Anatomic Pathology / Clonal Relationship of Ductal and Lobular Breast Lesions Clonal Relationship Between Closely Approximated Low-Grade Ductal and Lobular Lesions in the Breast A Molecular Study of 10 Cases

The relationship between ductal and lobular breast carcinoma is highlighted in cases in which these morphologically divergent carcinomas coexist in proximity within a single patient. We hypothesized that such cases may result from the proliferation of a precursor lesion into a tumor containing areas of divergent morphologic features. In this study, we analyzed loss of heterozygosity (LOH) in 10 cases of coexistent ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS), and invasive carcinoma. DNA from the separate components of each lesion was subjected to LOH analysis using 13 markers on 7 chromosomes. In 7 cases, the DCIS and LCIS shared loss of a common allele, suggesting a clonal relationship. The invasive component shared loss of the same allele in 5 tumors. This finding indicates that coexistent lobular and ductal carcinomas exhibit shared genetic abnormalities, contradicting the conventional concept that these lesions represent separate, exclusive pathways of breast neoplasia. Instead, these traditionally segregated classes of breast cancer may, in fact, share common precursor lesions. Carcinoma of the breast has traditionally been classified according to a system that emphasizes the distinction between ductal and lobular subtypes.1 However, recent advances have suggested that the molecular characteristics of breast carcinomas correspond more closely with tumor grade as opposed to conventional histologic subtypes. Specifically, molecular profiling has revealed the existence of a so-called low-nuclear-grade breast neoplasia family, including columnar cell lesions, low-grade ductal carcinoma in situ (DCIS), classical lobular carcinoma in situ (LCIS), tubular carcinoma, tubulolobular carcinoma and classic invasive lobular carcinoma.2 Such lesions share a pattern of genetic abnormalities, marked by diploidy or near diploidy, recurrent loss of chromosome 16q, and gain of chromosome 1q. These anomalies are distinct from those typically seen in high-grade breast carcinomas, in which aneuploidy without 16q deletion is the rule.3 The proposed relationship among morphologically different members of the low-grade breast neoplasia family is highlighted in cases in which ductal and lobular preinvasive and invasive carcinomas coexist in proximity to one another, a scenario occasionally encountered in daily pathology practice. In theory, the separate components comprising these tumors could represent the proliferation of a single clone with different morphologic appearances, as proposed by Buerger et al.4 Such a finding would support the idea of a close molecular relationship between low-grade ductal and lobular carcinoma, despite their different histologic types as defined by the conventional classification scheme. To further explore this possibility, we used loss-of-heterozygosity (LOH) analysis to assess a series of tumors consisting of coexistent DCIS, LCIS, and invasive carcinoma for evidence of a clonal relationship between the morphologically distinct components.