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 estrogen exposure and increasing incidence of obesity and metabolic syndrome as driving factors in the formation of hepatic adenoma. Note the following:
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Differentiation of HCA subtypes has important clinical implications, with magnetic resonance imaging (MRI) better able to differentiate HCA from focal nodular hyperplasia (FNH) as well as among certain subtypes of HCA (hepatocyte nuclear factor [HNF] 1a-mutated HCA [H-HCA], inflammatory HCA [I-HCA]). Other subtypes of HCA continue to be identified; not all are well differentiated by MRI.
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All steroid exposure should be avoided in patients diagnosed with HCA. Counsel overweight or obese patients with HCA weight loss.
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Complications of HCA include hemorrhage and malignant transformation. The risk of hemorrhage is greatest in HCAs with a diameter of at least 5 cm as well as with exophytic growth. The risk of malignant transformation is greatest with HCAs with a diameter of 5 cm or larger, male patients, and those with confirmed β-HCA subtype.
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Women who have HCAs with a diameter of at least 5 cm should be considered for resection or noninvasive treatment, especially if there is no response to lifestyle changes. Women with HCAs smaller than 5 cm should be monitored for growth with imaging at regular intervals.
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Men with HCA and patients with β-HCA subtype should be referred for resection regardless of 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 are most often found in women of childbearing age and are strongly associated with estrogen exposure, most commonly in the form of oral contraceptive pills (OCPs). [2] The use of OCPs in women reflects an up to 30-40-fold increase in incidence; the overall incidence in women taking OCPs has been estimated at 34 per million, whereas it is about 1-1.3 per million in women not taking OCPs. [3] However, more recent epidemiologic studies are lacking.
The incidence of HCAs dramatically increased following the introduction of OCP medications 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. [4] In 1973, Baum et al first suggested an association between hepatic adenomas and OCPs. [5] Klatskin [6] and Rooks et al [3] reported that the greatest risk occurred in women older than 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 hepatic adenomas are occasionally diagnosed after discontinuation of OCPs, [7] although they generally tend to regress following discontinuation. [1]
In women using OCPs, adenomas were found to be 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). [8] As reported by Edmonson et al, decreases in dosages and the types of hormones contained in OCPs since their introduction have led to a reduction in hepatic adenoma incidence [9] ; however, other factors are becoming more prominent in HCA formation. [10] Currently, benign liver tumors including HCAs may be detected more frequently, owing to the increased routine use of medical imaging. [10]
Other conditions associated with alterations in steroid exposure are implicated, including anabolic androgenic steroid use, [11] endogenous steroid exposure, [12] polycystic ovarian syndrome (PCOS), [13] and Klinefelter syndrome. [14] HCAs are also associated with androgenic steroid use for medical conditions including paroxysmal nocturnal hemoglobinuria [15] and aplastic anemia. [16] These adenomas are known to enlarge during pregnancy. [17] Rarer HCA associations have been noted in familial adenomatous polyposis, [18] mature onset diabetes of the young (MODY) 3, [19] and cases of iron overload such as beta-thalassemia [20] and primary hemochromatosis. [21]
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. [22] Based on limited case series, the incidence ranges between 22% and 75% in type 1 GSD and 25% in type 3 GSD. [23, 24]
Obesity and features of metabolic syndrome (insulin resistance/diabetes, hypertension, and hyperlipidemia) are also increasingly recognized as HCA risk factors. [25] Obesity has been linked with the development of multiple and bilobar hepatic adenomas [25] and this association has been shown to be independent of OCP use, although obese patients using OCPs are at increased risk for these lesions as well. [25] 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 the presence of metabolic syndrome being the primary factor. [26]
HCAs may be single or multiple, and they may occasionally reach a size larger than 20 cm. [27] 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. [28] Hepatic adenomatosis develops at equal frequency in either sex, has strong associations with GSD, anabolic steroids, and metabolic syndrome. [25, 29]
Major subtypes of hepatic adenomas have been defined to identify tumors at greatest risk of malignant transformation and hemorrhage. [30] This subclassification includes HCA inactivated for hepatocyte nuclear factor 1α (H-HCA), representing 30-40% of HCAs; inflammatory adenoma (I-HCA), representing 40-55% of HCAs; β-catenin activated HCA (β-HCA), representing 10-20% of HCAs; and unclassified HCA, representing 5-10% of HCAs. [20]
Among the subclassifications, β-catenin activation may promote tumor development, specifically HCC, especially when associated with coexisting I-HCA. [31, 32, 33, 34] Evidence also exists to suggest obesity may cause an increase in the I-HCA and β-catenin activated-inflammatory HCA subgroups. [35]
Pathophysiology
Since Baum et al first suggested oral contraceptive pills (OCPs) to be a causal factor in hepatocellular adenoma (HCA) (hepatic adenoma) formation in 1973, [5] the role of both female and male sex hormones have been generally accepted as main factors in the 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. [36] 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. [37] Rebouissou et al [38] and Bioulac-Sage et al [32, 39] postulated that hepatic adenomas are monoclonal tumors that develope from an interaction between gene defects and environmental changes such as OCPs and steatosis.
In addition to environmental factors, hepatic adenomas result from specific genetic mutations, with each subtype bearing significant clinical implications. There also remains an unclassified subtype of HCA, representing up to 5-10% of HCAs, without specific gene mutations or morphologic definitions. [20]
In HCA inactivated for hepatocyte nuclear factor 1α (HNF1A, also referred to as TCF1) (H-HCA), biallelic inactivation of HNF1A renders this tumor suppressor gene inactive, leading to predisposition for HCA formation in mature onset diabetes of the young (MODY) 3 and liver adenomatosis. [40] Typically, there is a female predominance. [41] Inactivation of HNF1A results in alterations in protein expression, with a characteristic loss of liver fatty acid binding protein (LFABP) in H-HCA compared to the surrounding hepatic tissue as a prime example, helping in the differentiation of micronodules from hepatic steatosis. [40]
I-HCAs are characterized by a variety of gene mutations, all of which result in activation of the JAK/STAT pathway. [31] They feature an inflammatory response with hepatocyte cystoplasm exhibiting C-reactive protein (CRP) and serum amyloid A (SAA), and they have associations with obesity and alcohol use. [2, 20] 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. [20] 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 are more closely related to hepatic adenoma and thus they are now characterized as I-HCA. [42, 43]
In β-HCA, activating mutation of the β-catenin1 gene (CTNNB1) 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 their stronger association with HCC development. [40] Both β-HCA and I-HCA with CTNNB1 mutation have an increased risk for malignant transformation. β-HCA subtype is seen more often in males, which may explain the increased incidence of malignant transformation in this population. [20]
In 2017, it was noted that an additional mutation in INBHE/GL1, resulting in sonic hedgehog activation in HCA (shHCA), 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. These findings show further delineation of subtypes may result in improving avoidance of such complications. [41] Up to eight subtypes have been identified following the most recent European Association for the Study of the Liver (EASL) guideline update, with two forms of mixed I-HCA/β-HCA and two forms of β-HCA. [41]
The increasing knowledge of genetic mutations in hepatic adenoma has shed light on possible mechanisms that could lead to HCA and malignant transformation in type 1 glycogen storage disease (GSD), which is most often of the I-HCA subtype. [20] GSD-related adenoma formation and progression have been reported to slow with dietary manipulation. [44] However, a study by Kishnani et al showed the most significant chromosomal aberration of simultaneous gain of 6p and loss of 6q could be high risk in the progression from HCA to HCC, regardless of metabolic control. [45]
Insulin and glucagon appear to play a role in HCA formation. Reznik et al described a germline mutation of HNFα in two families that had both diabetes mellitus and liver adenomatosis. [19] Tumor cell analysis showed biallelic inactivation of HNFα. Micro/small HNF1α-inactivated HCAs have also been incidental findings in pathological liver resected specimens. [46]
Epidemiology
United States data
Hepatocellular adenomas (HCAs) (hepatic adenomas) are extremely rare, occurring in less than 0.007-0.012% of the population. [1] The overall incidence in women not taking OCPs is estimated at 1-1.3 per million, but in women taking oral contraceptive pills (OCPs), it is estimated at 34 per million [3] —with increased risk associated with higher-dose estrogen exposure and duration of exposure. [8] However, 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. [10]
Race-, sex-, and age-related demographics
No racial predisposition exists for hepatic adenomas, but a large review of HCAs from 1998 to 2008 that compared 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 as well as the limited use of OCPs. [47]
Approximately 90% of patients with hepatic adenomas are female. [20] HCA in males is more likely to be associated with anabolic-androgenic steroid use and glycogen storage disease (GSD). [11, 20] Male HCA is also most often associated with the β-HCA subtype, with increased association for malignancy transformation. [20, 26]
Most affected patients are aged 20-50. [2]
Prognosis
Complete resolution of hepatocellular adenoma (HCA) (hepatic adenoma) is atypical. Prognosis depends on modification of risk factors and monitoring of lesions to reduce the risk of complications, which mainly include hemorrhage and malignant transformation.
Morbidity/mortality
Hepatic adenomas are relatively well vascularized, thus hemorrhage is a common complication. Intraperitoneal bleeding is seen 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 contraceptive pills (OCPs) 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 did not find 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. [3] 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 only indicated for persistent size of 5 cm and larger. [55]
The overall risk of malignant transformation is 4.2%, based on a systematic review incorporating reports on malignant degeneration of HCA into hepatocellular carcinoma (HCC), with only 4.4% of these malignant transformations occurring 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 is predominantly found among males, tumors with diameter of at least 5 cm, and with the β-HCA subtype. [31, 56] Somatic promoter mutations in telomerase reverse transcriptase (TERT) have been identified as a late event in conjunction with activating CTNNB1, which is associated with progression of HCA to HCC. [58] The risk of malignant transformation remains even after contraceptive or steroid use has been discontinued. [59]
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. [60] For pregnant patients with HCA smaller than 5 cm, there appears to be minimal maternal risk and no risk to the fetus in a 2020 prospective study. [61] 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. [20]
