Practice Essentials
Hepatocellular adenoma (HCA), also called hepatic adenoma, is an uncommon benign solid liver tumor. Its phenotype is changing from single lesions to multiple lesions owing to the reduction in exogenous estrogen exposure and the increasing incidence of obesity and metabolic syndrome as driving factors in HCA formation.
Major subtypes of HCA include the following [1, 2] :
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Inflammatory (~35-50% of cases)
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Hepatocyte nuclear factor 1α (HNF-1α) inactivated (~30-45% of cases)
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β-catenin activated (β-HCA)(~10-20%)
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Sonic hedgehog activated (< 5%)
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Unclassified (5-10%)
Differentiation of HCA subtypes has important clinical implications, as the principal complications—hemorrhage and malignant transformation—differ by subtype. Magnetic resonance imaging (MRI) can differentiate HCA from focal nodular hyperplasia (FNH) and can help differentiate the the inflammatory, HNF 1a–mutated and sonic hedgehog HCA subtypes.
Patients diagnosed with HCA should avoid all steroid exposure. Counsel overweight or obese patients with HCA on weight loss. In women who have HCAs with a diameter of 5 cm or more, surgical resection (or embolization or radiofrequency ablation, if surgery is not an option) should be considered, especially if the tumor shows no response to lifestyle changes. In women, HCAs smaller than 5 cm should be monitored for growth with imaging at regular intervals. Men with HCA and patients with the β-HCA subtype should be referred for resection regardless of tumor size.
Background
Hepatocellular adenomas (HCAs) are also known as hepatic adenomas, telangiectatic focal nodular hyperplasia (FNH) or, less commonly, liver cell adenomas. They are rare, benign tumors of epithelial origin and occur in less than 0.007-0.012% of the population. [1]
HCAs may originate in the bile duct or in liver cells. Those of bile duct origin are usually smaller than 1 cm and are not of clinical interest; typically, they are found incidentally on postmortem examinations. Hepatic adenomas of liver origin are larger—on average, they measure 8-15 cm—and are often clinically significant.
HCAs are most often found in women of childbearing age and are strongly associated with exogenous estrogen exposure, most commonly in the form of oral contraceptives (OCs). [3] The incidence of HCAs is as much as 30-40-fold higher in women who use OCs: the overall incidence in women taking OCs has been estimated at 34 per million, compared with about 1-1.3 per million in women not taking OCs. [4] That estimate is from a study published in 1979, and consequently reflects the higher estrogen doses contained in OCs at the time; typical estrogen doses in OCs declined from ≥100 μg in the 1960s to ~50 μg in 1970s to ≤30 μg in the1980s and subsequently. [5] However, more recent epidemiologic studies on HCAs are lacking.
The incidence of HCAs dramatically increased following the introduction of OCs in the 1960s. Prior to this, a study by Edmonson reported finding only two hepatic adenomas among 50,000 autopsy specimens at Los Angeles County Hospital between 1907 and 1958. [6] In 1973, Baum et al first suggested an association between hepatic adenomas and OCs. [7] Klatskin [8] and Rooks et al [4] reported that the greatest risk occurred in women older than 30 years taking OCs 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 hepatic adenomas are occasionally diagnosed after discontinuation of OCs, [9] although they generally tend to regress following discontinuation. [1]
In women using OCs, adenomas were found to be more common in patients taking OCs containing higher doses of estrogen and with prolonged use (73.4 mo) when compared with matched controls (36.2 mo) (P < 0.001). [10] As reported by Edmonson et al, decreases in dosages and the types of hormones contained in OCs since their introduction have led to a reduction in hepatic adenoma incidence [11] ; however, other factors, such as obesity are becoming more prominent in HCA formation. [12, 13] In addition, benign liver tumors, including HCAs, may be detected more frequently, owing to the increased routine use of medical imaging. [12]
Other conditions associated with alterations in steroid exposure are implicated, including anabolic androgenic steroid use, [14] endogenous steroid exposure, [15] polycystic ovarian syndrome (PCOS), [16] and Klinefelter syndrome. [17] HCAs are also associated with androgenic steroid use for medical conditions, including paroxysmal nocturnal hemoglobinuria [18] and aplastic anemia. [19] HCAs are known to enlarge during pregnancy. [20] Rarer HCA associations have been noted in familial adenomatous polyposis, [21] mature-onset diabetes of the young type 3 (MODY3), [22] and iron overload such as in beta-thalassemia [2] and primary hemochromatosis. [23]
Glycogen storage diseases (GSDs) are also a known risk factor for HCA development, most often occurring with multiple lesions and early onset (age < 20 years), and have a 2:1 male-to-female ratio. [24] Based on limited case series, the incidence ranges between 22% and 75% in type 1 GSD and 25% in type 3 GSD. [25, 26] Poor metabolic control may promote adenoma formation in GSD. [27]
Obesity and features of metabolic syndrome (insulin resistance/diabetes, hypertension, and hyperlipidemia) are also increasingly recognized as HCA risk factors. [28] Obesity has been linked with the development of multiple and bilobar hepatic adenomas [28] and this association has been shown to be independent of OC use, although obese patients using OCs are at increased risk for these lesions as well. [28] Importantly, HCA progression to hepatocellular carcinoma (HCC) is of particular concern in men, in whom the risk of transformation is up to 10 times the rate seen in women, with most cases occurring in those with β-HCA and metabolic syndrome being the most common associated condition. [29]
HCAs may be single or multiple, and they may occasionally reach a size larger than 20 cm. [30] Hepatic adenomatosis has been historically defined as at least 10 lesions, however, note that many patients with over three HCAs go on to develop more, and thus the definition can be applied to patients with four or more lesions. [31] Hepatic adenomatosis develops at equal frequency in either sex and has strong associations with GSD, anabolic steroids, and metabolic syndrome. [28, 32]
Major subtypes of hepatic adenomas have been defined. [33] These subtypes include inflammatory adenoma (I-HCA), representing 40-55% of HCAs; HCA inactivated for hepatocyte nuclear factor 1α (H-HCA), representing 30-45% of HCAs; β-catenin activated HCA (β-HCA), representing 10-20% of HCAs; and sonic hedgehog activated HCA (shHCA), representing less than 5% of HCAs. Approximately 5-10% of HCA are unclassified. [1, 2]
Risk of malignant transformation and hemorrhage varies with the different subtypes. [33] Malignant transformation, specifically to HCC, is seen especially in β-HCA, especially when associated with coexisting I-HCA. [34, 35, 36, 37]
Pathophysiology
Since Baum et al first suggested oral contraceptives (OCs) to be a causal factor in hepatocellular adenoma (HCA) (hepatic adenoma) formation in 1973, [7] the role of both female and male sex hormones have been generally accepted as main factors in the pathogenesis of these adenomas, although the exact mechanism is unclear. Nuclear estrogen receptors in HCAs have been identified in higher concentrations than in the surrounding hepatic tissue, suggesting increased responsiveness to estrogenic hormones. [38] However, this remains controversial, as adenomas can occur in males and children without predisposing risk factors, and other studies have not identified significant concentrations of receptors even with the use of monoclonal antibodies. [39]
Rebouissou et al [40] and Bioulac-Sage et al [35, 41] postulated that hepatic adenomas are monoclonal tumors that develop from an interaction between gene defects and environmental changes such as OCs and steatosis.
Hepatocellular adenoma subtypes
Subtypes of HCA include the following [1, 2] :
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Inflammatory (~35-45% of cases)
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Hepatocyte nuclear factor 1α (HNF-1α) inactivated (~35-45% of cases)
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β-catenin activated (β-HCA)(~10%)
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Sonic hedgehog activated (< 5%)
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Unclassified (5-10%)
Inflammatory HCA
Inflammatory HCAs (I-HCAs) are characterized by a variety of gene mutations, all of which result in activation of the JAK/STAT pathway. [34] They feature an inflammatory response with hepatocyte cystoplasm exhibiting C-reactive protein (CRP) and serum amyloid A (SAA). Risk factors include obesity, hepatic steatosis, excess alcohol use, and glycogen storage disease. [3, 2]
Genetic mutations activating the JAK/STAT pathway in I-HCA are generally mutually exclusive. The predominant form, present in 65% of cases, is a gain of function mutation of interleukin-6 signal transducer gene (IL6ST), which encodes glycoprotein (gp) 130, an IL-6 receptor component, which results in activation of STAT3 and subsequent inflammatory response. [2] Other causative mutations are in STAT3 (5% of cases), FRK (10%), JAK1 (3%), and GNAS (5%). [42]
The I-HCA subtype was previously referred to as telangiectatic focal nodular hyperplasia (FNH), as it was thought to be a type of FNH. However, further investigation showed these lesions to be more closely related to hepatic adenoma. [43, 44]
HNF-1α inactivated HCA
In HNF-1α–inactivated HCA (H-HCA), biallelic inactivation of the HNF1A tumor suppressor gene (also referred to as TCF1) leads to predisposition for HCA formation in individuals with mature-onset diabetes of the young type 3 (MODY3) and liver adenomatosis. [22, 45] Typically, there is a female predominance. [42] Inactivation of HNF1A results in alterations in protein expression—notably, loss of liver fatty acid binding protein (LFABP) in the adenoma compared with the surrounding hepatic tissue; this finding helps in the identification of this subtype. [45] Micro/small HNF1α-inactivated HCAs have also been incidental findings in liver nodules resected for other reasons. [46]
β-catenin activated HCA
In β-HCA, activating mutation of the β-catenin1 gene (CTNNB1) exon 3 activates the Wnt/β-catenin pathway, which plays a significant role in liver development. Mutations of the Wnt/β-catenin pathway are also seen in hepatocellular carcinomas (HCCs), possibly explaining the strong association of β-HCA with HCC development. [45, 2] β-HCA may also result from mutations in CTNNB1 exon 7 or 8; these cases are associated with a mild activation of the Wnt/β-catenin pathway, with HCA development but without an increased risk of malignant transformation. Finally, cases of I-HCA in combination with CTNNB1 exon 3 mutation have been reported. [42]
Sonic hedgehog activated HCA
Sonic hedgehog activated HCA (shHCA) is caused by GLI1 overexpression due its fusion with the INHBE gene, which activates the sonic hedgehog pathway. This subtype is significantly associated with histologic hemorrhage and symptomatic bleeding, whereas a hepatic adenoma size of at least 5 cm, the current defining HCA risk factor for hemorrhage, was significantly associated with histologic hemorrhage alone. [42]
Epidemiology
United States data
Hepatocellular adenomas (HCAs) (hepatic adenomas) are extremely rare, occurring in less than 0.007-0.012% of the population. [1] A 1979 study estimated the overall incidence at 1-1.3 per million in women not taking oral contraceptives (OCs), but at 34 per million in women taking OCs, [4] with increased risk associated with higher-dose estrogen exposure and duration of exposure. [10] Although the reduction in estrogen doses in OCs from the 1960s to the 1980s may have affected the incidence, more recent epidemiologic studies are lacking. Despite the introduction of lower-dose hormonal contraceptives, hepatic adenomas may be detected more frequently owing to the increased routine use of medical imaging as well as the increasing incidence of obesity and metabolic syndrome. [12]
Race-, sex-, and age-related demographics
No racial predisposition exists for HCAs, but a large review that compared data from China, Europe, North America, and Southeast Asia from 1998 to 2008 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 as well as the limited use of OCs. [47]
Approximately 90% of patients with HCAs are female. [2] HCA in males is more likely to be associated with anabolic-androgenic steroid use and glycogen storage disease (GSD). [14, 2] Male HCA is also most often associated with the β-HCA subtype, with increased association for malignancy transformation. [2, 29]
Most affected patients are aged 20-50 years. [3]
Prognosis
The principal complications of HCA are hemorrhage and malignant transformation to hepatocellular carcinoma (HCC). Risk of those complications varies by HCA subtype: risk of hemorrhage is low in all except sonic hedgehog HCA; risk of malignant transformation is low in sonic hedehog and HNF-1α HCA, moderate in inflammatory HCA, and high in β-HCA with exon 3 mutation. [1] Prognosis may be improved by modification of risk factors and monitoring of lesions to reduce the risk of complications, With risk factor reduction (eg, stopping oral contraceptives or anabolic steroids), the tumor can regress in size but the risk of malignant transformation remains. Complete resolution is atypical.
Hemorrhage
Hepatic adenomas are relatively well vascularized, so hemorrhage is a common complication. Intraperitoneal bleeding may occur, likely due to lack of a defined, fibrous capsule. [48] In a systematic review comprising 1176 patients, the overall frequency of hemorrhage was 27.2%. Hemorrhage occurred in 15.8% of all HCA lesions; rupture and intraperitoneal bleeding were reported in 17.5% of patients. Interestingly, a similar overall frequency of patients with HCA hemorrhage (25.4%) were found when earlier studies with oral contraceptives with higher estrogen content were excluded. [48] Risk factors involved in an increased risk of HCA hemorrhage include tumor size of at least 5 cm, location in the left hepatic lobe, and exophytic growth of the tumor. [48, 49]
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 hepatic adenomas smaller than 5 cm, even as small as 1 cm [50] ; however, the risk appears to be minimal. Size—not number of lesions—appears to be related to the risk of hemorrhage. Multiple studies have not found a difference between patients with a single or multiple HCAs. [51, 52, 53]
Rooks et al estimated mortality to be 21% after HCA rupture and intraperitoneal bleeding. [4] Although data are from limited case series of ruptured HCAs, mortality for emergency resection has been estimated between 5% and 10%, whereas that for elective surgery has been estimated to be less than 1%. [54] In cases of high surgical risk or anatomic difficulty, nonsurgical modalities such as embolization and conservative management with adequate resuscitation can be efficacious. [1] Following a massive hemorrhage with intervention or conservative management, the rebleeding risk has been estimated to be around 4.3%, with elective therapy indicated only for persistent size of 5 cm and larger. [55]
Malignant transformation
Malignant transformation of HCA into HCC may occur in up to 4% of β-HCA cases; this subtype is found more often in males, so males are at higher risk. However, a systematic review found that the overall risk of malignant transformation is 4.2%, with only 4.4% of malignancies developing in lesions smaller than 5 cm in diameter. [56] This transformation rate appears to have remained stable over the past four decades as HCA has been closely monitored, based on resected HCA specimens. [57] Malignant transformation occurs predominantly in tumors with diameter of at least 5 cm. [34, 56] The risk of malignant transformation remains even after contraceptive or steroid use has been discontinued. [58]
Growth during pregnancy
Pregnancy has been associated with hepatic adenoma growth, due to exposure to hormones. As growth of HCA is associated with an increased risk of rupture, this is of prime importance in pregnant patients, as rupture of the tumor during pregnancy has a 44% maternal mortality and a 38% fetal mortality rate. [59] A prospective study that followed 48 patients with hepatocellular adenoma < 5 cm during 51 pregnancies found minimal maternal risk and no risk to the fetus; HCA growth occurred in 25.5% of the pregnancies; the median increase was 14 mm. [60] In a setting where surgery is indicated, especially with lesions in the periphery of the hepatic anatomy, it is recommended the operation be planned prior to 24 weeks' gestation to reduce the risk of fetal complications. [2]
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Ultrasound in a patient with von Gierke disease (glycogen storage disease type 1) and several hepatic adenomas. This image shows a mass in the right lobe of the liver that is predominantly isoechoic relative to the liver parenchyma and contains a small, round, hypoechoic component. The 2 masses appear slightly hypoechoic. (Same patient as in the following image.)
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T2-weighted fat-saturated fast spin-echo axial magnetic resonance image in a patient with von Gierke disease. This image shows 2 heterogeneous, hyperintense masses in the right lobe of the liver. (Same patient as in the following image.)
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T1-weighted in-phase magnetic resonance image in a patient with von Gierke disease (same patient as in the following image). This image demonstrates normal hepatic signal intensity that is hyperintense relative to the spleen. Two heterogeneous masses that represent hepatic adenomas are seen in the right lobe and are slightly hypointense relative to the liver parenchyma.
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T1-weighted out-of-phase magnetic resonance image in a patient with von Gierke disease (same patient as in the following image). This image shows abnormal low signal intensity of the liver, hypointense relative to the spleen, representing fatty infiltration of the liver. The hepatic adenomas are heterogeneous and slightly hyperintense relative to the fatty liver.
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Single-shot fast spin-echo T2-weighted coronal magnetic resonance image in a patient with von Gierke disease (same patient as in the following image). This image shows a hyperintense mass in the right lobe of the liver and an additional hyperintense mass in the inferior tip of the liver, representing a third hepatic adenoma.
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Fat-saturated 3-dimensional T1-weighted gradient-echo magnetic resonance image in a patient with von Gierke disease (same patient as in the following image). This image shows 2 heterogeneous, slightly hyperintense masses in the right lobe of the liver.
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Gadolinium-enhanced fat-saturated 3-dimensional T1-weighted gradient-echo magnetic resonance image in a patient with von Gierke disease (same patient as in the following image). This image shows intense enhancement of the hepatic adenomas.
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Gadolinium-enhanced fat-saturated 3-dimensional T1-weighted gradient-echo magnetic resonance image in a patient with von Gierke disease. This image shows that the hepatic adenoma remains hyperintense relative to the liver parenchyma. (Same patient as in the following image.)
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Gadolinium-enhanced fat-saturated 3-dimensional T1-weighted gradient-echo magnetic resonance image in a patient with von Gierke disease (same patient in the previous image). This image shows that the hepatic adenoma remains hyperintense relative to the liver parenchyma.
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Noncontrast computed tomography scan in a 41-year-old woman with a history of oral contraceptive use. This image demonstrates a heterogeneous, low-attenuation mass in the right lobe of the liver, a hepatic adenoma. (Same patient as in the following image.)
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Contrast-enhanced computed tomography scan in the portal venous phase in a 41-year-old woman with a history of oral contraceptive use. This image demonstrates a heterogeneous, enhancing mass, a hepatic adenoma, predominantly isoattenuating relative to the liver with areas of low attenuation. (Same patient as in the following image.)
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Technetium-99m (99mTc)–labeled red blood cell single-photon emission computed tomography scintigraphy in a 41-year-old woman with a history of oral contraceptive use. This image shows no demonstrable activity in the hepatic mass, indicating that it does not represent a hemangioma. (Same patient as in the previous image.)
