title: Interobserver Agreement Between Pathologists Assessing Tumor-Infiltrating Lymphocytes (TILs) in Breast Cancer Using Methodology Proposed by the International TILs Working Group.
abstract: The presence of tumor-infiltrating lymphocytes (TILs) in breast tumors is prognostic and predictive, suggesting that TILs may be an important biomarker. Recently, an international TILs working group formulated consensus recommendations for TIL evaluation. The current study was performed to determine interobserver agreement using that methodology.
  
  
  
  Tumor-infiltrating lymphocytes were assessed on a single hematoxylin and eosin (H&E)-stained slide obtained from the core biopsy of 75 triple-negative breast cancers. Four pathologists independently reviewed each slide and evaluated stromal TILs (sTILs) and intratumoral TIL (iTILs). The kappa statistic was used to estimate interobserver agreement for identification of sTILs, and the intraclass correlation coefficient (ICC) was used to estimate the agreement among observers for iTILs. Cases with poor agreement were reviewed to identify pathologic factors that may contribute to the lack of agreement.
  
  
  
  The kappa statistic for sTIL evaluation was 0.57 (standard error, 0.04). For iTILs, the ICC calculated to determine internal consistency within raters was 0.65 (95 % confidence interval [CI] 0.56-0.74; p < 0.0001), and the ICC calculated to determine agreement among raters was 0.62 (95 % CI 0.50-0.72; p < 0.0001). In 10 cases (13 %), there was not agreement between three of four pathologists. The pathologic features contributing to difficulty in TIL enumeration included marked individual tumor cell necrosis or apoptosis, the presence of reactive plasma cells mimicking tumor cells, plasmatoid tumor cells, and accurate quantification of TILs in specimens with focal areas of heavy immune infiltrate.
  
  
  
  Acceptable agreement in TIL enumeration was observed, suggesting that the proposed methodology can be used to facilitate the use of TILs as a biomarker in research and clinical trial settings.
authors.affiliation: Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Shannon K
authors.initials: SK
authors.lastname: Swisher
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Clinical Medicine, Instituto Nacional de Enfermedades Neoplasicas (INEN), Lima, Peru.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Castaneda
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Genvieve R
authors.initials: GR
authors.lastname: Lyons
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Coya
authors.initials: C
authors.lastname: Tapia
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Xiuhong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pathology, Instituto Nacional de Enfermedades Neoplasicas (INEN), Lima, Peru.
authors.forename: Sandro A A
authors.initials: SA
authors.lastname: Casavilca
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Roland
authors.initials: R
authors.lastname: Bassett
authors.affiliation: Department of Clinical Medicine, Instituto Nacional de Enfermedades Neoplasicas (INEN), Lima, Peru.
authors.forename: Miluska
authors.initials: M
authors.lastname: Castillo
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Aysegul
authors.initials: A
authors.lastname: Sahin
authors.affiliation: Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. eamitten@mdanderson.org.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Mittendorf
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D005260:Female; D006801:Humans; D007390:International Agencies; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology*; D015588:Observer Variation; D000072142:Pathologists; D010338:Pathology, Clinical / Q000592:standards*; D011379:Prognosis; D064726:Triple Negative Breast Neoplasms / Q000276:immunology / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor