Morphophenotypic changes in human multistep hepatocarcinogenesis with translational implications.
OBJECTIVE
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.
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.
Amedeo
A
Sciarra
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.
Luca
L
Di Tommaso
Pathology Department, Shonan Fujisawa Tokushukai Hospital, Fujisawa, Kanagawa, Japan.
Masayuki
M
Nakano
Pathology Unit, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
Annarita
A
Destro
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.
Guido
G
Torzilli
Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
Matteo
M
Donadon
Pathology, Fondazione IRCCS Ca' Granda Ospedale Policlinico and University of Milan, School of Medicine, Milan, Italy.
Marco
M
Maggioni
Pathology, Fondazione IRCCS Ca' Granda Ospedale Policlinico and University of Milan, School of Medicine, Milan, Italy.
Silvano
S
Bosari
Department of Health Sciences, San Paolo Hospital Medical School, Milan, Italy.
Gaetano
G
Bulfamante
First Department of Surgery, University of Yamanashi, Yamanashi, Japan.
Masanori
M
Matsuda
First Department of Surgery, University of Yamanashi, Yamanashi, Japan.
Hideki
H
Fujii
Department of Radiology, University of Yamanashi, Yamanashi, Japan.
Tomoaki
T
Ichikawa
Department of Radiology, University of Yamanashi, Yamanashi, Japan.
Hiroyuki
H
Morisaka
Department of Radiology, University of Yamanashi, Yamanashi, Japan.
Katsuhiro
K
Sano
Department of Radiology, University of Yamanashi, Yamanashi, Japan.
Shintaro
S
Ichikawa
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.
Massimo
M
Roncalli
D000368:Aged; D018952:Antigens, CD34 / Q000032:analysis; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000473:pathology*; D005260:Female; D006801:Humans; D053552:Keratin-7 / Q000032:analysis; D008113:Liver Neoplasms / Q000209:etiology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010641:Phenotype; D066253:Vascular Remodeling
D018952:Antigens, CD34; D053552:Keratin-7
Early hepatocellular carcinoma; High grade dysplastic nodule; Human hepatocarcinogenesis; Tissue biomarkers