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Discordant Marker Expression Between Invasive Breast Carcinoma and Corresponding Synchronous and Preceding DCIS

Visser, Lindy L. MSc*; Elshof, Lotte E. MD, PhD*,†,‡; Van de Vijver, Koen MD, PhD§; Groen, Emma J. MD*,§; Almekinders, Mathilde M. MD*,§; Sanders, Joyce MD§; Bierman, Carolien BSc§; Peters, Dennis BSc; Hofland, Ingrid BSc; Broeks, Annegien PhD; van Leeuwen, Flora E. PhD; Rutgers, Emiel J. Th MD, PhD; Schmidt, Marjanka K. PhD*,†; Schaapveld, Michael PhD; Lips, Esther H. PhD*; Wesseling, Jelle MD, PhD*,§

The American Journal of Surgical Pathology: November 2019 - Volume 43 - Issue 11 - p 1574–1582
doi: 10.1097/PAS.0000000000001306
Original Articles

Ductal carcinoma in situ (DCIS) is considered a potential precursor of invasive breast carcinoma (IBC). Studies aiming to find markers involved in DCIS progression generally have compared characteristics of IBC lesions with those of adjacent synchronous DCIS lesions. The question remains whether synchronous DCIS and IBC comparisons are a good surrogate for primary DCIS and subsequent IBC. In this study, we compared both primary DCIS and synchronous DCIS with the associated IBC lesion, on the basis of immunohistochemical marker expression. Immunohistochemical analysis of ER, PR, HER2, p53, and cyclo-oxygenase 2 (COX-2) was performed for 143 primary DCIS and subsequent IBC lesions, including 81 IBC lesions with synchronous DCIS. Agreement between DCIS and IBC was assessed using kappa, and symmetry tests were performed to assess the pattern in marker conversion. The primary DCIS and subsequent IBC more often showed discordant marker expression than synchronous DCIS and IBC. Strikingly, 18 of 49 (36%) women with HER2-positive primary DCIS developed an HER2-negative IBC. Such a difference in HER2 expression was not observed when comparing synchronous DCIS and IBC. The frequency of discordant marker expression did not increase with longer time between primary DCIS and IBC. In conclusion, comparison of primary DCIS and subsequent IBC yields different results than a comparison of synchronous DCIS and IBC, in particular with regard to HER2 status. To gain more insight into the progression of DCIS to IBC, it is essential to focus on the relationship between primary DCIS and subsequent IBC, rather than comparing IBC with synchronous DCIS.

*Division of Molecular Pathology

Division of Psychosocial research and Epidemiology

Department of Surgery

§Department of Pathology, Division of Diagnostic Oncology

Core Facility Molecular Pathology and Biobanking, Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

L.L.V., F.E.v.L., E.J.R., M.S., M.K.S., E.H.L., and J.W.: designed the study. L.L.V. and L.E.E.: collected the data. D.P., I.H., and A.B.: set up and performed IHC stains. L.L.V., K.v.d.V., E.J.G., M.M.A., J.W., J.S., and C.B.: did the pathology review and IHC assessment. L.L.V., F.E.v.L., E.J.R., M.S., M.K.S., E.H.L., and J.W.: analyzed and interpreted the data. L.L.V.: wrote the report.

Conflicts of Interest and Source of Funding: This work was funded by Pink Ribbon (grant number 2013.WO29, to J.W.) and A Sister’s Hope (grant number 2011.WO19.C88, to J.W.), and it was jointly funded by Cancer Research UK and the Dutch Cancer Society (grant number C38317/A24043, to J.W.). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Jelle Wesseling, MD, PhD, Department of Pathology, Division of Diagnostic Oncology and Division of Molecular Pathology, The Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands (e-mail:

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