Laboratory Studies
Serologically, hepatocellular adenomas (HCAs) (hepatic adenomas) are a diagnosis of exclusion. No specific serologic studies exist.
Abnormal liver function tests, especially elevations in γ-glutamyl transferase and alkaline phosphatase are seen, likely due to mass effect of the tumor. [41]
Inflammatory syndrome, which can be characterized by serum elevations in C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), white blood cells (WBCs), or others, may be seen predominantly in the inflammatory subtype (I-HCA). [41, 64]
Serum alpha-fetoprotein (AFP) levels are within the reference range in patients with hepatic adenoma. Elevations of AFP should prompt consideration of either a primary hepatocellular carcinoma (HCC) or an adenoma that has undergone malignant transformation. [2] However, an AFP level within the reference range does not eliminate HCC from the differential diagnosis.
Elevated serum carcinoembryonic antigen (CEA) levels suggest metastasis from the colon.
Serologies for amebiasis and echinococcosis should be considered if the lesion appears cystic or there is clinical concern for these diseases.
Imaging Studies
Findings of hepatocellular adenomas (HCAs) (hepatic adenomas) on imaging studies have been difficult to characterize due to their heterogeneous nature. Advances in contrast-enhanced magnetic resonance imaging (MRI) have made imaging studies more prominent in the diagnosis of HCAs, with regard both to specific subtypes and differentiation from focal nodular hyperplasia (FNH). Utilization of imaging techniques have reduced the need for patients to undergo biopsy and the subsequent associated risks. [65, 66]
Ultrasonography
The ultrasonographic appearance of hepatic adenoma is nonspecific and generally requires further investigation. The tumors can appear well demarcated if hyperechoic in the presence of steatosis; HCAs will appear anechoic if intralesional hemorrhage is present. [65] Doppler flow patterns in HCAs show peripheral vessels and venous flow in most cases, as compared with the "spoked-wheel" arterial pattern noted in FNH. [67]
Contrast-enhanced ultrasonography (CEUS)
CEUS involves using a microbubble contrast medium that reveals rapid arterial enhancement progressing from the periphery to the center of the tumor, which correlates with the presence of higher concentrations of multiple, thin arteries in the periphery of HCA. [68, 69, 70, 71, 72] This finding is in contrast to the findings in FNH, which typically show hyperperfusion from a large feeding artery in the arterial phase from the center outward, producing a "spoked-wheel" appearance. [70] Hepatic adeomas can have a gradual washout phenomenon due to missing portal veins in the late phase; for this reason, HCA enhancement patterns can be confused with malignancy. [68, 71] The reported sensitivity in differentiating HCA from FNA with CEUS ranges from 86% to 95%, with a specificity of 74-79%. [73]
Computed tomography (CT) scanning
On noncontrast CT scans, HCA appears as a well-demarcated mass with low density and no lobulation. [74] On contrast-enhanced, multiphase, CT images, the tumor shows an early peripheral enhancement with a centripetal pattern during the portal venous phase. It then fades to isodensity in the portal or delayed phase. Rarely, the lesion can have a central necrotic area or calcifications. [65, 74, 75]
Magnetic resonance imaging (MRI)
The MRI appearance of hepatic adenoma is variable, owing to the presence or absence of hemorrhage. Hyperintense heterogeneous signals on T1- and T2-weighted imaging are often due to HCAs containing intratumoral lipids, which differentiates HCA from FNH. [76, 77] Hemorrhagic HCAs may also have hyperintense T1 imaging with subcapsular hemosiderin rings. [66]
Specific MRI contrast agents can be administered to further characterize HCAs. Administration of Kupffer cell–specific MRI agents (superparamagnetic iron oxides [SPIOs] and ultra-small superparamagnetic iron oxides [USPIOs]) typically show no uptake due to a lack of endothelial-reticular cells, resulting in decreased T2 signal intensity. [75] Gadolinium-enhanced dynamic gradient-echo MRI may display early arterial enhancement, resulting in visualization of the peritumoral vessels characteristic of HCA. [78]
A prospective study showed administration of gadoxetate disodium in a standard series combined with hepatobiliary phases helped to differentiate HCA from FNA in lesions larger than 2 cm. [66] Both gadobenate dimeglumine and gadoxetic acid are also liver-specific contrast agents; when utilized in the hepatobiliary phase, these agents have shown equivalent efficacy in differentiating HCA from FNH, [79] although a 2019 study has shown the possible superiority of gadoxetic acid. [80] Additionally, gadoxetic acid-enhanced MRI (EOB-MRI) has been found to be most cost effective in a 2018 study, although there was similar effectiveness among the EOB-MRI, conventional MRI, and biopsy strategies in patients with incidentally detected liver lesions in a noncirrhotic liver. [81]
MRI can also be helpful in differentiating specific subtypes of HCA, which improves their clinical characterization and follow-up without the need for biopsy. [1, 65, 76] However, newer discoveries of further subtype classifications has complicated MRI usefulness in differentiation. [41, 20] Any inconclusive imaging should be considered for biopsy, with an informed discussion with the patient of the risks involved. [65]
In HCA inactivated for hepatocyte nuclear factor 1α (H-HCA), typical findings on MRI include loss of signal on chemical shift as well as moderate arterial enhancement without persistent enhancement in the delayed phase. In a study by Laumonier et al, oss of chemical shift in H-HCA, which is associated with the presence of steatosis, had a sensitivity of 86.7% and specificity of 100%. [76]
In inflammatory hepatic adenomas (I-HCA), typical findings on MRI include a markedly hyperintense appearance on T2-weighted images, with a strong peripheral signal as well as persistent enhancement in delayed phase. If both findings are present, Laumonier et al found a sensitivity of 85.2% and specificity of 87.5%. [76] Ba-Ssalamah et al reported that use of gadoxetic acid resulted in lower sensitivity (80.9%) and specificity (77.3%). [82]
In β-catenin activated HCA (β-HCA), the MRI findings depend on the subtype. The inflammatory subtype of β-HCA has the same appearance as I-HCA. For noninflammatory β-HCA, typical MRI findings show a heterogeneous appearance in all sequences, no signal dropout on chemical shift, isointense appearance on T1- and T2-weighted images, and strong arterial enhancement and delayed washout. [76] Note that newly developed subtypes of β-HCA may not be able to be differentiated from each other and HCC with imaging alone, therefore a high index of suspicion is required. [20, 82]
Nuclear scans
Nuclear scans are rarely diagnostic for hepatic adenomas; however, when performed, HCAs have decreased colloid uptake and thus appear as cold nodules on technetium-99m (99mTc) sulfur colloid scans. This distinguishes them from FNH, which typically shows normal or increased colloid uptake. Decreased uptake in HCA is due to the altered blood flow through the lesions and the lack of phagocytic activity of Kupffer cells. [75, 83]
Other Tests
Although subtyping of hepatocellular adenoma (HCA) (hepatic adenoma) has not resulted in significant clinical management changes and imaging shows promise for noninvasive characterization, in the setting of indeterminate results or concern for malignancy, it is reasonable to perform biopsy. [20]
Initial differentiation from the surrounding hepatocytes can be accomplished with the use of CD34, which shows increased sinusoidal staining in both benign and malignant hepatocellular tumors. [84]
Immunohistochemistry
Immunoexpression of liver-type fatty acid binding protein (L-FABP) is reduced in HCA inactivated for hepatocyte nuclear factor 1α (H-HCA), but it will be present in the surrounding hepatocytes, helping to differentiate this subtype from other HCA subtypes as well as from the surrounding hepatic tissue. [85] H-HCA also shows negative staining for glutamine synthetase (GS), serum amyloid A (SAA), and C-reactive protein (CRP). [27]
A heterogeneous staining pattern of β-catenin in the nucleus and cytoplasm is a defining feature of β-catenin activated HCA (β-HCA). [27] GS, an enzyme involved in nitrogen metabolism, is also useful in differentiating β-HCA from other hepatic adeoma subtypes and focal nodular hyperplasia (FNH). [27] FNH has a maplike distribution that is distant from fibrous bands or arteries, whereas β-HCAs have a more diffuse, strong staining pattern. [86, 87] Relatively recent studies have shown the strongest GS positivity to be found in CTNNB1 mutations in exon 3. [41]
Immunoexpression of the acute phase reactants SAA and CRP are defining features of inflammatory adenoma (I-HCA), [41] differentiating it from other subtypes as well as surrounding hepatocytes. Notably, L-FABP expression is increased and GS is usually not expressed. [27] The finding of elevated GS and/or heterogeneous β-catenin should raise suspicion for mixed I-HCA and β-HCA. [27, 41]
Differentiation from hepatocellular carcinoma (HCC)
Differentiation of HCC from HCA is extremely important, especially in β-HCA, where HCC transformation is a known complication. [88] Generally, HCC demonstrates a loss of the reticulin framework on reticulin staining, whereas HCA and FNH maintain an intact reticulin network. [89] Glycipan-3 (GPC3) is a cell surface glycoprotein that is overexpressed in HCCs. Wang et al 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. [90] Lagana et al demonstrated GPC3 positivity had a sensitivity of 43% and specificity of 100% when differentiating low-grade, well-differentiated HCC from HCA. [91] Similarly, diffuse nuclear heat-shock protein-70 (HSP-70) staining has shown a 46% sensitivity and 100% specificity when differentiating low-grade, well-differentiated HCC from HCA. [91]
Tretiakova et al assessed tumor cell expression patterns of E-cadherin and matrix metalloproteinases (MMPs)-1,-2,-7 and -9 in a variety of liver tumors and controls, reporting that HCA was characterized by an absence of MMP-7 expression, whereas HCC without cirrhosis had low MMP-9 expression. [92]
Agrin is a proteoglycan component of bile duct and vascular basement membranes of the liver that 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. [93] 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 et al reported that a combination of cytokeratin 7 and 9 with neuronal cell adhesion molecule immunostains were very helpful not only in differentiating normal liver tissue from tumors but also in differentiating hepatic adenomas from FNH. [94]
Procedures
Results of histologic evaluation with a fine needle biopsy are nondiagnostic and insensitive for hepatocelllular adenoma (HCA) (hepatic adenoma) because the mass comprises normal-appearing hepatocytes. [95] Core needle biopsies, especially when combined with immunohistochemistry, can be considered in cases of nondiagnostic imaging or concern for malignancy. [95] Additionally, indeterminant lesions on imaging do not warrant empiric ablation without confirmation of the diagnosis; core biopsy should be considered in these cases. [20]
In a retrospective review (2000-2013) of patients undergoing hepatic mass biopsy revealing HCA, Doolittle et al investigated the safety and outcomes of biopsy of these lesions. [96] Of 60 identified patients with a total of 61 biopsy-proven hepatic adenomas, they found that one patient (2%) had a single major complication and six patients (10%) had a minor complication. In addition, there were six (10%) discordant biopsy results. [96]
Complete resection of HCA or suspected HCA remains the gold standard of diagnosis, but it is not always required for lesions smaller than 5 cm or those not increasing in size. [20]
Histologic Findings
Upon gross examination, hepatocellular adenomas (HCAs) (hepatic adenomas) appear as sharply circumscribed, light brown to yellow tumors that are soft in consistency and often lack a true fibrous tumor capsule. [97] Although these lesions are usually solitary, HCAs may be multiple, with sizes ranging from 1 to 30 cm, although most are between 8 and 15 cm. Hepatic adenomas tend to be larger in women taking oral contraceptive pills (OCPs). They also occur more frequently in the right lobe and are usually subcapsular, although pedunculated adenomas have also been described. [2]
On microscopic examination, the hallmark of adenomas is the normal appearance of the hepatocytes. These are arranged in sheets, have no malignant features, tend to be larger than normal hepatocytes. Their cytoplasm often contains fat or glycogen and thus 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. [27, 98] However, Bisceglia et al reported that subtypes of HCAs may have cytokeratin 7-positive ductules; they called hepatic adenoma with ductal/ductular differentiation. [99]
Peliosis hepatis (rare vascular condition with multiple blood-filled cavities scattered throughout the liver) may occasionally be seen and this is most often associated with the β-catenin activated HCA (β-HCA) and inflammatory adenoma (I-HCA) subtype (previously known as telangiectatic focal nodular hyperplasia [FNH]). [32, 100] Vessels, when observed, tend to have thickened walls. Areas of thrombosis and infarction may be noted. Most hepatic adenomas contain a variable degree of microscopic collections of fat. [101] Differentiation from a high-grade hepatocellular carcinoma (HCC) can be difficult, if not impossible. Hepatic adenomas tend to lack malignant-appearing mitotic structures, the cell plates are generally only two cells thick, and no cellular infiltration (invasion) into the capsule or surrounding liver parenchyma occurs. Unfortunately, these features may also be seen in HCC, especially if it is well differentiated. [102]
Hypervascularity is present upon the surface of the lesion. Because hepatic 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. [27]
