Zhao Qian, Yu Wen-Long, Lu Xin-Yuan, Dong Hui, Gu Yi-Jin, Sheng Xia, Cong Wen-Ming, Wu Meng-Chao
Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, P. R. China.
Department of Biliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, P. R. China.
Chin J Cancer. 2016 Aug 24;35(1):82. doi: 10.1186/s40880-016-0146-7.
Combined hepatocellular and cholangiocarcinoma (CHC) is a unique subtype of liver cancer comprising both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC); however, its cellular origin remains unclear. The purpose of this study was to investigate the clinicopathologic features and the clonal relationship between HCC and ICC in 34 patients with CHC.
The clinicopathologic features and prognosis of the 34 CHC patients were compared with those of 29 patients with separated HCC and ICC (SHC). Loss of heterozygosity (LOH) at 10 highly polymorphic microsatellite markers was detected in 16 CHC and 10 SHC tissues for determination of the clonal origin of CHC. Expression of hepatocyte markers [hepatocyte paraffin 1 (Hep Par 1) and glypican 3 (GPC3)] and cholangiocyte markers [cytokeratin (CK)7 and 19] in tumor tissues was examined by immuno histochemical analysis.
In the 16 CHC specimens, the difference in LOH patterns between HCC and ICC was less than 30%, suggesting the same clonal origin of HCC and ICC. Consistent with this finding, immunohistochemical analysis revealed that hepatocyte markers (Hep Par 1 and GPC3) and cholangiocyte markers (CK7 and CK19) were simultaneously expressed in both the HCC and ICC components in 52.9% of CHC specimens, suggesting that the two components shared a similar phenotype with hepatic progenitor cells (HPCs). On the contrary, in all 10 SHC cases, the difference in LOH patterns between the HCC and ICC components was greater than 30%, suggesting different clonal origins of HCC and ICC. Overall survival and disease-free survival were shorter for patients with CHC than for patients with SHC (P < 0.05).
Our results suggest that the HCC and ICC components of CHC may originate from the same clone, having the potential for dual-directional differentiation similar to HPCs. CHC tended to exhibit the biological behaviors of both HCC and ICC, which may enhance the infiltrative capacity of tumor cells, leading to poor clinical outcomes for patients with CHC.
肝细胞胆管癌（CHC）是一种独特的肝癌亚型，同时包含肝细胞癌（HCC）和肝内胆管癌（ICC）；然而，其细胞起源仍不清楚。本研究的目的是调查34例CHC患者的临床病理特征以及HCC和ICC之间的克隆关系。
将34例CHC患者的临床病理特征及预后与29例分别患有HCC和ICC的患者（SHC）进行比较。在16例CHC组织和10例SHC组织中检测10个高度多态性微卫星标记处的杂合性缺失（LOH），以确定CHC的克隆起源。通过免疫组织化学分析检测肿瘤组织中肝细胞标志物[肝细胞石蜡1（Hep Par 1）和磷脂酰肌醇蛋白聚糖3（GPC3）]和胆管细胞标志物[细胞角蛋白（CK）7和19]的表达。
在16例CHC标本中，HCC和ICC之间LOH模式的差异小于30%，提示HCC和ICC具有相同的克隆起源。与这一发现一致，免疫组织化学分析显示，在52.9%的CHC标本中，HCC和ICC成分中同时表达肝细胞标志物（Hep Par 1和GPC3）和胆管细胞标志物（CK7和CK19），提示这两种成分与肝祖细胞（HPC）具有相似表型。相反在所有10例SHC病例中，HCC和ICC成分之间LOH模式的差异大于30%，提示HCC和ICC具有不同克隆起源。CHC患者的总生存期和无病生存期短于SHC患者（P<0.05）。
我们的结果提示CHC中的HCC和ICC成分可能起源于同一克隆，具有与HPC相似的双向分化潜能CHC倾向于表现出HCC和ICC的生物学行为，这可能增强肿瘤细胞的浸润能力，导致CHC患者临床预后较差。
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