To Örebro University

INTRODUCTION: Primary cervical screening with testing for human papillomavirus (HPV) brings increased detection of women with low-grade squamous intraepithelial lesion recommended for follow-up with colposcopy. This study evaluates whether co-testing (HPV + cytology) or testing for HPV alone can safely replace colposcopy as follow-up for histologically confirmed low-grade squamous intraepithelial lesions. It estimates these strategies' diagnostic performance in detecting histological high-grade squamous intraepithelial or more severe lesions at follow-up and analyzes their relative cost-effectiveness.

MATERIAL AND METHODS: This is a retrospective cohort study on follow-up data of women aged 23-70 with histological low-grade squamous intraepithelial lesion, diagnosed during 2017-2018, with an analysis of data from the Swedish National Cervical Screening Registry. Out of the 14 643 women with low-grade squamous intraepithelial lesions, 4213 women with complete data on HPV, cytology, and histology results were analyzed. The primary outcome was to estimate the diagnostic performance of the strategies of co-testing (HPV + cytology) and human papillomavirus-alone in detecting histological high-grade squamous intraepithelial or more severe lesions in the follow-up of histological low-grade squamous intraepithelial lesions. The secondary outcome was to perform a cost-effectiveness analysis of these strategies.

RESULTS: Using co-testing as the primary follow-up and reserving colposcopy for women who tested positive for HPV or cytology results yielded a sensitivity of 96% for high-grade squamous intraepithelial or more severe lesions. HPV-alone testing had 88% sensitivity. Adding colposcopy to co-testing would require 1735 (70%) additional examinations to detect 14 (3.9%) more women with high-grade squamous intraepithelial or more severe lesions. No cancer cases were missed by co-testing or HPV-alone. The cost of detecting one extra high-grade squamous intraepithelial or more severe lesion by adding colposcopy to co-testing was 81 959 EUR.

CONCLUSIONS: Histological low-grade squamous intraepithelial lesion follow-up can be safely managed with co-testing, considerably reducing the number of colposcopies and associated costs.

OBJECTIVE: With the transition from cytology to human papilloma virus (HPV) testing in cervical cancer screening, it is possible to use self-sampling instead of professionally collected samples. Most studies have included women between 20 and 60 years age. Here we aimed to study postmenopausal women and investigate whether vaginal self-sampling is equally effective as professional sampling for detection of HSIL and the possibility to use a method for molecular triage directly on the screening sample.

METHODS: Postmenopausal women in Örebro county, Sweden, were invited (n = 7835) during 2018-2020 to participate in the study including both professional and self-sampling. In total 2258 women returned both sample types, that were analyzed for HPV followed by triage for cytology, HPV genotyping and methylation and clinical follow-up according to national guidelines.

RESULTS: The prevalence of HPV was 3.4 % in the professionally collected samples and 12.6 % in the self-collected. All women with high-grade squamous intraepithelial lesion (HSIL) were HPV-positive in both professionally and self-collected samples. For self-collected samples, we compared different triage strategies. Cytology was the most efficient strategy. Among the molecular triage methods, the combination of methylation and genotyping was most efficient but resulted in twice as many colposcopy referrals as cytology.

CONCLUSIONS: In conclusion, HPV self-sampling with molecular triage detects HSIL to the same extent as professional screening with cytological triage. The specificity of molecular triage is, however, unacceptably low, and to avoid overtreatment other triage methods following primary self-sampling need to be developed.

BACKGROUND: Women treated with cervical loop electrosurgical excision procedure require follow-up to detect residual or recurrent HSIL+, defined as high-grade squamous intraepithelial lesions, adenocarcinoma in situ or cervical cancer. Currently, co-testing with cytology and human papillomavirus (HPV) analysis is usually recommended. This study investigates whether HPV testing alone is comparable to co-testing in detecting HSIL + up to three years after treatment. Recurrence rates of HSIL + are also presented, with follow-up extending up to 18 years.

METHODS: This retrospective cohort study included all 3,540 women treated with a cervical excision in Uppsala County between 1 January 2005 and 31 December 2019. Women with cancer identified in the cone biopsy were excluded. The main outcome was HSIL + detected within three years of follow-up. Sensitivity, specificity and negative predictive value were calculated for the 1,938 women who had a co-testing result as part of their test of cure. Thus, the analysis for the main outcome could finally be performed on 1,938 out of the total number of 3,540 women. Additionally, long-term data on recurrence and time to HSIL+, along with a separate analysis of results prior to cervical cancer diagnosis, were collected for the whole cohort of 3,399 women.

RESULTS: The sensitivity and negative predictive value for detecting HSIL + were 69% and 97% for HPV alone, and 74% and 98% for co-testing, respectively. These differences were not statistically significant. Specificity was higher for HPV alone than for co-testing. The negative predictive value of HPV testing for excluding cervical cancer (n = 5) within three years was 100%. Recurrence rate of HSIL + in the three-year follow up was 8%, and the total recurrence rate of HSIL + with a mean follow-up of nine years was 10%. Mean time to recurrence was 28 months. None of 19 cervical cancer cases identified in the long-term follow-up had a co-testing result showing negative HPV but positive cytology.

CONCLUSIONS: HPV testing alone, as a single test, is comparable to co-testing in detecting HSIL + up to three years after treatment independently of margin status, and demonstrates a higher specificity. Cytology plays a very limited role in the test of cure analysis and could therefore be omitted.

BACKGROUND: Users of intrauterine devices (IUDs) have been found to have a lower incidence of cervical cancer in meta-analyses, but these studies have not been able to examine the influence of IUD type. The aim of this study is to investigate the incidence of de novo high-risk human papillomavirus (HPV) infections in relation to the reported use of contraceptive methods, with special regard to different types of IUDs.

METHODS: A sample of participants in the national screening program for cervical cancer (n = 11,702) with a negative HPV test in 2017-2018 were included. Their subsequent HPV test results in 2020-2023 were analyzed in relation to their reported contraceptive method.

RESULTS: Participants who reported use of hormonal contraception had higher incidence of a positive HPV screening test (5.6%) compared with women with no reported contraception (4.2%) (OR 1.29; 95% CI 1.01-1.64). There was no significant difference in HPV incidence among women who reported use of hormonal IUD (HIUD) or copper-containing IUD (CU-IUD). Women who reported use of the same contraceptive method in both screening rounds showed no significant differences in HPV incidence, regardless of the contraceptive method they had used.

CONCLUSION: The incidence of de novo HPV infections is not significantly different in users of different types of IUD.

BACKGROUND: Since 2022, self-sampling has been recommended in Sweden's cervical screening program. Despite still being used primarily for long-term non-attendees, its expected increase in use raises interest in molecular triage methods applicable to self-collected samples. Postmenopausal women face screening challenges due to physiological changes, making this group particularly relevant for evaluating alternative strategies. This study models the cost-effectiveness of different sampling and triage methods in identifying histological high-grade squamous intraepithelial lesions (HSIL) in women aged 60-69 years.

METHODS: Using real-world data, this study compares the cost-effectiveness of currently implemented strategy based on professional HPV sampling and combination triage with genotyping and cytology, with modelled strategies based on self-sampling and various molecular triage. The comparison evaluates healthcare resource use and the number of identified histological HSIL cases. The analysis focuses on a single screening cycle, re-testing of invalid samples or screening-positive/triage-negative women are not addressed.

RESULTS: Screening with molecular triage either leads to decreases in effect, i.e. fewer histological HSIL identified, or significant cost increases due to higher rate of HPV-positive screening samples and higher number of colposcopy follow-ups.

CONCLUSIONS: Molecular triage, whether used with self-sampling or professional sampling, does not appear cost-effective for identifying HSIL in this age group compared to the current screening strategy.

OBJECTIVE: To improve human papilloma virus (HPV) screening, more effective triage methods for HPV-positive samples need development and validation. Cytology, the most common triage method today, is subjective and can only be applied to professionally collected samples. Methylation status has been shown to be informative, as genes are highly methylated in HPV-induced cervical dysplasia and cancer. This study aimed to assess whether triaging HPV-positive samples using molecular methods, such as methylation and genotyping for high-risk HPV types, could be as effective as cytology in cervical screening.

METHODS: A retrospective biobank study was conducted on HPV-positive samples collected in 2017-2018, analyzing FAM19A4/MiR-124-2 hypermethylation and HPV genotyping for types 16, 18, 31, 33, 45, 52, and/or 59, comparing these results to cytology triage for detecting histologically confirmed high-grade squamous intraepithelial lesions (HSIL) and cancer.

RESULTS: Results from 1915 positive screening samples were analyzed, including 1052 follow-up biopsies with 402 HSIL or cancer cases. Genotyping showed slightly higher sensitivity than cytology but lower specificity, while methylation had higher specificity but much lower sensitivity. Cytology's positive predictive value (PPV) was 36%, with lower PPVs for the molecular methods. Combining molecular methods increased the PPV but significantly reduced sensitivity.

CONCLUSIONS: Based on these findings with molecular methods reducing sensitivity, we do not recommend adopting the molecular triage methods evaluated in this study in the Swedish setting. The trade-off between sensitivity and specificity does not support a change from the current cytology-based triage approach.

OBJECTIVE: To examine the prevalence of infections with high-risk human papillomavirus (HPV) and cervical dysplasia, and the clearance rate of HPV infections, in users of different kinds of intrauterine devices (IUDs) and other contraceptive methods.

METHODS: A cross-sectional register-based study including 16,181 women aged 30-49 years participating in the screening programme for cervical cancer in a Swedish County in 2017-2018. Data on contraception from screening records was paired with the HPV test results, cytological and histological follow-up tests and subsequent HPV test.

RESULTS: There was no difference in the risk of being HPV positive, or histological HSIL+, between users of copper-containing IUDs and women with no reported use of contraception. Use of levonorgestrel intrauterine system and hormonal contraception were associated with higher odds for HPV infection in age-adjusted models (aOR 1.21; 95% CI 1.04-1.41, and aOR 1.41; 95% CI 1.22-1.63, respectively) and for HSIL+ (aOR 1.45; 95% CI 1.02-2.06, and aOR 1.56; 95% CI 1.13-2.16, respectively). No significant differences were found in HPV clearance rates.

CONCLUSIONS: Reported use of levonorgestrel intrauterine system and hormonal contraception, but not use of copper IUD, was associated with a higher prevalence of HPV infections and histological HSIL + compared to no reported use of contraception.

BACKGROUND: With HPV screening the specificity of screening positives has decreased, even with a cytological triage test. Increases in colposcopies and detection of benign or low-grade dysplasia are reported, not least in older women. These results highlight the necessity to find other triage tests in HPV screening strategies, so that women can be more accurately selected for colposcopy, thus minimizing the clinically irrelevant findings.

METHODS: The study included 55- to 59-year-old women who exited the screening with normal cytology, but later in a follow-up test were positive for the HPV genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 and had a cervical cone biopsy done. To model a screening situation with hrHPV-positive women, three different triage strategies, namely, cytology, genotyping and methylation, were performed. The study considered the effect of direct referral to colposcopy for HPV genotypes 16, 18, 31, 33, 45, 52 and 58, and methylation for FAM19A4 and hsa-mir124-2 and/or any form of abnormal cytology.

RESULTS: Seven out of 49 women aged 55-59 years with hrHPV had a cone biopsy with high-grade squamous intraepithelial lesion. No triage method found all cases, and when comparing positive and negative predictive value and false negative rate, cytology showed better results than genotyping and methylation.

CONCLUSION: This study does not support a switch in triage strategies from cytology to hrHPV genotyping and methylation for women above 55 years of age yet, but demonstrates the need for more evidence on molecular triage strategies.

Swedish guidelines recommend cervical screening with primary HPV for women ≥ 30 years of age. The aim of this study was to compare an implemented HPV cervical screening programme in the Region of Örebro County from September 1, 2016, with the former cytology-based screening programme.

The clinical effectiveness by means of number of high-grade squamous intraepithelial lesions (HSILs) and cervical cancer cases detected in histology within 12 months after the screening test, together with cost implications were the main outcomes. Data were retrieved from the Swedish National Cervical Screening Registry between the years 2014-2015 (cytology based screening) and 2017-2018(HPV based screening), including screening information such as invitations and cytology and histology diagnoses.

The detection rate of HSIL + among women ≥ 30 years of age was 1.2 times higher with HPV screening, but data revealed an increase in direct colposcopy referral rate by 54% and a higher percentage of irrelevant findings (≤LSIL). Screening based on HPV for women ≥ 30 has increased yearly cost from 1 to 1.3 million EUR, while increasing the number of HSIL + identified. Two thirds of the total costs are from visits for screening samples in the programme.

HPV screening detected more cases of HSIL + compared to cytology screening among women ≥ 30 although high colposcopy rate, high rate of clinical irrelevant findings and higher costs were shown in the HPV-based screening programme, which implies that alterations in the screening programme in the future are important to consider.