title: Reproducibility and Prognostic Potential of Ki-67 Proliferation Index when Comparing Digital-Image Analysis with Standard Semi-Quantitative Evaluation in Breast Cancer.
abstract: In this study, the reproducibility of Ki-67 proliferation index (KIPI) was investigated by comparing the semi-quantitative (SQ) results of three assessors with those of digital image-analysis (DIA) methods. The prognostic significance of the two approaches was also correlated with clinical outcome. Tissue microarrays of duplicate 2 mm cores were constructed from representative areas of formalin-fixed and paraffin-embedded tumor blocks of 347 breast cancer patients. SQ evaluation of Ki-67 (MIB1 clone) immunostained slides was performed independently by three pathologists. DIA was completed using a fully automated histological pattern and cell recognition module for KIPI detection (DIA-1) and an adjustable module (DIA-2) with the possibility of manual corrections. To compare SQ and DIA evaluations intra-class correlation (ICC) and concordance correlation coefficients (CCC) were determined. The three SQ evaluations demonstrated a remarkable ICC (0.853). Significant difference and poor concordance occurred between SQ-1 and SQ-2 as well as between SQ-1 and SQ-3 (p ≤ 0.001, CCC ≤ 0.827 for both comparisons). Thus, the reference KIPI value (SQ-RV) was generated from the mean values of SQ-2 and SQ-3. SQ-RV and DIA-2 results showed substantial concordance (CCC = 0.963, at p = 0.754), while SQ-RV and DIA-1 values differed (p ≤ 0.001) at only moderate concordance (CCC = 0.906). In multivariate analysis, lymph node status and SQ-2 assessment were significantly associated with clinical outcome (p ≤ 0.012 for both comparisons). Our results confirm that KIPI is a significant prognostic marker in breast cancer, which can be can be reliably reproduced by using an adjustable DIA-2 image analysis module.
authors.affiliation: 2nd Department of Pathology, Semmelweis University, 93 Üllői út, Budapest, 1091, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Ács
authors.affiliation: 2nd Department of Pathology, Semmelweis University, 93 Üllői út, Budapest, 1091, Hungary.
authors.forename: Lilla
authors.initials: L
authors.lastname: Madaras
authors.affiliation: 2nd Department of Pathology, Semmelweis University, 93 Üllői út, Budapest, 1091, Hungary.
authors.forename: Kristóf Attila
authors.initials: KA
authors.lastname: Kovács
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 26 Üllői út, Budapest, 1085, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Micsik
authors.affiliation: MTA-SE Tumor Progression Research Group, 2nd Department of Pathology, Semmelweis University, 93 Üllői út, Budapest, 1091, Hungary.
authors.forename: Anna-Mária
authors.initials: AM
authors.lastname: Tőkés
authors.affiliation: MTA-TTK Lendület Cancer Biomarker Research Group, 2 Magyar tudósok körútja, Budapest, 1117, Hungary.|2nd Department of Pediatrics, Semmelweis University, Tűzoltó u. 7-9, Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Győrffy
authors.affiliation: 2nd Department of Pathology, Semmelweis University, 93 Üllői út, Budapest, 1091, Hungary.
authors.forename: Janina
authors.initials: J
authors.lastname: Kulka
authors.affiliation: 2nd Department of Pathology, Semmelweis University, 93 Üllői út, Budapest, 1091, Hungary. cac@korb2.sote.hu.|MTA-TTK Lendület Cancer Biomarker Research Group, 2 Magyar tudósok körútja, Budapest, 1117, Hungary. cac@korb2.sote.hu.
authors.forename: Attila Marcell
authors.initials: AM
authors.lastname: Szász
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods*; D019394:Ki-67 Antigen / Q000378:metabolism*; D008875:Middle Aged; D057054:Molecular Imaging / Q000379:methods*; D009361:Neoplasm Invasiveness; D011379:Prognosis; D015203:Reproducibility of Results
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen
keywords: Breast cancer; Concordance correlation; Digital image analysis; Intra-class correlation; Ki-67 proliferation index; Prognosis