title: Presence of High-Risk HPV mRNA in Relation to Future High-Grade Lesions among High-Risk HPV DNA Positive Women with Minor Cytological Abnormalities.
abstract: OBJECTIVE
  Continuous expression of E6- and E7-oncogenes of high-risk human papillomavirus (HPV) types is necessary for the development and maintenance of the dysplastic phenotype. The aim of the study was to determine the sensitivity and specificity of the APTIMA HPV mRNA assay (Hologic) in predicting future development of high-grade cervical intraepithelial neoplasia (CIN) among high-risk HPV-DNA-positive women with atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous epithelial lesion (LSIL) cytology.
  
  
  METHODS
  Archived SurePath cervical samples of women ≥ 35 years of age with high-risk HPV DNA-positive ASCUS (n = 211) or LSIL, (n = 131) were tested for the presence of high-risk HPV E6/E7 mRNA using the APTIMA HPV assay, and the women were monitored for development of histopathologically verified CIN2+.
  
  
  RESULTS
  Twenty-nine percent (61/211) of the women in the ASCUS group, and 34.3% (45/131) in the LSIL group developed CIN2+ within 4.5 years of follow-up. The prevalence of HPV mRNA was 90.0% (95% CI 85.9-94.0) among women with ASCUS and 95.4% (95% CI 91.8-99.0) among women with LSIL. The presence of HPV E6/E7 mRNA was associated with future development of CIN2+ among women with ASCUS and LSIL (p=0.02). The mRNA assay demonstrated high sensitivity in predicting future CIN2+ and CIN3 for index ASCUS (96.7%; 95% CI 87.6-99.4 and 100%; 95% CI 82.2-100, respectively) and LSIL (97.8%, 95% CI 86.8-99.9 and 100%, 95% CI 79.9-100, respectively). The corresponding specificity was low, 12.7% (95% CI 7.9-19.3) and 5.8% (95% CI 2.2-13.6), for future CIN2+, respectively. The negative predictive value of the HPV mRNA assay for detecting future CIN3 was 100%, since no mRNA-negative woman developed CIN3 (0/27) as compared to 13.6% (43/315) of the mRNA-positive women (p = 0.03).
  
  
  CONCLUSIONS
  The APTIMA mRNA assay demonstrated high sensitivity but low specificity in predicting future CIN2+ among women with minor cytological abnormalities. The assay had high negative predictive value for future CIN3, indicating that HPV-mRNA-negative women are at low risk of progression to high grade CIN.
authors.affiliation: Department of Laboratory Medicine, Medical Microbiology, Lund University, Malmö, Sweden.
authors.forename: Hanna
authors.initials: H
authors.lastname: Johansson
authors.affiliation: Regional Cancer Centre South, Lund, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Bjelkenkrantz
authors.affiliation: Department of Obstetrics and Gynecology, Skane University Hospital, Lund, Sweden.
authors.forename: Lotten
authors.initials: L
authors.lastname: Darlin
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden and Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Joakim
authors.initials: J
authors.lastname: Dilllner
authors.affiliation: Department of Laboratory Medicine, Medical Microbiology, Lund University, Malmö, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Forslund
mesh_terms: D000328:Adult; D004279:DNA, Viral / Q000235:genetics; D018450:Disease Progression; D005260:Female; D006801:Humans; D008403:Mass Screening; D008875:Middle Aged; D016017:Odds Ratio; D009856:Oncogene Proteins, Viral / Q000235:genetics; D027383:Papillomaviridae / Q000235:genetics; D030361:Papillomavirus Infections / Q000473:pathology*; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics; D012680:Sensitivity and Specificity; D002583:Uterine Cervical Neoplasms / Q000473:pathology / Q000821:virology*; D002578:Uterine Cervical Dysplasia / Q000473:pathology / Q000821:virology*
chemical_list: D004279:DNA, Viral; D009856:Oncogene Proteins, Viral; D012333:RNA, Messenger; D012367:RNA, Viral