Liver Cell Dysplasia and the Development of HCC

  • Jesse KresakEmail author
  • Naziheh Assarzadegan
Part of the Molecular Pathology Library book series (MPLB)


Hepatocellular carcinoma (HCC) is the fifth most common cancer and second leading cause of cancer-related death worldwide [1–4]. Due to a lack of specific symptomatology, HCC is most often diagnosed at an advanced stage leading to limited treatment options and a dismal prognosis [5]. Studies have shown that, when compared to smaller tumors, cure rates for HCC larger than 2 cm decrease and curative treatment become even less likely for lesions larger than 3 cm [6]. Therefore, the ability to identify the precursor lesions at an earlier stage in which resection and cure are still possible has received increased attention in recent years [2, 5, 7].


  1. 1.
    Park YN. Update on precursor and early lesions of hepatocellular carcinomas. Arch Pathol Lab Med. 2011;135(6):704–15.PubMedGoogle Scholar
  2. 2.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.PubMedCrossRefGoogle Scholar
  3. 3.
    Koo JS, Kim H, Park BK, et al. Predictive value of liver cell dysplasia for development of hepatocellular carcinoma in patients with chronic hepatitis B. J ClinGastroenterol. 2008;42(6):738–43.Google Scholar
  4. 4.
    Marquardt JU, Andersen JB, Thorgeirsson SS. Functional and genetic deconstruction of the cellular origin in liver cancer. Nat Rev Cancer. 2015;15(11):653–67.PubMedCrossRefGoogle Scholar
  5. 5.
    Roncalli M, Terracciano L, Di Tommaso L, et al. Liver precancerous lesions and hepatocellular carcinoma: the histology report. Dig Liver Dis. 2011;43(Suppl 4):S361–72.PubMedCrossRefGoogle Scholar
  6. 6.
    Sherman M. Hepatocellular carcinoma: epidemiology, surveillance, and diagnosis. Semin Liver Dis. 2010;30(1):3–16.PubMedCrossRefGoogle Scholar
  7. 7.
    Borzio M, Bruno S, Roncalli M, et al. Liver cell dysplasia is a major risk factor for hepatocellular carcinoma in cirrhosis: a prospective study. Gastroenterology. 1995;108(3):812–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Röcken C, Carl-McGrath S. Pathology and pathogenesis of hepatocellular carcinoma. Dig Dis. 2001;19(4):269–78.PubMedCrossRefGoogle Scholar
  9. 9.
    Schulze K, Imbeaud S, Letouzé E, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015;47(5):505–11.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Nault JC, Calderaro J, Di Tommaso L, et al. Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis. Hepatology. 2014;60(6):1983–92.PubMedCrossRefGoogle Scholar
  11. 11.
    Nault JC. Pathogenesis of hepatocellular carcinoma according to aetiology. Best Pract Res Clin Gastroenterol. 2014;28(5):937–47.PubMedCrossRefGoogle Scholar
  12. 12.
    Sung WK, Zheng H, Li S, et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat Genet. 2012;44(7):765–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Levrero M, Zucman-Rossi J. Mechanisms of HBV-induced hepatocellular carcinoma. J Hepatol. 2016;64(1):S84–S101.PubMedCrossRefGoogle Scholar
  14. 14.
    Bressac B, Kew M, Wands J, Ozturk M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature. 1991;350(6317):429–31.PubMedCrossRefGoogle Scholar
  15. 15.
    Anthony PP, Vogel CL, Barker LF. Liver cell dysplasia: a premalignant condition. J Clin Pathol. 1973;26(3):217–23.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Watanabe S, Okita K, Harada T, et al. Morphologic studies of the liver cell dysplasia. Cancer. 1983;51(12):2197–205.PubMedCrossRefGoogle Scholar
  17. 17.
    Adachi E, Hashimoto H, Tsuneyoshi M. Proliferating cell nuclear antigen in hepatocellular carcinoma and small cell liver dysplasia. Cancer. 1993;72(10):2902–9.PubMedCrossRefGoogle Scholar
  18. 18.
    International Working Party. Terminology of nodular hepatocellular lesions. Hepatology. 1995;22(3):983–93.CrossRefGoogle Scholar
  19. 19.
    Neoplasia ICGfH. Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. Hepatology. 2009;49(2):658–64.CrossRefGoogle Scholar
  20. 20.
    Hytiroglou P, Park YN, Krinsky G, Theise ND. Hepatic precancerous lesions and small hepatocellular carcinoma. Gastroenterol Clin North Am. 2007;36(4):867–87, vii.Google Scholar
  21. 21.
    Robert D, Odze JRG. Surgical pathology of the GI tract, liver, biliary tract and pancreas, vol 44. 3rd ed. New York: Elsevier; 2014. p. 1192–6.Google Scholar
  22. 22.
    Marchio A, Terris B, Meddeb M, et al. Chromosomal abnormalities in liver cell dysplasia detected by comparative genomic hybridisation. Mol Pathol. 2001;54(4):270–4.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Zondervan PE, Wink J, Alers JC, et al. Molecular cytogenetic evaluation of virus-associated and non-viral hepatocellular carcinoma: analysis of 26 carcinomas and 12 concurrent dysplasias. J Pathol. 2000;192(2):207–15.PubMedCrossRefGoogle Scholar
  24. 24.
    Terris B, Ingster O, Rubbia L, et al. Interphase cytogenetic analysis reveals numerical chromosome aberrations in large liver cell dysplasia. J Hepatol. 1997;27(2):313–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Roncalli M, Borzio M, Brando B, Colloredo G, Servida E. Abnormal DNA content in liver-cell dysplasia: a flow cytometric study. Int J Cancer. 1989;44(2):204–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Park YN, Roncalli M. Large liver cell dysplasia: a controversial entity. J Hepatol. 2006;45(5):734–43.PubMedCrossRefGoogle Scholar
  27. 27.
    Ganne-Carrié N, Chastang C, Chapel F, et al. Predictive score for the development of hepatocellular carcinoma and additional value of liver large cell dysplasia in Western patients with cirrhosis. Hepatology. 1996;23(5):1112–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Plentz RR, Park YN, Lechel A, et al. Telomere shortening and inactivation of cell cycle checkpoints characterize human hepatocarcinogenesis. Hepatology. 2007;45(4):968–76.PubMedCrossRefGoogle Scholar
  29. 29.
    Kim H, BK O, Roncalli M, et al. Large liver cell change in hepatitis B virus-related liver cirrhosis. Hepatology. 2009;50(3):752–62.PubMedCrossRefGoogle Scholar
  30. 30.
    Deugnier YM, Charalambous P, Le Quilleuc D, et al. Preneoplastic significance of hepatic iron-free foci in genetic hemochromatosis: a study of 185 patients. Hepatology. 1993;18(6):1363–9.PubMedGoogle Scholar
  31. 31.
    Park YN, Yang CP, Fernandez GJ, Cubukcu O, Thung SN, Theise ND. Neoangiogenesis and sinusoidal “capillarization” in dysplastic nodules of the liver. Am J Surg Pathol. 1998;22(6):656–62.PubMedCrossRefGoogle Scholar
  32. 32.
    Park YN, Kojiro M, Di Tommaso L, et al. Ductular reaction is helpful in defining early stromal invasion, small hepatocellular carcinomas, and dysplastic nodules. Cancer. 2007;109(5):915–23.PubMedCrossRefGoogle Scholar
  33. 33.
    Forner A, Vilana R, Ayuso C, et al. Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma. Hepatology. 2008;47(1):97–104.PubMedCrossRefGoogle Scholar
  34. 34.
    Bruix J, Sherman M, Practice Guidelines Committee AeAftSoLD. Management of hepatocellular carcinoma. Hepatology. 2005;42(5):1208–36.PubMedCrossRefGoogle Scholar
  35. 35.
    Theise ND, Park YN, Kojiro M. Dysplastic nodules and hepatocarcinogenesis. Clin Liver Dis. 2002;6(2):497–512.PubMedCrossRefGoogle Scholar
  36. 36.
    Nam SW, Park JY, Ramasamy A, et al. Molecular changes from dysplastic nodule to hepatocellular carcinoma through gene expression profiling. Hepatology. 2005;42(4):809–18.PubMedCrossRefGoogle Scholar
  37. 37.
    Tornillo L, Carafa V, Sauter G, et al. Chromosomal alterations in hepatocellular nodules by comparative genomic hybridization: high-grade dysplastic nodules represent early stages of hepatocellular carcinoma. Lab Investig. 2002;82(5):547–54.PubMedCrossRefGoogle Scholar
  38. 38.
    Sun M, Eshleman JR, Ferrell LD, et al. An early lesion in hepatic carcinogenesis: loss of heterozygosity in human cirrhotic livers and dysplastic nodules at the 1p36-p34 region. Hepatology. 2001;33(6):1415–24.PubMedCrossRefGoogle Scholar
  39. 39.
    BK O, Jo Chae K, Park C, et al. Telomere shortening and telomerase reactivation in dysplastic nodules of human hepatocarcinogenesis. J Hepatol. 2003;39(5):786–92.CrossRefGoogle Scholar
  40. 40.
    Lee YH, BK O, Yoo JE, et al. Chromosomal instability, telomere shortening, and inactivation of p21(WAF1/CIP1) in dysplastic nodules of hepatitis B virus-associated multistep hepatocarcinogenesis. Mod Pathol. 2009;22(8):1121–31.PubMedCrossRefGoogle Scholar
  41. 41.
    Takayama T, Makuuchi M, Hirohashi S, et al. Early hepatocellular carcinoma as an entity with a high rate of surgical cure. Hepatology. 1998;28(5):1241–6.PubMedCrossRefGoogle Scholar
  42. 42.
    Kojiro M, Nakashima O. Histopathologic evaluation of hepatocellular carcinoma with special reference to small early stage tumors. Semin Liver Dis. 1999;19(3):287–96.PubMedCrossRefGoogle Scholar
  43. 43.
    Kondo F, Kondo Y, Nagato Y, Tomizawa M, Wada K. Interstitial tumour cell invasion in small hepatocellular carcinoma. Evaluation in microscopic and low magnification views. J Gastroenterol Hepatol. 1994;9(6):604–12.PubMedCrossRefGoogle Scholar
  44. 44.
    Nakano M, Saito A, Yamamoto M, Doi M, Takasaki K. Stromal and blood vessel wall invasion in well-differentiated hepatocellular carcinoma. Liver. 1997;17(1):41–6.PubMedCrossRefGoogle Scholar
  45. 45.
    Nakashima Y, Nakashima O, Hsia CC, Kojiro M, Tabor E. Vascularization of small hepatocellular carcinomas: correlation with differentiation. Liver. 1999;19(1):12–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Capurro M, Wanless IR, Sherman M, et al. Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma. Gastroenterology. 2003;125(1):89–97.PubMedCrossRefGoogle Scholar
  47. 47.
    Libbrecht L, Severi T, Cassiman D, et al. Glypican-3 expression distinguishes small hepatocellular carcinomas from cirrhosis, dysplastic nodules, and focal nodular hyperplasia-like nodules. Am J SurgPathol. 2006;30(11):1405–11.CrossRefGoogle Scholar
  48. 48.
    Wang XY, Degos F, Dubois S, et al. Glypican-3 expression in hepatocellular tumors: diagnostic value for preneoplastic lesions and hepatocellular carcinomas. Hum Pathol. 2006;37(11):1435–41.PubMedCrossRefGoogle Scholar
  49. 49.
    Di Tommaso L, Franchi G, Park YN, et al. Diagnostic value of HSP70, glypican 3, and glutamine synthetase in hepatocellular nodules in cirrhosis. Hepatology. 2007;45(3):725–34.PubMedCrossRefGoogle Scholar
  50. 50.
    Garrido C, Gurbuxani S, Ravagnan L, Kroemer G. Heat shock proteins: endogenous modulators of apoptotic cell death. Biochem Biophys Res Commun. 2001;286(3):433–42.PubMedCrossRefGoogle Scholar
  51. 51.
    Jolly C, Morimoto RI. Role of the heat shock response and molecular chaperones in oncogenesis and cell death. J Natl Cancer Inst. 2000;92(19):1564–72.PubMedCrossRefGoogle Scholar
  52. 52.
    Chuma M, Sakamoto M, Yamazaki K, et al. Expression profiling in multistage hepatocarcinogenesis: identification of HSP70 as a molecular marker of early hepatocellular carcinoma. Hepatology. 2003;37(1):198–207.PubMedCrossRefGoogle Scholar
  53. 53.
    Christa L, Simon MT, Flinois JP, Gebhardt R, Brechot C, Lasserre C. Overexpression of glutamine synthetase in human primary liver cancer. Gastroenterology. 1994;106(5):1312–20.PubMedCrossRefGoogle Scholar
  54. 54.
    Osada T, Sakamoto M, Nagawa H, et al. Acquisition of glutamine synthetase expression in human hepatocarcinogenesis: relation to disease recurrence and possible regulation by ubiquitin-dependent proteolysis. Cancer. 1999;85(4):819–31.PubMedCrossRefGoogle Scholar
  55. 55.
    Reitzer LJ, Wice BM, Kennell D. Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells. J Biol Chem. 1979;254(8):2669–76.PubMedGoogle Scholar
  56. 56.
    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
  57. 57.
    Lee JM, Yang J, Newell P, et al. β-Catenin signaling in hepatocellular cancer: implications in inflammation, fibrosis, and proliferation. Cancer Lett. 2014;343(1):90–7.PubMedCrossRefGoogle Scholar
  58. 58.
    Zhao YJ, Ju Q, Li GC. Tumor markers for hepatocellular carcinoma. Mol Clin Oncol. 2013;1(4):593–8.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Wilkens L, Bredt M, Flemming P, et al. Diagnostic impact of fluorescence in situ hybridization in the differentiation of hepatocellular adenoma and well-differentiated hepatocellular carcinoma. J Mol Diagn. 2001;3(2):68–73.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Kakar S, Chen X, Ho C, et al. Chromosomal abnormalities determined by comparative genomic hybridization are helpful in the diagnosis of atypical hepatocellular neoplasms. Histopathology. 2009;55(2):197–205.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Pathology, Immunology, and Laboratory MedicineUniversity of FloridaGainesvilleUSA

Personalised recommendations