title: p16/Ki-67 Dual Stain Cytology for Detection of Cervical Precancer in HPV-Positive Women.
abstract: BACKGROUND
  Human papillomavirus (HPV)-based cervical cancer screening requires triage markers to decide who should be referred to colposcopy. p16/Ki-67 dual stain cytology has been proposed as a biomarker for cervical precancers. We evaluated the dual stain in a large population of HPV-positive women.
  
  
  METHODS
  One thousand five hundred and nine HPV-positive women screened with HPV/cytology cotesting at Kaiser Permanente California were enrolled into a prospective observational study in 2012. Dual stain cytology was performed on residual Surepath material, and slides were evaluated for dual stain-positive cells. Disease endpoints were ascertained from the clinical database at KPNC. We evaluated the clinical performance of the assay among all HPV-positive women and among HPV-positive, cytology-negative women. We used internal benchmarks for clinical management to evaluate the clinical relevance of the dual stain assay. We evaluated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the dual stain compared with Pap cytology. All statistical tests were two-sided.
  
  
  RESULTS
  The dual stain had lower positivity (45.9%) compared with cytology at an ASC-US threshold (53.4%). For detection of CIN2+, the dual stain had similar sensitivity (83.4% vs 76.6%, P = .1), and statistically higher specificity (58.9% vs 49.6%, P < .001), PPV (21.0% vs 16.6%, P < .001), and NPV (96.4% vs 94.2%, P = .01) compared with cytology. Similar patterns were observed for CIN3+. Women with a positive test had high enough risk for referral to colposcopy, while the risk for women with negative tests was below a one-year return threshold based on current US management guidelines.
  
  
  CONCLUSIONS
  Dual stain cytology showed good risk stratification for all HPV-positive women and for HPV-positive women with normal cytology. Additional follow-up is needed to determine how long dual stain negative women remain at low risk of precancer.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD (NW, MS, SNW, CB); Kaiser Permanente TPMG Regional Laboratory, Berkeley, CA (BF, ES, DT, NP, TL); Global Coalition Against Cervical Cancer, Arlington, VA (PEC); Albert Einstein College of Medicine, Bronx, NY (PEC); Division of Gynecologic Oncology, Kaiser Permanente Medical Care Program, Oakland, CA (WK). wentzenn@mail.nih.gov.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wentzensen
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD (NW, MS, SNW, CB); Kaiser Permanente TPMG Regional Laboratory, Berkeley, CA (BF, ES, DT, NP, TL); Global Coalition Against Cervical Cancer, Arlington, VA (PEC); Albert Einstein College of Medicine, Bronx, NY (PEC); Division of Gynecologic Oncology, Kaiser Permanente Medical Care Program, Oakland, CA (WK).
authors.forename: Barbara
authors.initials: B
authors.lastname: Fetterman
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD (NW, MS, SNW, CB); Kaiser Permanente TPMG Regional Laboratory, Berkeley, CA (BF, ES, DT, NP, TL); Global Coalition Against Cervical Cancer, Arlington, VA (PEC); Albert Einstein College of Medicine, Bronx, NY (PEC); Division of Gynecologic Oncology, Kaiser Permanente Medical Care Program, Oakland, CA (WK).
authors.forename: Philip E
authors.initials: PE
authors.lastname: Castle
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD (NW, MS, SNW, CB); Kaiser Permanente TPMG Regional Laboratory, Berkeley, CA (BF, ES, DT, NP, TL); Global Coalition Against Cervical Cancer, Arlington, VA (PEC); Albert Einstein College of Medicine, Bronx, NY (PEC); Division of Gynecologic Oncology, Kaiser Permanente Medical Care Program, Oakland, CA (WK).
authors.forename: Mark
authors.initials: M
authors.lastname: Schiffman
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD (NW, MS, SNW, CB); Kaiser Permanente TPMG Regional Laboratory, Berkeley, CA (BF, ES, DT, NP, TL); Global Coalition Against Cervical Cancer, Arlington, VA (PEC); Albert Einstein College of Medicine, Bronx, NY (PEC); Division of Gynecologic Oncology, Kaiser Permanente Medical Care Program, Oakland, CA (WK).
authors.forename: Shannon N
authors.initials: SN
authors.lastname: Wood
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD (NW, MS, SNW, CB); Kaiser Permanente TPMG Regional Laboratory, Berkeley, CA (BF, ES, DT, NP, TL); Global Coalition Against Cervical Cancer, Arlington, VA (PEC); Albert Einstein College of Medicine, Bronx, NY (PEC); Division of Gynecologic Oncology, Kaiser Permanente Medical Care Program, Oakland, CA (WK).
authors.forename: Eric
authors.initials: E
authors.lastname: Stiemerling
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD (NW, MS, SNW, CB); Kaiser Permanente TPMG Regional Laboratory, Berkeley, CA (BF, ES, DT, NP, TL); Global Coalition Against Cervical Cancer, Arlington, VA (PEC); Albert Einstein College of Medicine, Bronx, NY (PEC); Division of Gynecologic Oncology, Kaiser Permanente Medical Care Program, Oakland, CA (WK).
authors.forename: Diane
authors.initials: D
authors.lastname: Tokugawa
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD (NW, MS, SNW, CB); Kaiser Permanente TPMG Regional Laboratory, Berkeley, CA (BF, ES, DT, NP, TL); Global Coalition Against Cervical Cancer, Arlington, VA (PEC); Albert Einstein College of Medicine, Bronx, NY (PEC); Division of Gynecologic Oncology, Kaiser Permanente Medical Care Program, Oakland, CA (WK).
authors.forename: Clara
authors.initials: C
authors.lastname: Bodelon
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD (NW, MS, SNW, CB); Kaiser Permanente TPMG Regional Laboratory, Berkeley, CA (BF, ES, DT, NP, TL); Global Coalition Against Cervical Cancer, Arlington, VA (PEC); Albert Einstein College of Medicine, Bronx, NY (PEC); Division of Gynecologic Oncology, Kaiser Permanente Medical Care Program, Oakland, CA (WK).
authors.forename: Nancy
authors.initials: N
authors.lastname: Poitras
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD (NW, MS, SNW, CB); Kaiser Permanente TPMG Regional Laboratory, Berkeley, CA (BF, ES, DT, NP, TL); Global Coalition Against Cervical Cancer, Arlington, VA (PEC); Albert Einstein College of Medicine, Bronx, NY (PEC); Division of Gynecologic Oncology, Kaiser Permanente Medical Care Program, Oakland, CA (WK).
authors.forename: Thomas
authors.initials: T
authors.lastname: Lorey
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD (NW, MS, SNW, CB); Kaiser Permanente TPMG Regional Laboratory, Berkeley, CA (BF, ES, DT, NP, TL); Global Coalition Against Cervical Cancer, Arlington, VA (PEC); Albert Einstein College of Medicine, Bronx, NY (PEC); Division of Gynecologic Oncology, Kaiser Permanente Medical Care Program, Oakland, CA (WK).
authors.forename: Walter
authors.initials: W
authors.lastname: Kinney
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000032:analysis*; D002584:Cervix Uteri / Q000821:virology*; D003127:Colposcopy; D019941:Cyclin-Dependent Kinase Inhibitor p16; D055088:Early Detection of Cancer; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis*; D008403:Mass Screening; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis*; D027383:Papillomaviridae / Q000302:isolation & purification*; D030361:Papillomavirus Infections / Q000175:diagnosis*; D011230:Precancerous Conditions / Q000175:diagnosis* / Q000821:virology*; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012017:Referral and Consultation; D018570:Risk Assessment; D012307:Risk Factors; D012680:Sensitivity and Specificity; D002583:Uterine Cervical Neoplasms / Q000517:prevention & control
chemical_list: D014408:Biomarkers, Tumor; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins