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Main Subtypes of Hepatocellular Adenomas 

Hepatocellular adenomas are rare benign liver neoplasm with specific but varied morphological features and tumor biology. Typically, they are present as nodule or mass composed of hepatocytes in sheets with well preserved reticulin network and devoid of portal triads. Recent molecular genetic discoveries segregate them into four distinct genetic and pathologic subtypes: (a) inflammatory hepatocellular adenomas, (b) hepatocyte nuclear factor 1 á–mutated hepatocellular adenomas, and (c) â-catenin–mutated hepatocellular adenomas. In addition, less than 10% of hepatocellular adenomas cannot be classified. Different subtypes show different morphological features, biological behaviors, and thus variable clinical outcome.  As the results, the clinical management and surveillance may vary accordingly. Although this classification is new and is not widely accepted, it has definitive diagnostic and management implications.

Inflammatory Hepatocellular Adenoma

This is the most common subtype, constituting 40%–50% of all hepatocellular adenomas. Sustained activation of the JAK-STAT pathway, with resultant hepatocellular proliferation, is the proposed pathogenesis in the development of inflammatory hepatocellular adenomas. Aberrant function of glycoprotein 130 encoded by the interleukin-6 signal transducer gene (IL6ST) is the upstream event leading to the sustained activation of JAK-STAT signaling.  In addition, the chemokine CCL20 is also overexpressed in these tumors, responsible for the recruitment of polymorphous inflammatory cells within the tumors.

Inflammatory hepatocellular adenomas occur most frequently in young women with a history of oral contraceptive usage and in obese patients. Patients may present with “systemic inflammatory syndrome,” characterized by fever, leukocytosis, and elevated serum levels of C-reactive protein. Abnormal liver function tests may also be present. On MRI, inflammatory hepatocellular adenomas are diffusely hyper-intense on T2-weighted images, with higher signal intensity in the periphery, correlating with dilated sinusoids. On T1-weighted images, they are iso-intense or mildly hyper-intense, with minimal or no signal drop-off with chemical shift sequences. These patterns are reported to have a sensitivity of 85% and a specificity of 87% for the diagnosis.

The cut surface of inflammatory hepatocellular adenomas is heterogeneous with areas of congestion and hemorrhage. Microscopically, intense polymorphous inflammatory infiltrates, marked sinusoidal dilatation or congestion often with peliosis hepatic or frank hemorrhage, and thick-walled arteries are features of this subtype. Acute phase inflammatory markers such as serum amyloid A and C-reactive protein are detected in the patients with this inflammatory subtype.

About 30% of inflammatory hepatocellular adenomas have intratumoral hemorrhage, the highest risk of bleeding among all subtypes.  About 10% may undergo malignant transformation.

HNF-1á–mutated Hepatocellular Adenoma

This is the second most common subtype and constitutes about 30%–40% of all hepatocellular adenomas.  Bi-allelic inactivating mutations of the HNF-1á gene (HNF1A) are believed to be the underlying mechanism.  HNF-1á protein is a transcription factor involved in regulating hepatocellular differentiation and fat metablism. Some cases are also associated with the so called maturity-onset diabetes of the young (MODY).  Liver adenomatosis (adenomas >10) is most often found in this subtype.  The HNF-1á–mutated subtype develops exclusively in woman. More than 90% of patients have a history of oral contraceptive use. Many are asymptomatic and are identified incidentally during imaging studies performed for other reasons, such as trauma or nonspecific abdominal pain.

On MRI, HNF-1á–mutated subtype is predominantly hyper- or iso-intense on T1-weighted images, with diffuse signal drop-off with use of a chemical shift sequence because of steatosis.  They are iso-intense to slightly hyper-intense on T2-weighted images. The sensitivity and specificity of homogeneous signal drop-off on chemical shift images for the diagnosis of this subtype were as high as 86% and 100%, respectively.

HNF-1á–mutated hepatocellular adenomas are multiple in about 50% of patients. Grossly, the tumor nodules are lighter-brown or yellow than adjacent non-neoplastic liver parenchyma.  Microscopically, they are characterized by diffuse prominent steatosis.  Grade 2 and 3 steatosis are found in 27% and 36% of this subtype, respectively.  Sinusoidal congestion or dilatation is rare. Cytological atypia is minimal. This subtype typically lacks liver fatty acid–binding protein (L-FABP) by immunohistochemistry.

Among all hepatocellular adenomas, the HNF-1á–mutated hepatocellular adenomas are the least aggressive subtype: Tumors less than 5 cm in maximum dimension show minimal risk of bleeding and subsequent rupture and carry minimal or no risk for the development of malignancy.

â-Catenin–mutated Hepatocellular Adenoma

The â-Catenin–mutated subtype constitutes about 10%–15% of all hepatocellular adenomas and is due to activating mutations of the â-catenin gene. â-Catenin is an important downstream effector of the Wnt/â-catenin pathway. Sustained activation of â-catenin protein results in uncontrolled hepatocyte proliferation.  The adenomatous polyposis coli (APC) gene is also involved in â-Catenin metabolism.  â-Catenin–mutated hepatocellular adenomas occur more frequently in men and are associated with male hormone administration, glycogen storage disease, and familial adenomatosis polyposis. The tumors exhibit no diagnostic patterns in other imaging studies.

â-catenin–mutated subtype tends to show cytological atypia, such as a high nuclear-cytoplasmic ratio, nuclear atypia, and formation of acini, and is difficult to distinguish from the hepatocytes of well-differentiated hepatocellular carcinomas. The tumor cells of â-catenin–mutated subtype show heterogeneous aberrant nuclear and cytoplasmic distribution of â-catenin and an increased expression of glutamine synthetase encoded by glutamate-ammonia ligase gene (GLUL), a â-catenin–targeted gene. A strong and diffuse homogeneous positive immunostain for glutamine synthetase is a characteristic finding. In contrast, a ‘map-like’ staining pattern of glutamine synthetase is seen in focal nodular hyperplasia (FNH).

Of all hepatocellular adenomas, â-catenin–mutated subtype carries the highest risk of malignant transformation, overall 5 – 6%.  Hepatocellular carcinomas may develop either as a macroscopic solitary nodule or as multiple microscopic foci.  The Wnt/â-catenin pathway involved in the pathogenesis of this subtype is also a major player in the development of hepatocellular carcinoma.  Approximately 35% of hepatocellular carcinomas show â-catenin mutations. This finding explains the high incidence of malignant transformation of â-catenin–mutated hepatocellular adenomas compared with the incidence of other subtypes. One study also showed that the presence of malignancy in hepatocellular adenoma is 10 times more frequent in men than in women (47% in men vs. 4% in women). 

It is important to realize that there is overlap of the molecular events and phenotypic features of these subtypes in some tumors, limiting the role of this classification in guiding clinical management. Overall, the important risk factors for malignant transformation of hepatocellular adenomas are male sex, concomitant glycogen storage disease, anabolic steroid usage, the â-catenin–mutated subtype, and tumors larger than 5 cm in greatest dimension.

Suggested Readings / References

J. Zucman-Rossi, et al.: Genotype–phenotype correlation in hepatocellular adenoma: New classification and relationship with HCC. Hepatology. 43(3): 515–524, 2006

P. Bioulac-Sage, et al.: Hepatocellular adenoma management and phenotypic classification: the Bordeaux experience. Hepatology 50(2):481-489, 2009.

P. Bioulac-Sage, et al.: Subtype classification of hepatocellular adenoma. Dig Surg  27(1):39–45, 2010.

V.S. Katabathin,a et al.: Genetics and Imaging of Hepatocellular Adenomas: 2011 Update.    RadioGraphics 31:1529-1543, 2011.

S. M. van Aalten, et al.: Hepatocellular adenoma ‘A new perspective’ (a doctoral thesis). Erasmus Universiteit Rotterdam, The Netherlands. 2012.