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Page 12 of 17 Rastogi. Hepatoma Res 2020;6:47 I http://dx.doi.org/10.20517/2394-5079.2020.35

Figure 7. Genetic aberrations in non-cirrhotic hepatocellular carcinomas (HCCs)

Scirrhous HCC is another variant, which is less often associated with liver cirrhosis when compared with
[55]
conventional HCC . Genetic studies have highlighted TGF-β signaling, TSC1/TSC2 mutations and the
expression of stem cell markers as the main derangements [59,107] .

Fibrolamellar HCC is characterized by a chimeric transcript, found as a result of a deletion in the
chromosome 19 - DNAJB1-PRKACA chimeric protein [108] . This genetic signature is not reported in other
tumors, which indicates that the mutation plays a key role in FL-HCC tumorigenesis [46,109] . Interaction
between the fusion kinase and b-catenin [110] also contribute to the pathogenesis of FLC. Comparative
genomic hybridization studies have demonstrated that in contrast to the classical HCC, the TP53, Wnt/
β-catenin, or surviving pathways, are not mutated in FL-HCC [91,111] .

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) also occurs in the non-cirrhotic liver
background. Genomic sequencing shows a profile similar to conventional HCCs [112] . Studies have shown
that the same oncogenic drivers delivered to hepatocytes could generate tumors with either a hepatocellular
or biliary phenotype, and such differentiation is mainly dependent upon the microenvironment created by
the oncogenic process [113] . Recurrent alterations in TERT, TP53, cell cycle genes, receptor tyrosine kinase/
Ras/PI3K pathway genes, chromatin regulators etc. were identified in cHCC-CCA, while IDH1, IDH2,
[97]
FGFR2 and BAP1 mutations were absent . CCND1, MET and ERBB2 amplifications are present at higher
frequencies in CHCs compared with HCCs, whereas Wnt pathway alterations are relatively less frequent .
[114]
The literature shows that in comparison to HCCs, TP53 mutations occur twice as frequently in cHCC-
CCAs. TP53 mutations in HCC are usually associated with a worse prognosis and poorly differentiated
histomorphology [59,115] . This suggests that cHCC-CCA is more similar to poorly differentiated HCCs and
explains its worse prognosis [Figure 7].

CONCLUSION
HCCs arising in non-cirrhotic livers are distinct from cirrhotic HCCs in many ways. The risk factors,
etiologies, pathogenesis, histopathology and the differential diagnosis, along with genomic pathways, differ
from the typical cirrhotic HCC. Current knowledge of phenotypic-molecular alterations are based on
studies on HCC irrespective of the liver background. Studies devoted exclusively to non-cirrhotic HCCs