Line Winther Gustafson

High rate of persistent HPV detection after diagnostic cervical excision in older screen‐positive women

AbstractIntroductionDiagnostic work‐up of older women with a positive cervical cancer screening test is often challenging due to incomplete visualization of the transformation zone. To reduce the risk of missing disease, a diagnostic cervical excision may be performed. However, little is known on treatment efficacy and post‐treatment surveillance for older women. We aimed to investigate the proportion of women testing negative for human papillomavirus (HPV) following a diagnostic cervical excision due to an abnormal screening test.Material and MethodsWe conducted a prospective cohort study on women aged ≥45 years who were referred for colposcopy due to an abnormal screening test between March 2019 and June 2021. All women had incomplete visualization of the transformation zone and underwent colposcopy and a diagnostic cervical excision at the first visit. Women were followed from date of excision until January 30, 2023. Follow‐up data was retrieved from the Danish Pathology Databank, and baseline characteristics were obtained from medical records. Cox regression was used on interval‐censored data to estimate crude and adjusted hazard ratios for a negative HPV test after cervical excision, stratified by histology and age.ResultsA total of 100 women underwent a diagnostic cervical excision and had at least one HPV test during follow‐up. Median age was 67.4 years, and median follow‐up time was 2.9 years. At the end of follow‐up, 70% tested HPV negative. Women with cervical intraepithelial neoplasia grade two or worse in their excision specimen were more likely to test HPV negative at the first test after cervical excision compared to women with less than cervical intraepithelial neoplasia grade two, however, not statistically significant (adjusted hazard ratio 1.69, 95% CI 0.92–3.10). Women aged 65–84 years were less likely to test HPV negative compared to women <65 years (adjusted hazard ratio 0.49, 95% CI 0.28–0.87).ConclusionsIn older women undergoing a diagnostic cervical excision, 70% tested HPV negative after 2.9 years, leaving 30% with persistent HPV positivity. More studies are needed to determine the risks associated with continued HPV positivity in the absence of high‐grade disease. Furthermore, given the absence of specific guidelines, the optimal surveillance frequency remains unknown.

Implementation of p16/Ki67 dual stain cytology in a Danish routine screening laboratory: Importance of adequate training and experience

AbstractBackgroundImmunocytochemical staining with p16/Ki67 has been suggested as a promising triage biomarker in cervical cancer screening. As dual staining is a subjective method, proper training may be required to ensure safe implementation in routine laboratories and reduce risk of misclassification. We determined concordance between novice evaluators and an expert, stratified by number of slides reviewed at three reading points.MethodsThe study was conducted at the Department of Pathology, Randers, Denmark. Women were eligible if they were aged ≥45, had been enrolled in one of two ongoing clinical studies, and had a dual stain slide available. Dual staining was performed using the CINtec plus assay. Slides were randomly selected from three reading points at which novice evaluators had reviewed <30, ~300, and ≥500 dual stain slides respectively. Level of concordance was estimated using Cohen's Kappa, κ.ResultsOf 600 eligible slides, 50 slides were selected for review as recommended by the manufacturer. Median age was 68 years (range: 58‐74). Overall concordance was good (κ = 0.68, 95% confidence interval [CI]: 0.60‐0.76), with an overall agreement of 84% (95% CI: 70.9%‐92.8%). Concordance improved with increasing number of slides reviewed at a given reading point, from a moderate concordance (κ = 0.47, 95% CI: 0.05‐0.90) after reviewing <30 slides to a good concordance (κ = 0.66, 95% CI: 0.20‐0.88) and a very good concordance (κ = 0.88, 95% CI: 0.66‐1.00) after reviewing ~300 and ≥500 slides, respectively.ConclusionsWhen interpreting dual stain slides from older women, concordance increased slightly as novice evaluators received more training and experience. Although further evaluation is warranted, these findings indicate that a significant amount of training and experience of novice evaluators may be needed to ensure accurate dual stain interpretation in this age group. Future studies should accurately describe training and experience of evaluators to enable a better comparison of concordance and diagnostic accuracy across studies.Trial registrationNCT04114968 and NCT04298957.

Cervical cancer prevention among older women – challenges in screening, diagnostic workup and treatment

AbstractCervical cancer incidence and mortality have declined dramatically after screening for cervical cancer was implemented. Yet, studies have reported high cervical cancer incidence and mortality rates at older age despite low HPV prevalence and incidence of precursor lesions. The underlying reason for these findings remains unclear. However, it is well known that the impact of screening depends not only on the uptake and effectiveness of screening but also on the uptake and effectiveness of diagnostic workup (ie colposcopy), treatment and follow‐up. In older women, sensitivity of screening and performance of colposcopy are impaired due to age‐dependent changes to the cervix. In this commentary, we aimed to discuss challenges in screening and clinical management of older women, and to identify crucial areas of particular interest for future research.

Clinical utility of p16/Ki67 dual‐stain cytology for detection of cervical intraepithelial neoplasia grade two or worse in women with a transformation zone type 3: A cross‐sectional study

AbstractObjectiveTo evaluate the clinical utility of p16/Ki67 dual‐stain (DS) compared with cytology for detecting cervical intraepithelial lesion grade two or worse (CIN2+) in women with a transformation zone type 3 (TZ3).DesignCross‐sectional study.SettingColposcopy clinics in Central Denmark Region.PopulationWomen aged 45 years or older referred for colposcopy because of an abnormal screening test.MethodsAll women had a cervical sample collected for cytology and DS testing and underwent large‐loop excision of the transformation zone (LLETZ).Main outcome measureSensitivity, specificity and negative (NPV) and positive (PPV) predictive values of DS for CIN2+ detection were compared to those of cytology.ResultsOf 166 women eligible, 93 (56.0%) were included in the final analysis. Median age was 68 years (interquartile range [IQR] 63.4–70.5 years). Most women were postmenopausal (95.7%) and referred based on a positive human papillomavirus screening test (86.0%). Fifty‐two women (55.9%) were DS‐positive, 29 (55.8%) of whom had CIN2+ detected. Twenty‐seven (29.0%) women had atypical squamous cells of undetermined significance or worse (ASC‐US+), and CIN2+ was detected in 21 women (77.8%). DS had a higher sensitivity (96.7% versus 70.0% p = 0.021) and NPV (97.6% versus 86.4%, p = 0.018) compared with cytology for CIN2+ detection. In contrast, the specificity (63.5% versus 90.5% p < 0.001) and PPV (55.8% versus 77.8%, p = 0.001) were lower for DS compared with cytology.ConclusionsDual stain may be a valuable risk marker to guide clinical management of women with a TZ3. The superior NPV of DS suggests that a diagnostic excision may safely be avoided in DS‐negative women.

Negative margins and negative HPV tests after large loop excision of the transformation zone: A nationwide historical cohort study

Abstract Introduction Adequate treatment of cervical precancer, defined as negative margins and a negative HPV test post‐treatment, is essential for cervical cancer prevention, as inadequate excision of cervical precancer and a positive HPV test are associated with increased risk of recurrence. Here, we aimed to describe trends in the proportion of women receiving adequate treatment in Denmark. Material and Methods Nationwide historical cohort study including Danish women ≥18 years treated with large loop excision of the transformation zone (LLETZ) from 2013 to 2022. Using the Danish Pathology Register, we collected information on all LLETZ procedures performed due to cervical intraepithelial neoplasia grade 1 or worse (CIN1+). We calculated the proportion of negative margins and negative HPV tests post‐treatment, overall and stratified by histology, age, calendar time, and residing region. Results were mainly reported descriptively. Results We included 41 128 women (median age: 35 years, interquartile range: 28–44). A total of 20 744 (50.4%) had negative margins, with the lowest proportion in women with CIN3 (47.2%) or adenocarcinoma in situ (38.3%). The proportion of negative margins declined with increasing age, from 54.1% in women aged 18–29 years to 43.6% in women aged ≥50 years. Overall, 62.4% had a negative HPV test, with no major differences observed across histology groups. The proportion of negative HPV tests ranged from 62.8% to 66.9% in women aged 18–49, whereas it was lower in women aged ≥50 years (48.4%). Conclusions Women aged ≥50 years were less likely to have negative margins and a negative HPV test post‐treatment compared to women aged 18–49. These findings prompt a need to optimize treatment in this group of women to reduce the risk of cervical cancer.

Offering Cervical Cancer Screening to Older Women

This study evaluates the effect and feasibility of expanding the target population in the Danish cervical cancer screening program to include women aged 65 to 69 years. The study also evaluates if HPV self-sampling constitutes an appropriate screening method among older women.