title: p16(INK4a) immunostaining in cytological and histological specimens from the uterine cervix: a systematic review and meta-analysis.
abstract: BACKGROUND
  P16(INK4a) is a biomarker for transforming HPV infections that could act as an adjunct to current cytological and histological assessment of cervical smears and biopsies, allowing the identification of those women with ambiguous results that require referral to colposcopy and potentially treatment.
  
  
  METHODS
  We conducted a systematic review of all studies that evaluated the use of p16(INK4a) in cytological or histological specimens from the uterine cervix. We also estimated the mean proportion of samples that were positive for p16(INK4a) in cytology and histology, stratified by the grade of the lesion.
  
  
  RESULTS
  Sixty-one studies were included. The proportion of cervical smears overexpressing p16(INK4a) increased with the severity of cytological abnormality. Among normal smears, only 12% (95% CI: 7-17%) were positive for the biomarker compared to 45% of ASCUS and LSIL (95% CI: 35-54% and 37-57%, respectively) and 89% of HSIL smears (95% CI: 84-95%). Similarly, in histology only 2% of normal biopsies (95% CI: 0.4-30%) and 38% of CIN1 (95% CI: 23-53%) showed diffuse staining for p16(INK4a) compared to 68% of CIN2 (95% CI: 44-92%) and 82% of CIN3 (95% CI: 72-92%).
  
  
  CONCLUSIONS
  Although there is good evidence that p16(INK4a) immunostaining correlates with the severity of cytological/histological abnormalities, the reproducibility is limited due to insufficiently standardized interpretation of the immunostaining. Therefore, a consensus needs to be reached regarding the evaluation of p16(INK4a) staining and the biomarker needs to be assessed in various clinical settings addressing specific clinical questions.
authors.affiliation: Department of Obstetrics and Gynaecology, St Mary's Hospital, CMMC University Hospitals, Manchester M13 0JH, UK.
authors.forename: I
authors.initials: I
authors.lastname: Tsoumpou
authors.forename: M
authors.initials: M
authors.lastname: Arbyn
authors.forename: M
authors.initials: M
authors.lastname: Kyrgiou
authors.forename: N
authors.initials: N
authors.lastname: Wentzensen
authors.forename: G
authors.initials: G
authors.lastname: Koliopoulos
authors.forename: P
authors.initials: P
authors.lastname: Martin-Hirsch
authors.forename: V
authors.initials: V
authors.lastname: Malamou-Mitsi
authors.forename: E
authors.initials: E
authors.lastname: Paraskevaidis
mesh_terms: D052685:Alphapapillomavirus; D015415:Biomarkers / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis; D001706:Biopsy; D002584:Cervix Uteri / Q000737:chemistry* / Q000473:pathology / Q000821:virology; D003127:Colposcopy; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis*; D003584:Cytological Techniques / Q000706:statistics & numerical data; D005260:Female; D006652:Histological Techniques / Q000706:statistics & numerical data; D006801:Humans; D007150:Immunohistochemistry / Q000706:statistics & numerical data; D009363:Neoplasm Proteins / Q000032:analysis; D030361:Papillomavirus Infections / Q000175:diagnosis* / Q000378:metabolism; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012107:Research Design; D012189:Retrospective Studies; D002578:Uterine Cervical Dysplasia / Q000378:metabolism / Q000821:virology / Q000737:chemistry / Q000175:diagnosis; D002583:Uterine Cervical Neoplasms / Q000737:chemistry* / Q000175:diagnosis / Q000821:virology; D002575:Uterine Cervicitis / Q000175:diagnosis* / Q000378:metabolism; D014626:Vaginal Smears
chemical_list: D015415:Biomarkers; D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009363:Neoplasm Proteins