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Rastogi. Hepatoma Res 2020;6:47 I http://dx.doi.org/10.20517/2394-5079.2020.35 Page 9 of 17
[73]
tumors . Glands lying in desmoplastic stroma and immunohistochemical expression of mucin1, CK7 and
[74]
CK19, while negative for hepatocytic origin, aids in the diagnosis . Bile duct adenoma is often a difficult
differential, particularly in intra-operative frozen section examination. A subcapsular location and a well-
circumscribed appearance are important clues to the diagnosis. Vascular lesions such as hemangioma,
epithelioid hemangioendothelioma, angiosarcoma, and angiomyolipoma are other mimics of HCC
on imaging. The histopathology and immunohistochemical markers are quite distinct however, so the
diagnosis is straightforward.

Certain HCC variants have a predilection to occur in non-cirrhotic livers. Fibrolamellar, scirrhous,
steatohepatiic and mixed hepato-cholangiocarcinoma are the more frequent subtypes. Molecular pathways
and morpho-molecular features are reviewed in the molecular pathology section.

The fibrolamellar subtype merits special mention. It was first described by Edmondson in 1980, and is
a rare entity, accounting for less than 1% of all cases of primary liver cancer . It is mostly encountered
[44]
in the young population without any underlying chronic liver disease, or other known predisposing risk
[75]
factors . Its key histological features are the presence of lamellar stromal bands surrounding nests of large
polygonal eosinophilic tumor cells, which have prominent nucleoli. The tumor cells display the presence
of cytoplasmic inclusions - ground-glass pale bodies, eosinophilic cytoplasmic globules, and Mallory-
Denk bodies. The immunohistochemical markers CK7 and CD68 are expressed by tumor cells and have a
sensitivity of 100% and 96% respectively [76,77] , which are important for confirmation .
[47]
Metastasis is the most common hepatic malignancy and occurs in non-cirrhotic livers. In patients without
underlying liver disease, HCC accounts for only about 2% of malignant liver neoplasms [78,79] . The lung,
colon, pancreas and breast are the most common primary sites that metastasize to the liver. In some cases,
these mimic HCC, particularly clear-cell renal cell carcinoma, clear-cell adenocarcinoma of the female
genital organs, adrenal carcinoma and hepatoid adenocarcinoma of the stomach [78,79] .

PATHO-MOLECULAR CHARACTERIZATION OF HCC IN NON-CIRRHOTIC LIVERS
The etiology and etiopathogenesis for a vast number of non-cirrhotic HCCs still remain unknown.
Advancements in translational research have made it possible to analyse thousands of molecular targets
in HCC using microarray-based technologies as well as next-generation sequencing. However, unlike the
cirrhotic HCC and HCA, molecular pathways and classifications have not been exclusively studied in non-
cirrhotic HCCs. Genomic studies in this particular group would be able to elucidate the similarities and
distinctness of the underlying mechanisms and biology in comparison to the cirrhotic HCC. Despite the
scarcity of the literature, recent studies on the molecular pathology of HCC, regardless of the background
liver, provides vital information.

The most frequent mutations affect the TERT promoter (60%), which is associated with an increased
expression of telomerase. TP53 and CTNNB1 are the next most prevalent mutations. These, combined with
low-frequency mutated genes (e.g., AXIN1, ARID2, ARID1A, TSC1/TSC2, RPS6KA3, KEAP1, MLL2),
represent the main deregulated pathways in HCC .
[80]
Different pathways of genetic alterations point towards different hepatocarcinogenetic mechanisms in HCC
with and without cirrhosis. HCCs in non-cirrhotic livers are more often associated with higher β-catenin
mutation, p21 expression, p14 inactivation, and global gene methylation, in contrast to higher p53 and
Wnt/β-catenin pathway aberrations seen in cirrhotic HCCs [81,82] . However, one study showed nuclear p53
labeling in 30% of non-cirrhotic HCCs . Other studies have also suggested that tumor suppressor genes
[83]
[84]
play an important role in the development of HCC in the absence of cirrhosis [Figure 6].