Benign Liver Tumors

  • Jessica Zucman-Rossi
Part of the Molecular Pathology Library book series (MPLB, volume 5)


Focal nodular hyperplasia (FNH) and hepatocellular adenomas (HCA) are the two major types of hepatocellular benign tumors. They are defined by a benign proliferation of hepatocytes, but in the clinical practice, these lesions may be sometimes difficult to diagnose from well-differentiated hepatocellular carcinomas (HCC) [1, 2]. Recently, different molecular pathways, specifically altered in FNH and HCA, have been identified. Moreover, analysis of the genotype-phenotype correlation in HCA also enabled the identification of well-defined sub-types of adenomas leading to propose a new molecular classification of these tumors. Actually, this new molecular classification provides robust foundations to better understand bases of the benign hepatocellular tumorigenesis including its relationship with the malignant transformation. It is also an important step in the search of novel markers specific to these tumor subtypes that could be used in clinical practice for diagnosis or prognosis. In this chapter, we will review the recent progress we performed in the molecular characterization of FNH and HCA according to the clinical and pathological features of each defined subgroup.


Adenomatous Polyposis Coli Focal Nodular Hyperplasia Glycogen Storage Disease Hereditary Hemorrhagic Telangiectasia Hepatocellular Adenoma 
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  1. 1.
    Bioulac-Sage P, Balabaud C, Bedossa P, et al. Pathological diagnosis of liver cell adenoma and focal nodular hyperplasia: Bordeaux update. J Hepatol. 2007;46(3):521–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Bioulac-Sage P, Balabaud C, Wanless IR. Diagnosis of focal nodular hyperplasia: not so easy. Am J Surg Pathol. 2001;25(10):1322–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Edmondson HA. Tumors of the liver and intrahepatic bile ducts. In: Atlas of tumor pathology. Washington: Armed Forces Institute of Pathology; 1958.Google Scholar
  4. 4.
    Nguyen BN, Flejou JF, Terris B, Belghiti J, Degott C. Focal nodular hyperplasia of the liver: a comprehensive pathologic study of 305 lesions and recognition of new histologic forms. Am J Surg Pathol. 1999;23(12):1441–54.PubMedCrossRefGoogle Scholar
  5. 5.
    Heinemann LA, Weimann A, Gerken G, Thiel C, Schlaud M, DoMinh T. Modern oral contraceptive use and benign liver tumors: the German Benign Liver Tumor Case-Control Study. Eur J Contracept Reprod Health Care. 1998;3(4):194–200.PubMedCrossRefGoogle Scholar
  6. 6.
    Mathieu D, Kobeiter H, Cherqui D, Rahmouni A, Dhumeaux D. Oral contraceptive intake in women with focal nodular hyperplasia of the liver. Lancet. 1998;352(9141):1679–80.PubMedCrossRefGoogle Scholar
  7. 7.
    Scalori A, Tavani A, Gallus S, La Vecchia C, Colombo M. Oral contraceptives and the risk of focal nodular hyperplasia of the liver: a case-control study. Am J Obstet Gynecol. 2002;186(2):195–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Wanless IR, Mawdsley C, Adams R. On the pathogenesis of focal nodular hyperplasia of the liver. Hepatology. 1985;5(6):1194–200.PubMedCrossRefGoogle Scholar
  9. 9.
    Mortele KJ, Praet M, Van Vlierberghe H, Kunnen M, Ros PR. CT and MR imaging findings in focal nodular hyperplasia of the liver: radiologic-pathologic correlation. AJR Am J Roentgenol. 2000;175(3):687–92.PubMedCrossRefGoogle Scholar
  10. 10.
    Vilgrain V, Flejou JF, Arrive L, et al. Focal nodular hyperplasia of the liver: MR imaging and pathologic correlation in 37 patients. Radiology. 1992;184(3):699–703.PubMedGoogle Scholar
  11. 11.
    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. 1995;22(6):1674–81.PubMedCrossRefGoogle Scholar
  12. 12.
    Anon. Terminology of nodular hepatocellular lesions. International Working Party. Hepatology. 1995;22(3):983–93.Google Scholar
  13. 13.
    Fukukura Y, Nakashima O, Kusaba A, Kage M, Kojiro M. Angioarchitecture and blood circulation in focal nodular hyperplasia of the liver. J Hepatol. 1998;29(3):470–5.PubMedCrossRefGoogle Scholar
  14. 14.
    Wanless IR, Albrecht S, Bilbao J, et al. Multiple focal nodular hyperplasia of the liver associated with vascular malformations of various organs and neoplasia of the brain: a new syndrome. Mod Pathol. 1989;2(5):456–62.PubMedGoogle Scholar
  15. 15.
    Gaffey MJ, Iezzoni JC, Weiss LM. Clonal analysis of focal nodular hyperplasia of the liver. Am J Pathol. 1996;148(4):1089–96.PubMedGoogle Scholar
  16. 16.
    Chen TC, Chou TB, Ng KF, Hsieh LL, Chou YH. Hepatocellular carcinoma associated with focal nodular hyperplasia. Report of a case with clonal analysis. Virchows Arch. 2001;438(4):408–11.PubMedCrossRefGoogle Scholar
  17. 17.
    Zhang SH, Cong WM, Wu MC. Focal nodular hyperplasia with concomitant hepatocellular carcinoma: a case report and clonal analysis. J Clin Pathol. 2004;57(5):556–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Paradis V, Laurent A, Flejou JF, Vidaud M, Bedossa P. Evidence for the polyclonal nature of focal nodular hyperplasia of the liver by the study of X-chromosome inactivation. Hepatology. 1997;26(4):891–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Bioulac-Sage P, Rebouissou S, Sa Cunha A, et al. Clinical, morphologic, and molecular features defining so-called telangiectatic focal nodular hyperplasias of the liver. Gastroenterology. 2005;128(5):1211–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Raidl M, Pirker C, Schulte-Hermann R, et al. Multiple chromosomal abnormalities in human liver (pre)neoplasia. J Hepatol. 2004;40(4):660–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Kellner U, Jacobsen A, Kellner A, Mantke R, Roessner A, Rocken C. Comparative genomic hybridization. Synchronous occurrence of focal nodular hyperplasia and hepatocellular carcinoma in the same liver is not based on common chromosomal aberrations. Am J Clin Pathol. 2003;119(2):265–71.PubMedCrossRefGoogle Scholar
  22. 22.
    Heimann P, Ogur G, Debusscher C, et al. Multiple clonal chromosome aberrations in a case of childhood focal nodular hyperplasia of the liver. Cancer Genet Cytogenet. 1995;85(2):138–42.PubMedCrossRefGoogle Scholar
  23. 23.
    Chen YJ, Chen PJ, Lee MC, Yeh SH, Hsu MT, Lin CH. Chromosomal analysis of hepatic adenoma and focal nodular hyperplasia by comparative genomic hybridization. Genes Chromosomes Cancer. 2002;35(2):138–43.PubMedCrossRefGoogle Scholar
  24. 24.
    Gong L, Li YH, Su Q, Li G, Zhang WD, Zhang W. Use of X-chromosome inactivation pattern and laser microdissection to determine the clonal origin of focal nodular hyperplasia of the liver. Pathology. 2009;41(4):348–55.PubMedCrossRefGoogle Scholar
  25. 25.
    Nakayama S, Kanbara Y, Nishimura T, et al. Genome-wide microsatellite analysis of focal nodular hyperplasia: a strong tool for the differential diagnosis of non-neoplastic liver nodule from hepatocellular carcinoma. J Hepatobiliary Pancreat Surg. 2006;13(5):416–20.PubMedCrossRefGoogle Scholar
  26. 26.
    Blaker H, Sutter C, Kadmon M, et al. Analysis of somatic APC mutations in rare extracolonic tumors of patients with familial adenomatous polyposis coli. Genes Chromosomes Cancer. 2004;41(2):93–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Rebouissou S, Bioulac-Sage P, Zucman-Rossi J. Molecular pathogenesis of focal nodular hyperplasia and hepatocellular adenoma. J Hepatol. 2008;48(1):163–70.PubMedCrossRefGoogle Scholar
  28. 28.
    Rebouissou S, Couchy G, Libbrecht L, et al. The beta-catenin pathway is activated in focal nodular hyperplasia but not in cirrhotic FNH-like nodules. J Hepatol. 2008;49(1):61–71.PubMedCrossRefGoogle Scholar
  29. 29.
    Ladeiro Y, Couchy G, Balabaud C, et al. MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations. Hepatology. 2008;47(6):1955–63.PubMedCrossRefGoogle Scholar
  30. 30.
    Paradis V, Bieche I, Dargere D, et al. A quantitative gene expression study suggests a role for angiopoietins in focal nodular hyperplasia. Gastroenterology. 2003;124(3):651–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Benhamouche S, Decaens T, Godard C, et al. Apc tumor suppressor gene is the “zonation-keeper” of mouse liver. Dev Cell. 2006;10(6):759–70.PubMedCrossRefGoogle Scholar
  32. 32.
    de La Coste A, Romagnolo B, Billuart P, et al. Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci U S A. 1998;95(15):8847–51.CrossRefGoogle Scholar
  33. 33.
    Miyoshi Y, Iwao K, Nagasawa Y, et al. Activation of the beta-catenin gene in primary hepatocellular carcinomas by somatic alterations involving exon 3. Cancer Res. 1998;58(12):2524–7.PubMedGoogle Scholar
  34. 34.
    Monga SP, Monga HK, Tan X, Mule K, Pediaditakis P, Michalopoulos GK. Beta-catenin antisense studies in embryonic liver cultures: role in proliferation, apoptosis, and lineage specification. Gastroenterology. 2003;124(1):202–16.PubMedCrossRefGoogle Scholar
  35. 35.
    Monga SP, Pediaditakis P, Mule K, Stolz DB, Michalopoulos GK. Changes in WNT/beta-catenin pathway during regulated growth in rat liver regeneration. Hepatology. 2001;33(5):1098–109.PubMedCrossRefGoogle Scholar
  36. 36.
    Tan X, Behari J, Cieply B, Michalopoulos GK, Monga SP. Conditional deletion of beta-catenin reveals its role in liver growth and regeneration. Gastroenterology. 2006;131(5):1561–72.PubMedCrossRefGoogle Scholar
  37. 37.
    Cadoret A, Ovejero C, Terris B, et al. New targets of beta-catenin signaling in the liver are involved in the glutamine metabolism. Oncogene. 2002;21(54):8293–301.PubMedCrossRefGoogle Scholar
  38. 38.
    Moorman AF, de Boer PA, Geerts WJ, van den Zande L, Lamers WH, Charles R. Complementary distribution of carbamoylphosphate synthetase (ammonia) and glutamine synthetase in rat liver acinus is regulated at a pretranslational level. J Histochem Cytochem. 1988;36(7):751–5.PubMedCrossRefGoogle Scholar
  39. 39.
    Chen YW, Jeng YM, Yeh SH, Chen PJ. P53 gene and Wnt signaling in benign neoplasms: beta-catenin mutations in hepatic adenoma but not in focal nodular hyperplasia. Hepatology. 2002;36(4 Pt 1):927–35.PubMedGoogle Scholar
  40. 40.
    Bioulac-Sage P, Laumonier H, Couchy G, et al. Hepatocellular adenoma management and phenotypic classification: The bordeaux experience. Hepatology. 2009.Google Scholar
  41. 41.
    Edmondson HA, Henderson B, Benton B. Liver-cell adenomas associated with use of oral contraceptives. N Engl J Med. 1976;294(9):470–2.PubMedCrossRefGoogle Scholar
  42. 42.
    Baum JK, Bookstein JJ, Holtz F, Klein EW. Possible association between benign hepatomas and oral contraceptives. Lancet. 1973;2(7835):926–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Rooks JB, Ory HW, Ishak KG, et al. Epidemiology of hepatocellular adenoma. The role of oral contraceptive use. JAMA. 1979;242(7):644–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Vana J, Murphy GP, Aronoff BL, Baker HW. Primary liver tumors and oral contraceptives. Results of a survey. JAMA. 1977;238(20):2154–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Farrell GC, Joshua DE, Uren RF, Baird PJ, Perkins KW, Kronenberg H. Androgen-induced hepatoma. Lancet. 1975;1(7904):430–2.PubMedCrossRefGoogle Scholar
  46. 46.
    Henderson JT, Richmond J, Sumerling MD. Androgenic-anabolic steroid therapy and hepatocellular carcinoma. Lancet. 1973;1(7809):934.PubMedCrossRefGoogle Scholar
  47. 47.
    Lesna M, Spencer I, Walker W. Letter: liver nodules and androgens. Lancet. 1976;1(7969):1124.PubMedCrossRefGoogle Scholar
  48. 48.
    Bianchi L. Glycogen storage disease I and hepatocellular tumours. Eur J Pediatr. 1993;152 Suppl 1:S63–70.PubMedCrossRefGoogle Scholar
  49. 49.
    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. 1997;24(3):276–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Smit GP, Fernandes J, Leonard JV, et al. The long-term outcome of patients with glycogen storage diseases. J Inherit Metab Dis. 1990;13(4):411–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Bala S, Wunsch PH, Ballhausen WG. Childhood hepatocellular adenoma in familial adenomatous polyposis: mutations in adenomatous polyposis coli gene and p53. Gastroenterology. 1997;112(3):919–22.PubMedCrossRefGoogle Scholar
  52. 52.
    Jeannot E, Wendum D, Paye F, et al. Hepatocellular adenoma displaying a HNF1alpha inactivation in a patient with familial adenomatous polyposis coli. J Hepatol. 2006;45(6):883–6.PubMedCrossRefGoogle Scholar
  53. 53.
    Flejou JF, Barge J, Menu Y, et al. Liver adenomatosis. An entity distinct from liver adenoma? Gastroenterology. 1985;89(5):1132–8.PubMedGoogle Scholar
  54. 54.
    Kerlin P, Davis GL, McGill DB, Weiland LH, Adson MA, Sheedy 2nd PF. Hepatic adenoma and focal nodular hyperplasia: clinical, pathologic, and radiologic features. Gastroenterology. 1983;84(5 Pt 1):994–1002.PubMedGoogle Scholar
  55. 55.
    Foster JH, Berman MM. The malignant transformation of liver cell adenomas. Arch Surg. 1994;129(7):712–7.PubMedCrossRefGoogle Scholar
  56. 56.
    Grigsby P, Meyer JS, Sicard GA, Huggins MB, Lamar DJ, DeSchryver-Kecskemeti K. Hepatic adenoma within a spindle cell carcinoma in a woman with a long history of oral contraceptives. J Surg Oncol. 1987;35(3):173–9.PubMedCrossRefGoogle Scholar
  57. 57.
    Tao LC. Oral contraceptive-associated liver cell adenoma and hepatocellular carcinoma. Cytomorphology and mechanism of malignant transformation. Cancer. 1991;68(2):341–7.PubMedCrossRefGoogle Scholar
  58. 58.
    Johnson FL, Lerner KG, Siegel M, et al. Association of androgenic-anabolic steroid therapy with development of hepatocellular carcinoma. Lancet. 1972;2(7790):1273–6.PubMedCrossRefGoogle Scholar
  59. 59.
    Conti JA, Kemeny N. Type Ia glycogenosis associated with hepatocellular carcinoma. Cancer. 1992;69(6):1320–2.PubMedCrossRefGoogle Scholar
  60. 60.
    Franco LM, Krishnamurthy V, Bali D, et al. Hepatocellular carcinoma in glycogen storage disease type Ia: a case series. J Inherit Metab Dis. 2005;28(2):153–62.PubMedCrossRefGoogle Scholar
  61. 61.
    Bioulac-Sage P, Rebouissou S, Thomas C, et al. Hepatocellular adenoma subtype classification using molecular markers and immunohistochemistry. Hepatology. 2007;46(3):740–8.PubMedCrossRefGoogle Scholar
  62. 62.
    Rebouissou S, Amessou M, Couchy G, et al. Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Nature. 2009;457(7226):200–4.PubMedCrossRefGoogle Scholar
  63. 63.
    Zucman-Rossi J, Jeannot E, Nhieu JT, et al. Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC. Hepatology. 2006;43(3):515–24.PubMedCrossRefGoogle Scholar
  64. 64.
    Bluteau O, Jeannot E, Bioulac-Sage P, et al. Bi-allelic inactivation of TCF1 in hepatic adenomas. Nat Genet. 2002;32(2):312–5.PubMedCrossRefGoogle Scholar
  65. 65.
    Bacq T, Jacquemin E, Balabaud C, et al. Familial liver adenomatosis associated with Hepatocyte Nuclear Factor 1 alpha inactivation. Gastroenterology. 2003;125(5):1470–5.PubMedCrossRefGoogle Scholar
  66. 66.
    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. 2004;89(3):1476–80.PubMedCrossRefGoogle Scholar
  67. 67.
    Jeannot E, Poussin K, Chiche L, et al. Association of CYP1B1 germ line mutations with hepatocyte nuclear factor 1alpha-mutated hepatocellular adenoma. Cancer Res. 2007;67(6):2611–6.PubMedCrossRefGoogle Scholar
  68. 68.
    Courtois G, Morgan JG, Campbell LA, Fourel G, Crabtree GR. Interaction of a liver-specific nuclear factor with the fibrinogen and alpha 1-antitrypsin promoters. Science. 1987;238(4827):688–92.PubMedCrossRefGoogle Scholar
  69. 69.
    Pontoglio M, Barra J, Hadchouel M, et al. Hepatocyte nuclear factor 1 inactivation results in hepatic dysfunction, phenylketonuria, and renal Fanconi syndrome. Cell. 1996;84(4):575–85.PubMedCrossRefGoogle Scholar
  70. 70.
    Shih DQ, Screenan S, Munoz KN, et al. Loss of HNF-1alpha function in mice leads to abnormal expression of genes involved in pancreatic islet development and metabolism. Diabetes. 2001;50(11):2472–80.PubMedCrossRefGoogle Scholar
  71. 71.
    Lee YH, Sauer B, Gonzalez FJ. Laron dwarfism and non-insulin-dependent diabetes mellitus in the Hnf-1alpha knockout mouse. Mol Cell Biol. 1998;18(5):3059–68.PubMedGoogle Scholar
  72. 72.
    Rebouissou S, Imbeaud S, Balabaud C, et al. HNF1alpha inactivation promotes lipogenesis in human hepatocellular adenoma independently of SREBP-1 and carbohydrate-response element-binding protein (ChREBP) activation. J Biol Chem. 2007;282(19):14437–46.PubMedCrossRefGoogle Scholar
  73. 73.
    Pelletier L, Rebouissou S, Paris A, et al. Loss of HNF1a function in human hepatocellular adenomas leads to aberrant activation of signaling pathways involved in tumorigenesis. Hepatology. In press.Google Scholar
  74. 74.
    Van der Borght S, Libbrecht L, Katoonizadeh A, et al. Nuclear beta-catenin staining and absence of steatosis are indicators of hepatocellular adenomas with an increased risk of malignancy. Histopathology. 2007;51(6):855–6.PubMedCrossRefGoogle Scholar
  75. 75.
    Torbenson M, Lee JH, Choti M, et al. Hepatic adenomas: analysis of sex steroid receptor status and the Wnt signaling pathway. Mod Pathol. 2002;15(3):189–96.PubMedCrossRefGoogle Scholar
  76. 76.
    Zucman-Rossi J, Benhamouche S, Godard C, et al. Differential effects of inactivated Axin1 and activated ß(beta)-catenin mutations in human hepatocellular carcinomas. Oncogene. 2006. In press.Google Scholar
  77. 77.
    Sa Cunha A, Blanc JF, Lazaro E, et al. Inflammatory syndrome with liver adenomatosis: the beneficial effects of surgical management. Gut. 2007;56(2):307–9.Google Scholar
  78. 78.
    Paradis V, Champault A, Ronot M, et al. Telangiectatic adenoma: an entity associated with increased body mass index and inflammation. Hepatology. 2007;46(1):140–6.PubMedCrossRefGoogle Scholar
  79. 79.
    Akira S, Nishio Y, Inoue M, et al. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell. 1994;77(1):63–71.PubMedCrossRefGoogle Scholar
  80. 80.
    Hibi M, Murakami M, Saito M, Hirano T, Taga T, Kishimoto T. Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell. 1990;63(6):1149–57.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Oncology, Inserm U674Université Paris DescartesParisFrance

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