Immunostaining of grade 5 for CK-19 and CK-7 was observed in 13 (92.9%) of the 14 hilar PI ICCs, and in 7 (50%) of the 14 peripheral MF ICCs. Sasaki et al
) have reported that 22.2 and 22.2% of MF ICCs did not reveal immunostaining for CK-19 and CK-7, respectively, in more than 10% of cancer cells. Aishima et al
) have reported that 16 and 10% of MF ICCs did not express CK-19 and CK-7, respectively, in more than 10% of cancer cells. In addition, D'Errico et al
) have shown that all of their hilar ICCs and ICCs originating from major bile ducts expressed both CK-19 and CK-7, and all peripheral ICCs expressed CK-19, but 50% of peripheral ICCs did not express CK-7. Thus, it is likely that at least certain MF ICCs express less CK-19 or CK-7 compared to hilar PI ICCs. This difference may reflect the origin of MF ICCs in the periphery of the intrahepatic biliary tree. In support of this hypothesis, Guedj et al
) reported a difference in the protein expression profile between hilar and peripheral ICCs.
The expression of HepPar-1 antigen and AFP in ICCs has been reported to be 0–11% (8
) and 0–7% (7
), respectively. In agreement with these reports, AFP or HepPar-1 antigen was expressed in only 14.3% of the hilar ICCs and in only 14.3% of the peripheral ICCs in the present study.
The reason for ICCs expressing hepatocyte markers, such as AFP or HepPar-1 antigen, remains unclear. The double immunostaining for CK-7 and HepPar-1 antigen revealed the presence of cancer cells expressing both CK-7 and HepPar-1 antigen. Thus, certain ICCs expressing hepatocyte markers may be derived from hepatic progenitor cells capable of differentiating into cholangiocytes and hepatocytes (14
). It is also possible that cancer cells of ICCs originating from cholangiocytes may transdifferentiate into hepatocellular carcinoma (HCC) cells, since mouse gall bladder epithelial cells have been demonstrated to be capable of transdifferentiating into hepatocytes (6
Recently, Yan et al
) showed arginase-1 to be a more sensitive hepatocyte marker in HCCs, particularly in poorly differentiated HCCs, compared to HepPar-1 antigen. In that study, HepPar-1 antigen and arginase-1 were positively stained in 46.4 and 85.7% of poorly differentiated HCCs, respectively. Arginase-1 was shown to be positively stained in only 1 of 6 ICCs, and useful for distinguishing a poorly differentiated HCC from an adenocarcinoma. In the present study, ICCs were stained immunohistochemically for arginase-1 using the same antibody and the same procedure used by Yan et al
). However, our results show that 4 (28.6%) of 14 hilar ICCs, and 7 (50%) of 14 peripheral ICCs expressed arginase-1 in more than 10% of cancer cells. Furthermore, our results demonstrate that 3 (42.9%) of 7 peripheral ICCs, exhibiting a major histology of poorly differentiated adenocarcinoma, expressed arginase-1 in more than 10% of cancer cells. These results indicate that care should be taken when using arginase-1 as a hepatocyte marker for distinguishing a poorly differentiated HCC and a poorly differentiated peripheral ICC.
A ductal reaction, hyperplasia of ductules, observed in the cirrhotic liver, contains N-CAM-positive cells, and intermediate hepatobilliary cells that express hepatocyte and cholangiocyte markers (14
). Moreover, N-CAM has been reported to be a potential marker of hepatic progenitor cells (14
). However, in the present study the expression of N-CAM was not found to be associated with the expression of arginase-1, suggesting that the expression of arginase-1 in ICCs is independent of its origin.
In conclusion, findings of the present study indicate that the hepatocyte markers, AFP and HepPar-1 antigen, are rarely but definitely expressed in hilar and peripheral ICCs, and that another hepatocyte marker, arginase-1, is expressed at a high frequency in hilar and peripheral ICCs, irrespective of their histology.