Update: Radiologic-Pathologic Correlation of Hepatocellular Adenoma

Sadhna Dhingra MD, FCAP; Chakradhar Thupili, MD; Steven Chua, MD, PhD; Kaustubh Shirlakar MD; Srinivasa R Prasad, MD; Venkateswar R Surabhi, MD


Appl Radiol. 2019;48(6):21-29. 

In This Article

Radiologic and Pathologic Features of Subtypes of Hepatocellular Adenoma

Hepatocyte Nuclear Factor-1-α (HNF1A) Mutated Hepatocellular Adenoma. These comprise 35% to 40% of all HA. Their molecular signature is characterized by bi-allelic inactivating mutations of TCF-1, a tumor suppressor gene, located on long arm of chromosome 12, and encodes for transcription factor HNF-1A, which is involved in hepatocyte differentiation and expression of certain genes encoding for albumin, β-fibrinogen and α-1-antirypsin.[20] The mutations are largely somatic, however, germline mutations of TCF1 (HNF1A) gene are associated with type 3 maturity onset diabetes of the young (MODY 3). This is an autosomal dominant disease, which presents in early adulthood and is associated with development of familial adenomatosis.[17] HNF1A mutation down-regulates liver type-fatty acid binding protein (L-FABP) and causes lipogenesis by promoting fatty acid synthetase.[31]

Gross examination of HNF1A mutated HA shows a well-demarcated solid tumor with a tan-yellow soft to firm cut surface. The phenotypic correlate of above-mentioned molecular alterations is presence of moderate to diffuse steatosis in majority of HNF1A mutated HA. No significant inflammation or cellular atypia is seen. Immunostaining with antibodies to L-FABP shows loss of expression in the HA, whereas, the expression is preserved in the surrounding non-neoplastic liver parenchyma (Figure 1).

Figure 1.

HNF1A mutated hepatocellular adenoma. Immunostain for L-FABP showing loss of expression in tumor, versus retained expression in surrounding non-neoplastic liver.

HNF-1α–mutated HAs are associated with MODY type 3 and hepatic steatosis. MR imaging findings include isointense signal on T2WI, isointense on T1WI and typically show intracellular lipid as evidenced by diffuse signal drop-off on a chemical shift sequence (Figure 2).[10,18,19,32] HNF-1α–mutated HAs demonstrate intense enhancement in the arterial phase and become isointense to the liver parenchyma in the portal venous and delayed phases. These lesions remain hypointense on HBP phase with hepatocyte specific gadolinium agents. Tumors less than 5 cm in maximum dimension show minimal risk of bleeding and carry minimal or no risk for malignancy.[10,18,19]

Figure 2.

HNF1A mutated hepatocellular adenoma (Steatotic hepatocellular adenoma) in a 25-year-old woman. Arterial phase (A) shows a lesion in the right liver lobe with avid arterial enhancement. In-phase (B) and opposed-phase (C) shows uniform signal dropout of the lesion on the opposed phase suggestive of intracellular fat. Note that there is also signal drop out of background liver parenchyma indicative of underlying hepatic steatosis.

Inflammatory Hepatocellular Adenoma (IHCA). Historically, IHCAs were referred to as telangiectatic FNHs until 2004–2005, when studies showed these to be monoclonal neoplasms, which behave biologically similar to HAs. IHCA comprise about 30–35% of all HAs. This subtype of HA is characterized by activation of signal transducer and activation of transcription 3 (STAT 3) signaling pathway leading to induction of acute phase inflammatory response within the tumoral hepatocytes. About two-thirds of IHCA show mutations of interleukin 6-signal transducer gene (IL6ST gene), which encodes for glycoprotein 130 (gp130), a component of IL-6 receptor. Activation of IL-6 promotes the STAT3 signaling pathway. About one-third of the HAs do not show mutations of IL6ST gene, yet, show evidence of STAT 3 activation and gp130 protein expression through unknown mechanisms. About 10% of IHCA show concomitant β-catenin mutations.

Gross characteristics of IHCA include a well-demarcated tumor with red-brown variegated cut surface. Histologically, these are characterized by sinusoidal dilatation, peliosis, presence of pseudo-portal tracts like areas with dystrophic blood vessels, ductular reaction and varying degree of inflammatory infiltrates. Focal steatosis may be seen in some cases. Immunohistochemical staining with antibodies to acute phase inflammatory reactants, serum amyloid A (SAA) and C reactive protein (CRP), show diffuse cytoplasmic expression of both SAA and CRP. Immunostain for L-FABP shows retained cytoplasmic expression in tumoral hepatocytes (Figure 3). IHCA with β-catenin mutations show nuclear expression of β-catenin on immunohistochemical staining. Glutamine synthetase is a surrogate marker of β-catenin mutation.[33] Some IHCAs with β-catenin mutations maybe positive or negative for nuclear β-catenin expression on immunostaining, but will show strong diffuse/patchy cytoplasmic staining for glutamine synthetase.[34] These β-catenin mutations may occur on exon 3 or exon 7/8.[1,23]

Figure 3.

Inflammatory hepatocellular adenoma. Immunostain for L-fatty acid binding protein with retained cytoplasmic expression in tumor. X100.

Inflammatory HAs show mild to moderate hyperintense signal on T2WI and are iso-intense or mildly hyperintense on T1WI with no significant signal drop-off with chemical shift imaging.[32] After administration of extracellular gadolinium-based contrast material, IHAs usually show intense enhancement during the arterial phase, with persistent enhancement in the portal venous and delayed phases. IHAs may show uptake of hepatobiliary specific gadolinium agent and may show peripheral rim like uptake or heterogeneous internal retention of contrast on the hepatobiliary phase.[32,35] (Figure 4). Inflammatory HAs show the highest risk of bleeding due to the presence of sinusoidal dilatation, which can occur in about 30% of these tumors and particularly seen in tumors larger than 5 cm maximum dimension and subcapsular tumors (Figure 5). About 10% of inflammatory HAs show an increased risk of malignancy.[10,18,19]

Figure 4.

Large inflammatory hepatocellular adenoma (IHA) in a 30-year-old woman along with associated focal nodular hyperplasia (FNH). (A) Moderately heterogeneous, mildly hyperintense lesion (IHA) is seen in the right lobe on a T2-weighted image (red arrow). Incidental iso-intense lesion (FNH) with a central scar (blue arrow). In-phase (B) and out-of-phase (C) images demonstrate no signal loss within the both lesions. Arterial (D) and portal venous phase (E) post gadoxetic acid images show marked heterogeneous hyperenhancement of the adenoma (IHA) (red arrow) and moderate enhancement of the FNH with a central scar ( blue arrow). Hepatobiliary phase image (F) reveals the lateral lesion (IHA) with mild and heterogeneous retention of contrast (red arrow) and intense uptake within the medial lesion (FNH).

Figure 5.

Ruptured inflammatory hepatocellular adenoma in a 25-year-old woman presenting with acute right upper quadrant pain and hypovolemic shock. Precontrast (A) and arterial phase (B) MR images show a focal lesion involving the right lobe of the liver. On the pre-contrast image, the lesion is heterogeneously hyperintense (red arrow in A), with associated blood products (blue arrow in A) in the perihepatic space, a finding consistent with rupture. The mass shows heterogeneous enhancement during the arterial phase (red arrows in B). In addition, in the arterial phase, the left hepatic lobe has an enhancing focal lesion (green arrow in B), a finding consistent with a second adenoma.

β-catenin Activated Hepatocellular Adenoma (BHA). These adenomas comprise about 20% of all HAs.[8] Wnt/β-catenin pathway is involved in hepatocellular development and zonation. In normal, non-neoplastic hepatocytes, activation of β-catenin protein is transient followed by degradation. Mutations of β-catenin gene (CTNNB1 gene) lead to production of mutant protein that has prolonged half-life and is resistant to degradation.[36] In 10% of cases, there are deletions CTNNB1 exon 3 leading to decrease in β-catenin degradation.[1,23] In other cases, there are point mutations targeting hotspots in exon 3 or those in exon 7/8.[4,9]

Gross characteristics of β-catenin mutated HA are unremarkable. They may present as well-demarcated tumors with fleshy cut surface. Histologically, they lack a distinctive morphology. They are composed of sheets of hepatocytes with interspersed unpaired arteries. Some may show cytologic and architectural atypia characterized by pseudoacinar formation. Steatosis is not a typical feature. Immunostain for beta-catenin will show nuclear beta-catenin staining, however, this can be very focal in distribution. Glutamine synthetase is a surrogate marker for β-catenin mutation. Immunostain for glutamine synthetase shows strong diffuse cytoplasmic staining, however, the staining can be heterogeneous and variable.[23]

No specific imaging findings have been reported to diagnose β-catenin–mutated hepatocellular adenomas on imaging. T1 and T2 signal of these tumors is variable depending on the presence of hemorrhage and/or necrosis.[10,18,19] β-catenin–mutated HAs commonly demonstrate strong arterial enhancement with portal venous washout and no uptake on hepatobiliary phase (Figure 6). The risk of hepatocellular carcinoma is about 5%–10% in these HAs. β-catenin–mutated HAs carry the highest risk of malignancy.[10,18,19]

Figure 6.

β-catenin–mutated hepatocellular adenoma in a 35-year-old woman. Arterial phase post-gadobenate dimeglumine image (A) shows heterogeneous hyperenhancement of the lesion. The mass (red arrow) shows uniform hypoenhancement relative to adjacent liver on a hepatobiliary phase image (B) obtained 20 min following gadobenate dimeglumine injection. In addition, in the hepatobiliary phase, the right hepatic lobe has another hypoenhancing focal lesion (blue arrow in B), a finding consistent with a second adenoma.

Hepatocellular Adenoma Unclassified. Unclassified HA constitutes 10% of all HAs and these tumors do not show any specific genetic abnormalities. No specific MR imaging findings are reported to identify unclassified HAs.[10,18,19]