Flat Ductal Intraepithelial Neoplasia of the Breast: A Review of Diagnostic Criteria, Differential Diagnoses, Molecular-Genetic Findings, and Clinical Relevance—It Is Time to Appreciate the Azzopardi Concept!

Abstract

Abstract Context.—More than 25 years ago, John G. Azzopardi described a distinctive intraepithelial neoplastic breast lesion, which he designated “clinging carcinoma in situ”; he considered it as another variant of ductal carcinoma in situ, an early lesion that can easily be missed because the changes are mainly cytologic rather than architectural. The lesion remained widely unrecognized and/or ignored until recent years when its neoplastic nature was confirmed at the molecular-genetic level. Objective.—To deal with historical aspects of the evolving concept of “clinging” and to focus on several important issues such as characteristic morphologic features with particular attention to the diagnostic criteria and differential diagnoses, recent molecular-genetic findings, appropriate terminology and classification, as well as the significance of this type of lesion for both surgical pathologists and clinicians. Data Sources.—A thorough search of the literature was performed and publications using a variety of designations including “clinging carcinoma in situ,” “flat epithelial atypia,” “ductal intraepithelial neoplasia-flat type,” “atypical cystic lobules,” “columnar cell change with atypia,” “columnar cell hyperplasia with or without atypia,” “columnar alteration with prominent apical snouts and secretion,” and so forth were reviewed. Conclusions.—This distinctive lesion represents one of the earliest morphologically recognizable neoplastic alterations of the breast that is commonly associated with mammographically suspicious microcalcifications. It is characterized by mildly to severely atypical cells simply replacing the single layer of native epithelial cells in a flat fashion without appreciable proliferation; tufting, intraluminal bridging, micropapillary structures, and so forth are typically absent or very focal and minimal, if present at all. Based on the degree of cytologic atypia, low- and high-grade flat ductal intraepithelial neoplasia need to be separated. Although additional studies are needed to better understand the clinical significance of flat ductal intraepithelial neoplasia, several lines of evidence strongly support the concept of clinging. Indeed, as pointed out by Azzopardi, surgical pathologists need to pay more attention to the cytologic alterations of the breast lesions by analyzing the involved cell populations using high-power magnification.