Skip to main content
PMC home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1998 Apr;89(4):419–426. doi: 10.1111/j.1349-7006.1998.tb00580.x

Clinicopathological Criteria for Multicentricity of Hepatocellular Carcinoma and Risk Factors for Such Carcinogenesis

Shoji Kubo 1,✉, Shuhei Nishiguchi 2, Kazuhiro Hirohashi 1, Taichi Shuto 1, Tetsuo Kuroki 2, Shin Minamitani 2, Takashi Ikebe 3, Takatsugu Yamamoto 3, Kenichi Wakasa 4, Hiroaki Kinoshita 1
PMCID: PMC5921811  PMID: 9617348

Abstract

Multicentric occurrence is an important characteristic of hepatocellular carcinoma. We evaluated clinicopathological criteria for multicentric hepatocellular carcinoma and identified risk factors for such carcinogenesis. Subjects were 251 consecutive patients undergoing liver resection for hepatocellular carcinoma. One kind of multicentric hepatocellular carcinoma had at least one tumor consisting of well‐differentiated hepatocellular carcinoma, together with moderately or poorly differentiated hepatocellular carcinoma located in a separate region. The other kind had an area of well‐differentiated component around hepatocellular carcinoma with less differentiation in all occurrences. The outcome of patients with tumors classified in this way was studied. Univariate and multivariate analyses were done to identify risk factors for multicentric hepatocellular carcinoma. The cumulative survival rate was significantly higher in patients with multicentric hepatocellular carcinoma than in patients with hepatocellular carcinoma associated with intrahepatic metastasis. Analysis by Cox's proportional hazard model showed that multicentricity was not a factor in the outcome. The risk of multicentric occurrence increases with progression of chronic liver disease. Univariate analysis showed hepatitis C virus marker and hepatitis B core antibody to be risk factors. By multivariate analysis, the odds ratio for multicentric occurrence in patients infected with hepatitis C virus and with serum hepatitis B virus core antibody compared with patients without either hepatitis C virus or hepatitis B virus was 10.86. This ratio in patients with hepatitis C virus alone was 4.30. These criteria for multicentric hepatocellular carcinoma seem to be clinically useful. Hepatitis C virus infection with or without former infection by hepatitis B virus is a strong risk factor for multicentric hepatocarcinogenesis.

Keywords: Hepatocellular carcinoma, Hepatitis B virus, Hepatitis C virus, Multicentricity, Liver cirrhosis

Full Text

The Full Text of this article is available as a PDF (91.6 KB).

REFERENCES

  • 1. ) Tsuda , H. , Hirohashi , S. , Shimosato , Y. , Terada , M. and Hasegawa , H.Clonal origin of atypical adenomatous hyperplasia of the liver and clonal identity with hepatocellular carcinoma . Gastroenterology , 95 , 1664 – 1666 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Sakamoto , M. , Hirohashi , S. , Tsuda , H. , Shimosato , Y. , Makuuchi , M. and Hosoda , Y.Multicentric independent development of hepatocellular carcinoma revealed by analysis of hepatitis B virus integration pattern . Am. J. Surg. Pathol. , 13 , 1064 – 1067 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Hsu , H. C. , Chiou , T. J. , Chen , J. Y. , Lee , C. S. , Lee , P. H. and Peng , S. Y.Clonality and clonal evolution of hepatocellular carcinoma with multiple nodules . Hepatology , 13 , 923 – 928 ( 1991. ). [PubMed] [Google Scholar]
  • 4. ) Tsuda , H. , Oda , T. , Sakamoto , M. and Hirohashi , S.Different pattern of chromosomal allele loss in multiple hepatocellular carcinomas as evidence of their multifocal origin . Cancer Res. , 52 , 1504 – 1509 ( 1992. ). [PubMed] [Google Scholar]
  • 5. ) Okuda , K. , Tanaka , M. , Nakayama , K. , Saitsu , H. , Tanikawa , K. , Nakashima , O. and Kojiro , M.Clinicopathologic comparison between resected hepatocellular carcinoma (HCC) and recurrent tumors: a special reference to multicentric carcinogenesis of HCC . Inter. Hepatol. Commun. , 1 , 65 – 71 ( 1993. ). [Google Scholar]
  • 6. ) Takenaka , K. , Adachi , E. , Nishizaki , T. , Hiroshige , K. , Ikeda , T. , Tsuneyoshi , M. and Sugimachi , K.Possible multicentric occurrence of hepatocellular carcinoma: a clinicopathological study . Hepatology , 19 , 889 – 894 ( 1994. ). [PubMed] [Google Scholar]
  • 7. ) Miyagawa , S. , Kawasaki , S. and Makuuchi , M.Comparison of the characteristics of hepatocellular carcinoma between hepatitis B and C viral infection: tumor multicentricity in cirrhotic liver with hepatitis C . Hepatology , 24 , 307 – 310 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Nakano , S. , Haratake , J. , Okamoto , K. and Takeda , S.Investigation of resected multinodular hepatocellular carcinoma: assessment of unicentric or multicentric genesis from histological and prognostic viewpoint . Am. J. Gastroenterol. , 89 , 189 – 193 ( 1994. ). [PubMed] [Google Scholar]
  • 9. ) Sherlock , S.Viruses and hepatocellular carcinoma . Gut , 35 , 828 – 832 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. ) Ikeda , K. , Saitoh , S. , Koida , I. , Arase , Y. , Tsubota , A. , Chayama , K. , Kumada , H. and Kawanishi , M.A multivariate analysis of risk factors for hepatocellular carcinogenesis: a prospective observation of 795 patients with viral and alcoholic cirrhosis . Hepatology , 18 , 47 – 53 ( 1993. ). [PubMed] [Google Scholar]
  • 11. ) Takano , S. , Yokosuka , O. , Imazeki , F. , Tagawa , M. and Omata , M.Incidence of hepatocellular carcinoma in chronic hepatitis B and C: a prospective study of 251 patients . Hepatology , 21 , 650 – 655 ( 1995. ). [PubMed] [Google Scholar]
  • 12. ) Kubo , S. , Nishiguchi , S. , Hirohashi , K. , Tanaka , H. , Tsukamoto , T. , Hamba , H. , Shuto , T. , Okuda , T. , Tamori , A. , Kuroki , T. and Kinoshita , H.High prevalence of hepatitis B and C viruses in patients with hepatocellular carcinoma in Japan . Hepato‐Gastroenterology , in press [PubMed]
  • 13. ) Ganne‐Carrié , N. , Chastang , C. , Chapel , F. , Munz , C. , Pateron , D. , Sibony , M. , Dény , P. , Trinchet , J.‐C. , Callard , P. , Guettier , C. and Beaugrand , M.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 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 14. ) Takenaka , K. , Yamamoto , K. , Taketomi , A. , Itasaka , H. , Adachi , E. , Shirabe , K. , Nishizaki , T. , Yanaga , K. and Sugimachi , K.A comparison of the surgical results in patients with hepatitis B versus hepatitis C‐related hepatocellular carcinoma . Hepatology , 22 , 20 – 24 ( 1995. ). [PubMed] [Google Scholar]
  • 15. ) Shuto , T. , Hirohashi , K. , Kubo , S. , Tsukamoto , T. , Yamamoto , T. , Wakasa , K. and Kinoshita , H.Differences of resected hepatocellular carcinoma with hepatitis B or C virus . Hepato‐Gastroenterology , in press [PubMed]
  • 16. ) Nishiguchi , S. , Kuroki , T. , Nakatani , S. , Morimoto , H. , Takeda , T. , Nakajima , S. , Shiomi , S. , Seki , S. , Kobayashi , K. and Otani , S.Randomised trial of effects of interferon‐α on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis . Lancet , 346 , 1051 – 1055 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 17. ) Minamitani , S. , Nishiguchi , S. , Kuroki , T. , Otani , S. and Monna , T.Detection by ligase chain reaction of precore mutant of hepatitis B virus . Hepatology , 25 , 216 – 222 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Liver Cancer Study Group of Japan . “The General Rules for the Clinical and Pathological Study of Primary Liver Cancer ,” 3rd Ed. , pp. 1 – 76 ( 1992. ). Kanehara; , Tokyo ( in Japanese ). [Google Scholar]
  • 19. ) Kanai , T. , Hirohashi , S. , Upton , M. P. , Noguchi , M. , Kishi , K. , Makuuchi , M. , Yamasaki , S. , Hasegawa , H. , Takayasu , K. , Moriyama , N. and Shimosato , Y.Pathology of small hepatocellular carcinoma: a proposal for a new gross classification . Cancer , 60 , 810 – 819 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Kondo , F. , Wada , K. , Nagato , Y. , Nakajima , T. , Kondo , Y. , Hirooka , N. , Ebara , M. , Ohto , M. and Okuda , K.Biopsy diagnosis of well‐differentiated hepatocellular carcinoma based on new morphologic criteria . Hepatology , 9 , 751 – 755 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Sakamoto , M. , Hirohashi , S. and Shimosato , Y.Early stages of multistep hepatocarcinogenesis: adenomatous hyperplasia and early hepatocellular carcinoma . Hum. Pathol. , 22 , 172 – 178 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Sato , M. , Watanabe , Y. , Lee , T. , Kito , K. , Kimura , S. , Itoh , Y. , Akamatsu , K. and Ueda , N.Well‐differentiated hepatocellular carcinoma: clinicopathological features and results of hepatic resection . Am. J. Gastroenterol. , 90 , 112 – 116 ( 1995. ). [PubMed] [Google Scholar]
  • 23. ) 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]
  • 24. ) Kenmochi , K. , Sugihara , S. and Kojiro , M.Relationship of histologic grade of hepatocellular carcinoma (HCC) to tumor size, and demonstration of tumor cells of multiple different grades in single small HCC . Liver , 7 , 18 – 26 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 25. ) Arakawa , M. , Kage , M. , Sugihara , S. , Nakashima , T. , Suenaga , M. and Okuda , K.Emergence of malignant lesions within an adenomatous hyperplastic nodule in a cirrhotic liver: observations in five cases . Gastroenterology , 91 , 198 – 208 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 26. ) Sakurai , M. , Wakasa , K. , Monden , M. , Yamada , T. , Kuroda , C. , Marukawa , T. and Okamura , J.Hepatocellular carcinoma in adenomatous hyperplasia of the liver . Cancer Chemother. Pharmacol. , 23 , ( Suppl. ), S110 – S113 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 27. ) Takayama , T. , Makuuchi , T. , Hirohashi , S. , Sakamoto , M. , Okazaki , N. , Takayasu , K. , Kosuge , T. , Motoo , Y. , Yamazaki , S. and Hasegawa , H.Malignant transformation of adenomatous hyperplasia to hepatocellular carcinoma . Lancet , 336 , 1150 – 1153 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 28. ) Sugihara , S. , Nakashima , O. , Kojiro , M. , Majima , Y. , Tanaka , M. and Tanikawa , K.The morphologic transition in hepatocellular carcinoma: a comparison of the individual histologic features disclosed by ultrasound‐guided fine‐needle biopsy with those of autopsy . Cancer , 70 , 1488 – 1492 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 29. ) Liver Cancer Study Group of Japan. Primary liver cancer in Japan: clinicopathologic features and results of surgical treatment . Ann. Surg. , 211 , 277 – 287 ( 1990. ). [PMC free article] [PubMed] [Google Scholar]
  • 30. ) Desmet , V. , Gerber , M. , Hoofnagle , J. H. , Manns , M. and Scheuer , P. J.Classification of chronic hepatitis: diagnosis, grading and staging . Hepatology , 19 , 1513 – 1520 ( 1994. ). [PubMed] [Google Scholar]
  • 31. ) Oda , T. , Tsuda , H. , Scarpa , A. , Sakamoto , M. and Hirohashi , S.Mutation pattern of the p53 gene as a diagnostic marker for multiple hepatocellular carcinoma . Cancer Res. , 52 , 3674 – 3678 ( 1992. ). [PubMed] [Google Scholar]
  • 32. ) Yamanaka , N. , Okamoto , E. , Toyosaka , A. , Mitunobu , M. , Fujihara , S. , Kato , T. , Fujimoto , J. , Oriyama , T. , Furukawa , K. and Kawamura , E.Prognostic factors after hepatectomy for hepatocellular carcinoma: a univariate and multivariate analysis . Cancer , 65 , 1104 – 1110 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 33. ) Kosuge , T. , Makuuchi , M. , Takayama , T. , Yamamoto , J. , Shimada , K. and Yamasaki , S.Long‐term results after resection of hepatocellular carcinoma: experience of 480 cases . Hepato-Gastroenterology , 40 , 328 – 332 ( 1993. ). [PubMed] [Google Scholar]
  • 34. ) Di Carlo , V. , Ferrari , G. , Castoldi , R. , Nadalin , S. , Marenghi , C. , Molteni , B. , Taccagni , G. and Castrucci , M.Surgical treatment and prognostic variables of hepatocellular carcinoma in 122 cirrhotics . Hepato-Gastroenterology , 42 , 222 – 229 ( 1995. ). [PubMed] [Google Scholar]
  • 35. ) Yu , M. C. , Tong , M. J. , Coursaget , P. , Ross , R. K. , Govindarajan , S. and Henderson , B. E.Prevalence of hepatitis B and C viral markers in black and white patients with hepatocellular carcinoma in the United States . J. Natl. Cancer Inst. , 82 , 1038 – 1041 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 36. ) Kaklamani , E. , Trichopoulos , D. , Tzonou , A. , Zavitsanos , X. , Koumantaki , Y. , Hatzakis , A. , Hsieh , C. C. and Hatziyannis , S.Hepatitis B and C viruses and their interaction in the origin of hepatocellular carcinoma . JAMA , 265 , 1974 – 1976 ( 1991. ). [PubMed] [Google Scholar]
  • 37. ) Kubo , S. , Nishiguchi , S. , Tamori , A. , Hirohashi , K. , Kinoshita , H. and Kuroki , T.Development of hepatocellular carcinoma in patients with HCV infection, with or without past HBV infection, and relationship to age at the time of transfusion . Vox Sang. , 74 , 129 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 38. ) Bréchot , C. , Degos , F. , Lugassy , C. , Thiers , V. , Zafrani , S. , Franco , D. , Bismuth , H. , Trépo , C. , Benhamou , J.‐P. , Wands , J. , Isselbacher , K. , Tiollais , P. and Berthelot , P.Hepatitis B virus DNA in patients with chronic liver disease and negative tests for hepatitis B surface antigen . N. Engl. J. Med. , 312 , 270 – 276 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 39. ) Paterlini , P. , Gerken , G. , Nakajima , E. , Terre , S. , D'Errico , A. , Grigioni , W. , Nalpas , B. , Franco , D. , Wands , J. , Kew , M. , Pisi , E. , Tiollais , P. and Bréchot , C.Polymerase chain reaction to detect hepatitis B virus DNA and RNA sequences in primary liver cancers from patients negative for hepatitis B surface antigen . N. Engl. J. Med. , 323 , 80 – 85 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 40. ) Lai , M. Y. , Chen , P. J. , Yang , P. M. , Sheu , J. C. , Sung , J. L. and Chen , D. S.Identification and characterization of intrahepatic hepatitis B virus DNA in HBsAg‐seronegative patients with chronic liver disease and hepatocellular carcinoma in Taiwan . Hepatology , 12 , 575 – 581 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 41. ) Urashima , T. , Saigo , K. , Kobayashi , S. , Imaseki , H. , Matsubara , H. , Koide , Y. , Asano , T. , Kondo , Y. , Koike , K. and Isono , K.Identification of hepatitis B virus integration in hepatitis C virus‐infected hepatocellular carcinoma tissues . J. Hepatol. , 26 , 771 – 778 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 42. ) Hino , O. , Tabata , S. and Hotta , Y.Evidence for increased in vitro recombination with insertion of human hepatitis B virus DNA . Proc. Natl. Acad. Sci. USA , 88 , 9248 – 9252 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43. ) Pasquinelli , C. , Garreau , F. , Bougueleret , L. , Cariani , E. , Grezeschik , K. H. , Thiers , V. , Croissant , O. , Hadchouel , M. , Tiollais , P. and Bréchot , C.Rearrangement of a common cellular DNA domain on chromosome 4 in human primary liver tumors . J. Virol. , 62 , 629 – 632 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. ) Wang , J. , Chenivesse , X. , Henglein , B. and Bréchot , C.Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma . Nature , 343 , 555 – 557 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 45. ) Dejean , A. , Bougueleret , L. , Grzeschik , K.‐H. and Tiollais , P.Hepatitis B virus DNA integration in a sequence homologous to v‐erb‐A and steroid receptor genes in a hepatocellular carcinoma . Nature , 322 , 70 – 72 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 46. ) Graef , E. , Caselmann , W. H. , Wells , J. and Koshy , R.Insertional activation of mevalonate kinase by hepatitis B virus DNA in a human hepatoma cell line . Oncogene , 9 , 81 – 87 ( 1994. ). [PubMed] [Google Scholar]
  • 47. ) Kim , C.‐M. , Koike , K. , Saito , I. , Miyamura , T. and Jay , G.HBx gene of hepatitis B virus induces liver cancer in transgenic mice . Nature , 351 , 317 – 320 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 48. ) Koike , K. and Terada , S.Biochemistry and functions of hepatitis B virus X protein . Intervirology , 38 , 89 – 99 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 49. ) Shiratori , Y. , Shiina , S. , Imamura , M. , Kato , N. , Kanai , F. , Okudaira , T. , Teratani , T. , Tohgo , G. , Toda , N. , Ohashi , M. , Ogura , K. , Niwa , Y. , Kawabe , T. and Omata , M.Characteristic difference of hepatocellular carcinoma between hepatitis B‐ and C‐[sic] viral infection in Japan . Hepatology , 22 , 1027 – 1033 ( 1995. ). [DOI] [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES