Resilience of the Dutch HPV-based cervical screening programme during the COVID-19 pandemic

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 &lt; 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.</p

The efficacy of topical imiquimod in high-grade cervical intraepithelial neoplasia:A systematic review and meta-analysis

Objective: A major side effect of cervical excision for high-grade cervical intraepithelial neoplasia (CIN) is premature birth. A non-invasive treatment for reproductive age women is warranted. The aim of the present study was to determine the efficacy of topical imiquimod in the treatment of high-grade CIN, defined as a regression to ≤CIN 1, and to determine the clearance rate of high-risk human papillomavirus (hr-HPV), compared with surgical treatment and placebo. Methods: Databases were searched for articles from their inception to February 2023.The study protocol number was INPLASY2022110046. Original studies reporting the efficacy of topical imiquimod in CIN 2, CIN 3 or persistent hr-HPV infections were included. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses checklist. Results: Five studies were included (n = 463). Histological regression to ≤CIN 1 was 55% in imiquimod versus 29% in placebo, and 93% in surgical treatment. Imiquimod-treated women had a greater odds of histological regression to ≤CIN 1 than placebo (odds ratio [OR] 4.17, 95% confidence interval [CI] 2.03–8.54). In comparison to imiquimod, surgical treatment had an OR of 14.81(95% CI 6.59–33.27) for histological regression to ≤CIN 1. The hr-HPV clearance rate was 53.4% after imiquimod and 66% after surgical treatment (95% CI 0.62–23.77). Conclusions: The histological regression rate is highest for surgical treatment followed by imiquimod treatment and placebo.</p

Expression of p16 and HPV E4 on biopsy samples and methylation of FAM19A4 and miR124-2 on cervical cytology samples in the classification of cervical squamous intraepithelial lesions

The decision to treat a cervical squamous intraepithelial lesion (SIL) by loop electrosurgical excision procedure (LEEP) relies heavily on a colposcopy-directed biopsy showing high-grade (H)SIL. Diagnosis is often supported by p16, an immunohistochemical (IHC) biomarker of high-risk (hr)HPV E7 gene activity. Additional potential markers include methylation of tumor suppressor genes FAM19A4/miR124-2 in cervical cytology for advanced transforming HSIL and the IHC marker HPV E4 for productive, potentially regressing lesions. In 318 women referred for colposcopy, we investigated the relationship between staining patterns of p16 and E4 IHC in the worst biopsy, and the relation of these to FAM19A4/miR124-2 methylation status in cytology. E4-positive staining decreased with increasing SIL/CIN grade from 41% in LSIL to 3% in HSIL/CIN3. E4 positivity increased with grade of p16 when p16 expression was limited to the lower two third of the epithelium (r = 0.378), but fell with expression over. Loss of E4 expression in the worst lesion was associated with the methylation of FAM19A4/miR124-2. We also examined whether these biomarkers can predict the histological outcome of the LE

HPV testing on self collected cervicovaginal lavage specimens as screening method for women who do not attend cervical screening: cohort study

Objective To determine whether offering self sampling of cervicovaginal material for high risk human papillomavirus (HPV) testing is an effective screening method for women who do not attend regular cervical screening programmes

Triaging borderline/mild dyskaryotic Pap cytology with p16/Ki-67 dual-stained cytology testing: Cross-sectional and longitudinal outcome study

Background: Women with borderline/mildly dyskaryotic (BMD) cytology smears are currently followed up with repeat testing at 6 and 18 months. The objective of this study is to analyse the cross-sectional and longitudinal performance of p16/Ki-67 dual-stained cytology for the detection of cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) and CIN2+ in women with BMD, and to compare the results with baseline human papillomavirus (HPV) testing. Methods: Conventional Pap cytology specimens of 256 women with BMD were dual stained for p16/Ki-67 retrospectively, and compared with baseline HPV results and long-term follow-up results. Results: p16/Ki-67 dual-stained cytology showed a sensitivity of 100%, a specificity of 64.4% and a negative predictive value (NPV) of 100.% for CIN3+. Human papillomavirus testing demonstrated similar sensitivity (96.3%), and NPV (99.1%), but a significantly lower specificity (57.6%; P=0.024) for CIN3+. Sensitivity, specificity and NPV for CIN2+ of dual-stained cytology were 89.7%, 73.1% and 95.1%, respectively, which was similar when compared with HPV testing. Dual-stained cytology showed a significant lower referral rate than HPV testing (43.6% vs 49.1%; P=0.043). During long-term follow-up, no CIN3+ lesions developed in HPV-positive, dual-stained negative women. Conclusions: Comparable sensitivity and NPV of dual-stained cytology for CIN3+, combined with a significantly higher specificity, makes p16/Ki-67 dual-stained cytology a viable alternative to HPV testing for triaging BMD

The role of AIP variants in pituitary adenomas and concomitant thyroid carcinomas in the Netherlands: a nationwide pathology registry (PALGA) study

Purpose: Germline mutations in the aryl-hydrocarbon receptor interacting protein (AIP) have been identified often in the setting of familial isolated pituitary adenoma (FIPA). To date there is no strong evidence linking germline AIP mutations to other neoplasms apart from the pituitary. Our primary objective was to investigate the prevalence of AIP gene mutations and mutations in genes that have been associated with neuroendocrine tumors in series of tumors from patients presenting with both pituitary adenomas and differentiated thyroid carcinomas (DTCs). Methods: Pathology samples were retrieved from all pituitary adenomas in patients with concomitant DTCs, including one with a known germline AIP variant. Subsequently, two additional patients with known germline AIP variants were included, of which one presented only with a follicular thyroid carcinoma (FTC). Results: In total, 17 patients (14 DTCs and 15 pituitary adenomas) were investigated by targeted next generation sequencing (NGS). The pituitary tumor samples revealed no mutations, while among the thyroid tumor samples BRAF (6/14, 42.9%) was the most frequently mutated gene, followed by NRAS (3/11, 27.3%). In one AIP-mutated FIPA kindred, the AIP-variant c.853C>T; p.Q285* was confirme

Introduction of primary screening using high-risk HPV DNA detection in the Dutch cervical cancer screening programme:a population-based cohort study

Background: In January 2017, the Dutch cervical cancer screening programme transitioned from cytomorphological to primary high-risk HPV (hrHPV) DNA screening, including the introduction of self-sampling, for women aged between 30 and 60 years. The Netherlands was the first country to switch to hrHPV screening at the national level. We investigated the health impact of this transition by comparing performance indicators from the new hrHPV-based programme with the previous cytology-based programme. Methods: We obtained data from the Dutch nationwide network and registry of histo- and cytopathology (PALGA) for 454,573 women eligible for screening in 2017 who participated in the hrHPV-based programme between 1 January 2017 and 30 June 2018 (maximum follow-up of almost 21 months) and for 483,146 women eligible for screening in 2015 who participated in the cytology-based programme between 1 January 2015 and 31 March 2016 (maximum follow-up of 40 months). We compared indicators of participation (participation rate), referral (screen positivity; referral rate) and detection (cervical intraepithelial neoplasia (CIN) detection; number of referrals per detected CIN lesion). Results: Participation in the hrHPV-based programme was significantly lower than that in the cytology-based programme (61% vs 64%). Screen positivity and direct referral rates were significantly higher in the hrHPV-based programme (positivity rate: 5% vs 9%; referral rate: 1% vs 3%). CIN2+ detection increased from 11 to 14 per 1000 women screened. Overall, approximately 2.2 times more clinical irrelevant findings (i.e. ≤CIN1) were found in the hrHPV-based programme, compared with approximately 1·3 times more clinically relevant findings (i.e. CIN2+); this difference was mostly due to a national policy change recommending colposcopy, rather than observation, of hrHPV-positive, ASC-US/LSIL results in the hrHPV-based programme. Conclusions: This is the first time that comprehensive results of nationwide implementation of hrHPV-based screening have been reported using high-quality data with a long follow-up. We have shown that both benefits and potential harms are higher in one screening round of a well-implemented hrHPV-based screening programme than in an established cytology-based programme. Lower participation in the new hrHPV programme may be due to factors such as invitation policy changes and the phased roll-out of the new programme. Our findings add further to evidence from trials and modelling studies on the effectiveness of hrHPV-based screening

Long-term CIN3 risk in women with abnormal cytology; Role of hrHPV testing

Background: Many studies have examined the short-term value of high-risk human papillomavirus (hrHPV) testing in predicting cumulative risk of cervical intraepithelial neoplasia grade 3 or cancer (CIN3). This study focuses on long-term CIN3 risk after initial wait and see policy. Methods: A total of 342 women with abnormal cytology of borderline/mild dyskaryosis (BMD) or worse (>BMD), included between 1990 and 1992, were followed-up by cytology and hrHPV testing until 1996 and monitored by cytology thereafter. Primary endpoint was cumulative CIN3 risk by December 2009.Results:Women with BMD had a 5-year CIN3 risk of 22.5% (95% confidence interval (CI) 17.0-29.1) and of 0.7% (0.1-4.5) in the subsequent 5 years. High-risk human papillomavirus-negative women with BMD had a 5-year risk of <0.01% (95% CI <0.0-5.1) and of 0.01% (0.0-5.7) in the following 5 years, while for hrHPV-positive women these risks were 37.5% (29.0-46.9) and 1.6% (0.2-9.5), respectively. Women with BMD< had a 5-year risk of 45.1% (36.4-54.1) and of 3.5% (0.9-12.2) in the subsequent 5 years. High-risk human papillomavirus-negative women with < BMD had a 5-year risk of 7.3% (2.0-23.6) and hrHPV-positive women of 56.6% (46.4-66.3). Conclusion: Women with BMD have an elevated CIN3 risk for 5 years only; afterwards their risk is similar to the general population. High-risk human papillomavirus-negative women with BMD may return to regular screening directly. All other women with ≥ BMD should be referred for additional testing and/or colposcopy