Anne Hammer

The effect of healthcare disruptions during the COVID ‐19 pandemic on colposcopy services and practice: A systematic review and meta‐analysis

Abstract Introduction The healthcare reorganization during the COVID‐19 pandemic affected colposcopy services and cervical cancer prevention, particularly in those countries where healthcare systems were already under‐resourced. This review aimed to quantify the reduction in colposcopy services across countries during the COVID‐19 pandemic and to determine whether the data source per study and cervical cancer screening coverage per country influenced the extent of these reductions. Material and Methods Studies reporting comparative data on colposcopy services between the COVID‐19 pre‐pandemic and pandemic period were included. MEDLINE, Embase, EMCare, Covid‐19 Research, British Nursing Index, APA PsycINFO, and Allied and Complimentary Medicine databases were searched for studies published from March 2020 to December 2023. The Newcastle−Ottawa scale was used for risk of bias assessment. The number of colposcopies, cervical treatments, pre‐invasive lesions diagnoses, and cervical cancer diagnoses per month were compared between the pre‐pandemic (before March 2020) and pandemic period (after March 2020). The effect measure was the standardized mean difference. Heterogeneity was evaluated with the chi‐squared test and quantified with the I 2 method. A meta‐regression was performed, considering the data source (regional/national databases/registries or institutional databases) and the screening coverage according to World Health Organization data (≥70% or <70%) as moderators. The review was registered on PROSPERO (CRD42023447188). Results Thirteen studies were included. Twelve were of good/high quality according to the Newcastle−Ottawa scale. The standardized mean difference between the pre‐pandemic and pandemic periods was −1.60 (95% CI −2.49 to −0.72, p  = 0.004) for colposcopies (4 studies, I 2  = 60.97%, p  = 0.075), −1.70 (95% CI −2.50 to −0.90, p  < 0.001) for cervical treatments (5 studies, I 2  = 52.92%, p  = 0.081), −4.61 (95% CI ‐7.90 to −1.33, p  = 0.006) for pre‐invasive lesion diagnoses (4 studies, I 2  = 92.45%, p < 0.001), and −0.85 (95% CI −1.52 to −0.19, p  = 0.012) for cervical cancer diagnoses (9 studies, I 2  = 71.07%, p  = 0.002). At meta‐regression, further reductions for cervical treatments and pre‐invasive lesion diagnoses were observed in the case of screening coverage <70%. Conclusions During the COVID‐19 pandemic, a reduction in colposcopies, cervical treatments, pre‐invasive lesions diagnoses, and invasive cancer diagnoses was observed. Since a screening coverage of <70% heightened these declines, increasing such coverage could lead to better resilience of cervical cancer prevention services to future crises.

HPV vaccination following cervical intraepithelial neoplasia grade 2 diagnosis and risk of progression

Abstract Introduction Human papillomavirus (HPV) vaccination is associated with a significantly reduced risk of cervical cancer when administered before initial exposure to HPV. Women with high‐grade cervical intraepithelial neoplasia (CIN) have an increased risk of subsequent HPV‐related disease, including recurrent high‐grade CIN, compared to women without CIN. Some clinicians have advised women with high‐grade CIN to undergo HPV vaccination to reduce their subsequent risk, despite a lack of evidence for this practice. We aimed to evaluate whether HPV vaccination of women undergoing active surveillance for CIN grade 2 (CIN2) is associated with a decreased risk of progression to cervical intraepithelial neoplasia grade 3 or worse (CIN3+). Material and Methods We conducted a nationwide population‐based historical cohort study in Denmark on women aged 18–40 years undergoing active surveillance for CIN2 from 2007 to 2020. We compared women receiving at least one HPV vaccine dose within 6 months after their CIN2 diagnosis to women not receiving the vaccine. Our primary outcome was progression to CIN3+. We stratified by age at CIN2 diagnosis (18–29, 30–40), calendar year (2007–2012, 2013–2020), and index cytology (high‐grade, nonhigh‐grade). We used Cox proportional hazards regression to estimate hazard ratios of the outcomes with unvaccinated women as the reference. Age at diagnosis, calendar year, index cytology, income, and educational level were adjusted for. Results We included 4585 women, of whom 583 (12.7%) were vaccinated within 6 months after CIN2 diagnosis. A total of 1391 (30.3%) progressed to CIN3+ during follow‐up. The 5‐year cumulative risk was 29.9% (28.5–31.3). Overall, no protective effect of vaccination after CIN2 diagnosis was found (aHR 1.45 [1.24–1.69]). Stratified analyses showed increased progression risk with vaccination among women <30 years, in the early calendar period (2007–2012), and across both non‐high‐grade and high‐grade index cytology; no significant difference in risk was observed in women ≥30 years or in the latest calendar period (2013–2020). Conclusions HPV vaccination did not reduce the risk of progression in women undergoing active surveillance for CIN2. This finding indicates that HPV vaccination should not be recommended in this group of women.

Survey of practices in the European Federation for Colposcopy: HPV vaccination after treatment for cervical precancerous lesions

AbstractIntroductionPatients treated for cervical precancerous lesions have a long‐term increased risk for cervical cancer compared with the general population. As human papillomavirus (HPV) vaccination is effective in preventing cervical cancer and its precursors when given prior to sexual debut, adjuvant HPV vaccination in relation to the treatment of precursor lesions has been of great interest. Existing supporting data are of low quality, and recent meta‐analyses called for high‐quality randomized controlled trials. The European Federation for Colposcopy (EFC) observed a heterogeneity in clinical practices of adjuvant vaccination, and this survey aimed to assess potential differences in vaccination practices across Europe.Material and MethodsA survey was sent out to 100 representatives of the 32 member countries of the EFC. The survey was in English and contained questions on current general HPV vaccination programs, whether guidelines on vaccination after treatment exist, and questions on respondents' own practices of recommending vaccination after treatment. The survey was constructed using the Google Forms web platform and sent by email to representatives of each National Colposcopy Society.ResultsIn total, 44 answers from 32 different European countries were received. Overall, 12 countries (12/32, 37.5%) reported having a national guideline on HPV vaccination at the time of treatment for precursor lesions, and in nine of these countries, adjuvant HPV vaccination is recommended. A third, 31.8%, of respondents (14/44) found the available evidence sufficient to recommend vaccination at the time of treatment, and 54.5% (24/44) found the evidence to be nearly sufficient. Only 13.6% (6/44) of the respondents found the current evidence insufficient to be able to recommend vaccination. Altogether, 29.5% (13/44) of respondents would recommend vaccination, even if future randomized controlled trials would not show benefits.ConclusionsThe varying practices regarding adjuvant HPV vaccination across European countries are concerning and call for ethical evidence‐based practices across Europe and reliance on high‐quality evidence to assess whether vaccination at the time of treatment is effective.

p16INK4a and HPV E4 immunohistochemistry for the prediction of regression of cervical intraepithelial neoplasia grade 2—A historical cohort study

AbstractCervical intraepithelial neoplasia grade 2 (CIN2) is a heterogeneous diagnosis with a high likelihood of spontaneous regression. Therefore, active surveillance for CIN2 has been implemented as an option in younger women in many countries. Yet, little is known about markers that may accurately predict the likelihood of regression to support active surveillance. Here, we aimed to assess whether p16INK4a and HPV E4 status are associated with the likelihood of CIN2 regression. We conducted a historical cohort study on women aged 23–40 diagnosed with untreated CIN2 following cytology‐based screening. Women were diagnosed at Aarhus University Hospital, Denmark from January 2000 to December 2010. Archived tissue samples were sectioned for p16INK4a and HPV E4 immunohistochemistry and HPV genotyping. We used a modified Poisson model to estimate the relative risk of regression, adjusting for age and cytology (aRR). A total of 443 women with CIN2 were included. Most women (73.8%) were aged ≤30, and half had a high‐grade cytology (48.8%). Overall, 47.6% regressed, and regression was less likely in p16INK4a‐positive compared to p16INK4a‐negative women (aRR 0.77; 95% CI 0.64–0.94). Among p16INK4a‐positive women, the risk of regression varied by HPV type and HPVE4 status, with lower risk in HPV16‐positive women compared to those without (aRR 0.54; 95% CI 0.40–0.75) and in HPVE4‐negative compared to HPVE4 positive women (aRR 0.73; 95% CI 0.54–0.98). When we restricted to expert‐confirmed CIN2, the risk of regression did not vary by p16INK4a or HPVE4 status, while HPV16 positive remained at a lower risk of regression compared to women without HPV16.

An updated understanding of the natural history of cervical human papillomavirus infection—clinical implications

Recently, the International Papillomavirus Society convened a working group on cervical human papillomavirus latency, which resulted in an updated understanding of the human papillomavirus natural history. While the previous human papillomavirus natural history model considered human papillomavirus detection to be a result of human papillomavirus acquisition or possibly reinfection, and loss of human papillomavirus detection to be a result of viral clearance, the updated understanding of the human papillomavirus natural history is more nuanced. Thus, human papillomavirus detection may occur as a result of autoinoculation, deposition from a recent sex act, or as a redetection of a previously acquired infection. Similarly, loss of human papillomavirus detection likely reflects immune control rather than complete viral clearance. As it is practically impossible to identify the "true" source of a new human papillomavirus detection or determine why human papillomavirus is no longer detectable, we propose that healthcare providers and researchers use the terminology human papillomavirus detected vs human papillomavirus not detected. Moreover, we describe the updated understanding in a clinical context. Specifically, we discuss the potential implications of the updated understanding regarding clinical counseling in screening, recommendations on cervical screening, and human papillomavirus vaccination. We also suggest key phrases that healthcare providers may use when counseling women attending routine human papillomavirus-based cervical screening.

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.

Time trends in the clinical management of cervical intraepithelial neoplasia grade 2: A Danish register‐based study

AbstractIntroductionActive surveillance for cervical intraepithelial neoplasia grade 2 (CIN2) has been implemented recently in many countries, including the Nordic countries. In Denmark, the only eligibility criterion for active surveillance for CIN2 is that the woman should be of reproductive age. With this study, we aimed to evaluate clinical and socioeconomic characteristics in women with CIN2 managed by active surveillance or large loop excision of the transformation zone (LLETZ) and to evaluate temporal changes in the clinical management of CIN2.Material and MethodsWe conducted a Danish nationwide study using data from healthcare registries. All female residents aged 18–40 years, diagnosed with incident CIN2 from January 1, 1998, to February 29, 2020, were included. We collected data on age, index cytology result, year of CIN2 diagnosis, region of residence, civil status, HPV vaccination status, and socioeconomic position indicators. The variables were tabulated overall and by management group (active surveillance vs. LLETZ). To evaluate time trends, we used joinpoint regression to calculate the annual percentage change (APC), including 95% confidence intervals (CI).ResultsOf the 27 536 women with CIN2 included, 12 500 (45.4%) underwent active surveillance, and 15 036 (54.6%) underwent a LLETZ. Women undergoing active surveillance were younger, more often HPV‐vaccinated, and more likely to have a normal/low‐grade index cytology result than women undergoing LLETZ. Socioeconomic position indicators did not differ. Over time, the proportion of women undergoing active surveillance increased from 21.7% in 2004 to 73.6% in 2019 (APC 9.7, 95% CI 8.1–11.4). The proportion of women undergoing active surveillance aged <30 declined over time (APC −2.2, 95% CI −2.9 to −1.5). The proportion of women with normal/low‐grade index cytology increased slightly to 51.6% in 2019 (APC 0.8, 95% CI 0.4–1.3).ConclusionsThe use of active surveillance for CIN2 has increased over the past two decades in Denmark. Observed differences in characteristics between women undergoing active surveillance vs LLETZ are likely related to indications for clinical management.

Reproducibility of colposcopy quality indicators—A survey among members of the European Federation for Colposcopy

AbstractIntroductionColposcopy is an important part of the diagnostic work‐up of women with an abnormal cervical screening test as it is used to guide the collection of biopsies. Although quality assurance has been used in the evaluation of screening programs, not much is known about quality indicators for the diagnostics and treatment of screen‐positive women. Therefore, the European Federation for Colposcopy developed quality indicators aiming to support colposcopy practice across Europe. We performed a survey of colposcopy cases to determine if the quality indicators are understandable, relevant, and reproducible.Material and MethodsWe conducted a survey among all members of the European Federation for Colposcopy Quality and Standards Group from November 2022 to March 2023. Members were asked to collect information on a total of 17 quality indicators for 50 women who had been newly referred for colposcopy due to an abnormal screening test between January 1, 2020 to December 31, 2021. Results were reported descriptively.ResultsWe included data on 609 cases from 12 members across Europe. The majority of the quality indicators were either achieved or within reach of the agreed standard, often due to few countries with outlying data. One quality indicator had very low performance, although stratified results indicated that two countries had different clinical management of the patient type thereby skewing the results. In addition, discrepancies between the number of cases included in each quality indicator raised concerns regarding potential misunderstanding of the quality indicator and its objective.ConclusionsQuality indicators on colposcopy must be understandable to those collecting data, highlighting the importance of validating quality indicators before data collection.

Human papillomavirus genotypes and risk of persistence and progression in women undergoing active surveillance for cervical intraepithelial neoplasia grade 2

In recent years, active surveillance has been introduced as an alternative to excisional treatment in younger women with cervical intraepithelial neoplasia grade 2 because regression rates are high and excisional treatment is associated with increased risk of preterm birth. However, early identification of women at increased risk of persistence/progression is important to ensure timely treatment. Evidence is limited on biomarkers that may be used to identify women at increased risk of persistence/progression. This study aimed to describe human papillomavirus HPV type-specific persistence/progression in women undergoing active surveillance for cervical intraepithelial neoplasia grade 2. We conducted a historical cohort study of women aged 23 to 40 years diagnosed with cervical intraepithelial neoplasia grade 2 at Aarhus University Hospital from 2000 to 2010. Women were identified through the Danish Pathology Data Bank (DPDB) and were considered as undergoing active surveillance if they had a first record of a cervical biopsy within 2 years after index diagnosis and no loop electrosurgical excision procedure before this. Human papillomavirus genotyping was performed on archived tissue samples using the HPV SPF A total of 455 women were included. Two-thirds were aged ≤30 years (73.8%) at index diagnosis, and nearly half had a high-grade index cytology (48.8%). Overall, 52.2% of all women had cervical intraepithelial neoplasia grade ≥2 during follow-up; 70.5% were human papillomavirus-16-positive and 29.5% were positive for other human papillomavirus types. Human papillomavirus-16 was associated with a significantly higher risk of persistence/progression (relative risk, 1.64; 95% confidence interval, 1.37-1.95) compared with non-human papillomavirus-16. The risk of persistence/progression was highest in human papillomavirus-16-positive women with a high-grade index cytology compared with human papillomavirus-16-positive women with a low-grade cytology (relative risk, 1.29; 95% confidence interval, 1.03-1.61), whereas no differences were observed across age groups. The highest risk of persistence/progression was observed among human papillomavirus-16-positive women, particularly those with associated high-grade cytology. These findings suggest that early excisional treatment should be considered in this group of women.

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.

A study of the risks of CIN3+ detection after multiple rounds of HPV testing: Results of the 15‐year cervical cancer screening experience at Kaiser Permanente Northern California

Many countries are transitioning to HPV testing for cervical cancer screening, despite a lack of long‐term experience. To anticipate multi‐round screening performance, we analyzed 15‐year HPV testing results at Kaiser Permanente Northern California (KPNC). We evaluated HPV test result patterns among women aged 30–64 undergoing triennial HPV/cytology cotesting at KPNC during 2003–2018. We calculated incidence rates and proportion of CIN3+ diagnoses associated with the most frequent HPV testing patterns overall and stratified by age. From 2003 to 2018, a total of 1,361,581 women had a valid HPV test result, and 7,087 were diagnosed with CIN3+. Incidence rates of CIN3+ after HPV positivity were lowest when HPV detection was new and highest in women with prevalent infections (770 vs. 13,910/100,000 person‐years). Repeat test negativity reduced subsequent incidence rates of CIN3+ to extremely low levels (18/100,000 person‐years following four consecutive negative results). For mixed patterns of positivity/negativity, the recency and frequency of positive tests were associated with increased rates of CIN3+ diagnosis. Most CIN3+ cases (76%) were diagnosed in women who were positive at baseline (the first known positive HPV result); 16% were attributed to apparent newly detected infections and 3% to possible reappearing infections. These results corroborate previous findings that current HPV positivity, particularly when prevalent rather than new, is associated with the highest rates of CIN3+. In a screening program implementing HPV testing, most CIN3+ is detected at the first HPV positive test.

Clinical implications of transitioning from cytology to human papillomavirus‐based cervical cancer screening

Levels of anxiety in women aged ≥45 years undergoing diagnostic large loop excision of the transformation zone: A longitudinal study

AbstractObjectiveTo measure anxiety levels in women aged ≥45 years undergoing diagnostic large loop excision of the transformation zone (LLETZ) at the first colposcopy visit.DesignLongitudinal study.SettingThree colposcopy clinics in the Central Denmark Region.PopulationWomen aged ≥45 years undergoing diagnostic LLETZ.MethodsWomen completed the State–Trait Anxiety Inventory (STAI) and Short Form 12 (mental and physical health) questionnaires before, immediately after, and at 1 and 6 months after LLETZ.Main outcome measuresSTAI state anxiety median scores were calculated and stratified by health status, by letter with information about screening result and by LLETZ results.ResultsOf 109 eligible women, 11 were excluded, leaving 98 women for the final analyses. Response rates ranged from 84.7% to 100%. Overall, state anxiety levels were low; however, a decrease was observed from before to immediately after the LLETZ (33.4 vs 29.3, p < 0.001). The anxiety levels remained stable up to 6 months after LLETZ. Women with poor mental health were more likely to have higher anxiety levels compared with women with good mental health (before LLETZ, RR 3.77, 95% CI 2.12–6.70; 1 month after LLETZ, RR 3.37, 95% CI 1.59–7.15; 6 months after LLETZ, RR 1.93, 95%CI 1.06–3.51).ConclusionsOverall, colposcopy and diagnostic LLETZ in women aged ≥45 years were not associated with high levels of anxiety. Anxiety levels were highest before colposcopy, and the women seemed to experience immediate relief afterwards. Women with poor mental health had the highest anxiety levels throughout the study, which might call for special attention.

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.

Cervical intraepithelial neoplasia in women with transformation zone type 3: cervical biopsy versus large loop excision

AbstractObjectiveTo compare the proportion of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) in cervical biopsies with that in large loop excision of the transformation zone (LLETZ) specimens in women aged ≥45 years with transformation zone type 3 (TZ3).DesignMulticentre cross‐sectional study.SettingThree colposcopy clinics in the Central Denmark Region.PopulationWomen aged ≥45 years referred to colposcopy as a result of a positive human papillomavirus (HPV) test and/or abnormal cytology and with TZ3 at colposcopy.MethodsWomen had multiple biopsies taken and an LLETZ was performed.Main outcome measuresHistologically confirmed CIN2+ in biopsies compared with that in LLETZ specimens.ResultsOf 166 eligible women at colposcopy, 102 women with paired data from biopsies and LLETZ specimens were included for final analysis. The median age was 67.7 years (IQR 62.6–70.4 years), and most were postmenopausal (94.1%) and had undergone HPV‐based screening (81.3%). The CIN2+ detection rate was significantly higher in LLETZ specimens than in biopsies (32.4% vs 14.7%, difference 17.7%, 95% CI 6.3–29.0%), resulting in more than half of CIN2+ cases being missed in biopsies (54.5%, 95% CI 36.4–71.9%). The overall agreement between biopsies and LLETZ was 82.4% (95% CI 73.6–89.2%).ConclusionsCIN2+ detection is underestimated in women aged ≥45 years with TZ3 if detection relies on the results of biopsies alone. To reduce the risk of underdiagnosis and overtreatment, future studies should explore the use of new biomarkers for risk stratification to improve discrimination between women at increased risk of CIN2+ who need to undergo LLETZ and women who may undergo follow‐up.

Evidence of latent HPV infection in older Danish women with a previous history of cervical dysplasia

AbstractIntroductionUnderstanding whether human papillomavirus (HPV) may establish latency in the uterine cervix is important. A better understanding of HPV natural history is useful for clinical counseling of women attending screening and to accurately inform health prevention strategies such as screening and HPV vaccination. We evaluated the extent of latent HPV infections in older women with a history of abnormal cytology.Material and MethodsWe conducted a cross‐sectional study in Aarhus, Denmark, from March 2013 through April 2015. Women were enrolled if they underwent cervical amputation or total hysterectomy because of benign disease. Prior to surgery, women completed a questionnaire and a cervical smear was collected for HPV testing and morphological assessment. For evaluation of latency (i.e., no evidence of active HPV infection, but HPV detected in the tissue), we selected women with a history of abnormal cervical cytology or histology, as these women were considered at increased risk of harboring a latent infection. Cervical tissue underwent extensive HPV testing using the SPF10‐DEIA‐LipA25 assay.ResultsOf 103 women enrolled, 26 were included in this analysis. Median age was 55 years (interquartile range [IQR] 52–65), and most women were postmenopausal and parous. The median number of sexual partners over the lifetime was six (IQR 3–10), and 85% reported no recent new sexual partner. Five women (19.2%) had evidence of active infection at the time of surgery, and 19 underwent latency evaluation. Of these, a latent infection was detected in 11 (57.9%), with HPV16 being the most prevalent type (50%). Nearly 80% (n = 14) of the 18 women with a history of previous low‐grade or high‐grade cytology with no treatment had an active or latent HPV infection, with latent infections predominating. HPV was detected in two of the six women with a history of high‐grade cytology and subsequent excisional treatment, both as latent infections.ConclusionsHPV can be detected in cervical tissue specimens without any evidence of an active HPV infection, indicative of a latent, immunologically controlled infection. Modeling studies should consider including a latent state in their model when estimating the appropriate age to stop screening and when evaluating the impact of HPV vaccination.

Human papillomavirus vaccination in women undergoing excisional treatment for cervical intraepithelial neoplasia and subsequent risk of recurrence: A systematic review and meta‐analysis

AbstractIntroductionIn this review and meta‐analysis we aimed to investigate whether human papilloma virus (HPV) vaccination administered after excisional treatment of cervical intraepithelial neoplasia (CIN) is associated with a reduced risk of recurrence of CIN grade 2 or worse (CIN2+).Material and methodsWe performed a systematic literature search in three online databases through June 2021. Observational studies and randomized controlled trials (RCTs) were eligible for inclusion if the prophylactic HPV vaccine was administered after excisional treatment for histologically verified CIN. Only English language literature was included. The primary outcome measure was recurrence of CIN2+ after treatment. A meta‐analysis was performed using fixed and random‐effects models, and results were reported as pooled odds ratios (OR) with 95% confidence intervals (95% CI). Quality assessment was performed using ROB2‐tool for RCTs and ROBINS‐I for observational studies. The protocol was registered in PROSPERO (CRD42021238257).ResultsA total of 1561 studies were identified, of which nine, including 19 971 women, were included. Two studies were RCTs and seven were observational studies. Using the fixed‐effect model on the two RCTs, the OR for recurrence of CIN2+ was 0.29 (95% CI 0.16–0.53). Due to considerable heterogeneity in observational studies, the random‐effects model was used to estimate pooled OR for CIN2+ recurrence in these studies. Thus, using unadjusted data from observational studies, the OR for CIN2+ recurrence was 0.35 (95% CI 0.18–0.67), whereas when using adjusted data, the OR for CIN2+ recurrence was 0.54 (95% CI 0.21–1.35). However, quality assessment revealed a serious risk of bias for the majority of the studies included.ConclusionsHPV vaccination post‐treatment was associated with a significantly reduced risk of CIN2+ recurrence when using unadjusted estimates from observational studies and RCTs. We found no significant effect of HPV vaccination on risk of CIN2+ recurrence when using the outcome measure from observational studies with the least risk of bias. Large, well‐designed randomized placebo‐controlled trials are needed to determine whether post‐treatment HPV vaccination should be recommended to all women undergoing excisional treatment for CIN.

“I feel reassured, but there is no guarantee.” How do women with a future childbearing desire respond to active surveillance of cervical intraepithelial neoplasia grade 2? A qualitative study

AbstractIntroductionIn Denmark, women with a future childbearing desire diagnosed with cervical intraepithelial neoplasia grade 2 (CIN2) are recommended active surveillance instead of excisional treatment. However, we have limited and contradictory knowledge about how active surveillance of CIN2 may affect women emotionally. The aim of this study was to explore thoughts and emotional responses in women undergoing active surveillance of CIN2 and to explore how active surveillance may affect women’s future childbearing desire.Material and methodsThis qualitative study was conducted in the gynecological outpatient clinic, the Department of Obstetrics and Gynecology, Gødstrup Hospital, Denmark. Women of childbearing age undergoing active surveillance with colposcopy, biopsy and smear every 6 months due to CIN2 were eligible for enrollment. In‐depth semi‐structured interviews were conducted. The interviews were audiotaped and transcribed verbatim. A thematic analysis was performed using a phenomenological approach.ResultsA total of 20 women were included. All women experienced nervousness and anxiety when they were diagnosed with CIN2 initially. Their main concern was whether they had cancer. Most women carried on with their everyday lives with only minor occasional worries about CIN2, often prompted just before check‐up. However, some women were particularly nervous and found the period between check‐ups frustrating and challenging. Women did not want to postpone their plans for pregnancy because of CIN2, but experienced the worries and check‐ups associated with active surveillance as disruptive elements in their family planning. Women preparing for fertility treatment had their startup unnecessarily delayed due to active surveillance of CIN2, as clinical guidelines were inconsistent across subspecialties. Various factors influenced women’s emotional well‐being: life circumstances, information needs, and mental and physical discomfort during colposcopic examination.ConclusionsWomen felt that worries and check‐ups due to active surveillance of CIN2 were disrupting elements in their family planning, although they did not affect their every‐day life. Some women, however, were particularly anxious, demonstrating the importance of including women’s experiences and preferences in clinical counseling. The fact that fertility treatment was delayed due inconsistent guidelines across subspecialties, suggests a need for a revision of current guidelines.

High prevalence of HPV16 and high‐grade cytology in women undergoing active surveillance for cervical intraepithelial neoplasia grade 2

AbstractIntroductionMany countries have adopted active surveillance in women with cervical intraepithelial neoplasia grade 2 (CIN2), leaving the lesion untreated. However, there is a lack of consensus on the eligibility criteria for active surveillance across countries, with some abstaining from active surveillance in women with human papilloma virus 16 (HPV16) or a high‐grade cytology. Here, we aimed to describe the distribution of HPV genotypes, age, and cytology in women undergoing active surveillance for CIN2.Material and methodsWe conducted a single‐center cross‐sectional study on women aged 23–40 undergoing active surveillance for CIN2 during 2000–2010. Women were identified through the Danish Pathology Data Bank (DPDB) at Aarhus University Hospital, Denmark. We collected information on basic characteristics and results of histopathological examinations via DPDB. Women were deemed eligible for inclusion if they had a subsequent biopsy after index CIN2, and had no prior record of CIN2+, hysterectomy, or cone biopsy. Archived biopsies underwent HPV genotyping using the HPV SPF10‐ DEIA‐LiPA25 system, and the diagnosis was re‐evaluated by three expert pathologists. We used the Chi squared‐test (p‐value) for comparison across groups.ResultsWe identified 3623 women with CIN2 of whom 455 (12.6%) were included. Most women were 30 years or younger (73.8%), and half (48.8%) had a high‐grade index cytology. The prevalence of any high‐risk HPV was 87.0%, with HPV16 being the most prevalent genotype (35.6%). The prevalence of HPV16 was significantly higher in women aged 30 or younger (39.3%) compared to women older than 30 years (25.2%) (p = 0.006). Upon expert review, 261 (57.4%) had CIN2 confirmed, whereas 56 (12.3%) were upgraded to CIN3 and 121 (26.6%) were downgraded to CIN1/normal. While the HPV16 prevalence was similar between community and expert confirmed CIN2, the prevalence of HPV16 was significantly higher in women with expert CIN3 compared to women with expert CIN1/normal (64.3% vs. 19.0%, p = 0.001).ConclusionsThe high prevalence of HPV16 and high‐grade cytology imply that these women may be perceived as a high‐risk population and non‐eligible for active surveillance in countries outside Denmark. Future studies should investigate the importance of HPV, age, cytology, and expert review on risk of progression to help refine criteria for active surveillance.

Value of a catch-up HPV test in women aged 65 and above: A Danish population-based nonrandomized intervention study

Background High-risk human papillomavirus (HPV) test is replacing cytology as the primary cervical cancer screening test due to superior sensitivity, but in most countries women ≥65 years have never had an HPV test despite they account for around 50% of cervical cancer deaths. We explored the effect of a catch-up HPV test among 65- to 69-year-old women without previous record of HPV-based screening. Methods and findings This population-based nonrandomized intervention study (quasi-experimental design) included Danish women aged 65 to 69 with no record of cervical cancer screening in the last ≥5.5 years and no HPV-exit test at age 60 to 64 at the time of study inclusion. Eligible women residing in the Central Denmark Region were invited for HPV screening either by attending clinician-based sampling or requesting a vaginal self-sampling kit (intervention group, n = 11,192). Women residing in the remaining four Danish regions received standard care which was the opportunity to have a cervical cytology collected for whatever reason (reference group, n = 33,387). Main outcome measures were detection of cervical intraepithelial neoplasia (CIN) grade 2 or worse (CIN2+) per 1,000 women eligible for the screening offer and the benefit–harm ratio of the intervention and standard practice measured as the number of colposcopies needed to detect one CIN2+ case. The minimum follow-up time was 13 months for all tested women (range: 13 to 25 months). In the intervention group, 6,965 (62.2%) were screened within 12 months from the date of study inclusion and 743 (2.2%) women had a cervical cytology collected in the reference group. The CIN2+ detection was significantly higher in the intervention group (3.9, 95% confidence interval (CI): [2.9, 5.3]; p < 0.001; n = 44/11,192) as compared to the reference group (0.3, 95% CI: [0.2, 0.6]; n = 11/33,387). For the benefit–harm ratio, 11.6 (95% CI: [8.5, 15.8]; p = 0.69; n = 511/44) colposcopies were performed to detect one CIN2+ in the intervention group as compared to 10.1 (95% CI: [5.4, 18.8]; n = 111/11) colposcopies in the reference group. The study design entails a risk of confounding due to the lack of randomization. Conclusions The higher CIN2+ detection per 1,000 eligible women in the intervention group supports that a catch-up HPV test could potentially improve cervical cancer prevention in older women. This study informs the current scientific debate as to whether women aged 65 and above should be offered a catch-up HPV test if they never had an HPV test. Trial registration ClinicalTrials.gov NCT04114968.

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.