Hepatocellular-Cholangiocarcinomas in Non-Alcoholic Fatty Liver Disease: Evidence for Stem Cell Origin
DOI:
https://doi.org/10.21141/PJP.2016.008Keywords:
hepatocellular-cholangiocarcinoma, non-alcoholic fatty liver disease (NAFLD), steatohepatitis, stem cellAbstract
The authors present two cases of combined hepatocellular-cholangiocarcinoma in a background of non-cirrhotic, non-alcoholic fatty liver disease (NAFLD). The increasing incidence of NAFLD and the subsequent recognition of it being a pre-malignant condition even in the absence of significant fibrosis or established cirrhosis has led to the investigations of the different pathways involved in NAFLD-associated hepatocarcinogenesis, including speculations regarding the possibility that many derive from pre-malignant hepatocellular adenomas, tumors also increasingly associated with NAFLD, or reflect malignant transformation of mature hepatocytes through genetic and epigenetic alterations reflecting inflammatory changes in NAFLD. However, NAFLD, like most chronic liver diseases, leads to progressive activation of resident hepatobiliary stem/progenitor cells that are thought to give rise to malignant tumors in other settings. In particular, combined hepatocellular-cholangiocarcinomas (with and without stem cell features) are thought to reflect malignant transformation of these activated progenitors. Our two cases of combined hepatocellular-cholangiocarcinomas suggest that malignant transformation of hepatobiliary stem/progenitor cells in NAFLD are also a possible pathway to malignancy, even in the absence of established cirrhosis.
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References
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26. Unger RH, Orci L. Lipoapoptosis: its mechanism and its diseases. BBA-Mol Cell Biol L. 2002;1585(2-3):202-12.
27. Puri P, Mirshahi F, Cheung O, et al. Gastroenterology. 2008;134(2):568-76. https://doi.org/10.1053/j.gastro.2007.10.039.
28. Singh R, Wang Y, Xiang Y, Tanaka KE, Gaarde WA, Czaja MJ. Hepatology. 2009; 49(1):87-96. https://doi.org/10.1002/hep.22578.
29. Schattenberg JM, Singh R, Wang Y, et al. JNK1 but not JNK2 promotes the development of steatohepatitis in mice. Hepatology. 2006;43:163-72.
30. Clouston A, Powell E. Interaction of non-alcoholic fatty liver disease with other liver diseases. Best Pract Res Clin Gastroenterol. 2002;16(5):767-81. https://doi.org/10.1053/bega.2002.0329.
31. Bugianesi E. Non-alcoholic steatohepatitis and cancer. Clin Liver Dis. 2007;11(1):191-207,x-xi. https://pubmed.ncbi.nlm.nih.gov/17544979.
32. Yang S, Zhu H, Li Y, Lin H, Gabrielson K, Trush MA, et al. Mitochondrial adaptations to obesity-related oxidant stress. Arch Biochem Biophys. 2000;378(2):259-68. https://doi.org/10.1006/abbi.2000.1829.
33. Chen F, Beezhold k, Castranova V. JNK1, a potential therapeutic target for hepatocellular carcinoma. BBA-Rev Cancer. 2009;1796(2):242-51. https://doi.org/10.1016/j.bbcan.2009.06.005.
34. Park EJ, Lee JH, Yu GY, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010;140(2):197-208. https://doi.org/10.1016/j.cell.2009.12.052.
35. Hatziapostolou M, Polytarchou C, Aggelidou E, et al. An HNF4a-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis. Cell. 2011;147(6):1233-47. https://doi.org/10.1016/j.cell.2011.10.043.
36. Clouston AD, Powell EE, Walsh MJ, Richardson MM, Demetris AJ, Jonsson JR. Fibrosis correlates with a ductular reaction in hepatitis C: roles of impaired replication, progenitor cells and steatosis. Hepatology. 2005;41(4):809-18. https://doi.org/10.1002/hep.20650.
37. Sell S. Heterogeneity and plasticity of hepatocyte lineage cells. Hepatology. 2001;33(3):738-50. https://doi.org/10.1053/jhep.2001.21900.
2. Paradis V, Zalinski S, Chelbi E. et al. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology. 2009;49(3):851-9. https://doi.org/10.1002/hep.22734.
3. Guzman G, Brunt EM, Petrovic M, Chejfec G, Layden TJ, Cotler SJ. Does nonalcoholic fatty liver disease predispose patients to hepatocellular carcinoma in the absence of cirrhosis? Arch Pathol Lab Mab. 2008;132(11):1761-6. https://pubmed.ncbi.nlm.nih.gov/18976012. https://doi.org/10.1043/1543-2165-132.11.1761.
4. Bullock RE, Zaitoun AM, Aithal GP, Ryder SD, Beckingham IJ, Lobo DN. Association of non-alcoholic steatohepatitis without significant fibrosis with hepatocellular carcinoma. J Hepatol. 2004:41(4);685-6. https://doi.org/10.1016/j.jhep.2004.05.008.
5. Saxena R. Practical hepatic pathology: a diagnostic approach. Philadelphia: Elsevier-Saunders; 2011.
6. Herzer K, Hofmann TG, Teufel A, et al. IFN-alpha induced apoptosis in hepatocellular carcinoma involves promyelocytic leukemia protein and TRAIL independently of p53. Cancer Res. 2009;69:855-62. https://doi.org/10.1158/0008-5472.CAN-08-2831.
7. Cazanave SC, Mott JL, Elmi NA, et al. JNK1-dependent PUMA expression contributes to hepatocyte lipoapoptosis. J Biol Chem. 2009;284:26591-602. https://doi.org/10.1074/jbc.M109.022491.
8. Ertle J, Dechêne A, Sowa J, et al. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int J Cancer. 2011; 128(10):2436-43. https://doi.org/10.1002/ijc.25797.
9. Theise ND, Nakashima O, Park YN, Nakanuma Y. Combined hepatocellular-cholangicarcinoma. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, eds. WHO Classification of tumours of the digestive system. Lyon: IARC;2010
10. Theise ND, Yao JL, Harada K, et al. Hepatic “stem cell” malignancies in adults: four cases. Histopathology. 2003;43(3):263-71. https://pubmed.ncbi.nlm.nih.gov/12940779. https://doi.org/10.1046/j.1365-2559.2003.01707.x.
11. Yoon SM, Gerasimidou D, Kuwahara R, et al. Epithelial cell adhesion molecule (EpCAM) marks hepatocytes newly derived from stem/progenitor cells in humans. Hepatology. 2011;53(3):964-73. https://doi.org/10.1002/hep.24122.
12. Brunt EM. Nonalcoholic steatohepatitis. Semin Liver Dis.2004;24(1):3-20. https://doi.org/10.1055/s-2004-823098.
13. Harrison SA, Torgerson S, Hayashi PH. The natural history of nonalcoholic fatty liver disease: a clinical histopathological study. Am J Gastroenterol. 2003;98:2042-7. https://doi.org/10.1111/j.1572-0241.2003.07659.x.
14. Adams LA, Sanderson S, Limdor KD, Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol .2005;42(1):132-8. https://doi.org/10.1016/j.jhep.2004.09.012.
15. Fassio E, Álvarez E, Domínguez N, Landeira G, Longo C. Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies. Hepatology. 2004;40(4):820-6. https://doi.org/10.1002/hep.1840400411.
16. Lindor KD, Kowdley KV, Heathcote EJ, Harrison ME, Jorgensen R, Angulo P, et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a
randomized trial. Hepatology. 2004;39(3):770-8. https://doi.org/10.1002/hep.20092.
17. Caldwell Sh, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology. 1999;29(3):664-9. https://doi.org/10.1002/hep.510290347.
18. Bugianesi E, Leone N, Vann E, et al. Expanding the natural history of nonalcoholic steatiohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123(1):134-140. https://doi.org/10.1053/gast.2002.34168.
19. Hai S, Kubo S, Shuto T, et al. Hepatocellular carcinoma arising from nonalcoholic steatohepatitis: report of two cases. Surg Today. 2006;36(4):390-4. https://doi.org/10.1007/s00595-005-3167-4.
20. Mori S, Yamasaki T, Sakaida I et al. Hepatocellular carcinoma with nonalcoholic steatohepatitis. J Gastroenterol. 2004;39(4):391-6. https://doi.org/10.1007/s00535-003-1308-3.
21. Cuadrado A, Orive A, Garcia-Suárez C, et al. Nonalcoholicsteatohepatitis (NASH) and hepatocellular carcinoma. Obes Surg. 2005;15(3):442-6. https://doi.org/10.1381/0960892053576596.
22. Regimbeau JM, Colombat M, Mognol P, et al. Obesity and diabetes as a risk factor for hepatocellular carcinoma. Liver Transpl. 2004;10(Suppl 2):S69-73. https://doi.org/10.1002/lt.20033.
23. Stoot JHMB, Coelen RJS, De Jong MC, Dejong CHC. Malignant transformation of hepatocellular adenomas into hepatocellular carcinomas: a systematic review including more than 1600 adenoma cases. HPB. 2010;12(8):509-22.
httpS://doi.org/10.1111/j.1477-2574.2010.00222.x.
24. 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. https://doi.org/10.1002/hep.510260414.
25. Farges O, Dokmak S. Malignant transformation of liver adenoma: an analysis of the literature. Dig Surg. 2010;27(1):32-8. https://doi.org/10.1159/000268405.
26. Unger RH, Orci L. Lipoapoptosis: its mechanism and its diseases. BBA-Mol Cell Biol L. 2002;1585(2-3):202-12.
27. Puri P, Mirshahi F, Cheung O, et al. Gastroenterology. 2008;134(2):568-76. https://doi.org/10.1053/j.gastro.2007.10.039.
28. Singh R, Wang Y, Xiang Y, Tanaka KE, Gaarde WA, Czaja MJ. Hepatology. 2009; 49(1):87-96. https://doi.org/10.1002/hep.22578.
29. Schattenberg JM, Singh R, Wang Y, et al. JNK1 but not JNK2 promotes the development of steatohepatitis in mice. Hepatology. 2006;43:163-72.
30. Clouston A, Powell E. Interaction of non-alcoholic fatty liver disease with other liver diseases. Best Pract Res Clin Gastroenterol. 2002;16(5):767-81. https://doi.org/10.1053/bega.2002.0329.
31. Bugianesi E. Non-alcoholic steatohepatitis and cancer. Clin Liver Dis. 2007;11(1):191-207,x-xi. https://pubmed.ncbi.nlm.nih.gov/17544979.
32. Yang S, Zhu H, Li Y, Lin H, Gabrielson K, Trush MA, et al. Mitochondrial adaptations to obesity-related oxidant stress. Arch Biochem Biophys. 2000;378(2):259-68. https://doi.org/10.1006/abbi.2000.1829.
33. Chen F, Beezhold k, Castranova V. JNK1, a potential therapeutic target for hepatocellular carcinoma. BBA-Rev Cancer. 2009;1796(2):242-51. https://doi.org/10.1016/j.bbcan.2009.06.005.
34. Park EJ, Lee JH, Yu GY, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010;140(2):197-208. https://doi.org/10.1016/j.cell.2009.12.052.
35. Hatziapostolou M, Polytarchou C, Aggelidou E, et al. An HNF4a-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis. Cell. 2011;147(6):1233-47. https://doi.org/10.1016/j.cell.2011.10.043.
36. Clouston AD, Powell EE, Walsh MJ, Richardson MM, Demetris AJ, Jonsson JR. Fibrosis correlates with a ductular reaction in hepatitis C: roles of impaired replication, progenitor cells and steatosis. Hepatology. 2005;41(4):809-18. https://doi.org/10.1002/hep.20650.
37. Sell S. Heterogeneity and plasticity of hepatocyte lineage cells. Hepatology. 2001;33(3):738-50. https://doi.org/10.1053/jhep.2001.21900.
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Published
05/05/2016
How to Cite
Mendoza, P. G., Tsui, W., Ho, L., Wayne, M., Kagen, A., & Theise, N. (2016). Hepatocellular-Cholangiocarcinomas in Non-Alcoholic Fatty Liver Disease: Evidence for Stem Cell Origin. PJP, 1(1), 30–35. https://doi.org/10.21141/PJP.2016.008
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