Abstract
Intrahepatic cholangiocarcinoma (ICC) is a heterogeneous group of cancers of the intrahepatic biliary tract. However, few studies have evaluated integrin expression according to an ICC subgroup. We immunohistochemically investigated α6β4 (β4) and αvβ6 (β6) integrin expressions in 48 ICCs, and evaluated their relationship with clinical and pathological parameters and ligand expression, as well as transforming growth factor (TGF)-β1. β4 and β6 expressions were detected in 46 (96%) and 35 (73%) ICC cases, respectively. We classified ICC into negative, low (β4, 29 cases; β6, 36 cases), or high (β4, 19 cases; β6, 12 cases) integrin expression groups. β4 and β6 integrin levels were higher in the non-peripheral central localization type ICC than in the peripheral localization type; they were also higher in the periductal-infiltrating or intraductal-growth types than in the mass-forming type ICC; lastly, they were higher in the well-differentiated type than in the poorly-differentiated type ICC. High expression was related to bile duct invasion. In addition, β4 and β6 expressions were associated with mucin production and the expression of cytoplasmic epithelial membrane antigen, laminin-5, and tenascin-C. TGF-β1 was correlated with β6 expression and poor overall survival. These results suggest that integrin expression is associated with subclassification and clinicopathological features of ICC through the coincident expression of their ligands and TGF-β1.
Highlights
Intrahepatic cholangiocarcinoma (ICC) is the second most common cancer arising in the liver; it comprises 15% of primary liver cancers
High expression was related to bile duct invasion (p = 0.0053 and 0.0026, respectively). β4 and β6 integrin expressions were both high in cases; β4 only was high in nine cases, β6 only was high in two cases, and there was a negative to low expression of both in 27 cases. β4 or β6 integrin expressions were not significantly correlated with overall survival (p = 0.42 and 0.47, respectively, Supplemental Figure S1)
These results suggest that the subgroup of ICC with high integrin expression may partly resemble the large bile duct type defined by Aishima et al [22], the bile duct type defined by Liau et al [10], and the muc-ICC
Summary
Intrahepatic cholangiocarcinoma (ICC) is the second most common cancer arising in the liver; it comprises 15% of primary liver cancers. ICC is defined as cholangiocarcinoma that is located proximally in either the first-order or higher peripheral branches of the right and left hepatic bile duct, which is distinguished from perihilar and distal extrahepatic cholangiocarcinoma [3]. The incidence of ICC has increased in the past three decades, while the incidence of perihilar and distal extrahepatic cholangiocarcinoma has remained stable [2,4]. The large duct type of ICC is located in the first to third-order branches of the right and left hepatic bile ducts, which contain the peribiliary glands, while the peripheral small duct type involves the septal and interlobular bile ducts without the peribiliary glands [6]. ICC is classified into mass-forming (MF), periductal-infiltrating (PI), intraductal-growth (IG), and mixed
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