Departments of Morphology and Molecular Pathology, University Hospitals Leuven, Leuven, Belgium.
Hepatology. 2012 Jun;55(6):1876-88. doi: 10.1002/hep.25595.
Cholangiocellular carcinoma (CC) originates from topographically heterogeneous cholangiocytes. The cylindrical mucin-producing cholangiocytes are located in large bile ducts and the cuboidal non-mucin-producing cholangiocytes are located in ductules containing bipotential hepatic progenitor cells (HPCs). We investigated the clinicopathological and molecular features of 85 resected CCs (14 hilar CCs [so-called Klatskin tumor], 71 intrahepatic CCs [ICCs] including 20 cholangiolocellular carcinomas [CLCs], which are thought to originate from HPCs]) and compared these with the different cholangiocyte phenotypes, including HPCs. Immunohistochemistry was performed with biliary/HPC and hepatocytic markers. Gene expression profiling was performed in different tumors and compared with nonneoplastic different cholangiocyte phenotypes obtained by laser microdissection. Invasion and cell proliferation assay were assessed using different types of CC cell lines: KMC-1, KMCH-1, and KMCH-2. Among 51 ICCs, 31 (60.8%) contained only mucin-producing CC features (muc-ICCs), whereas 39.2% displayed histological diversity: focal hepatocytic differentiation and ductular areas (mixed-ICCs). Clinicopathologically, muc-ICCs and hilar CCs showed a predominantly (peri-)hilar location, smaller tumor size, and more lymphatic and perineural invasion compared with mixed-ICCs and CLCs (predominantly peripheral location, larger tumor size, and less lymphatic and perineural invasion). Immunoreactivity was similar in muc-ICCs and hilar CCs and in mixed-ICCs and CLCs. S100P and MUC1 were significantly up-regulated in hilar CCs and muc-ICCs compared with mixed-ICCs and CLCs, whereas NCAM1 and ALB tended to be up-regulated in mixed-ICCs and CLCs compared with other tumors. KMC-1 showed significantly higher invasiveness than KMCH-1 and KMCH-2.
Muc-ICCs had a clinicopathological, immunohistochemical, and molecular profile similar to that of hilar CCs (from mucin-producing cholangiocytes), whereas mixed-ICCs had a profile similar to that of CLCs (thought to be of HPC origin), possibly reflecting their respective cells of origin.
胆管细胞癌 (CC) 起源于具有不同拓扑结构的胆管细胞。柱状黏液产生型胆管细胞位于大胆管中，立方型非黏液产生型胆管细胞位于含有双潜能肝祖细胞 (HPC) 的胆管中。我们研究了 85 例切除的 CC（14 例肝门部 CC [所谓的 Klatskin 肿瘤]，71 例肝内 CC [ICC]，包括 20 例胆管细胞癌 [CLC]，被认为起源于 HPC）的临床病理和分子特征，并将其与不同的胆管细胞表型，包括 HPC 进行了比较。采用胆管/HPC 和肝细胞标记物进行免疫组织化学染色。对不同肿瘤进行基因表达谱分析，并与激光微切割获得的不同非肿瘤性胆管细胞表型进行比较。采用不同类型的 CC 细胞系（KMC-1、KMCH-1 和 KMCH-2）进行侵袭和细胞增殖测定。在 51 例 ICC 中，31 例（60.8%）仅含有黏液产生型 CC 特征（黏液 ICC），而 39.2%表现出组织学多样性：局灶性肝细胞分化和胆管区（混合 ICC）。临床病理上，黏液 ICC 和肝门部 CC 主要位于（肝门）周围，肿瘤较小，且淋巴管和神经周围侵犯较混合 ICC 和 CLC 更常见（主要位于周围，肿瘤较大，且淋巴管和神经周围侵犯较少）。黏液 ICC 和肝门部 CC 与混合 ICC 和 CLC 的免疫反应性相似。与混合 ICC 和 CLC 相比，S100P 和 MUC1 在肝门部 CC 和黏液 ICC 中显著上调，而 NCAM1 和 ALB 则在混合 ICC 和 CLC 中趋于上调。与其他肿瘤相比，KMC-1 的侵袭性明显高于 KMCH-1 和 KMCH-2。
黏液 ICC 的临床病理、免疫组织化学和分子特征与肝门部 CC（来自黏液产生型胆管细胞）相似，而混合 ICC 的特征与 CLC（被认为起源于 HPC）相似，可能反映了它们各自的起源细胞。
