Bryan BB, Schnitt SJ, Collins LCDuctal carcinoma in situ with basal-like phenotype: a possible precursor to invasive basal-like breast cancer. Mod Pathol 19: 617-621

Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Modern Pathology (Impact Factor: 6.19). 06/2006; 19(5):617-21. DOI: 10.1038/modpathol.3800570
Source: PubMed


Basal-like carcinomas have recently been identified in gene expression profiling studies as a subtype of invasive breast cancer. These lesions are estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative (triple negative), and typically express basal cytokeratins, epidermal growth factor receptor (EGFR), and/or c-kit. As poorly differentiated invasive ductal carcinomas, they presumably have a ductal carcinoma in situ (DCIS) precursor with similar cytologic and immunophenotypic features. However, the frequency and even the existence of a DCIS lesion with an immunophenotype analogous to that of invasive basal-like carcinomas have not been previously evaluated. We studied 66 cases of high nuclear grade DCIS using antibodies to ER, PR, HER2, three basal cytokeratins, EGFR, and c-kit to determine the frequency of the triple negative phenotype, and to determine the relationship between the triple negative phenotype and expression of basal cytokeratins and other biomarkers characteristically expressed by invasive basal-like carcinomas. Four cases (6%) exhibited the triple negative phenotype; the remaining cases showed other combinations of ER, PR, and HER2 expression (nontriple negative). Basal cytokeratins, EGFR, or both were expressed by all four triple negative lesions, but by only 21 of 51 (42%) nontriple negative cases (P = 0.04). We conclude that a small proportion of high-grade ductal carcinomas in situ exhibit an ER-negative/PR-negative/HER2-negative (triple negative) phenotype, and these lesions more commonly show expression of basal cytokeratins and/or EGFR than nontriple negative high-grade DCIS. Given that invasive breast cancers typically share immunophenotypic features with the ductal carcinoma in situ from which they arise, our findings raise the possibility that the triple-negative, basal cytokeratin and/or EGFR-positive DCIS lesions we identified represent a precursor lesion to invasive basal-like carcinomas.

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    • "DCIS is found adjacent to invasive disease in the vast majority of IBCs at the time of diagnosis (Evans et al., 1997; Fisher et al., 1975), where it was thought to be the precursor lesion, however the coexistence of DCIS with IBC varies according to the subtype of breast cancer (Abdel-Fatah et al., 2007). DCIS can be classified into similar molecular subtypes as IBC based primarily on the expression patterns of ER, PR, HER2, EGFR and cytokeratin 5/6 (Bryan et al., 2006; Clark et al., 2011; Livasy et al., 2007; Muggerud et al., 2010), and associated in situ and invasive components often, but not always (see below), exhibit a similar immunophenotype (Steinman et al., 2007; Tamimi et al., 2008). Also, nuclear grade is generally concordant between in situ and invasive components of invasive carcinomas, which have comparable nuclear morphology (Giardina et al., 2003) and DNA ploidy (Ottesen, 2003). "
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    ABSTRACT: Ductal carcinoma in situ (DCIS) is an intraductal neoplastic proliferation of epithelial cells that is separated from the breast stroma by an intact layer of basement membrane and myoepithelial cells. DCIS is a non-obligate precursor of invasive breast cancer, and up to 40% of these lesions progress to invasive disease if untreated. Currently, it is not possible to predict accurately which DCIS would be more likely to progress to invasive breast cancer as neither the significant drivers of the invasive transition have been identified, nor has the clinical utility of tests predicting the likelihood of progression been demonstrated. Although molecular studies have shown that qualitatively, synchronous DCIS and invasive breast cancers are remarkably similar, there is burgeoning evidence to demonstrate that intra-tumor genetic heterogeneity is observed in a subset of DCIS, and that the process of progression to invasive disease may constitute an 'evolutionary bottleneck', resulting in the selection of subsets of tumor cells with specific genetic and/or epigenetic aberrations. Here we review the clinical challenge posed by DCIS, the contribution of the microenvironment and genetic aberrations to the progression from in situ to invasive breast cancer, the emerging evidence of the impact of intra-tumor genetic heterogeneity on this process, and strategies to combat this heterogeneity.
    Molecular oncology 07/2013; 7(5). DOI:10.1016/j.molonc.2013.07.005 · 5.33 Impact Factor
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    • "In the last decade, invasive breast cancers have been characterized using gene expression analysis and classified into several molecular subtypes that have implications for treatment and long-term survival (Perou et al., 1999, 2000; Sorlie, 2004; Sorlie et al., 2001; Sotiriou et al., 2005). More recently, analysis of gene expression patterns in DCIS has identified similar molecular subtypes (Allred et al., 2008; Bryan et al., 2006; Dabbs et al., 2006; Hannemann et al., 2006; Livasy et al., 2007; Tamimi et al., 2008). The correspondence between molecular subtypes of DCIS and invasive cancers suggests that the DCIS lesions may be direct precursors of the invasive cancers. "
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    ABSTRACT: The natural history of breast cancer unfolds with the development of ductal carcinoma in situ (DCIS) in normal breast tissue, and evolution of this pre-invasive neoplasm into invasive cancer. The mechanisms that drive these processes are poorly understood, but evidence from the literature suggests that mammary carcinogenesis may occur through the process of field cancerization. Clinical observations are consistent with the idea that DCIS may arise in a field of altered breast epithelium, that narrow surgical margins do not remove the entire altered field (contributing to recurrence and/or disease progression), and that whole-breast radiation therapy is effective in elimination of the residual field of altered cells adjacent to the resected DCIS. Molecular studies suggest that the field of altered breast epithelial cells may carry cancer-promoting genetic mutations (or other molecular alterations) or cancer promoting epimutations (oncogenic alterations in the epigenome). In fact, most breast cancers develop through a succession of molecular events involving both genetic mutations and epimutations. Hence, in hereditary forms of breast cancer, the altered field reflects the entire breast tissue which is composed of cells with a predisposing molecular lesion (such as a BRCA1 mutation). In the example of a BRCA1-mutant patient, it is evident that local resection of a DCIS lesion or localized but invasive cancer will not result in elimination of the altered field. In sporadic breast cancer patients, the mechanistic basis for the altered field may not be so easily recognized. Nonetheless, identification of the nature of field cancerization in a given patient may guide clinical intervention. Thus, patients with DCIS that develops in response to an epigenetic lesion (such as a hypermethylation defect affecting the expression of tumor suppressor genes) might be treated with epigenetic therapy to normalize the altered field and reduce the risk of secondary occurrence of DCIS or progression to invasive cancer.
    Experimental and Molecular Pathology 11/2012; 93(3). DOI:10.1016/j.yexmp.2012.10.018 · 2.71 Impact Factor
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    • "The basal-like subgroup drew the special attention of researchers because of its unfavorable prognosis and limited therapy opportunities. The BLBCs constitute approximately 15% of invasive breast cancers [6]. These tumors occur frequently in premenopausal young patients [7]. "
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    ABSTRACT: Breast carcinomas can be classified into five subtypes based on gene expression profiling or immunohistochemical characteristics. Among these subtypes, basal-like breast carcinomas (BLBCs) are one of the most studied group, due to their poor prognosis. The aim of this study was to investigate the prevalance, morphological and immunohistochemical features of BLBCs, in Turkish population. Five hundred invasive breast carcinomas were reviewed for several morphological features and immunostained for oestrogen and progesterone receptors, c-ERB-B2, cytokeratin5/6, cytokeratin14, vimentin and epidermal growth factor receptor (EGFR). Basal-like breast carcinoma was defined as a triple negative tumor with cytokeratin5/6 and/or EGFR positive. The prevalance of BLBC was 9.6%. All medullary carcinomas and 55.6% of metaplastic carcinomas showed basal-like immunophenotype. Patients with BLBC were younger (p=0.04) and had higher-grade tumors (p<0.0001). Morphologic features associated with BLBC included increased mitosis, nuclear pleomorphism, presence of geographic and/or central necrosis, pushing margin of invasion and stromal lymphocytic response (p<0.0001). Presence of prominent nucleoli and vesicular nuclear chromatin were the cytological features correlated with basal-like phenotype (p<0.0001). On multivariate analyses, BLBCs were associated with high mitotic number (p<0.0001), the presence of vesicular chromatin (p=0.004), high tubular grade (p=0.011), lymphocytic response (p=0.031) and the absence of carcinoma insitu (p=0.039). Vimentin was positive in 53.2% of BLBCs, while cytokeratin14 was less frequently expressed (27.7%). BLBCs have some distinctive, but not pathognomonical, morphological features. Paying attention to these features and adding cytokeratin14 and vimentin to the immunohistochemical panel can help the definitive diagnosis of BLBCs. Virtual slide Http://
    Diagnostic Pathology 10/2012; 7(1):145. DOI:10.1186/1746-1596-7-145 · 2.60 Impact Factor
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