Norwegian Cervical Cancer Screening Program Research Articles

Risk of Intraepithelial Neoplasia Grade 3 or Worse (CIN3+) among Women Examined by a 5-Type HPV mRNA Test during 2003 and 2004, Followed through 2015.

The study's purpose was to evaluate the performance of a five-type HPV mRNA test to predict cervical intraepithelial neoplasia grade 3 or worse (CIN3+) during up to 12 years of follow-up. Overall, 19,153 women were recruited by gynecologists and general practitioners in different parts of Norway between 2003 and 2004. The study population comprised 9582 women of these women, aged 25-69 years with normal cytology and a valid five-type HPV mRNA test at baseline. Follow-up for CIN3+ through 2015 was conducted in the Norwegian Cervical Cancer Screening Programme. The cumulative incidence of CIN3+ by baseline status for HPV mRNA-positive and mRNA-negative women were 20.8% and 1.1%, respectively (p < 0.001). Age did not affect the long-term ability of the HPV mRNA test to predict CIN3+ during follow-up. The low long-term risk of CIN3+ among HPV mRNA-negative women and the high long-term risk among HPV mRNA-positive women strengthen the evidence that the five-type HPV mRNA test is an appropriate screening test for women of all ages. Our findings suggest that women with a negative result may extend the screening interval up to 10 years.

May Women with a Negative Co-Test at First Follow-Up Visit Return to 3-Year Screening after Treatment for Cervical Intraepithelial Neoplasia?

The Norwegian Cervical Cancer Screening Programme recommends that women treated for cervical intraepithelial neoplasia (CIN) only be returned to 3-year screening after receiving two consecutive negative co-tests, 6 months apart. Here we evaluate adherence to these guidelines and assessed the residual disease, using CIN3+ as the outcome. This cross-sectional study comprised 1397 women, treated for CIN between 2014 and 2017, who had their cytology, HPV, and histology samples analyzed by a single university department of pathology. Women who had their first and second follow-up at 4-8 and 9-18 months after treatment were considered adherent to the guidelines. The follow-up ended on 31 December 2021. We used survival analysis to assess the residual and recurrent CIN3 or worse among women with one and two negative co-tests, respectively. 71.8% (1003/1397) of women attended the first follow-up 4-8 months after treatment, and 38.3% were considered adherent at the second follow-up. Nearly 30% of the women had incomplete follow-up at the study end. None of the 808 women who returned to 3-year screening after two negative co-tests were diagnosed with CIN3+, whereas two such cases were diagnosed among the 887 women who had normal cytology/ASCUS/LSIL and a negative HPV test at first follow-up (5-year risk of CIN3+: 0.24, 95%, CI: 0.00-0.57 per 100 woman-years). The high proportion of women with incomplete follow-up at the end of the study period requires action. The risk of CIN3+ among women with normal cytology/ASCUS/LSIL and a negative HPV test at first follow-up is indicative of a return to 3-year screening.

Impact of the Mobile Game FightHPV on Cervical Cancer Screening Attendance: Retrospective Cohort Study

The wide availability of mobile phones has made it easy to disseminate health-related information and make it accessible. With gamification, mobile apps can nudge people to make informed health choices, including attending cervical cancer screening. This matched retrospective cohort study examined the association between exposure to the FightHPV mobile app gamified educational content and having a cervical exam in the following year. Women aged 20 to 69 years who signed an electronic consent form after downloading the FightHPV app in 2017 (intervention group) were matched 1:6 with women of the same age and with the same screening history (reference group) in 2015. To estimate the impact of exposure to the FightHPV app, we estimated cumulative incidence and hazard ratios (HRs) with 95% CIs. We used data from the Norwegian Cervical Cancer Screening Program database and Statistics Norway to determine screening participation and outcomes, respectively. We matched 3860 women in the control group to 658 women in the intervention group; 6 months after enrollment, 29.6% (195/658) of the women in the intervention group and 15.21% (587/3860) of those in the reference group underwent a cervical exam (P<.01). Women exposed to the FightHPV app were 2 times more likely to attend screening (adjusted HR 2.3, 95% CI 2.0-2.7), during which they were 13 times more likely to be diagnosed with high-grade abnormality (adjusted HR 12.7, 95% CI 5.0-32.5) than the women in the reference group. Exposure to the FightHPV app significantly increased cervical cancer screening attendance across the various analyses and improved detection of women with high risk for cervical cancer. For the first time, we demonstrated the effectiveness of gamification combined with mobile technology in cancer prevention by empowering women to make active health-related decisions. Gamification can significantly improve the understanding of complicated scientific concepts behind interventions and increase the acceptance of proposed cancer control measures.

Do they cope or mope? A survey of GPs’ experiences with the changes in the Norwegian Cervical Cancer Screening Programme

Objective To explore Norwegian general practitioners’ (GPs) experiences with the changes in the cervical cancer screening programme and to uncover which aspects of the programme they find most challenging. Design We conducted an electronic cross-sectional survey. Setting Norwegian GPs were invited to participate in the survey between February and September in 2020. Subjects One hundred and fifty-five of 429 invited Norwegian GPs responded. Main outcome measures Self-reported measures were used to analyse GPs experiences and beliefs related to the screening programme. Results Most GPs did not find it particularly challenging to keep up with the changes in the screening programme, regardless of whether they came from areas with HPV-based or cytology-based cervical cancer screening implemented. Challenges concerning the follow-up of patients after an abnormal test were a frequently reported issue. We did not find any differences in how often GPs were uncertain of the follow-up of an abnormal test result in areas with HPV-based compared to cytology-based screening. Conclusions The implementation of HPV-based cervical cancer screening in women 34–69 years does not seem to have affected how challenging the GPs perceive the screening programme. Key Points How Norwegian general practitioners (GPs) keep up with changes in the Norwegian Cervical Cancer Screening Programme (NCCSP) has not been assessed previously. Most GPs did not find it particularly challenging to keep up with changes in the NCCSP regardless of whether they belonged to an area of HPV-based or cytology-based screening. The follow-up of patients with an abnormal test result was one of the main challenges reported by the GPs.

Risk for Cervical Intraepithelial Neoplasia Grade 3 or Higher in Follow-Up of Women With a Negative Cervical Biopsy

The Norwegian Cervical Cancer Screening Programme recommends follow-up of histologically confirmed normal/cervical intraepithelial neoplasia (CIN) 1 with combined cytology and human papillomavirus testing within 6 to 12 months. This study examines adherence to guidelines and subsequent risk for CIN 3+ within this subset of women. Women aged 25 to 69 years attending the Norwegian Cervical Cancer Screening Programme in Norway's 2 northernmost counties were included. An exposed cohort with histologically confirmed normal/CIN 1 after an atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion or atypical squamous cells - cannot exclude high-grade squamous intraepithelial lesion/high-grade squamous intraepithelial lesion enrolment cytology (n = 374) was compared with a nonexposed cohort with a normal enrolment cytology attending primary screening (N = 25,948). Risk calculations were stratified by outcomes of the first follow-up cytology. The study end point was CIN 3+ or censored at 78 months of follow-up. In the exposed cohort, the 42-month cumulative incidence of CIN 3+ was 9.4% (95% CI = 4.1-14.7) for women with an abnormal first follow-up cytology and 1.6% (95% CI = 0.0-3.4) for women with a normal first follow-up cytology versus 0.21% (95% CI = 0.15-0.27) in the nonexposed cohort (p < .01). The CIN 3+ risk was higher in the exposed cohort when the first follow-up cytology was abnormal (hazard ratio = 20.4, 95% CI = 11.2-37.1) compared with normal (hazard ratio = 4.7, 95% CI = 1.9-11.6) with the nonexposed cohort as reference. After a negative cervical biopsy, a normal first follow-up cytology provided a CIN 3+ risk considered acceptable to recommend return to routine screening in 3 years. Cytology and human papillomavirus co-testing in post-colposcopy follow-up of negative biopsies may improve risk stratification.

Can an inadequate cervical cytology sample in ThinPrep be converted to a satisfactory sample by processing it with a SurePath preparation?

Background:The Norwegian Cervical Cancer Screening Program recommends screening every 3 years for women between 25 and 69 years of age. There is a large difference in the percentage of unsatisfactory samples between laboratories that use different brands of liquid-based cytology. We wished to examine if inadequate ThinPrep samples could be satisfactory by processing them with the SurePath protocol.Materials and Methods:A total of 187 inadequate ThinPrep specimens from the Department of Clinical Pathology at University Hospital of North Norway were sent to Akershus University Hospital for conversion to SurePath medium. Ninety-one (48.7%) were processed through the automated “gynecologic” application for cervix cytology samples, and 96 (51.3%) were processed with the “nongynecological” automatic program.Results:Out of 187 samples that had been unsatisfactory by ThinPrep, 93 (49.7%) were satisfactory after being converted to SurePath. The rate of satisfactory cytology was 36.6% and 62.5% for samples run through the “gynecology” program and “nongynecology” program, respectively. Of the 93 samples that became satisfactory after conversion from ThinPrep to SurePath, 80 (86.0%) were screened as normal while 13 samples (14.0%) were given an abnormal diagnosis, which included 5 atypical squamous cells of undetermined significance, 5 low-grade squamous intraepithelial lesion, 2 atypical glandular cells not otherwise specified, and 1 atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion. A total of 2.1% (4/187) of the women got a diagnosis of cervical intraepithelial neoplasia 2 or higher at a later follow-up.Conclusions:Converting cytology samples from ThinPrep to SurePath processing can reduce the number of unsatisfactory samples. The samples should be run through the “nongynecology” program to ensure an adequate number of cells.

Protecting Privacy in Large Datasets—First We Assess the Risk; Then We Fuzzy the Data

Background: Privacy of information is an increasing concern with the availability of large amounts of data from many individuals. Even when access to data is heavily controlled, and the data shared with researchers contain no personal identifying information, there is a possibility of reidentifying individuals. To avoid reidentification, several anonymization protocols are available. These include categorizing variables into broader categories to ensure more than one individual in each category, such as k-anonymization, as well as protocols aimed at adding noise to the data. However, data custodians rarely assess reidentification risks.Methods: We assessed the reidentification risk of a large realistic dataset based on screening data from over 5 million records on 0.9 million women in the Norwegian Cervical Cancer Screening Program, before and after we used old and new techniques of adding noise (fuzzification) of the data.Results: Categorizing date variables (applying k-anonymization) substantially reduced the possibility of reidentification of individuals. Adding a random factor, such as a fuzzy factor used here, makes it even more difficult to reidentify specific individuals.Conclusions: Our results show that simple techniques can substantially reduce the risk of reidentification.Impact: Registry owners and large-scale data custodians should consider estimating and if necessary, reducing reidentification risks before sharing large datasets. Cancer Epidemiol Biomarkers Prev; 26(8); 1-6. ©2017 AACR.

Clinical value of fully automated p16/Ki-67 dual staining in the triage of HPV-positive women in the Norwegian Cervical Cancer Screening Program.

More accurate biomarkers in cervical cytology screening could reduce the number of women unnecessarily referred for biopsy. This study investigated the ability of p16/Ki-67 dual staining to predict high-grade cervical intraepithelial neoplasia (CIN) in human papillomavirus (HPV)-positive women from the Norwegian Cervical Cancer Screening Program. Automated p16/Ki-67 dual staining was performed on liquid-based cytology samples from 266 women who were HPV-positive at their secondary screening. At a mean of 184 days after p16/Ki-67 staining, 201 women had a valid staining result and a conclusive follow-up diagnosis (histological diagnosis or HPV-negative diagnosis with normal cytology findings). The sensitivity and specificity for predicting the follow-up diagnosis were compared for cytology, p16/Ki-67 dual staining, and their combination. Sixty-seven percent of the study sample was p16/Ki-67-positive. The sensitivity of p16/Ki-67 staining for predicting CIN-2/3 was statistically significantly higher than the sensitivity of cytology (0.88 vs 0.79; P = .008), but this was not true for the prediction of CIN-3 (0.94 vs 0.88; P = .23). The specificity of cytology for predicting CIN-3 was significantly higher than the specificity of p16/Ki-67 staining (0.35 vs 0.28; P = .002), but this was not true for CIN-2/3 (0.35 vs 0.31; P = .063). For predicting CIN-2/3 and CIN-3, combination testing gave potentially better sensitivity (0.95 and 0.96, respectively) and better specificity (0.49 and 0.50, respectively). In a population of HPV-positive women, p16/Ki-67 dual staining was more sensitive but less specific than cytology for predicting high-grade CIN. The advantage of using both tests in different combinations is the potential for increasing the specificity or sensitivity in comparison with both methods performed individually. Cancer Cytopathol 2017;125:283-291. © 2016 American Cancer Society.

300O Assessment of the effectiveness of cervical cancer screening

Background According to the US Center for Disease Control (CDC 2013), a reliable statistical tendency of decreasing cervical cancer incidence and mortality caused by this disease has beenrecorded in the United States over the recent 40 years that isrelated tohigh rate coverage of the female population by Pap-test screening. This tendency is proved by American Cancer Society (ACS, 2012).According to Gold M.A. (2006), 7080% decrease of cervical cancer incidence has been achieved by Pap test screening in developed countries. According to the Norwegian Cervical Cancer Screening Program (NCCSP, 2014), screening has contributed to 25% decrease of cervical cancer incidence and 50% decrease of mortality caused by this disease in Norway.According to Nanda K. et al. (2000) data, in case of cervical cancer CIN 2/3, Pap test sensitivity and specificity vary within the range 47% - 62% and 60% - 85% correspondingly. Methods We have studied the cost-effectiveness of cervical cancer screening program, based on5 yearperiod data (2010 -2014): 66,324 women received gynecological examination and Pap test and 12,147 received colposcopy, targeted biopsy and morphologicalanalysis.In2013, 13 584womenreceivedcervicalcancerscreening, amongthem7,416womenattheNationalScreeningCenter(NCC).Theindicatorsof diagnostic effectiveness of gynecological examination, Pap test, colposcopy and combination of a Pap test and colposcopy have been studied based on NCC data with a purpose of assessment. Results In 2013, the prevalence of cervical severe dysplasia(CIN3) and intraepithelial carcinoma(CIS) per1,000 female population eligible forscreeningconstituted 9,8% and cancer prevalence was 6,1%. The study has found that making of alterations in a screening guideline and re-adjusting of a target group from 25-59 to 30-64 age group will increase the number of detected cervical cancer cases and decrease needed expenditures: in case of 50% coverage of a target group by ~93,000 GEL and by ~ 130,000 GEL in case of 70% coverage. Conclusions >Makingofalterationstothescreeningguidelineandreadjustingofa targetgroupto3064agegroupwillsignificantlyenhancethecosteffectivenessofcervical cancer screening. Legal entity responsible for the study National Screening Center Funding National Screening Center Disclosure All authors have declared no conflicts ofinterest.

Personal and provider level factors influence participation to cervical cancer screening: A retrospective register-based study of 1.3 million women in Norway

High coverage is essential for an effective screening programme. Here we present screening barriers and facilitators among 1.3 million women aged 25–69years eligible for screening within the Norwegian Cervical Cancer Screening Program (NCCSP). We defined non-adherence as no screening test in 2008–2012. We divided adherent women into those screened spontaneously, and those who had a smear after receiving a reminder from the NCCSP. Explanatory variables were extracted from several nationwide registers, and modelled by modified Poisson regression. In total, 34% of women were non-adherent. 31% of native Norwegians were non-adherent, compared to 50% of immigrants. Immigrant status was a strong predictor of non-adherence, but the vast majority of non-adherent women were still native Norwegians. Higher non-adherence rates were associated with having a male general practitioner (GP), a foreign GP, a young GP, and distance to the screening site. Being unmarried, having no children, having lower socioeconomic position and region of residence predicted non-adherence and, to a smaller extent, reminded adherence to screening. In contrast, previous experience with cervical abnormalities substantially increased adherence to screening. The population-based screening programme promotes equity by recruiting women who are less likely to participate spontaneously. However, socioeconomic disparities were evident in a country with a nationwide programme and a policy of equal access to health care. Initiatives aimed at removing practical and financial barriers to equitable screening delivery and at reducing the effect of sociodemographic attributes on screening participation are needed.

Using Decision-Analytic Modeling to Isolate Interventions That Are Feasible, Efficient and Optimal: An Application from the Norwegian Cervical Cancer Screening Program

BackgroundDecision makers often need to simultaneously consider multiple criteria or outcomes when deciding whether to adopt new health interventions. ObjectivesUsing decision analysis within the context of cervical cancer screening in Norway, we aimed to aid decision makers in identifying a subset of relevant strategies that are simultaneously efficient, feasible, and optimal. MethodsWe developed an age-stratified probabilistic decision tree model following a cohort of women attending primary screening through one screening round. We enumerated detected precancers (i.e., cervical intraepithelial neoplasia of grade 2 or more severe (CIN2+)), colposcopies performed, and monetary costs associated with 10 alternative triage algorithms for women with abnormal cytology results. As efficiency metrics, we calculated incremental cost-effectiveness, and harm-benefit, ratios, defined as the additional costs, or the additional number of colposcopies, per additional CIN2+ detected. We estimated capacity requirements and uncertainty surrounding which strategy is optimal according to the decision rule, involving willingness to pay (monetary or resources consumed per added benefit). ResultsFor ages 25 to 33 years, we eliminated four strategies that did not fall on either efficiency frontier, while one strategy was efficient with respect to both efficiency metrics. Compared with current practice in Norway, two strategies detected more precancers at lower monetary costs, but some required more colposcopies. Similar results were found for women aged 34 to 69 years. ConclusionsImproving the effectiveness and efficiency of cervical cancer screening may necessitate additional resources. Although efficient and feasible, both society and individuals must specify their willingness to accept the additional resources and perceived harms required to increase effectiveness before a strategy can be considered optimal.

Results of delayed triage by HPV testing and cytology in the Norwegian Cervical Cancer Screening Programme

Background. High-risk human papilloma virus (hrHPV) testing was added to the cytology triage of women with equivocal screening smears in the Norwegian programme for cervical cancer screening in 2005. In this population-based observational before and after study we assessed the effect of changing the screening algorithm.Material and methods. In periods before and after the change 75 852 and 66 616 women, respectively, were eligible for triage, i.e. they had smear results of unsatisfactory, atypical squamous cells of undetermined significance (ASC-US), or low-grade squamous intraepithelial lesion (LSIL) at routine screening. The triage was delayed as supplementary testing started six months after the initial screening. The groups were compared with respect to results of triage and later three-year cumulative incidence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+).Results. Before and after the change in the screening algorithm 5.2% (3964/75 852) and 8.1% (5417/66 616) of women, respectively, were referred to colposcopy. Among women referred to colposcopy cumulative incidence of CIN2+ (positive predictive value of referral) increased from 42.0% [95% confidence interval (CI): 40.3 − 43.7%] in the period with cytology only to 48.0% (95% CI 46.6 − 49.4%) after the start of HPV testing. For women recalled to ordinary screening the three-year cumulative incidence decreased from 2.7% (95% CI 2.5 − 2.9%) to 1.0% (95% CI 0.9 − 1.2%) during the same period. Among women with LSIL at routine screening and HPV testing in triage, 52.5% (1976/3766) were HPV positive.Conclusion. The new algorithm with HPV testing implemented in 2005 resulted in an increased rate of referral to colposcopy, but in a better risk stratification with respect to precancerous disease.

Comparative effectiveness study on human papillomavirus detection methods used in the cervical cancer screening programme

ObjectivesTo compare the short-term and long-term effectiveness of human papillomavirus (HPV) tests in Norwegian Cervical Cancer Screening Programme (NCCSP).DesignNationwide register-based prospective follow-up study.SettingIn 2005, the NCCSP implemented HPV testing in...

HPV mRNA test in women with minor cervical lesions: Experience of the University Hospital of North Norway

In the Norwegian Cervical Cancer Screening Programme tests for detection of human papillomavirus (HPV) are used to triage women with minor cytological cervical lesions. The material in this study comprises samples from 1798 women in the period 2006–2008. The HPV test was performed according to the guidelines of the Norwegian Cancer Registry. The HPV mRNA test (PreTect HPV-Proofer) detects and types 5 high-risk genotypes (16, 18, 31, 33 and 45). The HPV mRNA results were compared to cytology and then biopsy up to December 2009. Women with minor cytological cervical lesions and negative HPV test were followed with a new PAP smear after 12 months. A total of 327 women (18%) were HPV mRNA positive. Of the 1798 women with minor cytological lesions, 232 women (13%) had moderate dysplasia, severe dysplasia or cancer and 144 women (8%) had severe dysplasia or cancer in biopsy. 57% of the women with a positive HPV mRNA test had moderate dysplasia, severe dysplasia or cancer. 37% had severe dysplasia or cancer. The sensitivity of the HPV mRNA test to detect moderate dysplasia, severe dysplasia or cancer was 81%. The specificity for moderate dysplasia, severe dysplasia or cancer was 91%. The negative predictive value (NPV) of the HPV mRNA test for moderate dysplasia, severe dysplasia or cancer was 97%. Of 11 women with cervical cancer, 10 were positive for HPV type 16 or 18.The HPV mRNA test seems more suitable than HPV DNA tests to triage women with minor cytological cervical lesions due to its higher specificity.

Predicting CIN2+ when detecting HPV mRNA and DNA by PreTect HPV‐proofer and consensus PCR: A 2‐year follow‐up of women with ASCUS or LSIL pap smear

It has been suggested that human papillomavirus (HPV) testing improves follow-up of atypical cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) in cervical cancer screening programs. To evaluate the prognostic value of including HPV testing as an adjunct to cytology, we carried out a 2-year follow-up study of 77 women with ASCUS or LSIL Papanicolaou (Pap) smear in the Norwegian Cervical Cancer Screening Program (NCCSP) for detection of histological cervical intraepithelial neoplasia (CIN) 2+. The study includes a comparison between viral mRNA and DNA detection. PreTect HPV-Proofer was used for HPV E6/E7 mRNA detection from the 5 high-risk types 16, 18, 31, 33 and 45, and Gp5+/6+ consensus PCR was used for HPV DNA detection. Twice as many women were positive for HPV DNA (54.6%) than for HPV mRNA (23.4%). PreTect HPV-Proofer and consensus PCR had a sensitivity of 85.7% (95% confidence interval [CI] = 42.1-99.6) for detecting CIN2+ during follow-up. The specificity was significantly higher for PreTect HPV-Proofer, 84.9% (95% CI = 73.9-92.5), than for consensus PCR, 50.0% (95% CI = 37.4-62.6). PreTect HPV-Proofer positive women were 69.8 times (95% CI = 4.3-1137.3) more likely to be diagnosed with CIN2+ within 2 years than PreTect HPV-Proofer negative women. Consensus PCR-positive women were 5.7 times (95% CI = 0.6-52.0) more likely to be diagnosed with CIN2+ within 2 years than PCR-negative women. With equal sensitivity and higher specificity than consensus PCR, the PreTect HPV-Proofer might offer an improvement for the triage of women with ASCUS or LSIL Pap smear.