Table 1 Macro-, micro- histologica and genetic features of different HCC subtypes

Steatohepatitic HCC

Steatohepatitic HCC subtype shows a multinodular confluent, yellow–gray mass imparted by the presence of steatosis and fibrosis, respectively, within the tumor.

5-20%

This subtype displays a similitude at least 50% with to steatohepatitis, showing macrovesicular steatosis, lymphocytic inflammation, balloon cells, Mallory–Denk bodies, and pericellular fibrosis.

This subtype presents mutation at level of catenin beta 1 at late stage⁹⁵, tumor protein p53 (TP53)⁹⁶, and telomerase reverse transcriptase (TERT) promoter⁹⁷.

Clear Cell HCC

Clear Cell HCC subtype presents a grayish nodular mass, surrounded by a fibrous capsule, into the cirrhotic liver.

3-7%

This subtype is characterized by middle or high differentiated tumor cells showing clear cytoplasm in over 80%, and steatosis features are observed in one-third of HCC. It could be possible to detect tumor cells containing lipid drops.

This subtype shows positivity for hepatocyte paraffin 1 (Hep Par-1), arginase-1⁹⁸.

This subtype presents mutation at level of isocitrate dehydrogenase (NADP(+)) 1 (IDH1)⁹⁹.

Macrotrabecular massive HCC

Macrotrabecular massive HCC subtype is charaterized by multiple brown-tan nodules bulge over the surrounding flat fibrous strands.

5%

This subtype exhibits a large quantity over 50% of macrotrabecular growth tumor pattern (the most accepted cutoff: >6 and ≥10 cells thick) with tumor cells associated with high-grade nuclear atypia.

This subtype shows positivity for alpha Fetoprotein (AFP) serum¹⁰⁰, Cluster Differentiation (CD) 34¹⁰¹, endothelial cell-specific molecule 1 (ESM1)¹⁰², vessels that encapsulate tumor clusters (VETC)¹⁰⁰.

This subtype shows mutation at the level of TP53, and overproduction of fibroblast growth factor (FGF) 19, ataxia-telangiectasia mutated protein (ATM), angiopoietin 2 and vascular endothelial growth factor A (VEGFA)¹⁰⁰.

Scirrhous HCC

Scirrhous HCC subtype displays abundant intratumoural fibrous stroma (at least 50% of tumor).

4%

This subtype shows widespread intratumoural fibrosis over 50% of HCC and well and/or moderate differentiated tumor cells. It could be possible to appreciate hyaline bodies during histological analysis.

This subtype shows positivity for arginase-1 and glypican-3 in ~80% of cases. At the same time, around the 50% of cases are Hep Par-1 negative. Epithelial cell adhesion molecule (EpCAM), CK7, and CK19 are commonly detected^103,104.

This subtype displays mutation in TSC1/TSC2 genes and enhances activation epithelial-to-mesenchymal transition signaling pathway¹⁰⁵.

Chromophobe HCC

Chromophobe HCC subtype presents a well-circumscribed and encapsulated nodule with having white-yellowish appearance

3%

This subtype manifests clear to pale eosinophilic cytoplasm and mostly uniform color nuclei; cystic spaces loaded with a serum-like solution are often present. Moreover, it could be possible to observe abrupt focal areas presenting tumor cells with greater nuclear anaplasia.

This subtype shows positivity for Alternative lengthening of telomeres (ALT)¹⁰⁶

Fibrolamellar HCC

Fibrolamellar HCC subtype displays multilobulated and well-circumscribed nodules; moreover, a central stellate scarring area is present.

1%

This subtype displays neoplastic hepatocyte cells with intratumoral dense fibrosis, deposed in parallel or lamellar bands. Commonly, it could be possible to detect pale bodies, hyaline bodies, and pseudo-glands. Sometimes calcification, intratumoral cholestasis, mucin production, and copper accumulation were revealed.

This subtype shows low positivity for AFP serum (<200 ng/mL), Hep Par-1, co-expression of cytokeratin (CK) 7 and CD133 and CD44¹⁰⁷.

This subtype exhibits microdeletion in the chromosome 19 comporting DnaJ heat shock protein family (Hsp40) member B1 (DNAJB1):: protein kinase cAMP-activated catalytic subunit alpha (PRKACA) fusion gene^106,108.

Neutrophil-rich HCC

Neutrophil-rich HCC subtype presents a capsule showing a white and heterogeneous cleavage surface.

<1%

This subtype is characterized by the high number of tumor-infiltrating neutrophils and HCC tumor cells poorly differentiated.

This subtype shows strong positivity for granulocyte colony-stimulating factor (GCSF), and it shows high serum levels for interleukin (IL) 6 and C-reactive protein^106,109.

Lymphocyte-rich HCC

Lymphocyte-rich HCC is well-circumscribed with a color reddish brown to tan.

<1%

This subtype displays a higher number of intratumoral lymphocyte cells than HCC tumor cells. It could be possible to appreciate pale bodies into HCC tumor cells.

This subtype shows positivity for Hep Par-1 and arginase-1¹¹⁰.