Experiences with thermal ablation for cervical precancer treatment after self-collection HPV-based screening in the ASPIRE Mayuge randomized trial.

Cervical cancer remains a significant public health burden in low-resourced countries. Thus, the WHO prioritized cervix screening, and recently recommended thermal ablation treatment for cervical precancer. However, there is limited information on side effects during treatment and recovery, and acceptability among those treated. The ASPIRE Mayuge trial recruited women to participate in self-collection cervix screening between 2019 and 2020 (N = 2019). Screen-positive women (N = 531, 26.3%) were referred for visual inspection with acetic acid and thermal ablation treatment, per Uganda Ministry of Health recommendations; 71.2% of those referred attended follow-up. Six months post-screening, a subset of trial participants were recontacted. Those who received thermal ablation completed a survey assessing side effects during and after the procedure, and willingness to recommend the treatment to others. We summarized the results to describe the side effects and acceptability of thermal ablation treatment. Of 2019 participants, 349 (17%) received thermal ablation. A subset of 135 completed the follow-up survey, where 90% reported pain during treatment; however, intensity and duration were low. Over a third of women reported problems with recovery for reasons including pain, discharge and bleeding. Regardless, 98% reported they would recommend the treatment to others. The use of thermal ablation to treat cervical precancer appears to be highly acceptable in this population. While many women reported side effects during the procedure and recovery, the majority said they would recommend the treatment to others. However, given the substantial proportion who reported problems with recovery, efforts should be made to provide additional resources to women after receiving thermal ablation treatment for cervical precancer.

Human papillomavirus-based screening at extended intervals missed fewer cervical precancers than cytology in the HPV For Cervical Cancer (HPV FOCAL) trial.

While cervix screening using cytology is recommended at 2- to 3-year intervals, given the increased sensitivity of human papillomavirus (HPV)-based screening to detect precancer, HPV-based screening is recommended every 4- to 5-years. As organized cervix screening programs transition from cytology to HPV-based screening with extended intervals, there is some concern that cancers will be missed between screens. Participants in HPV FOr CervicAL Cancer (HPV FOCAL) trial received cytology (Cytology Arm) at 24-month intervals or HPV-based screening (HPV Arm) at 48-month intervals; both arms received co-testing (cytology and HPV testing) at exit. We investigated the results of the co-test to identify participants with cervical intraepithelial neoplasia grade 2 or higher (CIN2+) who would not have had their precancer detected if they had only their arm's respective primary screen. In the Cytology Arm, 25/62 (40.3%) identified CIN2+s were missed by primary screen (ie, normal cytology/positive HPV test) and all 25 had normal cytology at the prior 24-month screen. In the HPV arm, three CIN2+s (3/49, 6.1%) were missed by primary screen (ie, negative HPV test/abnormal cytology). One of these three misses had low-grade cytology findings and would also not have been referred to colposcopy outside of the trial. Multiple rounds of cytology did not detect some precancerous lesions detected with one round of HPV-based screening. In our population, cytology missed more CIN2+, even at shorter screening intervals, than HPV-based screening. This assuages concerns about missed detection postimplementation of an extended interval HPV-based screening program. We recommend that policymakers consider a shift from cytology to HPV-based cervix screening.

Declining rates of cervical intraepithelial neoplasia in British Columbia, Canada: An ecological analysis on the effects of the school-based human papillomavirus vaccination program.

Since 2008, girls in British Columbia (BC), Canada, have been offered HPV vaccination through a school-based, publicly funded immunization program. The oldest birth cohort eligible for the vaccination program was born in 1994 and uptake is on average 63%. To evaluate the impact of the HPV vaccine in BC, ecological trends in cervical intraepithelial neoplasia (CIN) rates were assessed in young women before and after the implementation of the HPV vaccination program. Information on all Pap smears and histopathological abnormalities, in calendar years 2004-2017 in women 16-28 years of age in BC were obtained from the population-based BC Cancer Cervix Screening Program database. Rates of CIN 2 and 3 were calculated as the number of cases divided by the number of cytology specimens for that period. Rate ratios (RR) were calculated by negative binomial piecewise regression. Age-centered incidence rates of CIN 2 and 3 in BC declined significantly among women 16-23 years of age after HPV vaccine introduction compared to before vaccine introduction. The overall reduction postvaccination for CIN2 and 3 in women 16-23 years was respectively 62% (95% CI 54-68%) and 65% (95% CI 58-71%). Age-specific rates for CIN2 significantly declined for those 18-22 years of age and for those 19, 20 and 23 years of age for CIN3. Among women 24-28 years of age no decline in CIN2 and 3 rate over time was observed. The observed reduction in CIN 2 and 3 rates since the introduction of the school-based HPV vaccine program might illustrate the population impact of the BC provincial school-based HPV vaccination program.

Long-term cervical precancer outcomes after a negative DNA- or RNA-based human papillomavirus test result.

BACKGROUND: Cervical cancer, a preventable disease associated with the human papillomavirus, is responsible for significant morbidity and mortality globally. Primary human papillomavirus testing is more sensitive in detecting precancerous cervical lesions than cytologic screening and can be conducted using either DNA- or RNA-based assays. Screening programs must select the most appropriate assay from several available assays for their population. It is not yet known whether these assays perform equivalently in the long term, particularly among women with a negative human papillomavirus test result. This study aims to compare long-term safety after a negative human papillomavirus test result across both DNA- and RNA-based testing assays. OBJECTIVE: This study aimed to compare long-term high-grade cervical intraepithelial neoplasia (grade 2 or higher and grade 3 or higher) outcomes of 2 DNA-based assays (Digene Hybrid Capture 2 High-Risk HPV DNA Test and cobas 4800 HPV Test) and 1 messenger RNA-based assay (Aptima HPV Assay) using data from the Human Papillomavirus For Cervical Cancer Trial-DECADEl (FOCAL-DECADE) cohort, by first comparing the positive and negative rates between the assays and then investigating the cumulative incidence of cervical intraepithelial neoplasia grade 2 and higher and grade 3 or higher detection among participants in the FOCAL DECADE cohort over follow-up according to human papillomavirus testing assays. STUDY DESIGN: The FOCAL Trial was a randomized controlled trial that evaluated human papillomavirus testing for primary cervical cancer screening. The FOCAL-DECADE cohort subsequently followed FOCAL Trial participants passively through the British Columbia Cervix Screening Program Database for approximately 10 years after the FOCAL Trial study exit to examine the rates of cervical intraepithelial neoplasia grade 2 or higher and grade 3 or higher. For this study, eligible participants had baseline human papillomavirus-negative results from at least 1 assay and had 1 or more cytologic screens after baseline (9509 participants for DNA-based and 3473 participants for DNA- vs RNA-based assay comparisons). We constructed cumulative incidence curves and compared the hazard ratios for cervical intraepithelial neoplasia grade 2 or higher and grade 3 or higher detection according to the assays. RESULTS: Over 10 years of follow-up, the cumulative incidence of cervical intraepithelial neoplasia grade 2 or higher and grade 3 or higher did not significantly differ between the DNA-based assays (hazard ratio, 0.95; 95% confidence interval, 0.84-1.06; P=.35 and hazard ratio, 0.82; 95% confidence interval, 0.66-1.01; P=.06 for cervical intraepithelial neoplasia grade 2 or higher and cervical intraepithelial neoplasia grade 3 or higher, respectively) or between the DNA- and RNA-based assays (hazard ratio, 0.97; 95% confidence interval, 0.87-1.06; P=.48 and hazard ratio, 0.94; 95% confidence interval, 0.79-1.13; P=.52 for cervical intraepithelial neoplasia grade 2 or higher and cervical intraepithelial neoplasia grade 3 or higher, respectively). CONCLUSION: Among participants who tested negative for human papillomavirus at baseline, the long-term risk of cervical intraepithelial neoplasia grade 2 or higher and grade 3 or higher did not significantly differ regardless of whether DNA- or RNA-based human papillomavirus testing assays were used. Screening program decision makers can be confident that for women who test negative for human papillomavirus, DNA- and RNA-based assays exhibit similar cervical intraepithelial neoplasia grade 2 or higher outcomes over several years.

Cervical Intraepithelial Neoplasia Rates in British Columbia Women: A Population-Level Data Linkage Evaluation of the School-Based HPV Immunization Program.

BACKGROUND: To understand real-world human papillomavirus (HPV) vaccine impact, continuous evaluation using population-based data is critical. We evaluated the early impact of the school-based HPV immunization program on cervical dysplasia in women in British Columbia, Canada. METHODS: Data linkage was performed using records from provincial cervical screening and immunization registries. Precancerous outcomes were compared between unvaccinated and HPV-vaccinated women born 1994-2005. Incidence rate, relative rate (RR), and vaccine effectiveness (VE), using unadjusted and adjusted Poisson regression of cytology (HSIL) and histopathology (CIN2, CIN3, and CIN2+) outcomes, were compared across vaccination status groups. RESULTS: Women who received a complete series of vaccine on schedule between age 9 and 14 years had an adjusted RR = 0.42 (95% confidence interval [CI], 0.31-0.57) for CIN2+ over 7 years of follow-up compared to unvaccinated women, resulting in a VE of 57.9% (95% CI, 43.2%-69.0%). Adjusted RR for HSIL was 0.53 (95% CI, .43-.64), resulting in a VE of 47.1% (95% CI, 35.6%-56.7%). CONCLUSION: Women vaccinated against HPV have a lower incidence of cervical dysplasia compared to unvaccinated women. Immunization between 9 and 14 years of age should be encouraged. Continued program evaluation is important for measuring long-term population impact.

Disease detection at the 48-month exit round of the HPV FOCAL cervical cancer screening trial in women per-protocol eligible for routine screening.

HPV FOCAL is a randomized control trial of cervical cancer screening. The intervention arm received baseline screening for high-risk human papillomavirus (HPV) and the control arm received liquid-based cytology (LBC) at baseline and 24 months. Both arms received 48-month exit HPV and LBC cotesting. Exit results are presented for per-protocol eligible (PPE) screened women. Participants were PPE at exit if they had completed all screening and recommended follow-up and had not been diagnosed with cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) earlier in the trial. Subgroups were identified based upon results at earlier trial screening. There were 9,457 and 9,552 and women aged 25-65 randomized to control and intervention and 7,448 (77.8%) and 8,281 (86.7%), respectively, were PPE and screened. Exit cotest results were similar (p = 0.11) by arm for PPE and the relative rate (RR) of CIN2+ for intervention vs. control was RR = 0.83 (95% CI: 0.56-1.23). The RR for CIN2+ comparing intervention women baseline HPV negative to control women with negative cytology at baseline and at 24 months, was 0.68 (95% CI: 0.43-1.06). PPE women who had a negative or CIN1 colposcopy in earlier rounds had elevated rates (per 1,000) of CIN2+ at exit, control 31 (95% CI: 14-65) and intervention 43 (95% CI: 25-73). Among PPE women HPV negative at exit LBC cotesting identified little CIN2+, Rate = 0.3 (95% CI: 0.1-0.7). This per-protocol analysis found that screening with HPV using a 4-year interval is as safe as LBC with a 2-year screening interval. LBC screening in HPV negative women at exit identified few additional lesions.

Evaluation of a validated methylation triage signature for human papillomavirus positive women in the HPV FOCAL cervical cancer screening trial.

Human papillomavirus (HPV)-based cervical cancer screening requires triage of HPV positive women to identify those at risk of cervical intraepithelial neoplasia grade 2 (CIN2) or worse. We conducted a blinded case-control study within the HPV FOCAL randomized cervical cancer screening trial of women aged 25-65 to examine whether baseline methylation testing using the S5 classifier provided triage performance similar to an algorithm relying on cytology and HPV genotyping. Groups were randomly selected from women with known HPV/cytology results and pathology outcomes. Group 1: 104 HPV positive (HPV+), abnormal cytology (54 CIN2/3; 50

Effect of Screening With Primary Cervical HPV Testing vs Cytology Testing on High-grade Cervical Intraepithelial Neoplasia at 48 Months: The HPV FOCAL Randomized Clinical Trial.

Importance: There is limited information about the relative effectiveness of cervical cancer screening with primary human papillomavirus (HPV) testing alone compared with cytology in North American populations. Objective: To evaluate histologically confirmed cumulative incident cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) detected up to and including 48 months by primary HPV testing alone (intervention) or liquid-based cytology (control). Design, Setting, and Participants: Randomized clinical trial conducted in an organized Cervical Cancer Screening Program in Canada. Participants were recruited through 224 collaborating clinicians from January 2008 to May 2012, with follow-up through December 2016. Women aged 25 to 65 years with no history of CIN2+ in the past 5 years, no history of invasive cervical cancer, or no history of hysterectomy; who have not received a Papanicolaou test within the past 12 months; and who were not receiving immunosuppressive therapy were eligible. Interventions: A total of 19 009 women were randomized to the intervention (n = 9552) and control (n = 9457) groups. Women in the intervention group received HPV testing; those whose results were negative returned at 48 months. Women in the control group received liquid-based cytology (LBC) testing; those whose results were negative returned at 24 months for LBC. Women in the control group who were negative at 24 months returned at 48 months. At 48-month exit, both groups received HPV and LBC co-testing. Main Outcomes and Measures: The primary outcome was the cumulative incidence of CIN3+ 48 months following randomization. The cumulative incidence of CIN2+ was a secondary outcome. Results: Among 19 009 women who were randomized (mean age, 45 years [10th-90th percentile, 30-59]), 16 374 (8296 [86.9%] in the intervention group and 8078 [85.4%] in the control group) completed the study. At 48 months, significantly fewer CIN3+ and CIN2+ were detected in the intervention vs control group. The CIN3+ incidence rate was 2.3/1000 (95% CI, 1.5-3.5) in the intervention group and 5.5/1000 (95% CI, 4.2-7.2) in the control group. The CIN3+ risk ratio was 0.42 (95% CI, 0.25-0.69). The CIN2+ incidence rate at 48 months was 5.0/1000 (95% CI, 3.8-6.7) in the intervention group and 10.6/1000 (95% CI, 8.7-12.9) in the control group. The CIN2+ risk ratio was 0.47 (95% CI, 0.34-0.67). Baseline HPV-negative women had a significantly lower cumulative incidence of CIN3+ at 48 months than cytology-negative women (CIN3+ incidence rate, 1.4/1000 [95% CI, 0.8-2.4]; CIN3+ risk ratio, 0.25 [95% CI, 0.13-0.48]). Conclusions and Relevance: Among women undergoing cervical cancer screening, the use of primary HPV testing compared with cytology testing resulted in a significantly lower likelihood of CIN3+ at 48 months. Further research is needed to understand long-term clinical outcomes as well as cost-effectiveness. Trial Registration: isrctn.org Identifier: ISRCTN79347302.

HPV for cervical cancer screening (HPV FOCAL): Complete Round 1 results of a randomized trial comparing HPV-based primary screening to liquid-based cytology for cervical cancer.

Complete Round 1 data (baseline and 12-month follow-up) for HPV FOCAL, a randomized trial establishing the efficacy of HPV DNA testing with cytology triage as a primary screen for cervical cancer are presented. Women were randomized to one of three arms: Control arm - Baseline liquid-based cytology (LBC) with ASCUS results triaged with HPV testing; Intervention and Safety arms - Baseline HPV with LBC triage for HPV positives. Results are presented for 15,744 women allocated to the HPV (intervention and safety combined) and 9,408 to the control arms. For all age cohorts, the CIN3+ detection rate was higher in the HPV (7.5/1,000; 95%CI: 6.2, 8.9) compared to the control arm (4.6/1,000; 95%CI: 3.4, 6.2). The CIN2+ detection rates were also significantly higher in the HPV (16.5/1,000; 95%CI: 14.6, 18.6) vs. the control arm (10.1/1,000; 95%CI: 8.3, 12.4). In women ≥35 years, the overall detection rates for CIN2+ and CIN3+ were higher in the HPV vs. the control arm (CIN2+:10.0/1,000 vs. 5.2/1,000; CIN3+: 4.2/1,000 vs. 2.2/1,000 respectively, with a statistically significant difference for CIN2+). HPV testing detected significantly more CIN2+ in women 25-29 compared to LBC (63.7/1,000; 95%CI: 51.9, 78.0 vs. 32.4/1,000; 95%CI: 22.3, 46.8). HPV testing resulted in significantly higher colposcopy referral rates for all age cohorts (HPV: 58.9/1,000; 95%CI: 55.4, 62.7 vs. CONTROL: 30.9/1,000; 95%CI: 27.6, 34.6). At completion of Round 1 HPV-based cervical cancer screening in a population-based program resulted in greater CIN2+ detection of across all age cohorts compared to LBC screening.

Post-Loop Electrosurgical Excision Procedure High-Risk Human Papillomavirus Testing as a Test of Cure: The British Columbia Experience.

OBJECTIVES: To determine whether Hybrid Capture 2 High-Risk HPV DNA Test (HC2) can be used as a test of cure in women treated for cervical intraepithelial neoplasia grade 2 or worse (CIN 2+) and allow discharge from colposcopy follow-up with a return to a cytology-based screening program for HC2-negative women. MATERIALS AND METHODS: Data were analyzed for all women who underwent a loop electrosurgical excision procedure between August 1, 2008, and June 30, 2011, and had a valid HC2 result after loop electrosurgical excision procedure and follow-up histopathology result, to determine risk of persistent or recurrent CIN 2+ in HC2-positive and HC2-negative women. RESULTS: Two thousand three hundred forty women had adequate biopsies and valid HC2 results. Of 460 HC2-positive women, 118 (25.7%) were diagnosed with CIN 2+, whereas of 1,880 HC2-negative women, 35 (1.9%) had a subsequent diagnosis of CIN 2+ (p < .0002) yielding a HC2-negative predictive value of 98.1% (95% confidence interval = 97.4-98.7). Of 460 HC2-positive women, 306 initially had negative biopsies. In the subsequent 36 months, 38 of the 306 were diagnosed with CIN 2+. CONCLUSIONS: We conclude that women with a negative HC2 test can safely return to routine annual cytology screening by primary care providers while women who test HC2 positive are at higher risk and should continue to be followed by colposcopy, even if their initial biopsy is negative.

Disease detection and resource use in the safety and control arms of the HPV FOCAL cervical cancer screening trial.

BACKGROUND: The HPV FOCAL Trial is a RCT comparing human papilloma virus (HPV) with Liquid Based Cytology (LBC) screening for cervical cancer. Results are presented for the comparison of the Safety and Control arms after two rounds. METHODS: HPV FOCAL included randomisation of women aged 25-65 into the Safety arm, where they were initially screened with HPV and the Control arm, where they received entry screening with LBC, with both arms screened again with LBC at 24 months. RESULTS: There are 6203 (Safety) and 6075 (Control) women included in this analysis. For the Safety vs Control arms, Round 1 screening resulted in increased detection of cervical intraepithelial neoplasia 2 or worse (CIN2+),15.3 vs 10.4 per 1000, RR=1.48 (95%CI=1.08-2.03) and higher colposcopy referral rates, 5.6% vs 3.2%. LBC screening at 24 months resulted in similar colposcopy referral rates, 1.5% vs 1.9%, and decreased CIN2+ detection, 2.0 vs 4.7 per 1000, RR=0.43 (95%CI=0.21-0.88) in the Safety vs Control arms. CIN2+ detection and colposcopy referral rates declined with increasing age in both arms. One round of HPV screening detected similar levels of CIN2+ as two rounds of LBC screening. INTERPRETATION: CIN2+ detection at 2 years was lower in those screened by HPV, indicating an improved 2-year negative predictive value of the HPV test.

Correlates of women's intentions to be screened for human papillomavirus for cervical cancer screening with an extended interval.

BACKGROUND: High-risk HPV DNA testing has been proposed as a primary tool for cervical cancer screening (HPV-CCS) as an alternative to the Papanicolaou cytology- method. This study describes factors associated with women's intentions to attend cervical cancer screening if high-risk HPV DNA testing (HPV-CCS) was implemented as a primary screening tool, and if screening were conducted every 4 years starting after age 25. METHODS: This online survey was designed using the Theory of Planned Behaviour to assess factors that impact women's intentions to attend HPV-CCS among women aged 25-69 upon exit of the HPV FOCAL trial. Univariate and regression analyses were performed to compare the demographic, sexual history, and smoking characteristics between women willing and unwilling to screen, and scales for intention to attend HPV-CCS. A qualitative analysis was performed by compiling and coding the comments section of the survey. RESULTS: Of the 981 women who completed the survey in full, only 51.4 % responded that they intended to attend HPV-CCS with a delayed start age and extended screening interval. Women who intended to screen were more likely to have higher education (AOR 0.59, 95 % CI [0.37, 0.93]), while both positive attitudes (AOR 1.26, 95 % CI [1.23, 1.30]) and perceived behavior control (AOR 1.06, 95 % CI [1.02, 1.10]) were significant predictors of intention to screen. Among women who provided comments in the survey, a large number of women expressed fears about not being checked more than every 4 years, but 12 % stated that these fears may be alleviated by having more information. CONCLUSIONS: Acceptability of increased screening intervals and starting age could be improved through enhanced education of benefits. Program planners should consider measures to assess and improve women's knowledge, attitudes and beliefs prior to the implementation of new screening programs to avoid unintended consequences.

Reduction in cervical intraepithelial neoplasia in young women in British Columbia after introduction of the HPV vaccine: An ecological analysis.

We report on the rates of cervical intraepithelial neoplasia (CIN) in young women aged 15-22 years of age in British Columbia before and after the introduction of an HPV vaccine program. Rates of cervical intraepithelial neoplasia (CIN) 2+ for each age stratum (15-22) in the calendar years 2004-2012 for the province of British Columbia were obtained from the BC Cancer Agency's population-based cervical cancer program. Incidence rate ratios (IRR) of CIN2+ were described and compared before and after HPV vaccine program introduction in cohorts born in vaccine eligible years, and in non-vaccine eligible years using piece-wise Poisson regression analysis, and adjusted for age. Between 2004 and 2012, rates of CIN2 and CIN2+ in young women aged 15-22 years in the province of British Columbia have decreased overall. After the introduction of the HPV vaccine program, the age adjusted IRR for CIN2+ for young women aged 15-17 years decreased significantly from 0.91 (95% CI: 0.86-0.98 p < 0.01) to 0.36 (95% CI: 0.18-0.73 p < 0.01). During the same time period, no similar reduction was found in young women 18-22 years. After introduction of HPV vaccine program, IRR for CIN2+ in young women 15-17 was significantly reduced for CIN2+ (0.14; 95% CI: 0.04- 0.47; p < 0.01) and CIN2 (0.1; 95% CI: 0.02-0.54; p < 0.01). This ecological analysis shows a significant reduction in CIN2+ lesions in young women aged 15-17 years in British Columbia after the introduction of the HPV vaccine in young women despite vaccine uptake levels below 70%.

Comparison of the Roche cobas® 4800 and Digene Hybrid Capture® 2 HPV tests for primary cervical cancer screening in the HPV FOCAL trial.

BACKGROUND: HPV FOCAL is a randomized trial (ISRCTN79347302, registered 20 Apr 2007) comparing high-risk (hr) HPV testing vs. liquid-based cytology (LBC) for cervical cancer screening of women aged 25-65. We compared the Digene Hybrid Capture® 2 High-Risk HPV DNA Test® (HC2) and the Roche cobas® 4800 HPV Test (COBAS) for primary screening. METHODS: Women (n=6,172) were screened at baseline by HC2 and COBAS and by LBC 24 months later. We assessed HPV genotyping and reflex LBC for colposcopy triage of baseline HPV positive women. RESULTS: Overall HC2/COBAS agreement was 96.1% (kappa 0.75) and positive agreement was 77.5%. Baseline CIN2 and CIN3+ rates based on HPV screening were 8.6/1,000 and 6.6/1,000 respectively; 24 month rates were 0.7/1,000 and 0.4/1,000 (LBC screening). HC2 and COBAS were concordant positive for 91% of round 1 CIN2 and 98% of CIN3+. CIN3+ was significantly associated with HPV 16 (Odds Ratio [OR] 5.11; 95% confidence interval [CI] 2.30, 11.37), but not HPV 18 (OR 2.62; 95% CI 0.73, 9.49), vs. non-HPV 16/18 HPV at baseline. There was no significant association between HPV genotype and CIN2. CIN3+ was significantly more likely for high-grade (OR 5.99; 95% CI 2.53, 14.18), but not low-grade (OR 0.54; 95% CI 0.20, 1.49), vs. negative LBC. No significant association was observed between LBC grade and CIN2. HPV 16 and 18 were associated with 33% of CIN2 and 68% of CIN3+ identified at baseline. CONCLUSIONS: For hrHPV positive women, abnormal reflex LBC is appropriate for colposcopy triage. In addition, immediate referral of women with HPV 16/18 and normal cytology may allow for earlier detection of CIN2+ lesions which would not be detected until after follow-up testing.

Diagnosis of Ovarian Carcinoma Histotype Based on Limited Sampling: A Prospective Study Comparing Cytology, Frozen Section, and Core Biopsies to Full Pathologic Examination.

Growing insights into the biological features and molecular underpinnings of ovarian cancer has prompted a shift toward histotype-specific treatments and clinical trials. As a result, the preoperative diagnosis of ovarian carcinomas based on small tissue sampling is rapidly gaining importance. The data on the accuracy of ovarian carcinoma histotype-specific diagnosis based on small tissue samples, however, remains very limited in the literature. Herein, we describe a prospective series of 30 ovarian tumors diagnosed using cytology, frozen section, core needle biopsy, and immunohistochemistry (p53, p16, WT1, HNF-1ß, ARID1A, TFF3, vimentin, and PR). The accuracy of histotype diagnosis using each of these modalities was 52%, 81%, 85%, and 84% respectively, using the final pathology report as the reference standard. The accuracy of histotype diagnosis using the Calculator for Ovarian Subtype Prediction (COSP), which evaluates immunohistochemical stains independent of histopathologic features, was 85%. Diagnostic accuracy varied across histotype and was lowest for endometrioid carcinoma across all diagnostic modalities (54%). High-grade serous carcinomas were the most overdiagnosed on core needle biopsy (accounting for 45% of misdiagnoses) and clear cell carcinomas the most overdiagnosed on frozen section (accounting for 36% of misdiagnoses). On core needle biopsy, 2/30 (7%) cases had a higher grade lesion missed due to sampling limitations. In this study, we identify several challenges in the diagnosis of ovarian tumors based on limited tissue sampling. Recognition of these scenarios can help improve diagnostic accuracy as we move forward with histotype-specific therapeutic strategies.

Quantification of confocal fluorescence microscopy for the detection of cervical intraepithelial neoplasia.

BACKGROUND: Cervical cancer remains a major health problem, especially in developing countries. Colposcopic examination is used to detect high-grade lesions in patients with a history of abnormal pap smears. New technologies are needed to improve the sensitivity and specificity of this technique. We propose to test the potential of fluorescence confocal microscopy to identify high-grade lesions. METHODS: We examined the quantification of ex vivo confocal fluorescence microscopy to differentiate among normal cervical tissue, low-grade Cervical Intraepithelial Neoplasia (CIN), and high-grade CIN. We sought to (1) quantify nuclear morphology and tissue architecture features by analyzing images of cervical biopsies; and (2) determine the accuracy of high-grade CIN detection via confocal microscopy relative to the accuracy of detection by colposcopic impression. Forty-six biopsies obtained from colposcopically normal and abnormal cervical sites were evaluated. Confocal images were acquired at different depths from the epithelial surface and histological images were analyzed using in-house software. RESULTS: The features calculated from the confocal images compared well with those features obtained from the histological images and histopathological reviews of the specimens (obtained by a gynecologic pathologist). The correlations between two of these features (the nuclear-cytoplasmic ratio and the average of three nearest Delaunay-neighbors distance) and the grade of dysplasia were higher than that of colposcopic impression. The sensitivity of detecting high-grade dysplasia by analysing images collected at the surface of the epithelium, and at 15 and 30 µm below the epithelial surface were respectively 100, 100, and 92 %. CONCLUSIONS: Quantitative analysis of confocal fluorescence images showed its capacity for discriminating high-grade CIN lesions vs. low-grade CIN lesions and normal tissues, at different depth of imaging. This approach could be used to help clinicians identify high-grade CIN in clinical settings.

Projected Impact of HPV and LBC Primary Testing on Rates of Referral for Colposcopy in a Canadian Cervical Cancer Screening Program.

OBJECTIVE: To estimate the impact of implementing primary human papilloma virus liquid-based cytology (LBC) screening on four-year rates of referral for colposcopy in the British Columbia screening program. METHODS: We used data on referral for colposcopy from an RCT (HPV FOCAL) comparing HPV testing every four years with LBC testing every two years. We also used data from population screening with conventional cytology among women aged 25 to 69. The predicted effect of adoption of either trial protocol on rates of referral for colposcopy was estimated using trial age-specific result and screening result-specific rates weighted by their screening program distribution. The cumulative age-specific rates of referral for colposcopy over four years were calculated. RESULTS: Use of HPV testing initially increased rates of referral for colposcopy in the trial, but over four years the cumulative rates of referral were similar to those for LBC except in women aged 25 to 29, in whom a substantial excess persisted. Four-year rates of referral for colposcopy declined with age in women screened with HPV testing, LBC, and conventional cytology. Extrapolating the trial results to the distribution in the provincial screening program, implementation of either HPV or LBC throughout the provincial population would approximately double the current rates of referral for colposcopy. CONCLUSION: Compared with LBC screening, primary screening for HPV increased rates of referral for colposcopy only among women aged 25 to 29. In contrast to current practice, referral for colposcopy was largely driven by the trial protocol recommendations for the management of abnormal results and not by which screening test was used.

Objectif : Estimer les effets de la mise en œuvre d'un dépistage primaire du virus du papillome humain par cytologie en milieu liquide (CML) sur les taux d'orientation en colposcopie sur quatre ans, dans le cadre du programme de dépistage de la Colombie-Britannique. Méthodes : Nous avons utilisé les données sur l'orientation en colposcopie issues d'un ECR (HPV FOCAL) comparant le dépistage du VPH tous les quatre ans au dépistage par CML tous les deux ans. Nous avons également utilisé des données issues du dépistage populationnel par cytologie conventionnelle mené auprès des femmes de 25 à 69 ans. Le taux d'orientation en colposcopie en fonction de l'âge et le taux d'orientation en colposcopie en fonction des résultats de dépistage ont été pondérés en fonction de la distribution de leurs programmes de dépistage respectifs, ce qui a permis d'estimer l'effet populationnel prévu de l'adoption de l'un ou l'autre des protocoles d'essai en question sur les taux d'orientation en colposcopie. Les taux cumulatifs (en fonction de l'âge) de l'orientation en colposcopie sur quatre ans ont été calculés. Résultats : Le recours au dépistage du VPH a initialement mené à la hausse des taux d'orientation en colposcopie dans le cadre de l'essai; toutefois, sur quatre ans, les taux cumulatifs d'orientation ont été semblables à ceux de la CML, sauf chez les femmes de 25 à 29 ans (chez lesquelles un excès substantiel a persisté). Les taux d'orientation en colposcopie sur quatre ans ont connu une baisse en fonction de l'âge chez les femmes ayant fait l'objet d'un dépistage du VPH, d'une CML et d'une cytologie conventionnelle. En extrapolant les résultats de l'essai à la distribution qui existe au sein du programme provincial de dépistage, nous avons constaté que la mise en œuvre du dépistage du VPH ou de la CML au sein de la population provinciale mènerait au doublement approximatif des taux actuels d'orientation en colposcopie. Conclusion : Par comparaison avec le dépistage par CML, le dépistage primaire du VPH n'a entraîné la hausse des taux d'orientation en colposcopie que chez les femmes de 25 à 29 ans. Contrairement à la pratique actuelle, l'orientation en colposcopie était largement motivée par les recommandations du protocole d'essai en ce qui concerne la prise en charge des résultats anormaux, et non par le test de dépistage utilisé.

Molecular fixative enables expression microarray analysis of microdissected clinical cervical specimens.

Formalin-fixed tissue has been a mainstay of clinical pathology laboratories, but formalin alters many biomolecules, including nucleic acids and proteins. Meanwhile, frozen tissues contain better-preserved biomolecules, but tissue morphology is affected, limiting their diagnostic utility. Molecular fixatives promise to bridge this gap by simultaneously preserving morphology and biomolecules, enabling clinical diagnosis and molecular analyses on the same specimen. While previous reports have broadly evaluated the use of molecular fixative in various human tissues, we present here the first detailed assessment of the applicability of molecular fixative to both routine histopathological diagnosis and molecular analysis of cervical tissues. Ten specimens excised via the loop electrosurgical excision procedure, which removes conical tissue samples from the cervix, were cut into alternating pieces preserved in either formalin or molecular fixative. Cervical specimens preserved in molecular fixative were easily interpretable, despite featuring more eosinophilic cytoplasm and more recognizable chromatin texture than formalin-fixed specimens. Immunohistochemical staining patterns of p16 and Ki-67 were similar between fixatives, although Ki-67 staining was stronger in the molecular fixative specimens. The RNA of molecular fixative specimens from seven cases representing various dysplasia grades was assessed for utility in expression microarray analysis. Cluster analysis and scatter plots of duplicate samples suggest that data of sufficient quality can be obtained from as little as 50ng of RNA from molecular fixative samples. Taken together, our results show that molecular fixative may be a more versatile substitute for formalin, simultaneously preserving tissue morphology for clinical diagnosis and biomolecules for immunohistochemistry and gene expression analysis.

Women's intentions to self-collect samples for human papillomavirus testing in an organized cervical cancer screening program.

BACKGROUND: Mounting evidence affirms HPV testing as an effective cervical cancer screening tool, and many organized screening programs are considering adopting it as primary testing. HPV self-collection has comparable sensitivity to clinician collected specimens and is considered a feasible option in hard-to-reach women. We explored women's intentions to HPV self-collect for cervical cancer screening from a cohort participating in a Canadian randomized controlled cervical cancer screening trial. METHODS: Women aged 25-65 were invited to complete an online survey assessing intentions to be screened with HPV testing instead of the Pap smear. The survey was based in the Theory of Planned Behaviour and questions were included to assess women's intentions to self-collect for HPV. Demographic characteristics of women who intended to self-collect were compared with those who did not. Demographic and scale variables achieving a p-value <0.1 in the univariate and bivariate analyses were included in the stepwise logistic regression model. The final model was created to predict factors associated with women's intentions to self-collect an HPV specimen for cervical cancer. Odds ratios were calculated with 95% confidence intervals to identify variables associated with a woman's intention to self-collect for cervical cancer screening. RESULTS: The overall survey response rate was 63.8% (981/1538) with 447 (45.6%) reporting they intended to self-collect, versus 534 (54.4%) reporting they did not. In the univariate analysis, women with more than high school education were more likely to self-collect. Women who intended to receive HPV testing versus the Pap smear were 1.94 times as likely to be in favour of self-collection and those who intended to self-collect had significantly higher attitudinal scores towards HPV self-collection. The adjusted odds ratio and 95% confidence interval from the multivariate analysis demonstrated attitude towards self-collection was the only significant variable predicting a woman's intention to self-collect (OR 1.25; 95% CI: 1.22, 1.29). CONCLUSIONS: The primary predictor of a woman's intention to HPV self-collect for cervical cancer screening was her attitude towards the procedure. From a program planning perspective, these results indicate that education and awareness may be significant contributing factors to improving acceptance of self-collection and subsequently, improving screening attendance rates.

Women's intentions to receive cervical cancer screening with primary human papillomavirus testing.

We explored the potential impact of human papillomavirus (HPV) testing on women's intentions to be screened for cervical cancer in a cohort of Canadian women. Participants aged 25-65 years from an ongoing trial were sent a questionnaire to assess women's intentions to be screened for cervical cancer with HPV testing instead of Pap smears and to be screened every 4 years or after 25 years of age. We created scales for attitudes about HPV testing, perceived behavioral control, and direct and indirect subjective norms. Demographic data and scales that were significantly different (p < 0.1) between women who intended to be screened with HPV and those who did not intend were included in a stepwise logistic regression model. Of the 2,016 invitations emailed, 1,538 were received, and 981 completed surveys for a response rate of 63% (981/1,538). Eighty-four percent of women (826/981) responded that they intended to attend for HPV-based cervical cancer screening, which decreased to 54.2% when the screening interval was extended, and decreased further to 51.4% when screening start was delayed to age of 25. Predictors of intentions to undergo screening were attitudes (odds ratio [OR]: 1.22; 95% confidence interval [CI]: 1.15, 1.30), indirect subjective norms (OR: 1.02; 95% CI: 1.01, 1.03) and perceived behavioral control (OR: 1.16; 95% CI: 1.10; 1.22). Intentions to be screened for cervical cancer with HPV testing decreased substantially when the screening interval was extended and screening started at age of 25. Use of primary HPV testing may optimize the screening paradigm, but programs should ensure robust planning and education to mitigate any negative impact on screening attendance rates.