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Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer

Authors
  • Kos, Zuzana1
  • Roblin, Elvire2, 3
  • Kim, Rim S.4
  • Michiels, Stefan2, 3
  • Gallas, Brandon D.5
  • Chen, Weijie5
  • van de Vijver, Koen K.6, 7
  • Goel, Shom8, 9
  • Adams, Sylvia10
  • Demaria, Sandra11
  • Viale, Giuseppe12
  • Nielsen, Torsten O.13
  • Badve, Sunil S.14
  • Symmans, W. Fraser15
  • Sotiriou, Christos16
  • Rimm, David L.17
  • Hewitt, Stephen18
  • Denkert, Carsten19
  • Loibl, Sibylle20
  • Luen, Stephen J.9, 21
  • And 235 more
  • 1 BC Cancer - Vancouver, Vancouver, BC, Canada , Vancouver (Canada)
  • 2 Gustave Roussy, University Paris-Saclay, Villejuif, France , Villejuif (France)
  • 3 University Paris-Saclay, labeled Ligue Contre le Cancer, Villejuif, France , Villejuif (France)
  • 4 National Surgical Adjuvant Breast and Bowel Project (NSABP)/NRG Oncology, Pittsburgh, PA, USA , Pittsburgh (United States)
  • 5 Division of Imaging, Diagnostics, and Software Reliability (DIDSR); Office of Science and Engineering Laboratories (OSEL); Center for Devices and Radiological Health (CDRH), US Food and Drug Administration (US FDA), Silver Spring, MD, USA , Silver Spring (United States)
  • 6 University Hospital Antwerp, Antwerp, Belgium , Antwerp (Belgium)
  • 7 Ghent University Hospital, Cancer Research Institute Ghent (CRIG), Ghent, Belgium , Ghent (Belgium)
  • 8 The Sir Peter MacCallum Cancer Centre, Melbourne, VIC, Australia , Melbourne (Australia)
  • 9 University of Melbourne, Melbourne, Victoria, Australia , Melbourne (Australia)
  • 10 New York University Medical School, New York, NY, USA , New York (United States)
  • 11 Weill Cornell Medicine, New York, NY, USA , New York (United States)
  • 12 University of Milan, Milan, Italy , Milan (Italy)
  • 13 University of British Columbia, Vancouver, Canada , Vancouver (Canada)
  • 14 Indiana University, Indianapolis, USA , Indianapolis (United States)
  • 15 The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA , Houston (United States)
  • 16 Université Libre de Bruxelles, Brussels, Belgium , Brussels (Belgium)
  • 17 Yale School of Medicine, New Haven, CT, USA , New Haven (United States)
  • 18 National Cancer Institute, NIH, Bethesda, MD, USA , Bethesda (United States)
  • 19 Universitätsklinikum Gießen und Marburg GmbH, Standort Marburg and Philipps-Universität Marburg, Marburg, Germany , Marburg (Germany)
  • 20 German Breast Group, Neu-Isenburg, Germany , Neu-Isenburg (Germany)
  • 21 University of Melbourne, Melbourne, VIC, Australia , Melbourne (Australia)
  • 22 Ontario Institute for Cancer Research, Toronto, ON, Canada , Toronto (Canada)
  • 23 University of Edinburgh Cancer Research Centre, Edinburgh, UK , Edinburgh (United Kingdom)
  • 24 IRCCS Fondazione Instituto Nazionale Tumori and University of Milan, School of Medicine, Milan, Italy , Milan (Italy)
  • 25 Brigham and Women’s Hospital, Boston, MA, USA , Boston (United States)
  • 26 Dana Farber Cancer Institute, Boston, MA, USA , Boston (United States)
  • 27 The Institute of Cancer Research, Surrey, UK , Surrey (United Kingdom)
  • 28 The Institute of Cancer Research, London, UK , London (United Kingdom)
  • 29 Vivactiv Ltd, Bellingdon, Bucks, UK , Bucks (United Kingdom)
  • 30 The Netherlands Cancer Institute, Amsterdam, The Netherlands , Amsterdam (Netherlands)
  • 31 Case Western Reserve University, Cleveland, OH, USA , Cleveland (United States)
  • 32 Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, USA , Cleveland (United States)
  • 33 Radboud University Medical Center, Nijmegen, Netherlands , Nijmegen (Netherlands)
  • 34 Department of Surgical Pathology Zealand University Hospital, Køge, Denmark , Køge (Denmark)
  • 35 Universidad de La Frontera, Temuco, Chile , Temuco (Chile)
  • 36 Forbius, Montreal, QC, Canada , Montreal (Canada)
  • 37 Department of Pathology, Peter MacCallum Cancer Centre Department of Pathology, Melbourne, VIC, Australia , Melbourne (Australia)
  • 38 Universidad de la Frontera, Temuco, Chile , Temuco (Chile)
  • 39 KU Leuven- Univerisity of Leuven, Department of Imaging and Pathology, Laboratory of Translational Cell & Tissue Research and KU Leuven- University Hospitals Leuven, Department of Pathology, Leuven, Belgium , Leuven (Belgium)
  • 40 PathAI, Inc, Boston, MA, USA , Boston (United States)
  • 41 Jules Bordet Institute, Brussels, Belgium , Brussels (Belgium)
  • 42 GZA-ZNA, Antwerp, Belgium , Antwerp (Belgium)
  • 43 Lund University, Lund, Sweden , Lund (Sweden)
  • 44 Fudan University Shanghai Cancer Centre, Shanghai, China , Shanghai (China)
  • 45 Icahn School of Medicine at Mt. Sinai, New York, NY, 10029, USA , New York (United States)
  • 46 University College London Cancer Institute, University College London, London, UK , London (United Kingdom)
  • 47 The University of Texas MD Anderson Cancer Center, Houston, TX, USA , Houston (United States)
  • 48 Tufts Medical Center, Boston, USA , Boston (United States)
  • 49 Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, Charitéplatz 1, Berlin, 10117, Germany , Berlin (Germany)
  • 50 Instituto Nacional de Enfermedades Neoplasicas, Lima, 15038, Peru , Lima (Peru)
  • 51 University of Milan, Istituto Europeo di Oncologia, IRCCS, Milan, Italy , Milan (Italy)
  • 52 Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy , Padova (Italy)
  • 53 University of Padova, Padova, Italy , Padova (Italy)
  • 54 Institut Gustave Roussy, Villejuif, France , Villejuif (France)
  • 55 Francis Crick Institute, Midland Road, London, UK , London (United Kingdom)
  • 56 Memorial Sloan Kettering Cancer Center, New York, NY, USA , New York (United States)
  • 57 Albert Einstein College of Medicine, Bronx, NY, USA , Bronx (United States)
  • 58 Herlev and Gentofte Hospital, Herlev, Denmark , Herlev (Denmark)
  • 59 National Taiwan University Cancer Center, Taipei, Taiwan , Taipei (Taiwan)
  • 60 National Taiwan University Hospital, Taipei, Taiwan , Taipei (Taiwan)
  • 61 National Taiwan University, Taipei, Taiwan , Taipei (Taiwan)
  • 62 Centre de Lutte contre le cancer - Centre Jean Perrin, Clermont-Ferrand, France , Clermont-Ferrand (France)
  • 63 The University of Queensland Centre for Clinical Research and Pathology Queensland, Brisbane, QLD, Australia , Brisbane (Australia)
  • 64 Institut Curie, Paris Sciences Lettres Université, Inserm U934, Department of Pathology, Paris, France , Paris (France)
  • 65 Pathology Department, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD) - CIBERONC, Madrid, Spain , Madrid (Spain)
  • 66 GEICAM-Spanish Breast Cancer Research Group, Madrid, Spain , Madrid (Spain)
  • 67 University Hospitals Bristol NHS Foundation Trust, Bristol, UK , Bristol (United Kingdom)
  • 68 Bellvitge University Hospital, IDIBELL. Breast Unit. Catalan Institut of Oncology. L ‘Hospitalet del Llobregat’, Barcelona, Catalonia, 08908, Spain , Barcelona (Spain)
  • 69 Institute of Pathology, Halle (Saale), Germany , Halle (Saale) (Germany)
  • 70 Universitè Libre de Bruxelles, Brussels, Belgium , Brussels (Belgium)
  • 71 Emory University, Atlanta, GA, USA , Atlanta (United States)
  • 72 Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx, NY, USA , Bronx (United States)
  • 73 Technical University of Denmark; Visiopharm A/S, Hørsholm, Denmark , Hørsholm (Denmark)
  • 74 Hospital del Mar, Parc de Salut Mar, Barcelona, Spain , Barcelona (Spain)
  • 75 Vanderbilt University Medical Center, Nashville, TN, USA , Nashville (United States)
  • 76 Stony Brook University, Stony Brook, NY, USA , Stony Brook (United States)
  • 77 Charité Universitätsmedizin Berlin, Berlin, Germany , Berlin (Germany)
  • 78 Northwestern University Feinberg School of Medicine, Chicago, IL, USA , Chicago (United States)
  • 79 Emory University School of Medicine, Atlanta, GA, USA , Atlanta (United States)
  • 80 UCL Cancer Institute, UCL, London, UK , London (United Kingdom)
  • 81 University College Hospitals NHS Trust, London, UK , London (United Kingdom)
  • 82 Department of Oral and Maxillofacial Diseases, Helsinki, Finland , Helsinki (Finland)
  • 83 Matsuyama Shimin Hospital, Matsuyama, Japan , Matsuyama (Japan)
  • 84 Baylor College of Medicine, Houston, TX, USA , Houston (United States)
  • 85 Roche Diagnostics, Machelen, Belgium , Machelen (Belgium)
  • 86 PhenoPath Laboratories, Seattle, WA, USA , Seattle (United States)
  • 87 Research Pathology, Genentech Inc., South San Francisco, CA, USA , South San Francisco (United States)
  • 88 University of Torino, Italy and Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Italy , Candiolo (Italy)
  • 89 New York University Langone Health, Center for Biospecimen Research and Development, New York, NY, USA , New York (United States)
  • 90 Johns Hopkins Hospital, Baltimore, MD, USA , Baltimore (United States)
  • 91 Insituto Nazionale dei Tumori, Milan, Italy , Milan (Italy)
  • 92 University of Iowa Hospitals and Clinics, Iowa City, IA, USA , Iowa City (United States)
  • 93 Department of Oncology, IVO Valencia, Valencia, Spain , Valencia (Spain)
  • 94 Cancer Centre at Guy’s Hospital, London, UK , London (United Kingdom)
  • 95 School of Life Sciences and Medicine, King’s College London, London, UK , London (United Kingdom)
  • 96 Dana-Farber Cancer Institute, Boston, MA, USA , Boston (United States)
  • 97 Harvard Medical School, Boston, MA, USA , Boston (United States)
  • 98 The Johns Hopkins Hospital, Baltimore, MD, USA , Baltimore (United States)
  • 99 Karolinska Institute, Solna, Sweden , Solna (Sweden)
  • 100 New York University Langone Medical Centre, New York, NY, USA , New York (United States)
  • 101 UNC School of Medicine, Chapel Hill, NC, USA , Chapel Hill (United States)
  • 102 Princess Margaret Cancer Center, Toronto, ON, Canada , Toronto (Canada)
  • 103 University of Melbourne, Parkville, VIC, Australia , Parkville (Australia)
  • 104 British Columbia Cancer Agency, Victoria, BC, Canada , Victoria (Canada)
  • 105 Providence Cancer Research Center, Portland, OR, USA , Portland (United States)
  • 106 Istituto Europeo di Oncologia, Milan, Italy , Milan (Italy)
  • 107 AZ Turnhout, Turnhout, Belgium , Turnhout (Belgium)
  • 108 St Vincent’s University Hospital and University College Dublin, Dublin, Ireland , Dublin (Ireland)
  • 109 University of Pittsburgh, Pittsburgh, PA, USA , Pittsburgh (United States)
  • 110 Regional Hospital of Aosta, Aosta, Italy , Aosta (Italy)
  • 111 Macquarie University, Sydney, NSW, Australia , Sydney (Australia)
  • 112 HistoGeneX NV, Antwerp, Belgium and AZ Sint-Maarten Hospital, Mechelen, Belgium , Mechelen (Belgium)
  • 113 Oncology Clinical Development, Bristol-Myers Squibb, Princeton, NJ, USA , Princeton (United States)
  • 114 Institut für Pathologie, Hamburg, Germany, UK , Hamburg (United Kingdom)
  • 115 Vanderbilt University Medical Centre, Nashville, TN, USA , Nashville (United States)
  • 116 Mayo Clinic, Jacksonville, FL, USA , Jacksonville (United States)
  • 117 Mayo Clinic, Rochester, MN, USA , Rochester (United States)
  • 118 Roche, Tucson, AZ, USA , Tucson (United States)
  • 119 Maria Sklodowska-Curie Memorial Cancer Center, Gliwice, Poland , Gliwice (Poland)
  • 120 Roche Innovation Center Munich, Penzberg, Germany , Penzberg (Germany)
  • 121 Sunnybrook Health Sciences Centre, Toronto, ON, Canada , Toronto (Canada)
  • 122 Tehran University of Medical Sciences, Tehran, Iran , Tehran (Iran)
  • 123 Oncology Biomarker Development, Genentech-Roche, San Francisco, CA, USA , San Francisco (United States)
  • 124 University of Colorado Anschutz Medical Campus, Aurora, CO, USA , Aurora (United States)
  • 125 Hospital de Oncología Maria Curie, Buenos Aires, Argentina , Buenos Aires (Argentina)
  • 126 SA Pathology, Adelaide, Australia , Adelaide (Australia)
  • 127 University Hospital Antwerp, Edegem, Belgium , Edegem (Belgium)
  • 128 University of Bristol, Bristol, UK , Bristol (United Kingdom)
  • 129 Cedars-Sinai Medical Center, Los Angeles, CA, USA , Los Angeles (United States)
  • 130 Helsinki University Central Hospital, Helsinki, Finland , Helsinki (Finland)
  • 131 Akademiska University Hospital, Uppsala, Sweden , Uppsala (Sweden)
  • 132 World Health Organization, Lyon, France , Lyon (France)
  • 133 Sanatorio Mater Dei, Buenos Aires, Argentina , Buenos Aires (Argentina)
  • 134 Medical University of Graz, Graz, Austria , Graz (Austria)
  • 135 National Cancer Centre Singapore, Singapore, Singapore , Singapore (Singapore)
  • 136 R&D UNICANCER, Paris, France , Paris (France)
  • 137 AstraZeneca, Gaithersberg, MD, USA , Gaithersberg (United States)
  • 138 Breast Unit, Champalimaud Clinical Centre, Lisboa, Portugal , Lisboa (Portugal)
  • 139 Massachusetts General Hospital, Boston, MA, USA , Boston (United States)
  • 140 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, USA , Rochester (United States)
  • 141 Karolinska Institutet and University Hospital, Solna, Sweden , Solna (Sweden)
  • 142 Comprehensive Cancer Centre Vienna, Medical University of Vienna, Vienna, Austria , Vienna (Austria)
  • 143 University of Leicester, Leicester, and MRC Toxicology Unit, University of Cambridge, Cambridge, UK , Cambridge (United Kingdom)
  • 144 Merck & Co., Inc, Kenilworth, NJ, USA , Kenilworth (United States)
  • 145 GHI Le Raincy-Montfermeil, Chelles, Île-de-France, Montfermeil, France , Montfermeil (France)
  • 146 Gustave Roussy, Grand Paris, France , Grand Paris (France)
  • 147 Vm Scope, Berlin, Germany , Berlin (Germany)
  • 148 Breast Pathology Section, Northwestern University, Chicago, IL, USA , Chicago (United States)
  • 149 Université Mohamed Premier, Oujda, Morocco , Oujda (Morocco)
  • 150 Stanford University Medical Centre, Stanford, CA, USA , Stanford (United States)
  • 151 Center for Pharmacogenomics and Fudan-Zhangjiang, Center for Clinical Genomics School of Life Sciences and Shanghai Cancer Center, Fudan University, Shanghai, China , Shanghai (China)
  • 152 Maastricht University Medical Centre, Maastricht, The Netherlands , Maastricht (Netherlands)
  • 153 University of California San Diego, San Diego, CA, USA , San Diego (United States)
  • 154 Gustave Roussy, Villejuif, France , Villejuif (France)
  • 155 Faculty of Medicine, University of São Paulo, Sao Paulo, Brasil , Sao Paulo (Brazil)
  • 156 Gustave Roussy Cancer Campus, Villejuif, France , Villejuif (France)
  • 157 Academic Medical Center, Amsterdam, The Netherlands , Amsterdam (Netherlands)
  • 158 Universite Libre de Bruxelles, Brussels, Belgium , Brussels (Belgium)
  • 159 Digital Pathology, Santa Clara, CA, USA , Santa Clara (United States)
  • 160 Roche Diagnostics Information Solutions, Belmont, CA, USA , Belmont (United States)
  • 161 Royal Melbourne Hospital, Parkville, VIC, Australia , Parkville (Australia)
  • 162 Newton-Wellesley Hospital, Newton, MA, USA , Newton (United States)
  • 163 Cliniques Universitaires Saint-Luc Bruxelles, Brussels, Belgium , Brussels (Belgium)
  • 164 University of Munich, Munich, Germany , Munich (Germany)
  • 165 Beth Israel Deaconess Medical Center, Boston, MA, USA , Boston (United States)
  • 166 University of Leuven, Leuven, Belgium , Leuven (Belgium)
  • 167 Jean Perrin Comprehensive Cancer Centre, Clermont-Ferrand, France , Clermont-Ferrand (France)
  • 168 West German Study Group, Mönchengladbach, Germany , Mönchengladbach (Germany)
  • 169 Vall d’Hebron Institute of Oncology, Barcelona, Spain , Barcelona (Spain)
  • 170 University of Marburg, Marburg, Germany , Marburg (Germany)
  • 171 Manipal Hospitals Dwarka, New Delhi, India , New Delhi (India)
  • 172 St Vincent’s Hospital Melbourne, Fitzroy, VIC, Australia , Fitzroy (Australia)
  • 173 Fred Hutchinson Cancer Research Center, Seattle, WA, USA , Seattle (United States)
  • 174 University of Oxford, Oxford, UK , Oxford (United Kingdom)
  • 175 Sunnybrook Research Institute, Toronto, ON, Canada , Toronto (Canada)
  • 176 Darlinghurst, Australian Clinical Labs, Darlinghurst, NSW, Australia , Darlinghurst (Australia)
  • 177 Georgetown University Medical Center, Washington, DC, USA , Washington (United States)
  • 178 Avera Cancer Institute, Sioux Falls, SD, USA , Sioux Falls (United States)
  • 179 Translational Medicine, Bristol-Myers Squibb, Princeton, NJ, USA , Princeton (United States)
  • 180 Ahfad University for Women, School of Medicine, Omdurman, Sudan , Omdurman (Sudan)
  • 181 Guy’s Hospital, London, UK; King’s College London, London, UK , London (United Kingdom)
  • 182 Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China , Chengdu (China)
  • 183 University of Florence, Florence, Italy , Florence (Italy)
  • 184 Department of Oncology, Champalimaud Clinical Centre, Lisbon, Portugal , Lisbon (Portugal)
  • 185 Department of Pathology, Fundación Valle del Lili, Cali, Colombia , Cali (Colombia)
  • 186 Laboratory of Experimental Urology, KU Leuven, Leuven, Belgium , Leuven (Belgium)
  • 187 Austin Health, Heidelberg, VIC, Australia , Heidelberg (Australia)
  • 188 Kansai Medical School, Hirakata, Japan , Hirakata (Japan)
  • 189 Pathology Department, H.U. Vall d’Hebron, Barcelona, Spain , Barcelona (Spain)
  • 190 Division of Bioinformatics and Biostatistics, U.S. Food and Drug Administration, Silver Spring, MD, USA , Silver Spring (United States)
  • 191 Rhode Island Hospital and Lifespan Medical Center, Providence, RI, USA , Providence (United States)
  • 192 Université Paris-Est, Créteil, France , Créteil (France)
  • 193 Praava Health, Dhaka, Bangladesh , Dhaka (Bangladesh)
  • 194 Medical University of Vienna, Vienna, Austria , Vienna (Austria)
Type
Published Article
Journal
npj Breast Cancer
Publisher
Nature Publishing Group UK
Publication Date
May 12, 2020
Volume
6
Issue
1
Identifiers
DOI: 10.1038/s41523-020-0156-0
Source
Springer Nature
License
Green

Abstract

Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls.

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