Hepatocellular adenomas (HCAs) are also known as hepatic adenomas or liver cell adenomas. They are rare, benign tumors of presumable epithelial origin and occur in less than 0.004% of the population at risk.
Causes of hepatocellular adenoma include oral contraceptive medications containing mestranol as well as anabolic steroids. Thus, hepatocellular adenomas occur mostly in women of childbearing age and are strongly associated with the use of oral contraceptive pills (OCPs) and other estrogens. This is reflected by a dramatic increase in the incidence of this disease since OCPs were introduced in the 1960s. For example, before the use of OCPs, no hepatic adenomas were reported at surgery at the Mayo Clinic between 1907 and 1954. Edmonson reported finding only 2 adenomas among 50,000 autopsy specimens at Los Angeles County Hospital between 1907 and 1958.[1] However, in women using OCPs, adenomas were more common in patients taking OCPs containing higher doses of estrogen and with prolonged use (73.4 mo) when compared with matched controls (36.2 mo) (P< 0.001).[2]
In a case series of 3 patients, Baum et al also suggested an association between hepatic adenomas and OCPs.[3] Klatskin[4] and Rooks et al[5] reported that the greatest risk occurs in women older than age 30 years taking OCPs for longer than 5 years, but in 10% of patients, exposure may be as short as 6-12 months. Cherqui et al also reported that adenomas are occasionally diagnosed after discontinuation of OCPs.[6]
Decreases in dosages and the types of hormones contained in OCPs have led to a reduction in adenoma incidence, as reported by another study by Edmonson et al.[7] Rooks et al reported that in women who have never used OCPs, the annual incidence of hepatic adenoma is 1 to 1.3 per million but increases to 3.4 per 100,000 in long-term users.[5] Currently, benign liver tumors may be detected more frequently though, owing to increased routine use of medical imaging.
Hepatic adenomas may be single or multiple, and they may occasionally reach a size larger than 20 cm. In addition to OCPs, other conditions associated with adenomas are anabolic steroids, androgenic steroids, beta-thalassemia, tyrosinemia, type 1 diabetes mellitus, hemochromatosis, barbiturate usage, clomiphene intake, and glycogen storage diseases (GSDs) (types 1 and 3). However, multiple hepatic adenomas are more common in glycogen storage disease, with an incidence between 22% and 75% in type 1 and 25% in type 3 disease.[8]
In addition to a multiplicity of adenomas, hepatic adenomas associated with GSD tend to occur more commonly in men than women (ratio 2:1) and often develop before the age of 20 years.[9, 10] This should not be confused with hepatic adenomatosis, which is an equally uncommon condition in which at least 10 lesions develop at equal frequency in either sex in the absence of the classic risk factors such as OCP or GSD.[11]
A new, not yet universally accepted, Bordeaux classification of hepatocelluar adenoma is currently being evaluated. This subclassification includes hepatocyte nuclear factor 1α-inactivated HCA (HNF1α HCA 30-35%), β-catenin-mutated HCA (β-cat HCA 10-15%), inflammatory HCA (50%), and a subgroup of less than 10% that remains unclassified.[12]
This classification may be important because the β-catenin mutation appears to be related to hepatocellular carcinoma.[13, 14, 15] A small study suggests that being overweight or obese may cause an increase in inflammatory HCA and β-catenin activated-inflammatory HCA subgroups.[16]
Telangiectatic adenoma is a recently recognized variant of HCA formerly classified as a type of focal nodular hyperplasia. This is in the subcategory of inflammatory hepatocellular adenomas.[12]
Hepatic adenomas consist of sheets of hepatocytes without bile ducts or portal areas. Kupffer cells, if present, are reduced in number and are nonfunctional. Hepatic adenomas are tan in color, smooth, well circumscribed, fleshy in appearance, and vary from 1 to 30 cm in size. They have large blood vessels on the surface, and the lesions may outgrow their arterial blood supply, causing necrosis within the lesions. A fibrous capsule may be present or absent; if absent, this may predispose to intrahepatic or extrahepatic hemorrhage. Most adenomas present as solitary lesions in the right lobe of the liver; however, tumors do occur in both the right lobe and the left lobe, and up to 20% of cases have multiple lesions.
The pathogenesis is thought to be related to a generalized vascular ectasia that develops due to exposure of the vasculature of the liver to oral contraceptives and related synthetic steroids. Estrogen may exert an influence via estrogen receptors in the cytoplasm or nucleus of hepatocytes. However, this remains controversial as adenomas can occur in males and children without predisposing risk factors, and these receptors have not been identified even with the use of monoclonal antibodies.[17] Rebouissou et al[18] and Bioulac-Sage et al[13, 19] also reported that hepatic adenomas are monoclonal tumors and probably develop from an interaction between gene defects and environmental changes such as OCPs and steatosis. HCAs are now believed to result from specific genetic mutations involving transcription factor 1 gene (TCF1), interleukin 6 signal transducer gene (IL6ST), and β catenin-1 gene (CTNNB1).[20]
Adenomas have also been associated with diabetes mellitus and GSD, leading to speculation as to whether imbalances between insulin and glucagon also play a role. Patients with GSD are more likely to present with multiple lesions. Lesions associated with GSD often appear in younger patients (early third decade of life) and have a male-to-female ratio of 2:1. In this group, the abnormal amounts of stored glycogen may have some effect, perhaps by oncogene stimulation.
Insulin and glucagon appear to play a larger role, because GSD-related adenomas have been reported to seemingly disappear with dietary manipulation. A germline mutation of the hepatocyte nuclear factor (HNFα) was described by Reznik et al in 2 families that had both diabetes mellitus and liver adenomatosis.[21] Tumor cell analysis showed biallelic inactivation of HNFα. Micro/small HNF1α-inactivated hepatocellular adenoma have also been found incidentally in pathological liver resected specimens.[22]
Hepatocellular adenomas are extremely rare. The annual incidence is 1 to 1.3 cases per 1 million persons per year. However, 3-4 cases per 100,000 people per year occur among women who have had exposure to estrogen-containing OCPs. A 5-fold increased risk exists with 5-7 years of OCP exposure, and a 25-fold increased risk exists with longer than 9 years of OCP exposure.
No racial predisposition exists, but a large review of HCA from 1998 to 2008 comparing data from China, Europe, North America, and South-East Asia found a male predominance of HCA in the Chinese population, which is in contrast to the female predominance everywhere else. This has been speculated to be due to the birth control policy in China and limited use of oral contraceptives.[23]
Approximately 90% of patients are female.
Most patients are aged 15-45 years.
Complete resolution of hepatocellular adenoma is atypical.
The risk of malignant transformation exists and is as high as 8-13% in previous studies, but a recent systematic review revealed a risk of malignant transformation of 4.2%.[24]
The risk of malignant transformation remains even after contraceptive or steroid use has been discontinued.
Nearly 20-25% of cases have right upper quadrant pain, and 30-40% experience hemorrhage (one third within the mass, two thirds into the abdomen).
In a systematic review including a total of 1176 patients, the overall frequency of hemorrhage was 27.2%. Hemorrhage occurred in 15.8% of all hepatocellular adenoma lesions. Rupture and intraperitoneal bleeding were reported in 17.5% of patients.[25]
Although a tumor size of 5 cm is the standard for resection owing to the increased risk of hemorrhage and malignant transformation, multiple case series have reported hemorrhage in sizes less than 5 cm, even as small as 1 cm.[26] The risk, though, appears to be minimal. The risk of hemorrhage appears to be related to size and not related to the number of lesions. Multiple studies did not find a difference between patients with a single or multiple hepatocellular adenomas.[27, 28, 29]
The mortality rate associated with an acute hemorrhage into the peritoneum may be as high as 25-30% in patients with large tumors (>5 cm).
The risk of malignant transformation is not completely known and may be as high as 13% based on small studies. A recent systematic review incorporating all reports on malignant degeneration of hepatocellular adenoma into hepatocellular carcinoma showed an overall risk of 4.2%, with only 4.4% of these malignant transformations occurring in lesions less than 5 cm in diameter.[24]
HCA combined with chronic hepatitis B infection could increase the risk of malignant transformation, but more studies are needed.[23]
Pregnancy has been associated with hepatic adenoma, and rupture of the adenoma during pregnancy has been associated with high rates of maternal and fetal mortality.
The clinical presentation varies widely. Salient features of the history and physical examination may include the following:
The physical examination findings are often nonspecific. Patients may be asymptomatic, or they may appear ill, with pallor and abdominal distress. Note the following:
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. Advances in contrast-enhanced MRI and contrast-enhanced ultrasonography may be helpful to distinguish HCA and possibly Bordeaux classification subtypes (see below).[33, 34]
A nonspecific finding reveals a hypoechoic lesion, which usually is subcapsular (7% pedunculated), well circumscribed, ranges from 2 to 20 cm in size, 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.
Contrast-enhanced ultrasonography (CEUS)
CEUS involves using a microbubble contrast that reveals an enhancement in the arterial phase of HCA and focal nodular hyperplasia, but rapidly washes out in the portal venous and delayed phase in HCA.[35, 36, 37, 38]
The reported sensitivity in differentiating HCA from focal nodular hyperplasia has ranged from 86% to 95%, and the specificity has ranged from 74% to 79%.[39]
HCA appears as a nonspecific, well-circumscribed mass that has a low density on noncontrast images and a marked centripetal pattern of enhancement on arterial phase. It then fades to isodensity in the portal or delayed phase. The lesion can have a central necrotic area or calcifications. Most adenomas are encapsulated on CT scan.
The appearance of hepatocellular adenoma on MRI is variable, owing to the presence or absence of hemorrhage. Hyperintense heterogeneous signals on T1- and T2-weighted imaging are often due to lipids contained within the lesion.[40] Hemorrhagic HCAs may also have hyperintense T1 imaging with subcapsular hemosiderin rings in 30% of patients.
Kupffer cell–specific MRI agents (superparamagnetic iron oxides [SPIO] and ultra-small 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.[41]
Unfortunately, HCC also has a predominance of hepatocytes, which makes these agents unable to differentiate between hepatocellular adenomas and HCC.
In a cost-effectiveness analysis of the diagnostic strategies for differentiating focal nodular hyperplasia from hepatocellular adenoma, investigators using a decision tree model found that although a gadoxetic acid-enhanced MRI (EOB-MRI) strategy was most cost-effective, there was similar effectiveness between the EOB-MRI, conventional MRI, and biopsy strategies in patients with incidentally detected liver lesions in a noncirrhotic liver.[42]
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.
This imaging modality is rarely performed and has been substituted by CT or MR angiography in most centers. Hepatocellular adenomas appear as well-defined, round or ovoid, hypervascular masses 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.
It may be reasonable to perform immunohistochemistry to further characterize the lesion under the new Bordeaux classification of HCA currently being evaluated. This subclassification includes hepatocyte nuclear factor 1α-inactivated HCA (HNF1α HCA 30-35%), β-catenin-mutated HCA (β-cat HCA 10-15%), inflammatory HCA (50%), and a subgroup of less than 10% that remains unclassified. Ten percent of inflammatory HCA can also be β-cat mutated.[12]
Glutamine synthetase staining may be useful in differentiating β-catenin-activated HCA and focal nodular hyperplasia owing to differences in their staining patterns. Focal nodular hyperplasia has a maplike distribution that is distant from fibrous bands or arteries, while β-catenin-activated HCAs have a more diffuse staining pattern.[43, 44]
Although HCAs 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 HCAs by sequencing the genes coding for HNF1α and β-cat.[45] The investigators reported that HCC is found in 46% of β-cat–mutated tumors, whereas they are rarely found in HNF1α tumors or tumors that lack β-cat or HNF1α.
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.[46] 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 that is 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.[47]
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.[48] 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 in differentiating normal liver tissue from tumors and also in differentiating hepatocellular adenomas from FNH.[49]
Results of histologic evaluation with a liver biopsy are nondiagnostic and insensitive because the mass is comprised of normal-appearing hepatocytes.
However, a study evaluating immunohistochemical markers on needle biopsies compared against surgical specimens found that immunohistochemistry allowed for the discrimination of focal nodular hyperplasia from hepatocellular adenoma and allowed for identification of hepatocelluar adenoma subtypes proposed in the new Bordeaux classification with 74.3% certainty. Further studies are needed.[50]
In a retrospective review (2000-2013) of the electronic medical records of all patients who underwent hepatic mass biopsy revealing hepatocelluar adenoma, Doolittle et al investigated the safety and outcomes of biopsy of these lesions.[51] Of 60 identified patients with a total of 61 biopsy-proven hepatocelluar adenomas, they found that 1 patient (2%) had a single major complication and 6 patients (10%) had a minor complication. In addition, they found 6 (10%) discordant biopsy results.[51]
Resection and evaluation may be required as the most specific way to confirm the diagnosis.
Upon gross examination, hepatocellular adenomas appear as sharply circumscribed, light brown to yellow tumors that are soft in consistency and often lack a true fibrous tumor capsule.[52] 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.
On 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.[53] However, Bisceglia et al reported that subtypes of HAs may have CK7 positive ductules and are called hepatocellular adenoma with ductal/ductular differentiation.[54]
Peliosis hepatis may occasionally be seen, and Kupffer cells are reduced in number or are absent.[55] 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 seen 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.
Patients should stop using oral contraceptives or anabolic steroids. This allows for regression in the size of the majority of the tumors. Complete resolution is atypical. The risk of malignant transformation remains even after the contraceptive or steroid use has been discontinued.[56]
Symptomatic tumors should be resected, regardless of size.
Pregnancy should be avoided because of the risk of tumor growth and rupture, but it is not an absolute contraindication. There are no consensus guidelines. Surgical resection may be the best option in patients with hepatocellular adenomas who desire to become pregnant. Large incidental HCAs found during pregnancy may be considered for resection during the second trimester, when the risk is lowest. Asymptomatic HCAs smaller than 5 centimeters may be managed with close monitoring. MRI seems to be preferred given the lack of radiation, but cost effectiveness remains to be studied. Ruptured hepatocellular adenomas during pregnancy should be managed with resuscitation and resection.
Yearly ultrasound imaging and an assessment of serum serum alpha-fetoprotein (AFP) levels is a consideration in all patients with hepatocellular adenomas, especially those with multiple lesions or single lesions larger than 5 cm in diameter who do not undergo surgical resection. However, there is little evidence to support this approach.[8]
Immediate abdominal imaging is required for patients with hepatocellular adenomas who present with new or worsened abdominal pain or signs of hemodynamic instability.
Emergency hepatic arteriography with embolization should be considered to control bleeding in high-risk surgical candidates.
Transarterial embolization has been used to electively reduce the tumor mass of a large HCA, but studies are limited in using it as an elective treatment for unruptured HCA.[57, 58]
Due to the increased risk of spontaneous life-threatening hemorrhage and the possible malignant transformation associated with larger-size tumors or in patients with GSD, elective surgical resection is considered for all lesions greater than 5 cm in diameter.[59] Elective resection should be undertaken only after a reasonable period of observation if OCPs have been discontinued only recently. However, several authorities recommend that all adenomas should be resected regardless of size due to rare cases of malignant transformation after adenomas have decreased in size or disappeared after discontinuation of OCPs.
In a multicenter study of 124 patients, Deneve et al reported that tumors that were more likely to rupture were larger tumors and in women with recent hormone use.[27] The investigators recommended surgical resection when HCAs approached 4 cm in size or if hormonal therapy was required.
All patients with significantly elevated AFP levels should undergo resection of the tumor regardless of size.
With regard to timing of resection, Klompenhouwer et al suggest that a 6-month cut-off point in women is too early for assessment of regression of hepatocellular adenomas larger than 5 cm to no more than 5 cm.[60] Rather, they indicate that in women with typical, non-β-catenin-activated hepatocellular adenomas, regardless of the baseline diameter, the cut-off point may be extended to 12 months.[60]
The majority of tumors can be resected locally or with segmental partial lobectomy. Elective resection carries approximately 13% morbidity. Mortality is rare. Complication rates associated with emergency surgery are higher, including a mortality rate of approximately 5-8%.
Laparoscopic resection can be used in patients who have small tumors within the anterolateral liver segments and for pedunculated tumors.
In a retrospective (1989-2013) multi-institutional European study of all patients who had undergone open or laparoscopic hepatectomies for hepatocellular adenomas to investigate the effects of the surgical approach on postoperative morbidities, Landi et al found that open surgery and laparoscopy showed similar postoperative morbidity rates and severities.[61] However, laparoscopy was associated with significantly less blood loss, a reduced need for transfusion, and a shorter hospital stay.[61]
Cho et al reported their experience with the management and outcomes of 41 patients with hepatocellular adenomas treated at the University of Pittsburgh between 1988 and 2007.[26] The investigators reported that surgical resection was preferable to observation if patients comorbidities and anatomical location are acceptable due to risks of hemorrhage (29%) and malignancy (5%).
In rare patients with multiple adenomas or glycogen storage disease, liver transplantation may be the only intervention that may remove all lesions and cure the underlying metabolic defect.[11, 62] Liver transplantation has also been successfully performed for spontaneous intrapartum rupture of an hepatocellular adenoma.[63]
Radiofrequency (RF) ablation can be used effectively in the treatment of hepatocellular adenoma.[64] However, multiple sessions are often required, and signs of residual adenoma might persist in some patients despite repetitive treatment. RF ablation might be especially beneficial in cases not amenable to surgery or in patients who would require major hepatic resection. Cases not amenable to surgery would include centrally located lesions or multiple HCAs in both lobes of the liver.
In a retrospective single-arm study of 36 patients with 58 hepatocellular adenomas who underwent 44 procedures with percutaneous thermal ablation, investigators reported a primary efficacy of 88% and a secondary efficacy of 100%, with a major complication rate of 4.5% (postprocedural hemorrhage).[65] At a median follow-up of 1.7 years, there was 100% clinical efficacy with no reports of malignant transformation, adenoma-related hemorrhages, or deaths.