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Table 1 Pathologic features and molecular signatures of liver lesions

From: The biology of Hepatocellular carcinoma: implications for genomic and immune therapies

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]
No mutation of APC, AXIN, CTNNB1, HNF1, TP53 [90,91,92]
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 Loss/mutation of TCF1 gene that encodes HNF1 (35–40% of HCA) [93, 94]
Activating mutation of beta-catenin (10% of HCA) [91, 94]
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] Increased mRNA expression of GPC3 and survivin and down regulation of LYVE1 [99,100,101,102,103]
Varying numbers of portal tracts inside the nodule Positive IHC staining for GS, HSP70, and GPC3 [104,105,106,107]
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] Inactivation of TP53 [108, 109]
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
  1. Abbreviations : APC Adenomatous Polyposis Coli, CSN5 COP9 Signalosome complex (CSN), CRP C reactive protein, DN Dysplastic nodules, DNAJB1-PRKACA(DnaJ (Hsp40) Homolog, Subfamily B, Member 1- Protein Kinase, CAMP-Dependent, Catalytic, Alpha), CTNNB1 Catenin Beta 1, EGFR Epidermal Growth Factor Receptor, EpCAM The epithelial cell adhesion molecule, GS Glutamine synthetase, HCA Hepatocellular adenomas, HNF1 Hepatocyte Nuclear Factor 1, HPCs Hepatic progenitor cells, HSP70 Heat-shock protein70, GPC3 Encodes glypican-3, IHC Immunohistochemistry, LYVE1 Lymphatic Vessel Endothelial Hyaluronic Acid Receptor 1, NCAM Neural Cell Adhesion Molecule, SAA Serum amyloid A, TCF1 Transcription Factor 1, TERT Telomerase reverse transcriptase