title: Triage of LSIL/ASC-US with p16/Ki-67 dual staining and human papillomavirus testing: a 2-year prospective study.
abstract: OBJECTIVE
  To investigate human papillomavirus (HPV) DNA testing and p16/Ki-67 staining for detecting cervical intraepithelial grade 2 or worse (CIN2+) and CIN3 in women referred to colposcopy with minor abnormal cervical cytology low-grade squamous intraepithelial lesions (LSIL) and atypical squamous cells of undermined significance (ASC-US). The clinical performance of both tests was evaluated as stand-alone tests and combined, for detection CIN2+ and CIN3 over 2 years.
  
  
  METHODS
  ThinPrep(®) liquid-based cytology (LBC) specimens were collected from 1349 women with repeat LSIL or ASC-US. HPV DNA was performed using Hybrid Capture. Where adequate material remained (n = 471), p16/Ki-67 overexpression was assessed. Clinical performance for detection of histologically diagnosed CIN2+ and CIN3 was calculated.
  
  
  RESULTS
  Approximately 62.2% of the population were positive for HPV DNA, and 30.4% were positive for p16/Ki-67. p16/Ki-67 showed no significant difference in positivity between LSIL and ASC-US referrals (34.3% versus 28.6%; P = 0.189). Women under 30 years had a higher rate of p16/Ki-67 compared to those over 30 years (36.0% versus 26.6%; P = 0.029). Overall HPV DNA testing produced a high sensitivity for detection of CIN3 of 95.8% compared to 79.2% for p16/Ki-67. In contrast, p16/Ki-67 expression offered a higher specificity, 75.2% versus 40.4% for detection of CIN3. Combining p16/Ki-67 with HPV DNA improved the accuracy in distinguishing between CIN3 and <CIN3. The absolute risk of CIN3 increased from 15.6% in women who were HPV DNA positive to 27% in women positive for HPV DNA and p16/Ki-67. Those negative for HPV DNA and p16/Ki-67 had a low risk of 1.2% of CIN3.
  
  
  CONCLUSIONS
  The addition of p16/Ki-67 to HPV DNA testing leads to a more accurate stratification of CIN in women presenting with minor cytological abnormalities.
authors.affiliation: Department of Histopathology, Trinity College Dublin, Dublin, Ireland.|Department of Pathology, Coombe Women and Infants University Hospital, Dublin, Ireland.
authors.forename: C
authors.initials: C
authors.lastname: White
authors.affiliation: Department of Pathology, Coombe Women and Infants University Hospital, Dublin, Ireland.
authors.forename: S
authors.initials: S
authors.lastname: Bakhiet
authors.affiliation: Department of Histopathology, Trinity College Dublin, Dublin, Ireland.|Department of Pathology, Coombe Women and Infants University Hospital, Dublin, Ireland.
authors.forename: M
authors.initials: M
authors.lastname: Bates
authors.affiliation: Department of Histopathology, Trinity College Dublin, Dublin, Ireland.|Department of Pathology, Coombe Women and Infants University Hospital, Dublin, Ireland.
authors.forename: H
authors.initials: H
authors.lastname: Keegan
authors.affiliation: Department of Pathology, Coombe Women and Infants University Hospital, Dublin, Ireland.
authors.forename: L
authors.initials: L
authors.lastname: Pilkington
authors.affiliation: Department of Pathology, Coombe Women and Infants University Hospital, Dublin, Ireland.
authors.forename: C
authors.initials: C
authors.lastname: Ruttle
authors.affiliation: National Cancer Registry Ireland, Cork, Ireland.
authors.forename: L
authors.initials: L
authors.lastname: Sharp
authors.affiliation: Department of Pathology, Coombe Women and Infants University Hospital, Dublin, Ireland.
authors.forename: S
authors.initials: S
authors.lastname: O' Toole
authors.affiliation: Department of Obstetrics and Gynaecology, National Maternity Hospital, Dublin, Ireland.
authors.forename: M
authors.initials: M
authors.lastname: Fitzpatrick
authors.affiliation: Department of Obstetrics and Gynaecology, National Maternity Hospital, Dublin, Ireland.
authors.forename: G
authors.initials: G
authors.lastname: Flannelly
authors.affiliation: Department of Histopathology, Trinity College Dublin, Dublin, Ireland.|Department of Pathology, Coombe Women and Infants University Hospital, Dublin, Ireland.
authors.forename: J J
authors.initials: JJ
authors.lastname: O' Leary
authors.affiliation: Department of Histopathology, Trinity College Dublin, Dublin, Ireland.|Department of Pathology, Coombe Women and Infants University Hospital, Dublin, Ireland.
authors.forename: C M
authors.initials: CM
authors.lastname: Martin
mesh_terms: D000328:Adult; D065309:Atypical Squamous Cells of the Cervix / Q000473:pathology; D003127:Colposcopy; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis* / Q000235:genetics; D003581:Cytodiagnosis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D060787:Neoplasm Grading; D027383:Papillomaviridae / Q000302:isolation & purification / Q000472:pathogenicity; D030361:Papillomavirus Infections / Q000175:diagnosis / Q000235:genetics / Q000473:pathology / Q000821:virology; D011247:Pregnancy; D065310:Squamous Intraepithelial Lesions of the Cervix / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000821:virology; D014626:Vaginal Smears; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000821:virology
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen
keywords: atypical squamous cells of undetermined significance; human papillomavirus; low-grade squamous intraepithelial lesion; p16/Ki-67; triage