Inter-observer agreement for the histological diagnosis of invasive lobular breast carcinoma

Christgen M, Kandt LD, Antonopoulos W, Bartels S, Van Bockstal MR, Bredt M, Brito MJ, Christgen H, Colpaert C, Cserni B, Cserni G, Daemmrich ME, Danebrock R, Dedeurwaerdere F, Van Deurzen CHM, Erber R, Fathke C, Feist H, Fiche M, Gonzalez CA, Ter Hoeve ND, Kooreman L, Krech T, Kristiansen G, Kulka J, Laenger F, Lafos M, Lehmann U, Martin-Martinez MD, Mueller S, Pelz E, Raap M, Ravarino A, Reineke-Plaass T, Schaumann N, Schelfhout AM, De Schepper M, Schlue J, Van De Vijver K, Waelput W, Wellmann A, Graeser M, Gluz O, Kuemmel S, Nitz U, Harbeck N, Desmedt C, Floris G, Derksen PWB, Van Diest PJ, Vincent-Salomon A, Kreipe H (2021)

Publication Type: Journal article

Publication year: 2021

Journal

DOI: 10.1002/cjp2.253

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 (INC). 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 kappa = 0.58, interquartile range [IQR]: 0.48-0.66) and substantial in set B (median kappa = 0.75, IQR: 0.56-0.86, p < 0.001). Agreement with the reference diagnosis was substantial in set A (median kappa = 0.67, IQR: 0.57-0.75) and almost perfect in set B (median kappa = 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.

Authors with CRIS profile

Involved external institutions

Champalimaud Foundation / Fundação Champalimaud Portugal (PT) Erasmus University Medical Center (MC) Netherlands (NL) Westdeutsche Studiengruppe GmbH (WSG) / Women's healthcare Study Group Germany (DE) Diakonissenkrankenhaus Flensburg Germany (DE) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) Pathologische Institut Celle / Institute of Pathology Celle Germany (DE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) University College Dublin (UCD) Ireland (IE) University Medical Centre Utrecht (UMC Utrecht) Netherlands (NL) Maastricht University Netherlands (NL) PSL Research University / Université de recherche Paris Sciences et Lettres France (FR) Universitätsklinikum Heidelberg Germany (DE) Martin-Luther-Universität Halle-Wittenberg (MLU) Germany (DE) Institut für Pathologie Viersen Germany (DE) Università degli Studi di Cagliari Italy (IT) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven Belgium (BE) University of Szeged / József Attila Tudományegyetem Szeged Hungary (HU) Onze-Lieve-Vrouwziekenhuis (OLV Ziekenhuis, OLVZ) Belgium (BE) Aurigen SA Switzerland (CH) Institut de Pathologie et de Génétique a.s.b.l. Belgium (BE) Vrije Universiteit Brussel (VUB) Belgium (BE) Universitätsklinikum Bonn Germany (DE) University Hospital Ghent Belgium (BE) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Semmelweis University / Semmelweis Egyetem Hungary (HU) Johannes Wesling Klinikum Minden Germany (DE) AZ Delta Belgium (BE) Cliniques universitaires Saint-Luc (CHU St-Luc) Belgium (BE) TNG Technology Consulting GmbH Germany (DE)

How to cite

APA:

Christgen, M., Kandt, L.D., Antonopoulos, W., Bartels, S., Van Bockstal, M.R., Bredt, M.,... Kreipe, H. (2021). Inter-observer agreement for the histological diagnosis of invasive lobular breast carcinoma. Journal of Pathology: Clinical Research. https://doi.org/10.1002/cjp2.253

MLA:

Christgen, Matthias, et al. "Inter-observer agreement for the histological diagnosis of invasive lobular breast carcinoma." Journal of Pathology: Clinical Research (2021).

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