Gry B. Skare

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.

The cervical cancer screening programme in Norway, 1992–2000: changes in Pap smear coverage and incidence of cervical cancer

OBJECTIVES: Changes in the incidence of cervical cancer were studied to assess the impact of the Norwegian coordinated cervical cancer screening programme introduced in 1995. Attention was given as to whether recommendation letters sent to women without a screen in the previous 3 years could be an alternative to a conventional screening programme that invites women irrespectively of their spontaneous screening. SETTING: A population based, nationwide, screening programme in which women of 25 to 69 are recommended to have a conventional Pap smear every 3 years. METHODS: The impact of the screening programme was assessed indirectly by comparing trends in invasive cervical cancer, changes in coverage, and changes in interval between Pap smears in the 3 year period (1992–4) before screening with the two first screening rounds (1995–7 and 1998–2000). All Pap smears taken from women of all ages were included, a total of 4 744 967 Pap smears from more than 1.4 million women. Further, the impact was assessed directly by logistic regression by comparing the screening results of women recruited for the programme with women who had regularly had Pap smears. RESULTS: In the last 2 years studied, the incidence of invasive cancer was 22% lower than in the period before the programme. The proportion of women who had a Pap smear was higher after the implementation of the coordinated screening programme. The number of smears taken was less as the interval after a normal smear was greater. The newly recruited women had a threefold risk of having a high grade precursor and a 20-fold higher risk of cancer than the women who had had regular smears. CONCLUSIONS: The coordinated screening programme provides a low cost way of increasing the coverage of the female population, and consequently has reduced the rate of invasive cervical cancer.

Prospective seroepidemiologic study of human papillomavirus and other risk factors in cervical cancer

Background: Several sexually transmitted infections (STI) have been reported to interact with human papillomavirus (HPV) in the etiology of cervical cancer. A large cohort study is required to obtain a both unbiased and stable estimate of their effects. Methods: Four major biobanks in the Nordic Countries containing samples from about 1,000,000 subjects were linked with nation-wide cancer registries. Serum samples from 604 women with invasive cervical cancer (ICC) diagnosed on average 10 years after sampling and 2,980 matched control women were retrieved and analyzed with serology for key STI. Results: Exposure to HPV16 was the strongest risk factor for cervical cancer [OR = 2.4; 95% confidence interval (CI), 2.0–3.0], particularly for squamous cell carcinoma (OR = 2.9; 95% CI, 2.2–3.7). HPV18 was strongly associated with increased risk for adenocarcinoma (OR = 2.3; 95% CI, 1.3–4.1). Baseline seropositivity for HPV16 did not confer any increased risk for HPV18 DNA-positive cancer and conversely HPV18 seropositivity had no association with HPV16 DNA-positive cancers. HPV6 had no effect on its own (OR = 1.1; 95% CI, 0.9–1.3), but had an antagonistic effect on the risk conferred by HPV16 (P < 0.01). Herpes simplex virus 2 had little or no association (OR = 1.1; 95% CI, 0.8–1.4). Previous exposure to Chlamydia trachomatis, as indicated by serum antibodies, had a strongly increased risk for cervical cancer (OR = 1.9; 95% CI, 1.5–2.3). Conclusions: A large prospective study has assessed the role of different STIs in cervical cancer. Impact: Prospective evidence supports cofactor role of some STI in cervical cancer. Cancer Epidemiol Biomarkers Prev; 20(12); 2541–50. ©2011 AACR.

Factors associated with non-attendance, opportunistic attendance and reminded attendance to cervical screening in an organized screening program: a cross-sectional study of 12,058 Norwegian women

BackgroundCervical cancer incidence and mortality may be reduced by organized screening. Participant compliance with the attendance recommendations of the screening program is necessary to achieve this. Knowledge about the predictors of compliance is needed in order to enhance screening attendance.MethodsThe Norwegian Co-ordinated Cervical Cancer Screening Program (NCCSP) registers all cervix cytology diagnoses in Norway and individually reminds women who have no registered smear for the past three years to make an appointment for screening. In the present study, a questionnaire on lifestyle and health was administered to a random sample of Norwegian women. The response rate was 68%. To address the predictors of screening attendance for the 12,058 women aged 25-45 who were eligible for this study, individual questionnaire data was linked to the cytology registry of the NCCSP. We distinguished between non-attendees, opportunistic attendees and reminded attendees to screening for a period of four years. Predictors of non-attendance versus attendance and reminded versus opportunistic attendance were established by multivariate logistic regression.ResultsWomen who attended screening were more likely than non-attendees to report that they were aware of the recommended screening interval, a history of sexually transmitted infections and a history of hormonal contraceptive and condom use. Attendance was also positively associated with being married/cohabiting, being a non-smoker and giving birth. Women who attended after being reminded were more likely than opportunistic attendees to be aware of cervical cancer and the recommended screening interval, but less likely to report a history of sexually transmitted infections and hormonal contraceptive use. Moreover, the likelihood of reminded attendance increased with age. Educational level did not significantly affect the womens attendance status in the fully adjusted models.ConclusionsThe likelihood of attendance in an organized screening program was higher among women who were aware of cervical screening, which suggests a potential for a higher attendance rate through improving the public knowledge of screening. Further, the lower awareness among opportunistic than reminded attendees suggests that physicians may inform their patients better when smears are taken at the physicians initiative.

Incidence, survival and mortality in cervical cancer in Norway, 1956–1990

Long-term trends in incidence, survival and mortality were examined in women with squamous cell carcinoma and adenocarcinoma of the uterine cervix, diagnosed in Norway in the 35-year period 1956-1990. During the 1970s the number of cervical smears increased substantially in Norway, although no organised screening programme was introduced. Special attention was paid to the time period 1971-1990 to evaluate the effect of the extensive spontaneous screening. In addition, the prognostic importance of clinical stage and age was explored. In the squamous cell carcinoma patients the incidence rate peaked in the time period 1971-1975, since when there has been a decrease. In the adenocarcinoma patients the incidence rate rose through the years 1976-1990. Also, the proportion of adenocarcinomas increased in this time period. The mortality rates in both histological types declined modestly through the years 1966-1990. A more favourable stage distribution was noted among the squamous cell carcinomas (P = 0.00), but not among the adenocarcinomas, when comparing the two diagnostic periods 1971-1975 and 1981-1985. The multivariate analysis (GLIM) revealed that stage was the most important prognostic factor in both histological types (P = 0.00). In the squamous cell carcinoma patients the relative rate increased (P = 0.04) in the last period. There was a tendency towards a poorer prognosis in younger women in this group, but age did not prove to be an important prognostic factor (P = 0.08).

CIN 2/3 and cervical cancer after an ASCUS pap smear. A 7-year, prospective study of the Norwegian population-based, coordinated screening program.

OBJECTIVE To estimate the risk of being diagnosed with cervical intraepithelial neoplasia (CIN) 2/3 or invasive cervical cancer (ICC) based on diagnostic and screening procedures performed after a diagnosis of atypical squamous cells of undetermined significance (ASCUS) and to compare this risk to that in women with a normal Pap smears. STUDY DESIGN A 7-year, prospective, cohort study was performed in the Norwegian population-based, coordinated screening program. After excluding women in the midst of follow-up of an abnormal Pap smear or with a history of CIN 2/3 or ICC, the study population consisted of women 25-69 years of age with a normal (n = 526,661) or ASCUS Pap smear (n = 10,037) in 1995-1996. Risk estimates were calculated by logistic and parametric survival regression. RESULTS Within 7 years of an ASCUS smear, 1,017 women (10.1%) were diagnosed with CIN 2/3 and 62 (0.62%) with ICC. Women with an ASCUS index Pap smear had a relative risk of 15-30 of being diagnosed with histologically verified CIN 2/3 or ICC within the first 2 years of follow-up as compared to women with a normal index smear. In long-term follow-up, women with an ASCUS index smear followed by a normal smear, which cancelled further clinical follow-up, were at > 3.5 times higher risk of both CIN 2/3 and invasive cancer as compared to women with a normal index smear. CONCLUSION Pap smear follow-up of women with an ASCUS smear does not identify all women at higher risk of CIN 2/3 and ICC. Other diagnostic procedures should be implemented to improve the screening program.

CIN 2/3 and cervical cancer in an organised screening programme after an unsatisfactory or a normal Pap smear: a seven-year prospective study of the Norwegian population-based screening programme

Objectives: To estimate the risk of cervical intraepithelial neoplasia (CIN) 2/3 and invasive cervical cancer (ICC) in an organised screening programme after an unsatisfactory or a normal Pap smear. Setting: A seven-year prospective cohort study of the Norwegian population-based co-ordinated screening programme based on the actual diagnostic and screening procedures performed. Observations of 526,661 women with a normal index Pap smear and 21,405 women with an unsatisfactory index Pap smear were made during 3.26 million women-years. Methods: The risk of being diagnosed with CIN 2/3 or ICC was calculated by logistic regression for the first two years of follow-up. The hazard of being diagnosed with CIN 2/3 or ICC for the women who were not diagnosed during the two first years was estimated by non-parametrical survival regression. Results: After two years of follow-up, 0.2% of the women were diagnosed with CIN 2/3 and 0.01% with ICC after a normal Pap smear. An unsatisfactory Pap smear indicated a 1.6-4.0 times higher risk of harbouring a CIN 2/3 or ICC compared to women with a normal Pap smear. No increased risk of ICC was found during long-term follow-up for the 70% of the women with an unsatisfactory Pap smear who were returned to ordinary screening. Prior series of low-grade Pap smears followed by a normal Pap were associated with an increased risk of CIN 2/3 and ICC. Conclusions: An unsatisfactory Pap smear indicates a risk of harbouring CIN II/III or ICC. Repeated Pap smears are adequate as a follow-up of an unsatisfactory Pap smear. Women with repeated series of equivocal/LSIL Pap smears followed by a normal Pap should be considered at high risk.

Awareness of human papillomavirus in a cohort of nearly 70,000 women from four Nordic countries

Objective. To assess the fraction of women who have heard of human papillomavirus (HPV) in four Nordic countries (Denmark, Iceland, Norway, and Sweden) and to study the correlates of this awareness, just before the vaccines were released. Design. Population‐based cross‐sectional study by means of a questionnaire. Setting. Denmark 2004–2005. Population. A total of 69,147 women participated (participation rate of 65%) in the study. Methods. A random sample of women from the general female population (18–45 years) in Denmark, Iceland, Norway, and Sweden were invited to answer a self‐administered questionnaire regarding HPV and lifestyle habits. Main outcome measures. Having heard of HPV. Results. Overall, a total of 32.6% had ever heard about HPV. Respectively, only 25.1% of Danish women, 33.0% Norwegian women, 32.5% Swedish women, and 41.0% Icelandic women had heard about HPV. The most important correlates associated with ever having heard of HPV were a history of genital warts (odds ratios, OR=2.57; 99% confidence intervals, CI: 2.38–2.76) and educational level (OR=2.06; 99% CI: 1.92–2.21). Other correlates associated with awareness of HPV were being single during pregnancy, never having been pregnant, former use of hormonal contraceptives and condom use. Conclusions. Our data suggest that at least two‐thirds of Nordic women have never heard of HPV. These data are important for developing and evaluating strategies to inform and educate the population about HPV infection and disease.

Mass screening for cervical cancer in Norway: evaluation of the pilot project

The Norwegian Department of Health and Social Affairs initiated a national screening program for cervical cancer in 1990, with all women aged 25 to 70 years to be offered cervical screening every three years. During the first three years of the program (November 1991–October 1994), all spontaneous cervical cytology in Norway was recorded at the Norwegian Cancer Registry. In addition, women in the counties of Vestfold and Sør-Trøndelag were invited individually to be screened. The aim of the present study was principally to evaluate the organizational aspects of a nationwide, population-based screening program for cervical cancer in Norway. Special attention was paid to the coverage, the attendance rate, and the cytologic findings in the two-county study area. A total of 1,581,379 Pap smears were recorded from November 1991 to October 1994. Most smears were taken from women under age 30 years (31.7 percent). About 25 percent of the women aged 25 to 29 years had more than one normal smear. In the study area, a coverage of about 71 percent in the age group 25 to 69 years was achieved. The pilot project also has shown that it is possible to recruit elderly women into screening. However, no difference was noted between the study and the reference area with regard to findings per smear of precursor lesions (CIN 3, modified SNOMED coding system). The experiences from three years of recording and the implementation of the pilot project have provided useful guidelines for the national screening which began in January 1995.

Validity of Self-reported Pap Smear History in Norwegian Women

Objectives To assess the validity of self-reported Papanicolau (Pap) smear history in Norwegian women and to identify characteristics that influence the validity. Methods Interview data from a sample of 16,574 Norwegian women, aged 18–45, in 2004–2005, was compared with information from the population-based cytology register. Crude validity in the self-reports with respect to ever/never having taken a Pap smear was summarized. The validity of the reported interval since last Pap smear was assessed by a smoothed distribution of the reported interval, stratified by the registered interval. Characteristics of influence on validity were identified by logistic regression for true positives (sensitivity and positive predictive value), true negatives (specificity and negative predictive value) and for more than one year discrepancy in time since last Pap smear, between reported and registered interval. Results Overall validity was summarized by: concordance = 0.9, sensitivity = 0.97, positive predictive value = 0.92, specificity = 0.55, negative predictive value = 0.78 and report-to-records ratio = 1.51. The variance in the reported interval increased proportionally with the registered interval, and women tended to underestimate the interval (telescoping). Age and registered number of years since last Pap smear had the strongest influence on ever/never and time interval validity, respectively. Conclusions Estimated screening rates, based on self-reporting without organized screening, are biased. Telescoping leads to increased risk for developing invasive disease, because women will postpone their next Pap smear.