{
  "abstract": "Objective To compare routine high risk human papillomavirus (hrHPV) screening with cytological screening in two screening rounds in a well established, routine screening programme for cervical cancer.Design Population based cohort study.Setting Finland’s Mass Screening Registry, 2012-22, with diagnostic follow-up examinations until October 2024.Participants 1 180 491 women participating at least once in cytological test (PAP smear) or hrHPV based cervical cancer screening between 2012 and 2022.Main outcome measures Numbers and proportions of attendees, positive routine test results, follow-up screening referrals, colposcopy referrals, and incidence of cervical intraepithelial neoplasia ≥grade 2 (CIN2+) in the first and second hrHPV and cytological screening rounds. Results adjusted for age, year, region, and education.Results Data for 1 574 688 full screening rounds were analysed. The overall referral rate for colposcopy was 3.37% (n=12 273) in the hrHPV group and 0.98% (n=11 895) in the cytology group, with an adjusted risk ratio of 2.97 (95% confidence interval (CI) 2.87 to 3.07). The overall rate for detection of CIN2+ was 0.92% in the hrHPV group and 0.35% in the cytology group, with an adjusted risk ratio of 2.17 (2.04 to 2.31). For the second hrHPV screening round compared with the first screening round, the adjusted risk ratio was 0.77 (0.71 to 0.84) for referral for colposcopy and 0.57 (0.46 to 0.72) for detection of CIN2+. Actual rates for referral for colposcopy were 3.54% (n=11 709) in the first hrHPV screening round and 2.42% (n=564) in the second screening round. The rate for detection of CIN2+ for hrHPV screening was 0.98% (n=3 248) in the first hrHPV screening round and 0.38% (n=88) in the second screening round. In cytological screening, no observed reduction was seen in either the referral rate or CIN2+ findings. After a negative hrHPV test in the first screening round, CIN2+ was detected in only 0.2% of women (n=44/314 286) in the second screening round.Conclusions Within a well established, population based national screening programme, the results of the study indicated that hrHPV screening with a five year interval was effective and safe. hrHPV screening identified precancerous lesions earlier than cytological screening. The incidence of CIN2+ was low in the second screening round in women with a negative hrHPV test result in the initial round and in those aged ≥50 years, and hence a longer screening interval for specific subgroups should be considered.",
  "authors": [
    {
      "affiliations": [
        "Department of Obstetrics and Gynaecology, Helsinki University Hospital, Helsinki, Finland",
        "Finnish Cancer Registry, Helsinki, Finland"
      ],
      "name": "Iiris Juulia Turunen"
    },
    {
      "affiliations": [
        "Department of Obstetrics and Gynaecology, Helsinki University Hospital, Helsinki, Finland",
        "Department of Metabolism, Digestion and Reproduction, Imperial College London Institute of Reproductive and Developmental Biology, London, UK"
      ],
      "name": "Ilkka Kalliala"
    },
    {
      "affiliations": [
        "Finnish Cancer Registry, Helsinki, Finland"
      ],
      "name": "Maiju Pankakoski"
    },
    {
      "affiliations": [
        "Finnish Cancer Registry, Helsinki, Finland"
      ],
      "name": "Veli-Matti Partanen"
    }
  ],
  "full_text": "WHAT IS ALREADY KNOWN ON THIS TOPIC Primary screening for human papillomavirus (HPV) is more effective than cytology in preventing cervical cancer, and has been adopted in national screening programmes in many countriesDuring the first screening round, HPV screening detects more precancerous lesions, but with an increase in colposcopy referral ratesLocal studies suggest that referral and detection rates of lesions decrease in the second screening round, but large scale nationwide studies to assess the broader implications are lackingWHAT THIS STUDY ADDS High risk HPV (hrHPV) screening was effective and safe with intervals of five yearsAmong women with a negative test result for hrHPV in the first round, the detection rate of cervical intraepithelial neoplasia grade ≥2 on the second round was lowHOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICY Screening programmes based on hrHPV testing should extend the screening interval to five yearsIntroduction Persistent high risk human papillomavirus (hrHPV) infection can cause precancerous cell changes leading to cervical cancer. 1 In 2018, the World Health Organization (WHO) called for a global initiative to eliminate cervical cancer as a public health problem.2 Together with the human papillomavirus (HPV) vaccine and treatment for cervical cancer, effective cervical cancer screening was one of the three main strategies, with WHO recommending hrHPV testing as the primary screening method. hrHPV screening provides greater protection against cervical cancer, although with lower specificity than traditional cytology based screening.3 Baseline hrHPV negativity is also associated with a significantly lower cumulative incidence of cervical intraepithelial neoplasia grade ≥3 (CIN3+), even after 13 or 14 years of follow-up, indicating that hrHPV testing offers better long term protection against cervical cancer.4 5 hrHPV screening has gradually been adopted as the primary screening method in an increasing number of European countries,6 highlighting the need for data on its real world performance on the first as well as subsequent screening rounds.hrHPV and cytological screening have been compared in large European and Canadian trials, and increasingly in routine settings. Both trial and real life data on hrHPV screening showed an initial increase in referrals for colposcopy and detection of cervical intraepithelial neoplasia grade ≥2 (CIN2+).7–12 In subsequent hrHPV screening rounds within three to five years, referral rates for colposcopy and findings of precancerous lesions decreased.10 13–15 Although several studies have looked at this topic, most have been clinical trials or local pilot studies, or analysed only one screening round without a cytology control group for comparison. In Finland, a well established and highly effective cervical cancer screening programme has been in place since the 1960s, with a reduction in cervical cancer mortality of about 80%.16 Screening based on cytology has been conducted for decades. Since 2012, the use of hrHPV testing has gradually increased in routine practice, exceeding cytology based testing in 2019.17 The transition to hrHPV screening has been implemented in stages across different regions of Finland, which allows for their comparison in routine practice.To study how the transition from cytological screening to hrHPV based screening has affected the performance of screening in a real world setting on a large scale, we conducted a retrospective population based cohort study. We compared the numbers and proportions of positive screening test results, follow-up recommendations, colposcopy referrals, and CIN2+ findings between hrHPV and cytology based screening in two full screening rounds, with a screening interval of five years.Material and methods Screening algorithms and clinical management During the study period in Finland, according to the government decree on cervical cancer screening, women aged 30-60 years were invited for a cervical screening test every five years. Data for sex were taken from information in the Finland Mass Screening Registry. Some municipalities in Finland extended invitations to women aged 25 years or 65 years, or both, at the discretion of individual municipalities. Women aged 25 years always had cytology based screening. Of the women who were invited, 99.5% attended screening during the invitation year and 0.5% attended within the next year. Each municipality independently decided whether to use hrHPV or cytological screening as the primary method. Over the course of the study, the proportion of hrHPV screening tests increased from 6% in 2012 to 79% by 2022. The invitation coverage remained consistently high (nearly 100%) for women aged 30-64 years. The overall participation rate over the years ranged from 67% to 73%. 17For hrHPV testing, a cytology triage test was performed if the initial hrHPV test result was positive. If the triage cytology result was normal or showed atypical squamous cells of undetermined significance (ASC-US), the woman was scheduled for a follow-up hrHPV test or tests in 12-24 months. In a few municipalities, two follow-up screenings with 12 month intervals were offered. If hrHPV positivity persisted in follow-up screenings at 12-24 months after the initial test, the woman was referred for colposcopy, regardless of the cytology result. In cytological screening, low grade squamous intraepithelial lesion or more severe squamous lesions and all glandular abnormalities were directly referred for colposcopy. Cytologies that showed ASC-US were invited for a follow-up screening test or tests after 12-24 months and, if the results persisted or progressed, women were referred for colposcopy. In real life settings, actual follow-up intervals were often longer than scheduled.Study design and data source We used individual level data on screening tests and associated follow-up tests from Finland’s Mass Screening Registry for the years 2012-22 with diagnostic follow-up examinations until October 2024. Data on education at the index date were obtained from Statistics Finland and linked to the screening data with individual personal identifiers. We restricted our analysis to individuals aged 30-65 years who had received a screening invitation and had participated in the screening. We excluded the region of Åland from the analysis and also test results with no regional data available. Our aim was to evaluate the overall performance of the screening programme and, therefore, we included all women irrespective of their previous screening history or possible symptoms.Statistical analysis To compare the performance of the hrHPV based screening programme with the cytology based programme, we calculated outcome variables for both groups: positive test results, defined as receiving a referral for follow-up screening or colposcopy; follow-up test recommendations; colposcopy referrals; and histological findings of CIN2+. For each outcome variable, we calculated the total number and proportion of all women screened with each method. We analysed the outcome variables separately for routine and follow-up screenings as well as for full screening rounds. Routine screening referred to tests offered to all eligible women every five years, whereas follow-up screening referred to tests offered in response to abnormal routine screening results. A full screening round included the routine screening test and possible follow-up screening tests along with the associated cytological and histological diagnoses within five years of the initial test.The screening method used for the routine test determined the screening group: hrHPV or cytological screening group. When analysing primary and follow-up screening results separately, we included all available test results from 2012 to 2022. When analysing the full screening rounds, however, we limited the analysis to rounds that began before 2021. This approach ensured that all potential follow-up tests could be captured within the dataset.For the hrHPV and cytology groups, a screening round was considered positive if follow-up screening or a colposcopy referral was advised. A follow-up recommendation was made if a positive hrHPV test result was accompanied by cytology showing either negative for intraepithelial lesion or malignancy or ASC-US. In cytology based screening, a follow-up recommendation was made after a finding of ASC-US. Referral to colposcopy was considered positive if the woman was referred for colposcopy or if the result required a referral based on national guidelines. Referral assigned by the screening provider was missing for 1% of screen positive test results. CIN2+ was classified as positive if a woman received a diagnosis of histological CIN2+ after a routine or follow-up test. Histological diagnoses made outside the screening programme were not included because the aim was to evaluate the organised screening programme. In incidences of multiple histological findings, the most severe diagnosis was considered.We then calculated the outcome variables for the first full screening round with both screening methods. We also conducted a subgroup analysis of women with complete data from a second full screening round with the same screening method. This subgroup was analysed separately for those screened repeatedly with hrHPV and those screened repeatedly with cytology. Most women had previously been screened with cytology in both groups. The availability of data for the second screening round depended on whether the woman was screened twice with the same method during our study period and whether the woman participated in screening as recommended.We calculated a risk ratio for each outcome variable comparing hrHPV screening with cytological screening in routine and follow-up screenings, as well as in full screening rounds. We also calculated risk ratios comparing the second screening round with the first screening round, separately in the hrHPV and cytological screening groups. Risk ratios were calculated with 95% confidence intervals (CIs) by using a Poisson regression model with the generalised estimating equations approach with an independence working correlation matrix, to take into account repeated observations on the same individual over time.18 Because hrHPV testing was introduced gradually across different regions of Finland, we adjusted the results for geographical region to account for potential bias arising from regional differences. To control the effects of women’s age, temporal changes over the study period, and socioeconomic status, we also adjusted the risk ratios for age, screening year, and level of education. Age was treated as a continuous variable. Education was categorised into three groups: comprehensive school or unknown, upper secondary education, and higher education. Regional classification followed the Finnish collaborative areas for healthcare, which are divided into southern, eastern, western, inland, and northern regions. In sensitivity analyses, the primary results were recalculated excluding women who had been screened at age 25 years (online supplemental tables 1 and 2).SP310.1136/bmjmed-2025-001435.supp3Supplementary dataSP410.1136/bmjmed-2025-001435.supp4Supplementary dataIn the hrHPV screened group, we also examined histological outcomes in women who were referred for colposcopy because of persistent hrHPV positivity in follow-up screening based on their triage cytology results. Triage cytology was classified according to the Bethesda system and grouped as: atypical squamous cells, cannot exclude high grade squamous intraepithelial lesion or atypical glandular cells, not otherwise specified; low grade squamous intraepithelial lesion; ASC-US; and normal. The proportion of women with histological CIN2+ was then calculated for each triage cytology group with 95% CIs with the exact method. All analyses were performed with R version 4.3.1, package gee, and Rstudio, version 2023.12.1+402.Patient and public involvement Patients and members of the public were not involved in the design, conduct, reporting, or dissemination plans of this research. This registry based study relied on aggregated screening data. In accordance with national legislation and the regulations of the collaborating institutions, the use of such data did not require ethical approval or informed consent. As no individual participants were directly recruited or contacted, results will not be returned to participants. Findings will be disseminated through publication in a peer reviewed journal and presentations at scientific and clinical meetings. In addition, we plan to prepare a short, plain language summary of the key results for sharing through relevant patient community channels, to ensure that the findings are understandable and accessible to a wider audience.Results In our study, we had data for 1 960 177 routine tests and 103 627 follow-up tests conducted in 1 180 491 women participating in the Finnish cervical cancer screening programme between 2012 and 2022. We also had data on 1 575 688 full screening rounds with routine screening tests for 2012-20. Of the full screening rounds, 363 838 were mainly conducted with a hrHPV test (23.1%) and 1 210 850 with cytology (76.9%). The mean interval between the routine and possible follow-up screening tests was two years. In a year-by-year analysis, the use of hrHPV testing in routine screening exceeded cytology testing in 2019. The overall screening participation rate was 71.0%. The prevalence of hrHPV was stable over the study period, ranging from 6.5% to 8.5%, with no upward trend. Mean age was 47 years in both the hrHPV and cytological screening groups. Table 1 provides an overview of the distribution of screening participants by age, education, and region, as well as the distribution of hrHPV and cytological tests for each calendar year. Figure 1 shows the screening algorithm and selection of participants in the hrHPV and cytology groups.Table 1Comparison of populations screened with high risk human papillomavirus (hrHPV) based screening tests or cytological based screening testsCharacteristicsRoutine and follow-up screening testshrHPV testsCytological testsTotal testsAge group (years): 3075 927 (31.7)163 282 (68.3)239 209 (100) 3588 682 (34.9)165 655 (65.1)254 337 (100) 4092 143 (34.6)173 795 (65.4)265 938 (100) 4589 969 (32.8)183 914 (67.2)273 883 (100) 5090 039 (29.8)212 095 (70.2)302 134 (100) 5597 800 (30.9)218 463 (69.1)316 263 (100) 6096 306 (30.0)224 565 (70.0)320 871 (100) 6551 766 (56.8)39 403 (43.2)91 169 (100)Education: Comprehensive school or unknown57 247 (29.4)137 563 (70.6)194 810 (100) Upper secondary education248 718 (30.7)561 379 (69.3)810 097 (100) Higher education376 667 (35.6)682 230 (64.4)1 058 897 (100)Region: Southern326 092 (36.8)560 841 (63.2)886 933 (100) Eastern85 955 (31.2)189 870 (68.8)275 825 (100) Inland188 709 (59.9)126 337 (40.1)315 046 (100) Western81 824 (24.9)247 359 (75.1)329 183 (100) Northern52 (0.02)256 765 (99.98)256 817 (100)Test year: 201211 133 (6.3)166 587 (93.7)177 720 (100) 20138310 (4.6)172 568 (95.4)180 878 (100) 20148740 (4.7)178 544 (95.3)187 284 (100) 201515 292 (8.4)166 052 (91.6)181 344 (100) 201624 085 (13.1)160 312 (86.9)184 397 (100) 201732 196 (17.3)153 896 (82.7)186 092 (100) 201834 508 (18.6)150 852 (81.4)185 360 (100) 2019124 489 (64.7)67 960 (35.3)192 449 (100) 2020119 368 (64.9)64 447 (35.1)183 815 (100) 2021140 652 (71.9)54 990 (28.1)195 642 (100) 2022163 859 (78.5)44 964 (21.5)208 823 (100) Total682 632 (33.1)1 381 172 (66.9)2 063 804 (100)Data are number (%).All routine and follow-up screening tests between 2012 and 2022 are included, allowing a woman to appear multiple times in the analysis if she has undergone both routine and follow-up screenings, or both screening rounds, during the study period.Figure 1Results of screening in high risk human papillomavirus group (hrHPV, top) and cytology group (bottom). Results of routine screening tests for 2012-20 and their follow-up tests, and histological diagnosis are included. Top=HPV routine screening tests for 2012-20 and their follow-up tests. *274 additional women attended follow-up screening despite having a referral. †17 589 (74.4%) women with a positive hrHPV test result attended the recommended follow-up screening. ‡1095 additional women with a negative hrHPV test result or with inadequate results attended follow-up screening, and 139 were given a referral to colposcopy because of cytology results analysed for unknown reasons or because of reported symptoms. Bottom=cytological routine screening tests for 2012-20 and their follow-up tests. *987 additional women attended follow-up screening despite having a referral. †29 714 (62%) women attended the recommended follow-up screening. ‡20 135 additional women attended follow-up screening despite normal cytology in routine screening because of reported symptoms. Inadequate refers to screening rounds where the woman has participated but the result could not be interpreted. Missing refers to screening rounds where women participated but for unknown reasons the result is missingRoutine and follow-up screening and full screening rounds Table 2 shows the results of hrHPV and cytological screening. Referral rates in routine screening were 1.08% in the hrHPV group and 0.79% in the cytology group, with an adjusted risk ratio of 1.30 (95% CI 1.24 to 1.36) comparing the hrHPV screened with the cytology screened group. In follow-up screening, referral rates were 32.1% in the hrHPV group and 3.43% in the cytology group, with an adjusted risk ratio of 5.96 (95% CI 5.66 to 6.28). In routine screening, the rate for detection of CIN2+ was 0.45% in the hrHPV group and 0.30% in the cytology group, with an adjusted risk ratio of 1.34 (95% CI 1.25 to 1.43). In follow-up screening, CIN2+ rates were 6.90% in the hrHPV group and 0.93% in the cytology group, with an adjusted risk ratio of 4.11 (95% CI 3.66 to 4.62). The risk of cervical cancer in routine screening was 0.02% (n=121) in the hrHPV group and 0.01% (n=130) in the cytology group, with an adjusted risk ratio of 1.45 (95% CI 0.99 to 2.13). In follow-up screening, the risk of cervical cancer was 0.11% (n=33) in the hrHPV group and 0.03% (n=19) in the cytology group, with an adjusted risk ratio of 2.99 (95% CI 1.26 to 7.07).Table 2Results of high risk human papillomavirus (hrHPV) based screening tests and cytological based screening tests, separately for routine screening, follow-up screening, and full screening roundsScreening roundhrHPV testsCytological testsTotal testsAdjusted risk ratio (95% CI)Routine screening 2012-22:* No of screening tests651 927 (100)1 308 250 (100)1 960 177 (100) Positive test results48 590 (7.45)62 208 (4.76)110 798 (5.65)1.50 (1.47 to 1.52) Follow-up recommendations41 572 (6.38)51 827 (3.96)93 399 (4.76)1.54 (1.51 to 1.56) Referrals7018 (1.08)10 381 (0.79)17 399 (0.89)1.30 (1.24 to 1.36) CIN2+ detected2966 (0.45)3866 (0.30)6832 (0.35)1.34 (1.25 to 1.43) Cervical cancers121 (0.02)130 (0.01)251 (0.01 %)1.45 (0.99 to 2.13)Follow-up screening 2012-22:* No of screening tests30 705 (100)72 922 (100)103 627 (100) Positive test results11 272 (36.71)10 485 (14.38)21 757 (21.00)2.33 (2.26 to 2.40) Follow-up recommendations1423 (4.63)7986 (10.95)9409 (9.08)0.63 (0.59 to 0.68) Referrals9849 (32.08)2499 (3.43)12 348 (11.92)5.96 (5.66 to 6.28) CIN2+ detected2120 (6.90)680 (0.93)2800 (2.70)4.11 (3.66 to 4.62) Cervical cancers33 (0.11)19 (0.03)52 (0.05)2.99 (1.26 to 7.07)Full screening rounds 2012-20:* No of screening rounds363 838 (100)1 210 850 (100)1 574 688 (100) Positive screening rounds27 901 (7.67)†58 800 (4.86)‡86 701 (5.51)1.52 (1.49 to 1.55) Follow-up recommendations24 028 (6.60)§49 295 (4.07)¶73 323 (4.60)1.57 (1.54 to 1.60) Referrals12 273 (3.37)11 895 (0.98)24 168 (1.53)2.97 (2.87 to 3.07) CIN2+ detected3336 (0.92)4297 (0.35)7633 (0.48)2.17 (2.04 to 2.31) Cervical cancers106 (0.03)134 (0.01)240 (0.02)2.02 (1.41 to 2.90)Data are number (%) unless indicated otherwise.Adjusted risk ratios (adjusted for screening age, screening year, education, and region) compare hrHPV screening with cytological screening.*Data for routine and follow-up screenings were collected from 2012 to 2022. Data for the full screening rounds were limited to 2012-20 to ensure inclusion of all follow-up information.†Number also includes follow-up recommendations and referrals for women with a negative test result for hrHPV, given because of a positive cytology result (n=487) or after a follow-up test (n=47).‡Number also includes follow-up recommendations and referrals of women with a normal routine screening result, given after a follow-up test (n=1441).§Number also includes follow-up recommendations of women with a negative test result for hrHPV, given because of a positive cytology result (n=348) or after a follow-up test (n=25), and follow-up recommendations after a referral (n=7).¶Number also includes follow-up recommendations of women whose routine screening result was either normal or warranting referral, given after a follow-up test (n=1388).CI, confidence interval; CIN2+, cervical intraepithelial neoplasia grade ≥2.For the full screening rounds, the overall referral rate was 3.37% in the hrHPV group and 0.98% in the cytology group, with an adjusted risk ratio of 2.97 (95% CI 2.87 to 3.07). The overall rate for CIN2+ findings was 0.92% in the hrHPV group and 0.35% in the cytology group, with an adjusted risk ratio of 2.17 (95% CI 2.04 to 2.31). Cervical cancer rates were 0.03% (n=106) in the hrHPV group and 0.01% (n=134) in the cytology group, with an adjusted risk ratio of 2.02 (95% CI of 1.41 to 2.90).First and second full screening rounds Table 3 shows the results of the first and the second screening rounds in the hrHPV and cytology groups. During the study period, we had results for 340 495 first hrHPV screening rounds and 23 343 second hrHPV screening rounds at five year screening intervals; numbers for cytological screening were 922 121 and 288 729, respectively. The referral rate was 3.54% in the first hrHPV screening round and 2.42% in the second screening round, with an adjusted risk ratio of 0.77 (95% CI 0.71 to 0.84). The corresponding values for the cytology group were 1.00% and 0.92%, respectively, with an adjusted risk ratio of 0.90 (95% CI 0.85 to 0.95). The CIN2+ detection rate for hrHPV screening was 0.98% in the first hrHPV screening round and 0.38% in the second screening round, with an adjusted risk ratio of 0.57 (95% CI 0.46 to 0.72). In the cytology group, the corresponding values were 0.36% and 0.33%, respectively, with an adjusted risk ratio of 0.97 (95% CI 0.88 to 1.06). The cervical cancer rate in the hrHPV group was 0.03% in the first and 0.00% in the second screening round (n=1); the adjusted risk ratio was not reliable because of the small sample size. In the cytological screening group, the risk of cervical cancer was 0.01% in both screening rounds (n=101 v n=33 cancers), with an adjusted risk ratio of 0.57 (95% CI 0.34 to 0.94). Online supplemental table 3 shows the number of screening rounds by age group, screening method, and screening round. Compared with the results at age 30 years, we saw no clear differences if women screened by cytology at age 25 years were included or excluded from the analysis (online supplemental tables 1 and 2).SP510.1136/bmjmed-2025-001435.supp5Supplementary dataTable 3First and second screening round results in high risk human papillomavirus (hrHPV) based screening tests and cytological based screening testsScreening testFirst screening roundSecond screening roundAdjusted risk ratio (95% CI)hrHPV test: No of screening rounds340 495 (100)23 343 (100) Positive screening rounds26 612 (8.05)1 289 (5.52)0.85 (0.80 to 0.90) Follow-up recommendations22 871 (6.92)1 157 (4.96)0.87 (0.82 to 0.93) Referrals11 709 (3.54)564 (2.42)0.77 (0.71 to 0.84) CIN2+ detected3248 (0.98)88 (0.38)0.57 (0.46 to 0.72) Cervical cancers105 (0.03)1 (0.00)0.17 (0.02 to 1.24)*Cytological test: No of screening rounds922 121 (100)288 729 (100) Positive screening rounds46 755 (5.07)12 045 (4.17)1.0 (0.98 to 1.03) Follow-up recommendations39 252 (4.26)10 043 (3.47)1.03 (1.01 to 1.07) Referrals9267 (1.00)2628 (0.92)0.9 (0.85 to 0.95) CIN2+ detected3335 (0.36)962 (0.33)0.97 (0.88 to 1.06) Cervical cancers101 (0.01)33 (0.01)0.57 (0.34 to 0.94)Data are number (%) unless indicated otherwise.Data were collected from 2012 to 2020 to ensure inclusion of all follow-up information.Adjusted risk ratios (adjusted for screening age, screening year, education, and region) compared the outcomes of the second screening round with the first screening round. *Estimates are unreliable because of the small number of women.CI, confidence interval; CIN2+, cervical intraepithelial neoplasia ≥grade 2.We conducted a separate analysis of the data from the second screening round for women who had a positive or negative test result for hrHPV during the first screening round five years earlier (online supplemental table 4). In women who had a negative test result for hrHPV in the first round (n=314 286), we obtained second screening round data for 21 633 women; for women with a positive test result for hrHPV in the first round (n=26 085), we had data for 1710 women. The referral rate for colposcopy in the second round was 1.74% (n=377, 95% CI 1.57% to 1.93%) in the hrHPV negative group compared with 10.9% (n=187, 9.50% to 12.5%) in the hrHPV positive group. The rate of CIN2+ detection in women with a negative test result for hrHPV in the first screening round was 0.20% (n=44, 95% CI 0.15% to 0.27%) compared with 2.57% (n=44, 1.88% to 3.44%) in women with a positive test result for hrHPV in the first screening round.SP610.1136/bmjmed-2025-001435.supp6Supplementary dataIn hrHPV screening, women aged <50 years had an increased risk of all endpoint outcomes compared with women aged ≥50 years (online supplemental table 5). The colposcopy referral rate was 4.42% (95% CI 4.32% to 4.52%) for women aged <50 years and 2.40% (2.33% to 2.48%) for women aged ≥50 years. For detection of CIN2+, the rates were 1.48% (95% CI 1.43% to 1.54%) for the younger group and 0.39% (0.37% to 0.43%) for the older group. The risk of cervical cancer was 0.043% (95% CI 0.034% to 0.054%) and 0.02% (0.012% to 0.025%) for the younger and older groups, respectively. In the second screening round, the risk of all endpoint outcomes decreased across all age groups, but the difference between the age groups was less pronounced. Detection of CIN2+ was the only endpoint outcome where the confidence intervals did not overlap between age groups. Online supplemental figure 1 shows a comparison of hrHPV and cytological screening across all age groups in the first and second screening rounds.SP710.1136/bmjmed-2025-001435.supp7Supplementary dataSP210.1136/bmjmed-2025-001435.supp2Supplementary dataIn total, 6060 routine cytology tests, 253 follow-up tests (with cytology), and 5517 full cytological screening rounds were conducted in women with previous routine hrHPV testing. In a sensitivity analysis, we recalculated the results in tables 2 and 3 after excluding these tests. We found only a negligible effect on the results, and therefore these tests were also included in the analyses.CIN2+ by triage cytology in women with persistent positive test results for hrHPV In total, 30 705 of the 41 572 women recommended for follow-up after primary screening attended, and 32.1% (n=9849) of those were referred for colposcopy. Figure 2 shows the risk of histological CIN2+ finding by triage cytology results in different age groups. Overall, 5729 referrals for colposcopy were made because of persistent positive test results for hrHPV with no cytological changes. Histological CIN2+ was later diagnosed in 12.6% of these women (95% CI 11.8 % to 13.5%). By comparison, in women with cytology positive for atypical squamous cells, high grade cannot be ruled out, or atypical glandular cells, histological CIN2+ was diagnosed in 60.4% (95% CI 57.5% to 63.2%). The risk of detecting CIN2+ was 13-30% percentage points higher in younger age groups in all triage cytology result categories (online supplemental table 6).SP810.1136/bmjmed-2025-001435.supp8Supplementary dataFigure 2Proportion of women with histological cervical intraepithelial neoplasia grade ≥2 (CIN2+) in different age groups referred to colposcopy after persistent positive test results for high risk human papillomavirus (hrHPV), by triage cytology results. Shaded areas represent 95% confidence intervals. AGC-NOS=atypical glandular cells, not otherwise specified; ASC-H=atypical squamous cells, cannot exclude high grade squamous intraepithelial lesion; ASC-US=atypical squamous cells of undetermined significance; LSIL=low grade squamous intraepithelial lesionDiscussion Principal findings The gradual implementation of hrHPV screening in different regions of Finland allowed us to compare the performance of hrHPV screening with cytological screening, based on nationwide data from two consecutive screening rounds. In the first screening round, the hrHPV group had threefold higher rates for referral for colposcopy and detection of CIN2+ than the cytology group. Colposcopy referrals decreased by about 20% and CIN2+ detection rate by 40% in the second hrHPV screening round compared with the first hrHPV screening round, after adjusting for age and other factors. In the cytology screening group, we found no corresponding changes between the first and second screening rounds, suggesting that hrHPV screening detected precancerous lesions earlier than cytological screening. Furthermore, in the second hrHPV screening round, the rate of detection of CIN2+ was particularly low in women with a negative screening test in the first round.After the transition to hrHPV screening, the overall referral rates for colposcopy increased substantially, with women with persistently positive test results for hrHPV and normal cytology constituting the largest group. In this group, CIN2+ was detected in one in eight women. These histological abnormalities would likely have been missed with cytology based screening alone, underscoring the increased sensitivity of hrHPV based screening. We found a marked difference in precancer rates between younger and older age groups in follow-up screening. The risk of CIN2+ in women with no cytological abnormalities aged 30-40 years was 17-18%, whereas the risk was 5-7% in women aged 55-65 years. This age gradient could be considered when optimising future screening algorithms.Strengths and limitations of this study The main strength of this study was that we used a real world setting of a national screening programme, with more than two million individual hrHPV and cytological screening test results, corresponding to >1.5 million full screening rounds. Potential bias from differences in personal characteristics and temporal changes was dealt with by adjusting for screening year, age, region, and level of education. Other effect modifiers (eg, age at first sexual intercourse, smoking, and number of sexual partners) could not be accounted for, but we expect the adjustments to mitigate these limitations. Hence our approach provided a robust, large scale perspective of the performance of hrHPV and cytological screening, enabling a direct comparison under real life conditions.Our aim was to evaluate the results of an organised screening programme among those attending routine screenings. Including diagnoses made outside of the screening programme would have made interpreting the results more difficult because referrals and diagnoses based on symptoms or more frequent screening than recommended would then have been included. In Finland, however, 30% of all women participate in both organised and opportunistic testing, and about 20% undergo only non-organised testing.19 According to Hakkila et al, in organised screening in Finland between 2003 and 2015, the proportion of women who received a diagnosis of CIN2+ outside the screening programme was 0.2%, for both cytology and HPV based screening.20 Therefore, lack of diagnoses from other sources may have affected our crude rates of positive test results and derived variables, and hence these results may be too low. On the other hand, outside testing should not affect comparisons between the two groups because outside testing has previously been equally common in both groups in Finland.21Another limitation was that we could not distinguish between diagnoses of CIN2+ and CIN3+. At the time of data collection, histological abnormalities were widely coded by pathological laboratories only as low grade squamous intraepithelial lesion or high grade squamous intraepithelial lesion. The clinical significance of a diagnosis of CIN2+ is debated because of the high likelihood of spontaneous regression; about half of CIN2 lesions are estimated to regress, with only 20% progressing to ≥CIN3 within two years.22 Even if alternative conservative management strategies have been adopted for CIN2+ in some specific patient groups, CIN2 is still widely used as the threshold diagnosis for surgical treatment, especially among women aged >30 years, underscoring its clinical importance.In this study, the five year screening interval in Finland was used. After the transition to hrHPV screening, many countries have then extended their screening intervals to five years. Only a few studies have been published based on data from routine settings with a five year screening interval, however,13 23 and our study is considerably larger than previous ones. This makes our findings particularly valuable in understanding the longer term performance of hrHPV screening over extended intervals.Comparison with other studies hrHPV screening has been shown to detect more incidences of CIN2+ at the cost of increased referral rates in trials as well as in routine screening. 7 8 10–12 14 In hrHPV screening, the risk of colposcopy referral was threefold compared with cytology screening, with a notable difference between referral rates in routine and follow-up screening. In our study, the difference between referral rates in routine and follow-up screening (1.1% v 32%, with an overall referral rate of 3.0%) was substantially higher than the rates reported in Denmark (3.6% v 2.7%, with an overall referral rate of 6.4%)10 and in the UK (4.2% v 2.8%, with an overall referral rate of 7.1%).11 This phenomenon is likely attributable to the Finnish screening algorithm, where women with a positive test result for hrHPV but accompanied by cytology showing either negative for intraepithelial lesion or malignancy or ASC-US are invited for follow-up screening rather than direct colposcopy. In the UK and Denmark, women were immediately referred for colposcopy if their hrHPV test result was positive and cytology showed any grade of abnormality. Overall, the total referral rate of 2.97% was lower than in previous research, where total referral rates ranged from 3.0% to 7.1%.8–11 14 24 This finding could be related to the volume of cervical testing conducted outside the organised screening programme.To illustrate real life screening performance, we included all women participating in cervical screening in our second round analysis, including those who had a positive test result in the first screening round, in contrast with studies from the UK15 and Denmark10 where results were reported only for first round participants with a negative hrHPV test result. Online supplemental table 2 shows the results by hrHPV status in the first screening round. In our study, in hrHPV screening, the overall referral rate decreased by one percentage point from the first to the second screening round (3.5% to 2.4%), with an adjusted relative risk of 0.77 for the second screening round compared with the first. Similar findings were reported in previous studies conducted in Finland (from 4% to 2.9%), Denmark (from 6.4% to 3%), Norway (from 1.6% to 0.6%), and Italy (from 4.1% to 3.7%).10 13 14 25 The reduction in referral rates seen in the second hrHPV screening round was encouraging because the decreased specificity and consequently increased referral rate in hrHPV screening has been a concern. Whether further decreases will occur in subsequent rounds, however, is uncertain, or when a stable referral rate will be obtained.In our study, in hrHPV screening, the overall rate of detection of CIN2+ decreased by 0.6 percentage points from the first to the second screening rounds (0.98% to 0.38%), with 40% lower adjusted relative risk for the second than for the first screening round. Previously reported CIN2 rates in the second screening round varied between 0.2% and 0.6%.10 13 14 Studies excluding women with positive test results for hrHPV in the first screening round have reported lower CIN2+ rates in the second screening round, and in our study we also saw a clear difference between these two groups in the second screening round. CIN2+ was detected in 0.2% of women with a negative hrHPV test result in the first screening round, in 0.38% of all screened women, and in 2.6% of women with a positive hrHPV test result in the first screening round.In our study of a non-vaccinated population, we saw that nearly 60% of referrals in hrHPV screening occurred after follow-up screening, and 58% of these women showed persistent positive test results for hrHPV with normal cytology. In this group, CIN2+ was detected in one in eight women. These histological abnormalities would likely have been missed with cytology based screening alone, underscoring the increased sensitivity of hrHPV based screening. We found a marked difference in precancer rates between younger and older age groups in follow-up screening. The risk of CIN2+ in women with no cytological abnormalities aged 30-40 years was 17-18%, whereas the risk was 5-7% in women aged 55-65 years. This age gradient could be considered when optimising future screening algorithms.The likelihood of detecting CIN2+ was twice as high in women referred directly from routine screening than in those referred only after follow-up screening. Among women referred within primary and follow-up screening, CIN2+ was identified in 27% of those screened for hrHPV and in 36% of those screened with cytology, showing that hrHPV loses some specificity compared with cytology.Looking ahead, as the number of women who have received a HPV vaccine within the screening programme increases, the overall risk of cervical cancer and CIN3+, as well as the prevalence of HPV infections for vaccine related genotypes, should decrease.26 Meanwhile, the burden of HPV infections related to non-vaccine high risk HPV genotypes is expected to increase.27 In this context, improved triage strategies are needed for women with hrHPV positive test results. HPV genotyping,28 viral methylation,29 p16/Ki-67 dual staining,30 31 and host DNA methylation32 have shown potential for enhancing specificity without compromising sensitivity in referrals, but further research is needed to evaluate the effectiveness and implementation of these new approaches.The risk of progression to cancer differs substantially by hrHPV type, with HPV16, HPV18, and HPV45 strains being the most carcinogenic.33 Triaging women with hrHPV positive test results with HPV genotyping has been adopted in several countries. This approach has shown a higher negative predictive value than cytology based triaging, meaning that the risk of subsequent cervical cancer is lower in those who have a negative test result.34 A recent Swedish study showed that women who had a positive test result for HPV16 or HPV18 but with normal cytology had an even higher risk of developing cervical cancer over the next eight years than women with a positive test result for any hrHPV type and any cytological abnormalities.28 To enhance the effectiveness of these screening programmes, incorporating extended hrHPV genotyping may be beneficial. Also, lengthening the screening interval in populations at lower risk, such as women aged ≥50 years, women who have received a HPV vaccine, or those with a history of negative hrHPV test results, should be considered.Conclusions In this study, we found that in the first round of hrHPV screening, the risk of both referral for colposcopy and detection of CIN2+ were higher than with cytological screening. In the second screening round at five years, the risk of referral and CIN2+ detection decreased in hrHPV screened but not in cytology screened women, indicating that hrHPV screening detected precancerous lesions earlier than cytological screening. The five year screening interval for hrHPV screening for all age groups seemed to be effective and safe. Screening programmes by hrHPV testing should extend the screening interval to five years. In populations at lower risk, such as women aged ≥50 years, women who have received a HPV vaccine, or those with a history of negative hrHPV test results, an even longer screening interval should be considered.SP110.1136/bmjmed-2025-001435.supp1Supplementary data",
  "title": "High risk human papillomavirus versus cytological screening over two rounds in Finnish screening programme for cervical cancer: population based cohort study",
  "uid": "c208fc28-d5b9-54b9-8dfd-1c2dae6125d8"
}