E-cadherin immunohistochemical expression in invasive lobular carcinoma of the breast: correlation with morphology and CDH1 somatic alterations

Grabenstetter, Anne; Mohanty, Abhinita; Rana, Satshil; Zehir, Ahmet; Brannon, A. Rose; D’Alfonso, Timothy M.; DeLair, Deborah F.; Tan, Lee K.; Ross, Dara S.

doi:10.1016/j.humpath.2020.06.002

Cited by 34 publications

(16 citation statements)

References 35 publications

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“…One expert panel has advocated that E-cadherin IHC should probably not be performed in cases considered as ILC on HE-stained sections [40]. Another work has argued that E-cadherin IHC is of limited value, because as much as 23% of CDH1-mutant BCs showed preserved E-cadherin expression [41]. This finding was not confirmed in the present study (3/34, 9%, in the present work).…”

contrasting

confidence: 76%

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

Christgen

Kandt

Antonopoulos

et al. 2021

The Journal of Pathology CR

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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.

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contrasting

confidence: 76%

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

Christgen

Kandt

Antonopoulos

et al. 2021

The Journal of Pathology CR

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“…Indeed, other mechanisms for the reduced expression or function of E-cadherin, such as transcriptional downregulation, promoter methylation of CDH1, and post-translational modifications of E-cadherin, have been detected in breast cancer [ 61 , 64 , 65 , 66 , 67 , 68 ]. It is well-known that E-cadherin antigen, detected by immunohistochemistry analysis, is mainly expressed in ductal carcinomas and absent in lobular ones [ 66 , 69 , 70 , 71 ]. In agreement with immunohistochemistry results, a previous analysis of TCGA data [ 45 ] reported that CDH1 transcript and protein levels are significantly lower in lobular carcinomas compared to ductal ones, confirming that CDH1 expression differentiates the two histological subtypes.…”

Section: Discussionmentioning

confidence: 99%

Aberrations of Chromosomes 1 and 16 in Breast Cancer: A Framework for Cooperation of Transcriptionally Dysregulated Genes

Privitera

Barresi

Condorelli

2021

Cancers

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Derivative chromosome der(1;16), isochromosome 1q, and deleted 16q—producing arm-level 1q-gain and/or 16q-loss—are recurrent cytogenetic abnormalities in breast cancer, but their exact role in determining the malignant phenotype is still largely unknown. We exploited The Cancer Genome Atlas (TCGA) data to generate and analyze groups of breast invasive carcinomas, called 1,16-chromogroups, that are characterized by a pattern of arm-level somatic copy number aberrations congruent with known cytogenetic aberrations of chromosome 1 and 16. Substantial differences were found among 1,16-chromogroups in terms of other chromosomal aberrations, aneuploidy scores, transcriptomic data, single-point mutations, histotypes, and molecular subtypes. Breast cancers with a co-occurrence of 1q-gain and 16q-loss can be distinguished in a “low aneuploidy score” group, congruent to der(1;16), and a “high aneuploidy score” group, congruent to the co-occurrence of isochromosome 1q and deleted 16q. Another three groups are formed by cancers showing separately 1q-gain or 16q-loss or no aberrations of 1q and 16q. Transcriptome comparisons among the 1,16-chromogroups, integrated with functional pathway analysis, suggested the cooperation of overexpressed 1q genes and underexpressed 16q genes in the genesis of both ductal and lobular carcinomas, thus highlighting the putative role of genes encoding gamma-secretase subunits (APH1A, PSEN2, and NCSTN) and Wnt enhanceosome components (BCL9 and PYGO2) in 1q, and the glycoprotein E-cadherin (CDH1), the E3 ubiquitin-protein ligase WWP2, the deubiquitinating enzyme CYLD, and the transcription factor CBFB in 16q. The analysis of 1,16-chromogroups is a strategy with far-reaching implications for the selection of cancer cell models and novel experimental therapies.

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“…In the series of Desmedt et al, immunoreactivity for the anti-E-cadherin antibody NCH-38 was retained in 8/156 (5%) ILCs harboring CDH1 mutations [43]. In the series of Grabenstetter et al, immunoreactivity for the anti-E-cadherin antibody clone-36 was retained in 47/202 (23%) BCs harboring somatic CDH1 mutations [91]. E-cadherin forms the core of the adherens junctions (AJs), structures that provide the cell-cell contacts in which cadherins bridge the neighboring plasma membranes via homophilic interactions and catenins bind to the actin cytoskeleton [92].…”

Section: Ilc As a Morpho-molecular Entitymentioning

confidence: 97%

Lobular Breast Cancer: Histomorphology and Different Concepts of a Special Spectrum of Tumors

Christgen

Floris

Marchiò

et al. 2021

Cancers

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Invasive lobular breast cancer (ILC) is the most common special histological type of breast cancer (BC). This review recapitulates developments in the histomorphologic assessment of ILC from its beginnings with the seminal work of Foote and Stewart, which was published in 1941, until today. We discuss different concepts of ILC and their implications. These concepts include (i) BC arising from mammary lobules, (ii) BC growing in dissociated cells and single files, and (iii) BC defined as a morpho-molecular spectrum of tumors with distinct histological and molecular characteristics related to impaired cell adhesion. This review also provides a comprehensive overview of ILC variants, their histomorphology, and differential diagnosis. Furthermore, this review highlights recent advances which have contributed to a better understanding of the histomorphology of ILC, such as the role of the basal lamina component laminin, the molecular specificities of triple-negative ILC, and E-cadherin to P-cadherin expression switching as the molecular determinant of tubular elements in CDH1-deficient ILC. Last but not least, we provide a detailed account of the tumor microenvironment in ILC, including tumor infiltrating lymphocyte (TIL) levels, which are comparatively low in ILC compared to other BCs, but correlate with clinical outcome. The distinct histomorphology of ILC clearly reflects a special tumor biology. In the clinic, special treatment strategies have been established for triple-negative, HER2-positive, and ER-positive BC. Treatment specialization for patients diagnosed with ILC is just in its beginnings. Accordingly, ILC deserves greater attention as a special tumor entity in BC diagnostics, patient care, and cancer research.

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E-cadherin immunohistochemical expression in invasive lobular carcinoma of the breast: correlation with morphology and CDH1 somatic alterations

Cited by 34 publications

References 35 publications

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

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

Aberrations of Chromosomes 1 and 16 in Breast Cancer: A Framework for Cooperation of Transcriptionally Dysregulated Genes

Lobular Breast Cancer: Histomorphology and Different Concepts of a Special Spectrum of Tumors

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