p16/Ki-67 Dual Stain Cytology for Detection of Cervical Precancer in HPV-Positive Women

Nicolas Wentzensen, Barbara Fetterman, Philip E. Castle, Mark Schiffman, Shannon N. Wood, Eric Stiemerling, Diane Tokugawa, Clara Bodelon, Nancy Poitras, Thomas Lorey, Walter Kinney

Research output: Contribution to journalArticle

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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.

CONCLUSION: 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.

Original languageEnglish (US)
Pages (from-to)djv257
JournalJournal of the National Cancer Institute
Volume107
Issue number12
DOIs
StatePublished - Dec 1 2015
Externally publishedYes

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Cell Biology
Coloring Agents
Colposcopy
Benchmarking
Triage
Early Detection of Cancer
Uterine Cervical Neoplasms
Observational Studies
Referral and Consultation
Biomarkers
Databases
Prospective Studies
Guidelines
Sensitivity and Specificity
Population

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

Wentzensen, N., Fetterman, B., Castle, P. E., Schiffman, M., Wood, S. N., Stiemerling, E., ... Kinney, W. (2015). p16/Ki-67 Dual Stain Cytology for Detection of Cervical Precancer in HPV-Positive Women. Journal of the National Cancer Institute, 107(12), djv257. https://doi.org/10.1093/jnci/djv257

p16/Ki-67 Dual Stain Cytology for Detection of Cervical Precancer in HPV-Positive Women. / Wentzensen, Nicolas; Fetterman, Barbara; Castle, Philip E.; Schiffman, Mark; Wood, Shannon N.; Stiemerling, Eric; Tokugawa, Diane; Bodelon, Clara; Poitras, Nancy; Lorey, Thomas; Kinney, Walter.

In: Journal of the National Cancer Institute, Vol. 107, No. 12, 01.12.2015, p. djv257.

Research output: Contribution to journalArticle

Wentzensen, N, Fetterman, B, Castle, PE, Schiffman, M, Wood, SN, Stiemerling, E, Tokugawa, D, Bodelon, C, Poitras, N, Lorey, T & Kinney, W 2015, 'p16/Ki-67 Dual Stain Cytology for Detection of Cervical Precancer in HPV-Positive Women', Journal of the National Cancer Institute, vol. 107, no. 12, pp. djv257. https://doi.org/10.1093/jnci/djv257
Wentzensen, Nicolas ; Fetterman, Barbara ; Castle, Philip E. ; Schiffman, Mark ; Wood, Shannon N. ; Stiemerling, Eric ; Tokugawa, Diane ; Bodelon, Clara ; Poitras, Nancy ; Lorey, Thomas ; Kinney, Walter. / p16/Ki-67 Dual Stain Cytology for Detection of Cervical Precancer in HPV-Positive Women. In: Journal of the National Cancer Institute. 2015 ; Vol. 107, No. 12. pp. djv257.
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AU - Wood, Shannon N.

AU - Stiemerling, Eric

AU - Tokugawa, Diane

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AU - Poitras, Nancy

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N2 - 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.CONCLUSION: 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.

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