of their genes suggest that they have unique roles and distri-To date, seven apomucins have been characterized bution. [9][10][11][12][13][14][15][16][17][18] Changes in apomucin expression in carcinoma tisand their expression in malignant and premalignant lesues and their precursor lesions, as well as their relationship sions is under evaluation. In this study, we examined to the biological behavior of carcinoma, are under evaluathe expression of MUC1, MUC2, MUC3, and MUC5/6 apotion. [10][11][12][13][14][15][16][17][18] Some carcinoma cells retain the cell-or tissue-spemucins in cholangiocarcinoma (CC) and biliary epithecific apomucin expression of their source, whereas others exlial dysplasia. We used 14 liver samples from patients press aberrant apomucin or lose the original pattern. 10 with hepatolithiasis and CC, 11 with hepatolithiasis There are a few reports describing the expression of aposhowing biliary epithelial dysplasia, 31 with CC alone mucins in normal and pathological livers. [11][12][13] We showed that (19 hilar, 10 peripheral, and 2 unclassifiable), and 14 with MUC1 apomucin is frequently expressed both in the develcombined hepatocellular-cholangiocellular carcinoma oping intrahepatic bile ducts in fetal liver 13 and in cholangio-(HC-CC) and immunohistochemically characterized the carcinoma (CC) but is absent in the normal adult intrahepatic expression profiles of apomucins. Nondysplastic biliary biliary tree. 11,12 Therefore, we proposed that MUC1 apomucin epithelial cells in the intrahepatic large bile ducts conis an ''oncofetal'' antigen in the intrahepatic biliary tree. 13 stantly expressed MUC3 apomucin. MUC5/6 and MUC3
CC occurs at any segment of the intrahepatic biliary tree, apomucin expression was widespread in dysplastic biliwhereas the cell origin and the precursor lesions remain ary epithelial cells in hepatolithiasis, although the latter largely uncharted. Biliary epithelial dysplasia is considered was reduced or absent in dysplastic foci. CC extensively to be a precursor lesion of CC as a complication of hepatolithiexpressed MUC1 apomucin and focally expressed MUC2 asis and primary sclerosing cholangitis. [19][20][21][22] However, little apomucin. In addition, CC of the hilar type, including is known about the distribution of apomucins other than those with hepatolithiasis, frequently expressed MUC3
MUC1 in CC and their precursor lesions. Furthermore, it apomucin (68% and 57%, respectively), whereas those of remains unclear whether and to what degree the apomucin the peripheral type infrequently expressed MUC3 apoprofiles of biliary epithelial cells are retained in CC. mucin (10%) (P Γ΅ .01). MUC5/6 apomucin was more fre-
In this study, we immunohistochemically examined the exquently expressed in well-differentiated (89%), compression of MUC1, MUC2, MUC3, and MUC5/6 apomucins pared with poorly differentiated CC (42%) (P Γ΅ .01).
in CC, combined hepatocellular-cholangiocellular carcinoma Cholangiocellular elements of combined HC-CC fre-(HC-CC), and biliary epithelial dysplasia in hepatolithiasis. quently expressed MUC1 apomucin, although they rarely expressed MUC2 and MUC3 apomucin and infre-
MATERIALS AND METHODS quently expressed MUC5/6 apomucin. The frequent and aberrant expression of ''gastric type'' MUC5/6 apomucin
Classification of Intrahepatic Bile Ducts and Definition of Biliary
in biliary epithelial dysplasia, as well as in CC, suggests Epithelial Dysplasia. Intrahepatic bile ducts were essentially sub- that biliary epithelial cells gain a gastric apomucin pheclassified as large and small bile ducts. 23 The intrahepatic large bile notype during carcinogenesis. MUC3 apomucin expresducts were grossly visible, characterized by the presence of a fibrous sion in CC is a marker that suggests that CC arises in the ductal wall and peribiliary glands. They corresponded to the right and left hepatic ducts, segmental ducts, area ducts, and their first intrahepatic large bile ducts. (HEPATOLOGY 1996;24:1074branches. The small bile ducts that were recognizable under micros-
1078.)
copy were classified as septal and interlobular bile ducts and bile ductules. 23 Biliary epithelial dysplasia, which is found in large intrahepatic
Mucin is a general term for several heterogeneous, highly bile ducts, was defined as follows: Structurally, the dysplastic epitheglycosylated glycoproteins that constitute the major struclial cells showed hyperplasia, such as piled-up nuclei and micropapiltural components of mucus. 1 These glycoproteins have a comlary projection into the ductal lumina. Cytologically, the dysplastic mon protein backbone, which is generally called apomucin or epithelial cells had an increased nucleo-cytoplasmic ratio, a partial mucin core protein. To date, seven apomucins (MUC1-7) have loss of nuclear polarity, and nuclear hyperchromasia. However, these been identified, 2-8 and the tissue-and cell-specific expression atypical features are mild and inadequate for diagnosing malig- nancy.
Tissues. We collected 31 livers from patients with CC (CC alone), 14 with HC-CC, 14 with hepatolithiasis associated with CC (CC with Abbreviations: CC, cholangiocarcinoma; HC-CC, hepatocellular-cholangiocellular carci-hepatolithiasis), and 11 with hepatolithiasis not associated with CC noma.