Atypical glandular cells and development of cervical cancer: Population-based cohort study.

The effect of cervical screening on cervical adenocarcinoma has been variable, possibly because the risk associated with the precursor atypical glandular cells (AGC) is not well known. A cohort of all 885 women in the capital region of Sweden with AGC, a concomitant human papillomavirus (HPV) analysis, and a histopathology was followed until 2019. Cumulative incidence proportions of cervical intraepithelial lesion grade 3 or worse (CIN3+) by HPV type was determined by 1-Kaplan-Meier estimates. Hazard ratios (HR) for CIN3+ or for invasive cancer were estimated with Cox regression. After 2 years of follow-up, the cumulative incidence proportions of CIN3+ were 80% (95% confidence interval [CI]: 74-86%), 58% (95% CI: 50-60%) and 10% (95% CI: 5-18%) among HPV16/18 positive, "other HPV" positive and HPV-negative women, respectively. Among the 300 women with HPV16/18 positive AGC, 217 developed CIN3+ of which 35 were invasive cervical cancer. The 2-year cumulative invasive cancer risk for HPV16/18 positive AGC was 17% (95% CI: 12-24%). Primary HPV-screening had a similar yield of CIN3+ as cytology screening, albeit HPV-negative AGC is by design not detected by HPV screening. Among 241 women with HPV-negative AGC, 11 developed CIN3+ mostly after clinically indicated samples. We found no significant risk differences depending on age or sampling indication. The low CIN3+ risk after HPV-negative AGC implies safety of primary HPV screening. The high risk of invasive cervical cancer after HPV16/18 positive AGC implies that management of this finding is a priority in cervical screening.

Expanding the upper age limit for cervical cancer screening: a protocol for a nationwide non-randomised intervention study.

INTRODUCTION: Cervical cancer screening ceases between the ages of 60 and 65 in most countries. Yet, a relatively high proportion of cervical cancers are diagnosed in women above the screening age. This study will evaluate if screening of women aged 65-69 years may result in increased detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) compared with women not invited to screening. Invited women may choose between general practitioner (GP)-based screening or cervico-vaginal self-sampling. Furthermore, the study will assess if self-sampling is superior to GP-based screening in reaching long-term unscreened women. METHODS AND ANALYSIS: This population-based non-randomised intervention study will include 10 000 women aged 65-69 years, with no record of a cervical cytology sample or screening invitation in the 5 years before inclusion. Women who have opted-out of the screening programme or have a record of hysterectomy or cervical amputation are excluded. Women residing in the Central Denmark Region (CDR) are allocated to the intervention group, while women residing in the remaining four Danish regions are allocated to the reference group. The intervention group is invited for human papillomavirus-based screening by attending routine screening at the GP or by requesting a self-sampling kit. The reference group receives standard care which is the opportunity to have a cervical cytology sample obtained at the GP or by a gynaecologist. The study started in April 2019 and will run over the next 4.5 years. The primary outcome will be the proportion of CIN2+ detected in the intervention and reference groups. In the intervention group, the proportion of long-term unscreened women attending GP-based screening or self-sampling will be compared. ETHICS AND DISSEMINATION: The study has been submitted to the Ethical Committee in the CDR which deemed that the study was not notifiable to the Committee and informed consent is therefore not required. The study is approved by the Danish Data Protection Regulation and the Danish Patient Safety Authority. Results will be disseminated in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04114968.

Adherence to international recommendations in the governance and organisation of Nordic cervical cancer screening programmes.

INTRODUCTION: Screening has been the primary reason for the decline in the incidence and mortality of cervical cancer in the Nordic countries since the beginning of screening in the 1960s. Recently, the incidence of cervical cancer has increased in the Nordic countries indicating the need to look closely at possibilities for further improvement in screening. This article provides an overview of cervical cancer screening programmes in the Nordic countries and whether the programmes adhere to international recommendations. MATERIALS AND METHODS: Relevant and unambiguous screening recommendations were extracted from applicable literature and classified into legal framework, governance, organisation, and monitoring and evaluation. The up-to-date status of screening programmes and adherence to selected recommendations was gathered from official documentation and co-authors representing cervical cancer screening programmes in all the Nordic countries. RESULTS: A total of 168 recommendations were extracted and 54 of them were considered to be unambiguous and relevant. Forty-nine recommendations were included after synthesising similar recommendations. All Nordic countries adhere to recommendations related to legal framework, but adherence was lower with recommendations related to governance and organisation of screening. Monitoring and evaluation are also areas where adherence to recommendations could be improved. CONCLUSIONS: The Nordic cervical cancer screening programmes have substantially decreased cancer burden despite not fully adhering to many of the recommendations. The presented gaps in adherence suggest that there is room for improvement in the screening programmes. Establishing clearer governance structures would still increase the ability to manage changes such as implementing HPV testing as the primary screening method or modifying the programme when HPV vaccinated cohorts of women enter the target age for screening.

NordScreen - an interactive tool for presenting cervical cancer screening indicators in the Nordic countries.

Introduction: Quality assurance and improvement of cancer screening programs require up-to-date monitoring systems and evidence-based indicators. National quality reports exist but the definition and calculation of indicators vary making comparisons between countries difficult. The aim is to stimulate collaborative research and quality improvements in screening through freely available, comparable and regularly updated quality indicators. The project currently includes data on cervical cancer screening but population-based screening programs for breast cancer and colorectal cancer may be included in the future. Material and methods: Through a network of Nordic and Baltic screening managers, population-based individual screening data from each country were converted to standard format in each collaborative center, aggregated by the same R program script and then uploaded to the NordScreen online platform. Registry data included all cervical tests except for Finland where only tests based on invitation are included. Results: The NordScreen collaboration has so far collated standardized indicators based on 32.8 million screening tests from four Nordic countries and Estonia. Interactive comparison of test coverage and distribution of women by number of tests are currently possible online. In 2016, the test coverage within a time interval of 5.5 years in the age group 30-64 year-olds was between 78 and 84% in Iceland, Norway and Sweden whereas 70% in Finland. The application allows users to choose indicator specifications interactively. Conclusions: NordScreen is a pilot model for comparable, reliable and accessible cross-country comparisons of cancer screening. Comparability between countries is enhanced by a uniform data structure and standardized calculations. The comparison of coverage rates to national figures shows that the methods used nationally and in the NordScreen project produce similar results.

Increasing participation in cervical screening by targeting long-term nonattenders: Randomized health services study.

High screening participation in the population is essential for optimal prevention of cervical cancer. Offering a high-risk human papillomavirus (HPV) self-test has previously been shown to increase participation. In this randomized health services study, we evaluated four strategies with regard to participation. Women who had not attended organized cervical screening in 10 years were eligible for inclusion. This group comprised 16,437 out of 413,487 resident women ages 33-60 (<4% of the screening target group). Among these 16,437 long-term nonattenders, 8,000 women were randomized to either (i) a HPV self-sampling kit sent directly; (ii) an invitation to order a HPV self-sampling kit using a new open source eHealth web application; (iii) an invitation to call a coordinating midwife with questions and concerns; or (iv) the standard annual renewed invitation letter with prebooked appointment time (routine practice). Overall participation, by arm, was (i) 18.7%; (ii) 10.7%; (iii) 1.9%; and (iv) 1.7%. The relative risk of participation in Arm 1 was 11.0 (95% CI 7.8-15.5), 6.3 (95% CI 4.4-8.9) in Arm 2 and 1.1 (95% CI 0.7-1.7) in Arm 3, compared to Arm 4. High-risk HPV prevalence among women who returned kits in study Arms 1 and 2 was 12.2%. In total, 63 women were directly referred to colposcopy from Arms 1 and 2; of which, 43 (68.3%) attended and 17 had a high-grade cervical lesion (CIN2+) in histology (39.5%). Targeting long-term nonattending women with sending or offering the opportunity to order self-sampling kits further increased the participation in an organized screening program.

Overdiagnosis in the population-based organized breast cancer screening program estimated by a non-homogeneous multi-state model: a cohort study using individual data with long-term follow-up.

BACKGROUND: Overdiagnosis, defined as the detection of a cancer that would not become clinically apparent in a woman's lifetime without screening, has become a growing concern. Similar underlying risk of breast cancer in the screened and control groups is a prerequisite for unbiased estimates of overdiagnosis, but a contemporary control group is usually not available in organized screening programs. METHODS: We estimated the frequency of overdiagnosis of breast cancer due to screening in women 50-69 years old by using individual screening data from the population-based organized screening program in Stockholm County 1989-2014. A hidden Markov model with four latent states and three observed states was constructed to estimate the natural progression of breast cancer and the test sensitivity. Piecewise transition rates were used to consider the time-varying transition rates. The expected number of detected non-progressive breast cancer cases was calculated. RESULTS: During the study period, 2,333,153 invitations were sent out; on average, the participation rate in the screening program was 72.7% and the average recall rate was 2.48%. In total, 14,648 invasive breast cancer cases were diagnosed; among the 8305 screen-detected cases, the expected number of non-progressive breast cancer cases was 35.9, which is equivalent to 0.43% (95% confidence interval (CI) 0.10%-2.2%) overdiagnosis. The corresponding estimates for the prevalent and subsequent rounds were 15.6 (0.87%, 95% CI 0.20%-4.3%) and 20.3 (0.31%, 95% CI 0.07%-1.6%), respectively. The likelihood ratio test showed that the non-homogeneous model fitted the data better than an age-homogeneous model (P <0.001). CONCLUSIONS: Our findings suggest that overdiagnosis in the organized biennial mammographic screening for women 50-69 in Stockholm County is a minor phenomenon. The frequency of overdiagnosis in the prevalent screening round was higher than that in subsequent rounds. The non-homogeneous model performed better than the simpler, traditional homogeneous model.

Status of implementation and organization of cancer screening in The European Union Member States-Summary results from the second European screening report.

The second report on the implementation status of cancer screening in European Union (EU) was published in 2017. The report described the implementation status, protocols and organization (updated till 2016) and invitation coverage (for index year 2013) of breast, cervical and colorectal cancer screening in the EU. Experts in screening programme monitoring (N = 80) from the EU Member States having access to requisite information in their respective countries provided data on breast, cervical and colorectal cancer screening through online questionnaires. Data was collected for screening performed in the framework of publicly mandated programmes only. Filled in questionnaires were received from 26 Member States for all three sites and from one Member State for breast cancer only. Substantial improvement in screening implementation using population-based approach was documented. Among the age-eligible women, 94.7% were residents of Member States implementing or planning population-based breast cancer screening in 2016, compared to 91.6% in 2007. The corresponding figures for cervical cancer screening were 72.3 and 51.3% in 2016 and 2007, respectively. Most significant improvement was documented for colorectal cancer screening with roll-out ongoing or completed in 17 Member States in 2016, compared to only five in 2007. So the access to population-based screening increased to 72.4% of the age-eligible populations in 2016 as opposed to only 42.6% in 2007. The invitation coverage was highly variable, ranging from 0.2-111% for breast cancer, 7.6-105% for cervical cancer and 1.8-127% for colorectal cancer in the target populations. In spite of the considerable progress, much work remains to be done to achieve optimal effectiveness. Continued monitoring, regular feedbacks and periodic reporting are needed to ensure the desired impacts of the programmes.

Randomised healthcare policy evaluation of organised primary human papillomavirus screening of women aged 56-60.

OBJECTIVE: The aim of this research is to implement and reliably evaluate primary human papillomavirus (HPV) screening in an established and routinely running organised, large-scale population-based screening programme. PARTICIPANTS: Resident women in the Stockholm/Gotland region of Sweden, aged 56-60 years were randomised to either (1) screening with cervical cytology, with HPV test in triage of low-grade cytological abnormalities (old policy) or (2) screening with HPV testing, with cytology in triage of HPV positives (new policy). OUTCOME: The primary evaluation was the detection rate of cervical intraepithelial neoplasia grade 2 or worse (CIN2+). RESULTS: During January 2012-May 2014, the organised screening programme sent 42 752 blinded invitations with a prebooked appointment time to the women in the target age group. 7325 women attended in the HPV policy arm and 7438 women attended in the cytology arm. In the new policy, the population HPV prevalence was 5.5%, using an accredited HPV test (Cobas 4800). HPV16 prevalence was 1.0% (73/7325) and HPV18 prevalence was 0.3% (22/7325). In the HPV policy arm, 78/405 (19%) HPV-positive women were also cytology positive. There were 19 cases of CIN2+ in histopathology, all among women who were both HPV positive and cytology positive. The positive predictive value for CIN2+ in this group was 33.3% (19/57). In the cytology policy, 153 women were cytology positive and there were 18 cases of CIN2+ in histopathology. Both the total number of cervical biopsies and the number of cervical biopsies with benign histopathology were much lower in thepositive predictive value policy (49 benign, 87 total vs 105 benign, 132 total). CONCLUSION: Primary HPV screening had a similar detection rate for CIN2+ as cytology-based screening, already before follow-up of HPV-positive, cytology-negative women with new HPV test and referral of women with persistence. TRIAL REGISTRATION NUMBER: NCT01511328.

Current cervical cancer prevention strategies including cervical screening and prophylactic human papillomavirus vaccination: a review.

PURPOSE OF REVIEW: As screening methods evolve and human papillomavirus (HPV) vaccination efforts gain traction, knowledge of the current evidence on effectiveness of prevention methods is critical to support further development of programs. RECENT FINDINGS: Screening has dramatically reduced cervical cancer incidence and mortality; however, further progress could be made with implementing new screening techniques, such as HPV DNA testing. Continued focus has been given to methods such as visual inspection with acetic acid/Lugol's iodine (VIA/VILI) and self-testing, which may provide an alternative in settings and populations wherein infrastructural challenges and logistical barriers pose challenges to achieving high screening coverage. Postlicensure studies of HPV vaccine show continued effectiveness against genital warts, the first outcome possible to measure. Of note, age-at-vaccination seems to play a pivotal role in effectiveness. Studies examining safety of the HPV vaccines could not confirm any increased risk associated with vaccination. SUMMARY: Existing cervical screening techniques are effective; however, programs should consider implementing HPV DNA testing where applicable and further process developments for alternative methods may result in improved results. The HPV vaccine is safe and effective and should be given before sexual debut to achieve maximum protection.