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 ("clin ging ductal carcinoma in situ [DCIS]") generally is a subtle epithelial alt eration 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 m isinterpreted easily as "normal" because of the frequent absence of multila yered proliferation and often subtle cytologic atypia. Because it presents as an often unrecognized lesion or in association with tubular carcinoma, t o the authors' knowledge the clinical and biologic significance of this les ion 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," incl uding 13 cases associated with infiltrating ductal carcinoma as well as 5 c ases 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 chromosom es 2p, 3p, 11q, 16q, and 17q. Two cases also were used for the assessment o f clonality by means of X chromosome inactivation (methylation pattern of t he 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 we re 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 infiltra ting ductal carcinoma. In contrast to the DIN-flat type, the perfectly norm al mammary epithelium was associated very infrequently (1 of 16 cases; 6%) with LOH. CONCLUSIONS. The DIN-nat type represents one of the earliest, morphological ly recognizable, neoplastic alterations of the breast. Recognition of the D IN-flat type is important not only for the early detection of intraductal n eoplasia but also to prevent misinterpretation and utilization of this lesi on 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 o f breast carcinoma recurrence observed despite ostensibly "negative" margin s of breast biopsies. (C) 2000 American Cancer Society.