Genetic abnormalities in mammary ductal intraepithelial neoplasia-flat type ("clinging ductal carcinoma in situ"): a simulator of normal mammary epithelium.

BACKGROUND: Mammary ductal intraepithelial neoplasia (DIN)-flat type ("clinging ductal carcinoma in situ [DCIS]") generally is a subtle epithelial alteration characterized by one or a few layer(s) of atypical cells replacing the native epithelium. The "low power" appearance of DIN-flat type can be misinterpreted easily as "normal" because of the frequent absence of multilayered proliferation and often subtle cytologic atypia. Because it presents as an often unrecognized lesion or in association with tubular carcinoma, to the authors' knowledge the clinical and biologic significance of this lesion has not been well established.
METHODS: Using polymerase chain reaction, the authors examined DNA extracts from microdissected areas of 22 cases with extensive "clinging DCIS," including 13 cases associated with infiltrating ductal carcinoma as well as 5 cases associated with more conventional types of DCIS. Eight polymorphic DNA markers with a high rate of loss of heterozygosity (LOH) in classic types of DCIS were selected to identify possible genetic alterations on chromosomes 2p, 3p, 11q, 16q, and 17q. Two cases also were used for the assessment of clonality by means of X chromosome inactivation (methylation pattern of the human androgen receptor [HUMARA] gene).
RESULTS: LOH was detected in 17 of 22 lesions (77%), and monoclonality was established in the 2 cases analyzed. The most common genetic alterations were at chromosomes 11q21-23.2, 16q23.1-24.2, and 3p14.2 with LOH in 50%, 45%, and 41%, respectively, of informative cases. The DIN-flat type showed the same genetic alterations (LOH) identified in adjacent in situ and infiltrating ductal carcinoma. In contrast to the DIN-flat type, the perfectly normal mammary epithelium was associated very infrequently (1 of 16 cases; 6%) with LOH.
CONCLUSIONS: The DIN-flat type represents one of the earliest, morphologically recognizable, neoplastic alterations of the breast. Recognition of the DIN-flat type is important not only for the early detection of intraductal neoplasia but also to prevent misinterpretation and utilization of this lesion as a normal control in studies. This distinctive lesion could be crucial as an explanation for at least part of the > 20% reported incidence rate of breast carcinoma recurrence observed despite ostensibly "negative" margins of breast biopsies.