Rosen's Breast Pathology, 4e

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Ductal Carcinoma In Situ

necrosis. Carcinoma cells have been observed by electron microscopy protruding through gaps in the basal lamina when invasion was not apparent by light microscopy. 285 In such regions, in H&E sections, the neoplastic epithelium ap- pears to protrude from the duct, coming in contact with the stroma as it remains connected to the intraductal neoplasm. This finding often elicits diagnostic uncertainty. It remains to be determined whether protruding cells detected by elec- tron microscopy or light microscopy still attached to their intraductal counterparts are capable of metastatic spread. Basement membrane integrity at sites of microinvasion has been investigated by IHC (Fig. 11.65). Barsky et al. 99 detected fragmentation and disruption of basement mem- branes in areas of microinvasion by employing antibodies to laminin and type IV collagen (Fig. 11.66). Type IV colla- gen is degraded by type IV collagenase, a metalloproteinase. The active enzyme is absent from normal and proliferative ducts, variably present in comedocarcinoma, and prominent in invasive carcinoma. 286 These and other observations sug- gest that the ability of carcinoma cells to form latent type IV collagenase and convert it to the active form is an im- portant attribute associated with the invasive phenotype. As noted earlier in this chapter, myoepithelial cells also appear to play a significant role in inhibiting invasion by DCIS. 171

One important function of myoepithelial cells is the elabo- ration of protease inhibitors that appear to counteract the invasion-promoting effects of metalloproteinases produced by DCIS cells. Another important function of myoepithelial cells in this setting is that they serve as a potential mechani- cal barrier, along with the basement membrane, between in- traductal epithelial cells and periductal stroma. The type IV collagenmolecule consists of a number of dis- tinctive alpha-chain subunits. The cross-linked alpha chains form a macromolecular network, which is a major structural component of the basement membrane. Studies using alpha (IV) chain-specific antibodies and in situ hybridization have shown that the expression of selected alpha chains is depen- dent on the presence of myoepithelial cells. 287 Discontinuous or absent expression of type IV collagen alpha-chain sub- units has been observed in invasive carcinomas. 287,288 The laminin molecule is also composed of cross-linked subunits designated alpha, beta, and gamma chains. Im- munohistochemical studies using chain-specific antibodies revealed discontinuous or absent expression of most sub- units in invasive carcinomas and no expression of the beta-2 chain. 288 Microinvasion should be distinguished from minimally invasive carcinoma, a term that refers to invasive lesions less

FIG. 11.65.  DCIS, basement membrane. A: The basement membrane is highlighted by the immunostain for ­laminin. B: Carcinoma cells in a break in the basement membrane. C: Carcinoma cells extending through the basement ­membrane are in continuitywith the intraductal component.