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Benign Liver Tumors

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Molecular Pathology of Liver Diseases

Part of the book series: Molecular Pathology Library ((MPLB,volume 5))

Abstract

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.

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References

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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. 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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  8. Wanless IR, Mawdsley C, Adams R. On the pathogenesis of focal nodular hyperplasia of the liver. Hepatology. 1985;5(6):1194–200.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  12. Anon. Terminology of nodular hepatocellular lesions. International Working Party. Hepatology. 1995;22(3):983–93.

    Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  15. Gaffey MJ, Iezzoni JC, Weiss LM. Clonal analysis of focal nodular hyperplasia of the liver. Am J Pathol. 1996;148(4):1089–96.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  40. Bioulac-Sage P, Laumonier H, Couchy G, et al. Hepatocellular adenoma management and phenotypic classification: The bordeaux experience. Hepatology. 2009.

    Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  42. Baum JK, Bookstein JJ, Holtz F, Klein EW. Possible association between benign hepatomas and oral contraceptives. Lancet. 1973;2(7835):926–9.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  45. Farrell GC, Joshua DE, Uren RF, Baird PJ, Perkins KW, Kronenberg H. Androgen-induced hepatoma. Lancet. 1975;1(7904):430–2.

    Article  PubMed  CAS  Google Scholar 

  46. Henderson JT, Richmond J, Sumerling MD. Androgenic-anabolic steroid therapy and hepatocellular carcinoma. Lancet. 1973;1(7809):934.

    Article  PubMed  CAS  Google Scholar 

  47. Lesna M, Spencer I, Walker W. Letter: liver nodules and androgens. Lancet. 1976;1(7969):1124.

    Article  PubMed  CAS  Google Scholar 

  48. Bianchi L. Glycogen storage disease I and hepatocellular tumours. Eur J Pediatr. 1993;152 Suppl 1:S63–70.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  53. Flejou JF, Barge J, Menu Y, et al. Liver adenomatosis. An entity distinct from liver adenoma? Gastroenterology. 1985;89(5):1132–8.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  55. Foster JH, Berman MM. The malignant transformation of liver cell adenomas. Arch Surg. 1994;129(7):712–7.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  57. Tao LC. Oral contraceptive-associated liver cell adenoma and hepatocellular carcinoma. Cytomorphology and mechanism of malignant transformation. Cancer. 1991;68(2):341–7.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  59. Conti JA, Kemeny N. Type Ia glycogenosis associated with hepatocellular carcinoma. Cancer. 1992;69(6):1320–2.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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. 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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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. 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. 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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

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Zucman-Rossi, J. (2011). Benign Liver Tumors. In: Monga, S. (eds) Molecular Pathology of Liver Diseases. Molecular Pathology Library, vol 5. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-7107-4_52

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