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Rastogi. Hepatoma Res 2020;6:47 I http://dx.doi.org/10.20517/2394-5079.2020.35 Page 11 of 17
[92]
whereas NASH-HCC without cirrhosis or fibrosis is mediated through the STAT-3 signaling pathway .
Tumor suppressor genes play an important role in the development of steatosis, liver cell damage and
HCC development in the absence of cirrhosis in fatty liver disease [27,84,94] . Patients whose tumors showed
heterogeneous staining patterns of glutamine synthetase in non-cirrhotic livers were more commonly
[39]
overweight or obese .

HBV infection has direct oncogenic potential and the accumulation of mutations in basal core promoters
and a high viral load is considered an independent predictor of HCC development. These mutational
patterns have the potential to identify those at risk of HCC development. HCC development in HCV
infected patients is mainly attributable to sustained necro-inflammatory processes and therefore, occurs
on a background of advanced liver fibrosis or frank cirrhosis. Studies have shown that several HCV gene
products (core, NS3, NS4B and NS5A) possess transformation potential in murine fibroblast culture,
suggesting that HCV also has direct hepatocarcinogenic potential [16,22,23] . Approximately 46% of HCV-
[95]
related HCCs exhibit CTNNB mutations . Of these, the majority arise in the absence of underlying
cirrhosis.

Overrepresentation of T>C at ApTpX with transcription strand bias, a pattern known to be strongly
associated with genotoxic injury, was reported in HCC developing in non-cirrhotic patients with high
[96]
alcohol and tobacco consumption . A variety of congenital and acquired conditions also induce the
development of HCC without underlying cirrhosis, often through alterations in cell cycle regulation,
oxidative stress, and increased levels of tumorigenic growth factors.

Dysregulation of molecular pathways in histological variants of HCC
Macrotrabecular massive HCC (MTM-HCC), a novel distinct subtype of HCC, is characterized by the
presence of a macrotrabecular pattern of more than 6 cells thick recorded in > 50% of the tumor as
described by Ziol et al. . In another recent study, taking a cut off of > 30% macrotrabecular pattern,
[97]
[98]
MTM-HCC was found to be less often associated with cirrhosis . This variant shows genetic aberrations,
which are related to cell cycle activation, chromosomal instability, the G3 transcriptomic subgroup, FGF19
amplifications and TP53 mutation [59,99] . MM-HCC is also characterized by the high expression of two key
regulators of neoangiogenesis and vascular remodeling, angiopoietin 2 and vascular endothelial growth
factor A (VEGFA) [59,100] . Endothelial-specific molecule 1 (ESM1) was identified as a biomarker for this
variant .
[59]
The steatohepatitic subtype is characterized by prominent steatotic changes in the tumor cells, namely
fat accumulation, ballooning degeneration, the presence of Mallory-Denk bodies and peri-cellular
fibrosis [48,101] . SH-HCC also often occurs in non-cirrhotic backgrounds as shown in a recent study that
reported SH-HCC in 20% of the 96 HCC cases reviewed [102] . IL6/JAK/STAT pathway activation, wild type
CTNNB1 and TP53 are the molecular pathways implicated in the pathogenesis [59,103] . However, the literature
reports that CTNNB1 mutations (beta catenin pathway alterations) are less frequent in steatohepatitic
HCCs compared to conventional HCCs [103] .

Lymphocyte-rich HCCs are characterized by an immune rich stroma and have been demonstrated to
have cirrhosis in only 46% of cases in a recent comprehensive review [104] . Molecular studies have revealed
that mutations of CTNNB1, AXIN1, APC, NOTCH1 and NOTCH2 were less frequently observed in
lymphocyte-rich HCCs than conventional HCCs [105] , suggesting a relation between these pathways and
immune exclusion. In lymphoepithelioma-like HCC, oncogenes expressed from chromosome 11q13.3
(CCND1FGF19, and FGF4) are strongly associated with the immune checkpoint signature (CD274,
PDCD1, BTLA, CTLA4, HAVCR2, IDO1, and LAG3). Such differences in genetic aberrations from
classical HCCs provide insight into the need for therapeutic strategies that evade immune surveillance seen
in classical HCCs [105,106] .