Clinical Evaluation of Human Papillomavirus Screening With p16/Ki-67 Dual Stain Triage in a Large Organized Cervical Cancer Screening Program | Cancer Biomarkers | JAMA Internal Medicine | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 34.239.150.57. Please contact the publisher to request reinstatement.
1.
Wentzensen  N, Arbyn  M, Berkhof  J,  et al.  Eurogin 2016 roadmap: how HPV knowledge is changing screening practice.  Int J Cancer. 2017;140(10):2192-2200. doi:10.1002/ijc.30579PubMedGoogle ScholarCrossref
2.
Gage  JC, Schiffman  M, Katki  HA,  et al.  Reassurance against future risk of precancer and cancer conferred by a negative human papillomavirus test.  J Natl Cancer Inst. 2014;106(8):dju153. doi:10.1093/jnci/dju153PubMedGoogle ScholarCrossref
3.
Wentzensen  N.  Triage of HPV-positive women in cervical cancer screening.  Lancet Oncol. 2013;14(2):107-109. doi:10.1016/S1470-2045(12)70568-5PubMedGoogle ScholarCrossref
4.
Cuschieri  K, Ronco  G, Lorincz  A,  et al.  Eurogin roadmap 2017: triage strategies for the management of HPV-positive women in cervical screening programs.  Int J Cancer. 2018;143(4):735-745. doi:10.1002/ijc.31261PubMedGoogle ScholarCrossref
5.
Wentzensen  N, Schiffman  M, Palmer  T, Arbyn  M.  Triage of HPV positive women in cervical cancer screening.  J Clin Virol. 2016;76(suppl 1):S49-S55. doi:10.1016/j.jcv.2015.11.015PubMedGoogle ScholarCrossref
6.
Huh  WK, Ault  KA, Chelmow  D,  et al.  Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance.  J Low Genit Tract Dis. 2015;19(2):91-96. doi:10.1097/LGT.0000000000000103PubMedGoogle ScholarCrossref
7.
Wright  TC, Stoler  MH, Behrens  CM, Sharma  A, Zhang  G, Wright  TL.  Primary cervical cancer screening with human papillomavirus: end of study results from the ATHENA study using HPV as the first-line screening test.  Gynecol Oncol. 2015;136(2):189-197. doi:10.1016/j.ygyno.2014.11.076PubMedGoogle ScholarCrossref
8.
Guan  P, Howell-Jones  R, Li  N,  et al.  Human papillomavirus types in 115,789 HPV-positive women: a meta-analysis from cervical infection to cancer.  Int J Cancer. 2012;131(10):2349-2359. doi:10.1002/ijc.27485PubMedGoogle ScholarCrossref
9.
Wright  TC  Jr, Stoler  MH, Behrens  CM, Sharma  A, Sharma  K, Apple  R.  Interlaboratory variation in the performance of liquid-based cytology: insights from the ATHENA trial.  Int J Cancer. 2014;134(8):1835-1843. doi:10.1002/ijc.28514PubMedGoogle ScholarCrossref
10.
Carozzi  F, Confortini  M, Dalla Palma  P,  et al; New Technologies for Cervival Cancer Screening (NTCC) Working Group.  Use of p16-INK4A overexpression to increase the specificity of human papillomavirus testing: a nested substudy of the NTCC randomised controlled trial.  Lancet Oncol. 2008;9(10):937-945. doi:10.1016/S1470-2045(08)70208-0PubMedGoogle ScholarCrossref
11.
Carozzi  F, Gillio-Tos  A, Confortini  M,  et al; NTCC working group.  Risk of high-grade cervical intraepithelial neoplasia during follow-up in HPV-positive women according to baseline p16-INK4A results: a prospective analysis of a nested substudy of the NTCC randomised controlled trial.  Lancet Oncol. 2013;14(2):168-176. doi:10.1016/S1470-2045(12)70529-6PubMedGoogle ScholarCrossref
12.
Clarke  MA, Cheung  LC, Castle  PE,  et al.  Five-year risk of cervical precancer following p16/Ki-67 dual-stain triage of HPV-positive women [published online October 11, 2018].  JAMA Oncol. doi:10.1001/jamaoncol.2018.4270PubMedGoogle Scholar
13.
Wentzensen  N, Fetterman  B, Castle  PE,  et al.  p16/Ki-67 Dual stain cytology for detection of cervical precancer in HPV-positive women.  J Natl Cancer Inst. 2015;107(12):djv257. doi:10.1093/jnci/djv257PubMedGoogle ScholarCrossref
14.
Wentzensen  N, Schwartz  L, Zuna  RE,  et al.  Performance of p16/Ki-67 immunostaining to detect cervical cancer precursors in a colposcopy referral population.  Clin Cancer Res. 2012;18(15):4154-4162. doi:10.1158/1078-0432.CCR-12-0270PubMedGoogle ScholarCrossref
15.
Wright  TC  Jr, Behrens  CM, Ranger-Moore  J,  et al.  Triaging HPV-positive women with p16/Ki-67 dual-stained cytology: results from a sub-study nested into the ATHENA trial.  Gynecol Oncol. 2017;144(1):51-56. doi:10.1016/j.ygyno.2016.10.031PubMedGoogle ScholarCrossref
16.
Solomon  D, Davey  D, Kurman  R,  et al; Forum Group Members; Bethesda 2001 Workshop.  The 2001 Bethesda System: terminology for reporting results of cervical cytology.  JAMA. 2002;287(16):2114-2119. doi:10.1001/jama.287.16.2114PubMedGoogle ScholarCrossref
17.
Leisenring  W, Alonzo  T, Pepe  MS.  Comparisons of predictive values of binary medical diagnostic tests for paired designs.  Biometrics. 2000;56(2):345-351. doi:10.1111/j.0006-341X.2000.00345.xPubMedGoogle ScholarCrossref
18.
Katki  HA, Schiffman  M, Castle  PE,  et al.  Benchmarking CIN 3+ risk as the basis for incorporating HPV and Pap cotesting into cervical screening and management guidelines.  J Low Genit Tract Dis. 2013;17(5)(suppl 1):S28-S35. doi:10.1097/LGT.0b013e318285423cPubMedGoogle ScholarCrossref
19.
Katki  HA, Kinney  WK, Fetterman  B,  et al.  Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice.  Lancet Oncol. 2011;12(7):663-672. doi:10.1016/S1470-2045(11)70145-0PubMedGoogle ScholarCrossref
20.
Wentzensen  N, Fetterman  B, Tokugawa  D,  et al.  Interobserver reproducibility and accuracy of p16/Ki-67 dual-stain cytology in cervical cancer screening.  Cancer Cytopathol. 2014;122(12):914-920. doi:10.1002/cncy.21473PubMedGoogle ScholarCrossref
21.
Grabe  N, Lahrmann  B, Pommerencke  T, von Knebel Doeberitz  M, Reuschenbach  M, Wentzensen  N.  A virtual microscopy system to scan, evaluate and archive biomarker enhanced cervical cytology slides.  Cell Oncol. 2010;32(1-2):109-119. doi:10.3233/CLO-2009-0508PubMedGoogle Scholar
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    Original Investigation
    May 13, 2019

    Clinical Evaluation of Human Papillomavirus Screening With p16/Ki-67 Dual Stain Triage in a Large Organized Cervical Cancer Screening Program

    Author Affiliations
    • 1Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland
    • 2Kaiser Permanente The Permanente Medical Group Regional Laboratory, Berkeley, California
    • 3Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York
    • 4Global Coalition Against Cervical Cancer, Arlington, Virginia
    JAMA Intern Med. 2019;179(7):881-888. doi:10.1001/jamainternmed.2019.0306
    Key Points

    Question  What are efficient approaches for triage of human papillomavirus–positive women in cervical cancer screening?

    Findings  This cohort study of 3225 women found that p16/Ki-67 dual stain, alone or in combination with human papillomavirus 16/18 genotyping, provides better risk stratification than comparable cytologic-based strategies.

    Meaning  Triage of human papillomavirus–positive women with dual stain may lead to lower referral to undergo colposcopy with similar detection of precancerous lesions compared with cytologic screening, making cervical cancer screening more efficient.

    Abstract

    Importance  As cervical cancer screening transitions from Papanicolaou cytologic screening to primary human papillomavirus (HPV) testing worldwide, effective triage tests are needed to decide who among the HPV-positive women should receive further diagnostic evaluation to avoid unnecessary colposcopies and biopsies.

    Objective  To evaluate the performance of the p16/Ki-67 dual stain (DS) and HPV16/18 genotyping for the triage of HPV-positive women.

    Design, Setting, and Participants  A prospective observational study was conducted within the cervical cancer screening program at Kaiser Permanente Northern California of 3225 HPV-positive women undergoing HPV and Papanicolaou cytologic testing with a valid DS result from September 16 to October 31, 2015, with follow-up through December 31, 2018.

    Exposures  Human papillomavirus screening with partial genotyping and cytologic triage compared with DS triage.

    Main Outcomes and Measures  Cervical intraepithelial neoplasia grade 3 or more severe (CIN3+) and grade 2 or more severe (CIN2+), diagnosed within 3 years after sample collection.

    Results  A total of 3225 women (mean [SD] age, 37.9 [11.3] years) participated in the study. For triage of HPV-positive women with partial genotyping, DS showed better risk stratification for CIN3+ than did Papanicolaou cytologic testing, with women with positive DS results having a higher risk than women with positive Papanicolaou test results for CIN3+ (218 of 1818 [12.0%; 95% CI, 10.5%-13.5%] vs 219 of 2128 [10.3%; 95% CI, 9.0%-11.6%]; P = .005). Similarly, DS showed better risk stratification for CIN3+ compared with Papanicolaou cytologic testing in HPV-positive women, irrespective of genotyping. The greatest reassurance against CIN3+ was observed in HPV16/18-negative women with negative DS results, with a risk low enough to extend retesting intervals. Dual stain triage strategies required substantially fewer colposcopies per detection of CIN3+ compared with Papanicolaou cytologic testing, with a 32.1% (859 of 2677) reduction of colposcopies compared with the currently recommended triage strategy of HPV screening with Papanicolaou cytologic testing. Results for CIN2+ were very similar.

    Conclusions and Relevance  Triage of HPV-positive women with DS was superior to Papanicolaou cytologic testing in this study, demonstrating equal immediate detection of precancerous lesions and substantially reduced referral to colposcopy. These findings suggest that DS can safely replace Papanicolaou cytologic testing as a triage strategy for primary HPV screening, and that retesting intervals in HPV16/18-negative women with negative DS results can be safely extended to 3 years.

    ×