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Alterations in the surrounding breast parenchyma may also be seen with DCIS. High-grade DCIS, in particular, has been associated with the breakdown of the myoepithelial cell layer and basement membrane surrounding the ductal lumen (28), proliferation of fibroblasts, lymphocyte infiltration, and angiogenesis in the surrounding stromal tissues (52,53). Whether these stromal changes reflect important steps that facilitate primary tumor transformation or secondary alterations in response to ductal epithelium that is being transformed is unknown. Quantitative changes in the expression of genes related to cell motility, adhesion, and extracellular-matrix composition, all of which may be related to the acquisition of invasiveness, occur as DCIS evolves into invasive carcinoma (5). Data suggest that DCIS represents a stage in the development of breast cancer in which most of the molecular changes that characterize invasive breast cancer are already present, although the lesion has not yet assumed a fully malignant phenotype. A final set of events, which probably includes gain of function by malignant cells and loss of function and integrity by surrounding normal tissues, is associated with the transition from a preinvasive DCIS lesion to invasive cancer. Most, if not all, clinically relevant features of breast cancer, such as hormone-receptor status, the level of oncogene expression, and histologic grade, are probably determined by the time DCIS has evolved (17,54,72,131).

An occult microinvasive tumor (one that does not exceed 0.1 cm in diameter) may be seen with some cases of DCIS. Such cases are classified as microinvasive breast cancer (115) and are generally treated according to the guidelines for invasive disease. Occult microinvasive tumors are most common in patients with DCIS lesions that are >2.5 cm in diameter (69), those presenting with palpable masses or nipple discharge, and those with high-grade DCIS or comedonecrosis (92,107).