Hepatocellular Adenoma

Updated: Oct 08, 2015
  • Author: Bradford A Whitmer, DO; Chief Editor: BS Anand, MD  more...
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Overview

Background

Hepatocellular adenomas (HCAs) are also known as hepatic adenomas or liver cell adenomas. They are rare, benign tumors of presumable epithelial origin and occur in less than 0.004% of the population at risk.

Hepatocellular adenomas occur mostly in women of childbearing age and are strongly associated with the use of oral contraceptive pills (OCPs) and other estrogens. This is reflected by a dramatic increase in the incidence of this disease since OCPs were introduced in the 1960s. For example, before the use of OCPs, no hepatic adenomas were reported at surgery at the Mayo Clinic between 1907 and 1954. Edmonson reported finding only 2 adenomas among 50,000 autopsy specimens at Los Angeles County Hospital between 1907 and 1958. [1] However, in women using OCPs, adenomas were 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). [2]

In a case series of 3 patients, Baum et al also suggested an association between hepatic adenomas and OCPs. [3] Klatskin [4] and Rooks et al [5] reported that the greatest risk occurs in women older than age 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 adenomas are occasionally diagnosed after discontinuation of OCPs. [6]

Decreases in dosages and the types of hormones contained in OCPs have led to a reduction in adenoma incidence, as reported by another study by Edmonson et al. [7] Rooks et al reported that in women who have never used OCPs, the annual incidence of hepatic adenoma is 1 to 1.3 per million but increases to 3.4 per 100,000 in long-term users. [5] Currently, benign liver tumors may be detected more frequently though, owing to increased routine use of medical imaging.

Hepatic adenomas may be single or multiple, and they may occasionally reach a size larger than 20 cm. In addition to OCPs, other conditions associated with adenomas are anabolic steroids, androgenic steroids, beta-thalassemia, tyrosinemia, type 1 diabetes mellitus, hemochromatosis, barbiturate usage, clomiphene intake, and glycogen storage diseases (GSDs) (types 1 and 3). However, multiple hepatic adenomas are more common in glycogen storage disease, with an incidence between 22% and 75% in type 1 and 25% in type 3 disease. [8]

In addition to a multiplicity of adenomas, hepatic adenomas associated with GSD tend to occur more commonly in men than women (ratio 2:1) and often develop before the age of 20 years. [9, 10] This should not be confused with hepatic adenomatosis, which is an equally uncommon condition in which at least 10 lesions develop at equal frequency in either sex in the absence of classic risk factors such as OCP or GSD. [11]

A new, not yet universally accepted, Bordeaux classification of hepatocelluar adenoma is currently being evaluated. This subclassification includes hepatocyte nuclear factor 1α-inactivated HCA (HNF1α HCA 30-35%), β-catenin-mutated HCA (β-cat HCA 10-15%), inflammatory HCA (50%), and a subgroup of less than 10% that remains unclassified. [12]

This classification may be important because the β-catenin mutation appears to be related to hepatocellular carcinoma. [13, 14, 15] A small study suggests that being overweight or obese may cause an increase in inflammatory HCA and β-catenin activated-inflammatory HCA subgroups. [16]

Telangiectatic adenoma is a recently recognized variant of HCA formerly classified as a type of focal nodular hyperplasia. This is in the subcategory of inflammatory hepatocellular adenomas. [12]

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Pathophysiology

Hepatic adenomas consist of sheets of hepatocytes without bile ducts or portal areas. Kupffer cells, if present, are reduced in number and are nonfunctional. Hepatic adenomas are tan in color, smooth, well circumscribed, fleshy in appearance, and vary from 1 to 30 cm in size. They have large blood vessels on the surface, and the lesions may outgrow their arterial blood supply, causing necrosis within the lesions. A fibrous capsule may be present or absent; if absent, this may predispose to intrahepatic or extrahepatic hemorrhage. Most present as solitary lesions in the lobe of the liver; however, tumors do occur in both the right lobe and the left lobe, and up to 20% of cases have multiple lesions.

The pathogenesis is thought to be related to a generalized vascular ectasia that develops due to exposure of the vasculature of the liver to oral contraceptives and related synthetic steroids. Estrogen may exert an influence via estrogen receptors in the cytoplasm or nucleus of hepatocytes. However, this remains controversial as adenomas can occur in males and children without predisposing risk factors, and these receptors have not been identified even with the use of monoclonal antibodies. [17] Rebouissou et al [18] and Bioulac-Sage et al [19, 13] also reported that hepatic adenomas are monoclonal tumors and probably develop from an interaction between gene defects and environmental changes such as OCPs and steatosis. HCAs are now believed to result from specific genetic mutations involving transcription factor 1 gene (TCF1), interleukin 6 signal transducer gene (IL6ST), and β catenin-1 gene (CTNNB1). [20]

Adenomas have also been associated with diabetes mellitus and GSD, leading to speculation as to whether imbalances between insulin and glucagon also play a role. Patients with GSD are more likely to present with multiple lesions. Lesions associated with GSD often appear in younger patients (early third decade of life) and have a male-to-female ratio of 2:1. In this group, the abnormal amounts of stored glycogen may have some effect, perhaps by oncogene stimulation.

Insulin and glucagon appear to play a larger role, because GSD-related adenomas have been reported to seemingly disappear with dietary manipulation. A germline mutation of the hepatocyte nuclear factor (HNFα) was described by Reznik et al in 2 families that had both diabetes mellitus and liver adenomatosis. [21] Tumor cell analysis showed biallelic inactivation of HNFα.

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Epidemiology

Frequency

United States

Hepatocellular adenomas are extremely rare. The annual incidence is 1 to 1.3 cases per 1 million persons per year. However, 3-4 cases per 100,000 people per year occur among women who have had exposure to estrogen-containing OCPs. A 5-fold increased risk exists with 5-7 years of OCP exposure, and a 25-fold increased risk exists with longer than 9 years of OCP exposure.

Race-, sex-, and age-related demographics

No racial predisposition exists, but a large review of HCA from 1998 to 2008 comparing 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 limited use of oral contraceptives. [22]

Approximately 90% of patients are female.

Most patients are aged 15-45 years.

Mortality/Morbidity

Nearly 20-25% of cases have right upper quadrant pain, and 30-40% experience hemorrhage (one third within the mass, two thirds into the abdomen).

In a systematic review including a total of 1176 patients, the overall frequency of hemorrhage was 27.2% among patients. Hemorrhage occurred in 15.8% of all hepatocellular adenoma lesions. Rupture and intraperitoneal bleeding were reported in 17.5% of patients. [23]

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 sizes less than 5 cm, even as small as 1 cm. [24] The risk, though, appears to be minimal. The risk of hemorrhage appears to be related to size and not related to the number of lesions. Multiple studies did not find a difference between patients with a single or multiple hepatocellular adenomas. [25, 26, 27]

The mortality rate associated with an acute hemorrhage into the peritoneum may be as high as 25-30% in patients with large tumors.

The risk of malignant transformation is not completely known and may be as high as 13% based on small studies. A recent systematic review incorporating all reports on malignant degeneration of hepatocellular adenoma into hepatocellular carcinoma showed an overall risk of 4.2%, with only 4.4% of these malignant transformations occurring in lesions less than 5 cm in diameter. [28]

HCA combined with chronic hepatitis B infection could increase the risk of malignant transformation, but more studies are needed. [22]

Pregnancy has been associated with hepatic adenoma, and rupture of the adenoma during pregnancy has been associated with high rates of maternal and fetal mortality.

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