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Observational Study
. 2019 Jul 1;179(7):881-888.
doi: 10.1001/jamainternmed.2019.0306.

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

Nicolas Wentzensen  1 , Megan A Clarke  1 , Renee Bremer  1 , Nancy Poitras  2 , Diane Tokugawa  2 , Patricia E Goldhoff  2 , Philip E Castle  3 , Mark Schiffman  1 , Julie D Kingery  2 , Kiranjit K Grewal  2 , Alex Locke  2 , Walter Kinney  4 , Thomas S Lorey  2
Affiliations
Observational Study

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

Nicolas Wentzensen et al. JAMA Intern Med. .

Erratum in

  • Errors in Caption to Figure 2.
    [No authors listed] [No authors listed] JAMA Intern Med. 2019 Jul 1;179(7):1007. doi: 10.1001/jamainternmed.2019.2636. JAMA Intern Med. 2019. PMID: 31260006 Free PMC article. No abstract available.

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Wentzensen reported being employed by the National Cancer Institute (NCI), which has received cervical cancer screening assays in-kind or at reduced cost from BD and Roche for studies that Dr Wentzensen is conducting. Dr Goldhoff reported receiving grants from the National Institutes of Health (NIH)/NCI during the conduct of the study. Dr Castle reported receiving cervical screening tests and diagnostics from Roche, Becton Dickinson, Cepheid, and Arbor Vita Corp at a reduced cost or no cost for research. Dr Schiffman reported being employed by the NCI, which has received cervical cancer screening assays in-kind or at reduced cost from companies involved in cervical screening, including Roche, BD, Qiagen, and MobileODT. Dr Kingery reported receiving grants from the NIH and the NCI during the conduct of the study and receiving grants from the NIH and the NCI outside the submitted work. Dr Grewal reported receiving grants from the NIH and the NCI during the conduct of the study and grants from the NIH and the NCI outside the submitted work. Dr Lorey reported receiving grants from the NIH and the NCI during the conduct of the study and grants from the NIH and the NCI outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram
ASC-US+ indicates atypical squamous cells of undetermined significance or worse; DS, dual stain; HPV, human papillomavirus; KPNC, Kaiser Permanente Northern California; and NILM, negative for intraepithelial lesions or malignant neoplasm.
Figure 2.
Figure 2.. Risk of Cervical Intraepithelial Neoplasia Grade 3 or Worse (CIN3+) in Strata of Cytologic Testing, Dual Stain (DS), and Human Papillomavirus (HPV)16/18
The risk of CIN3+ for combinations of cytologic testing with HPV16/18 genotyping, DS with HPV16/18 genotyping, and DS alone is plotted on the y-axis, with number and percentage of women for specific test combinations indicated. The dotted line corresponds to the 1-year return threshold (HPV-positive negative for intraepithelial lesions or malignant neoplasm [NILM], 2.8%), and the dashed line corresponds to the colposcopy referral threshold (HPV-positive atypical squamous cells of undetermined significance [ASC-US], 5.7%). FDA indicates US Food and Drug Administration.
See this image and copyright information in PMC

Comment in

References

    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.30579 - DOI - PubMed
    1. 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/dju153 - DOI - PMC - PubMed
    1. Wentzensen N. Triage of HPV-positive women in cervical cancer screening. Lancet Oncol. 2013;14(2):107-109. doi: 10.1016/S1470-2045(12)70568-5 - DOI - PMC - PubMed
    1. 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.31261 - DOI - PubMed
    1. 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.2015.11.015 - DOI - PMC - PubMed

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