Cervical intraepithelial neoplasia grade 1 and long-term risk of progression and treatment

Ingrid Baasland; Tone Bjørge; Birgit Engesæter; Ameli Tropé; Signe Opdahl

doi:10.1371/journal.pone.0320739

Abstract

Background

Cervical intraepithelial neoplasia grade 1 (CIN1) is often managed by active surveillance, as the risk of progression to high grade lesions is reported to be low, but long-term data is sparse. To inform management of CIN1, we estimated risk of progression and occurrence of treatment in women attending a cervical cancer screening program.

Methods

We used nationwide, registry data on all women aged 25–69 years attending the Norwegian Cervical Cancer Screening Program in 2002–2019. The eligible source population was women with at least one cytology registration (n = 1,771,876). Women with a histologically confirmed, first CIN1 diagnosis were included (n = 26,130) and followed for detection of CIN2+, defined as histologically confirmed CIN2, CIN3, adenocarcinoma in situ (AIS), or cervical cancer. CIN3+ was defined as CIN3, AIS, or cervical cancer. Treatment included both excision and ablation.

Results

Overall, the cumulative incidence of CIN2+ increased to 9.5% (95% confidence interval (CI), 8.8 to 9.5) during the first year and to 19.0% (95% CI, 18.4–19.5) during the first five years. For women with high-grade cytology, 5-year cumulative incidence reached 26.0% (95% CI, 25.0–27.0), whereas for women with normal or low-grade cytology, but HPV16 and/or HPV18 positive status, the corresponding estimate was 25.0% (95% CI, 23.3–26.8). Other high-risk HPV genotypes and HPV negative status were associated with lower risks (5-year cumulative incidence 15.5% (95% CI, 14.5–16.6) and 8.2% (95% CI, 7.1–9.5), respectively). Detection of CIN3+ was substantial (cumulative incidence 5.7% (95% CI, 5.4–6.0) and 12.7% (95% CI, 12.2–13.1) after 1 and 5 years, respectively), and overall, cumulative incidence of treatment was 15.2% (95% CI, 14.7–15.7) after 5 years, following similar patterns as observed for CIN2+.

Conclusions

A differentiation of follow-up guidelines by index cytology and HPV16/18 status for women diagnosed with CIN1, might be warranted.

Citation: Baasland I, Bjørge T, Engesæter B, Tropé A, Opdahl S (2025) Cervical intraepithelial neoplasia grade 1 and long-term risk of progression and treatment. PLoS ONE 20(4): e0320739. https://doi.org/10.1371/journal.pone.0320739

Editor: Ruofei Du, University of Arkansas for Medical Sciences, UNITED STATES OF AMERICA

Received: December 8, 2024; Accepted: February 24, 2025; Published: April 23, 2025

Copyright: © 2025 Baasland et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: Data were used under license for the current study and are not publicly available in accordance with Norwegian data protection and health research laws. Data may be requested from the data custodian (the Norwegian Institute of Public Health) following approval by the Regional Committee for Medical and Health Research Ethics, as well as the data custodian. The contact details (e-mail address) for the third party where data requests can be made: livmorhals@kreftregisteret.no.

Funding: IB got funds from The Norwegian Cancer Society. Grant number: 182675. https://kreftforeningen.no/The funder (The Norwegian Cancer Society) did not play any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Cervical carcinogenesis is considered a pathological continuum initiated by persistent human papillomavirus (HPV) infection, followed by the development of cervical intraepithelial neoplasia (CIN) grade 1, 2 and 3 and finally invasive cervical cancer [1]. The persistence of carcinogenic HPV genotypes predicts the risk of cervical cancer development, where the highest risk is associated with HPV16 infections [2,3].

There are different recommendations on control intervals and how to manage CIN1 lesions in national screening programs in high-income countries [4–7]. CIN1 reflects an ongoing HPV-infection [8] and is often managed conservatively by active surveillance by repeated cytology and HPV-testing, due to the high regression rate and the low progression rate to more severe premalignant lesions or cancer [9–11]. Excision of CIN1 lesions is, however, considered acceptable in some countries, but increases the risk of preterm birth [12–14]. Considering the low risk of progression of CIN1, excision may to some extent be over-treatment. Furthermore, frequent controls represent a burden on the women and the health care system.

Most previous studies on outcomes in women with CIN1 include only a couple of hundred participants, and very few studies have observation time beyond five years [11]. The evidence-base for guidelines on management of CIN1 in a population setting is therefore uncertain.

In this nationwide, population-based cohort study, we estimated the risk of progression and treatment in women with histologically confirmed CIN1 lesions in the Norwegian Cervical Cancer Screening Program (CervicalScreen Norway).

Methods

Data sources

Data were collected from national registries and linked at an individual level using the unique 11-digit national identity number assigned to all residents in Norway. Authors did not have access to information that could identify individual participants during or after data collection. The Cancer Registry of Norway has registered information on all incident cancer diagnoses in Norway since it was established in 1952 [15]. The nationwide CervicalScreen Norway was established in 1995 and is organized by the Cancer Registry of Norway, sending reminders to women aged 25–69 years to attend cytology-based screening every 3^rd year [16]. HPV-testing for 14 high-risk HPV-types in samples with low-grade cytology started in 2005, and test results are recorded in the HPV Registry (2005). Since 2015, there has been a gradual shift towards HPV based screening every 5^th year for women aged 25–69 years. CervicalScreen Norway receives mandatory reports on cervical samples from all pathology and microbiology laboratories, registered in the Cytology Registry (1991) and the Histology Registry (2002), and on treatment procedures from all gynecologists, registered in the CIN Registry (1997). The incidence database at the Cancer Registry of Norway collects data on invasive tumors of all types and is considered almost complete [17]. Data at the Cancer Registry of Norway are linked regularly to data from the National Population Registry and the Norwegian Cause of Death Registry [18], adding data on residency, emigration and death.

The guidelines in CervicalScreen Norway for referral to colposcopy and biopsy has changed over time. All women with high-grade cytology (atypical squamous cells, cannot exclude a high-grade lesion (ASC-H), high-grade intraepithelial lesion (HSIL), atypical glandular cells of uncertain significance (AGUS) and adenocarcinoma in situ (AIS)) have been referred. Women with repeated low-grade cytology over 6 months (low-grade intraepithelial lesion (LSIL), atypical squamous cells of uncertain significance (ASC-US)), or repeated HPV-positivity over 6 months with cytology negative for intraepithelial lesion or malignancy (NILM), have been referred [19]. If the biopsy result is negative histology or CIN1, women are usually recommended follow-up surveillance with cytology and HPV-testing within 6–12 months. If progression is confirmed, excision is normally recommended. Upon regression (HPV negative/NILM), women return to regular screening intervals.

Study population and variables

The study population was drawn from all women registered in CervicalScreen Norway with at least one cervical screening test from January 1^st, 2002 until December 31^st, 2019 (Fig 1), when data from the Histology Registry were available. Among these, 38,821 women were registered with CIN1 in the Histology Registry. In total, 12,691 women with a record of CIN1 (32.7%) were excluded, mainly due to prevalent unspecified CIN or other genital dysplasia before their first CIN1 lesion. Only 495 women with incident CIN1 (1.3%) were excluded due to missing data on cytology history and county of residence, and 153 were excluded due to follow-up time shorter than four months. Thus, the main analyses were based on 26,130 women with histologically confirmed, incident CIN1. A national school-based HPV vaccination program for girls aged 12 years was implemented in 2009, and the first vaccinated birth cohort entered the cervical screening in 2022. Hence, the vast majority of women in this study were unvaccinated.

Download:

Fig 1. Selection of the study population.

CIN – Cervical intraepithelial neoplasia.

https://doi.org/10.1371/journal.pone.0320739.g001

The primary outcome was histologically verified CIN2, CIN3, AIS, or invasive cervical carcinoma (hereafter referred to as ‘CIN2+’), diagnosed or occurring at least 4 months after the first CIN1 diagnosis. The 4 months’ cutoff was set to account for the registration practice in the Cancer Registry in Norway, where all reports within 4 months are considered as part of the same event. A report of CIN1 which is followed by a report of CIN2+ within 4 months, will therefore be considered as CIN2+. CIN2+ was chosen as the primary outcome, because CIN2 is the threshold for treatment in most cases. However, CIN3 represents more unambiguously premalignant lesions and hence, we included CIN3, AIS, or invasive cervical carcinoma (hereafter referred to as ‘CIN3+’) as a secondary outcome. Another secondary outcome was treatment, defined as either excision of a part of the cervix, with or without detection of CIN2+ on subsequent histological examination, or ablative treatment, with no subsequent histology.

Age at diagnosis was categorized as <30, 30–49 and ≥50 years. Women’s cytology history was obtained from the Cytology Registry, reported according to the 2001 Bethesda System [20]. Inadequate tests were excluded from further analyses. We categorized cytology results as ‘normal or low-grade’ (NILM, NILM with persistent high-risk HPV (hrHPV) infection, LSIL and ASC-US) versus ‘high-grade’ (ASC-H, HSIL, AGUS and AIS), allowing up to 4 months delay in reporting cytology results after CIN1 diagnosis. We restricted cytology results before CIN1 diagnosis (index cytology) to tests performed less than 3.5 years before diagnosis of CIN1. If more than one cytology result was available, the most abnormal result was used. We used HPV test results at or before the diagnosis of CIN1, including information on reported genotypes and analysis platform for each analysis, to further categorize samples without high-grade cytology as ‘HPV-’ (no hrHPV detected), ‘HPV16/18+’ (HPV16 and/or HPV18 positive) or ‘HPV other+’ (hrHPV positive, but HPV16 and HPV18 negative). The latter two categories were restricted to results from HPV platforms capable of separating HPV16 and HPV18 from other high-risk HPV genotypes, as outlined in S1 Table.

Statistical analyses

Women were followed from 4 months after their first CIN1 diagnosis until the date of CIN2+, cancers other than cervical cancer, death from other causes, emigration, or end of follow-up (December 31^st, 2019). The 4 months’ delay was introduced to avoid immortal follow-up time since registration practice made a diagnosis of CIN2+ within 4 months impossible. For women in the screening age range, more than 3.5 years without samples was considered as program drop-out, and for these women follow-up ended at 3.5 years after the last cytology or histology registered (S1 Fig).

We estimated the cumulative incidence of progression or treatment using a non-parametric competing risk approach with time-dependent weights, where death from causes other than cervical cancer (n = 337), cancers other than cervical cancer (n = 525) and drop-outs (n = 5353) were treated as separate competing events [21]. Cumulative incidence curves were estimated across the full duration of follow-up, overall and according to cytology and HPV status, with tabulation of estimates at 3 and 5 years. To account for the impact of age at diagnosis and county of residence, we used Cox proportional hazards regression to estimate hazard ratios (HRs) of progression or treatment, with censoring at diagnosis of cancers other than cervical cancer, death from causes other than cervical cancer, emigration (n = 239), drop-out or end of follow-up, and adjustment for age (if applicable) and county of residence. Because treatment generally does not eliminate the risk of progression, treatment was not considered a competing risk or reason for censoring in the analyses. The exception was hysterectomy, which was a censoring event when not accompanied by a CIN2+ diagnosis (n = 65). The proportional hazards assumption was checked by visual inspection of log-minus-log plots, and no clear violations were found. Precision was estimated as 95% confidence intervals (CIs).

To investigate the influence of screening program compliance, we repeated analyses of progression to CIN2+ with censoring at 1 year for women with no cytology control registered, in addition to the previously described censoring at 3.5 years. We also repeated analyses of progression to cervical cancer without taking program drop-out into account (i.e., follow-up to cervical cancer, other cancer, death from causes other than cervical cancer, emigration, or end of follow-up). The rationale for this was that drop-out could increase the risk of cancer, which would be captured in the incidence database regardless of program compliance.

Ethics approval and data availability

The study was approved by the Regional Committee for Medical and Health Research Ethics, South-East Region, Norway (2017/1910). Data were accessed for research purpose 01/09/2020. The need for consent was waived by the ethics committee. The study was performed in accordance with the Declaration of Helsinki.

Data were used under license for the current study and are not publicly available in accordance with Norwegian data protection and health research laws. Data may be requested from the data custodian (the Norwegian Institute of Public Health) following approval by the Regional Committee for Medical and Health Research Ethics, as well as the data custodian.

Results

Descriptive statistics

The median age at CIN1 diagnosis was 33 years (interquartile range [IQR] 27–45) and median follow-up was 3.6 years (IQR 1.8–6.2). For women diagnosed with CIN2+ during follow-up, median time to detected progression was 1.3 years (IQR 0.8–2.4). Characteristics of the included women are described in Table 1. Overall, 32.6% had a high-grade cytology preceding histological CIN1, with proportions increasing slightly with age. When CIN1 was preceded by normal or low-grade cytology, HPV was present in 75.1%, whereas 12.4% were negative and 12.5% were not examined for HPV. Prevalence of HPV16/18 decreased with increasing age, whereas other high-risk genotypes increased concordantly.

Download:

Table 1. Cohort characteristics by cytology in 26,130 women diagnosed with index CIN1 in CervicalScreen Norway, 2002–2019.

https://doi.org/10.1371/journal.pone.0320739.t001

Progression of histologically confirmed CIN1

Among 26,130 included women with CIN1, 4,491 were diagnosed with CIN2+ during follow-up. Overall, the cumulative incidence of CIN2+ increased mainly during the first years, reaching 9.1% within 1 year and 19.0% within 5 years and thereafter levelling off (Table 2 and S2 Fig). CIN2+ cumulative incidence curves according to cytology history showed similar patterns, with the highest increase in risk the first years after diagnosis, before levelling off after around 5 years (Fig 2, Panel A). Women with prior high-grade cytology had substantially higher incidence of CIN2+ than women with normal or low-grade cytology (26.0% vs 15.4% within 5 years) (Table 3). Further stratification of the latter group by HPV genotype indicated that in HPV16/18+ women, risk approached that seen for high-grade cytology (25.0%), whereas HPV other+ and HPV- status was associated with lower risks (15.5% and 8.2%, respectively). Progression was detected twice as often among younger women (21.3% vs 10.9% within 5 years for women <30 and ≥50 years, respectively). Results from Cox regression across the entire follow-up period were consistent with the cumulative incidence patterns, with little influence of adjustment for age and county (Table 3). Consistent with patterns of cumulative incidence, hazard rates of CIN2+ were high during the first year of follow-up, then declined before levelling off around 5 years after diagnosis of CIN1 (S3 Fig). Sensitivity analyses with censoring of women who missed the initial cytology control at 1 year, showed slightly lower cumulative incidence estimates, but associations with prognostic factors for progression (age, cytology history and HPV status) were similar to the main analyses (S2 Table and S4 Fig).

Download:

Table 2. Cumulative incidence of progression and treatment following an index CIN1 diagnosis in CervicalScreen Norway 2002-2019, by time since diagnosis.

https://doi.org/10.1371/journal.pone.0320739.t002

Download:

Table 3. Cumulative incidence and hazard ratios of progression and treatment following an index CIN1 diagnosis in CervicalScreen Norway 2002-2019, by patient and lesion characteristics.

https://doi.org/10.1371/journal.pone.0320739.t003

Download:

Fig 2. Cumulative incidence of progression to CIN2+ (Panel A, left column), progression to CIN3+ (Panel B, mid column), and treatment (Panel C, right column) following an index CIN1 diagnosis in CervicalScreen Norway 2002-2019, according to index cytology (top figure in each panel) and combinations of index cytology and HPV genotype status (bottom figure in each panel) preceding the index CIN1 diagnosis.

Abbreviations: CIN – cervical intraepithelial neoplasia, HPV – human papilloma virus. CIN2+ includes CIN2, CIN3, adenocarcinoma in situ (AIS) and cervical cancer. CIN3+ includes CIN3, AIS and cervical cancer. Treatment includes excision and ablation. HPV 16/18+ - HPV test positive for genotypes 16 and/or 18. HPV other HR+ - HPV test positive for HPV high risk genotypes other than 16 and 18 (i.e., HPV 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68). HPV- - HPV test negative. Shaded areas indicate 95% confidence intervals.

https://doi.org/10.1371/journal.pone.0320739.g002

There were 3,007 cases of progression to CIN3+, with an overall cumulative incidence of 12.7% within 5 years (Table 2). Patterns according to age, cytology history and HPV status were similar to those seen for CIN2+ (Table 3, Fig 2, Panel B and S3 Fig). Among women with CIN1 who attended CervicalScreen Norway with ≤3.5 years between samples, 54 cervical cancers were detected across the full study period, corresponding to a cumulative incidence of 0.30% (95% CI 0.22–0.40)(S2 Fig). These were diagnosed after a median follow-up of 1.7 years (IQR 1.0–4.2), the majority after high-grade index cytology (37 women, 68.5%). Altogether, 27 cases were diagnosed with stage I disease (50%), 7 cases with stage II or III (13%), and 20 women with unknown stage (37%).

Treatment

Altogether, 4,031 women were treated, where 522 women had their first ever CIN1 diagnosis in cone specimen and were excluded from treatment analyses, leaving 3,509 women treated during follow-up. The overall cumulative incidence of treatment was 15.2% after 5 years (Table 2 and S2 Fig), i.e., lower than the incidence of CIN2+, but higher than CIN3+. Cumulative incidence curves for treatment showed similar patterns as the progression curves, with the highest increase seen during the first 3–5 years. A substantially higher proportion of women with high-grade cytology or HPV16/18+ with normal or low-grade cytology was treated, compared to women with normal or low-grade cytology HPV- or HPV other+ (Table 3 and Fig 2, Panel C). Women aged 30–49 years at CIN1 diagnosis had a higher occurrence of treatment than younger and older women (Table 3). For women <30 years at detection of CIN1, treatment cumulative incidence (12.2 and 14.8% at 3 and 5 years, respectively) was somewhat lower than the incidence of CIN2+, but comparable to the incidence of CIN3+. In contrast, among the oldest women, cumulative incidence of treatment (10.5%) was twice that of CIN3+ (5.4%). Adjustment for age and county did not change the associations between cytology and HPV status and occurrence of treatment (Table 3), and hazard rates followed similar patterns as for progression (S3 Fig).

Discussion

To our knowledge, our study is the largest nationwide population-based, long-term cohort study, providing estimates of risk of progression (CIN2+) and treatment following histologically confirmed CIN1 with a follow-up time up to 18 years. In the context of CervicalScreenNorway, the overall risk of detecting CIN2+ among women with CIN1 was close to 20% within 5 years. Younger age, high-grade index cytology and HPV16/HPV18 positivity were associated with substantially higher risk of progression to CIN2+ and CIN3+ compared to NILM and low-grade cytology positive hrHPV types other than HPV16/18.

In our study, one third of index cytology samples were high-grade, in contrast to most studies on CIN1 where almost all index cytology samples were low-grade [7,11], with a reported lower risk of progression. A comparably high progression risk of 24% has been demonstrated in previous smaller studies, with a high proportion of high-grade index cytology [22,23]. A recent systematic review of natural history of CIN, including 63 studies with a total of 8,767 participants, reported considerable heterogeneity between studies according to sample size, follow-up, index cytology and histologically confirmed CIN1 diagnosis [11]. Most studies had from 6 to 54 months follow-up. In total, 11% of CIN1 progressed to CIN2+, 2% to CIN3+ and 0.03% to cervical cancer [11]. The differences in risk of progression between the studies may be due to differences in follow-up time and considerably different proportion in high-grade index cytology. Delayed or missed detection of prevalent CIN2+ might result from sampling error and interobserver variation in colposcopy [24] and pathology examination [25]. According to national Norwegian guidelines, biopsies should be obtained from any lesion detected at colposcopy, and from all quadrants if the colposcopy is normal according to national guidelines [5].

Consensus guidelines from American Society for Colposcopy and Cervical pathology in 2019 [6] are based on risk-estimates from 48,004 women with CIN1 registered at Kaiser Permanente Northern California (KPNC). The 5-year risk of CIN3+ in women with HPV positive NILM or low-grade cytology versus high-grade cytology was 2.3–2.8% and 3.8–6.5%, respectively, much lower than our estimates and may reflect higher sensitivity for diagnosing abnormalities, for referral to colposcopy and treatment in the US, but also a study population of relatively healthy women at low risk [7]. The authors commented that risk-estimates after CIN1 with high-grade index cytology were less reliable, as they were rare, with an inherently high risk of occult disease that should be managed carefully.

An Italian study including 434 women with CIN1 with adequate colposcopy and mainly low-grade index cytology, detected CIN2–3 in 7.4%, CIN3 in 0.9% and no cancers during 5 years of follow-up. The authors concluded that HPV status and index cytology should be included in the assessment together with colposcopic impression in women with CIN1 [26].

Although HPV16 confers the highest risk of developing CIN and cervical cancer, HPV types such as HPV18 and HPV33 also increases risk of progression compared to other hrHPV types [3]. A recent study from KPNC demonstrated that HPV16 and 18 positivity at screening increased the immediate and 5-years risk of CIN3+ substantially, leading to recommendations of referral for colposcopy even in women with NILM [27]. This is comparable to our results as HPV16/18 positivity conferred a doubled risk of progression to CIN2+ compared to HPV other+. Based on our results, yearly observation of CIN1 lesions in women with low-grade cytology negative for HPV16 and/or HPV18 seems acceptable, and justifiable even for women with high-grade index cytology or HPV16 and/or HPV18 positivity, although a shorter interval might be appropriate for the latter group.

Older women in our study had a lower risk of progression, despite similar distributions of index cytology results in younger and elderly women. Contrary to our findings, progression to CIN2+ and CIN3+ in HPV-positive women is reported to increase with age [28,29]. For newly detected infections, progression was not higher in older compared to younger women, but persistent infections were more frequent among the oldest [28]. Persistent HPV infections, particularly HPV16, are associated with progression [3]. In our cohort, a substantially lower proportion of older women were HPV16/18 positive, which might explain their lower progression rate compared to younger women. Also, older women would have had more screening rounds before the start of the study period, and hence, a first diagnosis of CIN1 might more often represent a recently developed lesion.

The occurrence of treatment corresponded well with estimates of progression, and hence provided no support for large extents of non-indicated treatment. To validate treatment registration in the CIN Registry, we obtained aggregated data on ablations and surgical treatment during 2008–2021 from the Norwegian Patient Registry, where diagnoses and procedures from all activity in specialist health care nationally are recorded since 2008 [30]. These data indicated under-reporting of ablation in the CIN Registry, where only 24 of 3,509 registered treatments between 2002 and 2019 were ablations, as opposed to 153 (5.9%) of 2,610 treatments registered in the Norwegian Patient Registry (S3 Table).

Treatment of CIN2 will influence the risk of developing CIN3+. Because treatment threshold is at CIN2+, our analyses of risk of progression to CIN3+ must be interpreted considering clinical practice where CIN2 lesions are removed. We believe our analyses of CIN3+ should be seen as an indication of how many of the progressing CIN1 lesions that have reached CIN3+ before being diagnosed, rather than the risk of progression to CIN3+ in a hypothetical scenario where treatment indication is CIN3+.

Finally, we expect that HPV vaccination has not substantially influenced progression and treatment rates of CIN1 in this study. Nationwide school-based HPV vaccination was implemented for 12-year-old girls in Norway in 2009. The oldest vaccinated birth cohort was therefore just 22 years at the end of the study period. Only very few women in earlier birth cohorts would have received the vaccine at their own initiative. Moreover, herd immunity in the vaccinated birth cohorts seems to provide limited protection in older birth cohorts [31]. With HPV vaccinated birth cohorts entering the screening program, the risk of progression from CIN1 might change. Although a wide range of HPV types can lead to CIN1, the HPV types covered by the vaccines show the highest rates of progression to higher-grade lesions such as CIN2, CIN3 and, ultimately, to cervical cancer [32]. HPV vaccination prevents infection with these HPV types [33–36]. As a result, CIN1 lesions detected in a vaccinated population may be expected to more often be caused by less oncogenic HPV types. Further research is needed to determine the optimal management of CIN1 in HPV-vaccinated populations and ensure that clinical recommendations and public health guidelines remain evidence-based.

Strengths and limitations

The strengths of our study include the population-based design and the large number of women in a wide age range, in the context of a national screening program. The long-follow-up (up to 18 years) allowed estimation of both short and long-term risk of progression. Mandatory reporting ensured nearly complete data on cytology and histology results. With linkage of individual level data, loss-to follow-up was limited to screening drop-out and emigration. Moreover, all baseline and follow-up diagnoses were confirmed through histopathology, which increases validity.

Importantly, our study does not describe the natural history of CIN1, nor the risk associated with persistent HPV-infection or persistent CIN1. Women with CIN1 not attending the screening program at least once every 3.5 years after CIN1 diagnosis, were censored, and our results apply to women reasonably compliant with screening guidelines. Screening-attendance in Norway during the study period was suboptimal at 69–76% [18], and under-screened women have an increased risk of CIN2+ and cervical cancer [37,38]. Hence, the steep increase in CIN2+ during the first two years might partly result from long-standing CIN1 with shorter time from detection to progression, or from prevalent high-grade disease missed in the first examination. Despite exclusion of all registered prevalent CIN cases, registration was likely incomplete before the Histology Registry started in 2002, resulting in some prevalent cases appearing as incident cases. Finally, we had no information on factors such as socioeconomic status, lifestyle, and immunosuppression [39–41], which might have been used for additional risk stratification.

Conclusions

This large, population-based cohort study contributes evidence on the risk of progression of CIN1 in the context of a national screening program. The overall risk of progression reached 20% after 5 years, but differed considerably according to age, HPV type and index cytology. Our results should be used to inform women with CIN1 about risk of progression, and tailored follow-up for women with CIN1 based on HPV genotyping and index cytology results may be warranted.

Supporting information

S1 Table. Overview of the HPV tests applied during the study period 2002–2019.

https://doi.org/10.1371/journal.pone.0320739.s001

(DOCX)

S2 Table. Cumulative incidence and hazard ratios of progression to CIN2+ following an index CIN1 diagnosis in CervicalScreen Norway 2002–2019, according to patient and lesion characteristics.

Sensitivity analyses with censoring of women with no cytology control within 1 year.

https://doi.org/10.1371/journal.pone.0320739.s002

(DOCX)

S3 Table. Treatment modalities performed in Norwegian public hospitals and outpatient clinics in women registered with an index CIN1 in the time-period 2008–2021, according to the Norwegian Patient Registry.

https://doi.org/10.1371/journal.pone.0320739.s003

(DOCX)

S1 Fig. Timeline and analytical decisions during follow-up.

https://doi.org/10.1371/journal.pone.0320739.s004

(TIFF)

S2 Fig. Cumulative incidence of progression and treatment following an index CIN1 diagnosis in CervicalScreen Norway 2002–2019.

https://doi.org/10.1371/journal.pone.0320739.s005

(TIFF)

S3 Fig. Hazard rates of progression and treatment following an index CIN1 diagnosis in CervicalScreen Norway 2002–2019, according to index cytology and HPV genotypes.

https://doi.org/10.1371/journal.pone.0320739.s006

(TIF)

S4 Fig. Cumulative incidence and Hazard rates of progression following an index CIN1 diagnosis in CervicalScreen Norway 2002–2019, according to index cytology and HPV genotypes.

Sensitivity analyses with censoring of women with no cytology control within 1 year.

https://doi.org/10.1371/journal.pone.0320739.s007

(TIF)

Acknowledgments

The authors thank Gry Baadstrand Skare at CervicalScreen Norway for her contribution to the data management required for this study.

Information from the Norwegian Patient Registry has been used in this publication. The interpretation and reporting of these data are the sole responsibility of the authors, and no endorsement by the Norwegian Patient Registry is intended nor should be inferred.

References

1. Woodman CBJ, Collins SI, Young LS. The natural history of cervical HPV infection: unresolved issues. Nat Rev Cancer. 2007;7(1):11–22. pmid:17186016
- View Article
- PubMed/NCBI
- Google Scholar
2. Kjær SK, Frederiksen K, Munk C, Iftner T. Long-term absolute risk of cervical intraepithelial neoplasia grade 3 or worse following human papillomavirus infection: role of persistence. J Natl Cancer Inst. 2010;102(19):1478–88. pmid:20841605
- View Article
- PubMed/NCBI
- Google Scholar
3. Sand FL, Munk C, Frederiksen K, Junge J, Iftner T, Dehlendorff C, et al. Risk of CIN3 or worse with persistence of 13 individual oncogenic HPV types. Int J Cancer. 2019;144(8):1975–82. pmid:30246864
- View Article
- PubMed/NCBI
- Google Scholar
4. Spitzer M, Apgar BS, Brotzman GL. Management of histologic abnormalities of the cervix. Am Fam Physician. 2006;73(1):105–12. pmid:16417073
- View Article
- PubMed/NCBI
- Google Scholar
5. Helsedirektoratet. Retningslinjer for gynekologisk kreft. Handlingsprogram premaligne lidelser i cervix uteri: Helsedirektoratet; 2021 [updated 28.06.21; cited 2023 23.10.23. ]. Available from: https://www.helsedirektoratet.no/retningslinjer/gynekologisk-kreft-handlingsprogram/premaligne-lidelser-i-cervix-uteri
6. Perkins R, Guido R, Castle P, Chelmow D, Einstein M, Garcia F, et al. 2019 ASCCP risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis. 2020;24(2):102–31.
- View Article
- Google Scholar
7. Egemen D, Cheung LC, Chen X, Demarco M, Perkins RB, Kinney W, et al. Risk Estimates Supporting the 2019 ASCCP Risk-Based Management Consensus Guidelines. J Low Genit Tract Dis. 2020;24(2):132–43. pmid:32243308
- View Article
- PubMed/NCBI
- Google Scholar
8. Darragh TM, Colgan TJ, Cox JT, Heller DS, Henry MR, Luff RD, et al. The lower anogenital squamous terminology standardization project for HPV-associated lesions: background and consensus recommendations from the college of american pathologists and the american society for colposcopy and cervical pathology. J Low Genit Tract Dis. 2012;16(3):205–42. pmid:22820980
- View Article
- PubMed/NCBI
- Google Scholar
9. Holowaty P, Miller AB, Rohan T, To T. Natural history of dysplasia of the uterine cervix. J Natl Cancer Inst. 1999;91(3):252–8. pmid:10037103
- View Article
- PubMed/NCBI
- Google Scholar
10. Ostör AG. Natural history of cervical intraepithelial neoplasia: a critical review. Int J Gynecol Pathol. 1993;12(2):186–92. pmid:8463044
- View Article
- PubMed/NCBI
- Google Scholar
11. Loopik DL, Bentley HA, Eijgenraam MN, IntHout J, Bekkers RLM, Bentley JR. The natural history of cervical intraepithelial neoplasia grades 1, 2, and 3: a systematic review and meta-analysis. J Low Genit Tract Dis. 2021;25(3):221–31.
- View Article
- Google Scholar
12. Bjorge T, Skare GB, Bjorge L, Trope A, Lonnberg S. Adverse pregnancy outcomes after treatment for cervical intraepithelial Neoplasia. Obstet Gynecol. 2016;128(6):1265–73.
- View Article
- Google Scholar
13. Kyrgiou M, Athanasiou A, Paraskevaidi M, Mitra A, Kalliala I, Martin-Hirsch P, et al. Adverse obstetric outcomes after local treatment for cervical preinvasive and early invasive disease according to cone depth: systematic review and meta-analysis. BMJ. 2016;354:i3633. pmid:27469988
- View Article
- PubMed/NCBI
- Google Scholar
14. Castanon A, Landy R, Brocklehurst P, Evans H, Peebles D, Singh N, et al. Risk of preterm delivery with increasing depth of excision for cervical intraepithelial neoplasia in England: nested case-control study. BMJ. 2014;349:g6223. pmid:25378384
- View Article
- PubMed/NCBI
- Google Scholar
15. Arnesen K. Establishment of the cancer registry. Tidsskr Nor Laegeforen. 2001;121(10):1256–7. pmid:11402755
- View Article
- PubMed/NCBI
- Google Scholar
16. Bjørge T, Engesæter B, Skare GB, Tropé A. CervicalScreen Norway – a screening programme in transition. Nor J Epidemiol. 2022;30(1–2).
- View Article
- Google Scholar
17. Larsen IK, Småstuen M, Johannesen TB, Langmark F, Parkin DM, Bray F, et al. Data quality at the cancer registry of Norway: an overview of comparability, completeness, validity and timeliness. Eur J Cancer. 2009;45(7):1218–31. pmid:19091545
- View Article
- PubMed/NCBI
- Google Scholar
18. Cancer Registry of Norway. Cancer in Norway 2021- Cancer incidence, mortality, survival and prevalence in Norway. Oslo: Cancer Registry of Norway; 2022. Available from: https://www.kreftregisteret.no/Generelt/Rapporter/Cancer-in-Norway/
19. The Norwegian Directorate of Health. Premaligne lidelser i cervix. 2023 [Available from: https://www.helsedirektoratet.no/retningslinjer/gynekologisk-kreft-handlingsprogram/premaligne-lidelser-i-cervix-uteri
- View Article
- Google Scholar
20. Solomon D, Davey D, Kurman R, Moriarty A, O’Connor D, Prey M, et al. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA. 2002;287(16):2114–9. pmid:11966386
- View Article
- PubMed/NCBI
- Google Scholar
21. Lambert P. The estimation and modeling of cause-specific cumulative incidence functions using time-dependent weights. The Stata Journal. 2017;17(1):181–207.
- View Article
- Google Scholar
22. Hu S-Y, Rezhake R, Chen F, Zhang X, Pan Q-J, Ma J-F, et al. Outcomes in women with biopsy-confirmed cervical intraepithelial neoplasia grade 1 or normal cervix and related cofactors: A 15-year population-based cohort study from China. Gynecol Oncol. 2020;156(3):616–23. pmid:31937451
- View Article
- PubMed/NCBI
- Google Scholar
23. Sørbye SW, Arbyn M, Fismen S, Gutteberg TJ, Mortensen ES. HPV E6/E7 mRNA testing is more specific than cytology in post-colposcopy follow-up of women with negative cervical biopsy. PLoS One. 2011;6(10):e26022. pmid:21998748
- View Article
- PubMed/NCBI
- Google Scholar
24. Massad LS, Jeronimo J, Schiffman M, National Institutes of Health/American Society for Colposcopy and Cervical Pathology (NIH/ASCCP) Research Group. Interobserver agreement in the assessment of components of colposcopic grading. Obstet Gynecol. 2008;111(6):1279–84. pmid:18515509
- View Article
- PubMed/NCBI
- Google Scholar
25. Dijkstra MG, Heideman DAM, de Roy SC, Rozendaal L, Berkhof J, van Krimpen K, et al. p16(INK4a) immunostaining as an alternative to histology review for reliable grading of cervical intraepithelial lesions. J Clin Pathol. 2010;63(11):972–7. pmid:20924035
- View Article
- PubMed/NCBI
- Google Scholar
26. Ciavattini A, Serri M, Di Giuseppe J, Liverani CA, Gardella B, Papiccio M, et al. Long-term observational approach in women with histological diagnosis of cervical low-grade squamous intraepithelial lesion: an Italian multicentric retrospective cohort study. BMJ Open. 2019;9(7):e024920. pmid:31272971
- View Article
- PubMed/NCBI
- Google Scholar
27. Demarco M, Egemen D, Raine-Bennett TR, Cheung LC, Befano B, Poitras NE, et al. A study of partial human papillomavirus genotyping in support of the 2019 ASCCP risk-based management consensus guidelines. J Low Genit Tract Dis. 2020;24(2):144–7. pmid:32243309
- View Article
- PubMed/NCBI
- Google Scholar
28. Rodríguez AC, Schiffman M, Herrero R, Hildesheim A, Bratti C, Sherman ME, et al. Longitudinal study of human papillomavirus persistence and cervical intraepithelial neoplasia grade 2/3: critical role of duration of infection. J Natl Cancer Inst. 2010;102(5):315–24. pmid:20157096
- View Article
- PubMed/NCBI
- Google Scholar
29. Mittal S, Basu P, Muwonge R, Banerjee D, Ghosh I, Sengupta MM, et al. Risk of high-grade precancerous lesions and invasive cancers in high-risk HPV-positive women with normal cervix or CIN 1 at baseline-A population-based cohort study. Int J Cancer. 2017;140(8):1850–9. pmid:28108997
- View Article
- PubMed/NCBI
- Google Scholar
30. Bakken IJ, Surén P, Håberg SE, Cappelen I, Stoltenberg C. The Norwegian patient register--an important source for research. Tidsskr Nor Laegeforen. 2014;134(1):12–3. pmid:24429748
- View Article
- PubMed/NCBI
- Google Scholar
31. Feiring B, Laake I, Christiansen I, Hansen M, Stålcrantz J, Ambur O. Substantial decline in prevalence of vaccine-type and nonvaccine-type human papillomavirus (HPV) in vaccinated and unvaccinated girls 5 years after implementing HPV vaccine in Norway. J Infect Dis. 2018;218(12):1900–10.
- View Article
- Google Scholar
32. Arbyn M, Tommasino M, Depuydt C, Dillner J. Are 20 human papillomavirus types causing cervical cancer?. J Pathol. 2014;234(4):431–5. pmid:25124771
- View Article
- PubMed/NCBI
- Google Scholar
33. Paavonen J, Naud P, Salmerón J, Wheeler CM, Chow S-N, Apter D, et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet. 2009;374(9686):301–14. pmid:19586656
- View Article
- PubMed/NCBI
- Google Scholar
34. Drolet M, Bénard É, Pérez N, Brisson M, HPV Vaccination Impact Study Group. Population-level impact and herd effects following the introduction of human papillomavirus vaccination programmes: updated systematic review and meta-analysis. Lancet. 2019;394(10197):497–509. pmid:31255301
- View Article
- PubMed/NCBI
- Google Scholar
35. Herweijer E, Sundström K, Ploner A, Uhnoo I, Sparén P, Arnheim-Dahlström L. Quadrivalent HPV vaccine effectiveness against high-grade cervical lesions by age at vaccination: A population-based study. Int J Cancer. 2016;138(12):2867–74. pmid:26856527
- View Article
- PubMed/NCBI
- Google Scholar
36. Lei J, Ploner A, Elfström KM, Wang J, Roth A, Fang F, et al. HPV vaccination and the risk of invasive cervical cancer. N Engl J Med. 2020;383(14):1340–8. pmid:32997908
- View Article
- PubMed/NCBI
- Google Scholar
37. Andrae B, Kemetli L, Sparén P, Silfverdal L, Strander B, Ryd W, et al. Screening-preventable cervical cancer risks: evidence from a nationwide audit in Sweden. J Natl Cancer Inst. 2008;100(9):622–9. pmid:18445828
- View Article
- PubMed/NCBI
- Google Scholar
38. Aasbø G, Tropè A, Nygård M, Christiansen IK, Baasland I, Iversen GA, et al. HPV self-sampling among long-term non-attenders to cervical cancer screening in Norway: a pragmatic randomised controlled trial. Br J Cancer. 2022;127(10):1816–26. pmid:35995936
- View Article
- PubMed/NCBI
- Google Scholar
39. International Collaboration of Epidemiological Studies of Cervical Cancer. Comparison of risk factors for invasive squamous cell carcinoma and adenocarcinoma of the cervix: collaborative reanalysis of individual data on 8,097 women with squamous cell carcinoma and 1,374 women with adenocarcinoma from 12 epidemiological studies. Int J Cancer. 2007;120(4):885–91. pmid:17131323
- View Article
- PubMed/NCBI
- Google Scholar
40. Kapeu AS, Luostarinen T, Jellum E, Dillner J, Hakama M, Koskela P, et al. Is smoking an independent risk factor for invasive cervical cancer? A nested case-control study within Nordic biobanks. Am J Epidemiol. 2009;169(4):480–8. pmid:19074773
- View Article
- PubMed/NCBI
- Google Scholar
41. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet. 2007;370(9581):59–67. pmid:17617273
- View Article
- PubMed/NCBI
- Google Scholar

[ref1] 1. Woodman CBJ, Collins SI, Young LS. The natural history of cervical HPV infection: unresolved issues. Nat Rev Cancer. 2007;7(1):11–22. pmid:17186016
View Article
PubMed/NCBI
Google Scholar

[2] View Article

[3] PubMed/NCBI

[4] Google Scholar

[ref2] 2. Kjær SK, Frederiksen K, Munk C, Iftner T. Long-term absolute risk of cervical intraepithelial neoplasia grade 3 or worse following human papillomavirus infection: role of persistence. J Natl Cancer Inst. 2010;102(19):1478–88. pmid:20841605
View Article
PubMed/NCBI
Google Scholar

[6] View Article

[7] PubMed/NCBI

[8] Google Scholar

[ref3] 3. Sand FL, Munk C, Frederiksen K, Junge J, Iftner T, Dehlendorff C, et al. Risk of CIN3 or worse with persistence of 13 individual oncogenic HPV types. Int J Cancer. 2019;144(8):1975–82. pmid:30246864
View Article
PubMed/NCBI
Google Scholar

[10] View Article

[11] PubMed/NCBI

[12] Google Scholar

[ref4] 4. Spitzer M, Apgar BS, Brotzman GL. Management of histologic abnormalities of the cervix. Am Fam Physician. 2006;73(1):105–12. pmid:16417073
View Article
PubMed/NCBI
Google Scholar

[14] View Article

[15] PubMed/NCBI

[16] Google Scholar

[ref5] 5. Helsedirektoratet. Retningslinjer for gynekologisk kreft. Handlingsprogram premaligne lidelser i cervix uteri: Helsedirektoratet; 2021 [updated 28.06.21; cited 2023 23.10.23. ]. Available from: https://www.helsedirektoratet.no/retningslinjer/gynekologisk-kreft-handlingsprogram/premaligne-lidelser-i-cervix-uteri

[ref6] 6. Perkins R, Guido R, Castle P, Chelmow D, Einstein M, Garcia F, et al. 2019 ASCCP risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis. 2020;24(2):102–31.
View Article
Google Scholar

[19] View Article

[20] Google Scholar

[ref7] 7. Egemen D, Cheung LC, Chen X, Demarco M, Perkins RB, Kinney W, et al. Risk Estimates Supporting the 2019 ASCCP Risk-Based Management Consensus Guidelines. J Low Genit Tract Dis. 2020;24(2):132–43. pmid:32243308
View Article
PubMed/NCBI
Google Scholar

[22] View Article

[23] PubMed/NCBI

[24] Google Scholar

[ref8] 8. Darragh TM, Colgan TJ, Cox JT, Heller DS, Henry MR, Luff RD, et al. The lower anogenital squamous terminology standardization project for HPV-associated lesions: background and consensus recommendations from the college of american pathologists and the american society for colposcopy and cervical pathology. J Low Genit Tract Dis. 2012;16(3):205–42. pmid:22820980
View Article
PubMed/NCBI
Google Scholar

[26] View Article

[27] PubMed/NCBI

[28] Google Scholar

[ref9] 9. Holowaty P, Miller AB, Rohan T, To T. Natural history of dysplasia of the uterine cervix. J Natl Cancer Inst. 1999;91(3):252–8. pmid:10037103
View Article
PubMed/NCBI
Google Scholar

[30] View Article

[31] PubMed/NCBI

[32] Google Scholar

[ref10] 10. Ostör AG. Natural history of cervical intraepithelial neoplasia: a critical review. Int J Gynecol Pathol. 1993;12(2):186–92. pmid:8463044
View Article
PubMed/NCBI
Google Scholar

[34] View Article

[35] PubMed/NCBI

[36] Google Scholar

[ref11] 11. Loopik DL, Bentley HA, Eijgenraam MN, IntHout J, Bekkers RLM, Bentley JR. The natural history of cervical intraepithelial neoplasia grades 1, 2, and 3: a systematic review and meta-analysis. J Low Genit Tract Dis. 2021;25(3):221–31.
View Article
Google Scholar

[38] View Article

[39] Google Scholar

[ref12] 12. Bjorge T, Skare GB, Bjorge L, Trope A, Lonnberg S. Adverse pregnancy outcomes after treatment for cervical intraepithelial Neoplasia. Obstet Gynecol. 2016;128(6):1265–73.
View Article
Google Scholar

[41] View Article

[42] Google Scholar

[ref13] 13. Kyrgiou M, Athanasiou A, Paraskevaidi M, Mitra A, Kalliala I, Martin-Hirsch P, et al. Adverse obstetric outcomes after local treatment for cervical preinvasive and early invasive disease according to cone depth: systematic review and meta-analysis. BMJ. 2016;354:i3633. pmid:27469988
View Article
PubMed/NCBI
Google Scholar

[44] View Article

[45] PubMed/NCBI

[46] Google Scholar

[ref14] 14. Castanon A, Landy R, Brocklehurst P, Evans H, Peebles D, Singh N, et al. Risk of preterm delivery with increasing depth of excision for cervical intraepithelial neoplasia in England: nested case-control study. BMJ. 2014;349:g6223. pmid:25378384
View Article
PubMed/NCBI
Google Scholar

[48] View Article

[49] PubMed/NCBI

[50] Google Scholar

[ref15] 15. Arnesen K. Establishment of the cancer registry. Tidsskr Nor Laegeforen. 2001;121(10):1256–7. pmid:11402755
View Article
PubMed/NCBI
Google Scholar

[52] View Article

[53] PubMed/NCBI

[54] Google Scholar

[ref16] 16. Bjørge T, Engesæter B, Skare GB, Tropé A. CervicalScreen Norway – a screening programme in transition. Nor J Epidemiol. 2022;30(1–2).
View Article
Google Scholar

[56] View Article

[57] Google Scholar

[ref17] 17. Larsen IK, Småstuen M, Johannesen TB, Langmark F, Parkin DM, Bray F, et al. Data quality at the cancer registry of Norway: an overview of comparability, completeness, validity and timeliness. Eur J Cancer. 2009;45(7):1218–31. pmid:19091545
View Article
PubMed/NCBI
Google Scholar

[59] View Article

[60] PubMed/NCBI

[61] Google Scholar

[ref18] 18. Cancer Registry of Norway. Cancer in Norway 2021- Cancer incidence, mortality, survival and prevalence in Norway. Oslo: Cancer Registry of Norway; 2022. Available from: https://www.kreftregisteret.no/Generelt/Rapporter/Cancer-in-Norway/

[ref19] 19. The Norwegian Directorate of Health. Premaligne lidelser i cervix. 2023 [Available from: https://www.helsedirektoratet.no/retningslinjer/gynekologisk-kreft-handlingsprogram/premaligne-lidelser-i-cervix-uteri
View Article
Google Scholar

[64] View Article

[65] Google Scholar

[ref20] 20. Solomon D, Davey D, Kurman R, Moriarty A, O’Connor D, Prey M, et al. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA. 2002;287(16):2114–9. pmid:11966386
View Article
PubMed/NCBI
Google Scholar

[67] View Article

[68] PubMed/NCBI

[69] Google Scholar

[ref21] 21. Lambert P. The estimation and modeling of cause-specific cumulative incidence functions using time-dependent weights. The Stata Journal. 2017;17(1):181–207.
View Article
Google Scholar

[71] View Article

[72] Google Scholar

[ref22] 22. Hu S-Y, Rezhake R, Chen F, Zhang X, Pan Q-J, Ma J-F, et al. Outcomes in women with biopsy-confirmed cervical intraepithelial neoplasia grade 1 or normal cervix and related cofactors: A 15-year population-based cohort study from China. Gynecol Oncol. 2020;156(3):616–23. pmid:31937451
View Article
PubMed/NCBI
Google Scholar

[74] View Article

[75] PubMed/NCBI

[76] Google Scholar

[ref23] 23. Sørbye SW, Arbyn M, Fismen S, Gutteberg TJ, Mortensen ES. HPV E6/E7 mRNA testing is more specific than cytology in post-colposcopy follow-up of women with negative cervical biopsy. PLoS One. 2011;6(10):e26022. pmid:21998748
View Article
PubMed/NCBI
Google Scholar

[78] View Article

[79] PubMed/NCBI

[80] Google Scholar

[ref24] 24. Massad LS, Jeronimo J, Schiffman M, National Institutes of Health/American Society for Colposcopy and Cervical Pathology (NIH/ASCCP) Research Group. Interobserver agreement in the assessment of components of colposcopic grading. Obstet Gynecol. 2008;111(6):1279–84. pmid:18515509
View Article
PubMed/NCBI
Google Scholar

[82] View Article

[83] PubMed/NCBI

[84] Google Scholar

[ref25] 25. Dijkstra MG, Heideman DAM, de Roy SC, Rozendaal L, Berkhof J, van Krimpen K, et al. p16(INK4a) immunostaining as an alternative to histology review for reliable grading of cervical intraepithelial lesions. J Clin Pathol. 2010;63(11):972–7. pmid:20924035
View Article
PubMed/NCBI
Google Scholar

[86] View Article

[87] PubMed/NCBI

[88] Google Scholar

[ref26] 26. Ciavattini A, Serri M, Di Giuseppe J, Liverani CA, Gardella B, Papiccio M, et al. Long-term observational approach in women with histological diagnosis of cervical low-grade squamous intraepithelial lesion: an Italian multicentric retrospective cohort study. BMJ Open. 2019;9(7):e024920. pmid:31272971
View Article
PubMed/NCBI
Google Scholar

[90] View Article

[91] PubMed/NCBI

[92] Google Scholar

[ref27] 27. Demarco M, Egemen D, Raine-Bennett TR, Cheung LC, Befano B, Poitras NE, et al. A study of partial human papillomavirus genotyping in support of the 2019 ASCCP risk-based management consensus guidelines. J Low Genit Tract Dis. 2020;24(2):144–7. pmid:32243309
View Article
PubMed/NCBI
Google Scholar

[94] View Article

[95] PubMed/NCBI

[96] Google Scholar

[ref28] 28. Rodríguez AC, Schiffman M, Herrero R, Hildesheim A, Bratti C, Sherman ME, et al. Longitudinal study of human papillomavirus persistence and cervical intraepithelial neoplasia grade 2/3: critical role of duration of infection. J Natl Cancer Inst. 2010;102(5):315–24. pmid:20157096
View Article
PubMed/NCBI
Google Scholar

[98] View Article

[99] PubMed/NCBI

[100] Google Scholar

[ref29] 29. Mittal S, Basu P, Muwonge R, Banerjee D, Ghosh I, Sengupta MM, et al. Risk of high-grade precancerous lesions and invasive cancers in high-risk HPV-positive women with normal cervix or CIN 1 at baseline-A population-based cohort study. Int J Cancer. 2017;140(8):1850–9. pmid:28108997
View Article
PubMed/NCBI
Google Scholar

[102] View Article

[103] PubMed/NCBI

[104] Google Scholar

[ref30] 30. Bakken IJ, Surén P, Håberg SE, Cappelen I, Stoltenberg C. The Norwegian patient register--an important source for research. Tidsskr Nor Laegeforen. 2014;134(1):12–3. pmid:24429748
View Article
PubMed/NCBI
Google Scholar

[106] View Article

[107] PubMed/NCBI

[108] Google Scholar

[ref31] 31. Feiring B, Laake I, Christiansen I, Hansen M, Stålcrantz J, Ambur O. Substantial decline in prevalence of vaccine-type and nonvaccine-type human papillomavirus (HPV) in vaccinated and unvaccinated girls 5 years after implementing HPV vaccine in Norway. J Infect Dis. 2018;218(12):1900–10.
View Article
Google Scholar

[110] View Article

[111] Google Scholar

[ref32] 32. Arbyn M, Tommasino M, Depuydt C, Dillner J. Are 20 human papillomavirus types causing cervical cancer?. J Pathol. 2014;234(4):431–5. pmid:25124771
View Article
PubMed/NCBI
Google Scholar

[113] View Article

[114] PubMed/NCBI

[115] Google Scholar

[ref33] 33. Paavonen J, Naud P, Salmerón J, Wheeler CM, Chow S-N, Apter D, et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet. 2009;374(9686):301–14. pmid:19586656
View Article
PubMed/NCBI
Google Scholar

[117] View Article

[118] PubMed/NCBI

[119] Google Scholar

[ref34] 34. Drolet M, Bénard É, Pérez N, Brisson M, HPV Vaccination Impact Study Group. Population-level impact and herd effects following the introduction of human papillomavirus vaccination programmes: updated systematic review and meta-analysis. Lancet. 2019;394(10197):497–509. pmid:31255301
View Article
PubMed/NCBI
Google Scholar

[121] View Article

[122] PubMed/NCBI

[123] Google Scholar

[ref35] 35. Herweijer E, Sundström K, Ploner A, Uhnoo I, Sparén P, Arnheim-Dahlström L. Quadrivalent HPV vaccine effectiveness against high-grade cervical lesions by age at vaccination: A population-based study. Int J Cancer. 2016;138(12):2867–74. pmid:26856527
View Article
PubMed/NCBI
Google Scholar

[125] View Article

[126] PubMed/NCBI

[127] Google Scholar

[ref36] 36. Lei J, Ploner A, Elfström KM, Wang J, Roth A, Fang F, et al. HPV vaccination and the risk of invasive cervical cancer. N Engl J Med. 2020;383(14):1340–8. pmid:32997908
View Article
PubMed/NCBI
Google Scholar

[129] View Article

[130] PubMed/NCBI

[131] Google Scholar

[ref37] 37. Andrae B, Kemetli L, Sparén P, Silfverdal L, Strander B, Ryd W, et al. Screening-preventable cervical cancer risks: evidence from a nationwide audit in Sweden. J Natl Cancer Inst. 2008;100(9):622–9. pmid:18445828
View Article
PubMed/NCBI
Google Scholar

[133] View Article

[134] PubMed/NCBI

[135] Google Scholar

[ref38] 38. Aasbø G, Tropè A, Nygård M, Christiansen IK, Baasland I, Iversen GA, et al. HPV self-sampling among long-term non-attenders to cervical cancer screening in Norway: a pragmatic randomised controlled trial. Br J Cancer. 2022;127(10):1816–26. pmid:35995936
View Article
PubMed/NCBI
Google Scholar

[137] View Article

[138] PubMed/NCBI

[139] Google Scholar

[ref39] 39. International Collaboration of Epidemiological Studies of Cervical Cancer. Comparison of risk factors for invasive squamous cell carcinoma and adenocarcinoma of the cervix: collaborative reanalysis of individual data on 8,097 women with squamous cell carcinoma and 1,374 women with adenocarcinoma from 12 epidemiological studies. Int J Cancer. 2007;120(4):885–91. pmid:17131323
View Article
PubMed/NCBI
Google Scholar

[141] View Article

[142] PubMed/NCBI

[143] Google Scholar

[ref40] 40. Kapeu AS, Luostarinen T, Jellum E, Dillner J, Hakama M, Koskela P, et al. Is smoking an independent risk factor for invasive cervical cancer? A nested case-control study within Nordic biobanks. Am J Epidemiol. 2009;169(4):480–8. pmid:19074773
View Article
PubMed/NCBI
Google Scholar

[145] View Article

[146] PubMed/NCBI

[147] Google Scholar

[ref41] 41. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet. 2007;370(9581):59–67. pmid:17617273
View Article
PubMed/NCBI
Google Scholar

[149] View Article

[150] PubMed/NCBI

[151] Google Scholar

Figures

Abstract

Background

Methods

Results

Conclusions

Introduction

Methods

Data sources

Study population and variables

Statistical analyses

Ethics approval and data availability

Results

Descriptive statistics

Progression of histologically confirmed CIN1

Treatment

Discussion

Strengths and limitations

Conclusions

Supporting information

S1 Table. Overview of the HPV tests applied during the study period 2002–2019.

S2 Table. Cumulative incidence and hazard ratios of progression to CIN2+ following an index CIN1 diagnosis in CervicalScreen Norway 2002–2019, according to patient and lesion characteristics.

S3 Table. Treatment modalities performed in Norwegian public hospitals and outpatient clinics in women registered with an index CIN1 in the time-period 2008–2021, according to the Norwegian Patient Registry.

S1 Fig. Timeline and analytical decisions during follow-up.

S2 Fig. Cumulative incidence of progression and treatment following an index CIN1 diagnosis in CervicalScreen Norway 2002–2019.

S3 Fig. Hazard rates of progression and treatment following an index CIN1 diagnosis in CervicalScreen Norway 2002–2019, according to index cytology and HPV genotypes.

S4 Fig. Cumulative incidence and Hazard rates of progression following an index CIN1 diagnosis in CervicalScreen Norway 2002–2019, according to index cytology and HPV genotypes.

Acknowledgments

References