Morphophenotypic changes in human multistep hepatocarcinogenesis with translational implications

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• 作者：Amedeo Sciarra¹ ; ² ; Luca Di Tommaso¹ ; ² ; Masayuki Nakano³ ; Annarita Destro¹ ; Guido Torzilli² ; ⁴ ; Matteo Donadon⁴ ; Marco Maggioni⁵ ; Silvano Bosari⁵ ; Gaetano Bulfamante⁶ ; Masanori Matsuda⁷ ; Hideki Fujii⁷ ; Tomoaki Ichikawa⁸ ; Hiroyuki Morisaka⁸ ; Katsuhiro Sano⁸ ; Shintaro Ichikawa⁸ ; Massimo Roncalli¹ ; ² ; ^{massimo.roncalli@hunimed.eu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：HCC ; hepatocellular carcinoma ; LGDN ; low grade dysplastic nodule ; HGDN ; high grade dysplastic nodule ; eHCC ; early hepatocellular carcinoma ; pHCC ; progressed hepatocellular carcinoma ; CK7 ; cytokeratin 7 ; GPC3 ; Glypican 3 ; HSP70 ; Heat shock protein 70 ; GS ; Glutamine synthetase ; CHC ; Clathrin heavy chain ; EZH2 ; Enhancer of zeste homologue 2 ; DR ; ductular reaction ; CD34 ; cluster of differentiation 34
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：64
• 期：1
• 页码：87-93
• 全文大小：2493 K

文摘

Human hepatocarcinogenesis in cirrhosis is thought to be multistep and characterized by a spectrum of nodular lesions, ranging from low to high grade dysplastic nodules (LGDN and HGDN) to early and progressed hepatocellular carcinoma (eHCC and pHCC). The aim of this study was to investigate the morphophenotypical changes of this sequence and their potential translational significance.

Methods

We scored the vascular profile, ductular reaction/stromal invasion and overexpression of five biomarkers (GPC3, HSP70, GS, CHC, and EZH2), in a series of 100 resected nodules (13 LGDN, 16 HGDN, 42 eHCC and 29 small pHCC).

Results

The score separated the four groups of nodules as individual entities (p <0.01). In the sequence, biomarker&rsquo;s overexpression progressively increased with parallel decrease of ductular reaction; the vascular remodeling started very early (LGDN) but did not further develop in a proportion of HCC. eHCC was the most heterogeneous entity, with marginal overlap with HGDN and pHCC. Liver environment (fibrosis, etiology) did not impact on the phenotype of the different nodules. A subclass of eHCC (16/42) without evidence of stromal invasion was identified, suggesting a “preinvasive stage&rdquo; (p <0.05). For diagnosis, the application of four and five biomarkers (rather than the usual three) improved the sensitivity of the assay for the detection of eHCC (76% and 93% vs. 52%); biomarkers in alternative combinations, and also increased the sensitivity of the assay (GS + CHC + EZH2: 76%; GS + CHC + EZH2 + HSP70: 90%).

Conclusions

This study supports the multistep nature of human hepatocarcinogenesis, and suggests that eHCC is more heterogeneous than previously thought. This provides further information of the potential translational significance into clinical practice.