Abstract
To examine whether the marked increase in DNA synthesis of hepatocytes in cirrhotic liver might elicit multicentric hepatocarcinogenesis, we examined the relationship between new development of hepatocellular carcinoma (HCC) and the bromodeoxyuridine (BrdU) labeling index (LI) of hepatocytes in the residual liver of hepatectomized patients with liver cirrhosis (LC) and HCC, Eighteen hepatectomized patients with LC and HCC, whose resected liver revealed neither portal nor hepatic vein invasion by histologic examination, were studied (to exclude cases with intrahepatic metastasis). DNA synthesis activity of hepatocytes from the residual cirrhotic liver was measured by a BrdU/ anti‐BrdU in vitro method. The incidence of HCC recurrence was studied during a 3‐year follow‐up period. Among 18 patients, 9 patients had recurrence and 9 did not. The average BrdU LI in the recurrent patients was 2.6 ±1.3% and was significantly higher than that in patients without recurrence (1.4+0.5%, P<0.05). All five patients who had a BrdU LI of 2.4% or above showed recurrence within 3 years, as compared with 4 of 13 (30.8%) patients with BrdU LI of less than 2.4% (P 0.05). Our data indicate that abnormally high DNA synthesis in hepatocytes in the background cirrhosis might lead to the development of multicentric carcinogenesis in human cirrhotic liver, and in the residual cirrhotic liver of hepatectomized patients with HCC and LC, it may be a predictor of new development of HCC.
Keywords: Multicentric carcinogenesis, activity, Hepatocellular, Residual liver, Recurrence of HCC, DNA synthesis
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REFERENCES
- 1. ) Gratzner , H. G.Monoclonal antibody to 5‐bromo‐ and 5‐iododeoxyuridine: a new reagent for detection of DNA replication . Science , 218 , 474 – 476 ( 1982. ). [DOI] [PubMed] [Google Scholar]
- 2. ) Tarao , K. , Shimizu , A. , Harada , M. , Kuni , Y. , Ito , Y. , Tamai , S. , Limori , K. , Sugimasa , Y. , Takemiya , S. , Okamoto , T. , Motohashi , H. , Sairenji , M. , Inoue , T. and Kanisawa , M.Difference in the in vitro uptake of bromo‐deoxyuridine between liver cirrhosis with and without hepatocellular carcinoma . Cancer , 64 , 104 – 109 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 3. ) Tarao , K. , Shimizu , A. , Ohkawa , S. , Harada , M. , Ito , Y. , Tamai , S. , Kuni , Y. , Okamoto , N. , Inoue , T. and Kanisawa , M.Development of hepatocellular carcinoma associated with increases in DNA synthesis in the surrounding cirrhosis . Gastroenterology , 103 , 595 – 600 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 4. ) Child , C. G.III and Turcotte , J. G.Surgery and portal hypertension . In “ The Liver and Portal Hypertension, ” ed. Dunphy U. E. , p. 50 ( 1964. ). W. B. Saunders Company; , Philadelphia . [Google Scholar]
- 5. ) Tong , M. J. , Sun , S. C. , Schaeffer , B. T. , Chang , N. K. , Lo , K. J. and Peters , R. L.Hepatitis associated antigen and hepatocellular carcinoma in Taiwan . Ann. Intern. Med. , 75 , 687 – 691 ( 1971. ). [DOI] [PubMed] [Google Scholar]
- 6. ) Beasley , R. P. , Hwant , L. Y. , Lin , C. C. and Chien , C. S.Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22,707 men in Taiwan . Lancet , ii , 1129 – 1133 ( 1981. ). [DOI] [PubMed] [Google Scholar]
- 7. ) Oka , H. , Kurioka , N. , Kim , K. , Kanno , T. , Kuroki , T. , Mizoguchi , Y. and Kobayashi , K.Prospective study of early detection of hepatocellular carcinoma in patients with cirrhosis . Hepatology , 12 , 680 – 687 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 8. ) Colombo , M. , Kuo , G. , Choo , Q. L. , Donate , M. F. , Ninno , E. D. , Tommasini , M. A. , Dioguardi , N. and Houghton , M.Prevalence of antibodies to hepatitis C virus in Italian patients with hepatocellular carcinoma . Lancet , ii , 1006 – 1008 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 9. ) Kobayashi , K. , Unoura , M. and Hattori , S.Diagnosis of hepatocellular carcinoma in its early stage for the aim of the curable hepatectomy; with special reference to high risk liver cirrhosis . Acta Hepatol. Jpn. , 30 ( Suppl.1 ), 37 ( 1989. ). [Google Scholar]
- 10. ) Yumoto , Y. , Jinno , K. , Tokuyama , K. , Araki , Y. , Ishimitsu , T. , Maeda , H. , Konno , T. , Iwamoto , S. , Ohnishi , K. and Okuda , K.Hepatocellular carcinoma detected by iodized oil . Radiology , 154 , 10 – 24 ( 1985. ). [DOI] [PubMed] [Google Scholar]
- 11. ) Edmondson , H. A. and Steiner , P. E.Primary carcinoma of the liver: a study of 100 cases among 48,900 necropsies . Cancer , 7 , 462 – 503 ( 1954. ). [DOI] [PubMed] [Google Scholar]
- 12. ) Tarao , K. , Shimizu , A. , Harada , M. , Tamai , S. , Ito , Y. , Kuni , Y. , Sugimasa , Y. , Takemiya , S. , Okamoto , T. and Inoue , T.A survey of the high‐risk group of developing hepatocellular carcinoma in cirrhotics: with special reference to DNA synthesis . Acta Hepatol. Jpn. , 30 , 866 – 871 ( 1989. ). [Google Scholar]
- 13. ) Tarao , K. , Ohkawa , S. , Shimizu , A. , Harada , M. , Nakamura , Y. , Ito , Y. , Tamai , S. , Hoshino , H. , Inoue , T. and Kanisawa , M.Significance of hepatocellular proliferation in the development of hepatocellular carcinoma from anti‐hepatitis C virus‐positive cirrhotic patients . Cancer , 73 , 1149 – 1154 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 14. ) Slaga , T. J. and Scribner , J. D.Inhibition of tumor initiation and promotion by antiinflammatory agents . J. Natl. Cancer Inst. , 51 , 1723 – 1725 ( 1973. ). [DOI] [PubMed] [Google Scholar]
- 15. ) Cameron , R. , Lee , G. and Farber , E.Chemical mitogens as effective alternatives to partial hepatectomy in the new model for the sequential analysis of hepatocarcinogenesis . Proc. Am. Assoc. Cancer Res. , 19 , 56 ( 1978. ). [Google Scholar]
- 16. ) Marks , F. , Bertsch , S. , Grimm , W. , and Schweizer , J.Hyperplastic transformation and tumor promotion in mouse epidermis: possible consequences of disturbances of endogenous mechanism controlling proliferation and differentiation . Carcinogenesis , 2 , 97 – 116 ( 1978. ). [Google Scholar]
- 17. ) Argyris , T. S.Tumor promotion by damage‐induced epidermal hyperplasia in the skin of mice . Proc. Am. Assoc. Cancer Res. , 20 , 4 ( 1979. ). [Google Scholar]
- 18. ) Meyer , J. S. and Bauer , W. C.In vitro determination of tritiated thymidine labeling index (LI) . Cancer , 36 , 1374 – 1380 ( 1975. ). [DOI] [PubMed] [Google Scholar]
- 19. ) Hamada , S.A double labeling technique combining 3H‐thymidine autoradiography with BrdUrd immuno‐cytochemistry . Acta Histochem. Cytochem. , 18 , 267 – 270 ( 1985. ). [Google Scholar]
- 20. ) Okuda , K. , Tanaka , M.Nakayama , T. , Saitsu , H. , Tanikawa , K. , Nakashima , O. and Kojiro , M.Clinico‐pathologic comparison between resected hepatocelhilar carcinomas (HCC) and recurrent tumors . Int. Hepatol. Commun. , 1 , 65 – 71 ( 1993. ). [Google Scholar]