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Liver Cancer Classification

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Book cover Studies on Hepatic Disorders

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Abstract

The current classification of primary adult liver cancer distinguishes two main diagnostic categories: hepatocellular carcinoma and cholangiocarcinoma. These are very heterogeneous tumors characterized by different morphological and clinical features, reflecting the variety of oncological agents and the complex pathways to tumorigenesis. Due to the copious amount of data collected from phenotypical and molecular studies, the classification of liver cancer is moving from the traditional approach, based on morphological features, to a more functional approach, oriented to the cell of origin and integrating morphological, immunophenotypical, and molecular characteristic, behavior, and, possibly, treatment sensitivity.

In this chapet, the current principles of liver cancer classification will be briefly outlined, with emphasis on clinically useful (or potentially useful) categories.

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References

  1. Edmondson HA, Steiner P (1954) Primary carcinoma of the liver. A study of 100 cases among 48,900 necropsies. Cancer 7:462–503

    CAS  PubMed  Google Scholar 

  2. Shanmugaratnam K (1956) Primary carcinomas of the liver and biliary tract. Br J Cancer 2:232–245

    Google Scholar 

  3. Berman C (1951) Primary carcinoma of the liver: a study in incidence, clinical manifestations, pathology and aetiology. H. K. Lewis, London

    Google Scholar 

  4. Bosman FT, Carneiro F, Hruban RH, Theise ND (2010) WHO classification of tumors of the digestive system. IARC, Lyon

    Google Scholar 

  5. Mittal S, El-Serag HB (2013) Epidemiology of hepatocellular carcinoma. Consider the population. J Clin Gastroenterol 47:S2–S6. doi:10.1097/MCG.0b013e3182872f29

    PubMed Central  PubMed  Google Scholar 

  6. El-Serag HB (2012) Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 142:1264–1273.e1. doi:10.1053/j.gastro.2011.12.061

  7. Qian GS, Ross RK, Yu MC, Yuan JM, Gao YT, Henderson BE, Wogan GN, Groopman JD (1994) A follow-up study of urinary markers of aflatoxin exposure and liver cancer risk in Shanghai, People’s Republic of China. Cancer Epidemiol Biomarkers Prev 3(1):3–10

    CAS  PubMed  Google Scholar 

  8. Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN (2010) The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 51:1972–1978. doi:10.1002/hep.23527

    PubMed  Google Scholar 

  9. Takayama T, Makuuchi M, Hirohashi S, Sakamoto M, Yamamoto J, Shimada K, Kosuge T, Okada S, Takayasu K, Yamasaki S (1998) Early hepatocellular carcinoma as an entity with high rate of surgical cure. Hepatology 28:1241–1246

    CAS  PubMed  Google Scholar 

  10. Kojiro M (2007) Diagnostic discrepancy of early hepatocellular carcinoma between Japan and West. Hepatol Res 37:S249–S252

    Google Scholar 

  11. International Consensus Group for Hepatocellular Neoplasia The International Consensus Group for Hepatocellular Neoplasia (2009) Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. Hepatology 49:658–664. doi:10.1002/hep.22709

    Google Scholar 

  12. Park YN, Kim MJ (2011) Hepatocarcinogenesis: imaging-pathologic correlation. Abdom Imaging 36:232–243. doi:10.1007/s00261-011-9688-y

    PubMed  Google Scholar 

  13. Takayama T, Makuuchi M, Kojiro M, Lauwers GY, Adams RB, Wilson SR, Jang HJ, Charnsangavej C, Taouli B (2008) Early hepatocellular carcinoma: pathology, imaging, and therapy. Ann Surg Oncol 15(4):972–978. doi:10.1245/s10434-007-9685-0

    PubMed  Google Scholar 

  14. Kojiro M, Nakashima O (1999) Histopathologic evaluation of hepatocellular carcinoma with a special reference to small early stage tumor. Semin Liver Dis 19:287–296

    CAS  PubMed  Google Scholar 

  15. Libbrecht L, Severi T, Cassiman D, Vander Borght S, Pirenne J, Nevens F, Verslype C, van Pelt J, Roskams T (2006) Glypican-3 expression distinguishes small hepatocellular carcinomas from cirrhosis, dysplastic nodules, and focal nodular hyperplasia-like nodules. Am J Surg Pathol 30(11):1405–1411

    PubMed  Google Scholar 

  16. Di Tommaso L, Franchi G, Park YN, Fiamengo B, Destro A, Morenghi E, Montorsi M, Torzilli G, Tommasini M, Terracciano L, Tornillo L, Vecchione R, Roncalli M (2007) Diagnostic value of HSP70, glypican 3, and glutamine synthetase in hepatocellular nodules in cirrhosis. Hepatology 45(3):725–734

    PubMed  Google Scholar 

  17. Di Tommaso L, Destro A, Seok JY, Balladore E, Terracciano L, Sangiovanni A, Iavarone M, Colombo M, Jang JJ, Yu E, Jin SY, Morenghi E, Park YN, Roncalli M (2009) The application of markers (HSP70 GPC3 and GS) in liver biopsies is useful for detection of hepatocellular carcinoma. J Hepatol 50(4):746–754. doi:10.1016/j.jhep.2008.11.014

    PubMed  Google Scholar 

  18. Llovet JM, Chen Y, Wurmbach E, Roayaie S, Fiel MI, Schwartz M, Thung SN, Khitrov G, Zhang W, Villanueva A, Battiston C, Mazzaferro V, Bruix J, Waxman S, Friedman SL (2006) A molecular signature to discriminate dysplastic nodules from early hepatocellular carcinoma in HCV cirrhosis. Gastroenterology 131(6):1758–1767

    CAS  PubMed  Google Scholar 

  19. Eggel H (1901) Ueber das primare carcinom der Leber. Beitr z Path Anat u z allgem Pathol 30:506–604

    Google Scholar 

  20. Jakate S, Yabes A, Giusto D, Naini B, Lassman C, Yeh MM, Ferrell LD (2010) Diffuse cirrhosis-like hepatocellular carcinoma: a clinically and radiographically undetected variant mimicking cirrhosis. Am J Surg Pathol 34(7):935–941. doi:10.1097/PAS.0b013e3181ddf52f

    PubMed  Google Scholar 

  21. Tátrai P, Somorácz A, Batmunkh E, Schirmacher P, Kiss A, Schaff Z, Nagy P, Kovalszky I (2009) Agrin and CD34 immunohistochemistry for the discrimination of benign versus malignant hepatocellular lesions. Am J Surg Pathol 33:874–885. doi:10.1097/PAS.0b013e318194b3ea

    PubMed  Google Scholar 

  22. Theise ND, Curado MP, Franceschi S, Hytiroglou P, Kudo M, Park YN, Sakamoto M, Torbenson M, Wee A (2010) Hepatocellular carcinoma. In: Bosman FT, Carneiro F, Hruban RH, Theise ND (eds) WHO classification of tumours of the digestive system. IARC, Lyon

    Google Scholar 

  23. Roayaie S, Blume IN, Thung SN, Guido M, Fiel MI, Hiotis S, Labow DM, Llovet JM, Schwartz ME (2009) A system of classifying microvascular invasion to predict outcome after resection in patients with hepatocellular carcinoma. Gastroenterology 137(3):850–855

    PubMed Central  PubMed  Google Scholar 

  24. Bedossa P, Paradis V (2011) Hepatocellular carcinoma. In: Saxena R (ed) Practical hepatic pathology. Elsevier, Philadelphia

    Google Scholar 

  25. Kim H, Choi GH, Na DC, Ahn EY, Kim GI, Lee JE, Cho JY, Yoo JE, Choi JS, Park YN (2011) Human hepatocellular carcinomas with “Stemness”-related marker expression: keratin 19 expression and a poor prognosis. Hepatology 54(5):1707–1717. doi:10.1002/hep.24559

    CAS  PubMed  Google Scholar 

  26. Govaere O, Komuta M, Berkers J, Spee B, Janssen C, de Luca F, Katoonizadeh A, Wouters J, van Kempen LC, Durnez A, Verslype C, De Kock J, Rogiers V, van Grunsven LA, Topal B, Pirenne J, Vankelecom H, Nevens F, van den Oord J, Pinzani M, Roskams T (2014) Keratin 19: a key role player in the invasion of human hepatocellular carcinomas. Gut 63(4):674–685. doi:10.1136/gutjnl-2012-304351

    PubMed Central  CAS  PubMed  Google Scholar 

  27. Torbenson M (2012) Fibrolamellar carcinoma: 2012 update. Scientifica (Cairo) 2012:743790. doi:10.6064/2012/743790

    Google Scholar 

  28. Craig JR, Peters RL, Edmondson HA, Omata M (1980) Fibrolamellar carcinoma of the liver: a tumor of adolescents and young adults with distinctive clinico-pathologic features. Cancer 46(2):372–379

    CAS  PubMed  Google Scholar 

  29. Berman MA, Burnham JA, Sheahan DG (1988) Fibrolamellar carcinoma of the liver: an immunohistochemical study of nineteen cases and a review of the literature. Hum Pathol 19(7):784–794

    CAS  PubMed  Google Scholar 

  30. Malouf GG, Job S, Paradis V, Fabre M, Brugières L, Saintigny P, Vescovo L, Belghiti J, Branchereau S, Faivre S, de Reyniès A, Raymond E (2014) Transcriptional profiling of pure fibrolamellar hepatocellular carcinoma reveals an endocrine signature. Hepatology 59(6):2228–2237. doi:10.1002/hep.27018

    CAS  PubMed  Google Scholar 

  31. Wood LD, Heaphy CM, Daniel HD, Naini BV, Lassman CR, Arroyo MR, Kamel IR, Cosgrove DP, Boitnott JK, Meeker AK, Torbenson MS (2013) Chromophobe hepatocellular carcinoma with abrupt anaplasia: a proposal for a new subtype of hepatocellular carcinoma with unique morphological and molecular features. Mod Pathol 26(12):1586–1593. doi:10.1038/modpathol.2013.68

    PubMed Central  CAS  PubMed  Google Scholar 

  32. Evason KJ, Grenert JP, Ferrell LD, Kakar S (2013) Atypical hepatocellular adenoma-like neoplasms with β-catenin activation show cytogenetic alterations similar to well-differentiated hepatocellular carcinomas. Hum Pathol 44(5):750–758. doi:10.1016/j.humpath.2012.07.019

    CAS  PubMed  Google Scholar 

  33. Bedossa P, Burt AD, Brunt EM, Callea F, Clouston AD, Dienes HP, Goodman ZD, Gouw AS, Hubscher SG, Roberts EA, Roskams T, Terracciano L, Tiniakos DG, Torbenson MS, Wanless IR (2014) Well-differentiated hepatocellular neoplasm of uncertain malignant potential: proposal for a new diagnostic category. Hum Pathol 45(3):658–660. doi:10.1016/j.humpath.2013.09.020

    PubMed  Google Scholar 

  34. Cillo U, Vitale A, Bassanello M, Boccagni P, Brolese A, Zanus G, Burra P, Fagiuoli S, Farinati F, Rugge M, D’Amico DF (2004) Liver transplantation for the treatment of moderately or well-differentiated hepatocellular carcinoma. Ann Surg 239:150–159

    PubMed Central  PubMed  Google Scholar 

  35. Decaens T, Roudot-Thoraval F, Badran H, Wolf P, Durand F, Adam R, Boillot O, Vanlemmens C, Gugenheim J, Dharancy S, Bernard PH, Boudjema K, Calmus Y, Hardwigsen J, Ducerf C, Pageaux GP, Hilleret MN, Chazouillères O, Cherqui D, Mallat A, Duvoux C (2011) Impact of tumour differentiation to select patients before liver transplantation for hepatocellular carcinoma. Liver Int 31:792–801. doi:10.1111/j.1478-3231.2010.02425.x

    PubMed  Google Scholar 

  36. Jonas S, Bechstein WO, Steinmller T, Herrmann M, Radke C, Berg T, Settmacher U, Neuhaus P (2001) Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology 33:1080–1086

    CAS  PubMed  Google Scholar 

  37. Villanueva A (2013) Rethinking future development of molecular therapies in hepatocellular carcinoma: a bottom-up approach. J Hepatol 59(2):392–395. doi:10.1016/j.jhep.2013.03.025

    PubMed  Google Scholar 

  38. Ozen C, Yildiz G, Dagcan AT, Cevik D, Ors A, Keles U, Topel H, Ozturk M (2013) Genetics and epigenetics of liver cancer. N Biotechnol 30(4):381–384. doi:10.1016/j.nbt.2013.01.007

    CAS  PubMed  Google Scholar 

  39. Buendia MA (2002) Genetic alterations in hepatoblastoma and hepatocellular carcinoma: common and distinctive aspects. Med Pediatr Oncol 39(5):530–535

    PubMed  Google Scholar 

  40. Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, Calderaro J, Bioulac-Sage P, Letexier M, Degos F, Clément B, Balabaud C, Chevet E, Laurent A, Couchy G, Letouzé E, Calvo F, Zucman-Rossi J (2012) Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet 44(6):694–698. doi:10.1038/ng.2256

    PubMed Central  CAS  PubMed  Google Scholar 

  41. Ozturk M (1999) Genetic aspects of hepatocellular carcinogenesis. Semin Liver Dis 19(3):235–242

    CAS  PubMed  Google Scholar 

  42. Bressac B, Galvin KM, Liang TJ, Isselbacher KJ, Wands JR, Ozturk M (1990) Abnormal structure and expression of p53 gene in human hepatocellular carcinoma. Proc Natl Acad Sci U S A 87(5):1973–1977

    PubMed Central  CAS  PubMed  Google Scholar 

  43. Fujimoto A, Totoki Y, Abe T, Boroevich KA, Hosoda F, Nguyen HH, Aoki M, Hosono N, Kubo M, Miya F, Arai Y, Takahashi H, Shirakihara T, Nagasaki M, Shibuya T, Nakano K, Watanabe-Makino K, Tanaka H, Nakamura H, Kusuda J, Ojima H, Shimada K, Okusaka T, Ueno M, Shigekawa Y, Kawakami Y, Arihiro K, Ohdan H, Gotoh K, Ishikawa O, Ariizumi S, Yamamoto M, Yamada T, Chayama K, Kosuge T, Yamaue H, Kamatani N, Miyano S, Nakagama H, Nakamura Y, Tsunoda T, Shibata T, Nakagawa H (2012) Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat Genet 44(7):760–764. doi:10.1038/ng.2291

    CAS  PubMed  Google Scholar 

  44. Huang J, Deng Q, Wang Q, Li KY, Dai JH, Li N, Zhu ZD, Zhou B, Liu XY, Liu RF, Fei QL, Chen H, Cai B, Zhou B, Xiao HS, Qin LX, Han ZG (2012) Exome sequencing of hepatitis B virus-associated hepatocellular carcinoma. Nat Genet 44(10):1117–1121. doi:10.1038/ng.2391

    CAS  PubMed  Google Scholar 

  45. Breuhahn K, Longerich T, Schirmacher P (2006) Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene 25(27):3787–3800

    CAS  PubMed  Google Scholar 

  46. Thorgeirsson SS, Grisham JW (2002) Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 31(4):339–346

    CAS  PubMed  Google Scholar 

  47. Yeh MM, Larson AM, Campbell JS, Fausto N, Rulyak SJ, Swanson PE (2007) The expression of transforming growth factor-alpha in cirrhosis, dysplastic nodules, and hepatocellular carcinoma: an immunohistochemical study of 70 cases. Am J Surg Pathol 31(5):681–689

    PubMed  Google Scholar 

  48. Li M, Zhao H, Zhang X, Wood LD, Anders RA, Choti MA, Pawlik TM, Daniel HD, Kannangai R, Offerhaus GJ, Velculescu VE, Wang L, Zhou S, Vogelstein B, Hruban RH, Papadopoulos N, Cai J, Torbenson MS, Kinzler KW (2011) Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat Genet 43(9):828–829. doi:10.1038/ng.903

    PubMed Central  CAS  PubMed  Google Scholar 

  49. Um TH, Kim H, Oh BK, Kim MS, Kim KS, Jung G, Park YN (2011) Aberrant CpG island hypermethylation in dysplastic nodules and early HCC of hepatitis B virus-related human multistep hepatocarcinogenesis. J Hepatol 54(5):939–947. doi:10.1016/j.jhep.2010.08.021

    CAS  PubMed  Google Scholar 

  50. Nishida N (2010) Impact of hepatitis virus and aging on DNA methylation in human hepatocarcinogenesis. Histol Histopathol 25(5):647–654

    CAS  PubMed  Google Scholar 

  51. Cardin R, Piciocchi M, Bortolami M, Kotsafti A, Barzon L, Lavezzo E, Sinigaglia A, Rodriguez-Castro KI, Rugge M, Farinati F (2014) Oxidative damage in the progression of chronic liver disease to hepatocellular carcinoma: an intricate pathway. World J Gastroenterol 20(12):3078–3086

    PubMed Central  CAS  PubMed  Google Scholar 

  52. Callegari E, Elamin BK, Sabbioni S, Gramantieri L, Negrini M (2013) Role of microRNAs in hepatocellular carcinoma: a clinical perspective. Onco Targets Ther 6:1167–1178

    PubMed Central  PubMed  Google Scholar 

  53. Negrini M, Gramantieri L, Sabbioni S, Croce CM (2011) microRNA involvement in hepatocellular carcinoma. Anticancer Agents Med Chem 11(6):500–521

    CAS  PubMed  Google Scholar 

  54. Lanford RE, Hildebrandt-Eriksen ES, Petri A, Persson R, Lindow M, Munk ME, Kauppinen S, Ørum H (2010) Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 327(5962):198–201. doi:10.1126/science.1178178

    PubMed Central  CAS  PubMed  Google Scholar 

  55. Lindow M, Kauppinen S (2012) Discovering the first microRNA-targeted drug. J Cell Biol 199(3):407–412. doi:10.1083/jcb.201208082

    PubMed Central  CAS  PubMed  Google Scholar 

  56. Anthony PP, Vogel CL, Barker LE (1973) Liver cell dysplasia: a premalignant condition. J Clin Pathol 26(3):217–223

    PubMed Central  CAS  PubMed  Google Scholar 

  57. Anthony PP, Vogel CL, Sadikali F, Barker LF, Peterson MR (1972) Hepatitis-associated antigen and antibody in Uganda: correlation of serological testing with histopathology. Br Med J 1(5797):403–406

    PubMed Central  CAS  PubMed  Google Scholar 

  58. Park YN (2011) Update on precursor and early lesions of hepatocellular carcinomas. Arch Pathol Lab Med 135(6):704–715. doi:10.1043/2010-0524-RA

    PubMed  Google Scholar 

  59. Kim H, Park YN (2009) Large liver cell change/dysplasia in hepatitis B virus-related liver cirrhosis. Korean J Hepatol 15(3):375–378. doi:10.3350/kjhep.2009.15.3.375

    PubMed  Google Scholar 

  60. Borzio M, Bruno S, Roncalli M, Mels GC, Ramella G, Borzio F, Leandro G, Servida E, Podda M (1995) Liver cell dysplasia is a major risk factor for hepatocellular carcinoma in cirrhosis: a prospective study. Gastroenterology 108:812–817

    CAS  PubMed  Google Scholar 

  61. Ganne-Carrié N, Chastang C, Chapel F, Munz C, Pateron D, Sibony M, Dény P, Trinchet JC, Callard P, Guettier C, Beaugrand M (1996) Predictive score for the development of hepatocellular carcinoma and additional value of liver large cell dysplasia in Western patients with cirrhosis. Hepatology 23:1112–1118

    PubMed  Google Scholar 

  62. Libbrecht L, Craninx M, Nevens F, Desmet V, Roskams T (2001) Predictive value of liver cell dysplasia for development of hepatocellular carcinoma in patients with non-cirrhotic and cirrhotic chronic viral hepatitis. Histopathology 39:66–73

    CAS  PubMed  Google Scholar 

  63. Koo JS, Kim H, Park BK, Ahn SH, Han KH, Chon CY, Park C, Park YN (2008) Predictive value of liver cell dysplasia for development of hepatocellular carcinoma in patients with chronic hepatitis B. J Clin Gastroenterol 42(6):738–743. doi:10.1097/MCG.0b013e318038159d

    PubMed  Google Scholar 

  64. Watanabe S, Okita K, Harada T, Kodama T, Numa Y, Takemoto T, Takahashi T (1983) Morphologic studies of the liver cell dysplasia. Cancer 51(12):2197–2205

    CAS  PubMed  Google Scholar 

  65. Makino Y, Shiraki K, Sugimoto K, Ito T, Yamanaka T, Fujikawa K, Takase K, Nakano T (2000) Histological features of cirrhosis with hepatitis C virus for prediction of hepatocellular carcinoma development: a prospective study. Anticancer Res 20(5C):3709–3715

    CAS  PubMed  Google Scholar 

  66. Hytiroglou P, Park YN, Krinsky G, Theise ND (2007) Hepatic precancerous lesions and small hepatocellular carcinoma. Gastroenterol Clin North Am 36(4):867–887

    PubMed  Google Scholar 

  67. International Working Party (1995) Terminology of nodular hepatocellular lesions. Hepatology 22:983–993

    Google Scholar 

  68. Roskams T (2006) Liver stem cells and their implication in hepatocellular and cholangiocarcinoma. Oncogene 25(27):3818–3822

    CAS  PubMed  Google Scholar 

  69. Su Q, Benner A, Hofmann WJ, Otto G, Pichlmayr R, Bannasch P (1997) Human hepatic preneoplasia: phenotypes and proliferation kinetics of foci and nodules of altered hepatocytes and their relationship to liver cell dysplasia. Virchows Arch 431:391–406

    CAS  PubMed  Google Scholar 

  70. Bannasch P, Mayer D, Hacker HJ (1980) Hepatocellular glycogenosis and hepatocarcinogenesis. Biochim Biophys Acta 605:217–245

    CAS  PubMed  Google Scholar 

  71. Ribback S, Calvisi DF, Cigliano A, Sailer V, Peters M, Rausch J, Heidecke CD, Birth B, Dombrowski F (2013) Molecular and metabolic changes in human liver clear cell foci resemble the alterations occurring in rat hepatocarcinogenesis. J Hepatol 58:1147–1156. doi:10.1016/j.jhep.2013.01.013

    CAS  PubMed  Google Scholar 

  72. Di Tommaso L, Sangiovanni A, Borzio M, Park YN, Farinati F, Roncalli M (2013) Advanced precancerous lesions in the liver. Best Pract Res Clin Gastroenterol 27(2):269–284. doi:10.1016/j.bpg.2013.03.015

    PubMed  Google Scholar 

  73. Borzio M, Fargion S, Borzio F, Fracanzani AL, Croce AM, Stroffolini T, Oldani S, Cotichini R, Roncalli M (2003) Impact of large regenerative, low grade and high grade dysplastic nodules in hepatocellular carcinoma development. J Hepatol 39:208–214

    PubMed  Google Scholar 

  74. Kobayashi M, Ikeda K, Hosaka T, Sezaki H, Someya T, Akuta N, Suzuki F, Suzuki Y, Saitoh S, Arase Y, Kumada H (2006) Dysplastic nodules frequently develop into hepatocellular carcinoma in patients with chronic viral hepatitis and cirrhosis. Cancer 106(3):636–647

    PubMed  Google Scholar 

  75. Theise ND, Park YN, Kojiro M (2002) Dysplastic nodules and hepatocarcinogenesis. Clin Liver Dis 6(2):497–512

    PubMed  Google Scholar 

  76. Maggioni M, Coggi G, Cassani B, Bianchi P, Romagnoli S, Mandelli A, Borzio M, Colombo P, Roncalli M (2000) Molecular changes in hepatocellular dysplastic nodules on microdissected liver biopsies. Hepatology 32(5):942–946

    CAS  PubMed  Google Scholar 

  77. Sun M, Eshleman JR, Ferrell LD, Jacobs G, Sudilovsky EC, Tuthill R, Hussein MR, Sudilovsky O (2001) An early lesion in hepatic carcinogenesis: loss of heterozygosity in human cirrhotic livers and dysplastic nodules at the 1p36-p34 region. Hepatology 33(6):1415–1424

    CAS  PubMed  Google Scholar 

  78. Oh BK, Jo Chae K, Park C, Kim K, Jung Lee W, Han KH, Nyun Park Y (2003) Telomere shortening and telomerase reactivation in dysplastic nodules of human hepatocarcinogenesis. J Hepatol 39(5):786–792

    CAS  PubMed  Google Scholar 

  79. Lee YH, Oh BK, Yoo JE, Yoon SM, Choi J, Kim KS, Park YN (2009) Chromosomal instability, telomere shortening, and inactivation of p21(WAF1/CIP1) in dysplastic nodules of hepatitis B virus-associated multistep hepatocarcinogenesis. Mod Pathol 22(8):1121–1131. doi:10.1038/modpathol.2009.76

    CAS  PubMed  Google Scholar 

  80. Cardinale V, Bragazzi MC, Carpino G, Torrice A, Fraveto A, Gentile R, Pasqualino V, Melandro F, Aliberti C, Bastianelli C, Brunelli R, Berloco PB, Gaudio E, Alvaro D (2013) Cholangiocarcinoma: increasing burden of classifications. Hepatobiliary Surg Nutr 2(5):272–280

    PubMed Central  PubMed  Google Scholar 

  81. Shaib Y, El-Serag HB (2004) The epidemiology of cholangiocarcinoma. Semin Liver Dis 24:115–125

    PubMed  Google Scholar 

  82. McGlynn KA, Tarone RE, El-Serag HB (2006) A comparison of trends in the incidence of hepatocellular carcinoma and intrahepatic cholangiocarcinoma in the United States. Cancer Epidemiol Biomarkers Prev 15:1198–1203

    PubMed  Google Scholar 

  83. Kaewpitoon N, Kaewpitoon SJ, Pengsaa P, Sripa B (2008) Opisthorchis viverrini: the carcinogenic human liver fluke. World J Gastroenterol 14:666–674

    PubMed Central  CAS  PubMed  Google Scholar 

  84. Kubo S, Nakanuma Y, Takemura S, Sakata C, Urata Y, Nozawa A, Nishioka T, Kinoshita M, Hamano G, Terajima H, Tachiyama G, Matsumura Y, Yamada T, Tanaka H, Nakamori S, Arimoto A, Kawada N, Fujikawa M, Fujishima H, Sugawara Y, Tanaka S, Toyokawa H, Kuwae Y, Ohsawa M, Uehara S, Sato KK, Hayashi T, Endo G (2014) Case series of 17 patients with cholangiocarcinoma among young adult workers of a printing company in Japan. J Hepatobiliary Pancreat Sci 21(7):479–488. doi:10.1002/jhbp.86

    PubMed  Google Scholar 

  85. Fujita T (2012) An unusual risk factor for intrahepatic cholangiocarcinoma. J Hepatol 57(6):1396–1397. doi:10.1016/j.jhep.2012.07.021

    PubMed  Google Scholar 

  86. Sirica AE (2012) The role of cancer-associated myofibroblasts in intrahepatic cholangiocarcinoma. Nat Rev Gastroenterol Hepatol 9:44–54. doi:10.1038/nrgastro.2011.222

    CAS  Google Scholar 

  87. Sirica AE, Gores GJ (2014) Desmoplastic stroma and cholangiocarcinoma: clinical implications and therapeutic targeting. Hepatology 59(6):2397–2402. doi:10.1002/hep.26762

    PubMed  Google Scholar 

  88. Sempoux C, Jibara G, Ward SC, Fan C, Qin L, Roayaie S, Fiel MI, Schwartz M, Thung SN (2011) Intrahepatic cholangiocarcinoma: new insights in pathology. Semin Liver Dis 31(1):49–60. doi:10.1055/s-0031-1272839

    PubMed  Google Scholar 

  89. Komuta M, Govaere O, Vandecaveye V, Akiba J, Van Steenbergen W, Verslype C, Laleman W, Pirenne J, Aerts R, Yano H, Nevens F, Topal B, Roskams T (2013) Histological diversity in cholangiocellular carcinoma reflects the different cholangiocyte phenotypes. Hepatology 55(6):1876–1888. doi:10.1002/hep.25595

    Google Scholar 

  90. Liau JY, Tsai JH, Yuan RH, Chang CN, Lee HJ, Jeng YM (2014) Morphological subclassification of intrahepatic cholangiocarcinoma: etiological, clinicopathological, and molecular features. Mod Pathol 27(8):1163–1173. doi:10.1038/modpathol.2013.241

    CAS  PubMed  Google Scholar 

  91. Sasaki M, Nakanuma Y, Shimizu K, Izumi R (1995) Pathological and immunohistochemical findings in a case of mucinous cholangiocarcinoma. Pathol Int 45:781–786

    CAS  PubMed  Google Scholar 

  92. Jeng YM, Chen CL, Hsu HC (2001) Lymphoepithelioma-like cholangiocarcinoma: an Epstein-Barr virus-associated tumor. Am J Surg Pathol 25(4):516–520

    CAS  PubMed  Google Scholar 

  93. Haas S, Gütgemann I, Wolff M, Fischer HP (2007) Intrahepatic clear cell cholangiocarcinoma: immunohistochemical aspects in a very rare type of cholangiocarcinoma. Am J Surg Pathol 31:902–906

    PubMed  Google Scholar 

  94. Shuangshoti S Jr, Shuangshoti S (2000) Primary mucoepidermoid carcinoma of the intrahepatic bile duct: a case report with review of literature. J Med Assoc Thai 83(2):197–203

    PubMed  Google Scholar 

  95. Simo KA, Mckillop IH, Ahrens WA, Martinie JB, Iannitti DA, Sindram D (2012) Invasive biliary mucinous cystic neoplasm: a review. HPB (Oxford) 14(11):725–740. doi:10.1111/j.1477-2574.2012.00532.x

    Google Scholar 

  96. Zen Y, Pedica F, Patcha VR, Capelli P, Zamboni G, Casaril A, Quaglia A, Nakanuma Y, Heaton N, Portmann B (2011) Mucinous cystic neoplasms of the liver: a clinicopathological study and comparison with intraductal papillary neoplasms of the bile duct. Mod Pathol 24:1079–1089. doi:10.1038/modpathol.2011.71

    PubMed  Google Scholar 

  97. Fassan M, Baffa R, Kiss A (2013) Advanced precancerous lesions within the GI tract: the molecular background. Best Pract Res Clin Gastroenterol 27:159–169. doi:10.1016/j.bpg.2013.03.009

    CAS  PubMed  Google Scholar 

  98. Borger DR, Tanabe KK, Fan KC, Lopez HU, Fantin VR, Straley KS, Schenkein DP, Hezel AF, Ancukiewicz M, Liebman HM, Kwak EL, Clark JW, Ryan DP, Deshpande V, Dias-Santagata D, Ellisen LW, Zhu AX, Iafrate AJ (2012) Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist 17:72–79. doi:10.1634/theoncologist. 2011-0386

    PubMed Central  CAS  PubMed  Google Scholar 

  99. Borger DR, Goyal L, Yau TC, Poon RT, Ancukiewicz M, Deshpande V, Christiani DC, Liebman HM, Yang H, Kim H, Ellwood-Yen K, Faris JE, Iafrate AJ, Kwak EL, Clark JW, Allen JN, Blaszkowsky LS, Murphy JE, Saha SK, Hong TS, Wo JY, Ferrone CR, Tanabe KK, Bardeesy N, Straley KS, Agresta S, Schenkein DP, Ellisen LW, Ryan DP, Zhu AX (2014) Circulating oncometabolite 2-hydroxyglutarate is a potential surrogate biomarker in patients with isocitrate dehydrogenase-mutant intrahepatic cholangiocarcinoma. Clin Cancer Res 20(7):1884–1890. doi:10.1158/1078-0432.CCR-13-2649

    PubMed Central  CAS  PubMed  Google Scholar 

  100. Jiao Y, Pawlik TM, Anders RA, Selaru FM, Streppel MM, Lucas DJ, Niknafs N, Guthrie VB, Maitra A, Argani P, Offerhaus GJ, Roa JC, Roberts LR, Gores GJ, Popescu I, Alexandrescu ST, Dima S, Fassan M, Simbolo M, Mafficini A, Capelli P, Lawlor RT, Ruzzenente A, Guglielmi A, Tortora G, de Braud F, Scarpa A, Jarnagin W, Klimstra D, Karchin R, Velculescu VE, Hruban RH, Vogelstein B, Kinzler KW, Papadopoulos N, Wood LD (2013) Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet 45:1470–1473. doi:10.1038/ng.2813

    PubMed Central  CAS  PubMed  Google Scholar 

  101. Johnson C, Han Y, Hughart N, McCarra J, Alpini G, Meng F (2012) Interleukin-6 and its receptor, key players in hepatobiliary inflammation and cancer. Transl Gastrointest Cancer 1(1):58–70

    PubMed Central  PubMed  Google Scholar 

  102. Okada K, Shimizu Y, Nambu S, Higuchi K, Watanabe A (1994) Interleukin-6 functions as an autocrine growth factor in a cholangiocarcinoma cell line. J Gastroenterol Hepatol 9:462–467

    CAS  PubMed  Google Scholar 

  103. Goydos JS, Brumfield AM, Frezza E, Booth A, Lotze MT, Carty SE (1998) Marked elevation of serum interleukin-6 in patients with cholangiocarcinoma: validation of utility as a clinical marker. Ann Surg 227:398–404

    PubMed Central  CAS  PubMed  Google Scholar 

  104. Meng F, Yamagiwa Y, Ueno Y, Patel T (2006) Over-expression of interleukin-6 enhances cell survival and transformed cell growth in human malignant cholangiocytes. J Hepatol 44:1055–1065

    PubMed Central  CAS  PubMed  Google Scholar 

  105. Isomoto H, Kobayashi S, Werneburg NW, Bronk SF, Guicciardi ME, Frank DA, Gores GJ (2005) Interleukin 6 upregulates myeloid cell leukemia-1 expression through a STAT3 pathway in cholangiocarcinoma cells. Hepatology 42(6):1329–1338

    CAS  PubMed  Google Scholar 

  106. Yamagiwa Y, Meng F, Patel T (2006) Interleukin-6 decreases senescence and increases telomerase activity in malignant human cholangiocytes. Life Sci 78:2494–2502

    PubMed Central  CAS  PubMed  Google Scholar 

  107. Rougemont AL, Genevay M, McKee TA, Gremaud M, Mentha G, Rubbia-Brandt L (2010) Extensive biliary intraepithelial neoplasia (BilIN) and multifocal early intrahepatic cholangiocarcinoma in nonbiliary cirrhosis. Virchows Arch 456(6):711–717. doi:10.1007/s00428-010-0899-3

    CAS  PubMed  Google Scholar 

  108. Wu TT, Levy M, Correa AM, Rosen CB, Abraham SC (2009) Biliary intraepithelial neoplasia in patients without chronic biliary disease: analysis of liver explants with alcoholic cirrhosis, hepatitis C infection, and noncirrhotic liver diseases. Cancer 115(19):4564–4575. doi:10.1002/cncr.24471

    PubMed  Google Scholar 

  109. Zen Y, Aishima S, Ajioka Y, Haratake J, Kage M, Kondo F, Nimura Y, Sakamoto M, Sasaki M, Shimamatsu K, Wakasa K, Park YN, Chen MF, Atomi Y, Nakanuma Y (2005) Proposal of histological criteria for intraepithelial atypical/proliferative biliary epithelial lesions of the bile duct in hepatolithiasis with respect to cholangiocarcinoma: preliminary report based on interobserver agreement. Pathol Int 55(4):180–188

    PubMed  Google Scholar 

  110. Sato Y, Harada K, Sasaki M, Nakanuma Y (2013) Histological characteristics of biliary intraepithelial neoplasia-3 and intraepithelial spread of cholangiocarcinoma. Virchows Arch 462(4):421–427. doi:10.1007/s00428-013-1384-6

    CAS  PubMed  Google Scholar 

  111. Zen Y, Adsay NV, Bardadin K, Colombari R, Ferrell L, Haga H, Hong SM, Hytiroglou P, Klöppel G, Lauwers GY, van Leeuwen DJ, Notohara K, Oshima K, Quaglia A, Sasaki M, Sessa F, Suriawinata A, Tsui W, Atomi Y, Nakanuma Y (2007) Biliary intraepithelial neoplasia: an international interobserver agreement study and proposal for diagnostic criteria. Mod Pathol 20(6):701–709

    PubMed  Google Scholar 

  112. Chen TC, Nakanuma Y, Zen Y, Chen MF, Jan YY, Yeh TS, Chiu CT, Kuo TT, Kamiya J, Oda K, Hamaguchi M, Ohno Y, Hsieh LL, Nimura Y (2001) Intraductal papillary neoplasia of the liver associated with hepatolithiasis. Hepatology 34:651–658

    CAS  PubMed  Google Scholar 

  113. Sibulesky L, Nguyen J, Patel T (2012) Preneoplastic conditions underlying bile duct cancer. Langenbecks Arch Surg 397(6):861–867. doi:10.1007/s00423-012-0943-7

    PubMed Central  PubMed  Google Scholar 

  114. Schlitter AM, Born D, Bettstetter M, Specht K, Kim-Fuchs C, Riener MO, Jeliazkova P, Sipos B, Siveke JT, Terris B, Zen Y, Schuster T, Höfler H, Perren A, Klöppel G, Esposito I (2013) Intraductal papillary neoplasms of the bile duct: stepwise progression to carcinoma involves common molecular pathways. Mod Pathol 27(1):73–86. doi:10.1038/modpathol.2013.112

    PubMed  Google Scholar 

  115. Singh S, Chakraborty S, Bonthu N, Radio S, Hussain SM, Sasson A (2013) Combined hepatocellular cholangiocarcinoma: a case report and review of literature. Dig Dis Sci 58(7):2114–2123. doi:10.1007/s10620-013-2585-1

    PubMed  Google Scholar 

  116. Wells H (1903) Primary carcinoma of the liver. Am J Sci 126:403–417

    Google Scholar 

  117. Allen RA, Lisa J (1949) Combined liver cell and bile duct carcinoma. Am J Pathol 25:647–655

    PubMed Central  CAS  PubMed  Google Scholar 

  118. Fujii H, Zhu XG, Matsumoto T, Inagaki M, Tokusashi Y, Miyokawa N, Fukusato T, Uekusa T, Takagaki T, Kadowaki N, Shirai T (2000) Genetic classification of combined hepatocellular-cholangiocarcinoma. Hum Pathol 31:1011–1017

    CAS  PubMed  Google Scholar 

  119. Jarnagin WR, Weber S, Tickoo SK, Koea JB, Obiekwe S, Fong Y, DeMatteo RP, Blumgart LH, Klimstra D (2002) Combined hepatocellular and cholangiocarcinoma: demographic, clinical, and prognostic factors. Cancer 94:2040–2046

    PubMed  Google Scholar 

  120. Kassahun WT, Hauss J (2008) Management of combined hepatocellular and cholangiocarcinoma. Int J Clin Pract 62:1271–1278. doi:10.1111/j.1742-1241.2007.01694.x

    CAS  PubMed  Google Scholar 

  121. Sapisochin G, de Lope CR, Gastaca M, de Urbina JO, López-Andujar R, Palacios F, Ramos E, Fabregat J, Castroagudín JF, Varo E, Pons JA, Parrilla P, González-Diéguez ML, Rodriguez M, Otero A, Vazquez MA, Zozaya G, Herrero JI, Antolin GS, Perez B, Ciria R, Rufian S, Fundora Y, Ferron JA, Guiberteau A, Blanco G, Varona MA, Barrera MA, Suarez MA, Santoyo J, Bruix J, Charco R (2014) Intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma in patients undergoing liver transplantation: a Spanish matched cohort multicenter study. Ann Surg 259(5):944–952. doi:10.1097/SLA.0000000000000494

    CAS  PubMed  Google Scholar 

  122. Sasaki M, Sato H, Kakuda Y, Sato Y, Choi JH, Nakanuma Y (2014) Clinicopathological significance of “subtypes with stem-cell feature” in combined hepatocellular-cholangiocarcinoma. Liv Intern, in press. doi:10.1111/liv.12563

  123. Yano H, Iemura A, Haramaki M, Momosaki S, Ogasawara S, Higaki K, Kojiro M (1996) A human combined hepatocellular and cholangiocarcinoma cell line (KMCH-2) that shows the features of hepatocellular carcinoma or cholangiocarcinoma under different growth conditions. J Hepatol 24:413–422

    CAS  PubMed  Google Scholar 

  124. Theise ND, Yao JL, Harada K, Hytiroglou P, Portmann B, Thung SN, Tsui W, Ohta H, Nakanuma Y (2003) Hepatic ‘stem cell’ malignancies in adults: four cases. Histopathology 43(3):263–271

    CAS  PubMed  Google Scholar 

  125. Komuta M, Spee B, Vander Borght S, De Vos R, Verslype C, Aerts R, Yano H, Suzuki T, Matsuda M, Fujii H, Desmet VJ, Kojiro M, Roskams T (2008) Clinicopathological study on cholangiocellular carcinoma suggesting hepatic progenitor cell origin. Hepatology 47:1544–1556. doi:10.1002/hep.22238

    CAS  PubMed  Google Scholar 

  126. Lo RC, Ng IO (2013) Hepatic progenitor cells: their role and functional significance in the new classification of primary liver cancers. Liver Cancer 2(2):84–92

    PubMed Central  CAS  PubMed  Google Scholar 

  127. Woo HG, Lee JH, Yoon JH, Kim CY, Lee HS, Jang JJ, Yi NJ, Suh KS, Lee KU, Park ES, Thorgeirsson SS, Kim YJ (2010) Identification of a cholangiocarcinoma-like gene expression trait in hepatocellular carcinoma. Cancer Res 70:3034–3041. doi:10.1158/0008-5472.CAN-09-2823

    PubMed Central  CAS  PubMed  Google Scholar 

  128. Roskams T, Katoonizadeh A, Komuta M (2010) Hepatic progenitor cells: an update. Clin Liver Dis 14(4):705–718. doi:10.1016/j.cld.2010.08.003

    PubMed  Google Scholar 

  129. Chiba T, Kamiya A, Yokosuka O, Iwama A (2009) Cancer stem cells in hepatocellular carcinoma: recent progress and perspective. Cancer Lett 286:145–153. doi:10.1016/j.canlet.2009.04.027

    CAS  PubMed  Google Scholar 

  130. Dumble ML, Croager EJ, Yeoh GC, Quail EA (2002) Generation and characterization of p53 null transformed hepatic progenitor cells: oval cells give rise to hepatocellular carcinoma. Carcinogenesis 23(3):435–445

    CAS  PubMed  Google Scholar 

  131. Lee JS, Heo J, Libbrecht L, Chu IS, Kaposi-Novak P, Calvisi DF, Mikaelyan A, Roberts LR, Demetris AJ, Sun Z, Nevens F, Roskams T, Thorgeirsson SS (2006) A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med 12(4):410–416

    CAS  PubMed  Google Scholar 

  132. Holczbauer A, Factor VM, Andersen JB, Marquardt JU, Kleiner DE, Raggi C, Kitade M, Seo D, Akita H, Durkin ME, Thorgeirsson SS (2013) Modeling pathogenesis of primary liver cancer in lineage-specific mouse cell types. Gastroenterology 145:221–231. doi:10.1053/j.gastro.2013.03.013

    PubMed Central  CAS  PubMed  Google Scholar 

  133. Fan B, Malato Y, Calvisi DF, Naqvi S, Razumilava N, Ribback S, Gores GJ, Dombrowski F, Evert M, Chen X, Willenbring H (2012) Cholangiocarcinomas can originate from hepatocytes in mice. J Clin Invest 122:2911–2915. doi:10.1172/JCI63212

    PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors are grateful to Dr. Alessio Mussato for his precious technical contribution.

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Authors and Affiliations

  1. Department of Medicine, General Pathology and Cytopathology Unit, University of Padova, Padova, Italy

    Maria Guido, Samantha Sarcognato, Matteo Fassan & Marco Pizzi

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  1. Maria Guido
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  2. Samantha Sarcognato
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  3. Matteo Fassan
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  4. Marco Pizzi
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Correspondence to Maria Guido .

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  1. Department of Health Sciences, University of Eastern Piedmont Amedeo Avogadro, Novara, Italy

    Emanuele Albano

  2. Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, School of Medicine, University of Torino, Torino, Italy

    Maurizio Parola

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Guido, M., Sarcognato, S., Fassan, M., Pizzi, M. (2015). Liver Cancer Classification. In: Albano, E., Parola, M. (eds) Studies on Hepatic Disorders. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, Cham. https://doi.org/10.1007/978-3-319-15539-5_19

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