Hepatocellular adenoma overview

# Overview
Hepatocellular adenoma is an uncommon benign liver adenoma that is most commonly associated with oral contraceptive use in women of childbearing age. It was first described by Edmondson in 1958 as an encapsulated liver tumor that does not contain bile ducts. In 1970s several case series supported the hypothesis of an association between oral contraceptives and hepatocellular adenoma. It is generally asymptomatic, the typical clinical manifestations include spontaneous rupture or hemorrhage leading to acute abdominal pain with progression to hypotension and even death. There are no specific physical examination findings associated with adenoma. The liver function tests and serum tumor markers are usually normal, but may be raised secondary to necrosis or hemorrhage and alkaline phosphatase may be raised in hepatocellular adenomatosis. The causes of hepatocellular adenoma include; oral contraceptive medications, long term anabolic androgenic steroids, obesity, metabolic syndrome and glycogen storage diseases. It is more commonly seen in western countries where they are exposed to higher doses of oral contraceptive medications. The estimated incidence is 3 per 1,000,000/year and is 3 to 4 per 100,000 with long term oral contraceptive use. The hepatocellular adenomas are classified on the basis of molecular patterns called phenotypic genotypic classification into 04 groups including; HNF1 alpha inactivated adenoma, beta catenin activated adenoma, inflammatory hepatic adenoma and unclassified type adenoma. The exact pathogenesis of hepatocellular adenoma is still unknown, however, its association with oral contraceptive use is well established. Other associations of adenoma include; long term use of anabolic androgenic steroids and glycogen storage diseases as well. It has been linked to mutations in HNF1a and beta catenin genes. On gross pathology, the hepatocellular adenoma appears as solitary or multiple, unencapsulated and well demarcated lesion, which can occasionally be pedunculated or encapsulated that can also form multiple masses. The intra tumoral hemorrhage can give rise to soft, necrotic, red brown lesion on gross appearance. The microscopic features of hepatocellular adenoma include benign hepatocytes arranged in mildly thickened cell plates with a preserved reticulin network and thin walled arteries. The arteries and arterioles are not accompanied by other portal tract elements such as bile ducts, portal veins or fibroconnective tissue. Hepatocellular adenoma must be differentiated from focal nodular hyperplasia, large regenerative hyperplasia, hepatocellular carcinoma in noncirrhotic patients & fibrolamellar hepatocellular carcinoma, cholangiocarcinoma and metastases. If left untreated, there is 30% bleeding risk. Complications include; bleeding, rupture and malignant transformation. The CT scan findings of hepatocellular adenoma include; non lobulated, well marginated mass that can be encapsulated and rarely calcified and heterogeneous hyperattenuating area within the tumor seen in necrosis or old hemorrhage. The MRI findings include; from hyperintense to mildly hypointense relative to the liver tissue on T1 weighted images. On T2 weighted images they are predominantly hyperintense relative to the liver, whereas in the presence of necrosis or hemorrhage they can be heterogeneous with hyper or hypoattenuating signal. The gold standard method for diagnosis of hepatocellular adenoma is excision biopsy of the liver lesions either by surgery or laparoscopically. There is no specific medical therapy for the adenoma, wait & watch policy is recommended for hepatocellular adenomas 5 cm in diameter, that increase in size, lesions with intra tumoral hemorrhage and male patients (irrespective of the adenoma size). The radiofrequency ablation (RFA) and transcatheter arterial embolization (TAE) may be tried in patients who are poor candidates for surgery.

# Historical Perspective
Hepatocellular adenoma was first described in 1958 by Edmondson as an encapsulated liver tumor that does not contain bile ducts. Baum reported the important relationship between the oral contraceptive use and hepatocellular adenoma development in 1973. Edmondson in 1976 published a case control study giving further evidence of this association.

# Classification
The hepatocellular adenomas are classified on the basis of molecular patterns called phenotypic-genotypic classification into 04 major groups including; HNF1 alpha inactivated adenoma, beta catenin activated adenoma, inflammatory hepatic adenoma and unclassified type adenoma.

# Pathophysiology
The exact pathogenesis of hepatocellular adenoma is still unknown, however, its association with oral contraceptive use is well established. It has also been associated with long term use of anabolic androgenic steroids and glycogen storage diseases. The hepatocellular adenoma have been linked to mutations in HNF1a and beta catenin genes. On gross pathology it appears as a solitary or multiple, unencapsulated and well demarcated mass lesion, which can occasionally be pedunculated or encapsulated that can also form multiple masses. The intratumoral hemorrhage can give rise to soft, necrotic, red brown lesion on gross appearance. The microscopic features of hepatocellular adenoma include benign hepatocytes arranged in mildly thickened cell plates, with a preserved reticulin network and this walled arteries. The arteries and arterioles are not accompanied by other portal tract elements such as bile ducts, portal veins or fibroconnective tissue.

# Causes
The causes of hepatocellular adenoma include; oral contraceptive medications, pregnancy, long term use of anabolic androgenic steroids, maturity onset diabetes of the young, metabolic syndrome, obesity, glycogen storage diseases, clomiphene and vascular disorders like portal vein agenesis, budd chiari syndrome and hereditary hemorrhagic telangiectasia.

# Epidemiology and Demographics
The hepatocellular adenoma is more common in women in western countries where they are exposed to higher doses of oral contraceptives. The estimated incidence is 3 per 1,000,000/year and is 3 to 4 per 100,000 with long term oral contraceptive use. It is more common in women of childbearing age who take oral contraceptives and can rarely occur in men who take long term anabolic androgenic steroids.

# Risk factors
The most important risk factor in the development of hepatocellular adenoma is use of oral contraceptive medications. Other risk factors include; glycogen storage diseases, familial adenomatous polyposis, klinefelters syndrome, metabolic syndrome, obesity, long term use of anabolic androgenic steroids, vascular disorders such as portal vein agenesis, budd chiari syndrome and hereditary hemorrhagic telangiectasia.

# Screening
There is insufficient evidence to recommend any screening test for the hepatocellular adenoma.

# Differentiating Hepatocellular adenoma from other Diseases
The hepatocellular adenoma must be differentiated from focal nodular hyperplasia, large regenerative hyperplasia, hepatocellular carcinoma in non cirrhotic patients and fibrolamellar hepatocellular carcinoma, cholangiocarcinoma, primary lymphoma and metastases on the basis of clinical presentation and MRI findings.

# Natural History, Complications and Prognosis
There is 30% bleeding risk for hepatocellular adenoma if left untreated. The natural course of hepatocellular adenoma after cessation of oral contraceptive use remains unclear, it may regress or remain stable in size. Complications include bleeding, rupture and malignant transformation. The prognosis is usually good after discontinuation of oral contraceptives, as it may regress. In cases where it does not regress after oral contraception withdrawal, surgery is the management of choice.

# Diagnosis

## History and Symptoms
The small hepatocellular adenoma is generally asymptomatic. Typical clinical manifestations include spontaneous rupture or hemorrhage leading to acute abdominal pain with progression hypotension and even death. There is history of oral contraceptive use in women and long term anabolic steroids use in men.

## Physical Examination
There are no specific physical examination findings associated with hepatocellular adenoma.

## Laboratory Findings
The hepatocellular adenoma usually have normal liver function tests and normal serum tumor markers, but may be raised secondary to necrosis or hemorrhage and alkaline phosphatase may be raised in hepatocellular adenomatosis.

## Chest X Ray
There are no chest x-ray findings associated with hepatocellular adenoma.

## CT
The CT scan appearances of hepatocellular adenoma are usually variable and characteristic lesions are best seen with multiphase helical CT scanning. The CT scan findings include; nonlobulated well marginated mass that can be encapsulated and is rarely, heterogeneous hypoattenuating area within the tumor seen in necrosis or old hemorrhage, and larger hepatocellular adenomas may be more heterogeneous than smaller lesions and their CT scan appearance is less specific.

## MRI
The MRI findings of hepatocellular adenoma include; from hyperintense to mildly hypointense relatvive to the liver tissue on T1 weighted images. On T2 weighted images they are predominantly hyperintense relative to the liver, whereas in the presence of necrosis and hemorrhage they can be heterogeneous with hyper or hypo attenuating signal. The central scar is on godalinium is not seen in hepatocellular adenoma. There is usually no significant uptake with injection of hepatocellular specific contrast agent, godalinium benzoyloxypropionictetraacetate (Gd-BOTA).

## Ultrasound
The ultrasonographic features of hepatocellular adenoma are non specific and may appear as hyper, iso or hypo echoic. It can show a hyper echoic mass. The color doppler ultrasound shows intratumoral veins associated with peritumoral veins and arteries. The contrast enhanced ultrasound is hypervascular in arterial phase and shows centripetal filling in portal venous and delayed phases.

## Other Imaging Findings
There are no other imaging findings associated with hepatocellular adenoma.

## Other Diagnostic Studies
The gold standard method for diagnosis of hepatocellular adenoma is excision biopsy of liver lesions either by surgery or laparoscopically. Percutaneous biopsy is not recommended due to the risk of bleeding and tumor dissemination. Other tests that can be used to differentiate between benign and carcinomatous lesions include; QBend10 and erbB2 immunostaining, comparative genomic insitu hybridization and fluorescence insitu hybridization.

# Treatment

## Medical Therapy
here is no specific medical therapy for the hepatocellular adenomas. The wait and watch policy is recommended for hepatocellular adenomas <5cm following cessation of offending drugs (OCPs) and no further growth detected. Annual followup is scheduled with MRI or ultrasound until menopause.

## Surgery
The surgical resection is treatment of choice for hepatocellular adenomas that are >5cm in diameter, that increase in size, lesions with intra tumoral hemorrhage and male patients (irrespective of the adenoma size). The liver transplantation may be considered for the hepatocellular adenomas associated with glycogen storage disease type 1. Radiofrequency ablation (RFA) and transcatheter arterial embolization (TAE) may be considered for the adenoma patients who are poor candidates for surgery.

## Primary Prevention
here are no primary preventive measures available for hepatocellular adenoma.

## Secondary Prevention
An yearly followup with MRI or ultrasound may be scheduled for female patients until menopause.