Usual ductal hyperplasia of the breast is a committed stem (progenitor) cell lesion distinct from atypical ductal hyperplasia and ductal carcinoma in situ

Abstract

Current classification systems in proliferative mammary gland pathology are based on a two-cell system, recognizing only glandular and myoepithelial lines of differentiation. A third cell type has recently been characterized in normal breast tissue by double-immunofluorescence analysis to express cytokeratin 5 (Ck5) only. These cells were shown to represent progenitor or adult stem cells that give rise to the glandular and myoepithelial cell lineage. The double-labelling technique has been applied to characterize a spectrum of intraductal epithelial proliferations, namely benign usual ductal hyperplasia, atypical ductal hyperplasia, and ductal carcinoma in situ, all of which are thought to represent the gradual steps of a sequence in the development of breast cancer. Immunofluorescence studies with specific antibodies against Ck5, Ck8/18/19, and smooth muscle actin were complemented by western blotting analysis of Ck5 and Ck8/18/19 expression in normal breast tissue and in proliferative lesions. Usual ductal hyperplasia appears to be a Ck5-positive committed stem (progenitor) cell lesion with the same differentiation potential as seen in the normal breast. This is in sharp contrast to atypical ductal hyperplasia/ductal carcinoma in situ, which display the differentiated glandular immunophenotype (Ck8/18/19-positive, but Ck5-negative). These data require the abandonment of the idea of an obligate biological continuum of intraductal proliferations from benign to malignant. This study provides evidence that cells undergoing malignant transformation tend to be fairly advanced in the glandular lineage of differentiation. The committed stem (progenitor) cell model may contribute to a better understanding of both benign proliferative breast disease and breast cancer development.

Luminal cytokeratin expression profiles of breast papillomas and papillary carcinomas and the utility of a cytokeratin 5/p63/cytokeratin 8/18 antibody cocktail in their distinction

“…Although not specifically addressed in this study, this combination may also be useful to better distinguish between papillomas secondarily involved by usual ductal hyperplasia and those secondarily involved by atypical ductal hyperplasia and/or ductal carcinoma in-situ, in a manner similar to their utility in discriminating between nonpapillary intraductal epithelial proliferations. 8,16,17 Another argument for using CK8/18 in the evaluation of papillary lesions is that its inclusion can provide a 'positive reaction' to support a diagnosis of malignancy (papillary carcinoma), instead of just a negative reaction that might be obtained with only CK5 (and/or p63). Of note, this latter rationale has been used to argue (successfully) for using amethylacyl-CoA racemase in the evaluation of atypical foci in prostate needle biopsy material, a widely accepted practice in contemporary surgical pathology.…”

“…[5][6][7] In addition to routine hematoxylin and eosin-stained sections, various immunohistochemical markers have been used to aid in the distinction between such intraductal epithelial proliferations. Of these, high-molecular weight cytokeratins (CKs) traditionally expressed by the basal epithelial/myoepithelial cells of normal breast, including those detected by the 34bE12 antibody (CK1, CK5, CK10 and CK14) and CK6, have been useful in evaluating both nonpapillary [8][9][10][11] and papillary [12][13][14][15] lesions. In general, these studies have found greater expression of high-molecular weight CKs in usual ductal hyperplasia compared with atypical ductal hyperplasia and ductal carcinoma in-situ, and in intraductal papillomas compared with papillary carcinomas.…”

“…8,16,17 Such expression, combined with decreased/absent high-molecular weight CK expression, has been used to further help distinguish atypical ductal hyperplasia and ductal carcinoma in-situ from usual ductal hyperplasia. There are, however, no studies that systematically evaluate the expression of such low-molecular weight CKs in papillary lesions of the breast.…”

Distinct spatial expression patterns of AP-2alpha and AP-2gamma in non-neoplastic human breast and breast cancer

“…It will therefore be of interest to identify the particular AP-2 isoform(s) expressed in the mammary stem cell compartment. As breast cancer may arise from these stem cells or CK18/SMA-positive progenitor cells, 28 this issue is not only of relevance for understanding breast tumorigenesis but may also be important for a refined diagnosis of subtypes of breast cancer.…”

Cytokeratin 5/14-positive breast cancer: true basal phenotype confined to BRCA1 tumors

“…5,9,10 However, some CK5/14-and CK8/ 18-coexpressing tumors have also been found. 2,4,6,8 It has been proposed that tumors positive for CK5 originate from multipotent CK5-expressing progenitor cells, 2,8,11,12 located between the basal/suprabasal and luminal cell layers in normal ducts. 8 CK5-positive progenitor epithelial cells can gradually differentiate towards glandular and myoepithelial lineages.…”