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According to current concepts, benign proliferative breast disease (BPBD) is a direct precursor of breast cancer, in a spectrum ranging from ductal hyperplasia to overtly invasive carcinoma. In this study, comparative genomic hybridization (CGH) was used to screen ductal hyperplasia and other BPBD lesions and ductal carcinoma in situ (DCIS) for common genomic abnormalities, to test the relationship between these hyperplastic and neoplastic lesions. Immunohistochemistry for cytokeratin 5/6 was used as a diagnostic adjunct to distinguish ductal hyperplasia from DCIS. A total of 42 cases of BPBD comprising ductal hyperplasia of the usual type (n=14), papilloma (n=22), tubular adenoma (n=3), and adenosis (n=3), as well as 52 cases of DCIS, were studied. All cases of BPBD consistently displayed the presence of a subpopulation of cytokeratin 5/6-expressing basal-type cells within the proliferative lesion, whereas all of the non-high-grade and most of the high-grade DCIS lesions lacked cytokeratin 5/6-positive cells. Whereas gross genomic alterations, as determined by CGH, were undetectable in BPBD, distinct genetic changes characterized all cases of DCIS, with one exception. These results confirm the usefulness of cytokeratin 5/6 immunohistology in the diagnosis of BPBD and neoplastic breast lesions and support the view that BPBD and DCIS are not closely related entities and that BPBD is not an obligate direct precursor of DCIS., (Copyright 2001 John Wiley & Sons, Ltd.)

Atypical proliferative lesions of the breast, such as atypical ductal hyperplasia and atypical papilloma, are considered to be precursors of breast carcinomas and have frequently been shown to have loss of heterozygosity (LOH) on chromosome 16q at the DNA level. We evaluated whether an atypical proliferative lesion and a carcinoma that subsequently occurred in the same area of the ipsilateral breast were of identical clonal origin in seven patients. Using DNA isolated from microdissected archival tissue of epithelial components of both the biopsy specimen of the atypical proliferative lesion and the mastectomy specimen of the carcinoma, the pattern of LOH on 16q was compared between these two lesions using polymerase chain reaction -microsatellite LOH analysis. As a control, LOH on 16q was examined in 13 cases of usual ductal hyperplasia, 10 usual papillomas, and 6 atypical ductal hyperplasias. In the seven cases, LOH on 16q was detected in three of the six atypical proliferative lesions and in five of the seven carcinomas, but the allele with LOH or a deleted region always differed between the two. LOH was detected in both atypical proliferative lesions and carcinomas in one case, only in the atypical proliferative lesion in two cases, and only in carcinomas in three cases. In the controls, LOH on 16q was absent in usual ductal hyperplasias or usual papillomas but was detected in two of six atypical ductal hyperplasias. Although atypical proliferative lesions were frequently confirmed to be of clonal nature with LOH on 16q, these lesions and carcinomas were considered to be clones, probably originated from a field with these clones.

Clonality of predominantly intraductal carcinoma (PIC) and precancerous lesions of the breast was analyzed by a method based on restriction fragment length polymorphism of the X-chromosome-linked phosphoglycerokinase gene and on random inactivation of the gene by methylation. The application of polymerase chain reaction to this method enabled clonal analysis of small lesions. In order to eliminate the contamination by normal stromal cells, intraductal components were microdissected from the frozen sections of PIC under a dissection microscope. Clonal analysis of the intraductal components from seven PICs revealed that all were monoclonal in origin. In three PICs with intraductal spreading of carcinoma cells over nearly a whole breast gland, the intraductal components were collected from eight widely separated sites in each case. Clonal analysis of these samples showed that every sample was monoclonal and the same allele of the phosphoglycerokinase gene was consistently inactivated in each case. These results suggest that PIC arises as a single monoclonal carcinoma and spreads through the ducts over the gland rather than having multicentric origins. Clonality of precancerous lesions such as atypical ductal hyperplasia and intraductal papilloma arising in the terminal ducts was also studied. Intraductal components were microdissected from the paraffin sections of these lesions and subjected to clonal analysis. Both atypical ductal hyperplasia and intraductal papilloma were found to be monoclonal in origin, suggesting that certain genetic changes had already occurred in the precancerous lesions. A further study is needed to elucidate these genetic changes, which would greatly help our understanding of the mechanism of carcinogenesis.