PT  - JOURNAL ARTICLE
AU  - Marjolein van Zummeren
AU  - Annemiek Leeman
AU  - Wieke W Kremer
AU  - Maaike C G Bleeker
AU  - David Jenkins
AU  - Miekel van de Sandt
AU  - Daniëlle A M Heideman
AU  - Renske Steenbergen
AU  - Peter J F Snijders
AU  - Wim G V Quint
AU  - Johannes Berkhof
AU  - Chris J L M Meijer
TI  - Three-tiered score for Ki-67 and p16<sup>ink4a</sup> improves accuracy and reproducibility of grading CIN lesions
AID  - 10.1136/jclinpath-2018-205271
DP  - 2018 Nov 01
TA  - Journal of Clinical Pathology
PG  - 981--988
VI  - 71
IP  - 11
4099  - http://jcp.bmj.com/content/71/11/981.short
4100  - http://jcp.bmj.com/content/71/11/981.full
SO  - J Clin Pathol2018 Nov 01; 71
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.