The Journal of Pathology: Clinical Research (Mar 2022)
Inter‐observer agreement for the histological diagnosis of invasive lobular breast carcinoma
- Matthias Christgen,
- Leonie Donata Kandt,
- Wiebke Antonopoulos,
- Stephan Bartels,
- Mieke R VanBockstal,
- Martin Bredt,
- Maria Jose Brito,
- Henriette Christgen,
- Cecile Colpaert,
- Bálint Cserni,
- Gábor Cserni,
- Maximilian E Daemmrich,
- Raihanatou Danebrock,
- Franceska Dedeurwaerdere,
- Carolien HM vanDeurzen,
- Ramona Erber,
- Christine Fathke,
- Henning Feist,
- Maryse Fiche,
- Claudia Aura Gonzalez,
- Natalie D terHoeve,
- Loes Kooreman,
- Till Krech,
- Glen Kristiansen,
- Janina Kulka,
- Florian Laenger,
- Marcel Lafos,
- Ulrich Lehmann,
- Maria Dolores Martin‐Martinez,
- Sophie Mueller,
- Enrico Pelz,
- Mieke Raap,
- Alberto Ravarino,
- Tanja Reineke‐Plaass,
- Nora Schaumann,
- Anne‐Marie Schelfhout,
- Maxim DeSchepper,
- Jerome Schlue,
- Koen Van de Vijver,
- Wim Waelput,
- Axel Wellmann,
- Monika Graeser,
- Oleg Gluz,
- Sherko Kuemmel,
- Ulrike Nitz,
- Nadia Harbeck,
- Christine Desmedt,
- Giuseppe Floris,
- Patrick WB Derksen,
- Paul J vanDiest,
- Anne Vincent‐Salomon,
- Hans Kreipe
Affiliations
- Matthias Christgen
- Institute of Pathology Hannover Medical School Hannover Germany
- Leonie Donata Kandt
- Institute of Pathology Hannover Medical School Hannover Germany
- Wiebke Antonopoulos
- Institute of Pathology University Clinics Heidelberg Heidelberg Germany
- Stephan Bartels
- Institute of Pathology Hannover Medical School Hannover Germany
- Mieke R VanBockstal
- Department of Pathology Cliniques Universitaires Saint‐Luc Brussels Belgium
- Martin Bredt
- Institute of Pathology Hannover Medical School Hannover Germany
- Maria Jose Brito
- Pathology and Breast Unit Champalimaud Foundation Lisbon Portugal
- Henriette Christgen
- Institute of Pathology Hannover Medical School Hannover Germany
- Cecile Colpaert
- Department of Pathology Universitair Ziekenhuis Leuven Leuven Belgium
- Bálint Cserni
- TNG Technology Consulting GmbH Budapest Hungary
- Gábor Cserni
- Department of Pathology University of Szeged Szeged Hungary
- Maximilian E Daemmrich
- Group Practice for Pathology Schweinfurt Schweinfurt Germany
- Raihanatou Danebrock
- Institute of Pathology Johannes Wesling Clinics Minden Minden Germany
- Franceska Dedeurwaerdere
- Laboratorium voor pathologie AZ Delta Roeselare Belgium
- Carolien HM vanDeurzen
- Department of Pathology Erasmus MC Cancer Institute Rotterdam The Netherlands
- Ramona Erber
- Institute of Pathology, University Hospital Erlangen Friedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU), and Comprehensive Cancer Center Erlangen‐EMN (CCC ER‐EMN) Erlangen Germany
- Christine Fathke
- Institute of Pathology Martin‐Luther‐University Halle‐Wittenberg Halle (Saale) Germany
- Henning Feist
- Institute of Pathology Diakonissenkrankenhaus Flensburg Flensburg Germany
- Maryse Fiche
- Institute of Pathology Aurigen Aurigen SA Lausanne Switzerland
- Claudia Aura Gonzalez
- Conway Institute of Biomolecular and Biomedical Research University College Dublin Dublin Ireland
- Natalie D terHoeve
- Department of Pathology University Medical Center Utrecht Utrecht The Netherlands
- Loes Kooreman
- Institute of Pathology and GROW – School for Oncology and Developmental Biology Maastricht University Medical Center Maastricht The Netherlands
- Till Krech
- Institute of Pathology University Clinics Hamburg‐Eppendorf Hamburg Germany
- Glen Kristiansen
- Institute of Pathology University Hospital Bonn Bonn Germany
- Janina Kulka
- 2nd Department of Pathology Semmelweis University Budapest Budapest Hungary
- Florian Laenger
- Institute of Pathology Hannover Medical School Hannover Germany
- Marcel Lafos
- Institute of Pathology Hannover Medical School Hannover Germany
- Ulrich Lehmann
- Institute of Pathology Hannover Medical School Hannover Germany
- Maria Dolores Martin‐Martinez
- Institut de Pathologie et Genetique Gosselies Gosselies Belgium
- Sophie Mueller
- Institute of Pathology Hannover Medical School Hannover Germany
- Enrico Pelz
- Institute of Pathology Viersen Viersen Germany
- Mieke Raap
- Institute of Pathology Hannover Medical School Hannover Germany
- Alberto Ravarino
- Institute of Pathology University of Cagliari Cagliari Italy
- Tanja Reineke‐Plaass
- Institute of Pathology Hannover Medical School Hannover Germany
- Nora Schaumann
- Institute of Pathology Hannover Medical School Hannover Germany
- Anne‐Marie Schelfhout
- Department of Pathology OLV Ziekenhuis Aalst Aalst Belgium
- Maxim DeSchepper
- Department of Pathology University Hospitals Leuven, Campus Gasthuisberg Leuven Belgium
- Jerome Schlue
- Institute of Pathology Hannover Medical School Hannover Germany
- Koen Van de Vijver
- Cancer Research Institute Ghent Ghent University Hospital Ghent Belgium
- Wim Waelput
- Department of Pathology UZ Brussel, Vrije Universiteit Brussel Brussels Belgium
- Axel Wellmann
- Institute of Pathology Celle Celle Germany
- Monika Graeser
- West German Study Group Moenchengladbach Germany
- Oleg Gluz
- West German Study Group Moenchengladbach Germany
- Sherko Kuemmel
- West German Study Group Moenchengladbach Germany
- Ulrike Nitz
- West German Study Group Moenchengladbach Germany
- Nadia Harbeck
- West German Study Group Moenchengladbach Germany
- Christine Desmedt
- Laboratory for Translational Breast Cancer Research, Department of Oncology KU Leuven Leuven Belgium
- Giuseppe Floris
- Department of Pathology University Hospitals Leuven, Campus Gasthuisberg Leuven Belgium
- Patrick WB Derksen
- Department of Pathology University Medical Center Utrecht Utrecht The Netherlands
- Paul J vanDiest
- Department of Pathology University Medical Center Utrecht Utrecht The Netherlands
- Anne Vincent‐Salomon
- Pathology‐Genetics‐Immunology Department, Institut Curie PSL Research University Paris France
- Hans Kreipe
- Institute of Pathology Hannover Medical School Hannover Germany
- DOI
- https://doi.org/10.1002/cjp2.253
- Journal volume & issue
-
Vol. 8,
no. 2
pp. 191 – 205
Abstract
Abstract Invasive lobular breast carcinoma (ILC) is the second most common breast carcinoma (BC) subtype and is mainly driven by loss of E‐cadherin expression. Correct classification of BC as ILC is important for patient treatment. This study assessed the degree of agreement among pathologists for the diagnosis of ILC. Two sets of hormone receptor (HR)‐positive/HER2‐negative BCs were independently reviewed by participating pathologists. In set A (61 cases), participants were provided with hematoxylin/eosin (HE)‐stained sections. In set B (62 cases), participants were provided with HE‐stained sections and E‐cadherin immunohistochemistry (IHC). Tumor characteristics were balanced. Participants classified specimens as non‐lobular BC versus mixed BC versus ILC. Pairwise inter‐observer agreement and agreement with a pre‐defined reference diagnosis were determined with Cohen's kappa statistics. Subtype calls were correlated with molecular features, including CDH1/E‐cadherin mutation status. Thirty‐five pathologists completed both sets, providing 4,305 subtype calls. Pairwise inter‐observer agreement was moderate in set A (median κ = 0.58, interquartile range [IQR]: 0.48–0.66) and substantial in set B (median κ = 0.75, IQR: 0.56–0.86, p < 0.001). Agreement with the reference diagnosis was substantial in set A (median κ = 0.67, IQR: 0.57–0.75) and almost perfect in set B (median κ = 0.86, IQR: 0.73–0.93, p < 0.001). The median frequency of CDH1/E‐cadherin mutations in specimens classified as ILC was 65% in set A (IQR: 56–72%) and 73% in set B (IQR: 65–75%, p < 0.001). Cases with variable subtype calls included E‐cadherin‐positive ILCs harboring CDH1 missense mutations, and E‐cadherin‐negative ILCs with tubular elements and focal P‐cadherin expression. ILCs with trabecular growth pattern were often misclassified as non‐lobular BC in set A but not in set B. In conclusion, subtyping of BC as ILC achieves almost perfect agreement with a pre‐defined reference standard, if assessment is supported by E‐cadherin IHC. CDH1 missense mutations associated with preserved E‐cadherin protein expression, E‐ to P‐cadherin switching in ILC with tubular elements, and trabecular ILC were identified as potential sources of discordant classification.
Keywords