Stages on the way to breast cancer.

Pathways to breast cancer have been difficult to define using morphology alone. Although epithelial hyperplasia of usual type (HUT) is associated with moderately elevated breast cancer risk, molecular evidence placing it in a cancer precursor pathway is not clear-cut. Recent evidence suggests that small numbers of cytokeratin 5/6 positive cells are precursors of separate lineages which acquire either cytokeratin 8/18/19 or smooth muscle actin (SMA) and cytokeratin 14 on separate pathways to fully differentiated epithelial and myoepithelial phenotypes (and may ultimately lose cytokeratin 5/6 expression). Immunohistochemistry shows that most HUT have a mixed precursor phenotype resembling normal breast with co-expression of cytokeratin 5/6, 8/18/19 and SMA, in contrast to atypical ductal hyperplasia (ADH) and ductal carcinoma in situ which typically have a 'mature' luminal phenotype positive for cytokeratin 8/18/19 but lacking cytokeratin 5/6 expression. While this supports the idea of a biological discontinuity between HUT and ADH/DCIS, caution is called for in the diagnostic use of these reagents until greater experience has been accumulated, and other published data do show features of HUT intermediate between normal breast lobules and ADH.