Hepatocellular Adenoma
- Author: Sandeep Mukherjee, MB, BCh, MPH, FRCPC; Chief Editor: Julian Katz, MD more...
Background
Hepatocellular adenomas (HAs) 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), as reported by Edmonson et al.[2]
In a case series of 3 patients, Baum et al suggested the 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]
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, and glycogen storage diseases (types 1 and 3). However, multiple hepatic adenomas are more common in glycogen storage disease,[8] with an incidence between 22% and 75% in type 1 and 25% in type 3 disease.
In addition to multiplicity of adenomas, hepatic adenomas associated with glycogen storage diseases (GSD) tend to be multiple, 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]
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 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 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.[12] Rebouissou et al[13] and Bioulac-Sage et al[14, 15] 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.
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 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 (HNF-1 alpha) was described by Reznik et al in 2 families that had both diabetes mellitus and liver adenomatosis.[16] Tumor cell analysis showed biallelic inactivation of HNF-1 alpha.
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.
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 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.
- 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.
Edmonson HA. Tumors of the liver and biliary tract. Fascicle 25. In: Atlas of Tumor Pathology. Washington, DC: Armed Forces Institute of Pathology; 1958.
Edmondson HA, Henderson B, Benton B. Liver-cell adenomas associated with use of oral contraceptives. N Engl J Med. Feb 26 1976;294(9):470-2. [Medline].
Baum JK, Bookstein JJ, Holtz F. Possible association between benign hepatomas and oral contraceptives. Lancet. Oct 27 1973;2(7835):926-9. [Medline].
Klatskin G. Hepatic tumors: possible relationship to use of oral contraceptives. Gastroenterology. Aug 1977;DA - 19770825(2):386-94. [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].
Cherqui D, Rahmouni A, Charlotte F, et al. Management of focal nodular hyperplasia and hepatocellular adenoma in young women: a series of 41 patients with clinical, radiological, and pathological correlations. Hepatology. Dec 1995;22(6):1674-81. [Medline].
Edmonson HA, Reynolds TB, Henderson B,et al. Regression of liver cell adenomas associated with oral contraceptives. Ann Int Med. 1977;86(2):180-182.
Labrune P, Trioche P, Duvaltier I, Chevalier P, Odievre M. Hepatocellular adenomas in glycogen storage disease type I and III: a series of 43 patients and review of the literature. J Pediatr Gastroenterol Nutr. Mar 1997;24(3):276-9. [Medline].
Volmar KE, Burchette JL, Creager AJ. Hepatic adenomatosis in glycogen storage disease type Ia: report of a case with unusual histology. Arch Pathol Lab Med. Oct 2003;127(10):e402-5. [Medline].
Grazioli L, Federle MP, Ichikawa T, et al. Liver adenomatosis: clinical, histopathologic, and imaging findings in 15 patients. Radiology. Aug 2000;216(2):395-402. [Medline].
Arsenault TM, Johnson CD, Gorman B, Burgart LJ. Hepatic adenomatosis. Mayo Clin Proc. May 1996;71(5):478-80. [Medline].
Masood S, West AB, Barwick KW. Expression of steroid hormone receptors in benign hepatic tumors. An immunocytochemical study. Arch Pathol Lab Med. Dec 1992;116(12):1355-9. [Medline].
Rebouissou S, Bioulac-Sage P, Zucman-Rossi J. Molecular pathogenesis of focal nodular hyperplasia and hepatocellular adenoma. J Hepatol. Jan 2008;48(1):163-70. [Medline].
Bioulac-Sage P, Blanc JF, Rebouissou S, Balabaud C, Zucman-Rossi J. Genotype phenotype classification of hepatocellular adenoma. World J Gastroenterol. May 21 2007;13(19):2649-54. [Medline].
Bioulac-Sage P, Laumonier H, Couchy G, et al. Hepatocellular adenoma management and phenotypic classification: the Bordeaux experience. Hepatology. Aug 2009;50(2):481-9. [Medline].
Reznik Y, Dao T, Coutant R, et al. Hepatocyte nuclear factor-1 alpha gene inactivation: cosegregation between liver adenomatosis and diabetes phenotypes in two maturity-onset diabetes of the young (MODY)3 families. J Clin Endocrinol Metab. Mar 2004;89(3):1476-80. [Medline].
Laumonier H, Bioulac-Sage P, Laurent C, et al. Hepatocellular adenomas: magnetic resonance imaging features as a function of molecular pathological classification. Hepatology. Sep 2008;48(3):808-18. [Medline].
Assy N, Nasser G, Djibre A, et al. Characteristics of common solid liver lesions and recommendations for diagnostic workup. World J Gastroenterol. Jul 14 2009;15(26):3217-27. [Medline].
Zucman-Rossi J, Jeannot E, Nhieu JT, et al. Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC. Hepatology. Mar 2006;43(3):515-24. [Medline].
Tretiakova MS, Hart J, Shabani-Rad MT, Zhang J, Gao ZH. Distinction of hepatocellular adenoma from hepatocellular carcinoma with and without cirrhosis using E-cadherin and matrix metalloproteinase immunohistochemistry. Mod Pathol. Aug 2009;22(8):1113-20. [Medline].
Wang HL, Anatelli F, Zhai QJ, et al. Glypican-3 as a useful diagnostic marker that distinguishes hepatocellular carcinoma from benign hepatocellular mass lesions. Arch Pathol Lab Med. Nov 2008;132(11):1723-8. [Medline].
Tatrai P, Somoracz A, Batmunkh E, et al. Agrin and CD34 immunohistochemistry for the discrimination of benign versus malignant hepatocellular lesions. Am J Surg Pathol. Jun 2009;33(6):874-85. [Medline].
Ahmad I, Iyer A, Marginean CE, et al. Diagnostic use of cytokeratins, CD34, and neuronal cell adhesion molecule staining in focal nodular hyperplasia and hepatic adenoma. Hum Pathol. May 2009;40(5):726-34. [Medline].
Ishak KG. Benign tumors and pseudotumors of the liver. Appl Pathol. 1988;6(2):82-104. [Medline].
Bisceglia M, Gatta A, Tomezzoli A, Donataccio M. Multiple spontaneous liver cell adenomas of different types (liver adenomatosis). Adv Anat Pathol. May 2009;16(3):172-9. [Medline].
Geller S, Petrovic L. Benign tumors and tumor-like conditions. Biopsy Interpretation of the Liver. 3rd ed. Philadelphia, Pa: Williams and Wilkins.; 2003:281-304.
Gyorffy EJ, Bredfeldt JE, Black WC. Transformation of hepatic cell adenoma to hepatocellular carcinoma due to oral contraceptive use. Ann Intern Med. Mar 15 1989;110(6):489-90. [Medline].
Terkivatan T, de Wilt JH, de Man RA, et al. Indications and long-term outcome of treatment for benign hepatic tumors: a critical appraisal. Arch Surg. Sep 2001;136(9):1033-8. [Medline].
Deneve JL, Pawlik TM, Cunningham S, et al. Liver cell adenoma: a multicenter analysis of risk factors for rupture and malignancy. Ann Surg Oncol. Mar 2009;16(3):640-8. [Medline].
Cho SW, Marsh JW, Steel J, et al. Surgical management of hepatocellular adenoma: take it or leave it?. Ann Surg Oncol. Oct 2008;15(10):2795-803. [Medline].
Selby R, Starzl TE, Ynis E, et al. Liver transplantation for type 1 and type glycogen storage disease. Eur J Pediatr. 1993;152:S71-76.
Santambrogio R, Marconi AM, Ceretti AP, et al. Liver transplantation for spontaneous intrapartum rupture of a hepatic adenoma. Obstet Gynecol. Feb 2009;113(2 pt 2):508-10. [Medline].
van Vledder MG, van Aalten SM, Terkivatan T, et al. Safety and efficacy of radiofrequency ablation for hepatocellular adenoma. J Vasc Interv Radiol. Jun 2011;22(6):787-93. [Medline].
Ryan IP, Havel RJ, Laros RK Jr. Three consecutive pregnancies in a patient with glycogen storage disease type IA (von Gierke's disease). Am J Obstet Gynecol. Jun 1994;170(6):1687-90; discussion 1690-1. [Medline].
Bioulac-Sage P, Laumonier H, Cubel G, Rossi JZ, Balabaud C. Hepatic resection for inflammatory hepatocellular adenomas: pathological identification of micronodules expressing inflammatory proteins. Liver Int. Jan 2010;30(1):149-54. [Medline].
Cai YR, Gong L, Teng XY, Zhang HT, Wang CF, Wei GL, et al. Clonality and allelotype analyses of focal nodular hyperplasia compared with hepatocellular adenoma and carcinoma. World J Gastroenterol. Oct 7 2009;15(37):4695-708. [Medline].
Curvo-Semedo L, Brito JB, Seco MF, Costa JF, Marques CB, Caseiro-Alves F. The Hypointense Liver Lesion on T2-Weighted MR Images and What It Means. Radiographics. Nov 18 2009;[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].
Jang HJ, Yu H, Kim TK. Contrast-enhanced ultrasound in the detection and characterization of liver tumors. Cancer Imaging. Nov 6 2009;9:96-103. [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].
van der Sluis FJ, Bosch JL, Terkivatan T, et al. Hepatocellular adenoma: cost-effectiveness of different treatment strategies. Radiology. Sep 2009;252(3):737-46. [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].
Print
