Histological High-grade Squamous Intraepithelial Lesions Research Articles

Prevalence and incidence of anal high-grade squamous intraepithelial lesions in a cohort of cisgender men and transgender women who have sex with men diagnosed and treated during acute HIV acquisition in Bangkok, Thailand.

Men who have sex with men (MSM), especially those living with HIV, are at an increased risk of anal cancer. The prevalence and incidence of its precursor, anal high-grade squamous intraepithelial lesions (HSILs), among MSM who started antiretroviral therapy during acute HIV acquisition are yet to be explored. Participants in an acute HIV acquisition cohort in Bangkok, Thailand, who agreed to take part in this study, were enrolled. All participants were diagnosed and started antiretroviral therapy during acute HIV acquisition. Human papillomavirus (HPV) genotyping and high-resolution anoscopy, followed by anal biopsy as indicated, were done at baseline and 6-monthly visits. A total of 89 MSM and four transgender women were included in the analyses. Median age at enrolment was 26 years. Baseline prevalence of histologic anal HSIL was 11.8%. With a total of 147.0 person-years of follow-up, the incidence of initial histologic anal HSIL was 19.7 per 100 person-years. Factors associated with incident anal HSIL were anal HPV 16 (adjusted hazards ratio [aHR] 4.33, 95% CI 1.03-18.18), anal HPV 18/45 (aHR 6.82, 95% CI 1.57-29.51), other anal high-risk HPV (aHR 4.23, 95% CI 1.27-14.14), syphilis infection (aHR 4.67, 95% CI 1.10-19.90) and CD4 count <350 cells/mm3 (aHR 3.09, 95% CI 1.28-7.48). With antiretroviral therapy initiation during acute HIV acquisition, we found the prevalence of anal HSIL among cisgender men and transgender women who have sex with men to be similar to those without HIV. Subsequent anal HSIL incidence, although lower than that of those with chronic HIV acquisition, was still higher than that of those without HIV. Screening for and management of anal HSIL should be a crucial part of long-term HIV care for all MSM.

Two-Year Incidence and Cumulative Risk and Predictors of Anal High-Grade Squamous Intraepithelial Lesions (Anal Precancer) Among Women With Human Immunodeficiency Virus.

Detection and treatment of anal histologic high-grade squamous intraepithelial lesions (hHSIL) prevents anal cancer. However, anal hHSIL incidence among women with human immunodeficiency virus (HIV, WHIV) remains unknown. Performance of anal high-risk human papillomavirus ([hr]HPV), anal cytology (anal-cyt), and both for hHSIL detection longitudinally over 2 years also remains undetermined. We determined 2-year incidence and cumulative risk estimates (2-y-CR) of anal hHSIL among WHIV using prevalence and incidence (per 100 person-years [py]) observations stratified by baseline hrHPV and/or anal-cyt results. In total, 229 WHIV with complete baseline data were included in the analysis; 114 women without prevalent anal hHSIL were followed with 2 annual evaluations. Median age was 51, 63% were Black, and 23% were Hispanic. Anal hrHPV or abnormal anal-cyt was associated with an increased risk of incident anal hHSIL at 2 years (18.9/100py [95% confidence interval {CI} 11.4-31.3] and 13.4/100py [95% CI 8.0-22.7], respectively) compared with no detection of anal HPV or negative cytology (2.8/100py [95% CI 1.1-7.4] and 4.2 [95% CI, 1.8-10.2]) The presence of anal hrHPV with abnormal cytology was associated with 2-y-CR of anal hHSIL of 65.6% (95% CI 55.4%-75%); negative hrHPV with negative cytology was associated with 2-y-CR of anal hHSIL of 9.2% (95% CI 7.0-16.0). Detection of anal hrHPV or abnormal anal cytology are comparable predictors for 2-y-CR of anal hHSIL. The absence of anal hrHPV combined with negative cytology was predictive of a lower (but measurable) risk of developing anal hHSIL. These findings provide important data to inform anal cancer screening guidelines for WHIV.

Anal cancer screening results from 18-to-34-year-old men who have sex with men living with HIV.

Men who have sex with men living with HIV (MSM LWH) are at highest risk for human papillomavirus (HPV)-associated anal cancer. There is no consensus on the optimal screening initiation age. This study aimed to assess the prevalence and severity of anal HPV disease among MSM LWH under the age of 35, which is a currently proposed screening age threshold. Between 2014 and 2020, 1255 18-to-34-year-old MSM LWH underwent anal cytology screening. 916 were co-tested for high-risk HPV (HR-HPV). 467 underwent high-resolution anoscopy (HRA) and biopsy. Cancer registry data were queried. Predictors of abnormal cytology (ie, ≥ASCUS) and histological high-grade squamous intraepithelial lesions (HSIL) were evaluated using unadjusted logistic regression models. Median age was 28 years (range, 18-34). 19% received at least one dose of HPV vaccine. Abnormal cytology rate was 65%. HR-HPV and HPV16 prevalence were 87% and 30%. Biopsy results were benign (10%), LSIL (43%) and HSIL (47%). No cases of prevalent or incident anal cancers were detected. Findings were similar between age subgroups (18-24, 25-29 and 30-34) except for a higher prevalence of AIN 3 in the 30-34 group (19%). Abnormal cytology was significantly associated with HR-HPV infection. Histological HSIL was associated with HR-HPV infection and cytological LSIL or worse. The absence of anal cancer in a large cohort of MSM LWH under the age of 35, despite high prevalence of anal HR-HPV infection and precancer, supports an age-based anal cancer screening strategy for MSM LWH.

Analysis of outcomes following loop electrosurgical excision and clinical features of patients with cervical high-grade squamous intraepithelial lesions with abnormal preoperative endocervical curettage

ObjectiveThe purpose of this study was to identify the clinical characteristics of patients with high-grade squamous intraepithelial lesions (HSIL) with abnormal endocervical curettage (ECC) and to evaluate the efficacy of abnormal preoperative ECC in predicting recurrence after a loop electrosurgical excision procedure (LEEP).MethodsWe retrospectively analyzed a total of 210 cases of histological HSIL in female patients diagnosed using cervical biopsy and/or indiscriminating ECC, and these included 137 cases with normal ECC and 63 cases with abnormal ECC. We also collected preoperative information and data on postoperative human papillomavirus (HPV) and histological outcomes within 2 years.ResultsThe additional detection rate of HSIL using indiscriminating ECC was 5%. Patients with abnormal ECC were older (P < 0.001), predominantly menopausal (P = 0.001), had high-grade cytology (P = 0.032), a type 3 transformation zone (P = 0.046), and a higher proportion of HPV type 16/18 infection (P = 0.023). Moreover, age (odds ratio [OR] = 1.078, 95% confidence interval [CI] = 1.0325–1.1333, P = 0.003) and HPV 16/18 infection (OR = 2.082, 95% CI = 1.042–4.2163, P = 0.038) were independent risk factors for abnormal ECC. With an observed residual lesion/recurrence rate of 9.5% over the 24-month follow-up, we noted a 9.3% higher rate in the abnormal ECC group when compared with the normal ECC group. Abnormal preoperative ECC (OR = 4.06, 95% CI = 1.09–15.14, P = 0.037) and positive HPV at the 12-month follow-up (OR = 16.55, 95% CI = 3.54–77.37, P = 0.000) were independent risk factors for residual disease/recurrence.ConclusionPreoperative ECC was one of the risk factors for post-LEEP residual/recurrent HSIL, and detecting abnormal ECC when managing older patients or patients with HPV 16/18 infection during colposcopy is critical.

The prevention of cervical cancer

Cervical cancer screening concerns women between the ages of 25 and 65. It consists of the collection of cervical cells with a spatula by rubbing the cervix. The material was initially spread out and fixed on a glass slide. It was subsequently fixed in a liquid preservative with an automated spread on a thin-layer slide after centrifugation or filtration, a process called liquid cytology. Microscopic reading was facilitated by field selection using an automated pre-reading system. In July 2019, the French High Authority for Health (HAS) recommended to position DNA research of high-risk human papillomavirus types by PCR (HPV HR test) in first position after the age of 30. This approach is more sensitive than cytology in diagnosing a histological high-grade squamous intraepithelial lesion, and more effective in preventing invasive cancers. The HPV HR test, if positive, is followed by a cytological examination on the same sample to select patients requiring examination of the cervix by colposcopy. Vaccination against the nine most common types of HPV in girls and boys aged 11 to 14 years is the other part of the prevention of invasive cancer.

Human papillomavirus testing on self-collected samples to detect high-grade cervical lesions in rural Bhutan: The REACH-Bhutan study.

"REACH-Bhutan" aimed to evaluate the feasibility and clinical performance of a community-based screening program for cervical cancer in rural Bhutan using self-collected samples for high-risk human papillomavirus (HR-HPV) testing. In April/May 2016, 2590 women aged 30-60 years were screened across rural Bhutan by providing a self-collected sample for careHPV testing. All careHPV-positive women, plus a random sample of careHPV-negative women, were recalled for colposcopy and biopsy. Self-samples also underwent GP5+/6+ polymerase chain reaction (PCR)-based HR-HPV DNA detection and genotyping. Cross-sectional screening indices were estimated against histological high-grade squamous intraepithelial lesions or worse (hHSIL+), including imputation of hHSIL+ in women without colposcopy. HR-HPV positivity was 10.2% by careHPV and 14.8% by GP5+/6+ PCR. Twenty-two cases of hHSIL+ were histologically diagnosed, including one invasive cancer; an additional 7 hHSIL+ were imputed in women without colposcopy. HR-HPV testing by GP5+/6+ showed higher sensitivity for hHSIL+ (89.7%, 95% CI 72.6-97.8) than careHPV (75.9%, 95% CI 56.5-89.7). Negative predictive value was also slightly higher for GP5+/6+ (99.9%, 95% CI 99.6-100) than careHPV (99.7%, 95% CI 99.4-99.9). Specificity, however, was lower for GP5+/6+ (86.1%, 95% CI 84.6-87.4) than careHPV (90.6%, 95% CI 89.4-91.7), as was positive predictive value (6.9%, 95% CI 4.5-9.9 vs. 8.5%, 95% CI 5.4-12.6). Of 377 HR-HPV-positive women by GP5+/6+, 173 (45.9%) were careHPV-positive, including 54.7% HPV16-positive and 30.2% HPV18-positive women. The final REACH-Bhutan results show that screening for cervical cancer with self-collection of samples and HR-HPV testing, in addition to our previous report of achieving high participation, can also perform well to detect women with hHSIL+.

Clinical implementation of a cervical cancer screening program via co-testing at a university hospital.

The Human Papillomavirus (HPV) test is a crucial technology for cervical cancer prevention because it enables programs to identify women with high-risk HPV infection who are at risk of developing cervical cancer. Current U.S. Preventive Services Task Force recommendations include cervical cancer screening every three years with cervical cytology alone or every five years with either high-risk HPV testing alone or high-risk HPV testing combined with cytology (co-testing). In Argentina, 7,548 new cervical cancer cases are diagnosed each year with 3,932 deaths attributed to this cause. Our study aims to show the clinical implementation of a cervical cancer screening program by concurrent HPV testing and cervical cytology (co-testing); and to evaluate the possible cervical cancer screening scenarios for Latin America, focusing on their performance and average cost. A cervical cancer screening five year program via co-testing algorithm (Hybrid-2-Capture/cytology) was performed on women aged 30-65 years old at a university hospital. Statistical analysis included a multinomial logistic regression, and two cancer screening classification alternatives were tested (cytology-reflex and HPV-reflex). A total of 2,273 women were included, 91.11% of the participants were double-negative, 2.55% double-positive, 5.90% positive-Hybrid-2-Capture-/negative-cytology, and 0.44% negative-Hybrid-2-Capture/positive-cytology. A thorough follow-up was performed in the positive-Hybrid-2-Capture group. Despite our efforts, 21 (10.93%) were lost, mainly because of changes on their health insurance coverage which excluded them from our screening algorithm. Of the 171 women with positive-Hybrid-2-Capture results and follow-up, 68 (39.77%) cleared the virus infection, 64 (37.43%) showed viral persistence, and 39 (22.81%) were adequately treated after detection via colposcopy/biopsy of histological HSIL (High-Grade Squamous Intraepithelial Lesion). The prevalence of high-risk HPV in this population was 192 women (8.45%), with HSIL histology detection rates of 17 per 1,000 screened women. A multinomial logistic regression analysis was performed over the women with positive-Hybrid-2-Capture considering the follow up (clearance, persistence and HSIL) as dependent variable, and the cytology test results (positive- or negative-cytology and Atypical Squamous Cells of Undetermined Significance, ASC-US) as independent variable. The model supported a direct association between cytology test results and follow up: negative-cytology/clearance, ASC-US/persistence, and positive-cytology/HSIL with the following probabilities of occurrence for these pairs 0.5, 0.647 and 0.647, respectively. Cytology could be considered a prognostic-factor in women with a positive-Hybrid-2-Capture. These findings suggest that the introduction of co-testing could diminish the burden of cervical cancer in low-and middle-income-countries, acting as a tool against inequity in healthcare.

Full genotyping and FAM19A4/miR124-2 methylation analysis in high-risk human papillomavirus-positive samples from women over 30 years participating in cervical cancer screening in Örebro, Sweden.

Currently, cervical cancer prevention is undergoing comprehensive development regarding human papillomavirus (HPV) vaccination and cervical cancer screening. In Sweden and many other countries, high coverage vaccinated cohorts are entering screening within the next few years. This entails demands for baseline HPV genotype data across the screening age range for surveillance and a basis for screening program adjustment. In 2016, Örebro County, Sweden, changed to primary HPV screening using HPV mRNA testing followed by cytology triage. An alternative triage method to cytology could allow for a fully molecular screening algorithm and be implemented in a screening program where self-sampling is included. Hypermethylation analysis of the human genes FAM19A4/miR124-2 has been suggested as a promising triage method. HPV mRNA-positive screening samples (n = 529) were included and subjected to genotyping targeting a broad range of both low-risk and high-risk genotypes in addition to hypermethylation analysis of the two human genes FAM19A4/miR124-2. Data were connected to cytological and histological status and age. The most commonly detected genotypes were HPV31, 16, and 52. In addition, HPV18 was one of the most common genotypes in high-grade squamous intraepithelial lesions (HSILs) samples. In relation to available vaccines, 26% of the women with histological HSIL or cancer (≥HSIL) tested positive for only hrHPV included in the quadrivalent vaccine and 77% of the genotypes in the nonavalent vaccine. According to these figures, a relatively large proportion of the HSILs will probably remain, even after age cohorts vaccinated with the quadrivalent vaccine enter the screening program. Hypermethylation positivity was associated with increasing age, but no HPV-related independently predictive factors were found. Accordingly, age needs to be considered in development of future screening algorithms including triage with hypermethylation methodology.

Co-testing in cervical screening among 40- to 42-year-old women is unreasonable.

The screening program for cervical cancer in Sweden recommends the use of primary human papillomavirus (HPV) screening for women aged ≥30 to 65years. Co-testing with both HPV analysis and cytology is recommended at the first screening after the age of 40 years. To fulfil co-testing, all screened women aged 40-42 years within the region of Skåne were co-tested. The aim of the audit was to investigate the proportion of severe dysplasia as diagnosed by cytology and histological follow-up among women with Aptima HPV-negative tests. We also calculated the cost of adding the cytology to the HPV primary screening program. The local cytology registry was used to identify women aged 40-42years who attended screening and were co-tested during the 4years from January 2017 to December 2020. The Aptima HPV messenger RNA assay detects 14 HPV types. For Aptima HPV-negative women with high-grade cytology or histological high-grade squamous intraepithelial lesions (HSILs), we performed extended HPV typing for 40 HPV types with polymerase chain reaction using modified GP5+/6+ primers followed by a Luminex assay. To estimate the added cost of using cytology to identify each histologically confirmed cervical HSIL case among Aptima HPV-negative women, we used the current cost of €21.2 per cytology evaluation at our laboratory. Of 19599 women, 5.8% (1137/19599) had abnormal cytology. Among Aptima HPV-negative women, 0.11‰ (2/18132) had histologically confirmed HSIL. One of the women was infected with HPV18 and the other with HPV73 at the diagnosis of HSIL. The calculated cost to find one HSIL, by adding cytology to HPV-negative cases, was approximately €200000. The clinical benefit of a single cytology co-test added to an HPV-based screening program in women aged 40-42years appears doubtful and economically unreasonable.

Abstract IA-15: Serum testosterone and estradiol modify risk of anal HPV16/18 infections but only estradiol and Estrogen Receptor 1-alpha influences risk for histological high-grade squamous intraepithelial lesions (HSIL)

Abstract Background: We reported higher serum free testosterone (FT) and anal-HPV16/18 infection prevalence in MSM. Associations between serum-FT and -estradiol, anal-HPV16/18 infections, and Estrogen Receptor 1α (ESR1) and histological HSIL (hHSIL) are unclear. Methods: Three serial cross-sectional analyses were performed using data for 489 HIV-infected/HIV-uninfected adult males enrolled in the Multicenter AIDS Cohort Study. For 340, anal cytology residuals were evaluated for 37 HPVs (PCR). For 214 men, 336 HRA/biopsies were evaluated for hHSIL; among them, &amp;lt;3 biopsy specimens for 47% (102) were assessed for ESR1 using immunohistochemistry. Serum specimen collection preceded HPV and HRA/biopsy visits by 24(+9) months. Each specimen was tested for Sex Hormone Binding Globulin (radioimmunoassay), and total testosterone and estradiol (TE2) (Liquid chromatography/mass spectrometry); serum-FT (pg/mL) was estimated. HPVs were classified: HPV16/18+, other Group-1 and -2 high-risk HPVs+ (hrHPVs); low-risk HPVs+ (lrHPVs), and none. Biopsies were evaluated as hHSIL vs. &amp;lt;hHSIL. Formalin-fixed paraffin-embedded anal biopsy (~4μm) were prepared and stained using a standard ESR1 immunohistochemistry protocol and were scored for immunofluorescence (0-3+) and percent affected (0-100%) by two pathologists. Multivariable-adjusted GEE logistic regression models assessed relationships between loge-transformed FT, TE2 and ESR1 (%), and HPV16/18+ and hHSIL separately. Self-reported sociodemographic/behavioral covariates were included. Results: Adjusted estimates showed higher FT increased odds of HPV16/18-infection (OR=1.87 (1.2-2.92)), but odds were inversely associated with TE2 (OR=0.68(0.49-0.94)). White race and other Group-1-hrHPVs+ increased odds for HPV16/18 infection (OR=2.61(1.16-5.87) and (OR=1.65(1.11-2.46)), but neither HIV-infection/CD4+count, receptive anal intercourse partnerships; exogenous-testosterone use, nor smoking increased HPV16/18-infection odds. Serum-TE2 and hHSIL were inversely associated (OR=0.51(0.3-0.89)) Serum-FT was not associated with odds of hHSIL (OR=1.09(0.78-1.74)), but. men testing HPV16/18+ showed higher odds of hHSIL than hrHPV-negative men (OR=4.27(1.71-10.66)). Median IHC ER1α-expression intensity was lower among hHSIL affected men: 10% (hHSIL) vs. 40% (&amp;lt;hHSIL). The percent of immunofluorescence intensity (%) was inversely associated with odds of hHSIL (OR=0.96(0.93-0.99). Conclusions: Higher serum-FT increased odds of anal HPV16/18-infection but not hHSIL. Higher serum-TE2 was inversely associated with the odds of both HPV16/18+ and hHSIL, and ESR1 expression in tissue is lower in hHSIL- than &amp;lt;hHSIL-affected epithelium. More research evaluating sex hormones and ERα expression in stroma and epithelial cells of HPV-associated HSIL/&amp;lt;HSIL-affected tissue is needed. Citation Format: Dorothy J. Wiley. Serum testosterone and estradiol modify risk of anal HPV16/18 infections but only estradiol and Estrogen Receptor 1-alpha influences risk for histological high-grade squamous intraepithelial lesions (HSIL) [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr IA-15.

Xpert HPV as a Screening Tool for Anal Histologic High-Grade Squamous Intraepithelial Lesions in Women Living With HIV.

Women living with HIV (WLWH) experience high rates of anal cancer. Screening using anal cytology, high-resolution anoscopy (HRA) with biopsies, can histologically diagnose anal cancer precursors called high-grade squamous intraepithelial lesions (HSIL). The low specificity of screening using anal cytology results in HRA referral for many WLWH without HSIL. Screening using high-risk human papillomavirus (HR-HPV) may improve specificity. Two hundred seven WLWH (63% non-Hispanic black) were screened for anal histologic HSIL (hHSIL) using cytology, HRA-guided biopsies, and Xpert HPV. Xpert performance for predicting anal hHSIL was compared with that of cytology. Usng Xpert 5 HPV genotypic results and accompanying cycle thresholds, receiver operator characteristic curve and recursive partitioning analyses were used to create predictive models for hHSIL. The performance of Xpert to predict hHSIL was not different from that of cytology with a sensitivity (Sn) of 89% and specificity (Sp) of 49%. Interpretation of Xpert was modified using genotypic results and receiver operator characteristic curve analysis, which produced a screen with an Sn and Sp of 75% and 84% for hHSIL, respectively. Another reinterpretation of Xpert was created using recursive partitioning and cycle thresholds, which predicted hHSIL with an Sn and Sp of 75% and 86%, respectively. The detection of HPV-16 was highly predictive of hHSIL in all analyses. These modified screening tests would reduce HRA referral in this population by almost half compared with anal cytology. Xpert HPV is an alternative to anal cytology to screen for anal HSIL and can be optimized to reduce the number of unnecessary HRAs performed in WLWH.

The CERTAIN Study Results: Adjunctive p16 Immunohistochemistry Use in Cervical Biopsies According to LAST Criteria.

The Lower Anogenital Squamous Terminology (LAST) Project recommends the use of p16 immunohistochemistry as an adjunct to morphologic assessment of cervical biopsies according to a specific set of criteria. We analyzed the effect of adjunctive p16 according to LAST criteria in a US-based diagnostic utility study involving 70 surgical pathologists providing a total of 38,500 reads on cervical biopsies. Compared with the results obtained using hematoxylin and eosin-stained slides only, including p16-stained slides per LAST criteria increased sensitivity and specificity for diagnosing histologic high-grade squamous intraepithelial lesions across all cases by 8.1% (95% confidence interval [95% CI], 6.5-9.7; P<0.0001) and 3.5% (95% CI, 2.8-4.2; P<0.0001), respectively, using expert consensus diagnoses on hematoxylin and eosin+p16 as reference. Within the subset of cases classified by the pathologists as fulfilling the LAST criteria, adding p16 significantly increased both sensitivity (+11.8%; 95% CI, 9.5-14.0; P<0.0001) and specificity (+9.7%; 95% CI, 7.8-11.5; P<0.0001). However, a comparable improvement in sensitivity (+11.0%; 95% CI, 7.8-14.1; P<0.0001) was found when p16 was used in cases for which p16 staining was not ordered per LAST by the pathologists, whereas specificity decreased by -0.8% (95% CI, -1.1 to -0.5; P<0.0001). The study demonstrates a clinically and statistically significant increase in sensitivity and specificity for high-grade squamous intraepithelial lesion when p16 is used according to LAST criteria. Expanding the use of p16 into non-LAST cases would lead to a comparable improvement in sensitivity within this subgroup of biopsies, at the cost of a minimal, but statistically significant difference in specificity.

Clinical Evaluation of DNA Ploidy for the Triage of HPV-Positive Chinese Women During Cervical Cancer Screening.

Quantification of DNA aneuploidy has great potential as a prognostic marker of cervical precancerous lesions. We aim to evaluate the performance of DNA ploidy analysis for the triage of HPV-positive women. 523 HPV-positive women ages 25-64 undergoing HPV and pap cytology testing with valid cervical biopsies in Renji Hospital were enrolled in a prospective observational study from June 2018 to June 2019. The clinical performances of DNA ploidy, with or without HPV16/18 genotyping, were evaluated for all HPV-positive women to detect histologic high-grade squamous intraepithelial lesion or worse (HSIL+). For HSIL+ detection, DNA ploidy had statistically higher specificity (83.89%) than Pap cytology (75.50%, P = 0.002) and HPV16/18 genotyping (77.92%, P = 0.023). Although the sensitivity of DNA ploidy (58.57%) remained similar with pap cytology (65.71%, P = 0.461) and HPV16/18 genotyping (55.71%, P = 0.734). A comparable sensitivity (84.29% vs. 84.29%, P = 1.000) and a higher specificity (66.00% vs. 58.94%, P < 0.001) compared with combination with Pap cytology. DNA ploidy triage strategy required fewer colposcopies per detection of HSIL+ compared with pap cytologic testing, with a 13.1% (34 of 258) reduction of colposcopies compared with routine triage strategy of HPV screening with Pap cytologic testing. HPV16/18-negative women with negative DNA ploidy results had the lowest risk of HSIL+ among HPV-positive women (3.55%). Automated DNA ploidy analysis, alone or in combination with HPV16/18 genotyping, shows the potential as a triage strategy of cervical cancer screening for HPV-positive women. PREVENTION RELEVANCE: Results from this study indicate that DNA ploidy analysis has good performance in early detection of high-grade precancerous and cancerous lesions of the cervix. This strategy could be used in the triage of HPV-positive women in cervical cancer screening.

Comparing Anal Cancer Screening Algorithms Using Cytology and Human Papillomavirus DNA Testing in 3 High-Risk Populations.

Screening strategies for high-risk human papillomavirus (hrHPV)-associated anal cancer are evolving. Herein, we compare anal cytology to hrHPV DNA testing and 2 novel cytology/hrHPV cotesting algorithms among 3 high-risk populations. Anal cytology, hrHPV DNA testing, and high-resolution anoscopy (HRA)-guided biopsy results were analyzed from 1837 participants (1504 HIV-infected men who have sex with men (MSM), 155 HIV-uninfected MSM, and 178 HIV-infected women). Performance to detect histological high-grade squamous intraepithelial lesions (HSIL)/cancer was compared between 4 strategies with distinct HRA referral thresholds: cytology (atypical squamous cells of undetermined significance, ASCUS); hrHPV testing (any hrHPV positive); algorithm A (benign cytology/HPV16/18 positive or ASCUS/hrHPV positive); and algorithm B (benign or ASCUS/hrHPV positive). Histological HSIL/cancer was detected in 756 (41%) participants. Cytology had the lowest sensitivity (0.76-0.89) but highest specificity (0.33-0.36) overall and for each subgroup. Algorithm B was the most sensitive strategy overall (0.97) and for MSM (HIV-infected 0.97; HIV-uninfected 1.00). For women, hrHPV testing and both algorithms yielded higher sensitivity than cytology (0.96, 0.98, and 0.96). Specificity was low for all strategies/subgroups (range, 0.16-0.36). Screening algorithms that incorporate cytology and hrHPV testing significantly increased sensitivity but decreased specificity to detect anal precancer/cancer among high-risk populations.

Primary HPV screening for cervical cancer: Results after two screening rounds in a regional screening program in Finland.

Since 2012, cervical cancer screening has been conducted with a primary high-risk human papillomavirus (hrHPV) test and conventional cytology triage in the city of Tampere, Finland. The women who were screened with the hrHPV test in 2012 were invited to participate in the second screening round in 2017. The aim of the present report was to compare the number of colposcopy referrals and the number of histological high-grade squamous intraepithelial lesion (HSIL)+ (cervical intraepithelial neoplasia [CIN2+]) lesions between the first and second screening rounds of women of a specific age group who were screened twice with the hrHPV test. The primary hrHPV test used was the RealTime hrHPV PCR assay by Abbott. Women with a positive hrHPV test and cytology triage equal to or worse than low-grade squamous intraepithelial lesion or atypical glandular cells, favor neoplasia, were directly referred to colposcopy, whereas hrHPV-positive women with a negative or equivocal cytology triage were re-screened after approximately 12-16months. hrHPV-negative women were scheduled for re-screening after 5years. The present report focuses on the cohort of women who were screened twice with the hrHPV test, who were 35-55years old in 2012, and 40-60years old in 2017. In all, 8076 women were invited for HPV screening in 2012 and 8331 women were invited for the second round 5years later, with attendance rates of 70% and 71%, respectively. Of the women who were screened in 2012, 4571 (69%) belonged to the 35- to 55-year age cohort. In 2017, 4807 (73%) of the women aged 40-60years participated in the screening. In this cohort, 185 (4.0%) colposcopies were performed in the first screening round, compared with 139 (2.9%) in the second round, and the colposcopy rate was 29% smaller in the second round (P=.002). The number of histological HSIL+ cases was 38 (0.8%) during the first screening round and 29 (0.6%) during the second round (P=.220). In the setting of routine organized cervical cancer screening, the initially high colposcopy rate associated with primary HPV screening seems to level off at the second screening round in women who were screened twice with an hrHPV test.

Human Papillomavirus Genotypes in Anal High-Grade Squamous Intraepithelial Lesion (HSIL): Anal Intraepithelial Neoplasia Grades 2 (AIN2) and 3 (AIN3) Are Different.

Anal high-grade squamous intraepithelial lesion (HSIL) can be histomorphologically categorized into anal intraepithelial neoplasia (AIN) grade 2 (AIN2) and grade 3 (AIN3). Different risk factors for these two categories have been described. We investigated whether there were also differences in lesion-specific human papillomavirus (HPV) genotypes. The Study of the Prevention of Anal Cancer (SPANC) recruited 617 gay and bisexual men (GBM); 36% of participants were HIV positive. At baseline, 196 men (31.8%) had histologic HSIL lesions. Tissue was available for genotyping in 171, with a total of 239 HSIL lesions (183 AIN3 and 56 AIN2). Using laser capture microdissection, each lesion revealed a maximum of one genotype. High-risk HPV (HR-HPV) genotypes were found in 220 (92.1%) HSIL lesions, with no significant difference between AIN3 (93.4%) and AIN2 (87.5%). AIN3 lesions had significantly more HPV16 (42.1%) than AIN2 lesions (12.5%; P < 0.001) and AIN2 lesions had significantly more non-16 HR-HPV types (75.0%) than AIN3 lesions (51.4%; P = 0.002). These associations were similar for HIV-negative men with HPV16 in 51.1% AIN3 and 18.2% AIN2 (P = 0.001) and non-16 HR-HPV in 40.0% AIN3 and 75.8% AIN2 (P < 0.001). For HIV-positive men, HPV16 remained more frequently detected in AIN3 (33.3% vs. 4.4% for AIN2; P = 0.004), but there was no difference between AIN3 and AIN2 for non-16 HR-HPV (62.4% vs. 73.9%; P = 0.300). As HPV16 has the strongest link with anal cancer, the subcategorization of HSIL may enable stratification of lesions for anal cancer risk and guide anal HSIL management. Stratification of anal cancer risk by histologic HSIL grade.

Screening strategies for the detection of anal high-grade squamous intraepithelial lesions in women living with HIV.

HIV-infected women (WLHIV) have more than 10-fold higher risk for squamous cell cancer of the anus. Experts suggest cytology-based strategies developed for cervical cancer screening may prevent anal cancer by detecting anal cytologic or histological high-grade squamous intraepithelial lesion (hHSIL) for treatment. Currently, there is no consensus on anal-hHSIL screening strategies for WLHIV. Between 2014 and 2016, 276 WLHIV were recruited at 12 US AIDS Malignancy Consortium clinical trials sites to evaluate hHSIL prevalence and (test) screening strategies. Participants completed detailed questionnaire, underwent anal assessments including high-risk human papillomavirus (hrHPV) testing using hrHPV-Hybrid Capture 2 (HC2) and hrHPV-APTIMA, anal cytology, and concurrent high-resolution anoscopy. Screening test characteristics for predicting hHSIL validated by central review of histologic diagnosis were estimated sensitivity, specificity, positive predictive value, and false-omission rate. Paired analyses compared sensitivity and specificity for hrHPV single tests to anal cytology alone. 83% (229/276) of enrolled WLHIV had complete anal assessment data and were included in this analysis. Mean age was 50, 62% black and 60 (26%) had hHSIL. Anal cyotology (>atypical squamous cells of undetermined significance), hrHPV-HC2, and hrHPV-APTIMA sensitivity estimates were similarly high (83, 77, and 75%, respectively, P values > 0.2). Specificity was higher for both hrHPV-APTIMA and hrHPV-HC2 compared with anal cytology (67 vs. 50%, P < 0.001) and (61 vs. 50%, P = 0.020), respectively. Anal hrHPV testing demonstrated similar sensitivity for anal cytology (>atypical squamous cells of undetermined significance) to predict anal hHSIL. Among tests with similar sensitivity, the specificity was significantly higher for hrHPV-APTIMA and hrHPV-HC2. Thus, anal hrHPV testing may be an important alternative strategy to anal cytology for anal hHSIL screening among WLHIV.

Brief Report: Recurrence of Anal High-Grade Squamous Intraepithelial Lesions Among Women Living With HIV

Women living with HIV (WLHIV) have a high risk of developing invasive anal cancer. Anal cancer may be prevented with early detection and treatment of anal histologic high-grade squamous intraepithelial lesions (HSIL). However, there are limited data on the efficacy of anal HSIL treatment in WLHIV. We conducted a retrospective study of WLHIV treated for anal HSIL under high-resolution anoscopy (HRA) guidance from January 1, 2007 to December 31, 2017 with at least one post-treatment visit at an urban tertiary care hospital. Forty-five WLHIV women with at least 1 follow-up evaluation after treatment for anal HSIL were identified. The median age was 46 years (range 35-66 years), 63% were African American, 27% were Hispanic/Latino, and 53% were current smokers. The mean absolute CD4 T-cell count was 516 cells/mm; 50% and 24% of the cohort had a history of cervical or vulvar HSIL respectively. The cumulative probability of anal HSIL recurrence was 29% at 12 months, 52% at 24 months, and 79% at 36 months post-treatment. Most WLHIV treated for anal HSIL recurred within 3 years, suggesting need for continued surveillance after treatment. Our data contribute to the information needed to develop effective anal cancer prevention guidelines in WLHIV.

2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors.

2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors.

P16 Positive Histologically Bland Squamous Metaplasia of the Cervix

With increasing use of p16 immunohistochemistry (IHC) in diagnosis of premalignant lesions of cervix, we occasionally encounter p16 positivity in squamous metaplasia that lacks morphologic characteristics of "atypical squamous metaplasia" or of squamous intraepithelial lesion (SIL). Our study aims to investigate if transcriptionally active human papilloma virus (HPV) can be identified in such foci and if they have any relationship with squamo-columnar junction (SCJ) cells. Twenty-two cases of cervical specimens with at least a focus of p16 positive bland squamous metaplasia, were selected. HPV E6/E7 mRNA in situ hybridization followed by IHC for CK7 (SCJ biomarker), Ki67, and HPV16 E2, were performed. Follow-up information was obtained. Four cases were excluded due to insufficient tissue. Of the final 18 cases, HPV E6/E7 mRNA in situ hybridization was positive in all. Nine cases showed positivity in >50% cells and the epithelial thickness involved was ≥lower two-thirds in 13 cases. Of the further evaluable 15 cases, CK7 was positive in 14, Ki67 was positive in 10, and HPV16 E2 was negative in all. Concomitant high-grade squamous intraepithelial lesion was identified in 10 cases. On follow-up (duration: 1 to 19 mo), 6 patients showed histologic high-grade squamous intraepithelial lesion. Our study demonstrates that p16 positivity in squamous metaplasia of cervix is associated with the presence of transcriptionally active high-risk HPV even when there are no clear morphologic features of dysplasia. Our results suggest that these lesions are early SILs or SILs that are not yet morphologically evident, most of which arise from SCJ and should be closely followed.