Hepatocellular Adenoma Workup

• Serologically, hepatocellular adenomas are a diagnosis of exclusion. No specific serologic studies exist.
• Serum aminotransferase (aspartate aminotransferase [AST]/alanine aminotransferase [ALT]) levels are mildly elevated in approximately 50% of patients, likely due to the mass effect of the tumor.
• Serum alpha-fetoprotein (AFP) levels are within the reference range in patients with hepatocellular adenoma. Elevations are noted in 50% of hepatocellular carcinoma (HCC) cases. Thus, finding an elevated AFP represents either a primary carcinoma or an adenoma that has undergone malignant transformation. An AFP level within the reference range does not eliminate HCC from the differential diagnosis.
• Elevated carcinoembryonic antigen (CEA) levels suggest metastasis from the colon.
• Serologies for amebiasis and echinococcus should be considered if the lesion appears cystic.

• Findings on imaging studies in cases of hepatocellular adenomas generally are nondiagnostic because the mass often is solitary and well demarcated. Distinguishing characteristics generally are absent. Ultrasound and CT imaging are more specific if intralesional hemorrhage is noted.
• Ultrasound

  • A nonspecific finding reveals a hypoechoic lesion, which usually is subcapsular (7% pedunculated), well circumscribed, ranges from 2-20 cm, and is located predominantly in the right lobe of the liver.
  • Doppler flow patterns in hepatocellular adenomas are venous, as compared to the arterial pattern noted in FNH.
• Computed tomography imaging

  • A nonspecific, well-circumscribed mass that has a low density on noncontrast and a marked centripetal pattern of enhancement on arterial phase
  • The lesion can have a central necrotic area or calcifications.
  • Most adenomas are encapsulated on CT scan.
• Magnetic resonance imaging (MRI)

  • Variable appearance due to the presence or absence of hemorrhage
  • Hyperintense heterogeneous signals on T1- and T2-weighted imaging often due to lipids contained within the lesion^[17]
  • Hemorrhagic hepatocellular adenomas may also have hyperintense T1 imaging with subcapsular hemosiderin rings in 30% of patients.
  • Kupffer cell–specific MRI agents (superparamagnetic iron oxides [SPIO] and ultrasmall superparamagnetic iron oxides [USPIO]) can be administered during the scan. They show no uptake due to a lack of endothelial-reticular cells.
  • Manganese–dipyridoxal diphosphate (DPDP), gadolinium, or gadobenate dimeglumine (Gd-BOPTA) can be administered during the scan. These show strong uptake due to the presence of hepatocytes. MRI with contrast can differentiate hepatocellular adenoma from FNH in 70% of cases.^[18]
  • Unfortunately, HCC also has a predominance of hepatocytes, which makes these agents unable to differentiate between hepatocellular adenomas and HCC.
• Nuclear scans

  • Hepatocellular adenomas appear as cold nodules on technetium-99m (^99m Tc) sulfur colloid scans, which distinguishes them from FNH, which typically shows normal or increased colloid uptake.
  • This is due to the altered blood flow through the lesions and the lack of phagocytic activity of Kupffer cells.
• Arteriography

  • This imaging modality is rarely performed and has been substituted by CT or MR angiography in most centers.
  • Well-defined, round or ovoid, hypervascular mass with hepatic arterial branches entering from the periphery
  • Vessels within the mass are tortuous and of varying calibers with flow moving centrally from the periphery.
  • Avascular areas and intralesional hematomas are indicators of hepatocellular adenomas.

Although hepatocellular adenomas may transform into HCC, the AFP is an insensitive test for HCC screening, yet few other tests are available. Zucman-Rossi et al classified 96 hepatocellular adenomas by sequencing the genes coding for hepatocyte nuclear factor-1 alpha (HNF1 alpha) and beta-catenin.^[19] The investigators reported that HCC is found in 46% of beta-catenin-mutated tumors, whereas they are rarely found in HNF1 alpha tumors or tumors which lack beta-catenin or HNF1 alpha.

Tumor cell expression patterns of E-cadherin and matrix metalloproteinases -1,-2,-7 and -9 were studied in a variety of liver tumors and controls by Tretiakova et al.^[20] The investigators reported that hepatocellular adenoma was characterized by an absence of matrix metalloproteinase-7 expression, whereas HCC without cirrhosis had low metalloproteinase-9 expression.

Glycipan-3 (GPC3) is a cell surface glycoprotein recently to be overexpressed in HCCs. Wang reported that GPC3 staining was not present in all 110 cases of benign liver tumors in their study, yet the staining was positive in 75.7% of HCCs.^[21]

Agrin is a proteoglycan component of bile duct and vascular basement membranes of the liver and is deposited in microscopic blood vessels of HCC. Tatrai et al reported that the combination of immunohistochemical staining for agrin and CD34 was helpful for differentiating HCC from benign lesions when the diagnosis was equivocal.^[22] In addition, agrin appeared to be more sensitive than GPC-3, as agrin is diffusely deposited in all malignant lesions, whereas GPC-3 may only be present in a few cells.

Ahmad reported that a combination of cytokeratin 7 and 9 with neuronal cell adhesion molecule immunostains were very helpful for differentiating normal liver tissue from tumors and also for differentiating hepatocellular adenomas from FNH.^[23]

• Results of histologic evaluation with a liver biopsy are nondiagnostic and insensitive because the mass is comprised of normal-appearing hepatocytes.
• Resection and evaluation may be required as the most specific way to confirm diagnosis.

Upon gross examination, hepatocellular adenomas appear as sharply circumscribed, light brown to yellow tumors that are soft in consistency and are often encapsulated. Although these lesions are usually solitary, hepatocellular adenomas may be multiple, with sizes ranging from 1 to 30 cm, although most are between 8 and 15 cm. Adenomas tend to be larger in women on OCPs. They also occur more frequently in the right lobe and are usually subcapsular, although pedunculated adenomas have also been described.

In a microscopic examination, the hallmark of adenomas is the normal appearance of the hepatocytes. These are arranged in sheets and have no malignant features. These cells tend to be larger than normal hepatocytes, and their cytoplasm often contains fat or glycogen. (Their cytoplasm may appear relatively pale due to abundant glycogen stores when compared with normal hepatocytes). Generally, few, if any, portal tracts are present, and no central veins or bile ducts should be present.^[24] However, Bisceglia et al reported that subtypes of HAs may have CK7 positive ductules and are called hepatocellular adenoma with ductal/ductular differentiation.^[25]

Peliosis hepatis may occasionally be seen, and Kupffer cells are reduced in number or absent.^[26] Vessels, when observed, tend to have thickened walls. Areas of thrombosis and infarction may be observed. Most hepatocellular adenomas contain a variable degree of microscopic collections of fat. Differentiation from a high-grade HCC can be difficult, if not impossible. Adenomas tend to lack malignant-appearing mitotic structures, the cell plates are generally only 2 cells thick, and no cellular infiltration (invasion) into the capsule or surrounding liver parenchyma occurs. Unfortunately, these features may also be absent in HCC, especially if it is well differentiated.

Hypervascularity is present upon the surface of the lesion. Because adenomas contain no portal vein branches, their blood supply is entirely arterial. The tendency for these lesions to bleed may be related to poor connective tissue support and their increased vasculature, which is made up of thin-walled, dilated sinusoids carrying blood at arterial pressure.