|Year : 2018 | Volume
| Issue : 1 | Page : 1-8
Hepatocellular adenoma: Review of contemporary diagnostic and therapeutic options
Saleema Begum, Muhammad Rizwan Khan
Department of Surgery, Aga Khan University Hospital, Karachi, Pakistan
|Date of Web Publication||21-Mar-2018|
Dr. Muhammad Rizwan Khan
Department of Surgery, Aga Khan University Hospital, Karachi
Source of Support: None, Conflict of Interest: None
Hepatocellular adenoma (HCA) is a rare benign lesion most often seen in young women with a history of oral contraceptive use. It is typically a solitary lesion located in the right hepatic lobe although multiple lesions have been reported. Diagnosis of HCA is important for prompt treatment because of risk of hemorrhage and malignant transformation. Adenomas are not specifically diagnosed at ultrasonography, and further evaluation with computerized tomography and magnetic resonance imaging is required to differentiate from other hepatic lesions such as focal nodular hyperplasia. The gold standard for diagnosis is excision biopsy. Better understanding of clinical history and imaging appearance is important to avoid misdiagnosis and facilitate effective treatment.
Keywords: Diagnosis, hepatocellular adenoma, management, risk factors
|How to cite this article:|
Begum S, Khan MR. Hepatocellular adenoma: Review of contemporary diagnostic and therapeutic options. IJS Short Rep 2018;3:1-8
| Introduction|| |
Hepatocellular adenoma (HCA) is one of the uncommon benign hepatic tumors, first described by Frerichs in 1861 with a reported incidence of 3/1,000,000/year. The incidence is substantially higher in females with long-term oral contraceptive (OC) use, estimated at 3–4/100,000/year. Regression of HCA after discontinuation of OC is controversial, but there is literature that supports the hypothesis., Pregnancy resulting in increased endogenous steroids is another risk factor for HCA. Consumption of anabolic steroids, iron metabolic diseases, endocrine disorders, vascular disorders such as portal vein agenesis, Budd–Chiari syndrome, and hereditary hemorrhagic telangiectasia and patients with genetic disorders such as glycogen storage disease (GSD) and familial adenomatous polyposis , are less common predisposing factors.
Hepatic adenomas are mostly single present in the right lobe of liver, but several simultaneous lesions in liver parenchyma can also be seen. The term hepatic adenomatosis is reserved for patients with over 10 lesions separated by normal parenchyma, and the reported incidence of this entity is 10%–24% of patients with adenoma.,
| Pathogenesis and Risk Factors|| |
Oral contraceptives and pregnancy
The exact pathogenesis of HCA is still unknown; however, its association with OC is well established. Baum et al. in 1973 first described the causal association of HCA with the intake of OC. Subsequently, Rooks et al. in 1979 reported that the relationship appears to be dose and duration dependent  and is highest in women over 30 years of age after using OC for >24 months. It is estimated that the risk of developing an adenoma increases by a factor of 5 after 5 years and by a factor of 5 25 after 9 years of OC use. Regression of tumor may occur after the cessation of OC usage, and there are reports of progression to hepatocellular carcinoma (HCC) many years after the cessation of OC. Hormone-induced growth and spontaneous rupture have been seen in pregnancy due to increased levels of steroid hormones that may threaten the life of both mother and child. Special consideration is required in terms of management of such patients. Despite the causal relationship between HCA incidence and steroid hormone use, studies have yet failed to demonstrate the presence of steroid hormone receptors in all HCAs.,
HCA has been associated with the long-term use of anabolic androgenic steroids, and the mechanism is similar to that of OC. Its use predisposes to emergence of HCA, and the discontinuity can lead to regression.
Glycogen storage diseases
GSD is associated with the development of HCA, but the exact mechanism is unknown. In a European cohort study, HCA was observed in 80% of patients with GSD-1a above the age of 30 years and they were multiple in two-third of the cases. In 10% of GSD-1a patients, HCAs undergo malignant transformation to HCC.
Other rare causal associations include inherited disorders such as familial adenomatous polyposis  and maturity-onset diabetes of young type. Obesity, metabolic syndrome, Klinefelter syndrome, and vascular disorders such as portal vein agenesis, Budd–Chiari syndrome, and hereditary hemorrhagic telangiectasia are also associated with HCA.
| Pathology|| |
HCA is usually a solitary (70%–80%), encapsulated, and well-demarcated mass and occasionally be pedunculated. It has a soft and fleshy consistency, and the size ranges from 1 to 30 cm. The cut surface may be solid tan or yellow, depending on the presence or absence of steatosis. Intralesional hemorrhage in mass can give rise to a soft, necrotic, red-brown color. Spontaneous rupture of the tumor can also cause subcapsular hematoma. The background liver is typically healthy and noncirrhotic.
Microscopic features show benign hepatocytes arranged in thickened cell plates, with a preserved reticulin network separated by dilated sinusoids. These sinusoids that are perfused by arterial pressure because adenomas lack a portal venous supply and are fed solely by peripheral arterial feeding vessels. The extensive sinusoids and feeding arteries form the hypervascular nature of HCA, and poor connective tissue support predisposes to hemorrhage within it. Because of deficient capsule, hemorrhage may spread into the liver or abdominal cavity. Kupffer cells are often found in reduced numbers and with little or no function and is reflected by absent or diminished uptake of technetium (Tc)-99 m sulfur colloid. Bile ductules are absent which is a key histologic feature that helps distinguish HCA from focal nodular hyperplasia (FNH). Adenoma cells are usually larger and contain large amounts of glycogen and lipid. Lipid accumulation is responsible for the characteristic yellow appearance of the cut surface of adenomas, and evidence of lipid on computerized tomography (CT) or magnetic resonance imaging (MRI) can be helpful in diagnosing HCA. Adenomas have the potential to undergo malignant transformation to HCC even after years of maintaining a stable appearance., Moreover, adenomas and HCC may have similar imaging and histopathological features, making differentiation difficult or impossible short of complete resection. Loss of normal reticulin stain in HCA may suggest HCC., Malignant transformation of HCA is based on the demonstration of a transition zone with dysplastic changes within HCC or a pattern of a nodule within a nodule or two adjacent tumors within a transition zone., Other features such as interval growth of a mass or elevated serum alpha-fetoprotein levels favor the diagnosis of HCC.
| Classification|| |
Four subtypes of HCA have been identified based on genotype–phenotype analyses. The classification described by Bioulac-Sage et al. is of great clinical importance. They divided HCA in four subtypes using immunohistochemical markers.
Hepatocyte nuclear factor-1 α mutation
Inactivating mutations in the hepatocyte nuclear factor 1α gene (HNF1-α) causing loss of HNF-1α expression defines H-HCA, which are histologically characterized by marked steatosis and bland hepatocyte cytology., This type is present in 35%–50% of HCA and exclusively in females. Germline HNF-1α mutation is associated with familial hepatic adenomatosis. On immunohistochemistry, lack of liver fatty acid-binding protein expression can be seen.
A second subtype, with activating mutations of β-catenin (b-HCA), is associated with an increased risk of malignant transformation into HCC.,, This type is seen in 10%–15% patients with HCA, more frequently in males with use of androgens, GSDs, and familial adenomatosis polyposis. Pathologically, this subtype is difficult to differentiate from well-differentiated HCC, and immunohistochemistry shows nuclear β-catenin staining and strong diffuse glutamine synthetase expression.
Inflammatory hepatocellular adenoma
Third subtype (inflammatory HCA [IHCA]) is seen in 40%–50% patients and in females. IHCA is associated with obesity and high body mass index, alcohol consumption, and systematic inflammatory syndromes. Pathologically, this is characterized by inflammatory infiltrates, sinusoidal dilatation, and hemorrhage. Immunohistochemistry shows increased serum amyloid A (SAA) and C-reactive protein (CRP) expression. IHCA has been linked with activating mutations in several genes.
Finally, a small proportion of HCA does not appear to fall into any of the above categories and is not classifiable by the current testing approaches (unclassified HCA).
| Complications|| |
Bleeding and rupture
The presence of HCA can be complicated by growth and rupture. The morphology of adenomas with their extensive proliferation of blood filled sinusoids which are supplied by high pressure arterial flow and poor soft tissue support with reticulin makes them prone to bleed. Bleeding in HCA ranges from small subclinical bleed to life-threatening intraperitoneal rupture, resulting in hemorrhagic shock requiring emergency care. In a recent systematic review, it was estimated that the overall frequency of bleeding was 27.2% with more severe bleeding in 17.5% of patients presenting with HCA. Bleeding and rupture in HCA are associated with tumor size and use of OC. Deneve et al. reported that no tumor <5 cm in diameter had evidence of rupture. Dokmak et al. described that the risk of bleeding was almost exclusively observed in HCA >5 cm in diameter, and <1% of HCA <5 cm had macroscopic hemorrhagic stigmata. There is also increased risk of rupture in pregnancy because of increased hormone levels. Risk of rupture does not seem to be associated with tumor number.
Malignant transformation into HCC is a serious but rare complication of HCA., The reported incidence varies from 4% to 18%. Stoot et al. reported an overall frequency of malignant transformation of HCA of 4.2%. Specific risk factors include HCA nodules with aberrant nuclear β-catenin expression. This subgroup seems over presented in male patients with a history of hormone administration. Literature also suggests the association of HCC with simultaneous occurrence of HCA and GSD-1a. Little literature is available about the size as risk factor for malignant transformation of HCA. Micchelli et al. reported malignant transformation in HCA >4 cm.
| Clinical Features|| |
Generally, patients are asymptomatic. Mild epigastric or right upper quadrant discomfort and bloating are the most common symptoms encountered. Symptomatic patients usually present with right upper quadrant pain secondary to bleeding within the HCA. At initial presentation, these symptoms are often attributed to gallstone disease. Liver function tests may be abnormal secondary to necrosis or hemorrhage. Some patients may present with an acute abdomen and life-threatening hemorrhage secondary to rupture and bleeding into peritoneal cavity. If not identified and appropriately treated, such an event is associated with 20% mortality. The actual risk of bleeding is difficult to establish, but studies have reported risk as high as 25%–64%. Risk factors for bleeding include diameter of 5 cm or more, visualization of arteries within the lesion, location in the left lateral liver, and exophytic growth. Most of the HCAs are picked up incidentally during imaging studies of liver for other conditions or intraoperatively during laparoscopic cholecystectomy.
The differential diagnosis includes FNH and well-differentiated HCC. These two lesions can be difficult to differentiate from adenoma and remain the diagnostic challenge as they have different therapeutic implications. Patients with FNH are less likely to be asymptomatic or have deranged liver functions.,
| Diagnosis|| |
The diagnosis of HCA can be challenging and requires strong clinical suspicion, combination of imaging studies, and histological confirmation.
Ultrasound (US) is the first imaging modality used for the evaluation of any liver lesion, but its value is debated in case of HCA. Some authors have reported that 50% diagnostic sensitivity and specificity is still lower. Lesions may be hypo-, iso- or hyper-echoic depending upon the tumor characteristics. High lipid content of adenomas may contribute to the hyperechoic appearance of the lesion. Intratumoral hemorrhage can also result in increased echogenicity and heterogeneity. Calcification may be present in areas of necrosis and manifest as hyperechoic foci with acoustic shadowing. Color Doppler US may demonstrate peripheral peritumoral vessels that typically have a flat continuous or less commonly, triphasic waveform. These features are reported to be absent in vessels within FNH and may be useful in distinguishing the two disease entities. The combination of US associated with intravenous (IV) contrast infusion (contrast-enhanced US [CEUS]) enhances the ability to differentiate HCA from other liver lesions. HCAs show homogeneous enhancement during the hepatic arterial phase preceding enhancement of normal liver parenchyma, sometimes with centripetal filling, with no radial vascular structures. Rapid wash out and no portal venous enhancement during the hepatic portal venous phase are seen, with isoechoic or more often slight hypoechoic appearance in the later parenchymal phases. This pattern allows its differentiation from FNH that enhances both in arterial and portal phase.,
The most important advantage of CT is to acquire images in arterial, portal venous, and delayed phases providing sequential dynamic images of liver lesions. CT findings of HCA depend on the characteristics of lesion and adjoining liver parenchyma. Before the injection of IV contrast, HCAs are usually isodense but may be heterogeneous with hyperdense areas due to the presence of bleeding or hypodense areas because of the presence of fat or lipid. During arterial phase, there is peripheral enhancement reflecting the presence of large subcapsular feeding vessels, with a centripetal pattern of enhancement during portal venous phase. The enhancement usually does not persist in adenomas because of arteriovenous shunting. The pattern of perfusion starting at periphery can be demonstrated on angiography and has been used to differentiate HCA from FNH where the vascular supply arises centrally from feeding artery (spoke wheel appearance). During the late phase, lesion may become isodense and then hypodense.
Magnetic resonance imaging
HCAs are usually well demarcated on MRI because of the fat or glycogen content of hepatocytes. However, MRI features differ depending upon fat content, old or new hemorrhage, necrosis, or foci of calcifications. On T1-weighted images, HCA appears as hyperintense lesions although not in all cases. Such hyperintensity is due to the presence of fat, glycogen, or bleeding. On T2-weighted images, most of these lesions are slightly hyperintense and heterogeneous because of a combination of hyper- and hypo-intense areas that correspond to hemorrhage and necrosis within the lesion.,, After IV contrast, they enhance quickly and heterogeneously during arterial phase and tend to homogenize with the surrounding parenchyma during the portal venous and delayed phases, sometimes showing washout.
Nuclear scintigraphy is rarely diagnostic for HCA. Adenomas usually show absent or decreased uptake of Tc-99 sulfur colloid, reflecting decreased number or function of Kupffer cells. While hepatobiliary scintigraphy (performed with Tc-99 m hepatobiliary iminodiacetic acid) is useful in diagnosing FNH, adenomas do not usually demonstrate the delayed clearance of radioactivity (hot spots).
Angiography is rarely used for the diagnosis of HCA due to a wide spectrum of angiographic appearances. Tumors may appear hypervascular with increased peripheral vascularity. Areas of hemorrhage and necrosis may further complicate the findings.
Percutaneous biopsy of HCA is not usually recommended as this can induce bleeding. It does not exclude malignancy if normal tissue is found in the provided sample and needle track tumor seeding in case of malignancy. The differentiation of HCA from FNH and well-differentiated HCC is often difficult on needle biopsy specimen with routine staining. There are numerous case reports of women using OCs who develop HCC, but preoperative or operative liver needle biopsies reveal HCA.,, An image-guided biopsy is only useful when radiologic findings are nonspecific for the diagnosis of hepatic nodules. Specific patterns of immunostains examined by an expert may be helpful in the distinction of HCA from FNH, well-differentiated HCC, or steatotic nontumoral liver.,,, In a review of 239 needle biopsies, a diagnosis of HCA was established with routine staining of core biopsy specimen in 58.6% of patients which increased to 74.3% after the use of specific immunostains with the identification of subtypes. In most of the cases, HNF-1α and inflammatory-type HCA with positive CRP and SAA staining should be feasible on a biopsy because of more or less homogeneous staining pattern. However, the interpretation of β-catenin staining may be difficult because of heterogeneous staining pattern, and additional molecular biology may be required as close relationships were found between genetic data and immunohistochemical data.
Excisional biopsy of liver lesion either by open surgery or laparoscopy  is the gold standard method for diagnosis. Even with tumor tissue, accurate microscopic differentiation between benign HCA and HCC can be difficult. QBend 10- and erbB2-immunostaining,, comparative genomic in-situ hybridization, and fluorescence in-situ hybridization  may differentiate HCA from HCC, but these investigations are not in routine clinical practice yet.
| Recent Advances|| |
Newly developed techniques of ultrasonography and MRI not only provide anatomical information but also provide quantitative functional evidence about liver diseases and focal lesions.
Dynamic contrast-enhanced ultrasonography
Conventional gray scale sonography is the most common imaging modality for screening purposes, but it lacks specificity and sensitivity. When augmented with color Doppler, it gives better description of lesions. It is further strengthened by the introduction of microbubble contrast agents. CEUS uses contrast agents that constitute microbubbles of gas, stabilized with coating of a biocompatible surfactant or polymer-like phospholipid or protein. These are purely intravascular, safe, well tolerated and are easy to administer. These contrast agents are not excreted by kidney, so deranged renal functions are not a contraindication for CEUS, which is an advantage over CT and MRI. It depicts changes, largely attributed to its real-time dynamic scans and high temporal resolution. Intraoperative CEUS can be used to determine the resectablility of hepatic tumors and nodule characterization in cirrhotic patients. Recent studies have suggested that intraoperative CEUS is more sensitive, specific, and accurate than unenhanced intraoperative US, contrast-enhanced CT, or contrast-enhanced MRI for assessing tumor resectability.
Dynamic magnetic resonance imaging with hepatobiliary-specific contrast agent
MRI including diffusion-weighted and dynamic MRI enhanced with specific hepatobiliary contrast agents such as gadoxetate disodium has the ability to provide more specific information of hepatocyte function/content of indeterminate liver lesions. Accurate characterization of diffuse and focal liver diseases with additional information about tissue cellularity, perfusion, hepatocyte transport function, and viscoelasticity with diffusion-weighted MRI, dynamic contrast-enhanced MRI, and magnetic resonance elastography has improved the diagnostic performance.
The dynamic MRI enhancement pattern for HCA is variable; typically, these lesions demonstrate homogeneous, hyperintense enhancement on arterial phase imaging secondary to their vascular histology. They typically remain hyperintense to isointense to liver parenchyma on portal venous imaging. The gadoxetate acid hepatocyte phase is instrumental in differentiating HCA from FNH. Adenomas are usually hypointense compared to liver parenchyma, whereas FNH is typically hyperintense to isointense. An additional differentiating feature is peripheral rim enhancement of pseudocapsule.
The natural history and prognosis of HCA are still not very well well-known. The primary clinical problem observed with HCAs is that the size of some adenomas remains stable, some show slow and progressive enlargement, and some of them show regression after discontinuation of estrogen therapy. The risk of hemorrhage and malignancy is the clinical problem associated with HCA.
Conservative approach for the HCA with cessation of hormone therapy is still controversial. Some of the recent studies have reported a 79% regression of adenoma after discontinuation of OCs. However, even after cessation of steroid medications, growth, rupture, and malignant transformation have been reported. Observation with cessation of OC is considered for the lesions smaller than 5 cm or lesions showing regression during radiological follow. There are not strict recommendations for surveillance; however, 6 monthly multiphasic CT or MRI with alpha-fetoprotein is recommended.
Resection is recommended for HCA measured 5 cm or larger because of correlation of adenoma size, risk of bleeding, and malignant potential., Adenomas of size <5 cm rarely bleed or undergo malignant transformation., Indications for resection of HCA include postmenopausal women with no history of OC use, symptomatic adenomas, enlarging size, and when malignancy cannot be ruled out. Adenomas in males regardless of the size and those with positive nuclear immunohistochemical staining for β-catenin on a biopsy should be resected as they have high risk of malignant transformation.,, Surgical approach does not require a wide resection margin or a regional lymphadenectomy even in case of suspected malignancy owing to the minimal risk of vascular invasion or lymph node involvement. Minimally invasive approach may also be considered over open procedure.,
Less invasive treatment options including radiofrequency ablation (RFA) and transcatheter arterial embolization (TAE) may be used in selected patients. RFA is indicated in patients when radical resection is not possible because of centrally located tumors, multiple lesions in both hepatic lobes, patients who refuse surgery, and patients who wish to conceive. RFA is particularly useful in patients with lesions <4 cm. TAE is an initial treatment option in bleeding HCA in emergency to control bleeding and electively to reduce the tumor size before resection of large tumors. Limited studies are available about TAE as an elective treatment for unruptured HCA.
Pregnant women with HCA require special attentions as the risk of hormone-induced growth and spontaneous rupture can threaten the life of mother and child. Pregnancy is not contraindicated in patients with HCA, but in women with HCAs >5 cm, surgical resection is mandatory before conception., RFA is reserved for patients with small and centrally placed tumors or patients who refuse for radical surgery. The morbidity and mortality of resection is low in the second trimester for both mother and fetus. Attentive waiting with strict clinical and US follow-up is recommended in the third trimester because of high estrogen levels and the associated risk of bleeding. Spontaneous rupture of HCA is low but can be life-threatening.
Bleeding and rupture
Management of ruptured HCA is a challenge because severe bleeding can produce hemorrhagic shock. Patients necessitate resuscitation followed by immediate intervention to control the source of bleeding. Emergent laparotomy or laparoscopic resection is the ideal intervention required in this situation. However, surgical procedure is not without significant risk. Another option is TAE as an initial treatment in patient with spontaneous bleeding with or without rupture to reduce the need for urgent laparotomy., Long-term results of TAE are still not available in the literature. There is no role of RFA in emergency rupture of HCA with bleeding.
| Conclusions|| |
Despite advancements in molecular genetic pathways and imaging modalities for the diagnosis of HCA, definite diagnosis without excision biopsy is still a challenge. Prompt diagnosis and treatment are mandatory because of risk of hemorrhage and malignant transformation. Treatment options should be individualized because of diverse presentation and patient population with HCA.
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Conflicts of interest
There are no conflicts of interest.
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