Anal Dysplasia Screening in People Living with HIV: Long-Term Follow-Up in a Large Cohort from Northwest Spain.

Anal squamous cell carcinoma (SCC) is not a common disease in the general population, although its incidence is higher in people living with human immunodeficiency virus (PLWH). Anal SCC is caused by human papillomavirus (HPV) infection and arises from premalignant lesions termed squamous intraepithelial lesions (SILs). SIL surveillance programs are based on the early detection and treatment of SILs, especially those with a higher risk of transforming into cancer. An anal surveillance program has been under development in our institution since 2011. In this context, we performed a retrospective cohort study at the anal dysplasia unit of Álvaro-Cunqueiro Hospital (Spain). Epidemiological and clinical data were gathered from our Infectious Diseases Sample Collection (an open sample cohort including PLWH) from January 2011 to January 2022. A total of 493 PLWH were considered, 122 (24.7%) of whom were diagnosed with anal dysplasia at baseline, including 2 cases of anal SCC. Briefly, most of individuals were young men (median age, 38 years old) born in Spain (76%), whose vaccination rate before their inclusion in the program was scarce (<3%). Throughout the study period, 81 (16.4%) cases were diagnosed with high-grade squamous-intraepithelial lesions (HSILs) and 3 with anal SCC. At the baseline, severe immunosuppression (i.e., nadir CD4+ lymphocyte count below 200 cell/µL), and prior diagnosis of condyloma acuminata were more frequent within the group with SILs. Conversely, the baseline CD4+ lymphocyte count was similar among both groups. HPV-16 was related to a higher risk of HSILs (odds ratio: 2.76). At the end of the follow-up, 385 PLWH had been retained in care; one patient had died of anal cancer. Anal dysplasia was common (25% of cases), especially among patients infected by HPV-16, diagnosed with condyloma acuminata, and who were severely immunosuppressed. HPV-16 was the main risk factor for the presentation of HSILs.

Vulvar High-Grade Squamous Intraepithelial Lesion and the Risk of Recurrence and Progression to Cancer.

OBJECTIVE: This study aimed to analyze which clinical characteristics are associated with recurrence and progression of vulvar high-grade squamous intraepithelial lesion (vHSIL). MATERIALS AND METHODS: This was a retrospective cohort study, including all women with vHSIL followed in 1 center between 2009 and 2021. Women with a concomitant diagnosis of invasive vulvar cancer were excluded. Medical records were reviewed for demographic factors, clinical data, treatment type, histopathologic results, and follow-up information. RESULTS: A total of 30 women were diagnosed with vHSIL. The median follow-up time was 4 years (range = 1-12 years). More than half of the women (56.7% [17/30]) underwent excisional treatment, whereas 26.7% (8/30) underwent combined (excisional plus medical) treatment, and 16.7% (5/30) only had medical treatment (imiquimod). Six women had recurrence of vHSIL (20% [6/30]), with a mean time to recurrence of 4.7 ± 2.88 years. The progression rate to invasive vulvar cancer was 13.3% (4/30), with a mean time to progression of 1.8 ± 0.96 years. Multifocal disease was associated with progression to vulvar cancer ( p = .035). We did not identify other variables associated with progression; no differences were found between women with and without recurrences. CONCLUSIONS: Multifocality of the lesions was the only variable associated with progression to vulvar cancer. This reinforces the idea that these lesions are a challenge in both treatment and surveillance, involving a more difficult therapeutic decision with greater associated morbidity.

Cervical High-Grade Squamous Intraepithelial Lesion Burden and Standard of Care Treatment Effectiveness and Safety in the United States, 2008-2018: The EACH-WOMAN Project.

OBJECTIVE: Management of cervical high-grade squamous intraepithelial lesions (HSILs), the immediate precursor of cervical cancer, consists largely of surgical treatment for women at higher risk for progression to cancer. The authors' objective was to describe the occurrence of cervical HSIL in the United States and various outcomes for women who received surgical treatment. METHODS: From a US commercial health insurer, a cohort of adult women with cervical HSIL diagnoses receiving surgical treatment within 3 months of diagnosis between January 2008 and September 2018 was identified. This cohort was followed for several outcomes, including cervical HSIL recurrence, human papillomavirus clearance, preterm birth, infection, and bleeding. RESULTS: The incidence rate of cervical HSIL declined from 2.34 (95% CI = 2.30-2.39) cases per 1,000 person-years in 2008 to 1.39 (95% CI = 1.35-1.43) cases per 1,000 person-years in 2014, remaining near that level through 2018. Among 65,527 women with cervical HSIL, 47,067 (72%) received surgical treatment within 3 months of diagnosis. Among the women receiving surgical treatment, cervical HSIL recurred in 6% of surgically treated women, whereas 45% of surgically treated women underwent subsequent virological testing that indicated human papillomavirus clearance. Preterm birth was observed in 5.9% by 5 years follow-up and bleeding and infection each at 2.2% by 7 days follow-up. CONCLUSIONS: From 2008 through 2018, the incidence of diagnosed cervical HSIL decreased for several years before stabilizing. Surgical treatment of HSIL may be beneficial in removing the precancerous lesion, but cervical HSIL may recur, and the surgery is associated with complications including preterm birth, infection, and bleeding.

Comorbid Vulvar Lichen Sclerosus and High-Grade Squamous Intraepithelial Lesions: A Management Conundrum.

OBJECTIVE: This study aimed to determine if treating lichen sclerosus (LS) with high-potency topical corticosteroids (TCS) increases the risk of high-grade squamous intraepithelial lesion (HSIL) recurrence in patients with comorbid vulvar LS and HSIL. METHODS: This is a retrospective study of patients with comorbid vulvar LS and HSIL treated with TCS between 2015 and 2020. Patients with clinically diagnosed or biopsy-proven LS and biopsy-proven HSIL of the vulva were included. Clinical data included demographics, tobacco use, immune-modifying conditions, specimen pathology, treatment types, and HSIL recurrence. Bivariate analysis was performed to compare demographic and clinical characteristics between patients with and without HSIL recurrence. RESULTS: Twenty-six patients with comorbid LS and HSIL were identified. The median age was 66.0 years and median time in treatment for LS was 5.5 years. Thirteen (50%) had recurrence of HSIL and 13 (50%) did not have recurrence. Exposure to high-potency TCS was present in 20 (77%) patients, with 17 (65%) having use of more than 1-year duration and 9 (35%) having use at the time of HSIL diagnosis. When comparing the groups with and without HSIL recurrence, there was no significant difference in high-potency TCS exposure, duration of use, or use at time of HSIL diagnosis. CONCLUSIONS: High-potency TCS use for the treatment of LS did not seem to increase the risk of HSIL recurrence in patients with comorbid vulvar LS and HSIL. This suggests that high-potency TCS can be appropriately used for the treatment of LS even when HPV-associated disease is present.

Prevalence and correlates of cervical squamous intraepithelial lesions among HIV-infected and uninfected women in Central Kenya.

INTRODUCTION: cervical intraepithelial neoplasia the precursor of cervical cancer occurs with increased frequency in women infected with human immunodeficiency virus (HIV). This study aimed at determining the prevalence and correlates of abnormal cervical cytology among HIV-infected women and compare to the uninfected women. METHODS: a cross-sectional study conducted among HIV-infected and uninfected women enrolled in a HIV study in Central Kenya. All women had baseline Pap smear examination assessed using Bethesda system. Bivariate and multivariate logistic regression methods were employed to assess the correlates of cervical squamous epithelial lesions (CSIL). RESULTS: a total 480 women had an acceptable baseline smear, 373 (78%) were HIV-infected. Median age was 30.2 years [IQR 25.4-35.5]. Overall prevalence of CSIL was 37% (176/480) with the prevalence of low grade squamous intraepithelial lesion (LSIL), atypical squamous cells undetermined significance (ASCUS), high grade squamous intraepithelial lesions (HSIL) and atypical glandular cells (AGC) were 17%, 14%, 4% and 2% respectively. HIV-infected women had a higher prevalence of CSIL at 42% as compared to HIV-uninfected women at 19%. HIV infection was the predictor associated with development of CSIL at multivariate analysis and specifically, HIV-infected women were 3 times (AOR 3.1, 95% CI: 1.8 - 5.4, p<0.005) more likely to have CSIL than HIV-uninfected women. The age 35 - 44 years was protective to developing CSIL (AOR 0.45, 95% CI: 0.24 - 0.87, p=0.018). CONCLUSION: cervical squamous epithelial lesions is a major problem among Kenyan women. HIV infection confers a higher risk to development of CSIL. Cervical cancer screening should be an established practice in HIV programs.

Epidemiology of anal human papillomavirus infection and high-grade squamous intraepithelial lesions in 29 900 men according to HIV status, sexuality, and age: a collaborative pooled analysis of 64 studies.

BACKGROUND: Robust age-specific estimates of anal human papillomavirus (HPV) and high-grade squamous intraepithelial lesions (HSIL) in men can inform anal cancer prevention efforts. We aimed to evaluate the age-specific prevalence of anal HPV, HSIL, and their combination, in men, stratified by HIV status and sexuality. METHODS: We did a systematic review for studies on anal HPV infection in men and a pooled analysis of individual-level data from eligible studies across four groups: HIV-positive men who have sex with men (MSM), HIV-negative MSM, HIV-positive men who have sex with women (MSW), and HIV-negative MSW. Studies were required to inform on type-specific HPV infection (at least HPV16), detected by use of a PCR-based test from anal swabs, HIV status, sexuality (MSM, including those who have sex with men only or also with women, or MSW), and age. Authors of eligible studies with a sample size of 200 participants or more were invited to share deidentified individual-level data on the above four variables. Authors of studies including 40 or more HIV-positive MSW or 40 or more men from Africa (irrespective of HIV status and sexuality) were also invited to share these data. Pooled estimates of anal high-risk HPV (HR-HPV, including HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68), and HSIL or worse (HSIL+), were compared by use of adjusted prevalence ratios (aPRs) from generalised linear models. FINDINGS: The systematic review identified 93 eligible studies, of which 64 contributed data on 29 900 men to the pooled analysis. Among HIV-negative MSW anal HPV16 prevalence was 1·8% (91 of 5190) and HR-HPV prevalence was 6·9% (345 of 5003); among HIV-positive MSW the prevalences were 8·7% (59 of 682) and 26·9% (179 of 666); among HIV-negative MSM they were 13·7% (1455 of 10 617) and 41·2% (3798 of 9215), and among HIV-positive MSM 28·5% (3819 of 13 411) and 74·3% (8765 of 11 803). In HIV-positive MSM, HPV16 prevalence was 5·6% (two of 36) among those age 15-18 years and 28·8% (141 of 490) among those age 23-24 years (ptrend=0·0091); prevalence was 31·7% (1057 of 3337) among those age 25-34 years and 22·8% (451 of 1979) among those age 55 and older (ptrend<0·0001). HPV16 prevalence in HIV-negative MSM was 6·7% (15 of 223) among those age 15-18 and 13·9% (166 of 1192) among those age 23-24 years (ptrend=0·0076); the prevalence plateaued thereafter (ptrend=0·72). Similar age-specific patterns were observed for HR-HPV. No significant differences for HPV16 or HR-HPV were found by age for either HIV-positive or HIV-negative MSW. HSIL+ detection ranged from 7·5% (12 of 160) to 54·5% (61 of 112) in HIV-positive MSM; after adjustment for heterogeneity, HIV was a significant predictor of HSIL+ (aPR 1·54, 95% CI 1·36-1·73), HPV16-positive HSIL+ (1·66, 1·36-2·03), and HSIL+ in HPV16-positive MSM (1·19, 1·04-1·37). Among HPV16-positive MSM, HSIL+ prevalence increased with age. INTERPRETATION: High anal HPV prevalence among young HIV-positive and HIV-negative MSM highlights the benefits of gender-neutral HPV vaccination before sexual activity over catch-up vaccination. HIV-positive MSM are a priority for anal cancer screening research and initiatives targeting HPV16-positive HSIL+. FUNDING: International Agency for Research on Cancer.

Characteristics of human papillomavirus infection among women with cervical cytological abnormalities in the Zhoupu District, Shanghai City, China, 2014-2019.

BACKGROUND: Human papillomavirus (HPV) infection is currently the main cause of cervical cancer and precancerous lesions in female patients. By analyzing 6-year patient data from Shanghai Zhoupu Hospital in China, we retrospectively analyzed the epidemiological characteristics of women to determine the relationship between HPV genotype and cytological test results. METHODS: From 2014 to 2019, 23,724 cases of cervical shedding were collected from Zhoupu Hospital in Shanghai, China. By comparing the results of HPV and ThinPrep cytology test (TCT), the HPV infection rate of patients was retrospectively analyzed. HPV genotyping using commercial kits can detect 21 HPV subtypes (15 high-risk and 6 low-risk). According to the definition of the Bethesda system, seven types of cervical cytology results were involved. RESULTS: 3816 among 23,724 women, nearly 16.08%, were infected with HPV. The top three highest HPV prevalence rates were high-risk type infection, including HPV52 (3.19%), 58 (2.47%) and 16 (2.34%). The number of single-type HPV infections (3480 (91.20%)) was much larger than the number of multi-type ones (336 (8.8%)). Single-type infections were mainly in women aged 50-60 (16.63%) and women under 30 (15.37%), while multi-type infections were more common in women over 60 (2.67%). By analyzing the long-term trends, between 2014 and 2019, HPV52, 58, and 16 subtypes changed significantly, and the HPV positive rate also changed significantly during this period. Among 4502 TCT positive women, 15 (4.04%), 125 (2.64%),159 (1.54%), 4202 (17.71%) and 1 (0.004%) had atypical glandular cells (AGC), high-grade squamous intraepithelial lesions (HSIL), low-grade squamous intraepithelial lesions (LSIL), atypical squamous cells (ASC)and cervical adenocarcinoma, respectively. The HPV infection rates were 66.08%, 63.99%, 115.20%, 119.50%, and 31.72% for NILM, AGCs, HSILs LSILs and ASCs, respectively. CONCLUSIONS: HPV and TCT screening were very important steps in the secondary prevention of cervical cancer. Through the tracking and analysis of HPV and TCT results in this study, it can provide valuable information for Shanghai's HPV screening and prevention strategies, and provide references for clinical decision-making in the treatment of cervical cancer and precancerous lesions.

Vulvar intraepithelial neoplasia: Incidence and long-term risk of vulvar squamous cell carcinoma.

The risk of vulvar squamous cell carcinoma (VSCC) in patients with high-grade vulvar intraepithelial neoplasia (VIN) is considered lower in high-grade squamous intraepithelial lesion (HSIL) compared to differentiated VIN (dVIN), but studies are limited. Our study investigated both the incidence of high-grade VIN and the cumulative incidence of VSCC in patients with HSIL and dVIN separately. A database of women diagnosed with high-grade VIN between 1991 and 2011 was constructed with data from the Dutch Pathology Registry (PALGA). The European standardized incidence rate (ESR) and VSCC risk were calculated, stratified for HSIL and dVIN. The effects of type of VIN (HSIL vs dVIN), age and lichen sclerosis (LS) were estimated by Cox regression. In total, 1148 patients were diagnosed with high-grade VIN between 1991 and 2011. Between 1991-1995 and 2006-2011, the ESR of HSIL increased from 2.39 (per 100 000 woman-years) to 3.26 and the ESR of dVIN increased from 0.02 to 0.08. The 10-year cumulative VSCC risk was 10.3%; 9.7% for HSIL and 50.0% for dVIN (log rank P < .001). Type of VIN, age and presence of LS were independent risk factors for progression to VSCC, with hazard ratios of 3.0 (95% confidence interval [CI] 1.3-7.1), 2.3 (95% CI 1.5-3.4) and 3.1 (95% CI 1.8-5.3), respectively. The incidence of high-grade VIN is rising. Because of the high cancer risk in patients with dVIN, better identification and timely recognition are urgently needed.

Peripheral inflammatory biomarkers as predictors of recurrence in surgically-treated anogenital condylomata acuminata patients.

The aim of this study was to examine the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) in patients with anogenital condylomata acuminata (CA) and their association with recurrence and squamous intraepithelial neoplasia development. We conducted a descriptive study in 95 patients that had undergone surgical treatment for CA. The descriptive data, disease characteristics, and pre-treatment peripheral inflammatory biomarkers (PIBs) were recorded retrospectively. All parameters were compared in those with recurrent and non-recurrent CA. All PIBs were significantly higher in patients with the greatest genital wart size of >2 cm in the squamous intraepithelial lesion (SIL) group. Human papillomavirus (HPV) types 16, 18, 31 and 33, known to carry high risk for anogenital cancer, were significantly related to higher SII. Greater wart size, high-grade squamous intraepithelial lesion (HSIL), and higher PLR and SII values were highly associated with recurrent disease (p = 0.003, 0.006, 0.005 and 0.000, respectively). Of all recurrences, 34.1% were explained by HSIL and increased PLR and SII values. The prediction of CA recurrence is important to determine those patients at high risk. PLR and SII can be used for risk analysis in selected patient groups.

14-type HPV mRNA test in triage of HPV DNA-positive postmenopausal women with normal cytology.

BACKGROUND: During 2013 and 2016 the region of Skåne, Sweden started to analyse human papillomavirus (HPV) and cytology in postmenopausal women 60-65 years of age. Our aim was to evaluate high-risk (HR) HPV mRNA testing for the triage of HPV DNA-positive postmenopausal women with normal cytology. METHODS: A total of 271 women, 60-65 years of age, underwent liquid-based cytology (LBC) and HPV testing by using the HR-HPV DNA MGP-PCR-Luminex assay. HR-HPV DNA-positive women with normal cytology underwent complimentary HPV mRNA testing (Aptima, Hologic Inc.). Over a period of 49 months (SD 11.0) the women received regular follow-ups at intervals of 12-18 months. Women with abnormal cytology and/or a positive HR-HPV DNA and/or mRNA result at two subsequent visits were scheduled for colposcopy and clinical examination. RESULTS: Over the surveillance period, 3.6% (10/271) of the HR-HPV DNA-positive women developed histologically confirmed high-grade squamous intraepithelial lesions (HSILs) or worse. The cumulative incidence rates (CIR) were 29.7% (CI 24.8-30.1) for HSIL or worse among HPV mRNA-positive women at enrolment (39.5% 107/271) and 0% among HPV mRNA-negative women (60.5%, 164/271), (p = 0.002). CONCLUSIONS: Postmenopausal women with normal cytology testing positive for HR-HPV mRNA are at increased risk for the development of high-grade cervical intraepithelial neoplasia (CIN), in contrast to women with a negative HR-HPV mRNA outcome. The HR-HPV mRNA APTIMA assay detecting 14 HR-HPV types may be a useful triage method among HPV DNA-positive postmenopausal women with normal cytology.

Prevalence and Association of Perianal and Intra-Anal Warts with Composite High-Grade Squamous Intraepithelial Lesions Among Gay and Bisexual Men: Baseline Data from the Study of the Prevention of Anal Cancer.

Human papillomavirus (HPV) causes anal warts and anal squamous cell carcinoma (SCC). A higher incidence of anal cancer has been found among individuals previously diagnosed with anogenital warts. We aimed to investigate the association between anal warts and the presumed anal SCC precursor high-grade squamous intraepithelial lesion (HSIL), among participants in the Study of the Prevention of Anal Cancer (SPANC). SPANC was a longitudinal study of anal HPV infections and related lesions among gay and bisexual men (GBM) age 35 years and older, in Sydney, Australia. Anal cytology and high-resolution anoscopy were performed. Logistic regression was used to investigate the association between clinically diagnosed anal warts and intra-anal composite-HSIL (cytology and/or histology) at the baseline visit. The prevalence of HSIL within biopsies from intra-anal warts was calculated. Laser capture microdissection (LCM) and HPV-genotyping was performed on HSIL lesions. Among 616 participants at study entry, 165 (26.8%) and 51 (8.3%) had intra-anal and perianal warts, respectively. Warts were associated with composite-HSIL, even after adjustment for HIV status, age, lifetime receptive anal intercourse partner number, and smoking (perianal: aOR 2.13, 95% CI 1.17-3.87, p = 0.013; intra-anal: aOR 1.69, 95% CI 1.16-2.46, p = 0.006). HSIL was detected in 24 (14.5%) of 165 biopsies from intra-anal warts. Of 17 HSIL lesions, 16 (94.1%) had high-risk HPV detected by LCM. Anal warts were common. Prevalent anal warts were associated with composite-HSIL. HSIL may be detected within biopsies of intra-anal warts. Anal warts may be a useful addition to risk stratification for HSIL among GBM.

ASCCP Risk-Based Colposcopy Recommendations Applied in Thai Women With Atypical Squamous Cells of Undetermined Significance or Low-Grade Squamous Intraepithelial Lesion Cytology.

OBJECTIVE: To compare the proportion of cervical intraepithelial neoplasia (CIN) 2 or worse pathology among different risk strata according to the ASCCP when applied in women who had atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesion (LSIL) cervical cytology; to assess performance of colposcopy; and to assess the independent predictors for detected CIN 2 or worse pathology. METHODS: This is a secondary analysis of a previous prospective study, which included Thai women with ASC-US or LSIL cytology who underwent high-risk human papillomavirus (HPV) testing and subsequent colposcopy with directed biopsy. Patients were classified as lowest-risk, intermediate-risk, or highest-risk based on cervical cytology, high-risk HPV testing, and colposcopic impression. The proportion of CIN 2 or worse pathology and associated prognostic factors were analyzed. RESULTS: Of 697 women, 103 (14.8%), 573 (82.2%) and 21 (3%) were classified into lowest-risk, intermediate-risk, and highest-risk groups, respectively. The proportion of CIN 2 or worse pathology was 1%, 11.2%, and 61.9% in those same groups, respectively (P<.001). Colposcopy to detect CIN 2 or worse pathology had a sensitivity, specificity, positive predictive value, and negative predictive value of 98.7%, 18%, 13.2%, and 99.1%, respectively. Independent predictors for detecting CIN 2 or worse pathology were positive high-risk HPV, HPV 16/18 positivity, and high-grade colposcopic impression. CONCLUSION: This study supports a no biopsy with follow-up strategy in the lowest-risk group, inconsistent with ASCCP recommendations, but is in alignment with a strategy of multiple targeted biopsies in the intermediate-risk and highest-risk groups.

Genetic variability, phylogeny and functional implication of the long control region in human papillomavirus type 16, 18 and 58 in Chengdu, China.

BACKGROUND: Long control region (LCR) of human papillomavirus (HPV) has shown multiple functions on regulating viral transcription. The variations of LCR related to different lineages/sub-lineages have been found to affect viral persistence and cervical cancer progression differently. In this study, we focused on gene polymorphism of HPV16/18/58 LCR to assess the effect variations caused on transcription factor binding sites (TFBS) and provided more data for further study of LCR in Southwest China. METHODS: LCR of HPV16/18/58 were amplified and sequenced to do polymorphic and phylogenetic anlysis. Sequences of each type were aligned with the reference sequence by MEGA 6.0 to identify SNPs. Neighbor-joining phylogenetic trees were constructed using MEGA 6.0. Transcription factor binding sites were predicted by JASPAR database. RESULTS: The prevalence of these three HPVs ranked as HPV16 (12.8%) > HPV58 (12.6%) > HPV18 (3.5%) in Chengdu, Southwest China. 59 SNPs were identified in HPV16-LCR, 18 of them were novel mutations. 30 SNP were found in HPV18-LCR, 8 of them were novel. 55 SNPs were detected in HPV58-LCR, 18 of them were novel. Also, an insertion (CTTGTCAGTTTC) was detected in HPV58-LCR between position 7279 and 7280. As shown in the neighbor-joining phylogenetic trees, most isolates of HPV16/18/58 were clustered into lineage A. In addition, one isolate of HPV16 was classified into lineage C and 3 isolates of HPV58 were classified as lineage B. JASPAR results suggested that TFBS were potentially influenced by 7/6 mutations on LCR of HPV16/18. The insertion and 5 mutations were shown effects in LCR of HPV58. CONCLUSION: This study provides more data for understanding the relation among LCR mutations, lineages and carcinogenesis. It also helps performing further study to demonstrate biological function of LCR and find potential marker for diagnosis and therapy.

Evidence of Passive Smoking as a Risk Factor of High-Grade Squamous Intraepithelial Lesion: A Case-Control Study.

This study aims to evaluate the association between passive smoking and high-grade squamous intraepithelial lesion (HSIL) at the sample of Chinese women. We conducted a case-control study to analyze the effect of passive smoking on the incidence that patients diagnosed with HSIL. The participants had undergone cervical cancer screening by cytology and human papillomavirus (HPV) co-testing within a year before the study. Multiple logistic regression was used to explore the effect and interactive effect of risk factors on HSIL. The odds ratio (OR) and 95% confidence interval (CI) were calculated. Passive smokers were 1.57 times (95% CI 1.05-2.35) higher than non-smokers to occur HSIL. The medium of the combined smoking index divided patients into low and high exposure, with the ORs of 1.64 (95%CI 1.02-2.64) and 1.71 (95%CI 1.06-2.77) relative to non-smokers, respectively. The combined smokers in the high exposure group experienced the most considerable risk of HSIL (OR = 4.67; 95%CI 1.17-18.70). The OR of HPV positive passive smoker relative to that of HPV negative non-smokers was 5.28 (95%CI 2.25-14.52;). Passive smokers who reported adolescent exposure history was 4.04 times (95%CI 1.44-11.37) more at risk of the disease than non-smokers. This study supported that passive smoking was a significant independent risk factor on the occurrence of HSIL and showed a positive correlated dose-response relationship. HPV infection interacting with passive smoking led to an even higher risk of the disease. Adolescent exposure to passive smoking persistent for more than 20 years would also increase the risk of HSIL.

Possibly carcinogenic HPV subtypes are a cause of HSIL and negative clinical HPV tests - A European prospective single center study.

OBJECTIVE: To correlate p16ink4a positive cervical precancers of 388 consecutive patients from a single European center with the preceding clinical HPV-DNA and HPV E6/E7 mRNA screening test. METHOD: 374/388 patients had a HSIL (CIN 2/3) and 14/388 AIS (6 pure and 8 combined AIS/HSIL). Lesional tissues of HSIL/AIS with negative Cobas and/or Aptima HPV tests underwent HPV genotyping with CHIPRON HPV 3.5 LCD-array. Selected cases were subjected to a cancer hot spot analysis. RESULTS: The Aptima test missed 10/388 (2.6%) and the Cobas test seven of 388 (1.8%) precancers associated HPV-HR. Both HPV tests were negative in 20/374 precancers (5.3%; 17 HSIL/CIN3, two HSIL/CIN2, one AIS). Due to insufficient DNA four of 20 double negative cases (three HSIL, one AIS) were not genotyped. In the remaining cases, two of 20 (10%) HSIL genotyping detected HR-HPV subtypes. 10/20 (50%) HSIL were associated with possibly carcinogenic and low risk HPV (four x HPV73, three x HPV 53, one x HPV 82, one x HPV 67 and one x HPV 6), all of which are not included in both HPV tests. Two of 20 (10%) HSIL were negative with all HPV tests; one of these HSIL had a somatic PIK3CA gene mutation and the other had a single nucleotide variant in the APC gene. Three of 20 HSIL (15%) were thin HSIL (≤9 cell layers thick). CONCLUSIONS: Possibly carcinogenic HPV subtypes not included in the clinical HPV tests may account for the small gap of missed HSIL in clinical HPV screening. True HPV negative HSIL are exceedingly rare. Expanding HPV testing to include more possibly carcinogenic HPV subtypes may further reduce cervical cancer.

HIV-Infected Patients With Anal Cancer Precursors: Clinicopathological Characteristics and Human Papillomavirus Subtype Distribution.

BACKGROUND: People living with HIV have high rates of anal human papillomavirus infection and anal precancer/cancer. OBJECTIVE: This study aims to: 1) determine human papillomavirus subtype distribution among people living with HIV with anal high-grade squamous intraepithelial lesions; 2) compare the clinicopathological characteristics of patients with anal high-grade squamous intraepithelial lesions by human papillomavirus 16 status; and 3) investigate high-risk human papillomavirus negative anal high-grade squamous intraepithelial lesion cases. DESIGN: In this retrospective study, 700 people living with HIV who have biopsy-proven anal high-grade squamous intraepithelial lesions were reviewed for demographics, cytological diagnoses, and human papillomavirus testing results for human papillomavirus 16, 18, and 12 other high-risk types. For human papillomavirus-negative subjects, corresponding biopsies were genotyped by using real-time polymerase chain reaction. SETTINGS: This study was conducted in a large urban HIV clinic system and major referral center for anal cancer screening. PATIENTS: Median age was 46 years (range, 20-76). Ninety-one percent of the patients were men who have sex with men. MAIN OUTCOME MEASURES: The primary outcome measure was the association between demographic variables and human papillomavirus 16 status. RESULTS: Anal cytology was unsatisfactory (5%), benign (13%), atypical squamous cells of undetermined significance (35%), low-grade squamous intraepithelial lesion (36%), and high-grade squamous intraepithelial lesions (11%). Human papillomavirus cotesting results were negative (n = 38, 5%), human papillomavirus 16 (n = 303, 43%), human papillomavirus 18 (n = 78, 11%), or exclusively non-16/18 types (n = 281, 40%). Human papillomavirus 16 positivity was associated with ≥3 high-grade lesions and ≥ low-grade squamous intraepithelial lesion cytology (p < 0.001). Age, race/ethnicity, sex, smoking, CD4+ T-cell count, and HIV viral load did not differ by status of human papillomavirus 16 (p > 0.05). For human papillomavirus-negative cases, human papillomavirus genotyping of biopsies was positive for high-risk (n = 14, 36%) or possibly carcinogenic types (n = 12, 32%), or negative (n = 12, 32%). LIMITATIONS: This was a retrospective data analysis, and it pooled the results for 12 high-risk human papillomavirus types rather than individual types. CONCLUSIONS: Nearly all people living with HIV and anal high-grade squamous intraepithelial lesions test positive for high-risk human papillomavirus on anal swabs; negative results may be due to sampling error, L1-based polymerase chain reaction assay, or human papillomavirus types not captured by standard clinical assays. Patients who have human papillomavirus 16-positive anal high-grade squamous intraepithelial lesions are indistinguishable from others based on demographic and clinical characteristics, underscoring the potential role of human papillomavirus testing for anal cancer screening. See Video Abstract at http://links.lww.com/DCR/B208. PACIENTES PORTADORES DE VIH CON PRECURSORES DE CÁNCER DE ANO: CARACTERÍSTICAS CLINICOPATOLÓGICAS Y DISTRIBUCIÓN DEL SUBTIPO VPH: Los pacientes portadores de VIH tienen altas tasas de infección por VPH y alto riesgo de desarrolar lesiones precáncerosas / cáncerosas del ano.(1) Determinar la distribución del subtipo de VPH entre las personas portadoras de VIH con lesiones intraepiteliales escamosas anales de alto grado. (2) Comparar las características clinicopatológicas de pacientes con lesiones intraepiteliales escamosas anales de alto grado del subtipo VPH 16. (3) Investigar casos de lesiones intraepiteliales escamosas anales de alto grado negativas para el VPH de alto riesgo.Estudio retrospectivo sobre 700 personas portadoras de VIH con lesiones intraepiteliales escamosas anales de alto grado confirmadas por biopsia. Los datos fueron revisados para determinar información demográfica, diagnósticos citológicos y resultados de tipización en el VPH subtipos 16 y 18, y otros 12 tipos de alto riesgo. Para los individuos negativos al VPH, se analizó el genotipo en las biopsias correspondientes mediante test de PCR en tiempo real.Extenso sistema de clinicas urbanas tratando VIH y un importante centro de referencia para la detección del cáncer analla mediana de edad poblacional fue de 46 años (rango, 20-76). 91% eran hombres que tenían sexo con hombres.Asociación entre las variables demográficas y el estado del VPH subtipo16.la citología anal fue insatisfactoria (5%), benigna (13%), células escamosas atípicas de importancia indeterminada (35%), lesión intraepitelial escamosa de bajo grado (36%) y lesiones intraepiteliales escamosas de alto grado (11%). Los resultados de la prueba conjunta del VPH fueron negativos (n = 38, 5%), el virus del VPH subtipo 16 (n = 303, 43%), el VPH subtipo 18 (n = 78, 11%) o los subtipos exclusivamente no 16/18 (n = 281, 40%). La positividad del VPH subtipo 16 se encotraba asociado con ≥3 lesiones de alto grado y ≥ células escamosas atípicas en la prueba de citología de indeterminada importancia (p < 0.001). La edad, la raza / etnia, el sexo, el tabaquismo, el recuento de células T CD4 + y la carga viral del VIH no difirieron según el estado del VPH subtipo 16 (p > 0.05). Para los casos negativos al VPH, el genotipo del virus del papiloma humano de las biopsias fue positivo para los tipos de alto riesgo (n = 14, 36%) o posiblemente carcinogénicos (n = 12, 32%), o negativo (n = 12, 32%).Análisis de datos retrospectivos, con resultados agrupados para 12 tipos de VPH de alto riesgo en lugar de tipos individuales.Casi todas las personas portadoras de VIH con lesiones intraepiteliales escamosas anales de alto grado dan positivo para el VPH de alto riesgo al muestreo de hisopos anales; Los resultados negativos pueden deberse a un error en el muestreo y al análisis de PCR basado en L1 o subtipos de VPH no obtenidos en los ensayos clínicos estándar. Los pacientes con lesiones intraepiteliales escamosas anales de alto grado positivas para el VPH subtipo 16 no son identificables de los demás, en función de las características demográficas y clínicas, lo que minimiza el rol potencial de la prueba del VPH en la detección del cáncer anal. Consulte Video Resumen en http://links.lww.com/DCR/B208. (Traducción-Dr. Xavier Delgadillo).

Cervical cancer screening coverage, management of squamous intraepithelial lesions and related costs in France.

Until 2018, cervical cancer screening in France was an unorganized individual screening, with the exception of some pilot programs in some territories. We aimed to assess, before the implementation of organized cervical cancer screening and human papillomavirus (HPV) nonavalent vaccine introduction in the vaccination schedule in 2018, (i) the individual cervical cancer screening coverage, (ii) the management of squamous intraepithelial lesions (SIL) and (iii) the related costs. We used the Système National des Données de Santé (SNDS) (Echantillon Généraliste de Bénéficiaires [EGB] and Programme de Médicalisation des systèmes d'information [PMSI]) to assess the cervical screening coverage rate in France between January 1st, 2012 and December 31st, 2014, and to describe diagnostic investigations and therapeutic management of SIL in 2013. After extrapolation to the general population, a total of 10,847,814 women underwent at least one smear test over the 3-year study period, corresponding to a coverage rate of 52.4% of the women aged 25 to 64 included. In 2013, 126,095 women underwent HPV test, 327,444 women underwent colposcopy, and 9,653 underwent endocervical curettage; 31,863 had conization and 12,162 had laser ablation. Besides, 34,067 women experienced hospital stays related to management of SIL; 25,368 (74.5%) had high-grade lesions (HSIL) and 7,388 (21.7%) low-grade lesions (LSIL). Conization was the most frequent in-hospital therapeutic procedure: 89.5% (22,704) of women with an in-hospital procedure for HSIL and 64.7% (4,781) for LSIL. Mean cost of smear test, colposcopy and HPV tests were around 50€. Total cost for hospital stays in 2013 was estimated at M41€, or a mean cost of 1,211€ per woman; 76% were due to stays with HSIL. This study highlights the low coverage rate of individual cervical cancer screening and a high burden related to SIL management.

Prevalence and associations of larger burden of intra-anal high-grade squamous intraepithelial lesions at baseline in an Australian cohort of gay and bisexual men: The Study of the Prevention of Anal Cancer.

OBJECTIVES: To investigate factors associated with larger burden of intra-anal high-grade squamous intraepithelial lesions (HSIL) in a natural history study of HSIL. METHODS: 617 gay and bisexual men (GBM) attended a baseline visit. High-resolution anoscopy-directed biopsy was performed of suspected HSIL. GBM with biopsy-confirmed HSIL (bHSIL) affecting a single-octant were compared with those who had bHSIL affecting a larger area. RESULTS: Of 196 men with bHSIL at baseline, 73 (37.2 %) had larger bHSIL burden. Larger burden was independently associated with anal HPV16 detection (aOR 2.06, 95 % CI 1.09-3.89, p = 0.026) and infection with a greater number of high-risk HPV types (aOR per type increase 1.25, 95 % CI 1.05-1.49, p-trend = 0.010). CONCLUSION: The observation that men with a larger burden of HSIL also had more risk factors for anal cancer suggests this group may warrant closer observation to ensure earlier detection, and thus improved prognosis, of individuals whose HSIL may progress to anal cancer.

Co-existence of Herpes simplex virus type 2 and two other oncoviruses is associated with cervical lesions in women living with HIV in South-Western Nigeria.

BACKGROUND: The prevalence of Herpes simplex virus type 2 (HSV-2) in cervical lesions is under-reported, especially in Human immunodeficiency virus (HIV), Epstein-Barr virus (EBV) and Human Papillomavirus (HPV) infected persons. OBJECTIVES: This study determined the prevalence of viral mono-infections, co-infections and squamous cell intraepithelial lesions (SIL) in HIV seropositive (HIV+) and HIV seronegative (HIV-) women. METHODS: This study included HIV+ and HIV- women (105 each). Cervical smears and viral antibodies were evaluated by Papanicolaou's technique and ELISA method, respectively. RESULTS: The prevalence of HSV-2, HPV and EBV infections, and SIL were higher in HIV+ women (75.2, 41.9, 41 and 32.4%) than in HIV- women (45.7, 26.7, 26.7 and 13.3%) at p< 0.0001, p= 0.029, 0.041 and 0.002, respectively. Higher prevalence of viral mono-infection and tri-infection was observed in HIV+ women (43.8 and 24.8%) than in HIV- women (27.6 and 8.6%) at p= 0.021, and 0.003, respectively. The prevalence of SIL was also higher in HIV+ women with viral mono-infection, bi-infection and tri-infection (15.2, 42.9, and 53.8%) than in HIV- women (6.9, 12.5, and 44.4%) at p= 0.468, 0.041, and 0.711, respectively. CONCLUSION: This study suggests that the high prevalence of SIL in HIV+ women could be associated with viral co-infections.

Anal Squamous Intraepithelial Lesions (SILs) in Human Immunodeficiency Virus-Positive Men Who Have Sex With Men: Incidence and Risk Factors of SIL and of Progression and Clearance of Low-Grade SILs.

BACKGROUND: Human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) are at risk of anal squamous cell carcinoma. Data are limited on the natural history of the precursor to this carcinoma, anal squamous intraepithelial lesions (SILs). METHODS: HIV-positive MSM were screened for histopathological SILs by means of high-resolution anoscopy (HRA). For participants without SILs at baseline, we estimated the cumulative incidence and risk factors for SILs. For those with low-grade SILs (LSILs) at baseline, the risk of progression to high-grade SILs (HSILs) and the clearance rate were estimated at the lesion level. RESULTS: Of 807 men without SILs at baseline, 107 underwent follow-up HRA between 1 to 4.5 years later. At the second visit 18 men (16.8%) showed LSIL, and 25 (23.4%) HSIL. Age was associated with incident LSILs (adjusted odds ratio [aOR], 2.10 per 10-year increase in age; P = .01). Of 393 men with LSILs at baseline, 114 underwent follow-up HRA 0.5 to 2.5 years later. Of the 177 LSILs found at baseline, 87 (49.2%) had cleared at the second visit, and 29 (16.4%) had progressed to HSILs. CONCLUSION: Incident LSILs and HSILs were common during follow-up among HIV-positive MSM without dysplasia at baseline. Among men with LSILs at baseline, nearly half of these lesions cleared, and a small portion progressed.