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  • 1. Andrae, Bengt
    et al.
    Andersson, Therese M-L
    Lambert, Paul C
    Kemetli, Levent
    Silfverdal, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Strander, Björn
    Ryd, Walter
    Dillner, Joakim
    Törnberg, Sven
    Sparén, Pär
    Screening and cervical cancer cure: population based cohort study2012In: BMJ. British Medical Journal, E-ISSN 1756-1833, Vol. 344, p. e900-Article in journal (Refereed)
    Abstract [en]

    Objective To determine whether detection of invasive cervical cancer by screening results in better prognosis or merely increases the lead time until death.

    Design Nationwide population based cohort study. Setting Sweden.

    Participants All 1230 women with cervical cancer diagnosed during 1999-2001 in Sweden prospectively followed up for an average of 8.5 years. Main outcome measures Cure proportions and five year relative survival ratios, stratified by screening history, mode of detection, age, histopathological type, and FIGO (International Federation of Gynecology and Obstetrics) stage.

    Results In the screening ages, the cure proportion for women with screen detected invasive cancer was 92% (95% confidence interval 75% to 98%) and for symptomatic women was 66% (62% to 70%), a statistically significant difference in cure of 26% (16% to 36%). Among symptomatic women, the cure proportion was significantly higher for those who had been screened according to recommendations (interval cancers) than among those overdue for screening: difference in cure 14% (95% confidence interval 6% to 23%). Cure proportions were similar for all histopathological types except small cell carcinomas and were closely related to FIGO stage. A significantly higher cure proportion for screen detected cancers remained after adjustment for stage at diagnosis (difference 15%, 7% to 22%).

    Conclusions Screening is associated with improved cure of cervical cancer. Confounding cannot be ruled out, but the effect was not attributable to lead time bias and was larger than what is reflected by down-staging. Evaluations of screening programmes should consider the assessment of cure proportions.

  • 2.
    Andrae, Bengt
    et al.
    Department of Obstetrics and Gynecology, Gävle Hospital, Gävle, Sweden.
    Kemetli, Levent
    Cancer Screening Unit, Oncologic Center M8, Karolinska University Hospital, Stockholm, Sweden.
    Sparén, Pär
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Silfverdal, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Strander, Björn
    Oncologic center, Western Region, Sahlgrenska University Hospital, Göteborg, Sweden .
    Ryd, Walter
    Department of Pathology and Clinical Cytology, Sahlgrenska University Hospital, Göteborg, Sweden .
    Dillner, Joakim
    Department of Medical Microbiology, Lund University, University Hospital, Malmö, Sweden.
    Törnberg, Sven
    Cancer Screening Unit, Oncologic Center M8, Karolinska University Hospital, Stockholm, Sweden.
    Screening-preventable cervical cancer risks: evidence from a nationwide audit in Sweden2008In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 100, no 9, p. 622-629Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The effectiveness of cervical cancer screening programs differs widely in different populations. The reasons for these differences are unclear. Routine and comprehensive audits have been proposed as an ethically required component of screening. We performed a nationwide audit of the effectiveness of the Swedish cervical cancer screening program.

    METHODS: We identified all invasive cervical cancer cases that were diagnosed in Sweden from January 1, 1999, through December 31, 2001, and had been reported to the Swedish Cancer Registry (n = 1230 cases). We verified the diagnoses by histopathologic rereview and matched each case subject to five (population-based) age-matched control subjects who were identified from the National Population Register. The Pap smear screening histories for case and control subjects were reviewed for a 6-year period using the National Cervical Cancer Screening Register, which contains data on essentially all relevant cytological and histological diagnoses in Sweden. Odds ratios (ORs), and their 95% confidence intervals (CIs), of cervical cancer according to screening history were calculated in conditional logistic regression models. All statistical tests were two-sided.

    RESULTS: Women who had not had a Pap smear within the recommended screening interval had higher risk of cervical cancer than women who had been screened (OR = 2.52, 95% CI = 2.19 to 2.91). This risk was similarly increased for all age groups (P(homogeneity) = .96). The risk for non-squamous cell cervical cancers (OR = 1.59, 95% CI = 1.20 to 2.11) was also increased. Women who had not had a Pap smear within the recommended screening interval had a particularly high risk of advanced cancers (OR = 4.82, 95% CI = 3.61 to 6.44). Among women who had been screened within the recommended interval, those with abnormal Pap smears had a higher risk of cervical cancer than those with normal smears (OR = 7.55, 95% CI = 5.88 to 9.69) and constituted 11.5% of all women with cervical cancer.

    CONCLUSIONS: Nonadherence to screening intervals was the major reason for cervical cancer morbidity. The screening program was equally effective for women of all ages and was also effective against non-squamous cancers.

  • 3.
    Bjerre, Pontus
    et al.
    Department of Obstetrics and Gynecology, Central Hospital, Karlstad, Sweden.
    Silfverdal, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Dillner, Lena
    Department of Medical Microbiology, Lund University, University Hospital at Malmö, Malmö, Sweden.
    Hagmar, Björn
    Department of Pathology, Norwegian National Hospital, University of Oslo, Oslo, Norway.
    Edvardsson, Henrik
    Department of Pathology, Central Hospital, Karlstad, Sweden.
    Dillner, Joakim
    Department of Medical Microbiology, Lund University, University Hospital at Malmö, Malmö, Sweden.
    Andersson-Ellström, Agneta
    Department of Obstetrics and Gynecology, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden.
    A randomized trial of basing treatment on human papillomavirus and/or cytology results in low-grade cervical lesion triage2008In: American Journal of Obstetrics and Gynecology, ISSN 0002-9378, E-ISSN 1097-6868, Vol. 199, no 1, p. 24.e1-24.e7Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: This study was undertaken to compare management algorithms that base treatment with loop electrosurgical excision procedure on human papillomavirus and/or repeat Papanicolaou test smear results.

    STUDY DESIGN: A randomized trial that referred 674 women with either atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesions cytology results, detected in organized screening to treatment either (1) if they were positive in a repeat Papanicolaou test smear and/or a human papillomavirus test or (2) if they were positive in the repeat Papanicolaou test smear test only. Women who tested positive were treated, regardless of colposcopic findings.

    RESULTS: There were 208 of 337 (62%) women who were treated in the human papillomavirus /Papanicolaou test smear group (187/337 because of HPV positivity) and 138 of 337 (41%) in the Papanicolaou test smear only group. Histopathologically diagnosed cervical intraepithelial neoplasia grade 2 or worse was found among 112 of 337 (33.2%) women in the human papillomavirus/Papanicolaou test smear group compared with 85 of 337 (25.2%) women in the Papanicolaou test smear only group (P < .05). Twenty-one women with cervical intraepithelial neoplasia 2+ had normal colposcopy.

    CONCLUSION: For adequate cervical intraepithelial neoplasia 2+ sensitivity, the decision to use loop electrosurgical excision procedure needs to be based on human papillomavirus testing results and should not exclude women with normal colposcopy.

  • 4.
    Edblad-Svensson, Ann
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Silfverdal, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Collberg, Pia
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Tunón, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    High-Risk Types of Human Papilloma Virus DNA Testing in Women with False Negative Cytology2018In: Acta Cytologica, ISSN 0001-5547, E-ISSN 1938-2650, Vol. 62, no 5-6, p. 411-417Article in journal (Refereed)
    Abstract [en]

    Objective: To determine whether high-risk types of human papilloma virus (hrHPV) DNA testing is reliable for selection patients in need of further investigation with colposcopy in women with increased risk of high-grade cervical lesions as a result of false negative cytology. The secondary objective was to compare the sensitivity of hrHPV testing on self-collected versus physician-collected samples for the detection of histological high-grade cervical intraepithelial neoplasia (CIN2+). Methods: Sixty-three patients identified with a missed abnormality following the re-evaluation of benign cervical cytology were included. A patient-collected and a physician-collected sample for HPV, colposcopy and cervical specimen collection for histology and cytology were performed. Results: The sensitivity of hrHPV testing of physician-collected samples for CIN2+ was 100% (95% CI 82.7-100), and the negative predictive value (NPV) was 100% (95% CI 93.3-100). The sensitivity of the self-sampling device to identify CIN2+ was 84.6% (95% CI 59.1-96.7), and the NPV was 94.4% (95% CI 83.4-98.8). The differences in the sensitivity and NPV between the 2 methods were non-significant. The agreement between the 2 methods regarding the HPV results was good, with a kappa value of 0.74 (95% CI 0.57-0.91). Conclusion: The current findings indicate that physician-collected samples for hrHPV DNA testing may be used as triage for the colposcopy of women with false negative cytology.

  • 5.
    Gottlieb, Philip
    et al.
    Kvinnokliniken, Karlskoga lasarett.
    Bergström, Staffan
    IHCAR, Karolinska institutet, Uppsala.
    Silfverdal, Sven Arne
    Barn- och ungdomskliniken, Universitetssjukhuset, Örebro.
    Wesström, Göran
    Barn- och ungdomskliniken, Universitetssjukhuset, Örebro.
    Silfverdal, Lena
    Kvinnokliniken, Universitetssjukhuset, Örebro.
    Lindmark, Gunilla
    IMHC (International maternal and child health), Akademiska sjukhuset, Uppsala.
    [Time for the Medical Society to comment the issue of the apathetic refugee children]2005In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 102, no 32-33, p. 2236-2237Article in journal (Other academic)
  • 6.
    Silfverdal, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Cervical cancer prevention: studies on outcome of cervical screening and on management of abnormal cytology findings2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background Screening by cytology has been highly effective in reducing the incidence and mortality from squamous invasive cervical cancer (ICC), but the effectiveness is less established regarding non-squamous ICC and regarding women above screening ages and below 30 years of age. Cervical cancer still occurs despite the presence of an organised screening programme. A substantial proportion of screened women with ICC are reported to have had previous abnormal cytology findings. The significance of negative cytology with limited evaluation is not quite determined, the most effective management of women with low-grade abnormalities is controversial, and evaluation of long-term effect of different treatment methods is limited.

    Aims To identify possible areas of improvements in the prevention of cervical cancer by evaluating the effectiveness of the Swedish cervical screening programme, and by exploring risk factors for ICC in the cytological screening histories and in the management of women with abnormal cytology findings.

    Methods The screening histories of all ICC cases in Sweden 1999-2001 (n=1230) and of five population-based control women per case were reviewed, using data from the Swedish Cancer Registry, the national population register, the Swedish national cervical screening quality register, histopathological reports and questionnaires to clinicians. The risk of cervical cancer according to screening histories 0.5-6.5 years before cancer diagnosis was estimated as odds ratios (ORs) in logistic regression models with 95% confidence interval (CI) (Paper I). Risk related to different cytological reports was assessed in women below 67 years of age with cytology (n=572, n=3569) in Paper II. The initial follow-up of women with abnormal or unsatisfactory cytology reports (n=159, n=258) was evaluated in Paper III, and further investigation and treatment of abnormalities (n=143 cases, n=176 controls) in Paper IV.

    Results The cancer cases were above screening ages (31%), had not been screened according to recommendations (33%), had negative cytology (23%), or had previous positive screening tests (13%). No screening within the recommended interval increased the risk of squamous (OR 2.97, 95% CI 2.51-3.50) as well as non-squamous cancer (OR 1.59, 95% CI 1.20-2.11), and increased the risk in all ages. Negative cytology with partially obscuring factors and unsatisfactory cytology increased the risk of subsequent early stage ICC. All cytological abnormalities increased the risk of ICC, and women with glandular atypia or atypia in cells of uncertain origin carried a particularly high risk (OR 11.69, 95% CI 7.02-19.46). After a low-grade squamous abnormal smear finding, further investigation with biopsy was more effective than repeated cytology (OR 0.46, 95% CI 0.24-0.89). Lack of biopsy increased the risk in women with both low-grade and high-grade squamous abnormalities. Neither repeat cytology, nor biopsy, decreased the risk in women with glandular atypia or atypia in cells of uncertain origin. Treatment decreased the risk, even when the biopsy before treatment was negative or showed low-grade atypia only. Ablative therapy was less effective than excision and laser conisation was the most effective therapy.

    Conclusions Improved adherence to screening recommendations and including older women at increased risk in the programme would have significant cancer preventive gains. Women with negative cytology with limited evaluation and with unsatisfactory cytology may need further evaluation. Assessment with biopsy should be recommended for women with low-grade as well as high-grade squamous abnormalities. The diagnosing of precancer lesions and the identification of women in need of treatment warrant improvements, in particular in cases of glandular or “other” atypia in cytology. Treatment techniques need further evaluation.

  • 7.
    Silfverdal, Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Kemetli, Levent
    Cancer Screening Unit, Oncologic Center, Karolinska University Hospital, Stockholm, Sweden.
    Andrae, Bengt
    Department of Obstetrics and Gynecology, Gävle Hospital, Gävle, Sweden.
    Sparén, Pär
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Ryd, Walter
    Department of Pathology and Clinical Cytology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Dillner, Joakim
    Department of Medical Microbiology, Lund University, Malmö University Hospital, Malmö, Sweden.
    Strander, Björn
    Oncologic Center, Sahlgrenska University Hospital, Göteborg, Sweden.
    Törnberg, Sven
    Cancer Screening Unit, Oncologic Center, Karolinska University Hospital, Stockholm, Sweden.
    Risk of invasive cervical cancer in relation to management of abnormal Pap smear results2009In: American Journal of Obstetrics and Gynecology, ISSN 0002-9378, E-ISSN 1097-6868, Vol. 201, no 2, p. 188.e1-188.e7Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: We sought to evaluate the management of women with abnormal cytology in terms of subsequent risk of invasive cervical cancer.

    STUDY DESIGN: The screening histories of all invasive cervical cancer cases diagnosed in Sweden 1999-2001 and of 5 population-based controls per case were reviewed. In all, 159 patients and 258 control subjects aged < 67 years had an abnormal smear result 0.5-6.5 years prior to cancer diagnosis. The cervical cancer risk was estimated in relation to management by calculating odds ratios.

    RESULTS: Histologic assessment of low-grade squamous abnormalities strongly reduced the risk compared to repeated cytology (odds ratio, 0.46; 95% confidence interval, 0.24-0.89). Delaying histologic assessment was also associated with a higher risk (odds ratio, 5.65; 95% confidence interval, 1.39-23.05). After high-grade squamous atypia, absence of any cytologic or histologic specimen was a major determinant of cancer risk (odds ratio, 12.52; 95% confidence interval, 1.42-infinitive).

    CONCLUSION: For adequate protection against invasive cervical cancer, further assessment with histology must be recommended also for women with low-grade squamous abnormalities.

  • 8.
    Silfverdal, Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Kemetli, Levent
    Sparén, Pär
    Andrae, Bengt
    Strander, Björn
    Dillner, Joakim
    Törnberg, Sven
    Risk of invasive cervical cancer in relation to cytologic results in the screening history: a population‐based case‐control studyManuscript (preprint) (Other academic)
  • 9.
    Silfverdal, Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Kemetli, Levent
    Sparén, Pär
    Andrae, Bengt
    Strander, Björn
    Ryd, Walter
    Dillner, Joakim
    Törnberg, Sven
    Risk of invasive cervical cancer in relation to clinical investigation and treatment after abnormal cytology: a population-based case-control study2011In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 129, p. 1450-1458Article in journal (Refereed)
    Abstract [en]

    A substantial proportion of women with cervical cancer that have participated in cervical screening have a history of an abnormal cytology result. Our objective was to assess the impact of histological investigation and treatment of women with abnormal cytology on the subsequent risk of invasive cervical cancer. All invasive cervical cancer cases in Sweden 1999-2001 and five population-based control women per case were investigated. Clinical investigations and treatment were analysed in case women (N = 143) and control women (N = 176) below 67 with abnormal cytology results 0.5-6.5 years before the cases' diagnosis. Cervical cancer risk in relation to investigation [histology or not, punch biopsy, cervical curettage or cone/large loop excision of the transformation zone (LLETZ)], and treatment (treatment or not, excisional or ablative) was estimated as odds ratios (ORs) using logistic regression. Absence of histological assessment was associated with increased cancer risk, both after low-grade [OR 2.37; 95% confidence intervals (CI): 1.27-4.43] and high-grade squamous atypia (8.26; 2.37-28.8). Among women with histology, absence of treatment was associated with increased cancer risk (3.68; 1.53-8.84), also when biopsy showed low-grade atypia or normal findings (3.57; 1.18-10.8). Ablative therapy associated with increased risk compared with excisional (3.82; 1.01-14.4), and laser conisation associated with decreased risk compared with LLETZ (0.06; 0.01-0.36). In conclusion, low-grade as well as high-grade squamous atypical cytology results may warrant histological investigation, treatment reduced cancer risk even when histology was negative or showed low-grade atypia indicating a need for improvements in the diagnosis of high-grade lesions, and laser conisation was the most effective treatment.

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