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Page 4 of 7 Lo. Hepatoma Res 2019;5:41 I http://dx.doi.org/10.20517/2394-5079.2019.021

deletion in chromosome 19 detected by whole genome sequencing, which in turn leads to the generation
[48]
of the DNAJB1-PRKACA chimeric protein, with the kinase activity is retained in the latter component .
This discovery is significant since it provides a pathognomonic genetic feature for this subtype. The
tumorigenicity of the fusion transcript was validated by in vivo mouse model with hydrodynamic tail vein
[49]
injection of Crispr/cas9 generated DNAJB1-PRKACA vector . Subsequent study revealed an interaction
[50]
between the fusion kinase and b-catenin , suggesting a contributory role of the fusion protein and
b-catenin in the pathogenesis of FLC. In addition, analysis of clinical samples suggested the recruitment
of heat shock protein 70 by the fusion enzyme and further in phosphoproteomic profiling using cell line
[51]
models highlights the activation of ERK signaling in DNAJ-PKAC cells .

cHCC-CCA
cHCC-CCA is defined as a primary liver cancer showing unequivocal presence of both hepatocytic
and cholangiocytic differentiation in the same tumor [2,52] . The 2 components histologically can either
be juxtaposed with or intermingled with each other. There is no definite cutoff value as to the minimal
proportion of each component present in a tumor to render a diagnosis of cHCC-CCA. In this type of liver
cancer, small uniform epithelial cells with scanty cytoplasm and showing CK19, EpCAM, CD56, CD117
[2]
or CD133 expression has been observed . The radiological feature with CT scan/magnetic resonance
[53]
imaging was reviewed by a French group . In the study, a mixed pattern comprising HCC, intrahepatic
cholangiocarcinoma and atypical radiological pattern was observed in cHCC-CCA; and this mixed pattern
showed a sensitivity of 48% and a specificity of 81%. Protein expression for of diagnostic purpose of cHCC-
CCA has been investigated, and malic enzyme 1 (ME1) was proposed as a potential immunohistochemical
[54]
marker for cHCC-CCA, in which 77% express ME1 .

Previous study demonstrated an intermediate clinical outcome of cHCC-CCA between HCC and
intrahepatic cholangiocarcinoma (iCCA), when overall survival after resection, disease-free survival
[55]
after resection, and overall survival after liver transplantation were considered . A more recent study
comprising 250 cHCC-CCA in the training cohort and 99 cases in the validation cohort demonstrated
that the 1-, 2 and 3-year overall survival was 67.7%, 46.8% and 37.9% respectively; and the 1-, 2 and 3-year
[56]
cancer-specific survival was 73.1%, 52.0% and 43.0%, respectively . At times of recurrence or metastasis,
[56]
as reported by He et al. , the heterogeneity tends to be retained rendering the clinical behavior of cHCC-
[57]
CCA recurrence is largely unpredictable .
Despite the deviation in clinical outcome, a study on 20 cHCC-CCA samples by capture-based next-
generation sequencing revealed similar genomic profiles to conventional HCC. Recurrent alterations in
TERT, TP53, cell cycle genes, receptor tyrosine kinase/Ras/PI3K pathway genes, chromatin regulators, etc.,
[58]
were identified in cHCC-CCA, while IDH1, IDH2, FGFR2 or BAP1 mutations were absent . On a side
note, genomic and genetic profiling of cholangiolocellular carcinoma, which was previously classified as
[59]
a subtype of cHCC-CCA in the 4th edition of WHO Classification of Digestive Tumors , showed that
this entity was likely biliary tract origin featuring NCAM expression, chromosomal stability and TGF-b
[61]
[60]
activation . Consistent findings were reported by Balitzer et al. . By comparing immunohistochemical
expressions, mutational profiles and copy number variation patterns, cholangiolocellular carcinoma was
shown to display a highly similar pattern with iCCA, suggesting that the former should instead be classified
as a form of well differentiated iCCA.

FUTURE PERSPECTIVES
In this review, latest understanding on 5 HCC subtypes and the distinct entity cHCC-CCA were discussed.
These entities in common demonstrate peculiar pathognomonic histological features. Among these entities,
MTM-HCC, lymphocyte-rich HCC and cHCC-CCA are known carry potential prognostic significance.