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BackgroundIn many low-resourced settings, self-collected HPV-based cervical cancer screening (SCS) is being rolled out through task shifting to community health workers (CHWs). Process evaluations are needed to ensure SCS programs are effective and translate to community-based contexts.MethodsThe Advances in Screening and Prevention in Reproductive Cancers (ASPIRE) study in Mayuge, Uganda was a two-arm, pragmatic randomized trial comparing two SCS implementation strategies facilitated by CHWs: Door-to-door and Community health day recruitment. This adjunct study uses the RE-AIM evaluation framework to assess the Reach, Efficacy, Adoption, Implementation and Maintenance of each implementation strategy in a subpopulation using process data collected throughout the trial.ResultsOf the trial population (n=2019), 781 women participated in both the baseline and exit surveys (door-to-door: n=406; community health day: n=375) and are included in this analysis. Both implementation strategies demonstrated high Reach, Efficacy, Adoption, Implementation and Maintenance. Trial consent rate was high and 100% of consenting participants in both arms participated in SCS (Reach). Follow-up rates among HPV positive participants were also high in both arms (door-to-door: 84% and community health day: 74%) (Efficacy). The intervention employed 61 CHWs, 7 nurses, 3 health facilities and other local staff within the health system to implement the intervention (Adoption). The community health day arm received HPV screening results and visual inspection with acetic acid (VIA) quicker than the door-to-door arm, but reported higher dissatisfaction with wait times (Implementation). While women had knowledge of cervical cancer symptoms and prevention measures at six-months post-intervention, no one in either arm recalled that cervical cancer could be asymptomatic (Maintenance).ConclusionBoth SCS implementation strategies performed well, demonstrating high Reach, Efficacy, Adoption, Implementation and Maintenance throughout participating communities. Implementing pragmatic approaches including task-shifting to CHWs can reduce health worker burden and improve screening access in low-resourced, community-based settings.

Editorial from Primary hrHPV DNA Testing in Cervical Cancer Screening: How to Manage Screen-Positive Women? A POBASCAM Trial Substudy

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.

The Human Papillomavirus FOr CervicAL cancer (HPV FOCAL) trial is a large randomized controlled trial comparing the efficacy of primary HPV testing to cytology among women in the population‐based Cervix Screening Program in British Columbia, Canada. We conducted a cost‐effectiveness analysis based on the HPV FOCAL trial to estimate the incremental cost per detected high‐grade cervical intraepithelial neoplasia of grade 2 or worse lesions (CIN2+). A total of 19,009 women aged 25 to 65 were randomized to one of two study groups. Women in the intervention group received primary HPV testing with reflex liquid‐based cytology (LBC) upon a positive finding with a screening interval of 48 months. Women in the control group received primary LBC testing, and those negative returned at 24 months for LBC and again at 48 months for exit screening. Both groups received HPV and LBC co‐testing at the 48‐month exit. Incremental costs during the course of the trial were comparable between the intervention and control groups. The intervention group had lower overall costs and detected a larger number of CIN2+ lesions, resulting in a lower mean cost per CIN2+ detected ($7551) than the control group ($8325), a difference of ‐$773 [all costs in 2018 USD]. Cost per detected lesion was sensitive to the costs of sample collection, HPV testing, and LBC testing. The HPV FOCAL Trial results suggest that primary HPV testing every 4 years produces similar outcomes to LBC‐based testing every 2 years for cervical cancer screening at a lower cost., The Human Papillomavirus FOr CervicAL cancer (HPV FOCAL) trial is a large randomized controlled trial comparing primary HPV testing to liquid‐based cytology for cervical cancer screening. We conducted a cost‐effectiveness analysis alongside the HPV FOCAL trial. Results showed the intervention group yielded a higher rate of detected cervical intraepithelial neoplasia of grade 2 or worse lesions (CIN2+) at a lower mean cost per CIN2+ detected ($7551) than the control group ($8325), a difference of −$773. Findings suggest that primary HPV testing is cost‐effective compared to liquid‐based cytology.

Background: Long-term safety of a single negative human papillomavirus (HPV) test for cervical cancer screening is unclear. The HPV FOr cerviCAL Cancer Trial (FOCAL) was a randomized trial comparing HPV testing with cytology. The FOCAL-DECADE cohort tracked women who received one HPV test during FOCAL, and were HPV negative, for up to 10 years to identify cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and grade 3 or worse (CIN3+) detected through a provincial screening program. Methods: FOCAL participants who received one HPV test, were negative, and had at least one post-FOCAL cervix screen were included (N = 5,537). We constructed cumulative incidence curves of CIN2+/CIN3+ detection, analyzed cumulative risk of detection at intervals post-HPV test, calculated average incidence rates for detection, and compared hazard across ages. Results: Ten years after one negative HPV test, the probability of CIN2+ detection was lower than 1%, with most lesions detected 7 years or later. Average incidence rates of CIN2+/CIN3+ lesions over follow-up were 0.50 [95% confidence interval (CI), 0.31–0.78] and 0.18 (95% CI, 0.07–0.36) per 1,000 person-years, respectively. Hazards were higher for younger ages (nonsignificant trend). Conclusions: Among women with a single negative HPV test, long-term risk of CIN2+ detection was low, particularly through 7 years of follow-up; thus, one negative HPV test appears to confer long-term protection from precancerous lesions. Even 10-year risk is sufficiently low to support extended testing intervals in average-risk populations. Impact: Our findings support the safety of screening policies using HPV testing alone at 5-year or longer intervals.

There have been 4 reported cases of squamous cell carcinoma (SCC) of the neovagina in transgender women. In this report, we present another case of neovaginal SCC in a transgender woman, which was HPV-related, with lung metastasis as the initial presentation, and which was also complicated by her previous history of metastatic renal cell carcinoma. This unique case highlights the diagnostic challenges in these unusual scenarios. Through this report, we hope to address the benefits of multidisciplinary tumor board rounds, provision of detailed clinical information, and familiarization of the transgender anatomy within the pelvis in this group of patients. We also propose that transgender women undergo a continuous annual follow-up after postoperative follow-up is completed.

Cervical cancer remains a common cancer affecting women in Canada. While cervical cancer incidence and mortality in Canada have declined for several decades due to the success of organized, provincial cervical cancer screening programs, further decreases will require enhancement of primary, secondary, and tertiary prevention efforts. The present commentary provides a historical overview of cervical cancer trends in Canada, presents current statistics on cervical cancer incidence, mortality and survival, and discusses future directions in relation to cervical cancer elimination.

ObjectiveTo study participant’s acceptability of and attitudes towards human papillomavirus (HPV) testing compared with cytology for cervical cancer screening and what impact having an HPV positive result may have in future acceptability of screening.DesignCross-sectional online survey of clinical trial participants.SettingPrimary care, population-based Cervix Screening Program, British Columbia, Canada.ParticipantsA total of 5532 participants from the HPV FOCAL trial, in which women received HPV and cytology testing at study exit, were included in the analysis. Median age was 54 years. The median time of survey completion was 3 years after trial exit.Outcome measuresAcceptability of HPV testing for primary cervical cancer screening (primary); attitudes and patient perceptions towards HPV testing and receipt of HPV positive screen results (secondary).ResultsMost respondents (63%) were accepting of HPV testing, with the majority (69%) accepting screening to begin at age 30 years with HPV testing. Only half of participants (54%) were accepting of an extended screening interval of 4–5 years. In multivariable logistic regression, women who received an HPV positive screen test result during the trial (OR=1.41 95% CI 1.11 to 1.80) or were older (OR=1.01, 95% CI 1.00 to 1.02) were more likely to report HPV testing as acceptable.ConclusionsIn this evaluation of acceptability and attitudes regarding HPV testing for cervix screening, most are accepting of HPV testing for screening; however, findings indicate heterogeneity in concerns and experiences surrounding HPV testing and receipt of HPV positive results. These findings provide insights for the development of education, information and communication strategies during implementation of HPV-based cervical cancer screening.Trial registration numbersISRCTN79347302 and NCT00461760.

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.

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.

BACKGROUND: British Columbia (BC) introduced a publicly funded, school-based human papillomavirus (HPV) immunization program in 2008 with the quadrivalent vaccine. In 2010/2011, a baseline evaluation of HPV prevalence was conducted among women undergoing cervical cancer screening. After 10 years of publicly funded HPV vaccination, HPV-type prevalence was re-evaluated.METHODS: From August 2017 to March 2018, 1107 physicians were invited to return cytobrushes used during routine Pap screening to the Cervical Cancer Screening Laboratory for HPV testing. Only age or year of birth was collected. Specimens were screened for high-risk HPV (hrHPV) and positive samples were genotyped. HPV type prevalence was compared for females 15-22 yrs (those eligible for the school-based vaccination) and 23+ yrs (ineligible for school-based vaccination) for the 2010/2011 and the 2017/2018 data.RESULTS: There were 3309 valid samples received for testing; of these, 3107 were included in the analysis. The overall hrHPV prevalence was 12.2% (95% CI 11.3-13.3) in 2010/11, and 12.0% (95% CI 10.9-13.2) in 2017/18. For the 15-22 age group, the prevalence for any hrHPV was 26.8% (95% CI 23.1-30.8) in 2010/11 and 25.4% (95% CI 15.3-37.9) in 2017/18. For those aged 15-22, HPV16 prevalence in 2010/11 was 8.8% (95% CI 6.5-11.5) and in 2017/18 was 6.3% (95% CI 1.8-15.5), with corresponding figures for HPV18 3.7% (95% CI 2.3-5.7) and 0% (95% CI 0.0-5.7), respectively. For all hrHPV types, there were no statistically significant differences between the 2010/11 and 2017/18 periods.CONCLUSIONS: This study illustrates the prevalence of hrHPV in BC over time in women undergoing cervical cancer screening, where an indication of a decline in HPV16/18 is seen in vaccine eligible women.

Purpose To inform recommendations by the Canadian Task Force on Preventive Health Care on screening in primary care for the prevention and early detection of cervical cancer by systematically reviewing evidence of (a) effectiveness; (b) test accuracy; (c) individuals’ values and preferences; and (d) strategies aimed at improving screening rates. Methods De novo reviews will be conducted to evaluate effectiveness and to assess values and preferences. For test accuracy and strategies to improve screening rates, we will integrate studies from existing systematic reviews with search updates to the present. Two Cochrane reviews will provide evidence of adverse pregnancy outcomes from the conservative management of cervical intraepithelial neoplasia. We will search Medline, Embase, and Cochrane Central (except for individuals’ values and preferences, where Medline, Scopus, and EconLit will be searched) via peer-reviewed search strategies and the reference lists of included studies and reviews. We will search ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform for ongoing trials. Two reviewers will screen potentially eligible studies and agree on those to include. Data will be extracted by one reviewer with verification by another. Two reviewers will independently assess risk of bias and reach consensus. Where possible and suitable, we will pool studies via meta-analysis. We will compare accuracy data per outcome and per comparison using the Rutter and Gatsonis hierarchical summary receiver operating characteristic model and report relative sensitivities and specificities. Findings on values and preferences will be synthesized using a narrative synthesis approach and thematic analysis, depending on study designs. Two reviewers will appraise the certainty of evidence for all outcomes using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and come to consensus. Discussion The publication of guidance on screening in primary care for the prevention and early detection of cervical cancer by the Task Force in 2013 focused on cytology. Since 2013, new studies using human papillomavirus tests for cervical screening have been published that will improve our understanding of screening in primary care settings. This review will inform updated recommendations based on currently available studies and address key evidence gaps noted in our previous review.

Purpose: Due to the increased sensitivity but reduced specificity of HPV testing compared to cytology to detect cervical lesions, a shift from cytology to HPV-based screening will initially raise population colposcopy referrals rates, which could put a strain on the healthcare system. However, it is unclear if this increase persists past the initial round of HPV screening or if rates will subsequently decrease due to earlier detection of precancer using HPV screening, which once treated may not reoccur. Methods: Participants of the HPV FOr CervicAL Cancer (FOCAL) randomized controlled trial (N = 25,223; 2008-2016) received up to two rounds of HPV-based cervix screening during the trial before returning to the cytology-based screening program in British Columbia, Canada (BC). After trial exit, participants were followed through the provincial screening program, which collects results from all screens received in BC, to detect any referral to colposcopy. A comparison cohort from the BC general screening population was created by selecting individuals who were eligible for FOCAL but not invited to participate and pulling their screening data from the provincial registry over the same time period. Post-trial colposcopy rates, calculated per-screen (not per participant), were calculated for the FOCAL population and comparison cohort overall and for those who received one round of HPV testing, those who received two rounds, those who received a negative result on their one round of testing, and those who received two negative results on their two rounds of testing. Results: The post-trial colposcopy referral rate in the overall FOCAL population was lower than in the comparison cohort. FOCAL had 180 referrals out of 30654 screens (5.9 per 1000 screens, 95%CI: 5.1-6.8), whereas the comparison cohort had 1765/177880 (9.9/1000, 95%CI: 9.5-10.4). The rates between those who had one versus two HPV tests were similar: one test: 99/17599 (5.6/1000, 95%CI: 4.6-6.8); two tests: 100/16945 (5.9/1000, 95%CI: 4.9-7.2). Rates were much lower among those who received negative results: one negative result: 55/15551 (3.5/1000, 95%CI: 2.7-4.6); two negative results: 40/12438 (3.2/1000, 95%CI: 2.4-4.4). Conclusions: After the first round of HPV-based cervix screening, colposcopy rates may decrease potentially below that seen in a cytology-based program. To avoid a surge in colposcopy referrals that could exceed health system capacity, the introduction of HPV-based screening should be done in waves, for example by inviting a new age group each year to HPV-based screening. Citation Format: Anna Gottschlich, Jennifer J. Anderson, Lovedeep Gondara, Marette Lee, Dirk van Niekerk, Laurie W. Smith, Darrel Cook, Lily Proctor, Joy Melnikow, Gavin Stuart, Ruth E. Martin, Stuart Peacock, Eduardo L. Franco, Mel Krajden, Gina Ogilvie. Colposcopy referral rates in an organized cytology-based cervix screening program after receipt of multiple rounds of HPV-based screening in the FOCAL trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6239.

Purpose. To inform recommendations by the Canadian Task Force on Preventive Health Care on cervical cancer screening by systematically reviewing evidence of: (a) the effectiveness; (b) test accuracy; (c) individuals’ values and preferences, and (d) strategies aimed at improving screening rates.Methods. De novo reviews will be conducted to evaluate effectiveness and to assess values and preferences. For test accuracy and strategies to improve screening rates, we will integrate studies from existing systematic reviews with search updates to the present. Two Cochrane reviews will provide evidence of adverse pregnancy outcomes from the conservative management of cervical intraepithelial neoplasia. We will search Medline, Embase, and Cochrane Central (except for individuals’ values and preferences, where Medline, Scopus, and EconLit will be searched) via peer-reviewed search strategies, and the reference lists of included studies and reviews. We will search ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform for ongoing trials. Two reviewers will screen potentially eligible studies and agree on those to include. Data will be extracted by one reviewer with verification by another. Two reviewers will independently assess risk of bias and reach consensus. Where possible and suitable, we will pool studies via meta-analysis. We will compare accuracy data per outcome and per comparison using the Rutter and Gatsonis hierarchical summary receiver operating characteristic model and report relative sensitivities and specificities. Findings on values and preferences will be synthesized using a narrative synthesis approach and thematic analysis, depending on study designs. Two reviewers will appraise the certainty of evidence for all outcomes using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and come to consensus.Discussion. The publication of guidance on cervical cancer screening by the Task Force in 2013 focused on cytology. Since 2013, new studies using human papillomavirus tests for detection of cervical cancer have been published that will improve our understanding of screening in primary care settings. This review will inform updated recommendations based on currently available studies and address key evidence gaps noted in our previous review.Systematic review registration: not registered.

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., A data linkage of the cervix screening program registry to the immunization registry in British Columbia showed that women vaccinated against HPV have a lower incidence of cervical dysplasia compared to unvaccinated women.

HPV FOCAL is a randomized trial comparing high-risk HPV [Hybrid Capture 2 (HC2)] vs. liquid-based cytology (LBC) for primary cervical screening.The present study objective was to compare Aptima HPV (AHPV) and HC2 assay performance at the intervention arm baseline and 48 mo. screens in relation to the rates of cervical intraepithelial neoplasia (CIN) grade 2 or worse (CIN2+).Women enrolled after December 2010 (n = 3475) were screened at baseline with both AHPV and HC2 (AHPV was blinded). Women with CIN2+ exited the trial; HC2 negative (-) women and those HC2 positive (+) withCIN2 returned for 48 mo. screening with AHPV, HC2, and LBC.At baseline, 7.2% were AHPV + vs. 8.4% for HC2 (p = 0.06). Round 1 AHPV CIN2+ sensitivity (relative to HC2) was 96.0% (95%CI: 86.5-99.0; p = 0.15) and 100% (95%CI: 82.4-100) for CIN3+. AHPV and HC2 specificities (CIN2) were 94.1% vs. 93.0% respectively (p = 0.05). At 48 mo., 4.8% and 5.2% were AHPV+ and HC2+ respectively (p = 0.41), and both tests had the same CIN2+ and CIN3+ sensitivities (87.5% and 85.0% respectively). AHPV specificity (95.8%) was higher, but not significantly, than HC2 (95.3%; p = 0.38). Of 3226 baseline AHPV- women, 12/2,858 (0.4%) had CIN2+ vs. 13/2821 (0.5%) for the 3184 baseline HC2- women.There was no significant difference in CIN2+ detection for AHPV vs. HC2 at baseline or at 48 mo. Baseline AHPV- and HC2- women had similar CIN2+ rates at 48 mo., demonstrating the safety of a four year screening interval for AHPV- women.

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.

Background Cervical cancer screening programs are switching from Pap screening to high-risk HPV testing. Objectives To compare the Aptima HPV Assay (AHPV) with the Hybrid Capture® 2 High-Risk HPV DNA Test® (HC2) for primary cervical screening. Study design HPV FOCAL is a randomized trial comparing HC2 to liquid-based cytology (LBC) for screening women aged 25–65. AHPV and HC2 were compared at the baseline screen (n = 3473). Genotyping was by the Aptima HPV 16 18/45 Genotype Assay. We assessed HPV genotyping and reflex LBC for colposcopy triage. Results AHPV/HC2 agreement was 96.5% (kappa 0.76); positive agreement was 77.4%. The AHPV positive rate was 7.2% vs. 8.4% for HC2 (p = 0.06). Based on HC2 screening, round 1 CIN2 and CIN3+ rates were 9.2/1000 and 5.2/1000 respectively. Using HC2 as the comparator test, AHPV CIN2+ and CIN3+ relative sensitivities were 0.96 and 1.00 (p = 1.00) respectively. High-grade reflex LBC and HPV 16 infection were significantly associated with CIN3+. AHPV specificity was 0.94 vs. 0.93 (p = 0.05) for HC2. Compared with triage of HC2+ with abnormal cytology or HPV persistence for 12 months, colposcopy referral would be significantly reduced (38.3/1000 vs. 60.8/1000; p Conclusions AHPV vs. HC2 screening had equivalent CIN2+ and CIN3+ detection. Triage of AHPV+ by abnormal reflex LBC and the presence of HPV 16/18/45 would result in a significantly lower colposcopy referral rate with similar CIN2+ and CIN3+ detection rates as the overall HC2+ referral algorithm.

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]). 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. [Table: see text] 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

Background Although the Pap test has been the standard screening method for cervical precancer/cancer detection, it has been criticized for having a relatively low sensitivity and a low reproducibility between pathologists. There is limited knowledge about inter-rater agreement and what clinical and demographic factors are associated with disagreements between pathologists reading the same Pap smear. Methods This study aimed to assess inter- and intra- rater agreement of the Pap smear in 1619 cytologic slides with biopsy confirmation, using kappa statistics. Clinical and demographic factors associated with higher odds of inter-rater agreement were also examined and stratified by histologic diagnosis grade. Results Using a five grade classification system, the overall kappa statistics for total, inter-rater, and intra-rater samples were 0.62, 0.57, and 0.88 (unweighted) and 0.83, 0.81, and 0.95 (weighted), respectively. In stratified analyses by histologic grade, total kappas ranged from 0.40 (atypia) to 0.64 (human papilloma virus/CIN 1). Factors such as referral for abnormal Pap test (diagnostic vs screening population), recruiting site, and parity were found to be associated with higher agreement between the two cytologic readings. Conclusions We observed relatively higher levels of agreement compared with other studies. However, variability was considerable and agreement was generally moderate, suggesting that cervical screening test accuracy and reproducibility needs to be improved.

Background Globally, cervical screening is moving from cytology (Pap) to HPV-based testing. Cytology-based screening has occurred for decades; therefore, engaging the screened population is critical to success of this significant paradigm shift. HPV FOCAL, a large clinical trial, compared primary HPV testing every 4 years to liquid-based cytology (LBC) every 2 years. Participants were surveyed to assess experiences surrounding HPV screening. Methods Women aged 25–65 (n=19,009) from two urban centres were randomized to control (LBC) or intervention (HPV) arms, and 16,374 women attended 48 month exit with HPV/LBC co-testing. At trial entry, women were provided information about HPV, cervical cancer, HPV testing and results. Women completing exit screening were invited to complete a survey assessing attitudes to HPV vs. Pap testing, screening intervals, and receipt of HPV results. Results Of 14,535 invites sent, 5,532(38%) responders completed some or all of the survey with 63% reporting that HPV vs. Pap testing was acceptable; and 54% willing to have HPV testing every 4–5 yrs vs. a Pap every 3 yrs. Concerns regarding HPV positive results differed by age. More women >50 yrs reported it important for them to know who gave them HPV than younger women (25–34 yrs: 68%; 35–49 yrs: 69%; 50+yrs: 76%). More women 25–34 yrs than >35 yrs would feel judged for having HPV (25–34 yrs: 44%; 35–49 yrs: 36%; 50+yrs: 34%). More women >50 yrs reported being HPV positive would affect the relationship with a sexual partner (25–34 yrs: 36%; 35–49 yrs: 41%; 50+: 45%). Response differences by education will also be presented. Conclusion In this large HPV screening trial, the majority of women reported that HPV vs. Pap testing was acceptable and over half would be willing to have HPV testing every 4–5 yrs. Women had varied concerns regarding HPV positive results and responses varied by age. These findings illustrate the importance of comprehensive, targeted communication strategies prior to implementation of primary HPV screening. Disclosure No significant relationships.

Background Although originally approved for three-doses, two doses of the HPV vaccine are now approved for 9–14 year olds in British Columbia (BC), Canada. Post-hoc analyses have shown similar efficacy compared to three-doses even after one-dose. Vaccinated cohorts that include incompletely vaccinated individuals offer the opportunity to evaluate the effectiveness of reduced dosing schedules. We aimed to estimate effectiveness of one-dose of quadrivalent vaccine against high-grade squamous intraepithelial lesion (HSIL) and cervical intraepithelial neoplasia grade 2 or higher (CIN2+). Methods Data-linkage was performed between the population-based Cervical Cancer Screening Program and immunization registries in BC. Occurrence of HSIL and CIN2+ were compared in a screening cohort of YW born between 1994–2005 who were either (a) unvaccinated; (b) completely vaccinated per-schedule (2-doses 150 days apart or 3-doses) between 9–14 years of age; or (c) vaccinated between 9–14 years of age with one-dose. Relative incidence rates (RR, (95%CI)) were calculated using Poisson regression and adjusted for birth year and age at first screening. Results Overall, 19,496 women were unvaccinated, 14,130 were completely vaccinated (mean age at vaccination 13.3±1.2), and 471 vaccinated with one dose only (mean age at vaccination 13.4±1.1). We found significant protection among completely vaccinated compared to unvaccinated women. The adjusted RR for HSIL was 0.52 (0.43–0.64) and for CIN2+ 0.42 (0.31–0.57). No significant protection after one dose against HSIL and CIN2+ was observed compared with unvaccinated women, respective adjusted RR 0.69 (0.27–1.41) and 1.21 (0.43–2.86). Conclusion In this observational study, no evidence of protection of one-dose against HSIL and CIN2+ was observed, while protection was found amongst completely vaccinated. The small sample size and the potential for administrative data biases may have impacted this preliminary analysis. This methodological approach provides a platform for further analyses, with larger numbers, to determine the potential impact of single dose HPV vaccination. Disclosure No significant relationships.

Background In 2008 British Columbia (BC), Canada, implemented a voluntary school-based HPV vaccination program for girls, born 1994 or later, with an average uptake of 63%. Given the long time-lead between infection and malignant disease, effects on cancer incidence will take decades to assess. To evaluate the early 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. Methods From the population-based cervical cancer screening program database in BC, information on all Pap smears and histopathological abnormalities, in calendar years 2004–2017 in women under age 28 were obtained. Rates of cervical intraepithelial neoplasia (CIN) were calculated as the number of cases divided by the number of cytology specimens for that period. Incidence rate ratios (IRR) comparing pre- and post-vaccination years, adjusted for age and screening year, were calculated by piece-wise Poisson regression analysis. We performed a sensitivity analysis including only women eligible for routine screening. Results The total number of screens in the unvaccinated cohort was 1,417,512 and in the vaccinated cohort 73,343. After the introduction of the HPV vaccination program in BC, a decrease in the incidence of CIN was observed in vaccine-eligible birth cohorts. The adjusted IRR for CIN1, 2 and 3 were respectively 0.60 (95%CI 0.53–0.67), 0.49 (95%CI 0.41–0.57) and 0.39 (95%CI 0.32–0.47). Sensitivity analysis confirmed these findings, also indicating a significant decline in CIN rates in birth cohorts eligible for the HPV vaccination program. Conclusion This study illustrates the population impact of the provincial school-based HPV vaccination program, by an observed decline in rates of CIN since introduction of the program. Further evaluation of the population-based impact includes a linkage between vaccination and screening registry. Disclosure No significant relationships.

Background HPV FOCAL, a large clinical trial conducted within an organized screening program setting, compared high-risk human papillomavirus (HPV) testing (Liquid based cytology (LBC) triage for HPV positives) to LBC for primary screening for cervical cancer. Primary endpoints included detection of high grade cervical intraepithelial neoplasia (CIN) grade 2 or greater (CIN2+) or grade 3 or greater (CIN3+) over 48 months in women 25–65 yrs of age. Methods Over 18,000 women were randomized into the HPV and LBC arms. HPV arm: baseline HPV testing; if HPV negative, exit at 48 months with HPV/LBC co-testing. LBC arm: baseline LBC testing; if LBC negative, screen at 24 months with LBC and exit at 48 months with HPV/LBC co-testing (in LBC arm, 48 months disease detection includes disease found at 24 months). We present 48 month exit CIN2+ results by age for baseline negative women. Results At baseline, in the HPV arm, 8769 were HPV negative and in the cytology arm, 9074 were cytology negative. For all ages, at 48 months significantly more CIN2+ was detected in the LBC vs. HPV arm (10/1000 [95%CI: 8, 12] vs 4/1000 [95% CI: 3,5], respectively, p Conclusion At FOCAL exit where women were co-tested with LBC and HPV, less CIN2+ was detected across all age strata in women who were baseline HPV negative, than in baseline cytology negative women, confirming the safety of a 48 month interval for HPV negative women. In addition, the highest CIN2+ rates were detected in women who were 25–29 yrs at baseline and lowest in those 50+ at baseline, informing for age appropriate HPV-based program planning. Disclosure No significant relationships.

Background Women who do not regularly attend cervical cancer screening are at increased risk for cervical cancer. In British Columbia (BC), approximately 30% of women aged 21–69 years are under-screened. As cervical cancer screening in BC moves towards the use of primary HPV testing, there is an opportunity to address screening barriers women face through self-collected, rather than clinician collected specimens. CervixCheck is an internet-based program for HPV self-collection being piloted in communities across BC with low screening rates. To inform the implementation of CervixCheck, we investigated digital health literacy (DHL) in South Asian women. Methods A cross-sectional anonymous survey was administered July-August 2018 through collaborating primary care clinics in predominantly South Asian communities in the Fraser Health Region of BC. The study population was a convenience sample of women 30–65 years of age, presenting at a primary care clinic. Women were administered the survey on a tablet, which collected demographic, screening history, and internet use information. DHL was measured using the validated eHEALS and Digital Health Literacy Instruments. Results 51 women participated from four family practices where 30% of women were 50 years or older. 29.4% of women self-reported not having had a Pap test in the last 3 years. English (86%) and Punjabi (58%) were the most common languages participants reported reading and speaking. Majority of women reported using the internet daily (82.4%), with mobile phones being the most common device (72.6%). DHL was higher in under-screened women. Over 80% of women responded that they would be likely to very likely to participate in self-collected screening using CervixCheck. Conclusion The survey revealed CervixCheck is a promising digital health platform to increase cervical cancer screening uptake among under-screened South Asian women. Findings were used to inform CervixCheck website design and program resources in preparation for its launch. Disclosure No significant relationships.

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.

Objectives To estimate the impact of increased participation in screening, and of the proposed change from Pap to human papillomavirus screening on the incidence of cervical cancer in British Columbia. Methods For invasive cervical cancer cases diagnosed in British Columbia between 2002 and 2011, data were extracted on age and cancer morphology from the British Columbia Cancer Registry, and Pap screening history was obtained from the British Columbia Cervical Cancer Screening Program database. Only screening performed two to seven years prior to diagnosis was assumed to reduce subsequent risk of cancer. Results from randomized trials of human papillomavirus versus cytology screening and population based estimates of cytology screening were used to estimate the effect of a change in screening test and increases in participation. Results Between 2002 and 2011, there were 1663 cases of cervical cancer reported; 660 (367 squamous and 293 non-squamous) were eligible and screened two to seven years prior to diagnosis. The predicted reduction by changing to human papillomavirus screening was 363 (95% confidence interval = 124–496) representing 22% of all cases. If 50% of subjects not screened two to seven years prior had undergone Pap screening, it is projected that a further 268 cases (16%) could have been prevented; if they had undergone human papillomavirus screening, a further 365 cases (22%) could have been prevented. Conclusions For many women who develop cervical cancer, primary human papillomavirus testing could have substantially reduced their cancer risk. Human papillomavirus rather than Pap testing would further increase the gains from any increases in population screening participation.

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 (7.5/1000; 95% CI: 6.2, 8.9) compared to the control arm (4.6/1000; 95% CI: 3.4, 6.2). The CIN2+ detection rates were also significantly higher in the HPV (16.5/1000; 95% CI: 14.6, 18.6) vs. the control arm (10.1/1000; 95%CI: 8.3, 12.4). In women ≥35yrs, the overall detection rates for CIN2+ and CIN3+ were higher in the HPV vs. the control arm (CIN2+:10.0/1000 vs. 5.2/1000; CIN3+: 4.2/1000 vs. 2.2/1000 respectively, with a statistically significant difference for CIN2+). HPV testing detected significantly more CIN2+ in women 25-29 compared to LBC (63.7/1000; 95%CI: 51.9, 78.0 vs. 32.4/1000; 95%CI: 22.3, 46.8). HPV testing resulted in significantly higher colposcopy referral rates for all age cohorts (HPV: 58.9/1000; 95% CI: 55.4, 62.7 vs. control: 30.9/1000; 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. This article is protected by copyright. All rights reserved.

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.

This paper addresses the problem of quantifying biomarkers in multi-stained tissues based on the color and spatial information of microscopy images of the tissue. A deep learning-based method that can automatically localize and quantify the regions expressing biomarker(s) in any selected area on a whole slide image is proposed. The deep learning network, which we refer to as Whole Image (WI)-Net, is a fully convolutional network whose input is the true RGB color image of a tissue and output is a map showing the locations of each biomarker. The WI-Net relies on a different network, Nuclei (N)-Net, which is a convolutional neural network that classifies each nucleus separately according to the biomarker(s) it expresses. In this study, images of immunohistochemistry (IHC)-stained slides were collected and used. Images of nuclei (4679 RGB images) were manually labeled based on the expressing biomarkers in each nucleus (as p16 positive, Ki-67 positive, p16 and Ki-67 positive, p16 and Ki-67 negative). The labeled nuclei images were used to train the N-Net (obtaining an accuracy of 92% in a test set). The trained N-Net was then extended to WI-Net that generated a map of all biomarkers in any selected sub-image of the whole slide image acquired by the scanner (instead of classifying every nucleus image). The results of our method compare well with the manual labeling by humans (average F-score of 0.96). In addition, we carried a layer-based immunohistochemical analysis of cervical epithelium, and showed that our method can be used by pathologists to differentiate between different grades of cervical intraepithelial neoplasia by quantitatively assessing the percentage of proliferating cells in the different layers of HPV positive lesions.

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-1β, 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.

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

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.