title: Human papillomavirus mRNA and DNA testing in women with atypical squamous cells of undetermined significance: A prospective cohort study.
abstract: In this prospective cohort study, we compared the performance of human papillomavirus (HPV) mRNA and DNA testing of women with atypical squamous cells of undetermined significance (ASC-US) during cervical cancer screening. Using a nationwide Danish pathology register, we identified women aged 30-65 years with ASC-US during 2005-2011 who were tested for HPV16/18/31/33/45 mRNA using PreTect HPV-Proofer (n = 3,226) or for high-risk HPV (hrHPV) DNA using Hybrid Capture 2 (HC2) (n = 9,405) or Linear Array HPV-Genotyping test (LA) (n = 1,533). Women with ≥1 subsequent examination in the register (n = 13,729) were followed for up to 9.5 years for high-grade cervical intraepithelial neoplasia (CIN) or cancer. After 3 years' follow-up, mRNA testing had higher specificity for CIN3 or worse (CIN3+) than HC2 testing (88.1% [95% confidence interval (CI): 86.8-89.6%] versus 59.3% [95% CI: 58.1-60.4%]) and higher positive predictive value (PPV) (38.2% [95% CI: 33.8%-43.1%] versus 19.5% [95% CI: 17.8-20.9%]). However, the sensitivity of mRNA testing was lower than that of HC2 testing (66.7% [95% CI: 59.3-74.5%] versus 97.0% [95% CI: 95.5-98.4%]), and women testing mRNA negative had higher 3-year risk for CIN3+ than those testing HC2 negative (3.2% [95% CI: 2.2-4.2%] versus 0.5% [95% CI: 0.3-0.7%]). Patterns were similar after 18 months and 5 years'; follow-up; for CIN2+ and cancer as outcomes; across all age groups; and when comparing mRNA testing to hrHPV DNA testing using LA. In conclusion, the HPV16/18/31/33/45 mRNA test is not optimal for ASC-US triage due to its low sensitivity and the substantial risk for precancer following a negative test.
authors.affiliation: Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark.
authors.forename: Louise T
authors.initials: LT
authors.lastname: Thomsen
authors.affiliation: Unit of Statistics, Bioinformatics and Registry, Danish Cancer Society Research Center, Copenhagen, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Dehlendorff
authors.affiliation: Department of Pathology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark.
authors.forename: Jette
authors.initials: J
authors.lastname: Junge
authors.affiliation: Department of Clinical Pathology, Vejle Hospital, Vejle, Denmark.
authors.forename: Marianne
authors.initials: M
authors.lastname: Waldstrøm
authors.affiliation: Department of Clinical Pathology, Odense University Hospital, Odense, Denmark.
authors.forename: Doris
authors.initials: D
authors.lastname: Schledermann
authors.affiliation: Unit of Statistics, Bioinformatics and Registry, Danish Cancer Society Research Center, Copenhagen, Denmark.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Frederiksen
authors.affiliation: Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark.|Department of Gynecology, Rigshospitalet University Hospital, Copenhagen, Denmark.
authors.forename: Susanne K
authors.initials: SK
authors.lastname: Kjaer
mesh_terms: D000328:Adult; D000368:Aged; D065309:Atypical Squamous Cells of the Cervix / Q000473:pathology / Q000821:virology*; D015331:Cohort Studies; D004279:DNA, Viral / Q000032:analysis*; D005260:Female; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D027383:Papillomaviridae / Q000235:genetics* / Q000302:isolation & purification; D030361:Papillomavirus Infections / Q000473:pathology / Q000821:virology*; D011446:Prospective Studies; D012333:RNA, Messenger / Q000032:analysis*; D012367:RNA, Viral / Q000032:analysis*; D002583:Uterine Cervical Neoplasms / Q000473:pathology / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000473:pathology / Q000821:virology
chemical_list: D004279:DNA, Viral; D012333:RNA, Messenger; D012367:RNA, Viral
keywords: : atypical squamous cells of undetermined significance; DNA; HPV; cervical cancer screening; cervical intraepithelial neoplasia; human papillomavirus testing; mRNA