potential impacts of screening and vaccination strategies. However, multiple infections are common, making attribution of causative types difficult. Algorithms developed for predicting HSIL-causative genotype fractions have never been compared with a reference standard in GBM. METHOD: Samples were from the Study of the Prevention of Anal Cancer. Baseline HPV genotypes detected in anal swab samples (160 participants) were compared with HPV genotypes in anal HSILs (222 lesions) determined by laser capture microdissection (LCM). Five algorithms were compared: proportional, hierarchical, maximum, minimum, and maximum likelihood estimation. RESULTS: All algorithms predicted HPV-16 as the most common HSIL-causative genotype, and proportions differed from LCM detection (37.8%) by algorithm (with differences of -6.1%, +20.9%, -20.4%, +2.9%, and +2.2% respectively). Fractions predicted using the proportional method showed a strong positive correlation with LCM, overall (R = 0.73 and P = .002), and by human immunodeficiency virus (HIV) status (HIV positive, R = 0.74 and P = .001; HIV-negative, R = 0.68 and P = .005). CONCLUSIONS: Algorithms produced a range of inaccurate estimates of HSIL attribution, with the proportional algorithm performing best. The high occurrence of multiple HPV infections means that these algorithms may be of limited use in GBM.

Detection of cervical high-grade squamous intraepithelial lesions and assessing diagnostic performance of colposcopy among women with oncogenic HPV.

BACKGROUND: HPV screening tests may improve cervical cancer risk stratification and better guide decisions about follow-up with colposcopy/biopsy. This study aimed to estimate the risk of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) among women with oncogenic HPV types and evaluate the performance of colposcopy in the diagnosis of histologic CIN2 + at Putuo Hospital, Shanghai, China. METHODS: This cross-sectional survey was conducted from February 2020 to December 2022 among women who were referred to colposcopy. Women with high-risk (HR) HPV-positive, cytology testing and colposcopy-directed biopsy were included. RESULTS: Univariate and multivariate analysis indicated that high-grade colposcopic impression ((OR, 17.61%, 95%CI: 11.54-26.85%) was associated with the highest risk for detecting CIN2+, followed by HSIL + cytology (OR, 6.90%, 95%CI: 3.56-13.37%) and HPV16/18 positive (OR, 2.91%, 95%CI: 2.12-3.99%). Overall, CIN2 + was detected in 14.6% of 2007 women. HPV16/18 had higher CIN2 + risks than other HR-HPV genotypes (30.1% vs. 10.2%, P<0.001). Among women with low-grade cytology, 24.1% had CIN2+, and the risks for HPV16/18 (58.2%) were higher than for other HR-HPV(16.8%). For those with high-grade cytology, there was no significant difference between HPV groups ( 75.0% vs. 72.9%, P > 0.05). The diagnostic performance of colposcopy in diagnosis of CIN2 + by senior and junior colposcopists was comparable. CONCLUSIONS: The results indicated that referral to colposcopy is recommended in managing women with HR-HPV positive, and colposcopic impressions provide key clues for identification CIN2+.

Endocervical curettage for diagnosing high-grade squamous intraepithelial lesions or worse in women with type 3 transformation zone lesions: a retrospective, observational study.

BACKGROUND: This study aimed to assess the value of endocervical curettage (ECC) in detecting high-grade squamous intraepithelial lesion or worse (HSIL+) in women with type 3 transformation zone (TZ3) lesions, and to identify the clinical characteristics of patients with TZ3 lesions who benefit most from ECC. METHODS: This retrospective, multicenter study included 1,905 women with TZ3 lesions who attended cervical screening in one of seven tertiary hospitals in China between January 2020 and November 2021. All participants had received abnormal results and had been referred to colposcopy. Risk factors were identified through univariate and multifactorial logistic analyses. RESULTS: In total, 20.5% (n = 391) of HSIL+ cases with TZ3 lesions had been diagnosed with biopsy and ECC. ECC detected 0.8% (n = 15) HSIL+ cases otherwise missed by biopsy alone. Multivariate analysis identified four factors which influenced detection performance. The probability of detecting HSIL+ with ECC is 2.653 (95% confidence interval [CI] 1.009-6.977) times greater in women aged 40-49 years and 2.545 (95% CI 0.965-6.716) times greater for those aged 50 years and older compared to those younger than 30 years. The probability of ASC-H (atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion) and HSIL cytologies were respectively 2.415 (95% CI 1.213-4.808) and 2.933 (95% CI 1.648-5.220) times higher than for NILM (negative for intraepithelial lesion or malignancy). Women with human papillomavirus 16/18 infections were 2.299 (95% CI 0.942-5.613) times more likely to be HSIL+. Precancerous lesions were 35.884 (95% CI 12.214-105.426) times more likely in women who had high-grade colposcopic impressions compared to those with normal impressions. CONCLUSIONS: ECC should be performed for patients with ASC-H or HSIL cytologies, human papillomavirus 16/18 infections, and for those with high-grade colposcopic impressions. This will increase the number of HSIL+ cases identified using biopsy by reducing the number of false negatives.

Are "additional cuts" effective for positive margins in cervical conization? It varies according to the doctor.

BACKGROUND: High-grade squamous intraepithelial lesion (HSIL) is a disease that is closely related to the development of cervical cancer. In clinical work, cold knife conization and a loop electrosurgical excision procedure (LEEP) are often selected for diagnosis and treatment. OBJECTIVE: In this paper, we aimed to discuss additional cuts, a common practice in cervical conization, and determine whether the doctor's choice to use additional cuts in conization can reduce the occurrence of a positive cone margin. METHODS: From January 2018 to October 2019, 965 patients underwent cervical conization at the First Affiliated Hospital of Dalian Medical University (Dalian, China). Of these, 174 were in the positive cone margin group, and 791 were in the negative cone margin group. Age, preoperative pathology, pathological results of conization, additional cuts, cone depth, and cone volume were studied. Additionally, the additional cut rate and the efficiency of doctors with a habit of additional cuts were analyzed. RESULTS: Of the 965 patients included in the study, the median age was 41 years (range 35-50). Multivariable logistic regression analysis suggested that additional cuts (OR, 2.480; 95% CI 1.608 to 3.826; p = 0.01) and smaller cone depth (OR, 0.591; 95% CI, 0.362 to 0.965, p = 0.036) were independent risk factors for positive margins. Six of the 64 doctors who performed conizations had a habit of making additional cuts, and there was no positive correlation between their additional cut rate and their effective additional cut rate. CONCLUSION: This study showed that a certain proportion of additional cuts can be effectively excised from the positive margin that cannot be removed in the initial conization. The practice of additional cuts in conization tends to be the personal habit of a small number of doctors.

Cervical intraepithelial neoplasia grade 3: development during pregnancy and postpartum.

PURPOSE: The aims of the present study were to evaluate the development of untreated cervical intraepithelial neoplasia (CIN) 3 during pregnancy and to assess persistence, progression, and regression rates postpartum to identify factors associated with regression. METHODS: In a tertiary gynecology and obstetrics department, a total of 154 pregnant women with CIN 3 were treated in the dysplasia unit. The follow-up findings were analyzed retrospectively on the basis of histological, cytological, and human papillomavirus (HPV) testing of 154 pregnant women confirmed as having CIN 3 in colposcopically guided biopsies. RESULTS: The rates of persistence, regression, and progression of CIN 3 in these women were 76.1%, 20% and 3.2%, respectively. Data for the delivery mode was available for 126 women. The rate of regression was almost twice as high with vaginal delivery as with cesarean section, at 27.4 vs. 15.2%, whereas the rate of progression was lower with vaginal delivery, at 2.7 vs. 6.5%. CONCLUSION: The rate of persistence of CIN observed in this study is comparable to that reported in other studies. The study provides strong evidence for greater regression among women who have vaginal deliveries. Careful work-up is recommended postpartum for this group of women in order to rule out persistent CIN 3 or invasive disease.

Improving colposcopic accuracy for cervical precancer detection: a retrospective multicenter study in China.

BACKGROUND: Colposcopy alone can result in misidentification of high-grade squamous intraepithelial or worse lesions (HSIL +), especially for women with Type 3 transformation zone (TZ) lesions, where colposcopic assessment is particularly imprecise. This study aimed to improve HSIL + case identification by supplementing referral screening results to colposcopic findings. METHODS: This is an observational multicenter study of 2,417 women, referred to colposcopy after receiving cervical cancer screening results. Logistic regression analysis was conducted under uni- and multivariate models to identify factors which could be used to improve HSIL + case identification. Histological diagnosis was established as the gold standard and is used to assess accuracy, sensitivity, and specificity, as well as to incrementally improve colposcopy. RESULTS: Multivariate analysis highlighted age, TZ types, referral screening, and colposcopists' skills as independent factors. Across this sample population, diagnostic accuracies for detecting HSIL + increased from 72.9% (95%CI 71.1-74.7%) for colposcopy alone to 82.1% (95%CI 80.6-83.6%) after supplementing colposcopy with screening results. A significant increase in colposcopic accuracy was observed across all subgroups. Although, the highest increase was observed in women with a TZ3 lesion, and for those diagnosed by junior colposcopists. CONCLUSION: It appears possible to supplement colposcopic examinations with screening results to improve HSIL + detection, especially for women with TZ3 lesions. It may also be possible to improve junior colposcopists' diagnoses although, further psychological research is necessary. We need to understand how levels of uncertainty influence diagnostic decisions and what the concept of "experience" actually is and what it means for colposcopic practice.

Topical imiquimod compared with conization to treat cervical high-grade squamous intraepithelial lesions: Multicenter, randomized controlled trial.

OBJECTIVE: In a previous phase II trial, we showed that topical imiquimod (IMQ) therapy is an efficacious treatment for high-grade squamous intraepithelial lesion (HSIL). Aim of the present study was to investigate the non-inferiority of a 16-week topical, self-applied IMQ therapy compared to large loop excision of the transformation zone (LLETZ) in patients diagnosed with HSIL. METHODS: Phase III randomized, controlled, multicenter, open trial performed by Austrian Gynecologic Oncology group. Patients with histologically proven cervical intraepithelial neoplasia (CIN)2 (30 years and older) or CIN3 (18 years and older) and satisfactory colposcopy were randomized to topical IMQ treatment or LLETZ. Successful treatment was defined as negative HPV high-risk test result 6 months after start of the treatment. Secondary endpoints were histological outcome and HPV clearance rates. RESULTS: Within 3 years 93 patients were randomized, received the allocated treatment and were available for ITT analysis. In the IMQ group negative HPV test at 6 months after treatment start was observed in 22/51 (43.1%) of patients compared to 27/42 (64.3%) in the LLETZ group on ITT analysis (rate difference 21.2%-points, 95% two-sided CI: 0.8 to 39.1). In the IMQ group histologic regression 6 months after treatment was observed in 32/51 (63%) of patients and complete histologic remission was observed in 19/51 (37%) of patients. Complete surgical resection was observed in 84% after LLETZ. CONCLUSION: In women with HSIL, IMQ treatment results in lower HPV clearance rates when compared to LLETZ. LLETZ remains the standard for women with HSIL when treatment is required. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01283763, EudraCT number: 2012-004518-32.

Assessing colposcopic accuracy for high-grade squamous intraepithelial lesion detection: a retrospective, cohort study.

BACKGROUND: Inappropriate management of high-grade squamous intraepithelial lesions (HSIL) may be the result of an inaccurate colposcopic diagnosis. The aim of this study was to assess colposcopic performance in identifying HSIL+ cases and to analyze the associated clinical factors. METHODS: Records from 1130 patients admitted to Shenzhen Maternal and Child Healthcare Hospital from 12th January, 2018 up until 30th December, 2018 were retrospectively collected, and included demographics, cytological results, HPV status, transformation zone type, number of cervical biopsy sites, colposcopists' competencies, colposcopic impressions, as well as histopathological results. Colposcopy was carried out using 2011 colposcopic terminology from the International Federation of Cervical Pathology and Colposcopy. Logistic regression modelling was implemented for uni- and multivariate analyses. A forward stepwise approach was adopted in order to identify variables associated with colposcopic accuracy. Histopathologic results were taken as the comparative gold standard. RESULTS: Data from 1130 patient records were collated and analyzed. Colposcopy was 69.7% accurate in identifying HSIL+ cases. Positive predictive value, negative predictive value, sensitivity and specificity of detecting HSIL or more (HSIL+) were 35.53%, 64.47%, 42.35% and 77.60%, respectively. Multivariate analysis highlighted the number of biopsies, cytology, and transformation zone type as independent factors. Age and HPV subtype did not appear to statistically correlate with high-grade lesion/carcinoma. CONCLUSION: Evidence presented here suggests that colposcopy is only 69.7% accurate at diagnosing HSIL. Even though not all HSIL will progress into cancer it is considered pre-cancerous and therefore early identification will save lives. The number of biopsies, cytology and transformation zone type appear to be predictors of misdiagnosis and therefore should be considered during clinical consultations and by way of further research.

Visual appearance of the uterine cervix differs on the basis of HPV type status in high-grade squamous intraepithelial lesion: the results of a reliable method.

BACKGROUND: This study aimed to evaluate the differences in cervical appearance among different human papillomavirus (HPV) genotypes in patients with high-grade squamous intraepithelial lesions (HSILs). METHODS: A total of 239 histopathological HSIL patients were included and divided into eight groups on the basis of HPV genotype in this prospective study. We present a reliable imaging method that provides reproducible, sensitive and unbiased assessments of cervical appearance characteristics. Colorimetric and morphometric data of colposcopic patterns after the application of acetic acid and iodine were acquired using ImageJ software and the surrounding normal regions were used as controls. RESULTS: The differences in red, green, blue and mean greyscale values in acetowhite epithelium obtained from ImageJ were not significant between the HPV16 and HPV18 groups (P < 0.05). The differences in red, green, and mean greyscale values in iodine staining were significant between the HPV18 and the other groups (P < 0.05). The frequency of the occurrence of the coarse mosaic patterns was significantly different among groups (P < 0.05), reducing in sequence were the HPV16, HPV-negative, HPV18, HPV31/33 and HPV52/58 groups. For the lesion area of HSILs, the HPV-negative group was the largest. The sensitivity of colposcopic impression varied among HPV genotypes (P < 0.01), being lowest in the HPV52 group. CONCLUSIONS: Although being nonspecific, iodine negativity should be concerned in HPV18-positive lesions which is closely related to glandular epithelium. Vascular patterns in HPV52/58-positive HSIL are quite occult and tend to be missed by colposcopists. HPV-negative lesions are prone to be large and present typical vascular patterns despite being rare.