Performance of p16INK4a-cytology, HPV mRNA, and HPV DNA testing to identify high grade cervical dysplasia in women with abnormal screening results

Miriam Reuschenbach, Andreas Clad, Christina Von Knebel Doeberitz, Nicolas Wentzensen, Janina Rahmsdorf, Frauke Schaffrath, Henrik Griesser, Nikolaus Freudenberg, Magnus Von Knebel Doeberitz

Research output: Contribution to journalArticle

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Abstract

Objective: The prognostic value of dysplastic lesions of the uterine cervix cannot be adequately determined by Pap cytology alone. Detection of HPV DNA increases the diagnostic sensitivity. However, due to the very high prevalence of transient HPV infections, HPV DNA testing suffers from poor diagnostic specificity. Biomarkers that highlight the shift from self limited transient to potentially dangerous transforming HPV infections may improve the accuracy of cervical cancer screening. We evaluated HPV E6/E7 mRNA detection (APTIMA), p16INK4a-immunocytology (CINtec), and HPV DNA testing (HC2) to identify women with high grade cervical neoplasia in a disease-enriched cross-sectional cohort. Methods: Liquid based cytology specimens were collected from 275 patients. All assays were performed from these vials. Detection rates of each test were evaluated against conventional H&E based histopathology alone and stratified by p16INK4a-immunohistochemistry (IHC). Results: All assays yielded a high sensitivity for the detection of CIN3+ (96.4% (95% CI, 90.4-98.8) for HC2, 95.5% (89.2-98.3) for APTIMA and CINtec) and CIN2+ (91.5% (85.8-95.1) for HC2, 88.4% (82.3-92.7) for APTIMA, 86.6% (80.2-91.2) for CINtec). The specificity to detect high grade dysplasia was highest for CINtec p16INK4a-cytology (60.6% (52.7-68.0) in CIN3+ and 74.8% (65.5-82.3) in CIN2+), followed by APTIMA (56.4% (48.4-64.0) in CIN3+ and 71.2% (61.7-79.2) in CIN2+) and HC2 (49.1% (41.3-56.9) in CIN3+ and 63.4% (53.7-72.1) in CIN2+). All tests had higher sensitivity using p16INK4a-IHC-positive CIN2+ lesions as endpoint. Conclusions: Biomarkers that detect HPV induced dysplastic changes in the transforming stage are promising tools to overcome the current limitations of cervical cancer screening.

Original languageEnglish (US)
Pages (from-to)98-105
Number of pages8
JournalGynecologic oncology
Volume119
Issue number1
DOIs
StatePublished - Oct 1 2010

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Uterine Cervical Dysplasia
Cell Biology
Early Detection of Cancer
Uterine Cervical Neoplasms
Messenger RNA
DNA
Biomarkers
Immunohistochemistry
Infection
Cervix Uteri
Neoplasms

Keywords

  • Cervical cancer
  • Cervical intraepithelial neoplasia
  • HPV DNA
  • HPV mRNA
  • Screening
  • p16

ASJC Scopus subject areas

  • Oncology
  • Obstetrics and Gynecology

Cite this

Performance of p16INK4a-cytology, HPV mRNA, and HPV DNA testing to identify high grade cervical dysplasia in women with abnormal screening results. / Reuschenbach, Miriam; Clad, Andreas; Von Knebel Doeberitz, Christina; Wentzensen, Nicolas; Rahmsdorf, Janina; Schaffrath, Frauke; Griesser, Henrik; Freudenberg, Nikolaus; Von Knebel Doeberitz, Magnus.

In: Gynecologic oncology, Vol. 119, No. 1, 01.10.2010, p. 98-105.

Research output: Contribution to journalArticle

Reuschenbach, M, Clad, A, Von Knebel Doeberitz, C, Wentzensen, N, Rahmsdorf, J, Schaffrath, F, Griesser, H, Freudenberg, N & Von Knebel Doeberitz, M 2010, 'Performance of p16INK4a-cytology, HPV mRNA, and HPV DNA testing to identify high grade cervical dysplasia in women with abnormal screening results', Gynecologic oncology, vol. 119, no. 1, pp. 98-105. https://doi.org/10.1016/j.ygyno.2010.06.011
Reuschenbach, Miriam ; Clad, Andreas ; Von Knebel Doeberitz, Christina ; Wentzensen, Nicolas ; Rahmsdorf, Janina ; Schaffrath, Frauke ; Griesser, Henrik ; Freudenberg, Nikolaus ; Von Knebel Doeberitz, Magnus. / Performance of p16INK4a-cytology, HPV mRNA, and HPV DNA testing to identify high grade cervical dysplasia in women with abnormal screening results. In: Gynecologic oncology. 2010 ; Vol. 119, No. 1. pp. 98-105.
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abstract = "Objective: The prognostic value of dysplastic lesions of the uterine cervix cannot be adequately determined by Pap cytology alone. Detection of HPV DNA increases the diagnostic sensitivity. However, due to the very high prevalence of transient HPV infections, HPV DNA testing suffers from poor diagnostic specificity. Biomarkers that highlight the shift from self limited transient to potentially dangerous transforming HPV infections may improve the accuracy of cervical cancer screening. We evaluated HPV E6/E7 mRNA detection (APTIMA), p16INK4a-immunocytology (CINtec), and HPV DNA testing (HC2) to identify women with high grade cervical neoplasia in a disease-enriched cross-sectional cohort. Methods: Liquid based cytology specimens were collected from 275 patients. All assays were performed from these vials. Detection rates of each test were evaluated against conventional H&E based histopathology alone and stratified by p16INK4a-immunohistochemistry (IHC). Results: All assays yielded a high sensitivity for the detection of CIN3+ (96.4{\%} (95{\%} CI, 90.4-98.8) for HC2, 95.5{\%} (89.2-98.3) for APTIMA and CINtec) and CIN2+ (91.5{\%} (85.8-95.1) for HC2, 88.4{\%} (82.3-92.7) for APTIMA, 86.6{\%} (80.2-91.2) for CINtec). The specificity to detect high grade dysplasia was highest for CINtec p16INK4a-cytology (60.6{\%} (52.7-68.0) in CIN3+ and 74.8{\%} (65.5-82.3) in CIN2+), followed by APTIMA (56.4{\%} (48.4-64.0) in CIN3+ and 71.2{\%} (61.7-79.2) in CIN2+) and HC2 (49.1{\%} (41.3-56.9) in CIN3+ and 63.4{\%} (53.7-72.1) in CIN2+). All tests had higher sensitivity using p16INK4a-IHC-positive CIN2+ lesions as endpoint. Conclusions: Biomarkers that detect HPV induced dysplastic changes in the transforming stage are promising tools to overcome the current limitations of cervical cancer screening.",
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T1 - Performance of p16INK4a-cytology, HPV mRNA, and HPV DNA testing to identify high grade cervical dysplasia in women with abnormal screening results

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AU - Clad, Andreas

AU - Von Knebel Doeberitz, Christina

AU - Wentzensen, Nicolas

AU - Rahmsdorf, Janina

AU - Schaffrath, Frauke

AU - Griesser, Henrik

AU - Freudenberg, Nikolaus

AU - Von Knebel Doeberitz, Magnus

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N2 - Objective: The prognostic value of dysplastic lesions of the uterine cervix cannot be adequately determined by Pap cytology alone. Detection of HPV DNA increases the diagnostic sensitivity. However, due to the very high prevalence of transient HPV infections, HPV DNA testing suffers from poor diagnostic specificity. Biomarkers that highlight the shift from self limited transient to potentially dangerous transforming HPV infections may improve the accuracy of cervical cancer screening. We evaluated HPV E6/E7 mRNA detection (APTIMA), p16INK4a-immunocytology (CINtec), and HPV DNA testing (HC2) to identify women with high grade cervical neoplasia in a disease-enriched cross-sectional cohort. Methods: Liquid based cytology specimens were collected from 275 patients. All assays were performed from these vials. Detection rates of each test were evaluated against conventional H&E based histopathology alone and stratified by p16INK4a-immunohistochemistry (IHC). Results: All assays yielded a high sensitivity for the detection of CIN3+ (96.4% (95% CI, 90.4-98.8) for HC2, 95.5% (89.2-98.3) for APTIMA and CINtec) and CIN2+ (91.5% (85.8-95.1) for HC2, 88.4% (82.3-92.7) for APTIMA, 86.6% (80.2-91.2) for CINtec). The specificity to detect high grade dysplasia was highest for CINtec p16INK4a-cytology (60.6% (52.7-68.0) in CIN3+ and 74.8% (65.5-82.3) in CIN2+), followed by APTIMA (56.4% (48.4-64.0) in CIN3+ and 71.2% (61.7-79.2) in CIN2+) and HC2 (49.1% (41.3-56.9) in CIN3+ and 63.4% (53.7-72.1) in CIN2+). All tests had higher sensitivity using p16INK4a-IHC-positive CIN2+ lesions as endpoint. Conclusions: Biomarkers that detect HPV induced dysplastic changes in the transforming stage are promising tools to overcome the current limitations of cervical cancer screening.

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KW - Cervical cancer

KW - Cervical intraepithelial neoplasia

KW - HPV DNA

KW - HPV mRNA

KW - Screening

KW - p16

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