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Mod Pathol. 2016 Oct;29(10):1155-64. doi: 10.1038/modpathol.2016.109. Epub 2016 Jul 1.

Standardized evaluation of tumor-infiltrating lymphocytes in breast cancer: results of the ring studies of the international immuno-oncology biomarker working group.

Author information

1
Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.
2
German Cancer Consortium (DKTK), Partner site Berlin, Berlin, Germany.
3
VMscope GmbH, Berlin, Germany.
4
Service de Biostatistique et d'Epidémiologie; Institute Gustave Roussy, Villejuif, France.
5
German Breast Group (GBG), Neu-Isenburg, Germany.
6
Clinic of Gynecology and Obstetrics, Sana Klinikum Offenbach, Offenbach, Germany.
7
Indiana University School of Medicine, Indianapolis, IN, USA.
8
Clinical Institute of Pathology, Medizinische Universität Wien, Wien, Austria.
9
Department of Pathology & Molecular Medicine, McMaster University, Hamilton, ON, Canada.
10
Weill Cornell Medical College, Doha, Qatar.
11
Harvard Medical School, Boston, MA, USA.
12
Tumor Pathology Department, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland.
13
Institut für Pathologie, Medizinische Hochschule Hannover, Hannover, Germany.
14
Pathology, GZA Ziekenhuizen, Sint-Augustinus, Wilrijk, Belgium.
15
Radiation Oncology and Pathology, Weill Cornell Medical College, New York, NY, USA.
16
Department of Pathology and Cytology GZA Hospitals, Wilrijk, Belgium.
17
Department of Pathology University Hospitals Leuven, Leuven, Belgium.
18
Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
19
Anatomical Pathology, Vancouver Hospital, Vancouver, BC, Canada.
20
Division of Pathology, NSABP, Pittsburgh, PA, USA.
21
Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON, Canada.
22
UQ School of Medicine and Pathology Queensland, The University of Queensland Centre for Clinical Research, Brisbane, QLD, Australia.
23
ERTICa Research Team, Department of Pathology, Jean Perrin Comprehensive Cancer Center, University of Auvergne EA4677, Clermont-Ferrand, France.
24
Division of Pathology and Laboratory Medicine, University of Milan, Milan, Italy.
25
Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
26
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
27
Department for Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
28
Sektion Gynäkopathologie, Pathologisches Institut, University of Heidelberg, Heidelberg, Germany.
29
Anatomie Pathologique, Institut Jules Bordet, Brussels, Belgium.
30
Molecular Diagnostic Oncology, Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
31
Department of Pathology, European Institute of Oncology, University of Milan, Milan, Italy.
32
Department of Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands.
33
Jules Bordet Institute, Brussels, Belgium.
34
Department of Gynecology, Helios-Klinikum Berlin-Buch, Berlin, Germany.
35
Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen EMN, Friedrich-Alexander University Erlangen, Erlangen, Germany.
36
Department of Gynecology, Klinikum Südstadt Rostock, Rostock, Germany.
37
Molecular Immunology Unit, Institut Jules Bordet, Brussels, Belgium.
38
Service de Biostatistique et d'Epidémiologie, Gustave Roussy, CESP, Inserm U1018, Univ. Paris Sud, Univ. Paris-Saclay, Villejuif, France.
39
Division of Research and Clinical Medicine, Peter MacCallum Cancer Center, Melbourne, VIC, Australia.
40
Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Brussels, Belgium.

Abstract

Multiple independent studies have shown that tumor-infiltrating lymphocytes (TIL) are prognostic in breast cancer with potential relevance for response to immune-checkpoint inhibitor therapy. Although many groups are currently evaluating TIL, there is no standardized system for diagnostic applications. This study reports the results of two ring studies investigating TIL conducted by the International Working Group on Immuno-oncology Biomarkers. The study aim was to determine the intraclass correlation coefficient (ICC) for evaluation of TIL by different pathologists. A total of 120 slides were evaluated by a large group of pathologists with a web-based system in ring study 1 and a more advanced software-system in ring study 2 that included an integrated feedback with standardized reference images. The predefined aim for successful ring studies 1 and 2 was an ICC above 0.7 (lower limit of 95% confidence interval (CI)). In ring study 1 the prespecified endpoint was not reached (ICC: 0.70; 95% CI: 0.62-0.78). On the basis of an analysis of sources of variation, we developed a more advanced digital image evaluation system for ring study 2, which improved the ICC to 0.89 (95% CI: 0.85-0.92). The Fleiss' kappa value for <60 vs ≥60% TIL improved from 0.45 (ring study 1) to 0.63 in RS2 and the mean concordance improved from 88 to 92%. This large international standardization project shows that reproducible evaluation of TIL is feasible in breast cancer. This opens the way for standardized reporting of tumor immunological parameters in clinical studies and diagnostic practice. The software-guided image evaluation approach used in ring study 2 may be of value as a tool for evaluation of TIL in clinical trials and diagnostic practice. The experience gained from this approach might be applicable to the standardization of other diagnostic parameters in histopathology.

PMID:
27363491
DOI:
10.1038/modpathol.2016.109
[Indexed for MEDLINE]
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