title: Performance of p16INK4a-cytology, HPV mRNA, and HPV DNA testing to identify high grade cervical dysplasia in women with abnormal screening results.
abstract: OBJECTIVE
  The prognostic value of dysplastic lesions of the uterine cervix cannot be adequately determined by Pap cytology alone. Detection of HPV DNA increases the diagnostic sensitivity. However, due to the very high prevalence of transient HPV infections, HPV DNA testing suffers from poor diagnostic specificity. Biomarkers that highlight the shift from self limited transient to potentially dangerous transforming HPV infections may improve the accuracy of cervical cancer screening. We evaluated HPV E6/E7 mRNA detection (APTIMA), p16(INK4a)-immunocytology (CINtec), and HPV DNA testing (HC2) to identify women with high grade cervical neoplasia in a disease-enriched cross-sectional cohort.
  
  
  METHODS
  Liquid based cytology specimens were collected from 275 patients. All assays were performed from these vials. Detection rates of each test were evaluated against conventional H&E based histopathology alone and stratified by p16(INK4a)-immunohistochemistry (IHC).
  
  
  RESULTS
  All assays yielded a high sensitivity for the detection of CIN3+ (96.4% (95% CI, 90.4-98.8) for HC2, 95.5% (89.2-98.3) for APTIMA and CINtec) and CIN2+ (91.5% (85.8-95.1) for HC2, 88.4% (82.3-92.7) for APTIMA, 86.6% (80.2-91.2) for CINtec). The specificity to detect high grade dysplasia was highest for CINtec p16(INK4a)-cytology (60.6% (52.7-68.0) in CIN3+ and 74.8% (65.5-82.3) in CIN2+), followed by APTIMA (56.4% (48.4-64.0) in CIN3+ and 71.2% (61.7-79.2) in CIN2+) and HC2 (49.1% (41.3-56.9) in CIN3+ and 63.4% (53.7-72.1) in CIN2+). All tests had higher sensitivity using p16(INK4a)-IHC-positive CIN2+ lesions as endpoint.
  
  
  CONCLUSIONS
  Biomarkers that detect HPV induced dysplastic changes in the transforming stage are promising tools to overcome the current limitations of cervical cancer screening.
authors.affiliation: Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. miriam.reuschenbach@med.uni-heidelberg.de
authors.forename: Miriam
authors.initials: M
authors.lastname: Reuschenbach
authors.forename: Andreas
authors.initials: A
authors.lastname: Clad
authors.forename: Christina
authors.initials: C
authors.lastname: von Knebel Doeberitz
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wentzensen
authors.forename: Janina
authors.initials: J
authors.lastname: Rahmsdorf
authors.forename: Frauke
authors.initials: F
authors.lastname: Schaffrath
authors.forename: Henrik
authors.initials: H
authors.lastname: Griesser
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Freudenberg
authors.forename: Magnus
authors.initials: M
authors.lastname: von Knebel Doeberitz
mesh_terms: D000328:Adult; D003430:Cross-Sectional Studies; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D004279:DNA, Viral / Q000032:analysis*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis / Q000235:genetics; D027383:Papillomaviridae / Q000235:genetics*; D030361:Papillomavirus Infections / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D012333:RNA, Messenger / Q000032:analysis*; D012680:Sensitivity and Specificity; D002578:Uterine Cervical Dysplasia / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology / Q000821:virology
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; D009856:Oncogene Proteins, Viral; D012333:RNA, Messenger