Article Text
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.
- cervical cancer
- immunohistochemistry
- HPV
- Ki 67
- diagnosis
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Footnotes
AL and WWK contributed equally.
Handling editor Cheok Soon Lee.
Contributors MZ and CJLMM have set up the trial. MZ, AL, WWK, MCGB, DJ, MvdS, DAMH, RDMS, PJFS, JB, WGVQ and CJLMM were involved in data collection. MZ and HB performed the statistical analysis. MZ managed the database. MZ, MCGB, DJ and CJLMM drafted the manuscript. All authors critically reviewed the manuscript and approved the final version. All authors had full access to all of the data in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis and believe that the manuscript represents honest work. CJLMM affirms that the manuscript is an honest, accurate and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests DAMH, PJFS, RDMS and CJLMM are minority shareholders of Self-screen, a spin-off company of VUmc, of which CJLMM is part-time director since September 2017. Self-screen holds patents related to the work (ie, hrHPV test and methylation markers for cervical cancer screening). DAMH serves occasionally on the scientific advisory board of Pfizer. PJFS has been on the speakers bureau of Roche diagnostics, Gen-Probe, Abbott, Qiagen and Seegene and has been a consultant for Crucell. JB received travel support from DDL Diagnostic Laboratory, speakers’ fees from Qiagen and consultancy fees from Roche, GlaxoSmithKline and Merck/SPMSD; all JB’s fees were collected by his employer. WGVQ is shareholder of DDL Diagnostic Laboratory. CJLMM has received speakers’ fee from Qiagen and SPMSD/Merck, served occasionally on the scientific advisory board (expert meeting) of Qiagen and SPMSD/Merck and has been by occasion consultant for Qiagen. CJLMM has a very small number of shares in Qiagen, and was minority shareholder of Diassay until April 2016. All other authors have no conflict of interest to declare.
Patient consent Not required.
Provenance and peer review Not commissioned; externally peer reviewed.