Carcinoma in situ and Intraductal Invasion

Intraductal components of IDC include both CIS and also infiltrating components of IDC [12, 14, 18]. It is often difficult to determine whether the carcinoma initially spreads through the duct without invasion (CIS/colonization of ducts), or infiltrating components secondarily involve the ducts (intraductal invasion/cancerization of ducts) [4, 12, 14]. Colonization of ducts is defined as intraductal carcinoma in another location to which CIS has spread. Although it may not always be possible to distinguish between CIS and intraductal invasion on a morphologic basis, serial sections are helpful in defining the relationship between the duct lesion and the infiltrating carcinoma component [12, 14].

The intraductal components of IDC are classified into three histological patterns as follows: low papillary (including flat), tubular (including solid and cribriform) and mixed (low papillary plus tubular) (fig. 4). The low papillary pattern is characterized by low papillary projections lacking a fibromuscular core or by irregular stratification and pleomorphism of epithelial cells. The tubular pattern is associated with desmoplasia. The incidences of the low papillary, tubular and mixed patterns are 39%, 56%, and 5%, respectively. IDC venous invasion shows the tubular type histological pattern, so a tubular pattern of intraductal components in IDC indicates intraductal invasion, while a low papillary pattern indicates CIS/colonization of ducts [18].

Cell proliferative activity is generally low in CIS compared to infiltrating carcinoma [19-21]. The proliferation index, evaluated using Ki67, is significantly lower in the intraductal components of IDC than in the associated infiltrating components (figs. 5, 6). The difference between the Ki67 labeling indexes in the intraductal and associated infiltrating carcinoma components suggests that these components show different biological behaviors [14]. The lower cell proliferative activity in intraductal components may explain why intraductal carcinoma spread is limited to the vicinity of the infiltrating focus. Wilentz et al. demonstrated that the pattern of Dpc4 expression in intraductal carcinoma components did not match that in the associated infiltrating carcinoma components [22]. Dpc4 is a tumor suppressor gene targeted in IDC. They concluded that loss of Dpc4 expression occurred biologically late in pancreatic tumor progression. These data imply that intraductal components associated with IDC represent CIS rather than intraductal invasion. The frequency of p53 protein overexpression is similar in both the intraductal and associated infiltrating

Fig. 4. Intraductal components of IDC. Low papillary (a), flat (b), cribriform (c) and mixed patterns (d).

components, suggesting that it represents an early genetic event in the process of pancreatic neoplasia [13, 23].

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