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J Hepatol. 2016 Jan;64(1):87-93. doi: 10.1016/j.jhep.2015.08.031. Epub 2015 Sep 5.

Morphophenotypic changes in human multistep hepatocarcinogenesis with translational implications.

Author information

1
Pathology Unit, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Department of Medical Biotechnology and Translational Medicine (BIOMETRA), University of Milan, School of Medicine, Milan, Italy.
2
Pathology Department, Shonan Fujisawa Tokushukai Hospital, Fujisawa, Kanagawa, Japan.
3
Pathology Unit, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
4
Department of Medical Biotechnology and Translational Medicine (BIOMETRA), University of Milan, School of Medicine, Milan, Italy; Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
5
Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
6
Pathology, Fondazione IRCCS Ca' Granda Ospedale Policlinico and University of Milan, School of Medicine, Milan, Italy.
7
Department of Health Sciences, San Paolo Hospital Medical School, Milan, Italy.
8
First Department of Surgery, University of Yamanashi, Yamanashi, Japan.
9
Department of Radiology, University of Yamanashi, Yamanashi, Japan.
10
Pathology Unit, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Department of Medical Biotechnology and Translational Medicine (BIOMETRA), University of Milan, School of Medicine, Milan, Italy. Electronic address: massimo.roncalli@hunimed.eu.

Abstract

BACKGROUND & AIMS:

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'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" (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.

KEYWORDS:

Early hepatocellular carcinoma; High grade dysplastic nodule; Human hepatocarcinogenesis; Tissue biomarkers

PMID:
26343958
DOI:
10.1016/j.jhep.2015.08.031
[Indexed for MEDLINE]
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