title: Improved abnormal Pap smear triage using cervical cancer biomarkers.
abstract: OBJECTIVE
  The current system of Pap smear screening and management of abnormal cytology has resulted in a marked reduction in invasive cervical cancer. Many women, however, are not found to have significant precursor lesions. This is due to the poor specificity of high-risk human papillomavirus (HPV) triage. More specific cervical cancer biomarkers may be more effective triage tools than hr-HPV. We evaluated whether a dual stain for p16 and Ki-67 might improve the triage of abnormal Pap smears.
  
  
  METHODS
  p16/Ki-67 immunostaining was performed on additional slides prepared from 515 women with abnormal Pap smears (301 atypical squamous cells of undetermined significance [ASCUS], 169 low-grade squamous intraepithelial lesion [LSIL], 29 atypical squamous cells-cannot exclude high-grade lesion [ASC-H], 16 high-grade squamous intraepithelial lesion [HSIL]). High-risk HPV typing was performed on all cases. Immunostaining and hr-HPV were compared in relation to their diagnostic accuracy for the detection of biopsy-proven cervical intraepithelial neoplasia (CIN) 2/3. A cost analysis comparing hr-HPV versus immunostaining as the initial triage tool used for abnormal Pap smears was also performed.
  
  
  RESULTS
  High-risk HPV was positive in 127 (42.2%) ASCUS, 129 (76.3%) LSIL, 20 (69.0%) ASC-H, and 15 (93.8%) HSIL. p16/Ki-67 was positive in 54 (17.9%) ASCUS, 73 (43.2%) LSIL, 19 (65.5%) ASC-H, and 15 (93.8%) HSIL. For detection of CIN 2/3, sensitivity/specificity of hr-HPV and p16/Ki-67 was 89.29%/14.94% and 96.43%/60.92%, respectively. Overall, diagnostic accuracy was statistically significantly higher for p16/Ki-67 compared with hr-HPV. Compared to HPV, immunostain triage could have generated approximately $46,000 savings in the study population.
  
  
  CONCLUSIONS
  The triage of abnormal Pap smears by p16/Ki-67 immunostaining shows comparable sensitivity, improved specificity, and significantly improved diagnostic performance when compared to hr-HPV. Immunostaining is of value in triaging LSIL and ASC-H Pap smears in addition to ASCUS. The widespread utilization of biomarker triage could result in significant health care cost savings without compromising the detection of significant cervical cancer precursors.
authors.affiliation: Kapi'olani Medical Center for Women and Children, Honolulu, HI.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Killeen
authors.forename: Timothy
authors.initials: T
authors.lastname: Dye
authors.forename: Chelestes
authors.initials: C
authors.lastname: Grace
authors.forename: Mark
authors.initials: M
authors.lastname: Hiraoka
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D055088:Early Detection of Cancer / Q000379:methods*; D005260:Female; D061809:Human Papillomavirus DNA Tests / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D019394:Ki-67 Antigen / Q000032:analysis*; D008875:Middle Aged; D065006:Papanicolaou Test / Q000379:methods*; D027383:Papillomaviridae / Q000145:classification / Q000302:isolation & purification; D012680:Sensitivity and Specificity; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis*; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000175:diagnosis*
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen