Cervical Cancer Screening: Comparison of Conventional Pap Smear Test, Liquid-Based Cytology, and Human Papillomavirus Testing as Stand-alone or Cotesting Strategies
Abstract
Background: Some countries have implemented stand-alone human papillomavirus (HPV) testing while others consider cotesting for cervical cancer screening. We compared both strategies within a population-based study. Methods: The MARZY cohort study was conducted in Germany. Randomly selected women from population registries aged ≥30 years (n = 5,275) were invited to screening with Pap smear, liquid-based cytology (LBC, ThinPrep), and HPV testing (Hybrid Capture2, HC2). Screen-positive participants [ASC-US+ or high-risk HC2 (hrHC2)] and a random 5% sample of screen-negatives were referred to colposcopy. Post hoc HPV genotyping was conducted by GP5+/6+ PCR-EIA with reverse line blotting. Sensitivity, specificity (adjusted for verification bias), and potential harms, including number of colposcopies needed to detect 1 precancerous lesion (NNC), were calculated. Results: In 2,627 screened women, cytological sensitivities (Pap, LBC: 47%) were lower than HC2 (95%) and PCR (79%) for CIN2+. Cotesting demonstrated higher sensitivities (HC2 cotesting: 99%; PCR cotesting: 84%), but at the cost of lower specificities (92%–95%) compared with HPV stand-alone (HC2: 95%; PCR: 94%) and cytology (97% or 99%). Cotesting versus HPV stand-alone showed equivalent relative sensitivity [HC2: 1.06, 95% confidence interval (CI), 1.00–1.21; PCR: 1.07, 95% CI, 1.00–1.27]. Relative specificity of Pap cotesting with either HPV test was inferior to stand-alone HPV. LBC cotesting demonstrated equivalent specificity (both tests: 0.99, 95% CI, 0.99–1.00). NNC was highest for Pap cotesting. Conclusions: Cotesting offers no benefit in detection over stand-alone HPV testing, resulting in more false positive results and colposcopy referrals. Impact: HPV stand-alone screening offers a better balance of benefits and harms than cotesting. See related commentary by Wentzensen and Clarke, p. 432
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HPV DNA testing is more sensitive than cytology in detecting precancerous lesions and cervical cancers.
“Numerous studies affirm that HPV DNA testing is more sensitive than cytology in detecting precancerous lesions and cervical cancers [21, 22, 23] and any HPV DNA test is better than none.”
From Comparative analysis of SD biosensor standard™ M10 HPV and seegene anyplex™ II HPV HR for detecting high-risk human papillomavirus: a concordance study (2025) · cites this paper as [23]
Cotesting offers no additional benefit over stand-alone hrHPV DNA testing, and may result in higher colposcopy referrals due to false positives.
“While cotesting offers no additional benefit over stand-alone hrHPV DNA testing, it may result in higher colposcopy referrals due to false positives [23].”
From Comparative analysis of SD biosensor standard™ M10 HPV and seegene anyplex™ II HPV HR for detecting high-risk human papillomavirus: a concordance study (2025) · cites this paper as [23]
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References 50 · Cited by 73
- Authors
- Liang, L. A., Einzmann, T., Franzen, A., Schwarzer, K., Schauberger, G., Schriefer, D., Radde, K., Zeissig, S. R., Ikenberg, H., Meijer, C. J. L. M., Kirkpatrick, C. J., Kölbl, H., Blettner, M., & Klug, S. J.
- Affiliations
- Technical University of Munich (DE)
- University Hospital Cologne (DE)
- Gemeinschaftsklinikum Mittelrhein (DE)
- 4VivaQ MVZ, Mainz, Germany.
- University Hospital Carl Gustav Carus (DE)
- 6Cancer Registry of Rhineland-Palatinate, Mainz, Germany.
- 7Cytomol MVZ, Frankfurt, Germany.
- Amsterdam University Medical Centers (NL)
- Johannes Gutenberg University Mainz (DE)
- Comprehensive Cancer Center Vienna (AT)
- Corresponding author
- Klug, Stefanie J.
- ORCID
- Venue
- Cancer Epidemiology, Biomarkers & Prevention
- Published
- 2021-03-01
- Volume
- 30
- Issue
- 3
- Pages
- 474-484
- ISSN
- 1055-9965 (ISSN-L)
- 1538-7755
- OpenAlex
- W3099661372
- Cited by
- 73
- References
- 50
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 20 · 2023: 20 · 2022: 8 · 2021: 2
- FWCI
- 5.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Epidemiology Biomarkers & Prevention (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Funders
- German Cancer Aid
- Deutsche Krebshilfe (105827, 106619, 107247, 108047, 107159)
- Topics
- Health Sciences › Medicine › Epidemiology › Cervical Cancer and HPV Research
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Women's cancer prevention and management
- Life Sciences › Immunology and Microbiology › Microbiology › Reproductive tract infections research
- Keywords
- cervical cancer screening, HPV testing, Pap smear, liquid-based cytology, Hybrid Capture 2, HPV genotyping, cervical intraepithelial neoplasia, screening sensitivity and specificity, colposcopy referral, false positives
- MeSH terms
- Uterine Cervical Neoplasms, Colposcopy, Female, Humans, Pregnancy, Sensitivity and Specificity, Vaginal Smears, Cohort Studies, Papillomaviridae, Papillomavirus Infections, Alphapapillomavirus, Early Detection of Cancer, Papanicolaou Test
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