Different expression patterns of mucin core proteins and cytokeratins during intrahepatic cholangiocarcinogenesis from biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct--an immunohistochemical study of 110 cases of hepatolithiasis.
OBJECTIVE
Two types of neoplastic lesions preceding invasive intrahepatic cholangiocarcinoma (ICC) are identified: a flat-type neoplastic lesion called 'biliary intraepithelial neoplasia (BilIN)' and an intraductal papillary neoplasm of the bile duct (IPN-B). Multi-step carcinogenesis has been suggested in both lesions, although phenotypic changes during this process remain unclarified.


METHODS
We immunohistochemically examined expression patterns of MUC1, MUC2, MUC5AC, cytokeratin 7 (CK7), and CK20 in BilIN, IPN-B, and ICC in 110 cases of hepatolithiasis.


RESULTS
Thirty-seven cases of ICC in hepatolithiasis were divided into 18 tubular adenocarcinomas with BilIN, 10 tubular adenocarcinomas with IPN-B and nine colloid carcinomas with IPN-B. Carcinogenesis via BilIN was characterized by MUC2-/CK7+/CK20-with increasing MUC1 expression. IPN-B was characterized by the intestinal phenotype (MUC2+/CK20+), and carcinogenesis leading to tubular adenocarcinoma was associated with increasing MUC1 expression and that to colloid carcinoma with MUC1-negativity. Pathological stages of tubular adenocarcinoma of ICC with BilIN or IPN-B were more advanced than those of colloid carcinoma with IPN-B.


CONCLUSIONS
Immunophenotypes of MUCs and cytokeratins might characterize three cholangiocarcinogenetic pathways in hepatolithiasis. Increased expression of MUC1 in BilIN and also IPN-B is associated with tubular adenocarcinoma, while colloid carcinoma in IPN-B is characterized by MUC1-negativity and less advanced pathologic stages.
Zen
Yoh
Y
Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa 920-8640, Japan.
Sasaki
Motoko
M
Fujii
Takahiko
T
Chen
Tse-Ching
TC
Chen
Miin-Fu
MF
Yeh
Ta-Sen
TS
Jan
Yi-Yin
YY
Huang
Shiu-Feng
SF
Nimura
Yuji
Y
Nakanuma
Yasuni
Y
D000231:Adenocarcinoma, Papillary / Q000378:metabolism / Q000473:pathology*; D001650:Bile Duct Neoplasms / Q000378:metabolism / Q000473:pathology*; D001653:Bile Ducts, Intrahepatic / Q000473:pathology*; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D018281:Cholangiocarcinoma / Q000378:metabolism / Q000473:pathology*; D002769:Cholelithiasis / Q000378:metabolism / Q000473:pathology*; D003937:Diagnosis, Differential; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D007633:Keratins / Q000096:biosynthesis*; D009077:Mucins / Q000096:biosynthesis*; D009367:Neoplasm Staging; D011230:Precancerous Conditions
D014408:Biomarkers, Tumor; D009077:Mucins; D007633:Keratins