Background
Tumor type | Pathologic features | Molecular signatures |
---|---|---|
Focal nodular hyperplasia (FNH) | Well-differentiated hepatocytes [88] | IHC staining positive for CK19, NCAM in proliferating ductules [88] |
Intervening fibrous bands radiating from a central scar, Abundant, proliferating bile ductules | GS staining pattern: map-like pattern [89] | |
Hepatocellular Adenoma (HCA) | Well differentiated proliferating hepatocytes in cords one to two cells thick and lacking portal tracts [88] | IHC staining positive for CK7 [88] |
Rare bile ductules | GS staining pattern: diffuse pattern (beta-catenin activating pattern) or absent/irregular pattern (beta-catenin normal pattern) [88] | |
Naked arterioles | ||
Overexpressed SAA, CRP, and gp130 in inflammatory subtype (50% of HCA) [95] | ||
Dysplastic nodules (DN) | Vaguely (low-grade DN) or distinctly (high-grade DN) nodular with peripheral fibrous scar [96] | TERT promoter mutation in 6% of low-grade DN; 19% of high-grade DN [97] |
Mild increase in cell density with monotonous pattern, with no cytologic atypia (low-grade DN) or increased cellularity in irregular trabecular pattern with moderate atypia (high-grade DN) | ||
No pseudoglands or markedly thickened trabeculae | ||
Unpaired arteries sometimes present | ||
No stromal invasion | ||
Early HCC | Increased cell density with an elevated nuclear/cytoplasm ratio and irregular thin-trabecular pattern [98] | |
Varying numbers of portal tracts inside the nodule | ||
Pseudo-glandular pattern | ||
Diffuse fatty change |
TERT promoter mutations in 61% of early HCC [97] | |
Varying numbers of unpaired arteries | ||
Stromal invasion present | ||
Fibrolamellar HCC | Arising in non-cirrhotic liver [11] | Fusion gene--DNAJB1-PRKACA [10] |
Nests of well-differentiated oncocytic cells in a background of acellular but dense collagen bundles arranged in parallel lamellae | Overexpression of EGFR [11]. | |
Advanced HCC | Unifocal, multifocal, or diffusely infiltrative soft tumor [98] | |
Polygonal cells with distinct cell membranes, abundant granular eosinophilic cytoplasm, round nuclei with course chromatin, and higher nucleus/cytoplasm ratio, | ||
Tumor capsule present | Activating mutations of CTNNB1 [108] | |
Invasion and minute intrahepatic metastasis | Other alterations listed in Table 2
| |
Unpaired arteries | ||
Absent portal tracts |
Genomic aberrations in HCC
Gene | Aberration Frequency (% of patients) | Pathway | Function | Examples of Potential Targeted Agenta
|
---|---|---|---|---|
TERT promoter
| Telomere maintenance | Adds telomere repeats (TTAGGG) onto chromosome ends, compensating for the erosion of protective telomeric ends that is a normal part of cell division [110] | ||
TP53
| Mutations: 3–40% | P53 pathway | Tumor suppressor [23] | Bevacizumab [33] |
TP53 gene regulates the expression of VEGF-A. Anti-angiogenic agents were correlated with longer PFS in patients harboring TP53- mutant tumors [32] | Ramucirumab [111] | |||
Sorafenib [13] | ||||
Wee-1 inhibitors [36] | ||||
CTNNB1
| Wnt pathway | Regulates cell adhesion, growth, and differentiation [23]. | BBI608 is a potent small molecule inhibitor [112] | |
PRI-724[112] | ||||
Sulindac [113] | ||||
AXIN1
| Wnt pathway | Regulates cell adhesion, growth, and differentiation. | Small molecule inhibitor XAV939 [31] | |
ARID1A
| Chromatin remodeling | Transcriptional activation and repression of selected genes via chromatin remodeling [23] | ||
CDKN2A
| Cell cycle | Tumor suppressor gene promotes cell cycle arrest in G1 and G2 phases. Suppresses MDM2 [23] | CDK4/6 inhibitor palbociclib [13] | |
ARID2
| Chromatin remodeling | Tumor suppressor gene with a role in the transcriptional activation and repression of selected genes [23] | ||
RPS6KA3
| Dual function-regulation of the MAPK/ERK and mTOR signaling | Mediates stress-induced and mitogenic activation of transcription factors and cellular differentiation, proliferation, and survival [23]. | ||
CCND1
| P53 pathway Cell cycle | Functions as a regulatory subunit of CDK4 or CDK6, whose activity is required for cell cycle progression [23]. | Palbociclib [13] | |
FGF3, FGF4 or FGF19
| FGF pathway | FGF family members possess broad mitogenic and cell survival activities and are operative in tumor growth and invasion, and tissue repair [23]. | Brivanib [44] | |
[114] | ||||
BIBF 1120 [114] | ||||
Dovitinib [114] | ||||
Lenvatinib [114] |