Precursors of Conventional PC and PanIN Classification

In Japan, historically, atypical intraductal lesions have been studied in detail using resected or autopsied pancreata. Kuzuka and colleagues documented in their 1,174 autopsied pancreata study that atypical ductal lesions were found in 0.7 and 29.2% of pancreata without and with PC, respectively [5]. An atypical epithelium was often observed in pancreatic ducts and ductules away from the tumor in resected pancreata with PC. However, an atypical epithelium is rarely found in pancreata without PC. Therefore, it has been assumed that PC occurs from an atypical epithelium. Moreover, the reason why tiny PCs were rarely found is that an atypical epithelium occurring from peripheral ducts or ductules immediately progresses to an invasive carcinoma, i.e. conventional PC is thought to occur de novo and immediately invade the pancreatic parenchyma.

Recently, the pancreatic intraepithelial neoplasia (PanIN) classification proposed by Klimstra DS and Longnecker DS [6] was examined as a progression model of conventional PC concerning both histological changes and genetic alterations in caliber pancreatic ducts [7, 8]. Histological diagnoses used in Japan such as mucinous metaplasia/hyperplasia, papillary hyperplasia, atypical hyperplasia, and CIS are almost the same as those of the PanIN classifications: PanIN-1A, PanIN-1B, PanIN-2, and PanIN-3. In terms of molecular

Fig. 1. CIS morphologically shifting to invasive carcinoma.

biology, a point mutation of K-ras gene is found in PanIN-1A, genetic alterations of Her2/neu (c-erbB-2) and p16 occur in PanIN-2, and genetic alterations in p53 and DPC4/smad4 occur in PanIN-3. Moreover, there are many CISs (corresponding to PanIN-3) adjacent to the invasive tumor. It has been proved that there are no differences in genetic alterations between some CIS components and invasive carcinoma components [9]. Therefore, CIS is recognized as a precursor of IDC of the pancreas.

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