Dina O. Eriksen

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.

Active surveillance of cervical intraepithelial neoplasia grade 2 is not associated with an increased risk of noncervical anogenital human papillomavirus–related cancer and precancer: a population-based cohort study

In recent years, many countries have implemented active surveillance (ie, leaving the lesion untreated) as an option in younger women with cervical intraepithelial neoplasia grade 2 instead of excisional treatment. This is mainly due to the high regression rates of cervical intraepithelial neoplasia grade 2 and the observed increased risk associated with excisional treatment. Women with a previous history of excisional treatment for cervical precancer are at an increased risk of subsequent anogenital cancer and precancer. For a full assessment of the benefits and harms of active surveillance for cervical intraepithelial neoplasia grade 2, we investigated the risk of noncervical anogenital cancers and precancers in women undergoing active surveillance. We aimed to investigate whether women undergoing active surveillance for cervical intraepithelial neoplasia grade 2 are at an increased risk of vulva, vaginal, or anal cancer and precancer compared to women treated with loop electrosurgical excision procedure. We conducted a nationwide population-based cohort study in Denmark. We included all female residents diagnosed with incident cervical intraepithelial neoplasia grade 2 at age 18 to 40 years from 1998 to 2020. The primary outcome was vulva, vaginal, or anal cancer or precancer. We stratified by age at cervical intraepithelial neoplasia grade 2 diagnosis (<30 years and ≥30 years), calendar year (1998-2012 and 2013-2020), and index cytology (nonhigh-grade and high-grade). As a secondary outcome, we considered low-grade lesions of the vulva, vagina, and anus. We used Cox regression to estimate hazard ratios of the outcomes with loop electrosurgical excision procedure as the reference group. We used inverse probability treatment weighting to calculate adjusted hazard ratios, considering age, calendar year, and index cytology as confounders. Overall, 27,505 women with cervical intraepithelial neoplasia grade 2 were included; 12,507 (45.5%) underwent active surveillance and 14,998 (54.5%) underwent loop electrosurgical excision procedure. A total of 162 women had a subsequent diagnosis of vulva, vaginal, or anal cancer or precancer. The cumulative risk after 10 years was 0.5% (95% confidence interval, 0.3-0.6). We found no difference in risk between women undergoing active surveillance and those having a loop electrosurgical excision procedure (adjusted hazard ratio, 1.00 [95% confidence interval, 0.71-1.40]). Similar findings were observed when stratifying by age, year of diagnosis, and index cytology. We found that the risk of low-grade lesions of the vulva, vagina, and anus was lower in women undergoing active surveillance than in women treated with loop electrosurgical excision procedure (adjusted hazard ratio, 0.75 [0.62-0.91]). Active surveillance for cervical intraepithelial neoplasia grade 2 is not associated with an increased risk of noncervical anogenital cancer and precancer compared to loop electrosurgical excision procedure. This finding contributes to the assessment of the benefits and harms of active surveillance and is useful for clinical counseling of women diagnosed with cervical intraepithelial neoplasia grade 2.

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 &lt;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.

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.