Continuing Education Activity

Hepatic adenomas, also called hepatocellular adenomas, are rare but benign epithelial tumors of the liver frequently associated with oral contraceptive pill use. They are also seen in patients treated with anabolic steroids for athletic enhancement, Fanconi anemia, or aplastic anemia. Although benign, they are associated with risks of hemorrhage and malignant transformation. Elective resection is recommended in all men with adenomas and in women with adenomas greater than 5 cm. Hepatic adenoma rupture leads to severe abdominal pain and hypotension and/or shock, particularly in patients using oral contraceptive pills. This is not an uncommon event and can be associated with significant mortality requiring immediate recognition. This activity describes the evaluation and management of hepatic adenoma and reviews the interprofessional team's role in evaluating and treating patients with this condition.

Objectives:

• Review the risk factors for developing hepatic adenomas.
• Describe the pathophysiology of hepatic adenomas.
• Outline the typical presentation of a patient with hepatic adenoma rupture.
• Explain the importance of collaboration and communication amongst the interprofessional team to ensure the appropriate selection of candidates for surgical removal of hepatic adenomas.

Introduction

Hepatic adenomas, also called hepatocellular adenomas, are rare but benign epithelial tumors of the liver frequently associated with women of reproductive age who are taking exogenous estrogens in the form of oral contraceptive pills. They are also seen in patients treated with anabolic steroids for athletic enhancement, Fanconi anemia, or aplastic anemia. Although benign, they are associated with risks of hemorrhage and malignant transformation. Elective resection is recommended in all men with adenomas and in women with adenomas greater than 5 cm. Advances in the radiologic diagnosis and subtype classifications based on molecular behavior have emerged, which provide a more systematic approach to treating patients with hepatic adenomas. Although typically singular, multiple adenomas can occur. Hepatic adenomatosis refers to the presence of ten or more tumors.[1][2][3]

Etiology

Understanding the molecular behavior of hepatic adenomas deepened with the discovery by Chen et al. of the role of beta-catenin from the Wnt signaling pathway in the formation of hepatic adenomas in 2002. In 2007, Bioulac-Sage and associates from Bordeaux came up with a classification scheme for hepatic adenomas based on molecular behavior patterns called phenotypic-genotypic classification.[4][5] Other groups have since validated this classification scheme. This scheme distributes hepatic adenomas into 4 main groups:

HNF-1alpha Inactivated Mutations (35% to 40%)

It involves biallelic mutations of the TCF-1 gene that encodes the hepatocyte nuclear factory family transcription factor HNF-1alpha. HNF-1alpha is associated with hepatocyte differentiation and liver development, as well as glucose and lipid metabolism. This type occurs mostly in women and is often associated with mature-onset diabetes of the young (MODY3). Ninety percent of the mutations are somatic, although those associated with MODY3 can be germline and common in patients with adenomatosis.

Beta-catenin Activated Mutations (15% to 20%)

These are frequently associated with exposure to male hormones, glycogenesis, and familial adenomatous polyposis. Mild cytological or architectural abnormalities in the liver parenchyma lead to an acinar pattern. It is rarely detected in patients with steatosis and those with inflammatory changes in the liver. This group has a higher risk of malignant transformation, and the Wnt pathway has been implicated in 10% to 25% of the cases of hepatocellular carcinomas. On immunohistochemical staining, these adenomas tend to stain for glutamine synthetase rather than beta-catenin, which stains patchily.

Inflammatory Hepatic Adenomas (40% to 50%)

Predominantly seen in women with a high body mass index, alcohol consumption, and systemic inflammatory syndrome. It is associated with the activation of the IL-6 inflammatory pathway with dystrophic vessels (thickened wall arteries with sinusoidal dilatation called peliosis) and telangiectasia. These were formerly called “telangiectatic focal nodular hyperplasia.”  These tumors stain with serum amyloid A (SAA) and with C-reactive protein.

Unclassified Type (10%)

These adenomas do not stain for C-reactive protein, SAA, beta-catenin, or glutamine synthetase. They also have typical liver fatty acid-binding protein (L-FABP) staining.

Epidemiology

The annual incidence of hepatic adenomas in oral contraceptive pill users ranges from 30 to 40 cases per million compared to 1 to 1.3 cases per million among nonusers. This risk increases with more than 5 years of use. Thus, in one study, the relative risk for hepatic adenomas for women who used oral contraceptive pills for more than 109 months was calculated as 25 times that of women who used it for less than 12 months. The incidence increased with the advent of the use of oral contraceptive pills. Discontinuation of the pills can lead to spontaneous regression of these tumors, making the case stronger for association with sex hormones. Adenomas can also occur with pregnancy. The ratio of women to men who develop these tumors is 4 to 1. This ratio appears to be changing because of the widespread use of anabolic drugs in sports. Other populations that exhibit this condition include those with glycogen storage disease (GSD) types I and III, iron-overload associated with beta-thalassemia and hemochromatosis, and perhaps those with an endogenous imbalance of sex hormones such as Klinefelter and polycystic ovarian syndromes (PCOS). In these cases, except for PCOS, there is a male predominance, and the diagnosis is made during childhood.[6][7]

Pathophysiology

Hepatic adenomas are typically solitary tumors with monoclonal cell lines. In appearance, they are light brown to yellow, soft and sharply circumscribed, but do not have a true capsule enclosing them. They have a "pseudo-capsule" formed by sheets of hepatocytes comprising the outer boundaries. These hepatocytes are compressed by surrounding otherwise normal liver tissue. The tumor is well-vascularized with small thin-walled arterioles. The tumor has no biliary ducts, which distinguishes it from the normal liver tissue in the vicinity.

Genetic mutations and our understanding of them have begun to provide new insight into these tumors' behavior. However, the traditional knowledge based on the link between sex hormones, particularly oral contraceptive pills and anabolic steroids, seems to provide the strongest insight into the etiology of the development of hepatic adenomas. Other drugs have been implicated in the development of hepatic adenomas. Understandably, clomiphene and recombinant human growth hormones play a prominent role. Barbiturates are also linked to the development of these tumors.[8]

Histopathology

Gross examination of hepatocellular adenomas reveals that the lesions are well-circumscribed, may appear yellow or light brown in color, and have a soft consistency. Most are solitary and range in size from 2 to 15 cm. These lesions tend to be larger in women on the oral contraceptive pill. Most are located in the right lobe and are subscapular. The microscopic exam usually reveals no sign of malignancy, but the cells contain abundant glycogen or fat. The liver architecture is absent, and one may not visualize central veins, bile ducts, or portal tracts.

History and Physical

Typically about half of patients with adenomas are asymptomatic, and the tumor is found incidentally on imaging. The remaining patients have symptoms that could range from a mild, often ill-defined abdominal pain in the right hypochondrium or epigastrium to bloating. Labs outside of the reference range may include elevated alkaline phosphatase and gamma-glutamyl transferase. In the case of malignant transformation to HCC, alpha-fetoprotein (AFP) can be elevated. Hepatomegaly with mild tenderness can be seen. The sudden presentation occurs when the hepatic adenoma ruptures, resulting in acute hemoperitoneum. An enlarged liver would be smooth but slightly tender. It presents with severe abdominal pain with hypotension and/or shock. This event is not uncommon and is often seen with oral contraceptive pill use. It is associated with a significant mortality rate. Tumors that rupture are typically greater than 5 cm, solitary, and superficially located. Often, women are either menstruating or pregnant at the time.

Evaluation

Laboratory tests are not typically helpful in diagnosing hepatic adenomas. A-fetoprotein is usually negative. Hepatitis B and C should be checked to exclude malignant disease. A two- or threefold increase in alkaline phosphatase and g-glutamyl transferase has been seen, particularly with inflammatory hepatic adenomas. WBC count, fibrinogen, and C-reactive protein may be elevated as well.[9][10][11]

Core needle biopsy also has limited diagnostic value, although immunohistochemical markers can be helpful in expert centers.

Ultrasonography fails to distinguish between benign and malignant tumors. Doppler can demonstrate arterial hypervascularity with vessels running along the border of the lesion in a "basket pattern."

Dynamic magnetic resonance imaging with a hepatocyte-specific contrast agent, such as gadobenate dimeglumine, is the best modality for diagnosing hepatic adenomas. This method is most able to distinguish between hepatic adenomas and other benign and malignant tumors of the liver. The tumor can have a clearly defined central margin with nearly parallel vessels entering from the periphery, giving the appearance of a spoked wheel. Alternatively, it could have a tortuosity of peripheral vessels with central necrosis. A dynamic CT scan is another modality that can be useful in imaging. Equivocal imaging may need core needle biopsy for further clarification.

Treatment / Management

Conservative management is the initial policy for all single or multiple tumors less than 5 cm in size and associated with oral contraceptive pills. Management includes cessation of oral contraceptive pills and imaging surveillance and has been shown to cause near-total to complete regression in the size of the tumors in many cases. Resumption of oral contraceptive pill use must be followed with radiologic surveillance. The optimal duration of follow-up has not been established, and surveillance has been recommended until menopause by some authors. Tumors refractory to conservative management are typically associated with obesity.[12][13][14]

The majority of hepatic adenomas remain stable during pregnancy. Most tertiary centers monitor adenomas less than 5 cm serially in pregnant women every three months and during the postpartum period. They do not discourage patients with small adenomas from getting pregnant.

Surgery with resection is recommended for all male patients regardless of the tumor size and for women with tumors greater than 5 cm. Surgical resection does not require a wide margin or regional lymphadenectomy. Elective resection is associated with a mortality rate of less than 1%. Emergent surgery for a ruptured hepatic adenoma with intraperitoneal bleeding has a mortality rate of 5% to 10%.

Transarterial embolization (TAE) is recommended for hepatic adenomas complicated by hemorrhage. Patients with intra-tumoral hemorrhage rarely present with hemodynamic instability, which allows for TAE 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. It is not appropriate for hormone-sensitive tumors, underlying liver disease, surgical candidates, or those with a desire for pregnancy. It should be used to treat patients with adenomas less than 4 cm in size.

Obesity, nonalcoholic steatohepatitis, and metabolic syndromes are associated with hepatic adenomatosis. The development of complications of hemorrhage or malignant transformation is not related to the development of adenomatosis but rather to the molecular signatures. Moreover, most liver adenomatoses are typically associated with HNF-1alpha mutations, which have a low risk for malignant transformations. For this reason, a liver transplant is not indicated for nonresectable hepatic adenomas as a rule. Exceptions involve men with an intrahepatic portosystemic venous shunt with nonresectable hepatic adenomas. Meanwhile, genetic counseling is recommended for patients with liver adenomatosis, particularly those associated with familial adenomatous polyposis or MODY3.

About 5% of hepatic adenomas are at risk for malignant transformation to hepatocellular carcinoma. Patients with Fanconi anemia and those with androgen treatment are at particular risk. The Wnt and beta-catenin pathways are particularly associated with malignant transformation. For this reason, surgical resections are typically recommended for this subtype.

Differential Diagnosis

• Hemangioma
• Lymphoma
• Echinococcal cyst
• Hepatoblastoma
• Metastatic lesion
• Localized fatty change

Prognosis

The prognosis for patients with hepatic adenoma remains poorly established. If the patient discontinues oral contraceptives, ome lesions have been known to regress or resolve. Hepatocellular adenomas may also experience spontaneous hemorrhage and rupture and undergo malignant transformation. 

Complications

• Hemorrhage
• Malignant transformation
• Shock
• Death

Deterrence and Patient Education

Patients need to understand that the risk for malignant transformation of these lesions is about 5 percent. Females do not necessarily need to avoid pregnancy with lesions of 5 cm or less, but becoming pregnant will require coordinated care from all interprofessional team members, and the patient needs counsel on the risks involved. If resection is needed during pregnancy, this should occur during the second trimester when risks to both mother and fetus are at their lowest. These decisions require the patients to be fully informed of their condition and the options, risks, and benefits of any course of action.

Pearls and Other Issues

1. Hepatic adenomas are rare benign epithelial tumors of the liver frequently associated with women of reproductive age who are taking exogenous estrogens in the form of oral contraceptive pills.
2. The classification scheme of hepatic adenomas based on molecular behavior patterns called the phenotypic-genotypic classification has been validated and is a useful classification scheme.
3. HNF-1alpha type is associated with hepatocyte differentiation, mostly seen in women or with mature-onset diabetes of the young.
4. Beta-catenin activated mutations that account for 15% to 20% of hepatic adenomas are most frequently associated with exposure to male hormones. Because this population has a higher risk of malignant transformation to hepatocellular carcinoma, surgical resection is recommended in this type of adenoma.
5. Inflammatory hepatic adenoma is predominantly seen in women with higher body mass index, alcohol consumption, and systemic inflammatory syndrome. These tumors stain positive with serum amyloid A and with C-reactive protein.
6. Discontinuation of oral contraceptive pills can lead to spontaneous regression of tumors in cases of single or multiple tumors less than 5 cm in size. Imaging surveillance is still recommended to monitor for regression.
7. Surgery is recommended for all tumors greater than 5 cm in size but does not require wide margins or regional lymphadenectomy.
8. Obesity, nonalcoholic steatohepatitis, and metabolic syndromes are associated with hepatic adenomatosis.

Enhancing Healthcare Team Outcomes

Hepatic adenomas are benign liver lesions and have been linked to anabolic steroids and the oral contraceptive pill. The majority of these lesions are seen in women of childbearing age who are on the pill. Even though the lesions are benign, there is a risk of bleeding and malignant transformation.

While interprofessional management of the disorder is primarily by the gastroenterologist and the surgeon, the primary focus today is on prevention. Both the pharmacist and nurse play a vital role in patient education. Interprofessional management will result in improved patient outcomes. [Level 5]

All women who are prescribed the oral contraceptive should be warned about the possibility of developing this lesion—the lower the dose, the lower the risk. If the female has no other contraception options, she should be educated on the symptoms of a hepatic adenoma and when to seek help. Before getting pregnant, the female should be encouraged to have a liver ultrasound to ensure no lesion is present. Pregnancy in the presence of a hepatic adenoma can significantly increase the risk of hemorrhage and maternal mortality. All females who develop symptoms should be encouraged to have the lesion excised. Finally, the patient should undergo annual screening for liver cancer, especially if the lesion is larger than 5 cm.[15][16] [Level 5]

Outcomes

• In the majority of patients with a hepatocellular adenoma, a complete resolution is not possible.
• About 25% of women will continue to have right upper quadrant pain, and hemorrhage may occur in 30% to 45% of women. The hemorrhage may be within the lesion or the peritoneum. The larger the lesion, the higher the risk of hemorrhage.
• Pregnancy has been associated with hepatic adenoma. Further, the risk of rupture is also known to increase during pregnancy, resulting in high maternal and fetal mortality.
• The overall risk of malignancy ranges from 4% to 10%. The risk of malignancy persists even after the oral contraceptives have been discontinued.[17] [Level 5]