提示肝祖细胞起源的胆管细胞癌临床病理研究

Clinicopathological study on cholangiolocellular carcinoma suggesting hepatic progenitor cell origin.

作者信息

Komuta Mina, Spee Bart, Vander Borght Sara, De Vos Rita, Verslype Chris, Aerts Raymond, Yano Hirohisa, Suzuki Tetsuya, Matsuda Masanori, Fujii Hideki, Desmet Valeer J, Kojiro Masamichi, Roskams Tania

机构信息

Department of Morphology and Molecular Pathology, University Hospitals Leuven, Leuven, Belgium.

出版信息

Hepatology. 2008 May;47(5):1544-56. doi: 10.1002/hep.22238.

DOI:10.1002/hep.22238

PMID:18393293

Abstract

UNLABELLED

Cholangiolocellular carcinoma (CLC), a subtype of cholangiocellular carcinoma (CC), is thought to originate from the ductules/canals of Hering, where hepatic progenitor cells (HPCs) are located. We investigated the clinicopathological features of 30 CLCs and their relationship to HPCs. We evaluated the expression of hepatocytic markers (hepatocyte paraffin-1, canalicular polyclonal carcinoembryonic antigen, and CD10), biliary/HPC markers (keratin [K]7, K19, and neural cell adhesion molecule), the adenosine triphosphate binding cassette transporters: multidrug resistance protein 1, multidrug resistance-associated protein (MRP)1, MRP3, and breast cancer resistance protein, using immunohistochemistry and electron microscopy. In addition, gene expression profiling of CLC was performed and compared with the profile of hepatocellular carcinoma (HCC) with or without HPC features (K19 expression). In surrounding nontumoral tissue, K7-positive and K19-positive HPCs/ductular reaction were observed. More than 90% of the tumor was composed of CLC areas that showed small monotonous and/or anastomosing glands, strongly positive for K7 and K19. Especially at the tumor boundary, all cases showed a HCC-like trabecular area characterized by canalicular CD10/polyclonal carcinoembryonic antigen expression, and submembranous K7 expression, similar to intermediate hepatocytes. K7-positive/K19-positive HPCs were also seen. Out of 30 cases, 19 showed papillary and/or clear glandular formation with mucin production, representing CC areas. These three different areas showed transitional zones with each other. We observed an increased expression of MRP1, MRP3, and breast cancer resistance protein in the tumor. Electron microscopy findings in HCC-like trabecular areas confirmed the presence of HPCs and intermediate hepatocytes. HPC markers, K7, K19, prominin-1, receptor for stem cell factor c-kit, octamer-4 transcription factor, and leukemia inhibitory factor were upregulated (P < 0.05), while albumin was downregulated in CLC (P = 0.007) toward K19-negative HCCs. Comparison of CLC with K19-positive HCCs indicated a high homology.

CONCLUSION

All these findings highly suggest a progenitor cell origin of CLC.

摘要

未标记

细胆管细胞癌（CLC）是胆管细胞癌（CC）的一种亚型，被认为起源于赫林管/胆小管，即肝祖细胞（HPC）所在之处。我们研究了30例CLC的临床病理特征及其与HPC的关系。我们采用免疫组织化学和电子显微镜评估了肝细胞标志物（肝细胞石蜡-1、胆小管多克隆癌胚抗原和CD10）、胆管/HPC标志物（细胞角蛋白[K]7、K19和神经细胞黏附分子）、三磷酸腺苷结合盒转运蛋白：多药耐药蛋白1、多药耐药相关蛋白（MRP）1、MRP3和乳腺癌耐药蛋白的表达。此外，还进行了CLC的基因表达谱分析，并与具有或不具有HPC特征（K19表达）的肝细胞癌（HCC）的基因表达谱进行了比较。在周围非肿瘤组织中，观察到K7阳性和K19阳性的HPC/小胆管反应。超过90%的肿瘤由CLC区域组成，这些区域表现为小的单调和/或吻合腺管，K7和K19呈强阳性。特别是在肿瘤边界处，所有病例均显示出类似HCC的小梁区域，其特征为胆小管CD10/多克隆癌胚抗原表达以及膜下K7表达，类似于中间型肝细胞。也可见K7阳性/K19阳性的HPC。30例病例中，19例显示有乳头样和/或透明腺管形成并伴有黏液分泌，代表CC区域。这三个不同区域相互之间呈现过渡带。我们观察到肿瘤中MRP1、MRP3和乳腺癌耐药蛋白的表达增加。HCC样小梁区域的电子显微镜检查结果证实了HPC和中间型肝细胞的存在。与K19阴性的HCC相比，CLC中HPC标志物、K7、K19、prominin-1、干细胞因子c-kit受体、八聚体-4转录因子和白血病抑制因子上调（P < 0.05），而白蛋白下调（P = 0.007）。CLC与K19阳性HCC的比较显示出高度同源性。