Molecular classification of hepatocellular adenomas: impact on clinical practice

Figures & data

Table 1. Molecular classification of hepatocellular adenomas.

HCA classification	Frequency	Mutations	Pathway disregulated	Risk factors	Clinical features	Histological features	Immunohistochemical markers	Imaging (MRI)	Complications
H-HCA	30–35%	HNF1A biallelic inactivation	Disturbance in metabolic profile	HNF1A germline mutations OC	Women: familial adenomatosis (HNF1A germline)	Tumor, diffuse steatosis	Decreased FABP1 expression in the tumor	T1 chemical shift sequence: signal dropout on opposed Phase l	No risk of malignant transformation if HHCA <5 cm
I-HCA	30–35%	IL6ST (65%) FRK (10%) STAT3 (5%) GNAS (5%) JAK1 (2%)	IL6/JAK/STAT	OC High alcohol consumption Obesity	Inflammatory syndrome	Inflammatory infiltrates Dystrophic arteries Sinusoidal dilatation	Tumor overexpression of SAA/CRP	Hyperintense signal on T2, arterial enhancement persisting in delayed phases	–
β-catenin HCA exon 3	7%	Exon 3 CTNNB1 mutation	Strong β-catenin activation	Androgen Liver vascular disease	Male Only one tumor Young patient	Cellular atypia Pseudo-glandular formation Cholestasis	Nuclear β-catenin Increased glutamine synthase expression	–	High risk of malignant transformation in HCC
β-catenin HCA exon 7–8	3%	Exon 7–8 CTNNB1 mutation	Weak β-catenin activation	OC	Only one tumor Young patient	–	Faint glutamine synthase expression	–	–
Sonic hedgehog HCA	4%	INBHE/GLI1 fusion	Sonic hedgehog activation	OC Obesity	–	Hemorrhage	–	–	Bleeding
Unclassified HCA	7%	–	–	–	–	–	–	–	–

A total of 50% of CTNNB1-mutated HCA (either in exon 3 or in exon 7/8) are also inflammatory.

CRP: C reactive protein; HCA: Hepatocellular adenoma; HCC: Hepatocellular carcinoma; HHCA: HNF1A-inactivated hepatocellular adenoma; HNF1A: Hepatocyte nuclear factor 1A; IHCA: Inflammatory hepatocellular adenoma; OC: Oral contraception; SAA: Serum amyloid A.

Figure 1. Biopsy samples of hepatocellular adenomas.

β-catenin exon-3-mutated hepatocellular adenoma: thick trabeculae with mild nuclear atypia and pseudo-gland (arrow) are frequently observed (A). Strong diffuse staining for glutamine synthase (B), as well as nuclear translocation of β-catenin (C), when present, enable diagnosis. Inflammatory hepatocellular adenoma with sinusoidal dilatations, inflammatory foci and isolated arteries (arrow) (D). No glutamine synthase expression is observed (E). Immunostaining with amyloid A (SAA) shows strong cytoplasmic staining; normal adjacent liver in the upper part is negative for SAA (F). HNF1A-inactivated adenoma with tumor steatosis (G). Glutamine synthase (H) is negative or weak (similar to adjacent nontumor liver with perivenular staining, arrow). In contrast to the adjacent nontumor liver (I, arrows), HNF1a-inactivated adenoma characteristically lacks L-FABP staining in the tumor (I).

SAA: Serum amyloid A.

Figure 2. Imaging features of HNF1A inactivated hepatocellular adenoma.

Large HNF1A-inactivated hepatocellular adenoma (HCA) in a 26-year-old woman. In chemical shift T1-weighted sequence, HCA has moderate hyperintensity in-phase (A), with a marked signal dropout on opposed-phase images (B). The lesion is hypointense in both T1 (C) and T2 (D) fat-suppressed sequences due to the lipid content. After contrast medium injection, there is only slight arterial enhancement (E), but the lesion remains hypointense compared with the normal liver on portal venous phase (F).

Figure 3. Imaging features of inflammatory hepatocellular adenoma.

Two large inflammatory hepatocellular adenomas in a 33-year-old woman. Note: typical MRI appearance with marked hyperintensity on T2-weighted images (A), together with hypointensity on T1-weighted fat-suppressed images (B). After contrast medium injection, there is strong heterogeneous arterial enhancement of the two lesions (C) that persists in the portal venous phase (D).

Figure 4. Surgical samples of sonic hedgehog hepatocellular adenoma and β-catenin exon-3-mutated hepatocellular adenoma.

Sonic hedgehog hepatocellular adenoma: macroscopic view of a large liver nodule with hemorrhagic areas (A). Low magnification demonstrating a sharply limited hepatocellular nodule with hemorrhagic areas (B) and (C). β-catenin exon-3-mutated HCA with cellular atypia: microscopic examination shows a well-differentiated hepatocellular tumor with cellular atypia (large, hyperchromatic nuclei and bi-nucleated cells) (D). Glutamine synthase is strongly expressed in the tumor (E).

HCA: Hepatocellular adenoma; NT: Nontumor; T: Tumor.

Figure 5. Algorithm for the treatment of hepatocellular adenoma based on molecular classification.

We propose an algorithm for treatment of HCA based on our knowledge of molecular classification.

HCA: Hepatocellular adenoma; OC: Oral contraception; shHCA: Sonic hedgehog hepatocellular adenoma.