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Lo. Hepatoma Res 2019;5:41 I http://dx.doi.org/10.20517/2394-5079.2019.021 Page 3 of 7

Regarding correlation with other histological tumor parameters, there was a lack of microsatellite nodules
[8]
or microvascular invasion in SH-HCC . On the immunohistochemical phenotype, C reactive protein
[8]
(CRP) expression was frequent . Immunohistochemical expression of serum amyloid A and CRP was
[16]
significantly higher in this subtype than conventional HCC as revealed by another study . It was also
found that the cancer-associated fibroblasts in SH-HCC more frequently expressed senescence-associated
[14]
secretory phenotype by immunohistochemical staining . On genetic and genomic levels, SH-HCC was
[8]
shown to associate with IL6/JAK/STAT pathway activation, as well as wild type CTNNB1 [8,17] and TP53 .
[12]
[18]
By multivariate modeling, it was shown to be related to the S1 subclass according to Hoshida et al. .
LYMPHOCYTE-RICH HCC
Previously known as lymphoepithelioma-like HCC, lymphocyte-rich HCC is characterized by an
[21]
immune-rich stroma [19,20] . Wada et al. defined this subtype by the presence of more than 100 tumor-
infiltrating lymphocytes in 10 high-power fields. Despite a difference in immune cells infiltration,
immunohistochemically the tumor cells express epithelial markers and HepPar-1 [22-27] . The tumor-
infiltrating lymphocytes were largely composed of CD3+ T cells [19-29] . In contrast to lymphoepithelioma-
like carcinoma originating in the nasopharynx, vast majority of lymphocyte-rich HCC were EBER
[31]
negative [19,22,23,26,28,30] . In 2017, Labgaa et al. published a comprehensive review on a total of 66 lymphocyte-
rich HCC cases. In this report, 64% patients were male and liver cirrhosis was present in 46%. While a
few studies demonstrated a trend of better survival with this subtype [19-21,28] , the prognostic significance of
this subtype remains to be clarified due to its rarity. The genomic landscape of 12 lymphocyte-rich HCC
[32]
was determined by whole-exome sequencing in a recent report . Mutations of CTNNB1, AXIN1, APC,
NOTCH1 and NOTCH2 were less frequently observed in lymphocyte-rich HCC than conventional HCC.
Since activation of Wnt/beta-catenin pathway was correlated with poorer clinical response to immune
[33]
checkpoint inhibitors , lymphocyte-rich HCC is possibly more susceptible to immunotherapies. The
potential significance in terms of treatment response was in line with in a recent study examining the
immunohistochemical expression in 217 HCCs, that a high programmed death-ligand 1 expression was
[34]
correlated with the lymphocyte-rich subtype .

SCIRRHOUS HCC
Scirrhous HCC shows peculiar histology with small oval cells arranged in nests or trabecular among an
[35]
abundant fibrous stroma . It comprises 0.19% of all HCC from the National Cancer Database from 2004-
[36]
2015 . The survival outcome for this subtype remains to be further delineated. Overall survival of patients
[35]
was found comparable with non-scirrhous HCC in some studies [36,37] , while both better [38-40] and worse
survival outcomes were also reported. Furthermore, scirrhous HCC was associated with less frequent
[37]
HBV infection, lower serum AFP level and less liver cirrhosis when compared with conventional HCC .
Radiologically, scirrhous HCC was reported to show distinct computed tomography (CT) scan features
[41]
including presence of washout areas . Immunohistochemical analyses revealed expression of stem/
[35]
progenitor markers in scirrhous HCC; and gene expression profiling highlighted a TGF-b signature .

FLC
[42]
FLC was first introduced in 1956 illustrating a primary liver cancer displaying characteristic large
eosinophilic tumor cells with prominent nucleoli and pale bodies, and the prominent fibrotic bands
[43]
traversing the tumor cells in lamellae. The latter feature led to the coining of its nomenclature . FLC
occurs more often in young adults with a mean age of diagnosis at 25 years [43-45] . FLC express CK7 and
[46]
HepPar-1 immunohistochemical staining . From a nationwide study published in 2014 using the SEER
[47]
data base, the incidence of FLC was 1% among 7225 patients . In the same study, it was reported that
patients tend to be younger, female, and associated with longer overall survival on univariate analysis.
In 2014, it was reported that a chimeric transcript was identified, which was further found to be due to a