Rikke Kamp Damgaard

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.

Performance of HPV E4 and p16 INK4a biomarkers in predicting regression of cervical intraepithelial neoplasia grade 2 (CIN2): protocol for a historical cohort study

Introduction Cervical intraepithelial neoplasia grade 2 (CIN2) represents a spectrum of lesions with variable progression and regression. Pathological diagnosis of CIN2 is subjective and poorly reproducible. Accurate diagnosis and identification of different patterns of CIN2 related to outcome are essential to reduce the risks of overtreatment or undertreatment. It is important to explore novel methods for risk stratification of CIN2 to enable targeted treatment of women at high risk of progression or persistent disease and follow-up of women at low risk. The combination of the novel biomarker human papillomavirus (HPV) E4 with p16 INK4a targets steps in the transition from a productive oncogenic HPV infection (CIN1) to a transformed lesion (CIN3) within CIN2. Previous cross-sectional studies suggest that HPV E4 combined with p16 INK4a may be valuable for risk assessment of CIN2. However, data on HPV E4/p16 INK4a as a predictor for CIN2 regression is lacking. Methods and analysis We will conduct a historical cohort study including 500 women aged 23–40 years with a first CIN2 diagnosis in Aarhus, Denmark during 2000–2010. Women will be eligible if they have undergone active surveillance and have no previous record of hysterectomy, cone biopsy, and CIN2 or worse. Women will be randomly selected through the Danish Pathology Databank. Tissue samples from women included will be sectioned for p16 INK4a and HPV E4 immunohistochemical staining in addition to conventional hematoxylin and eosin (H&E) staining. A positive result will be defined as HPV E4 positive. Through the Danish Pathology Databank, we will collect results on all subsequent cervical biopsies. Regression will be used as the primary outcome. Ethics and dissemination The study has been approved by the Ethical Committee in Central Denmark Region (1-10-72-60-20) and registered at the Faculty of Health, Aarhus University. Results will be published in a peer-reviewed journal and presented at scientific meetings. Trial registration number NCT05049252 .

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.