Hepatocellular Adenoma

Etiology

Chen and colleagues enhanced our understanding of hepatocellular adenoma formation when their 2002 study identified the role of β-catenin in the Wnt signaling pathway.[5] Subsequently, Bioulac-Sage and associates developed a phenotypic-genotypic classification system for hepatocellular adenomas based on molecular behavior patterns.[6][7] Other groups have since validated this classification scheme, which categorizes hepatocellular adenomas into 4 main groups:

Hepatocyte Nuclear Factor -1α Inactivated Mutations

Patients with hepatocyte nuclear factor-1α (HNF-1α) inactivated mutations comprise 35% to 40% of cases. The condition involves biallelic mutations of the T-cell factor-1 gene that encodes the transcription factor HNF-1α. This protein is involved in hepatocyte differentiation, liver development, and glucose and lipid metabolism. HCA lesions in this group are noticeably more steatotic on biopsy. Women are mostly affected. The mutation is likewise often associated with mature-onset diabetes of the young (MODY3). About 90% of the mutations are somatic, although MODY3 association can involve the germline and commonly manifests with adenomatosis. Lesion size smaller than 5 cm reduces complication risk.

β-Catenin Activated Mutations

Individuals with β-catenin activated mutations constitute 15% to 20% of liver adenoma cases. The condition is frequently linked to androgen exposure, glycogenesis, and familial adenomatous polyposis. Mild hepatic cytological or architectural abnormalities lead to an acinar, pseudoglandular pattern. The mutation is rarely detected in liver steatosis and inflammatory cases. Adenomas in this group have an increased malignant transformation risk. The lesions typically exhibit positivity for glutamine synthetase and abnormal β-catenin expression on immunohistochemical staining.

Inflammatory Hepatocellular Adenomas

Inflammatory HCA (IHCA) is seen in 40% to 50% of patients with HCA (see Image. Inflammatory Hepatocellular Adenoma Histopathology). Risk factors include female sex, high body mass index (BMI), excessive alcohol consumption, and systemic inflammatory syndrome. The lesions lack both HNF-1α and β-catenin mutations. IL-6 inflammatory pathway activation is implicated in IHCA development, manifesting with dystrophic vessels and telangiectasia. Specifically, the arteries have thick walls, and the sinusoids are dilated, a condition called "peliosis." Adenomas in this category were formerly called “telangiectatic focal nodular hyperplasia.” The tumors exhibit positivity for serum amyloid A (SAA) and C-reactive protein (CRP) and demonstrate inflammatory infiltrates and ductular reactions.

Unclassified Type

Patients with unclassified HCA comprise 10% of cases. The lesions are negative for CRP, SAA, β-catenin, and glutamine synthetase but exhibit typical liver fatty acid-binding protein (LFABP) staining.[8][9]

Epidemiology

HCA's annual incidence among patients taking oral contraceptive pills is 30 to 40 cases per million, compared to 1 case per million in people who do not take these medications. A higher risk is seen after more than 2 years of use.[10] A study found a 25-fold relative risk increase in women using oral contraceptive pills for over 109 months compared to those using them for less than 12 months. Discontinuation of oral contraceptives often results in spontaneous tumor regression, supporting the link to sex hormones. HCA is more common in women than men, with a ratio of 4 to 1, although this ratio is changing due to sports-related anabolic drug use.

Other populations at risk for developing HCA include individuals with GSD types I and III, iron-overload conditions like β-thalassemia and hemochromatosis, and states of endogenous sex hormonal imbalance such as Klinefelter and polycystic ovarian syndromes. Except for polycystic ovarian syndrome, these other conditions predominantly affect men and are often diagnosed during childhood.[11][12]

Pathophysiology

Genetic mutations offer new insights into the behavior of these tumors. However, traditional knowledge highlights the strong association between sex hormones, notably oral contraceptive pills and anabolic steroids, and HCA development. Other drugs that have been implicated include clomiphene, recombinant human growth hormones, and barbiturates.[13]

Histopathology

Gross examination of HCAs reveals yellow or light brown well-circumscribed lesions with a soft consistency. The lesions are usually solitary, with sizes ranging from 2 to 15 cm. HCAs tend to be larger in women on oral contraceptives. Most are located in the right lobe and are subscapular. Microscopic examination shows a lack of malignancy features and abundant glycogen or fat. Liver architecture is absent, with central veins, bile ducts, and portal tracts often not visualized. However, HCAs are well-vascularized with small, thin-walled arterioles.

HCAs are typically solitary tumors with monoclonal cell lines. These tumors lack a true capsule, though hepatocyte sheets in the outer boundaries form their "pseudo-capsule" and are surrounded by otherwise normal liver tissue.  The lack of biliary ducts distinguishes the lesion from normal liver tissue (see Image. Hepatocellular Adenoma Histopathology).

History and Physical

History

About half of patients with HCAs are asymptomatic, with the tumor discovered incidentally on imaging. The condition presents variably in symptomatic individuals, ranging from mild, ill-defined epigastric pain with bloating to severe, acute RUQ pain.[14] Adenoma rupture may be accompanied by dizziness, intractable vomiting, and lethargy.[15] The pain may radiate to the right flank in some cases, resembling cholecystitis or a urinary tract pathology. Rupture occurs in up to 27% of HCAs, resulting in a 5% to 10% mortality rate.[16]

Individuals with suspected HCA should be asked about the symptoms, especially abdominal pain and its characteristics. Risk factors must be assessed, including prolonged sex hormone use and underlying conditions like GSD and obesity. The family history may reveal liver diseases or malignancies and other genetic conditions predisposing to HCA evolution.

Physical Examination

A complete physical examination helps determine the diagnosis and the patient's hemodynamic status. Individuals with abdominal pain due to gastrointestinal pathology often lie still, in contrast to patients with renal colic. Tachycardia and hypotension are possible indicators of shock. Fever may manifest due to inflammation and is a physical feature shared with many other conditions, including hepatitis.

Some patients may have dry oral mucosa and poor skin turgor from dehydration. Pallor and poor pulses may be appreciated due to hemorrhage. Normal chest auscultation findings may rule out a cardiac or pulmonary cause of referred abdominal pain unless such illnesses coexist. The abdominal examination may reveal hepatomegaly with tenderness. Abdominal rigidity may be a sign of peritoneal irritation from hemoperitoneum due to tumor rupture.

Evaluation

Laboratory tests are generally unhelpful in diagnosing hepatocellular adenomas, though they can help rule out other disorders and determine hematologic and metabolic status. α-fetoprotein (AFP) levels are typically normal but can rise if malignant transformation to hepatocellular carcinoma (HCC) occurs. Hepatitis tests should be conducted to rule out these infections. Alkaline phosphatase and γ-glutamyl transferase levels may increase two- to threefold, especially in IHCAs. White blood cell count, fibrinogen, and CRP may also be elevated.[17][18][19]

Core needle biopsy has limited diagnostic value in HCA. However, immunohistochemical markers may be helpful in expert centers. Biopsy should be limited to rare cases where imaging is equivocal, and the diagnosis may alter management strategy.

Ultrasonography often fails to distinguish between benign and malignant tumors. Doppler ultrasonography may demonstrate arterial hypervascularity with vessels running along the lesion's border in a "basket" pattern. Some tumors may appear hyperechoic due to the hepatocytes' steatotic content.

Dynamic magnetic resonance imaging (MRI) with a hepatocyte-specific contrast agent like gadobenate dimeglumine is the modality of choice for diagnosing HCAs. This method can distinguish between hepatocellular adenomas and other benign and malignant liver tumors (see Image. Hepatocellular Adenoma on Magnetic Resonance Imaging). The lesion may exhibit a clearly defined central margin with nearly parallel vessels entering from the periphery, giving the appearance of a spoked wheel. In some cases, dynamic MRI may demonstrate a tortuosity of peripheral vessels with central necrosis.

A dynamic computed tomography (CT) scan is also potentially useful in evaluating HCAs. Dynamic CT may show peripheral enhancement of the tumors during the early phase, transitioning to centripetal flow in the later portal venous phase. 

Treatment / Management

HCAs less than 5 cm in size and linked to oral contraceptive pills are initially approached conservatively. Oral contraceptive withdrawal with regular imaging surveillance has demonstrated significant tumor regression in numerous cases. Resuming oral contraceptive intake requires careful radiologic monitoring. The optimal follow-up duration remains unestablished, with some authors suggesting surveillance until menopause. Refractory tumors often correlate with obesity.

Most hepatic adenomas remain stable during pregnancy. Tertiary centers often monitor adenomas smaller than 5 cm serially in pregnant women every 3 months and during the postpartum period. Patients with small adenomas are not discouraged from getting pregnant.

Surgical resection is recommended for all male patients regardless of the tumor size and for women with tumors larger than 5 cm. The technique does not require a wide margin or regional lymphadenectomy. Emergent surgery for a ruptured hepatic adenoma with intraperitoneal bleeding has a mortality rate of 5% to 10%. In contrast, elective resection's mortality rate is less than 1%. 

Transarterial embolization (TAE) is recommended for hepatic adenomas complicated by hemorrhage. Patients with intratumoral hemorrhage rarely present with hemodynamic instability. In such cases, TAE may be followed by elective surgical resection of the adenoma. TAE is indicated within 2 to 3 days of tumoral hemorrhage.

Radiofrequency ablation is appropriate only for a very select patient population. The modality is not appropriate for surgical candidates and individuals with hormone-sensitive tumors, underlying liver disease, or a desire for pregnancy. Radiofrequency ablation should be used to treat patients with adenomas less than 4 cm in size.

Obesity, nonalcoholic steatohepatitis, and metabolic syndromes increase the risk of developing hepatic adenomatosis. Complications like hemorrhage or malignant transformation correlate less with adenomatosis than the tumors' molecular signatures. Moreover, most liver adenomatoses are typically associated with HNF-1α mutations, which have a low risk for malignant transformations. Thus, a liver transplant is generally not indicated for nonresectable hepatic adenomas. Exceptions involve men with intrahepatic portosystemic venous shunts with nonresectable hepatic adenomas. Genetic counseling is recommended for patients with liver adenomatosis, especially if associated with familial adenomatous polyposis or MODY3.

About 4% to 5% of hepatic adenomas are at risk for malignant transformation to HCC, with the risk increased by Fanconi anemia and androgen treatments. The Wnt and β-catenin pathways are particularly associated with malignant transformation. Surgical resection is typically recommended for this subtype.[20]

Differential Diagnosis

The differential diagnosis of liver lesions suspicious for HCA includes hemangioma, focal nodular hyperplasia (FNH), HCC, and metastatic tumors. Dynamic contrast-enhanced MRI can differentiate between HCA and hemangiomas, which generally exhibit peripheral enhancement and a centripetal fill-in pattern.[21] Gadolinium-based contrast MRI often shows FNH taking up more contrast in the hepatobiliary phase than HCA, along with a central scar and lobulated appearance.[22]

The clinical scenario is crucial in distinguishing between HCA and HCC or metastatic disease. Individuals with HCC typically have underlying chronic liver disease with or without cirrhosis. People with metastatic disease typically have a known extrahepatic primary malignancy and associated risk factors.

Prognosis

The prognosis for patients with hepatocellular adenoma remains poorly established. Oral contraceptive discontinuation may result in the regression or resolution of some lesions. As previously stated, about 27% of HCAs may rupture, which has a 5% to 10% mortality risk. The risk of HCA's malignant transformation is 4.2%.[23] The risk of malignancy generally persists even after discontinuing oral contraceptives.

Complete HCA resolution is unlikely in most patients. About 25% of women will continue to have RUQ pain, with hemorrhage potentially occurring in up to 30% to 45% of women. Bleeding may occur within the lesion or peritoneum. The larger the lesion, the higher the risk of hemorrhage. Pregnancy has been associated with HCA enlargement and increased rupture risk.

Complications

HCA's complications include tumor rupture and hemorrhage, which may result in hemorrhagic shock and death. Tumors larger than 5 cm have an increased rupture risk. The malignant transformation of HCAs is greater in men than women with tumors larger than 5 cm.