Table 2.

WHO subtypes of HCC [24]

Subtype	Frequency	Clinical features	Histology	Molecular features
Steatohepatitic	5–20%	May be associated with steatohepatitis	Fatty change, ballooning, inflammatory foci, Mallory-Denk bodies	IL-6/JAK/STAT activation; low frequency of CTNNB1, TERT, and TP53 mutations
Clear cell	3–7%	Unknown	> 80% of tumor cells with clear cell morphology, mild fatty change is acceptable	Unknown
Macrotrabecular-massive	5%	High-serum AFP, poor prognosis	Macrotrabecular growth in > 50% of tumor, vascular invasion common	TP53 mutation, FGF19 amplification
Scirrhous	4%	May mimic cholangiocarcinoma on imaging	> 50% of tumor showing a dense intratumoral fibrosis	TSC1/2 mutation; activated TGFβ-signaling
Chromophob	3%	Unknown	Tumor cells with chromophobe cytoplasm, mainly bland nuclei, but areas with anaplasia and microcysts	Alternative lengthening of telomeres
Fibrolamellar	1%	Young, no background liver disease	Large oncocytic tumor cells (K7 and CD68 positive) with prominent nucleoli, dense lamellar intratumoral fibrosis	DNAJB1-PRKACA fusion gene
Neutrophil-rich	< 1%	Leukocytosis, CRP and IL-6 elevation, poor prognosis	Prominent infiltration by polymorphic granulocytes, sarcomatoid areas may be seen	G-CSF expression by tumor cells
Lymphocyte-rich	< 1%	Unknown	Lymphocytes > tumor cells	Unknown, not EBV-related