AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Background

Hepatocellular adenomas (HA) are uncommon benign liver tumors that occur mostly in women of childbearing age and are associated primarily with the use of birth control pills.

Since the 1960s, a dramatic increase in the incidence of the disease has occurred; this increase is attributed to the advent of oral contraceptive pills (OCPs). In 1958, Edmonson reported finding only 2 adenomas among 50,000 autopsy specimens. In a case series of 3 patients, Baum (1973) suggested the association between hepatic adenomas and OCPs. Klatskin (1977) and Rooks (1979) later showed that patients taking higher potency hormones, patients of advanced age, or patients with prolonged duration of use have a significantly increased risk of developing hepatocellular adenomas. Currently, decreases in dosages and the types of hormones contained in OCPs have led to a reduction in incidence.

Other risk factors include the use of androgen steroid therapy and the presence of type 1 glycogen storage disease.

Pathophysiology

Hepatocellular adenomas consist of sheets of hepatocytes without bile ducts or portal areas. Kupffer cells, if present, are reduced in number and are nonfunctional. Hepatocellular adenomas are tan in color, smooth, well circumscribed, fleshy in appearance, and vary from 1-30 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 hepatocellular adenomas 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 involve 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 on hepatocytes. However, this remains controversial. Adenomas also have been associated with diabetes mellitus and glycogen storage disease (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 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 distinct pathologic entity known as hepatic adenomatosis has been identified. Although overlap is possible, adenomatosis is generally defined as the presence of more than 10 adenomas within the liver in the absence of steroid use or by persistence after steroid withdrawal. Adenomatosis affects both men and women and is associated with elevations of alkaline phosphatase.

Frequency

United States

The annual incidence of hepatic adenoma is 1 case 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 greater than 9 years of OCP exposure. Associations also exist with diabetes mellitus; pregnancy; the use of anabolic steroids by men; and type 1 or 3 GSD, galactosemia, beta-thalassemia, or tyrosinemia.

Mortality/Morbidity

• From 20-25% of cases involve right upper quadrant pain, and 30-40% involve hemorrhage (one third within mass, two thirds into the abdomen).
• The mortality rate associated with an acute hemorrhage into the peritoneum may be as high as 20%.
• The risk of malignant transformation is not completely known and may be as high as 13% based on small studies.
• 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.

Race

No racial predisposition exists.

Sex

Approximately 90% of patients are female.

Age

Most patients are aged 15-45 years.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

History

The clinical presentation of patients with hepatocellular adenoma can vary widely. Salient features of the history and physical examination may include the following:

• Pain in the right upper quadrant or epigastric region is common, occurring in 25-50% of patients with hepatocellular adenomas.
• Lesions may be noticed by patients as a palpable mass. Lesions may also be discovered incidentally during an abdominal imaging study for an unrelated reason.
• History of birth control or anabolic steroid use should be elicited in patients with suspected hepatocellular adenomas.
• Patients may also present with severe, acute abdominal pain with bleeding into the abdomen, which results in signs of shock (eg, hypotension, tachycardia, diaphoresis).
• Hemoperitoneum occurs more frequently if the patient is taking a high-dose OCP, is actively menstruating or pregnant, or is within 6 weeks postpartum. Location of the lesion also is important, with those near the surface of the liver more prone to causing hemoperitoneum.

Physical

The physical examination findings are often nonspecific. Patients may be asymptomatic, or they may appear ill, with pallor and abdominal distress.

• Palpable tender or nontender mass in the right hypochondrium
• Findings consistent with hemorrhage
• Vital signs
• Tachycardia
• Hypotension
• Orthostasis
• Head, ears, eyes, nose, and throat (HEENT) examination
• Anicteric sclera (Jaundice has been reported due to compression of the biliary tree by the tumor.)
• Possible pale conjunctiva, if hemorrhage has occurred
• Cardiovascular findings - Tachycardia if actively bleeding
• Abdominal findings
• Possible right hypochondrial mass with or without tenderness
• Possible hepatomegaly
• Possible fluid wave in cases of hemoperitoneum
• Possible peritoneal signs, including guarding or rebound in cases of tumor rupture
• Skin findings - Possible Grey-Turner sign or Cullen sign in cases of hemoperitoneum
• Examination findings of the neck, chest, and extremities - Unremarkable
• Neurologic examination findings - Unremarkable

Causes

• Oral contraceptive medications containing mestranol
• Anabolic steroids

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Echinococcal cyst
Focal fatty change
Focal nodular hyperplasia
Hepatoblastoma
Infiltrative liver disease
Inflammatory pseudotumor
Leiomyosarcoma
Lymphoma
Nodular regenerative hyperplasia

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Lab Studies

• Serologically, hepatocellular adenomas are a diagnosis of exclusion. No specific serologic studies exist.
• Serum aminotransferase (aspartate aminotransferase [AST]/alanine aminotransferase [ALT]) levels are mildly elevated in approximately 50% of patients, likely due to the mass effect of the tumor.
• Serum alpha-fetoprotein (AFP) levels are within the reference range in patients with hepatocellular adenoma. Elevations are noted in 50% of hepatocellular carcinoma (HCC) cases. Thus, finding an elevated AFP represents either a primary carcinoma or an adenoma that has undergone malignant transformation. An AFP level within the reference range does not eliminate HCC from the differential diagnosis.
• Elevated carcinoembryonic antigen (CEA) levels suggest metastasis from the colon.
• Serologies for amoebiasis and echinococcus should be considered if the lesion appears cystic.

Imaging Studies

• Findings on imaging studies in cases of hepatocellular adenomas generally are nondiagnostic because the mass often is solitary and well demarcated. Distinguishing characteristics generally are absent. Ultrasound and CT imaging are more specific if intralesional hemorrhage is noted.
• Ultrasound
• • A nonspecific finding reveals a hypoechoic lesion, which usually is subcapsular (7% pedunculated), well circumscribed, ranges from 2-20 cm, and is located predominantly in the right lobe of the liver.
  • Doppler flow patterns in adenomas are venous, as compared to the arterial pattern noted in focal nodular hyperplasia.
• Computed tomography imaging
• • A nonspecific, well-circumscribed mass that has a low density on noncontrast and a marked centripetal pattern of enhancement on arterial phase
  • The lesion can have a central necrotic area or calcifications.
  • Most adenomas are encapsulated on CT scan.
• Magnetic resonance imaging
• • Variable appearance due to the presence or absence of hemorrhage
  • Hyperintense heterogeneous signals on T1- and T2-weighted imaging often due to lipids contained within the lesion
  • Hemorrhagic hepatocellular adenomas also may have hyperintense T1 imaging with subcapsular hemosiderin rings.
  • Kupffer cell–specific MRI agents (superparamagnetic iron oxides [SPIO] and ultrasmall superparamagnetic iron oxides [USPIO]) can be administered during the scan. They show no uptake due to a lack of endothelial-reticular cells.
  • Manganese–dipyridoxal diphosphate (DPDP), gadolinium, or gadobenate dimeglumine (Gd-BOPTA) can be administered during the scan. They show strong uptake due to the presence of hepatocytes.
  • Unfortunately, HCC also has a predominance of hepatocytes, which makes these agents unable to differentiate between hepatocellular adenomas and HCC.
• Nuclear scans
• • Adenomas appear as cold nodules on technetium Tc 99m sulfur colloid scans.
  • This is due to the altered blood flow through the lesions and the lack of phagocytic activity of Kupffer cells.
• Arteriography
• • Well-defined, round or ovoid, hypervascular mass with hepatic arterial branches entering from the periphery
  • Vessels within the mass are tortuous and of varying calibers with flow moving centrally from the periphery.
  • Avascular areas and intralesional hematomas are indicators of hepatocellular adenoma.

Procedures

• Results of histological evaluation with a liver biopsy are nondiagnostic and insensitive because the mass is comprised of normal-appearing hepatocytes.
• Resection and evaluation may be required as the most specific way to confirm diagnosis.

Histologic Findings

In a gross examination, hepatocellular adenomas appear as sharply circumscribed, light brown to yellow tumors that are soft in consistency and may or may not be encapsulated. Their sizes range to over 20 cm in diameter. Hypervascularity is present upon the surface of the lesion. Because adenomas contain no portal vein branches, their blood supply is entirely arterial. Multiple lesions, ranging in diameter from 1-20 cm, may be present within a single liver. Adenomas may hang on a stalk from the surface of the liver.

In a microscopic examination, the hallmark of adenomas is the normal appearance of the hepatocytes. These are arranged in sheets and have no malignant features. These cells tend to be larger than normal hepatocytes, and their cytoplasm often contains fat or glycogen. Generally, few, if any, portal tracts are present, and no central veins or bile ducts are present. Kupffer cells are reduced in number or absent. Vessels, when observed, tend to have thickened walls. Areas of thrombosis and infarction may be observed. Most hepatocellular adenomas contain a variable degree of microscopic collections of fat. Differentiation from a high-grade HCC can be difficult, if not impossible. Adenomas tend to lack malignant-appearing mitotic structures, the cell plates generally are only 2 cells thick, and no cellular infiltration (invasion) into the capsule or surrounding liver parenchyma occurs. Unfortunately, these features also may be absent in HCC, especially if it is well differentiated.

The tendency for these lesions to bleed may be related to their increased vasculature, which is made up of thin-walled, dilated sinusoids carrying blood at arterial pressure.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Medical Care

• Patients should stop using oral contraceptives or anabolic steroids.
• • This allows for regression in the size of the majority of the tumors. Complete resolution is atypical.
  • The risk of malignant transformation remains even after the contraceptive or steroid use has been discontinued.
• Symptomatic hepatocellular adenomas may be considered for resection, regardless of size.
• Pregnancy should be avoided because of the risk of growth and rupture.
• • Surgical resection may be the best option in patients with hepatocellular adenomas who desire to become pregnant.
  • Resection of large incidental hepatocellular adenomas found during pregnancy may be considered for resection during the second trimester when the risk is lowest.
  • Ruptured hepatocellular adenomas during pregnancy should be managed with resuscitation and resection.
• Yearly ultrasound imaging and an assessment of serum AFP levels is a consideration in all patients with hepatocellular adenomas, especially those with multiple lesions or single lesions greater than 5 cm in diameter who do not undergo surgical resection.
• Immediate abdominal imaging is required for patients with hepatocellular adenomas who present with new or worsened abdominal pain or signs of hemodynamic instability.
• Emergency hepatic arteriography with embolization should be considered to control bleeding in high-risk surgical candidates.

Surgical Care

• Due to the increased risk of spontaneous life-threatening hemorrhage and the possible malignant transformation associated with larger-size tumors or in patients with GSD, elective surgical resection is considered for all lesions greater than 5 cm in diameter. Elective resection should be undertaken only after a reasonable period of observation if OCPs have been discontinued only recently.
• All patients with significant elevated AFP levels should undergo resection of the tumor regardless of size.
• The majority can be resected locally or with segmental partial lobectomy.
• • Elective resection carries approximately 13% morbidity. Mortality is rare.
  • Complication rates associated with emergency surgery are higher, including a mortality rate of approximately 5-8%.
• Laparoscopic resection can be used in patients who have small tumors within the anterolateral liver segments.
• A similar approach also can be considered for pedunculated lesions.

FOLLOW-UP

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Yearly ultrasound imaging and an assessment of serum AFP levels is a consideration in all patients with hepatocellular adenomas.

Prognosis

• Complete resolution is atypical.
• The risk of malignant transformation remains even after the contraceptive or steroid use has been discontinued.
• The risk of malignant transformation exists and is as high as 8-13%.

MISCELLANEOUS

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Differentiation of a hepatocellular adenoma from a high-grade HCC can be difficult, if not impossible.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

• Baum JK, Bookstein JJ, Holtz F. Possible association between benign hepatomas and oral contraceptives. Lancet. Oct 27 1973;2(7835):926-9. [Medline].
• De Carlis L, Pirotta V, Rondinara GF. Hepatic adenoma and focal nodular hyperplasia: diagnosis and criteria for treatment. Liver Transpl Surg. Mar 1997;3(2):160-5. [Medline].
• Klatskin G. Hepatic tumors: possible relationship to use of oral contraceptives. Gastroenterology. Aug 1977;DA - 19770825(2):386-94. [Medline].
• Lee RG. Neoplasms and other masses: Benign hepatocellular tumors. In: Diagnostic Liver Pathology. St. Louis, Mo:. Mosby-Yearbook;1994:422-430.
• Mergo PJ, Ros PR. Benign lesions of the liver. Radiol Clin North Am. Mar 1998;36(2):319-31. [Medline].
• Mortele KJ, Ros PR. Benign liver neoplasms. Clin Liver Dis. Feb 2002;6(1):119-45.
• Reddy KR, Schiff ER. Approach to a liver mass. Semin Liver Dis. Nov 1993;13(4):423-35. [Medline].
• Rooks JB, Ory HW, Ishak KG. Epidemiology of hepatocellular adenoma. The role of oral contraceptive use. JAMA. Aug 17 1979;242(7):644-8. [Medline].
• Weimann A, Ringe B, Klempnauer J. Benign liver tumors: differential diagnosis and indications for surgery. World J Surg. Nov-Dec 1997;21(9):983-90; discussion 990-1. [Medline].

Article Last Updated: Aug 3, 2006