title: A systematic review of p16/Ki-67 immuno-testing for triage of low grade cervical cytology.
abstract: BACKGROUND
  Screening for cervical cancer precursors by Papanicolaou cytology is a public health success story; however, its low sensitivity entails unnecessary referrals to colposcopy of healthy women with equivocal (ASCUS) or mild dysplasia (LSIL) cytology.
  
  
  OBJECTIVE
  We assessed the accuracy of p16/Ki-67 immuno-testing for triage of low grade cervical cytology.
  
  
  METHODS
  We systematically searched Medline, Embase, CRD and Cochrane databases, and handsearched key references.
  
  
  METHODS
  Eligible studies included women with ASCUS or LSIL cervical cytology who had undergone p16/Ki-67 testing and subsequent verification by colposcopy-directed biopsies and histologic analysis.
  
  
  METHODS
  We extracted data on patient characteristics and test conduct, diagnostic accuracy measures and assessed the methodological quality of the studies. R software was used to perform a bivariate analysis of test performance data.
  
  
  RESULTS
  Five eligible studies were identified. Four of the studies had high risk of bias. In the LSIL subgroup, the sensitivity of p16/Ki-67 testing ranged from 0.86 to 0.98, compared with 0.92-0.96 of high-risk HPV testing (hrHPV); specificity ranged from 0.43 to 0.68 versus 0.19 to 0.37, respectively. In the ASCUS subgroup, sensitivity ranged from 0.64 to 0.92 (p16/Ki67 test) versus 0.91 to 0.97 (hrHPV); specificity ranged from 0.53 to 0.81 versus 0.26 to 0.44, respectively.
  
  
  CONCLUSIONS
  p16/Ki-67 testing cannot be recommended for triage women with ASCUS or LSIL cytology due to insufficient high-quality evidence. Further studies on test performance and the impact of p16/Ki-67-based triage on health outcomes are needed for a definitive evaluation of its clinical utility.
authors.affiliation: Ludwig Boltzmann Institute for Health Technology Assessment, Vienna, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Kisser
authors.forename: I
authors.initials: I
authors.lastname: Zechmeister-Koss
mesh_terms: D065309:Atypical Squamous Cells of the Cervix; D019941:Cyclin-Dependent Kinase Inhibitor p16; D055088:Early Detection of Cancer; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D065006:Papanicolaou Test; D011379:Prognosis; D018570:Risk Assessment; D065310:Squamous Intraepithelial Lesions of the Cervix / Q000175:diagnosis / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D014626:Vaginal Smears
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins
keywords: Cervical cancer screening; Ki-67; human papillomavirus; molecular diagnosis and prognosis; p16INK4A