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Context: Liquid-based cytology has been developed as an alternative for conventional cervical cytology. Despite numerous studies and systematic reviews, controversy remains about its diagnostic accuracy.Objective: To assess the performance of liquid-based cytology compared with conventional cytology in terms of detection of histologically confirmed cervical intraepithelial neoplasia (CIN).Design, Setting, and Participants: Cluster randomized controlled trial involving 89,784 women aged 30 to 60 years participating in the Dutch cervical screening program at 246 family practices. One hundred twenty-two practices were assigned to use liquid-based cytology and screened 49,222 patients and 124 practices were assigned to use the conventional Papanicolaou (Pap) test and screened 40,562 patients between April 2004 and July 1, 2006. Patients were followed up for 18 months through January 31, 2008.Intervention: Screening for CIN using liquid-based cytology or conventional papanicolaou (Pap) test and the blinded review of all follow-up of screen-positive women (blinded to the type of cytology and the initial result).Main Outcome Measures: Intention-to-treat and per-protocol analysis of the detection rates of and positive predictive values for histologically verified CIN in both cytology systems. Outcomes are presented as crude and adjusted rate ratios (adjustment for age, urbanization, study site, and period).Results: The adjusted detection rate ratios for CIN grade 1+ was 1.01 (95% confidence interval [CI], 0.85-1.19); for CIN grade 2+, 1.00 (95% CI, 0.84-1.20); for CIN grade 3+, 1.05 (95% CI, 0.86-1.29); and for carcinoma, 1.69 (95% CI, 0.96-2.99). The adjusted positive predictive value (PPV) ratios, considered at several cytological cutoffs and for various outcomes of CIN did not differ significantly from unity.Conclusion: This study indicates that liquid-based cytology does not perform better than conventional Pap tests in terms of relative sensitivity and PPV for detection of cervical cancer precursors.Trial Registration: trialregister.nl Identifier: NTR1032. [ABSTRACT FROM AUTHOR]

Objective: To compare test positivity rates of liquid-based and conventional cytology.Methods: This study was a cluster randomized controlled trial with family practice as the unit of randomization, performed within the Dutch national cervical screening program. Women aged 30-60 years (n=89,784) recruited from 246 family practices were included. One-hundred twenty-two practices (49,222 individuals) were randomly assigned to the experimental arm, and 124 practices (40,562 participants), to the conventional arm. Inclusion was performed during a 3-year period between April 2003 and July 2006. Cytologic test positivity rates of liquid-based compared with conventional cytology was compared in terms of crude and adjusted odds ratios, applying a per-protocol analysis.Results: Crude ratios of the odds of test positivity rates of liquid-based compared with conventional cytology for atypical squamous cells of undetermined significance or more severe, low-grade squamous intraepithelial lesion or more severe, and high-grade squamous intraepithelial lesion or more severe were 0.95 (95% confidence interval [CI] 0.82-1.10), 1.00 (95% CI 0.83-1.20), and 0.97 (95% CI 0.77-1.22), respectively. Liquid-based cytology resulted in fewer unsatisfactory tests (odds ratio 0.30, 95% CI 0.23-0.38). The results did not change when the odds ratios were adjusted for age, study site, study period, and urbanization level. Of 128 women screened with liquid-based cytology, one unsatisfactory preparation is avoided.Conclusion: This study found no statistically significant difference in cytologic test positivity rates between liquid-based and conventional cytology. However, liquid-based cytology resulted in significantly fewer unsatisfactory tests.Clinical Trial Registration: Nederlands Trial Register, www.trialregister.nl, NTR1032Level Of Evidence: I. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The objective of the study was to assess the screening history of women with cervical cancer and review normal cervical smears 5 years preceding the diagnosis. STUDY DESIGN: Cytological and histological results of 401 women treated for invasive cervical cancer between 1991 and 2008 at the Radboud University Nijmegen Medical Center were studied. Ninety-eight normal smears were reviewed. RESULTS: Of the 401 women, 269 (67%) received at least 1 invitation for the national screening program for cervical cancer (NCSP). One- third fell outside the target age of the NCSP. Seventeen percent never responded to the invitation(s). Twenty-one percent had 1 or more normal smears within 5 years preceding the diagnosis. After review, only 39% of those smears were reviewed as a normal smear. CONCLUSION: Half of the women with cervical cancer were never screened because of the limited target age range or nonattendance. Twenty-one percent had a normal smear within 5 years preceding the diagnosis, caused by interpretation and/or sampling errors. [ABSTRACT FROM AUTHOR]

Internationally, little consensus exists about the best treatment for cervical adenocarcinoma in situ (AIS). This study aimed to determine the incidence of recurrent high-grade cervical dysplasia and development of local cervical cancer after treatment for AIS. This nationwide, retrospective cohort study included patients with AIS, who were treated by a large loop excision of the transformation zone (LLETZ), cold-knife conization (CKC), or hysterectomy between January 1, 1990 and December 31, 2021 in the Netherlands. Pathology reports were retrieved from the Dutch Nationwide Pathology Databank (Palga). Primary outcomes were the cumulative incidences of high-grade cervical dysplasia (cervical intraepithelial neoplasia grade 2 or 3, and AIS) and local cervical cancer up to 20 years after primary treatment. In total, 4243 patients with AIS were included. The primary treatment was a LLETZ, CKC, or hysterectomy in 1593, 2118, and 532 patients, respectively. The incidence of recurrent high-grade cervical dysplasia after LLETZ (10.5%; 95%CI: 8.6-12.3) was higher than after CKC (5.5%; 95%CI: 4.4-6.6, p <.0001). When a radical excision, that is, surgical margins free of dysplasia at end of treatment, was achieved, the incidence of recurrent high-grade dysplasia and local cervical cancer did not differ between LLETZ (5.6% [95%CI: 3.3-7.9] and 1.9% [95%CI: 0-4.4]) and CKC (4.7% [95%CI: 3.5-5.8], p = .631 and 1.5% [95%CI: 0.7-2.3], p = .918). After hysterectomy, none of the patients developed cervical dysplasia or local cervical cancer. Conservative treatment for AIS can be considered a safe and final treatment modality when a radical excision is achieved., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Aim: Recommendations for surveillance after colonoscopy are based on risk factors for metachronous advanced colorectal neoplasia (AN) and colorectal cancer (CRC). The value of these risk factors remains unclear in populations enriched by individuals with a positive faecal immunochemical test and were investigated in a modern setting., Methods and Results: This population-based cohort study included all individuals in the Netherlands of ≥55 years old with a first adenoma diagnosis in 2015. A total of 22,471 patients were included. Data were retrieved from the Dutch Nationwide Pathology Databank (Palga). Primary outcomes were metachronous AN and CRC. Patient and polyp characteristics were evaluated by multivariable Cox regression analyses. During follow-up, 2416 (10.8%) patients were diagnosed with AN, of which 557 (2.5% from the total population) were CRC. Adenomas with high-grade dysplasia (hazard ratio [HR] 1.60, 95% confidence interval [CI] 1.40-1.83), villous histology (HR 1.91, 95% CI 1.59-2.28), size ≥10 mm (HR 1.12, 95% CI 1.02-1.23), proximal location (HR 1.12, 95% CI 1.02-1.23), two or more adenomas (HR 1.28, 95% CI 1.16-1.41), and serrated polyps ≥10 mm (HR 1.67, 95% CI 1.42-1.97) were independent risk factors for metachronous AN. In contrast, only adenomas with high-grade dysplasia (HR 2.49, 95% CI 1.92-3.24) were an independent risk factor for metachronous CRC., Conclusions: Risk factors for metachronous AN and CRC were identified for populations with access to a faecal immunochemical test (FIT)-based screening programme. If only risk factors for metachronous CRC are considered, a reduction in criteria for surveillance seems reasonable., (© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.)

Loss to follow-up (LTFU) within cervical screening programmes can result in missed clinically relevant lesions, potentially reducing programme effectiveness. To examine the health impact of losing women during the screening process, we determined the proportion of women LTFU per step of the Dutch hrHPV-based screening programme. We then determined the probability of being LTFU by age, screening history and sampling method (self- or clinician-sampled) using logistic regression analysis. Finally, we estimated the number of missed CIN2+/3+ lesions per LTFU moment by using the CIN-risk in women compliant with follow-up. Data from the Dutch nationwide pathology databank (Palga) was used. Women eligible for screening in 2017 and 2018 were included (N = 840,428). For clinician collected (CC) samples, the highest proportion LTFU was found following 'referral advice for colposcopy' (5.5% after indirect referral; 3.8% after direct referral). For self-sampling, the highest proportions LTFU were found following the advice for repeat cytology (13.6%) and after referral advice for colposcopy (8.2% after indirect referral; 4.3% after direct referral). Self-sampling users and women with no screening history had a higher LTFU-risk (OR: 3.87, CI: 3.55-4.23; OR: 1.39, CI: 1.20-1.61) compared to women that used CC sampling and women that have been screened before, respectively. Of all women LTFU in 2017/18, the total number of potentially missed CIN2+ was 844 (21% of women LTFU). Most lesions were missed after 'direct referral for colposcopy' (N = 462, 11.5% of women LTFU). So, this indicates a gap between the screening programme and clinical care which requires further attention, by improving monitoring of patients after referral., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Objectives: Organisation of a screening programme influences programme resilience to a disruption as COVID-19. Due to COVID-19, the Dutch human papillomavirus-based cervical screening programme was temporarily suspended. Afterwards, multiple measures have been taken to catch-up participation. This study aimed to investigate programme resilience by examining the effect of COVID-19 and programme measures taken on participation in cervical screening., Study Design: Observational cohort study., Methods: Data from the national screening registry and Dutch nationwide pathology databank (Palga) were used on invitations and follow-up in 2018/2019 (pre-COVID) and 2020 (COVID). Sending invitations, reminders and self-sampling kits were suspended from March to July 2020. Main outcome measures include distribution of participant characteristics (age, region and screening history), participation rates by age and region, time between invitation and participation (i.e. response time) and self-sampling use per month., Results: Participation rate was significantly lower in 2020 (49.8%) compared to 2018/19 (56.8%, P < 0.001), in all ages and regions. Compared to 2018/19, participation rates decreased most in women invited from January to March 2020 (-6.7%, -9.1% and -10.4%, respectively). From August, participation rates started to recover (difference between -0.8% and -2.7%). Median response time was longer in February and March (2020: 143 and 173 days; 2018/19: 53 and 55 days) and comparable from July onwards (median difference 0-6 days). Self-sampling use was higher in 2020 (16.3%) compared to 2018/19 (7.6%)., Conclusions: The pandemic impacted participation rates in the Dutch cervical screening programme, especially of women invited before the programme pause. Implementation of self-sampling in national cervical screening programmes could increase participation rates and could serve as an alternative screening method in times of exceptional health care circumstances, such as a pandemic. Due to the well-organised programme and measures taken to catch-up participation, the impact of COVID-19 on the screening programme remained small., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The optimal follow-up strategy to detect recurrence after fertility-sparing surgery for early stage cervical cancer is unknown. Tailored surveillance based on individual risks could contribute to improved efficiency and, subsequently, reduce costs in health care. The aim of this study was to establish the predictive value of cervical cytology and high-risk human papillomavirus (HPV) testing to detect recurrent cervical intraepithelial neoplasia grade 2 or worse (CIN2+; including recurrent cervical cancer) after fertility-sparing surgery., Methods: In this nationwide, population-based, retrospective cohort study, we used data from the Netherlands Cancer Registry and the Dutch Nationwide Pathology Databank. All patients aged 18-40 years with cervical cancer of any histology who received fertility-sparing surgery (ie, large loop excision of the transformation zone, conisation, or trachelectomy) between Jan 1, 2000, and Dec 31, 2020, were included. Pathology data from diagnosis, treatment, and during follow-up were analysed. The primary and secondary outcomes were the cumulative incidence of recurrent CIN2+ and recurrence-free survival, overall and stratified by results for cytology and high-risk HPV., Findings: 1548 patients were identified, of whom 1462 met the inclusion criteria. Of these included patients, 19 568 pathology reports were available. The median age at diagnosis was 31 years (IQR 30-35). After a median follow-up of 6·1 years (IQR 3·3-10·8), recurrent CIN2+ was diagnosed in 128 patients (cumulative incidence 15·0%, 95% CI 11·5-18·2), including 52 patients (cumulative incidence 5·4%, 95% CI 3·7-7·0) with recurrent cervical cancer. The overall 10-year recurrence-free survival for CIN2+ was 89·3% (95% CI 87·4-91·3). By cytology at first follow-up visit within 12 months after fertility-sparing surgery, 10-year recurrence-free survival for CIN2+ was 92·1% (90·2-94·1) in patients with normal cytology, 84·6% (77·4-92·3) in those with low-grade cytology, and 43·1% (26·4-70·2) in those with high-grade cytology. By high-risk HPV status at first follow-up visit within 12 months after surgery, 10-year recurrence-free survival for CIN2+ was 91·1% (85·3-97·3) in patients who were negative for high-risk HPV and 73·6% (58·4-92·8) in those who were positive for high-risk HPV. Cumulative incidence of recurrent CIN2+ within 6 months after any follow-up visit (6-24 months) in patients negative for high-risk HPV with normal or low-grade cytology was 0·0-0·7% and with high-grade cytology was 0·0-33·3%. Cumulative incidence of recurrence in patients positive for high-risk HPV with normal or low-grade cytology were 0·0-15·4% and with high-grade cytology were 50·0-100·0%. None of the patients who were negative for high-risk HPV without high-grade cytology, at 6 months and 12 months, developed recurrence., Interpretation: Patients who are negative for high-risk HPV with normal or low-grade cytology at 6-24 months after fertility-sparing surgery, could be offered a prolonged follow-up interval of 6 months. This group comprises 80% of all patients receiving fertility-sparing surgery. An interval of 12 months seems to be safe after two consecutive negative tests for high-risk HPV with an absence of high-grade cytology, which accounts for nearly 75% of all patients who receive fertility-sparing surgery., Funding: KWF Dutch Cancer Society., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Regular participation in cervical cancer screening is critical to reducing mortality. Although certain sociodemographic factors are known to be associated with one-time participation in screening, little is known about other factors that could be related to regular participation. Therefore, this study evaluated the association between health-related behavioral factors and regular participation in cervical cancer screening., Methods: The Lifelines population-based cohort was linked to data for cervical cancer screening from the Dutch Nationwide Pathology Databank. We included women eligible for all four screening rounds between 2000 and 2019, classifying them as regular (4 attendances), irregular (1-3 attendances), and never participants. Multinomial logistic regression was performed to evaluate the association between behavioral factors and participation regularity, with adjustment made for sociodemographic factors., Results: Of the 48,325 included women, 55.9%, 35.1%, and 9% were regular, irregular, and never screening participants. After adjustment for sociodemographic factors, the likelihood of irregular or never screening participation was increased by smoking, obesity, marginal or inadequate sleep duration, alcohol consumption and low physical activity, while it was decreased by hormonal contraception use., Conclusion: An association exists between unhealthy behavioral factors and never or irregular participation in cervical cancer screening., (© 2023. The Author(s).)

Background: Compared to the previous cytology-based program, the introduction of primary high-risk human papillomavirus (hrHPV) based screening in 2017 has led to an increased number of referrals. To counter this, triage of hrHPV-positive women in cervical cancer screening can potentially be optimized by taking sociodemographic and lifestyle risk factors for cervical abnormalities into account. Therefore, it is essential to gain knowledge of the views of women (30-60 years) eligible for cervical cancer screening., Objective: The main goal of this qualitative study was to gain insight in the aspects that influence acceptability of risk-based triage in cervical cancer screening., Design: A focus group study in which participants were recruited via four general medical practices, and purposive sampling was used to maximize heterogeneity with regards to age, education level, and cervical cancer screening experiences., Approach: The focus group discussions were transcribed verbatim and analyzed using reflexive thematic analysis., Participants: A total of 28 women (average age: 45.2 years) eligible for cervical cancer screening in The Netherlands participated in seven online focus group discussions. Half of the participants was higher educated, and the participants differed in previous cervical cancer screening participation and screening result., Key Results: In total, 5 main themes and 17 subthemes were identified that determine the acceptability of risk-stratified triage. The main themes are: 1) adequacy of the screening program: an evidence-based program that is able to minimize cancer incidence and reduce unnecessary referrals; 2) personal information (e.g., sensitive topics and stigma); 3) emotional impact: fear and reassurance; 4) communication (e.g., transparency); and 5) autonomy (e.g., prevention)., Conclusion: The current study highlights several challenges regarding the development and implementation of risk-based triage that need attention in order to be accepted by the target group. These challenges include dealing with sensitive topics and a transparent communication strategy., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Bas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Women with inflammatory bowel disease (IBD) are at increased risk of high-grade cervical intraepithelial neoplasia and cervical cancer (CIN2+)., Aim: To assess the association between cumulative exposure to immunomodulators (IM) and biologic agents (BIO) for IBD and CIN2+ METHODS: Adult women diagnosed with IBD before December 31st 2016 in the Dutch IBD biobank with available cervical records in the nationwide cytopathology database were identified. CIN2+ incidence rates in IM- (i.e., thiopurines, methotrexate, tacrolimus and cyclosporine) and BIO- (anti-tumour necrosis factor, vedolizumab and ustekinumab) exposed patients were compared to unexposed patients and risk factors were assessed. Cumulative exposure to immunosuppressive drugs was evaluated in extended time-dependent Cox-regression models., Results: The study cohort comprised 1981 women with IBD: 99 (5%) developed CIN2+ during median follow-up of 17.2 years [IQR 14.6]. In total, 1305 (66%) women were exposed to immunosuppressive drugs (IM 58%, BIO 40%, IM and BIO 33%). CIN2+ risk increased per year of exposure to IM (HR 1.16, 95% CI 1.08-1.25). No association was observed between cumulative exposure to BIO or both BIO and IM and CIN2+. In multivariate analysis, smoking (HR 2.73, 95%CI 1.77-4.37) and 5-yearly screening frequency (HR 1.74, 95% CI 1.33-2.27) were also risk factors for CIN2+ detection., Conclusion: Cumulative exposure to IM is associated with increased risk of CIN2+ in women with IBD. In addition to active counselling of women with IBD to participate in cervical screening programs, further assessment of the benefit of intensified screening of women with IBD on long-term IM exposure is warranted., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: The first HPV-vaccine eligible cohorts in the Netherlands will enter the cervical screening program in 2023. However, a substantial number of young women already have had a cervical sample taken before entry into the regular screening program. This study was initiated to explore early effects of HPV vaccination on detection of cytological abnormalities in cervical samples of women younger than the screening age., Methods: Results of cervical samples were obtained from the Dutch National Pathology Databank (PALGA) and were linked to the women's HPV vaccination status from the national vaccination registry (Praeventis) (N = 42,171). Occurrence of low-grade and high-grade squamous intraepithelial lesions or worse (LSIL and HSIL+) and high-risk HPV positive tests (hrHPV) in the first cervical sample were compared between vaccinated and unvaccinated women by multivariable logistic regression analysis, corrected for age at cervical sampling and age of vaccination (12/13 years, ≥ = 14 years)., Results: For fully vaccinated women (three- or two-dose schedule), statistically significant reductions were seen for all outcomes compared to unvaccinated women (hrHPV: adjusted OR, 0.70, 95% CI, 0.63-0.79; LSIL: 0.70, 0.61-0.80; HSIL+: 0.39, 0.30-0.51)., Conclusions: By linking nation-wide registries on pathology and vaccination, we show significant beneficial early effects of HPV-vaccination on LSIL, HSIL+, CIN3/AIS/carcinoma and hrHPV detection in young women upto 24 years of age who have a cervical sample taken before entry into the cervical cancer screening program., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Research has long since confirmed the benefits of regular cervical cancer screening (CCS) worldwide. However, some developed countries have low participation rates despite well-organized screening programs. Given that studies in Europe typically define participation in 12-month windows from an invitation, we evaluated both whether extending this defined time window could reveal the true participation rate and how sociodemographic determinants affect participation delays. This involved linking data from the Lifelines population-based cohort with CCS-related data from the Dutch Nationwide Pathology Databank and including data for 69 185 women eligible for screening in the Dutch CCS program between 2014 and 2018. We then estimated and compared the participation rates for 15- and 36-month time windows and categorized women by the primary screening window into timely participation (within 15 months) and delayed participation (within 15-36 months) groups, before performing multivariable logistic regression to evaluate the association between delayed participation and the sociodemographic determinants. Participation rates for the 15- and 36-month windows were 71.1% and 77.0%, respectively, with participation considered timely in 49 224 cases and delayed in 4047 cases. Delayed participation was associated with age 30-35 years (odds ratio [OR]: 2.88, 95 %CI: 2.67-3.11), higher education (OR: 1.50, 95 %CI: 1.35-1.67), the high-risk human papillomavirus test-based program (OR: 1.67, 95 %CI: 1.56-1.79), and pregnancy (OR: 4.61, 95 %CI: 3.88-5.48). These findings show that a 36-month window for monitoring attendance at CCS better reflects the actual participation rate by accommodating possible delayed uptake among younger, pregnant, and highly educated women., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Research into the quality of cancer screening programs often lacks the perspective of clinicians, missing insights into the performance of individual hospitals. This retrospective cohort study aimed to identify guideline deviation (specifically, overtreatment and undertreatment) related to the cervical cancer screening program in Dutch hospitals by deterministically linking nationwide insurance data with pathology data for cervical intraepithelial neoplasia (CIN). We then constructed quality indicators using the Dutch CIN guideline and National Health Care Institute recommendations to assess compliance with CIN management, treatment outcomes, and follow-up, using an empirical Bayes shrinkage model to correct for case-mix variation and hospitals with few observations. Data were linked for 115,899 of 125,751 (92%) eligible women. Overtreatment was observed in the see-and-treat approach (immediate treatment) for women with low-grade referral cytology (4%; hospital range, 0%-25%), CIN ≤ 1 treatment specimens (26%; hospital range, 10%-55%), and follow-up cervix cytology ≥2 months before the guideline recommendation after treatment for CIN 2 (2%; hospital range, 0%-9%) or CIN 3 (5%; hospital range, 0%-19%). By contrast, undertreatment was observed for treatment within 3 months after a CIN 3 biopsy result (90%; hospital range 59%-100%) and follow-up ≥2 months beyond the guideline recommendation after treatments for CIN 2 (21%, hospital range 7%-48%) and CIN 3 (20%, hospital range 7%-90%). In conclusion, we found evidence of CIN overtreatment and undertreatment in all measured domains at the hospital level. Guideline adherence could be improved by implementing the developed indicators in an audit and feedback instrument for use by healthcare professionals in routine practice., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Background: In the Netherlands, lower high-risk human papillomavirus (hrHPV) positivity but higher cervical intraepithelial neoplasia (CIN) 2+ detection were found in self-collected compared with clinician-collected samples. To investigate the possible reason for these differences, we compared sociodemographic and screening characteristics of women and related these to screening outcomes., Methods: We extracted data from PALGA on all primary hrHPV screens and associated follow-up tests for 857,866 screened women, invited in 2017 and 2018. We linked these data with sociodemographic data from Statistics Netherlands. Logistic regression was performed for hrHPV positivity and CIN 2+/3+ detection., Results: Out of the 857,866 women, 6.8% chose to use a self-sampling device. A higher proportion of self-sampling users was ages 30 to 35 years, was not previously screened, was living in a one-person household, or was the breadwinner in the household. After adjustment for these factors self-sampling had lower hrHPV positivity (aOR, 0.65; 95% CI, 0.63-0.68)) as compared with clinician-collected sampling, as well as lower odds of CIN 2+ (aOR, 0.76; 95% CI, 0.70-0.82) and CIN 3+ (aOR, 0.86; 95% CI, 0.78-0.95) detection., Conclusions: It is likely that the observed differences between the two sampling methods are not only related to sociodemographic differences, but related to differences in screening test accuracy and/or background risk., Impact: Self-sampling can be used for targeting underscreened women, as a more convenient screening tool. Further investigation is required to evaluate how to implement self-sampling, when it is used as a primary instrument in routine screening. See related commentary by Arbyn et al., p. 159., (©2022 The Authors; Published by the American Association for Cancer Research.)

Objective: Cytology performed directly on hrHPV-positive self-samples (reflex cytology) is feasible and for women with abnormal cytology, an additional cytology test at the general practitioner could be omitted. The aim of this study is to assess the added value of digital imaging (ThinPrep® Imaging System) on the clinical utility of reflex cytology by reducing screening error., Design: A secondary analysis of a prospective cohort study., Setting: One of five Dutch screening laboratories., Population: Women tested hrHPV-positive on self-samples between December 2018 and August 2019., Methods: Self-samples were used for reflex cytology with and without digital imaging. The follow-up data (cytological and histological results within 1 year of follow-up) were obtained through the Dutch Pathology Registry (PALGA)., Main Outcome Measures: Test performance of the reflex cytology was determined by comparing it with physician-collected follow-up results., Results: The sensitivity for detecting abnormal cells by reflex cytology on self-samples increased significantly from 26.3% (42/160; 95% confidence interval [CI] 19.6-33.8) without digital imaging to 35.4% (56/158; 95% CI 28-43.4) with digital imaging (P < 0.05) without compromising specificity. Importantly, 41.7% of women with ≥CIN2 (35/84) and 45.6% with ≥CIN3 (26/57) were detected by reflex cytology with digital imaging on hrHPV-positive self-samples., Conclusion: Digital imaging is of added value to reflex cytology on hrHPV-positive self-samples with a 9% increase in sensitivity. If reflex cytology on self-samples analysed with digital imaging had been implemented in the screening programme, 35.4% of the hrHPV-positive women with abnormal cytology on additional physician-collected samples could have been referred directly for colposcopy., (© 2022 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Little is known about the long-term association between high-risk human papillomavirus (hrHPV) test results in women participating in a hrHPV-based cervical cancer screening program. To address this question, we collected data of 2217 women who participated in the POBASCAM hrHPV-based screening trial (enrolment 1999/2002) and also attended the Dutch hrHPV-based screening program between January 2017 and March 2018. Among 143 women who tested hrHPV-positive in 1999/2002, 45 (31.5%) had ≥ CIN2 or hysterectomy before 2017 and 17 (11.9%) tested hrHPV-positive at the 2017/2018 screen. In comparison, among 2074 women who tested hrHPV-negative in 1999/2002, 10 (0.5%) had ≥ CIN2 or hysterectomy before 2017 and 119 (5.7%) tested hrHPV-positive at the 2017/2018 screen. It follows that in the group of women who were not treated for ≥ CIN2 or had a hysterectomy in between the two screens 15 years apart (N = 2162), women who were hrHPV-positive in 1999/2002 had a higher risk of being hrHPV-positive in 2017/2018 than those who were hrHPV-negative in 1999/2002 (OR 3.4, 95% CI 1.8-6.1). A similar association was found at the genotype level for genotype-concordant results (5.1, 1.0-11.3) and for genotype non-concordant results (3.7, 1.6-6.7). Women who were hrHPV-positive in 2017/2018 had a higher risk of CIN3 after a hrHPV-positive result in 1999/2002 than after a hrHPV-negative result (5.8, 1.0-27.8). In conclusion, a positive hrHPV result in screening gives a long-term increased risk of a hrHPV-positive result, also for different genotypes, and a long-term increased risk of CIN3. This supports the concept of risk-stratification in hrHPV-based cervical cancer screening where previous hrHPV results are included in screening recommendations., Competing Interests: Conflict of interest CJLMM and DAMH declare the following financial interests/personal relationships which may be considered as potential competing interests: CJLMM is minority shareholder and part-time CEO of Self-screen B.V., a spin-off company of Amsterdam UMC, location VUMC, which develops, manufactures and licenses high-risk HPV assays and methylation marker assays for cervical cancer screening and holds patents on these tests. CJLMM formerly had a small number of shares of Qiagen and MDXHealth. He has received consultancy fees from GlaxoSmithKline, Qiagen, Sanofi Pasteur MSD/Merck, and Asieris/Ismar Healthcare NV, and served occasionally on the scientific advisory boards (expert meetings) of these companies. DAMH is minority shareholder of Self-screen B.V. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Immunostaining with p16 INK4a (p16), a tumor-suppressor surrogate protein biomarker for high-risk human papillomavirus (hrHPV) oncogenic activity, may complement standard hematoxylin and eosin (H&E) histology review, and provide more objective criteria to support the cervical intraepithelial neoplasia (CIN) diagnosis. With this study we assessed the impact of p16 immunohistochemistry on CIN grading in an hrHPV-based screening setting., Material and Methods: In this post-hoc analysis, 326 histology follow-up samples from a group of hrHPV-positive women were stained with p16 immunohistochemistry. All H&E samples were centrally revised. The pathologists reported their level of confidence in classifying the CIN lesion., Results: Combining H&E and p16 staining resulted in a change of diagnosis in 27.3% (n = 89) of cases compared with the revised H&E samples, with a decrease of 34.5% (n = 18) in CIN1 and 22.7% (n = 15) in CIN2 classifications, and an increase of 18.3% (n = 19) in no CIN and 20.7% (n = 19) in CIN3 diagnoses. The level of confidence in CIN grading by the pathologist increased with adjunctive use of p16 immunohistochemistry to standard H&E., Conclusions: This study shows that adjunctive use of p16 immunohistochemistry to H&E morphology reduces the number of CIN1 and CIN2 classifications with a proportional increase in no CIN and CIN3 diagnoses, compared with standard H&E-based CIN diagnosis alone. The pathologists felt more confident in classifying the material with H&E and p16 immunohistochemistry than by using H&E alone, particularly during assessment of small biopsies. Adjunctive use of p16 immunohistochemistry to standard H&E assessment of CIN would be valuable for the diagnostic accuracy, thereby optimizing CIN management and possibly decreasing overtreatment., (© 2022 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Background: Because most cervical cancers are caused by high-risk human papillomaviruses (hrHPVs), cervical cancer prevention programs increasingly employ hrHPV testing as a primary test. The high sensitivity of HPV tests is accompanied by low specificity, resulting in high rates of overdiagnosis and overtreatment. Targeted circular probe-based RNA next generation sequencing (ciRNAseq) allows for the quantitative detection of RNAs of interest with high sequencing depth. Here, we examined the potential of ciRNAseq-testing on cervical scrapes to identify hrHPV-positive women at risk of having or developing high-grade cervical intraepithelial neoplasia (CIN)., Methods: We performed ciRNAseq on 610 cervical scrapes from the Dutch cervical cancer screening program to detect gene expression from 15 hrHPV genotypes and from 429 human genes. Differentially expressed hrHPV- and host genes in scrapes from women with outcome "no CIN" or "CIN2+" were identified and a model was built to distinguish these groups., Results: Apart from increasing percentages of hrHPV oncogene expression from "no CIN" to high-grade cytology/histology, we identified genes involved in cell cycle regulation, tyrosine kinase signaling pathways, immune suppression, and DNA repair being expressed at significantly higher levels in scrapes with high-grade cytology and histology. Machine learning using random forest on all the expression data resulted in a model that detected 'no CIN' versus CIN2+ in an independent data set with sensitivity and specificity of respectively 85 ± 8% and 72 ± 13%., Conclusions: CiRNAseq on exfoliated cells in cervical scrapes measures hrHPV-(onco)gene expression and host gene expression in one single assay and in the process identifies HPV genotype. By combining these data and applying machine learning protocols, the risk of CIN can be calculated. Because ciRNAseq can be performed in high-throughput, making it cost-effective, it can be a promising screening technology to stratify women at risk of CIN2+. Further increasing specificity by model improvement in larger cohorts is warranted., (© 2022. The Author(s).)

Objective: To assess the incidence of ovarian cancer in women with histologically proven endometriosis after bilateral salpingo-oophorectomy (BSO)., Design: Retrospective nationwide cohort study., Setting: Dutch pathology database., Patient(s): Women with histologically proven endometriosis who had undergone BSO between 1990 and 2015 (n = 7,984). This study consists of 2 control cohorts: women with histologically proven endometriosis without BSO (n = 42,633) and women with a benign dermal nevus (n = 132,535)., Intervention(s): Observational study., Main Outcome Measure(s): Number of histologic diagnoses of (extra-)ovarian cancers. Incidence rate ratios (IRR) were estimated for (extra-)ovarian cancer. The number needed to treat was calculated., Result(s): We identified 9 (0.1%) (extra-)ovarian cancers in the BSO cohort and 170 (0.4%) and 444 (0.3%) ovarian cancers in the endometriosis and nevus control cohorts, respectively. We found an age-adjusted IRR of 0.34 (95% confidence interval [CI], 0.15-0.76) when the BSO cohort was compared with the endometriosis cohort. Comparing the BSO cohort with the nevus control cohort resulted in an age-adjusted IRR of 0.38 (95% CI, 0.17-0.85). The number needed to treat when the BSO cohort was compared with the endometriosis control cohort was 351 (95% CI, 272-591)., Conclusion(s): In this nationwide study, we found that the (extra-)ovarian cancer incidence in women with histologically proven endometriosis decreased to less than the background population risk after BSO. Additionally, we found a significant reduction of the incidence of ovarian cancer when compared with women with histologically proven endometriosis without BSO. Endometriosis surgery could in the future be a preventive strategy in women with endometriosis and a high-risk profile for ovarian cancer., (Copyright © 2022 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

We aim to compare endometrial cancer survival in women with or without histological proven endometriosis or adenomyosis. We identified all women with endometrial cancer between 1990 and 2015 from the Netherlands Cancer Registry (NCR). Data were linked to the Dutch pathology database (PALGA) to select all women with histological proven endometriosis/adenomyosis. Overall survival was compared between women with endometrial cancer with or without endometriosis/adenomyosis. We used multivariable Cox proportional hazard analysis to estimate hazard ratios (HRs). We included 1701 women with endometrial cancer and endometriosis/adenomyosis, of whom 1236 (72.7%) women had adenomyosis, 320 (18.8%) had endometriosis and 145 (8.5%) had both. We compared these women to 39 139 women with endometrial cancer without endometriosis/adenomyosis. Women in the combined endometriosis/adenomyosis cohort were younger at endometrial cancer diagnosis, had earlier disease stage, more often had endometrioid endometrial cancer and low grade tumors. The 5-year survival rate in the combined endometriosis/adenomyosis cohort was 84.8% (95% CI 84.6-88.1) and 71.6% (95% CI 71.1-72.0) in the nonendometriosis/adenomyosis cohort. Univariable analysis resulted in a crude HR of 0.63 (95% CI 0.59-0.69). Significant confounding factors were age, stage, cancer subtype, histological grading, surgery and chemotherapy rate. Correction for these confounders resulted in a HR of 0.98 (95% CI 0.90-1.06). Including endometriosis/adenomyosis status as a categorical factor resulted in similar HRs. In conclusion, women with endometrial cancer and histologically proven endometriosis/adenomyosis have a better overall survival when compared to women with endometrial cancer without endometriosis/adenomyosis. This better survival was correlated to stage, grade, age and histological subtype, but not to the presence of endometriosis/adenomyosis., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: The cervicovaginal microbiome (CVM) plays a significant role in women's cervical health and disease. Microbial alterations at the species level and characteristic community state types (CST) have been associated with acquisition and persistence of high-risk human papillomavirus (hrHPV) infections that may result in progression of cervical lesions to malignancy. Current sequencing methods, especially most commonly used multiplex 16S rRNA gene sequencing, struggle to fully clarify these changes because they generally fail to provide sufficient taxonomic resolution to adequately perform species-level associative studies. To improve CVM species designation, we designed a novel sequencing tool targeting microbes at the species taxonomic rank and examined its potential for profiling the CVM., Results: We introduce an accessible and practical circular probe-based RNA sequencing (CiRNAseq) technology with the potential to profile and quantify the CVM. In vitro and in silico validations demonstrate that CiRNAseq can distinctively detect species in a mock mixed microbial environment, with the output data reflecting its ability to estimate microbes' abundance. Moreover, compared to 16S rRNA gene sequencing, CiRNAseq provides equivalent results but with improved sequencing sensitivity. Analyses of a cohort of cervical smears from hrHPV-negative women versus hrHPV-positive women with high-grade cervical intraepithelial neoplasia confirmed known differences in CST occurring in the CVM of women with hrHPV-induced lesions. The technique also revealed variations in microbial diversity and abundance in the CVM of hrHPV-positive women when compared to hrHPV-negative women., Conclusions: CiRNAseq is a promising tool for studying the interplay between the CVM and hrHPV in cervical carcinogenesis. This technology could provide a better understanding of cervicovaginal CST and microbial species during health and disease, prompting the discovery of biomarkers, additional to hrHPV, that can help detect high-grade cervical lesions., (© 2021. The Author(s).)

Background: High-risk human papillomavirus (hrHPV) testing on self-collected samples has potential as a primary screening tool in cervical screening, but real-world evidence on its accuracy in hrHPV-based screening programmes is lacking., Methods: In the Netherlands, women aged 30-60 years invited for cervical screening can choose between sampling at the clinician's office (Cervex Brush) or self-sampling at home (Evalyn Brush). HrHPV testing is performed using Roche Cobas 4800. We collected screening test results between January 2017 and March 2018 and histological follow-up until August 2019. The main outcome measures were mean cycle threshold (Ct) value, cervical intraepithelial neoplasia (CIN) grade 3 or cancer (CIN3+) and CIN grade 2 or worse (CIN2+)., Findings: 30,808 women had a self-collected and 456,207 had a clinician-collected sample. In hrHPV-positive women with adequate cytology, Ct values were higher for self-collection than clinician-collection with a mean Ct difference of 1·25 (95% CI 0·98-1·52) in women without CIN2+, 2·73 (1·75-3·72) in CIN2 and 3·59 (3·03-4·15) in CIN3+. The relative sensitivity for detecting CIN3+ was 0·94 (0·90-0·97) for self-collection versus clinician-collection and the relative specificity was 1·02 (1·02-1·02)., Interpretation: The clinical accuracy of hrHPV testing on a self-collected sample for detection of CIN3+ is high and supports its use as a primary screening test for all invited women. Because of the slightly lower sensitivity of hrHPV testing on a self-collected compared to a clinician-collected sample, an evaluation of the workflow procedure to optimise clinical performance seems warranted., Funding: National Institute for Public Health and the Environment (the Netherlands) and the European Commission., Competing Interests: FI and JB report grants from the European Commission (RISCC, grant number 847845) during the conduct of the study. CA, IdK, and JB report grants from the Dutch National Institute for Public Health and the Environment (Rijksinstituut voor Volksgezondheid en Milieu, RIVM) during the conduct of the study. DAMH is minority shareholder of Self-screen B.V., a spin-off company of VUmc, which develops, manufactures and licences hrHPV and methylation marker assays for cervical cancer screening and holds patents on these tests. DAMH has been on the speakers’ bureau of Qiagen and serves occasionally on the scientific advisory boards of Pfizer and Bristol-Myers Squibb. All other authors declare no competing interests., (© 2021 The Authors.)

Background and Aims: Women with inflammatory bowel disease [IBD] may be at higher risk for cervical intraepithelial neoplasia [CIN]. However, data are conflicting. The aim of this study was to assess the risk of high-grade dysplasia and cancer [CIN2+] in IBD women and identify risk factors., Methods: Clinical data from adult IBD women in a multicentre Dutch IBD prospective cohort [PSI] from 2007 onwards were linked to cervical cytology and histology records from the Dutch nationwide cytology and pathology database [PALGA], from 2000 to 2016. Patients were frequency-matched 1:4 to a general population cohort. Standardised detection rates [SDR] were calculated for CIN2+. Longitudinal data were assessed to calculate CIN2+ risk during follow-up using incidence rate ratios [IRR] and risk factors were identified in multivariable analysis., Results: Cervical records were available from 2098 IBD women [77%] and 8379 in the matched cohort; median follow-up was 13 years. CIN2+ detection rate was higher in the IBD cohort than in the matched cohort (SDR 1.27, 95% confidence interval [CI] 1.05-1.52). Women with IBD had an increased risk of CIN2+ [IRR 1.66, 95% CI 1.21-2.25] and persistent or recurrent CIN during follow-up (odds ratio [OR] 1.89, 95% CI 1.06-3.38). Risk factors for CIN2+ in IBD women were smoking and disease location (ileocolonic [L3] or upper gastrointestinal [GI] [L4]). CIN2+ risk was not associated with exposure to immunosuppressants., Conclusions: Women with IBD are at increased risk for CIN2+ lesions. These results underline the importance of human papillomavirus [HPV] vaccination and adherence to cervical cancer screening guidelines in IBD women, regardless of exposure to immunosuppressants., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Women with histologically proven endometriosis/adenomyosis have an increased risk of ovarian cancer. Small studies show conflicting results on the endometrial cancer risk in women with endometriosis/adenomyosis. Therefore, we assessed the incidence of endometrial cancer in women with histologically proven endometriosis or adenomyosis. We performed a population-based retrospective cohort study of 129,862 women with histologically proven endometriosis/adenomyosis, matched with 132,700 women with a nevus selected from the Dutch pathology registry between 1990 and 2015. Histology results for endometrial cancer were retrieved. Crude and age-adjusted odds ratios for endometrial cancer were estimated. In the endometriosis/adenomyosis group, 1827 (1.4%) women had a histological report on endometrial cancer, and in the nevus group, 771 (0.6%) women. The age-adjusted OR for endometrial cancer was 2.58 (95%CI 2.37-2.81). After excluding the first year of follow-up, the age-adjusted OR was 0.76 (95%CI 0.63-0.92), indicating that endometrial cancer is most often found at time of histological diagnosis of endometriosis/adenomyosis. In around 20% of the endometrial cancer cases, the endometrial cancer was not recognized until after hysterectomy. Of these women, 35% had no prior (micro)curettage or biopsy. This study shows an increased incidence of endometrial cancer in women with histologically proven endometriosis and adenomyosis.

Objective: Assessing the association between endometriosis and/or adenomyosis and ovarian cancer., Methods: We identified all women with histological proven endometriosis (51,544 women) and/or adenomyosis (85,015 women) from the Dutch pathology database (1990-2015) and matched with women with a benign dermal nevus (132,654 women). Histology results for ovarian cancer were retrieved. We estimated crude and age-adjusted incidence rate ratios (IRR) for ovarian cancer., Results: We found 1017 (2.0%), 1284 (1.5%) and 471 (0.4%) ovarian cancer cases in the endometriosis, adenomyosis and nevus cohort, respectively. The age-adjusted IRRs were 19.75 (95% CI 16.70-23.35) in the endometriosis cohort and 5.93 (95% CI 4.91-7.16) in the adenomyosis cohort. The highest IRRs were found for endometrioid and clear cell ovarian cancer subtypes. Excluding the first year of follow-up did not result in a significant IRR for ovarian cancer overall but resulted in a statistically significant age-adjusted IRR of 3.92 (95% CI 2.19-7.01) for clear cell ovarian cancer and 2.39 (95% CI 1.28-4.45) for endometrioid ovarian cancer in the endometriosis cohort. Additionally, we found a statistically significant age-adjusted IRR of 2.51 (95% CI 1.29-4.90) for endometrioid ovarian cancer in the adenomyosis cohort., Conclusion: We found an increased ovarian cancer incidence in both histological proven endometriosis and adenomyosis. This increased incidence was largest for endometriosis. Excluding the first year of follow-up resulted in an increased incidence for endometrioid ovarian cancer in both cohorts and clear cell ovarian cancer in the endometriosis cohort. This study shows that gynecologist should also be aware of an increased ovarian cancer incidence in women with adenomyosis., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Excisional procedures of cervical intraepithelial neoplasia (CIN) may increase the risk of preterm birth. It is unknown whether this increased risk is due to the excision procedure itself, to the underlying CIN, or to secondary risk factors that are associated with both preterm birth and CIN. The aim of this study is to assess the risk of spontaneous preterm birth in women with treated and untreated CIN and examine possible associations by making a distinction between the excised volume of cervical tissue and having cervical disease., Methods and Findings: This Dutch population-based observational cohort study identified women aged 29 to 41 years with CIN between 2005 and 2015 from the Dutch pathology registry (PALGA) and frequency matched them with a control group without any cervical abnormality based on age at and year of pathology outcome (i.e., CIN or normal cytology) and urbanization (<100,000 inhabitants or ≥100,000 inhabitants). All their 45,259 subsequent singleton pregnancies with a gestational age ≥16 weeks between 2010 and 2017 were identified from the Dutch perinatal database (Perined). Nineteen potential confounders for preterm birth were identified. Adjusted odds ratios (ORs) were calculated for preterm birth comparing the 3 different groups of women: (1) women without CIN diagnosis; (2) women with untreated CIN; and (3) women with treated CIN prior to each childbirth. In total, 29,907, 5,940, and 9,412 pregnancies were included in the control, untreated CIN, and treated CIN group, respectively. The control group showed a 4.8% (1,002/20,969) proportion of spontaneous preterm birth, which increased to 6.9% (271/3,940) in the untreated CIN group, 9.5% (600/6,315) in the treated CIN group, and 15.6% (50/321) in the group with multiple treatments. Women with untreated CIN had a 1.38 times greater odds of preterm birth compared to women without CIN (95% confidence interval (CI) 1.19 to 1.60; P < 0.001). For women with treated CIN, these odds 2.07 times increased compared to the control group (95% CI 1.85 to 2.33; P < 0.001). Treated women had a 1.51 times increased odds of preterm birth compared to women with untreated CIN (95% CI 1.29 to 1.76; P < 0.001). Independent from cervical disease, a volume excised from the cervix of 0.5 to 0.9 cc increased the odds of preterm birth 2.20 times (37/379 versus 1,002/20,969; 95% CI 1.52 to 3.20; P < 0.001). These odds further increased 3.13 times and 5.93 times for women with an excised volume of 4 to 8.9 cc (90/724 versus 1,002/20,969; 95% CI 2.44 to 4.01; P < 0.001) and ≥9 cc (30/139 versus 1,002/20,969; 95% CI 3.86 to 9.13; P < 0.001), respectively. Limitations of the study include the retrospective nature, lack of sufficient information to calculate odds of preterm birth <24 weeks, and that the excised volume could only be calculated for a select group of women., Conclusions: In this study, we observed a strong correlation between preterm birth and a volume of ≥0.5 cc excised cervical tissue, regardless of the severity of CIN. Caution should be taken when performing excisional treatment in women of reproductive age as well as prudence in case of multiple biopsies. Fertile women with a history of performing multiple biopsies or excisional treatment for CIN may benefit from close surveillance during pregnancy., Competing Interests: All authors have completed the ICMJE uniform disclosure form and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work.

Background: Atypical glandular cells (AGC) are rare abnormalities found on cervical cytology associated with a range of lesions of the female reproductive system. We compared the risk of cervical and other gynecologic cancers following AGC on cervical cytology with the risk following squamous cell abnormalities of comparable severity., Methods: We used data from the Dutch Pathology Archive (PALGA) from 2000 to 2015 to categorize cervical cytology tests into groups based on most severe cytologic abnormality and correlated follow-up advice (normal cytology and "no follow-up" advice, squamous-cell-based, AGC-based, and combined AGC/squamous-cell based each with either repeat testing or referral advice). Cancer data were linked from the Netherlands Cancer Registry. Cox proportional hazard models were calculated stratified by age [younger (<50 years) and older (50+ years)], adjusted for number of previous primary cytology tests., Results: 8,537,385 cytology smears and 9,061 cancers were included. When repeat cytology testing was advised, HRs of cervical cancer (younger women: HR, 6.91; 95% CI, 5.48-8.71; older women: HR, 3.98; 95% CI, 2.38-6.66) or other gynecologic cancer diagnosis in younger women (HR, 2.82; 95% CI, 1.39-5.74) were significantly higher after an AGC-based abnormality compared with squamous-based abnormalities. Hazards were also significantly higher for "referral" advice cytology, except for cervical cancer among older women (HR, 0.88; 95% CI, 0.63-1.21)., Conclusions: AGC indicates an increased risk of gynecologic cancer compared with squamous-based abnormalities of comparable severity., Impact: Gynecologists should be alert for cervical and endometrial cancers when examining women referred following AGC., (©2021 American Association for Cancer Research.)

Background: Contradicting results regarding ovarian cancer prognosis in women with endometriosis have been reported in the literature. Owing to the small sample size of previous studies, larger studies are required to elucidate the role of endometriosis in ovarian cancer prognosis., Objective: This study aimed to evaluate the survival rate in women with ovarian cancer with or without histologically proven endometriosis in a Dutch population-based cohort., Study Design: All women with ovarian cancer diagnosed between 1990 and 2015 were identified from the Netherlands Cancer Registry. We linked these women with the Dutch nationwide registry of histopathology and cytopathology (Pathologisch-Anatomisch Landelijk Geautomatiseerd Archief) to identify all women with histologically proven endometriosis. We compared the prognosis of patients with ovarian cancer with and without histologically proven endometriosis. Primary outcome was the overall survival with subgroup analyses stratified by histologic ovarian cancer subtype and stage. Multivariable Cox proportional hazard analysis was used to estimate hazard ratios with 95% confidence intervals., Results: We included 32,419 patients with ovarian cancer, of whom 1979 (6.1%) had histologically proven endometriosis. The median age of histologic endometriosis diagnosis was 53 years (interquartile range, 46-62). Of all women with ovarian cancer and endometriosis, 81.2% received a diagnosis of synchronous endometriosis and ovarian cancer. The endometriosis cohort was younger at ovarian cancer diagnosis, had more favorable tumor characteristics, and more often had surgical treatment for ovarian cancer than the women without endometriosis. These variables were included in the multivariable model as confounders. Women with histologically proven endometriosis had a significantly better prognosis in both crude and adjusted analyses (hazard ratio, 0.46; 95% confidence interval, 0.43-0.49; P<.0005, and adjusted hazard ratio, 0.89; 95% confidence interval, 0.83-0.95; P<.05, respectively)., Conclusion: Women with ovarian cancer and histologically proven endometriosis had longer overall survival than women with ovarian cancer without endometriosis, even after adjustment for confounders. Future studies on ovarian cancer treatment and prognosis should consider stratifying by endometriosis status to elucidate its role. Furthermore, women diagnosed as having ovarian cancer and concurrent endometriosis should be explained the role of endometriosis in ovarian cancer survival., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Declining attendance in the Dutch cervical cancer screening programme was recently observed, coinciding with preparations for implementing primary hrHPV-based screening, which was implemented in January 2017. We aimed to investigate which factors were related to decreased attendance. We conducted a population-based cohort study including all women aged 30 to 60 years who were eligible for screening between 2014 and 2018. Attendance was defined as participation in the screening programme within 15 months of the start of the invitation-eligible year. We used data from the Dutch pathology archive (PALGA) linked with data from Statistics Netherlands to investigate population characteristics (position in the household, household income, socio-economic status, number of people in the household, migration background, age) and data from the five Dutch screening organisations (SO) to investigate the effect of cessing self-inviting GP's ('inviting organisation'). SO's were termed SO 1 to 5. Higher attendance rates were observed in women who were employed (60.8%), married (62.9%), Dutch (61.2%), in the highest income bracket (63.4%), living in households with four persons (65.3%) and women who were invited by their GP (69.8%). Differences in personal characteristics did not explain the decline in attendance rates. By adjusting for whether the GP or the SO sent the invitation, the differences in attendance rates between 2014 and 2015 and 2016 and between 2014 and 2015 and 2017-2018 were explained in some screening organisations. Removing the possibility for GPs to send invitations explains some of the decline in participation, although this did not account for the total change in attendance., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Background: In 2017, the Dutch cervical cancer screening program had replaced the primary cytology-based screening with primary high-risk human papillomavirus-based screening, including the opportunity to participate through self-sampling. Evaluation and balancing benefit (detection of high-grade cervical intraepithelial neoplasia) and burden of screening (unnecessary referrals, invasive diagnostics, and overtreatment) is needed., Objective: This study aimed to compare the referral rates, detection of high-grade cervical intraepithelial neoplasia, overdiagnosis, and overtreatment in the new high-risk human papillomavirus-based screening program, including physician-sampled and self-sampled material, with the previous cytology-based screening program in the Netherlands., Study Design: A retrospective cohort study was conducted within the Dutch population-based cervical cancer screening program. Screenees with referrals for colposcopy between 2014 and 2015 (cytology-based screening) and 2017 and 2018 (high-risk human papillomavirus-based screening) were included. Data were retrieved from the Dutch Pathology Registry (PALGA) and compared between the 2 screening programs. The main outcome measures were referral rate, detection of high-grade cervical intraepithelial neoplasia or worse, overdiagnosis (cervical intraepithelial neoplasia grade 1 or less in the histologic specimen), and overtreatment (cervical intraepithelial neoplasia grade 1 or less in the treatment specimen)., Results: Of the women included in the study, 19,109 received cytology-based screening, and 26,171 received high-risk human papillomavirus-based screening. Referral rates increased from 2.5% in cytology-based screening to 4.2% in high-risk human papillomavirus-based screening (+70.2%). Detection rates increased to 46.2% for cervical intraepithelial neoplasia grade 2 or worse, 32.2% for cervical intraepithelial neoplasia grade 3 or worse, and 31.0% for cervical cancer, and overdiagnosis increased to 143.4% with high-risk human papillomavirus-based screening. Overtreatment rates were similar in both screening periods. The positive predictive value of referral for detection of cervical intraepithelial neoplasia grade 2 or worse in high-risk human papillomavirus-based screening was 34.6% compared with 40.2% in cytology-based screening. Women screened through self-sampling were at higher risk of cervical intraepithelial neoplasia grade 2 or worse detection (odds ratio, 1.38; 95% confidence interval, 1.20-1.59) and receiving treatment (odds ratio, 1.31; 95% confidence interval, 1.16-1.48) than those screened through physician-sampling., Conclusion: Compared with cytology-based screening, high-risk human papillomavirus-based screening increases detection of high-grade cervical intraepithelial neoplasia, with 462 more cervical intraepithelial neoplasia grade 2 or worse cases per 100,000 women but at the expense of 850 more cases per 100,000 women with invasive diagnostics indicating cervical intraepithelial neoplasia grade 1 or less., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Study Question: What is the effect of salpingectomy for ectopic pregnancy or hydrosalpinx at a young age on ovarian cancer risk compared to no salpingectomy for any reason?, Summary Answer: We found no significant reduction in ovarian cancer risk after salpingectomy for ectopic pregnancy or hydrosalpinx., What Is Known Already: Salpingectomy may reduce ovarian cancer incidence, although the lag-time between intervention and therapeutic effect remains to be elucidated., Study Design, Size, Duration: This nationwide population-based database study uses the Dutch pathology database to identify all women who underwent salpingectomy for ectopic pregnancy or hydrosalpinx between January 1990 and December 2012 and compared ovarian cancer incidence to a control group of women who had a benign dermal nevus removed, matched for age at the time and year of procedure., Participants/materials, Setting, Methods: After selection and manual control of intervention and control group, ovarian cancer incidence was recorded. Hazard ratios (HRs) with 95% CI for the development of ovarian cancer were calculated with Cox regression analyses, both unadjusted and adjusted for age. Subgroup analyses were performed to investigate lag-time between intervention and protective effect., Main Results and the Role of Chance: In all, 18 961 women were included in the intervention group; 17 106 women had a unilateral salpingectomy and 1855 had a bilateral salpingectomy. The control group consisted of 23 686 women. With 14 ovarian cancer cases in the intervention group, the incidence rate (IR) of ovarian cancer was 5.4 (95% CI 3.1-8.9) per 100 000 person-years. In the control group, there were 24 ovarian cancer cases, resulting in an IR of 7.1 (95% CI 4.7-10.5) per 100 000 person-years (P = 0.34). The age-adjusted HR for ovarian cancer was 0.76 (95% CI 0.39-1.47) after salpingectomy. Unilateral salpingectomy resulted in an age-adjusted HR of 0.81 (95% CI 0.41-1.59) and bilateral salpingectomy resulted in an age-adjusted HR of 0.43 (95% CI 0.06-3.16) based on one case. None of our subgroup analysis for lag-time resulted in a significant difference in ovarian cancer incidence between intervention and control group. The difference in ovarian cancer incidence appeared largest in women with at least 8 years of follow-up (P = 0.08)., Limitations, Reasons for Caution: Due to the young population, ovarian cancer incidence is low, even at the end of follow-up. Furthermore, due to the anonymous nature of the pathology registry, we were unable to adjust for confounding factors., Wider Implications of the Findings: Although results did not reach statistical significance, they add to the available data on ovarian cancer incidence after salpingectomy. Our subgroup analysis suggests there may be no benefit in the first years following salpingectomy., Study Funding/competing Interest(s): None., Trial Registration Number: N/A., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: The aim was to evaluate the cross-sectional and long-term triage performance of FAM19A4/miR124-2 methylation analysis in human papillomavirus (HPV)-based cervical screening., Methods: We conducted a post hoc analysis within a Dutch population-based HPV-positive study cohort of women aged 30-60 years (n = 979). Cross-sectional cervical intraepithelial neoplasia (CIN) 3+ sensitivity, specificity, positive predictive value and negative predictive value as well as cumulative CIN3+ or cervical cancer risks after 9 and 14 years were compared for three baseline triage strategies: (1) cytology, (2) FAM19A4/miR124-2 methylation analysis and (3) combined FAM19A4/miR124-2 methylation with cytology., Results: CIN3+ sensitivity of FAM19A4/miR124-2 methylation analysis was similar to that of cytology (71.3% vs 76.0%, ratio 0.94, 95% CI 0.84 to 1.05), at a lower specificity (78.3% vs 87.0%, ratio 0.90, 95% CI 0.86 to 0.94). Combining FAM19A4/miR124-2 methylation analysis with cytology resulted in a CIN3+ sensitivity of 84.6% (95% CI 78.3 to 90.8) at a specificity of 69.6% (95% CI 66.5 to 72.7). Similar 9- and 14-year CIN3+ risks for baseline cytology-negative women and baseline FAM19A4/miR124-2 methylation-negative women were observed, with risk differences of -0.42% (95% CI -2.1 to 1.4) and -0.07% (95% CI -1.9 to 1.9), respectively. The 14-year cumulative cervical cancer incidence was significantly lower for methylation-negative women compared to cytology-negative women (risk difference 0.98%, 95% CI 0.26 to 2.0)., Discussion: FAM19A4/miR124-2 methylation analysis has a good triage performance on baseline screening samples, with a cross-sectional CIN3+ sensitivity and long-term triage-negative CIN3+ risk equalling cytology triage. Therefore, FAM19A4/miR124-2 methylation analysis appears to be a good and objective alternative to cytology in triage scenarios in HPV-based cervical screening., (Copyright © 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objective: High-risk human papillomavirus (HrHPV)-positive women detected by self-sampling require an extra visit at the general practitioner for additional cytology testing, but the loss to follow up within this triage is substantial. The aim of this study was to evaluate the clinical utility of reflex cytology on hrHPV-positive self-samples for immediate stratification of women who need referral for colposcopy., Design: A prospective cohort study., Setting: Two Dutch cervical cancer-screening laboratories., Population: 1014 screenees who tested hrHPV-positive on self-samples between 1 December 2018 and 1 August 2019., Methods: Self-samples were directly used for cytological analysis. Cytological and histological outcomes during follow up were obtained from the Dutch Pathology Registry (PALGA)., Main Outcome Measures: Test performance of reflex cytology on self-samples was determined for different thresholds and compared with physician-taken cytology and histological outcomes., Results: Reflex cytology on self-samples for detecting abnormal cytology showed a sensitivity of 26.4% (95% CI 21.8-31.3) and specificity of 90.5% (95% CI 87.7-92.8). Of all ≥CIN2 cases, 29.4% (95% CI 22.5-37.1) were detected with reflex cytology on self-samples. The positive predictive value for detection of ≥CIN2 was higher with cytology on self-collected samples than on physician-collected samples. Of women who were lost to follow up, 12.9% were found to have abnormal cytology on their self-sampled material., Conclusion: Cytology testing is achievable on hrHPV-positive self-samples, could decrease the loss to follow up in screening and is easily implementable in the current clinical practice. Of all hrHPV-positive women with abnormal cytology on additional physician-collected samples, 26.4% could have been directly referred for colposcopy if triage with reflex cytology on self-sampled material had been performed., Tweetable Abstract: Reflex cytology for triage of hrHPV + self-samples is of added value for direct referral of women for colposcopy., (© 2020 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.)

Women with cervical intraepithelial neoplasia grade 3 (CIN3) have a long-lasting increased risk for noncervical high-risk human papillomavirus (hrHPV)-related (pre)malignancies. The aim of our study was to estimate this risk in women with recurrent CIN3 compared to women without a history of CIN3 and women with a single episode of CIN3. Women with a CIN3 diagnosis between 1990 and 2010 were obtained from the Dutch Pathology Registry (PALGA) and matched with a control group of women without CIN3. Analysis has been conducted in a subset of women with recurrent CIN3, defined as reoccurrence minimally 2 years post-treatment. Cases of noncervical hrHPV-related (pre)malignancies of the anus, vulva, vagina and oropharynx were identified until 2015 and incidence rate ratios (IRRs) were estimated. Then, 1,797 women with recurrent CIN3 were included with a median age of 34 years (range 18-76) and 31,594 person-years of follow-up. Women with recurrent CIN3 had an increased risk of developing noncervical hrHPV-related (pre)malignancies compared to women without CIN3 with an IRR of 25.96 (95%CI 6.32-106.58). The IRR was 2.48 (95% CI 1.87-3.30) compared to women with a single episode of CIN3. Studies on posttreatment follow-up and prophylactic hrHPV vaccination are warranted., (© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Several studies have suggested that endometriosis is associated with an increased risk of ovarian cancer, especially for the clear-cell and endometrioid subtypes. However, previous studies lack sufficient power or diagnostic certainty., Objective: The objective of the study was to assess the association between histologically proven endometriosis and ovarian cancer in a large population-based cohort study., Study Design: We identified 131,450 women with a histological diagnosis of endometriosis between 1990 and 2015 from the Dutch nationwide registry of histopathology and cytopathology (PALGA). For the control cohort 132,654 women with a benign dermal nevus were matched on age and inclusion year with the endometriosis cases. Histological diagnoses of ovarian, fallopian tubes, and peritoneal cancers between January 1990 and July 2017 were retrieved. Incidence rate ratios were estimated for ovarian cancer and its subtypes for the whole follow-up period as well as for women with more than 1 person-year at risk., Results: We found a crude incidence rate ratio of 4.79 (95% confidence interval, 4.33-5.31) and an age-adjusted incidence rate ratio of 7.18 (95% confidence interval, 6.17-8.36) for ovarian cancer overall. Endometrioid and clear-cell ovarian cancer had the highest age-adjusted incidence rate ratio of 29.06 (95% confidence interval, 20.66-40.87) and 21.34 (95% confidence interval, 14.01-32.51), respectively. Median age at ovarian cancer diagnosis was 56 years (interquartile range, 49-63) for the endometriosis cohort and 60 years (interquartile range, 53-67) for the nevus cohort, (P < .05). After excluding women with less than 1 person-year at risk following an endometriosis diagnosis, we found a crude incidence rate ratio of 1.04 (95% confidence interval, 0.91-1.19) and an age-adjusted incidence rate ratio of 1.08 (95% confidence interval, 0.87-1.35) for ovarian cancer overall. However, statistically significant age-adjusted incidence rate ratios of 2.29 (95% confidence interval, 1.24-4.20) for clear-cell ovarian cancer and 2.56 (95% confidence interval, 1.47-4.47) for endometrioid ovarian cancer were found., Conclusion: A significantly higher incidence of clear-cell and endometrioid ovarian cancer was found in women with histologically proven endometriosis. Additionally, we found an increased incidence of all ovarian cancer subtypes in histologically proven endometriosis; however, in many of these women, endometriosis and ovarian cancer were diagnosed synchronously after the average menopausal age, which may suggest that the risk of ovarian cancer in endometriosis patients remains, even when clinical endometriosis symptoms are no longer present., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Only a few small studies have compared the 2-step method (biopsy followed by treatment) with a see-and-treat (immediate treatment) approach in women both low-grade or high-grade referral cytology. The clinical practice variation in the Netherlands has not been reviewed before., Objectives: To determine overtreatment rates in the 2-step versus see-and-treat approach in women referred for colposcopy because of abnormal cytology results, and to evaluate clinical practice variation in the Netherlands., Materials and Methods: This was a population-based retrospective cohort study including 36,581 women with a histologic result of the cervix identified from the Dutch Pathology Registry (PALGA) between 2016 and 2017. Odds ratios for overtreatment, defined primarily as cervical intraepithelial neoplasia grade 1 or less, were determined for the 2-step and see-and-treat approach in relation to age, high-risk human papillomavirus status, and referral cytology., Results: Of the included women 10,713 women (29.3%) received the 2-step method; 6,851 women (18.7%) underwent see-and-treat; and 19,017 women (52.0%) received conservative management after colposcopy with histologic assessment with cytologic follow-up or another type of treatment. Despite the existence of a national guideline advising see-and-treat only in case of suspected high-grade disease in women who have completed their childbearing, there is a wide practice variation between the 2 strategies in the Netherlands, with 7.0-88.3% of the women receiving see-and-treat per laboratory. The median time between cytology and treatment was 1-2 months (range, 0-12 months) in women receiving see-and-treat and the 2-step method, respectively. A total of 4119 women (23.5%) were overtreated, with older women, high-risk human papillomavirus-negative women, and women with low-grade cytology results being more likely to be overtreated. Women with low-grade cytology results and see-and-treat were associated with a higher overtreatment rate than women receiving the 2-step method (65.0% [1414 of 2174] versus 32.1% [1161 of 3613], respectively; odds ratio, 3.34; 95% confidence interval, 2.92-3.82). However, in women with high-grade cytology results, see-and-treat was inversely associated with overtreatment (11.3% [529 of 4677] versus 14.3% [1015 of 7100], respectively; odds ratio, 0.68; 95% confidence interval, 0.58-0.81)., Conclusion: A see-and-treat approach is justified only in women with high-grade cytology results who have completed their childbearing. There is a wide practice variation between the 2 strategies in the Netherlands, and gynecologists should adhere to the guideline to prevent overtreatment., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Nearly all cervical cancers are initiated by a persistent infection with one of the high-risk human papillomaviruses (high-risk HPV). High-risk HPV DNA testing is highly sensitive but cannot distinguish between active, productive infections and dormant infections or merely deposited virus. A solution for this shortcoming may be the detection of transcriptional activity of viral oncogenes instead of mere presence of high-risk HPVs. In this study, fresh-frozen cervical tissues (n = 22) were subjected to high-risk HPV DNA detection using the line probe assay and to targeted RNA next-generation sequencing using single-molecule molecular inversion probes. Targeted RNA sequencing was applied for (1) RNA-based genotyping of high-risk HPV, giving information on specific HPV-subtype (2) discrimination of E2, E6, and E7 transcripts and (3) discovery of possible non-HPV cancer biomarkers. Data were analyzed using computational biology. Targeted RNA sequencing enabled reliable genotyping of high-risk HPV subtypes and allowed quantitative detection of E2, E6, and E7 viral gene expression, thereby discriminating cervical lesions from normal cervical tissues. Moreover, targeted RNA sequencing identified possible cervical cancer biomarkers other than high-risk HPV. Interestingly, targeted RNA sequencing also provided high-quality transcription profiles from cervical scrape samples, even after 1 week of dry storage or storage in Preservcyt fixative. This proof of concept study shows that targeted RNA sequencing can be used for high-risk HPV genotyping and simultaneous detection of high-risk HPV gene activity. Future studies are warranted to investigate the potential of targeted RNA sequencing for risk assessment for the development of cervical lesions, based on molecular analysis of cervical scrapes.