肝细胞肝癌与胆管细胞癌混合癌:混而不同
  • HCC-CCA是罕见,鲜知原理的原发性肝癌,通过对18例HCC-CCA病人,HCC(n = 164)和肝内胆管癌(iCCA)(n = 149)数据库综合基因组分析;
  • 发现与传统分类,干细胞类和经典肿瘤比较,CLC是NCAM阳性,染色体更稳定,胆管来源,无HCC特征, TGF-b 信号上调且富集炎症相关免疫信号。
  • 干细胞类瘤是SALL4阳性,祖细胞样特征富集,癌基因激活,恶性很难预后。经典型与HCC和iCCA有相同起源细胞;
  • 倡议病理细化HCC-CCA为干细胞类,经典型和CLC。
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Mixed hepatocellular cholangiocarcinoma tumors: Cholangiolocellular carcinoma is a distinct molecular entity

混合性肝细胞胆管癌肿瘤(HCC-CCA)中胆管细胞癌(CLC)是一个独特的分子实体

10.1016/j.jhep.2017.01.010

2017-01-23, Article

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BACKGROUND & AIMS: Mixed hepatocellular cholangiocarcinoma (HCC-CCA) is a rare and poorly understood type of primary liver cancer. We aimed to perform a comprehensive molecular characterization of this malignancy.
METHODS: Gene expression profiling, DNA copy number detection, and exome sequencing using formalin-fixed samples from 18 patients with mixed HCC-CCA were performed, encompassing the whole histological spectrum of the disease. Comparative genomic analysis was carried out, using independent datasets of HCC (n=164) and intrahepatic cholangiocarcinoma (iCCA) (n=149).
RESULTS: Integrative genomic analysis of HCC-CCAs revealed that cholangiolocellular carcinoma (CLC) represents a distinct biliary-derived entity compared with the stem-cell and classical types. CLC tumors were neural cell adhesion molecule (NCAM) positive (6/6 vs. 1/12, p<0.001), chromosomally stable (mean chromosomal aberrations 5.7 vs. 14.1, p=0.008), showed significant upregulation of transforming growth factor (TGF)-β signaling and enrichment of inflammation-related and immune response signatures (p<0.001). Stem-cell tumors were characterized by spalt-like transcription factor 4 (SALL4) positivity (6/8 vs. 0/10, p<0.001), enrichment of progenitor-like signatures, activation of specific oncogenic pathways (i.e., MYC and insulin-like growth factor [IGF]), and signatures related to poor clinical outcome. In the classical type, there was a significant correlation in the copy number variation of the iCCA and HCC components, suggesting a clonal origin. Exome sequencing revealed an average of 63 non-synonymous mutations per tumor (2 mean driver mutations per tumor). Among those, TP53 was the most frequently mutated gene (6/21, 29%) in HCC-CCAs.
CONCLUSIONS: Mixed HCC-CCA represents a heterogeneous group of tumors, with the stem-cell type characterized by features of poor prognosis, and the classical type with common lineage for HCC and iCCA components. CLC stands alone as a distinct biliary-derived entity associated with chromosomal stability and active TGF-β signaling.
LAY SUMMARY: Molecular analysis of mixed hepatocellular cholangiocarcinoma (HCC-CCA) showed that cholangiolocellular carcinoma (CLC) is distinct and biliary in origin. It has none of the traits of hepatocellular carcinoma (HCC). However, within mixed HCC-CCA, stem-cell type tumors shared an aggressive nature and poor outcome, whereas the classic type showed a common cell lineage for both the HCC and the intrahepatic CCA component. The pathological classification of mixed HCC-CCA should be redefined because of the new molecular data provided.

First Authors:
Agrin Moeini

Correspondence Authors:
Josep M Llovet

All Authors:
Agrin Moeini,Daniela Sia,Zhongyang Zhang,Genis Camprecios,Ashley Stueck,Hui Dong,Robert Montal,Laura Torrens,Iris Martinez-Quetglas,M Isabel Fiel,Ke Hao,Augusto Villanueva,Swan N Thung,Myron E Schwartz,Josep M Llovet

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