Three-tiered score for Ki-67 and p16 improves accuracy and reproducibility of grading CIN lesions

Marjolein van Zummeren, Annemiek Leeman, Wieke W Kremer, Maaike C G Bleeker, David Jenkins, Miekel van de Sandt, Daniëlle A M Heideman, Renske Steenbergen, Peter J F Snijders, Wim G V Quint, Johannes Berkhof, Chris J L M Meijer

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

AIMS: To investigate the accuracy and reproducibility of a scoring system for cervical intraepithelial neoplasia (CIN1-3) based on immunohistochemical (IHC) biomarkers Ki-67 and p16ink4a.

METHODS: 115 cervical tissue specimens were reviewed by three expert gynaecopathologists and graded according to three strategies: (1) CIN grade based on H&E staining only; (2) immunoscore based on the cumulative score of Ki-67 and p16ink4a only (0-6); and (3) CIN grade based on H&E supported by non-objectified IHC 2 weeks after scoring 1 and 2. The majority consensus diagnosis of the CIN grade based on H&E supported by IHC was used as the Reference Standard. The proportion of test positives (accuracy) and the absolute agreements across pathologists (reproducibility) of the three grading strategies within each Reference Standard category were calculated.

RESULTS: We found that immunoscoring with positivity definition 6 yielded the highest proportion of test positives for Reference Standard CIN3 (95.5%), in combination with the lowest proportion of test positives in samples with CIN1 (1.8%). The proportion of test positives for CIN3 was significantly lower for sole H&E staining (81.8%) or combined H&E and IHC grading (84.8%) with positivity definition ≥CIN3. Immunoscore 6 also yielded high absolute agreements for CIN3 and CIN1, but the absolute agreement was low for CIN2.

CONCLUSIONS: The higher accuracy and reproducibility of the immunoscore opens the possibility of a more standardised and reproducible definition of CIN grade than conventional pathology practice, allowing a more accurate comparison of CIN-based management strategies and evaluation of new biomarkers to improve the understanding of progression of precancer from human papillomavirus infection to cancer.

Original languageEnglish
Pages (from-to)981-988
Number of pages8
JournalJournal of Clinical Pathology
Volume71
Issue number11
Early online date16 Jul 2018
DOIs
Publication statusPublished - 1 Nov 2018

Cite this

@article{500631abdff241ef8a9827cb8d6f62d9,
title = "Three-tiered score for Ki-67 and p16 improves accuracy and reproducibility of grading CIN lesions",
abstract = "AIMS: To investigate the accuracy and reproducibility of a scoring system for cervical intraepithelial neoplasia (CIN1-3) based on immunohistochemical (IHC) biomarkers Ki-67 and p16ink4a.METHODS: 115 cervical tissue specimens were reviewed by three expert gynaecopathologists and graded according to three strategies: (1) CIN grade based on H&E staining only; (2) immunoscore based on the cumulative score of Ki-67 and p16ink4a only (0-6); and (3) CIN grade based on H&E supported by non-objectified IHC 2 weeks after scoring 1 and 2. The majority consensus diagnosis of the CIN grade based on H&E supported by IHC was used as the Reference Standard. The proportion of test positives (accuracy) and the absolute agreements across pathologists (reproducibility) of the three grading strategies within each Reference Standard category were calculated.RESULTS: We found that immunoscoring with positivity definition 6 yielded the highest proportion of test positives for Reference Standard CIN3 (95.5{\%}), in combination with the lowest proportion of test positives in samples with CIN1 (1.8{\%}). The proportion of test positives for CIN3 was significantly lower for sole H&E staining (81.8{\%}) or combined H&E and IHC grading (84.8{\%}) with positivity definition ≥CIN3. Immunoscore 6 also yielded high absolute agreements for CIN3 and CIN1, but the absolute agreement was low for CIN2.CONCLUSIONS: The higher accuracy and reproducibility of the immunoscore opens the possibility of a more standardised and reproducible definition of CIN grade than conventional pathology practice, allowing a more accurate comparison of CIN-based management strategies and evaluation of new biomarkers to improve the understanding of progression of precancer from human papillomavirus infection to cancer.",
author = "{van Zummeren}, Marjolein and Annemiek Leeman and Kremer, {Wieke W} and Bleeker, {Maaike C G} and David Jenkins and {van de Sandt}, Miekel and Heideman, {Dani{\"e}lle A M} and Renske Steenbergen and Snijders, {Peter J F} and Quint, {Wim G V} and Johannes Berkhof and Meijer, {Chris J L M}",
note = "{\circledC} Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.",
year = "2018",
month = "11",
day = "1",
doi = "10.1136/jclinpath-2018-205271",
language = "English",
volume = "71",
pages = "981--988",
journal = "Journal of Clinical Pathology",
issn = "0021-9746",
publisher = "BMJ Publishing Group",
number = "11",

}

Three-tiered score for Ki-67 and p16 improves accuracy and reproducibility of grading CIN lesions. / van Zummeren, Marjolein; Leeman, Annemiek; Kremer, Wieke W; Bleeker, Maaike C G; Jenkins, David; van de Sandt, Miekel; Heideman, Daniëlle A M; Steenbergen, Renske; Snijders, Peter J F; Quint, Wim G V; Berkhof, Johannes; Meijer, Chris J L M.

In: Journal of Clinical Pathology, Vol. 71, No. 11, 01.11.2018, p. 981-988.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Three-tiered score for Ki-67 and p16 improves accuracy and reproducibility of grading CIN lesions

AU - van Zummeren, Marjolein

AU - Leeman, Annemiek

AU - Kremer, Wieke W

AU - Bleeker, Maaike C G

AU - Jenkins, David

AU - van de Sandt, Miekel

AU - Heideman, Daniëlle A M

AU - Steenbergen, Renske

AU - Snijders, Peter J F

AU - Quint, Wim G V

AU - Berkhof, Johannes

AU - Meijer, Chris J L M

N1 - © Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2018/11/1

Y1 - 2018/11/1

N2 - AIMS: To investigate the accuracy and reproducibility of a scoring system for cervical intraepithelial neoplasia (CIN1-3) based on immunohistochemical (IHC) biomarkers Ki-67 and p16ink4a.METHODS: 115 cervical tissue specimens were reviewed by three expert gynaecopathologists and graded according to three strategies: (1) CIN grade based on H&E staining only; (2) immunoscore based on the cumulative score of Ki-67 and p16ink4a only (0-6); and (3) CIN grade based on H&E supported by non-objectified IHC 2 weeks after scoring 1 and 2. The majority consensus diagnosis of the CIN grade based on H&E supported by IHC was used as the Reference Standard. The proportion of test positives (accuracy) and the absolute agreements across pathologists (reproducibility) of the three grading strategies within each Reference Standard category were calculated.RESULTS: We found that immunoscoring with positivity definition 6 yielded the highest proportion of test positives for Reference Standard CIN3 (95.5%), in combination with the lowest proportion of test positives in samples with CIN1 (1.8%). The proportion of test positives for CIN3 was significantly lower for sole H&E staining (81.8%) or combined H&E and IHC grading (84.8%) with positivity definition ≥CIN3. Immunoscore 6 also yielded high absolute agreements for CIN3 and CIN1, but the absolute agreement was low for CIN2.CONCLUSIONS: The higher accuracy and reproducibility of the immunoscore opens the possibility of a more standardised and reproducible definition of CIN grade than conventional pathology practice, allowing a more accurate comparison of CIN-based management strategies and evaluation of new biomarkers to improve the understanding of progression of precancer from human papillomavirus infection to cancer.

AB - AIMS: To investigate the accuracy and reproducibility of a scoring system for cervical intraepithelial neoplasia (CIN1-3) based on immunohistochemical (IHC) biomarkers Ki-67 and p16ink4a.METHODS: 115 cervical tissue specimens were reviewed by three expert gynaecopathologists and graded according to three strategies: (1) CIN grade based on H&E staining only; (2) immunoscore based on the cumulative score of Ki-67 and p16ink4a only (0-6); and (3) CIN grade based on H&E supported by non-objectified IHC 2 weeks after scoring 1 and 2. The majority consensus diagnosis of the CIN grade based on H&E supported by IHC was used as the Reference Standard. The proportion of test positives (accuracy) and the absolute agreements across pathologists (reproducibility) of the three grading strategies within each Reference Standard category were calculated.RESULTS: We found that immunoscoring with positivity definition 6 yielded the highest proportion of test positives for Reference Standard CIN3 (95.5%), in combination with the lowest proportion of test positives in samples with CIN1 (1.8%). The proportion of test positives for CIN3 was significantly lower for sole H&E staining (81.8%) or combined H&E and IHC grading (84.8%) with positivity definition ≥CIN3. Immunoscore 6 also yielded high absolute agreements for CIN3 and CIN1, but the absolute agreement was low for CIN2.CONCLUSIONS: The higher accuracy and reproducibility of the immunoscore opens the possibility of a more standardised and reproducible definition of CIN grade than conventional pathology practice, allowing a more accurate comparison of CIN-based management strategies and evaluation of new biomarkers to improve the understanding of progression of precancer from human papillomavirus infection to cancer.

U2 - 10.1136/jclinpath-2018-205271

DO - 10.1136/jclinpath-2018-205271

M3 - Article

VL - 71

SP - 981

EP - 988

JO - Journal of Clinical Pathology

JF - Journal of Clinical Pathology

SN - 0021-9746

IS - 11

ER -