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Semin Liver Dis 2005; 25(2): 143-154
DOI: 10.1055/s-2005-871194
Copyright © 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Hepatocellular Carcinoma: Epidemiology, Risk Factors, and Screening

Morris Sherman1
  • 1Associate Professor, Department of Medicine, University Health Network, Toronto, Canada
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Publication History

Publication Date:
25 May 2005 (online)

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ABSTRACT

In this article, the epidemiology of hepatocellular carcinoma (HCC), risk factors for the development of HCC, and how these factors affect the decision about whether an individual should or should be entered into a screening program are considered. The factors determining the risk for HCC include age, male gender, and the nature of the underlying liver disease. In particular, cirrhosis is associated with a significant risk for HCC. However, in hepatitis B HCC also occurs in noncirrhotic liver. Decision analysis can be used to identify patients at greatest risk for HCC and who might be candidates for screening. Screening itself should be developed in a programmatic manner to ensure that appropriate target populations are identified, that appropriate screening tests are chosen, and that appropriate recall and enhanced follow-up are instituted for patients who have positive screening test results. Screening should be by ultrasonography at 4- to 12-month intervals. Patients with abnormal screening tests require additional investigation using computed tomography scanning, magnetic resonance imaging, or liver biopsy. Negative results do not exclude the possibility of cancer and further follow-up is necessary.

KEYWORDS

Hepatocellular carcinoma - chronic hepatitis B - chronic hepatitis C - cancer screening

REFERENCES

  • 1 Parkin D M, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000.  Int J Cancer. 2001;  94 153-156
    CrossrefPubMedGoogle Scholar
  • 2 Ferlay J, Bray F, Pisani P, Parkin D M. Globocan 2000: Cancer Incidence, Mortality and Prevalence Worldwide. Version 1.0 Lyon, France; IARC Press 2001
    Google Scholar
  • 3 World Health Organization .Mortality database. WHO Statistical Information System Available at: http://www.who.int/whosis 2001
    Google Scholar
  • 4 Bosch F X, Ribes J, Díaz M, Clèries R. Primary liver cancer: worldwide incidence and trends.  Gastroenterology. 2004;  127(suppl 1) S5-S16
    CrossrefPubMedGoogle Scholar
  • 5 McGlynn K A, Tsao L, Hsing A W, Devesa S S, Fraumeni Jr J F. International trends and patterns of primary liver cancer.  Int J Cancer. 2001;  94 290-296
    CrossrefPubMedGoogle Scholar
  • 6 Taylor-Robinson S D, Foster G R, Arora S, Hargreaves S, Thomas H C. Increase in primary liver cancer in the UK, 1979-94.  Lancet. 1997;  350 1142-1143
    PubMedGoogle Scholar
  • 7 Okuda K, Fujimoto I, Hanai A, Urano Y. Changing incidence of hepatocellular carcinoma in Japan.  Cancer Res. 1987;  47 4967-4972
    PubMedGoogle Scholar
  • 8 El-Serag H B, Mason A C. Rising incidence of hepatocellular carcinoma in the United States.  N Engl J Med. 1999;  340 745-750
    CrossrefPubMedGoogle Scholar
  • 9 El Serag H B, Davila J A, Petersen N J, McGlynn K A. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update.  Ann Intern Med. 2003;  139 817-823
    PubMedGoogle Scholar
  • 10 Khan S A, Taylor-Robinson S D, Toledano M B, Beck A, Elliott P, Thomas H C. Changing international trends in mortality rates for liver, biliary and pancreatic tumours.  J Hepatol. 2002;  37 806-813
    CrossrefPubMedGoogle Scholar
  • 11 Levi F, Lucchini F, Negri E, Boyle P, la Vecchia C. Cancer Mortality in Europe, 1995-1999, and overview of trends since 1960.  Int J Cancer. 2004;  110 155-169
    CrossrefPubMedGoogle Scholar
  • 12 Hassan M M, Frome A, Patt Y Z, El-Serag H B. Rising prevalence of hepatitis C virus infection among patients recently diagnosed with hepatocellular carcinoma in the United States.  J Clin Gastroenterol. 2002;  35 266-269
    CrossrefPubMedGoogle Scholar
  • 13 McCredie M, Williams S, Coates M. Cancer mortality in East and Southeast Asian migrants to New South Wales, Australia, 1975-1995.  Br J Cancer. 1999;  79 1277-1282
    CrossrefPubMedGoogle Scholar
  • 14 King H, Locke F B. Cancer mortality among Chinese in the United States.  J Natl Cancer Inst. 1980;  65 1141-1148
    PubMedGoogle Scholar
  • 15 Rosenblatt K A, Weiss N S, Schwartz S M. Liver cancer in Asian migrants to the United States and their descendants.  Cancer Causes Control. 1996;  7 345-350
    CrossrefPubMedGoogle Scholar
  • 16 Naimark D, Naglie G, Detsky A S. The meaning of life expectancy: what is a clinically significant gain?.  J Gen Intern Med. 1994;  9 702-707
    PubMedGoogle Scholar
  • 17 Laupacis A, Feeny D, Detsky A S, Tugwell P X. How attractive does a new technology have to be to warrant adoption and utilization? Tentative guidelines for using clinical and economic evaluations.  CMAJ. 1992;  146 473-481
    PubMedGoogle Scholar
  • 18 Sarasin F P, Giostra E, Hadengue A. Cost-effectiveness of screening for detection of small hepatocellular carcinoma in western patients with Child-Pugh class A cirrhosis.  Am J Med. 1996;  101 422-434
    CrossrefPubMedGoogle Scholar
  • 19 Arguedas M R, Chen V K, Eloubeidi M A, Fallon M B. Screening for hepatocellular carcinoma in patients with hepatitis C cirrhosis: a cost-utility analysis.  Am J Gastroenterol. 2003;  98 679-690
    CrossrefPubMedGoogle Scholar
  • 20 Beasley R P, Hwang L Y. Epidemiology of hepatocellular carcinoma in viral hepatitis and liver disease. Vyas AN, Dienstag JL, Hoofuagle JH New York; Grune and Stratton 1984: 209-224
    Google Scholar
  • 21 Beasley R P. Hepatitis B virus as the etiologic agent in hepatocellular carcinoma.  Hepatology. 1982;  2(suppl) 21-26s
    PubMedGoogle Scholar
  • 22 Sakuma K, Saitoh N, Kasai M et al.. Relative risks of death due to liver disease among Japanese male adults having various statuses for hepatitis B s and e antigen/antibody in serum: a prospective study.  Hepatology. 1988;  8 1642-1646
    CrossrefPubMedGoogle Scholar
  • 23 Yu M W, Chang H C, Liaw Y F et al.. Familial risk of hepatocellular carcinoma among chronic hepatitis B carriers and their relatives.  J Natl Cancer Inst. 2000;  92 1159-1164
    CrossrefPubMedGoogle Scholar
  • 24 Villeneuve J P, Desrochers M, Infante-Rivard C et al.. A long-term follow-up study of asymptomatic hepatitis B surface antigen-positive carriers in Montreal.  Gastroenterology. 1994;  106 1000-1005
    PubMedGoogle Scholar
  • 25 McMahon B J, Alberts S R, Wainwright R B et al.. Hepatitis B-related sequelae: a prospective study of 1400 hepatitis B surface antigen-positive Alaska native carriers.  Arch Intern Med. 1990;  150 1051-1054
    CrossrefPubMedGoogle Scholar
  • 26 Sherman M, Peltekian K M, Lee C. Screening for hepatocellular carcinoma in chronic carriers of hepatitis B virus: incidence and prevalence of hepatocellular carcinoma in a North American urban population.  Hepatology. 1995;  22 432-438
    CrossrefPubMedGoogle Scholar
  • 27 Fattovich G, Brollo L, Giustina G et al.. Natural history and prognostic factors for chronic hepatitis type B.  Gut. 1991;  32 294-298
    PubMedGoogle Scholar
  • 28 de Franchis R, Meucci G, Vecchi M et al.. The natural history of asymptomatic hepatitis B surface antigen carriers.  Ann Intern Med. 1993;  118 191-194
    PubMedGoogle Scholar
  • 29 Sanchez-Tapias J M, Costa J, Mas A et al.. Influence of hepatitis B virus genotype on the long-term outcome of chronic hepatitis B in western patients.  Gastroenterology. 2002;  123 1848-1856
    CrossrefPubMedGoogle Scholar
  • 30 Kew M C, Marcus R, Geddes E W. Some characteristics of Mozambican Shangaans with primary hepatocellular cancer.  S Afr Med J. 1977;  51 306-309
    PubMedGoogle Scholar
  • 31 Kew M C, Macerollo P. Effect of age on the etiologic role of the hepatitis B virus in hepatocellular carcinoma in blacks.  Gastroenterology. 1988;  94 439-442
    PubMedGoogle Scholar
  • 32 Fattovich G, Giustina G, Degos F et al.. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients.  Gastroenterology. 1997;  112 463-472
    CrossrefPubMedGoogle Scholar
  • 33 Bruix J, Barrera J M, Calvet X et al.. Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis.  Lancet. 1989;  2 1004-1006
    PubMedGoogle Scholar
  • 34 Niederau C, Lange S, Heintges T et al.. Prognosis of chronic hepatitis C: results of a large, prospective cohort study.  Hepatology. 1998;  28 1687-1695
    CrossrefPubMedGoogle Scholar
  • 35 Degos F, Christidis C, Ganne-Carrie N et al.. Hepatitis C virus related cirrhosis: time to occurrence of hepatocellular carcinoma and death.  Gut. 2000;  47 131-136
    CrossrefPubMedGoogle Scholar
  • 36 Sun C A, Wu D M, Lin C C et al.. Incidence and cofactors of hepatitis C virus-related hepatocellular carcinoma: a prospective study of 12,008 men in Taiwan.  Am J Epidemiol. 2003;  157 674-682
    CrossrefPubMedGoogle Scholar
  • 37 Bruix J, Sherman M, Llovet J M et al.. Clinical management of hepatocellular carcinoma: conclusions of the Barcelona-2000- EASL conference.  J Hepatol. 2001;  35 421-430
    CrossrefPubMedGoogle Scholar
  • 38 Ganne-Carrie 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 1112-1118
    PubMedGoogle Scholar
  • 39 Velazquez R F, Rodriguez M, Navascues C A et al.. Prospective analysis of risk factors for hepatocellular carcinoma in patients with liver cirrhosis.  Hepatology. 2003;  37 520-527
    CrossrefPubMedGoogle Scholar
  • 40 Moriyama M, Matsumura H, Aoki H et al.. Long-term outcome, with monitoring of platelet counts, in patients with chronic hepatitis C and liver cirrhosis after interferon therapy.  Intervirology. 2003;  46 296-307
    CrossrefPubMedGoogle Scholar
  • 41 Hassan M M, Hwang L Y, Hatten C J et al.. Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus.  Hepatology. 2002;  36 1206-1213
    CrossrefPubMedGoogle Scholar
  • 42 Schoniger-Hekele M, Muller C, Kutilek M et al.. Hepatocellular carcinoma in Austria: aetiological and clinical characteristics at presentation.  Eur J Gastroenterol Hepatol. 2000;  12 941-948
    PubMedGoogle Scholar
  • 43 El Serag H B, Mason A C. Risk factors for the rising rates of primary liver cancer in the United States.  Arch Intern Med. 2000;  160 3227-3230
    CrossrefPubMedGoogle Scholar
  • 44 Adami H O, Chow W H, Nyren O et al.. Excess risk of primary liver cancer in patients with diabetes mellitus.  J Natl Cancer Inst. 1996;  88 1472-1477
    CrossrefPubMedGoogle Scholar
  • 45 Bugianesi E, Leone N, Vanni E et al.. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma.  Gastroenterology. 2002;  123 134-140
    CrossrefPubMedGoogle Scholar
  • 46 Elmberg M, Hultcrantz R, Ekbom A et al.. Cancer risk in patients with hereditary hemochromatosis and in their first-degree relatives.  Gastroenterology. 2003;  125 1733-1741
    CrossrefPubMedGoogle Scholar
  • 47 Hsing A W, McLaughlin J K, Olsen J H, Mellemkjar L, Wacholder S, Fraumeni Jr J F. Cancer risk following primary hemochromatosis: a population-based cohort study in Denmark.  Int J Cancer. 1995;  60 160-162
    PubMedGoogle Scholar
  • 48 Fracanzani A L, Conte D, Fraquelli M et al.. Increased cancer risk in a cohort of 230 patients with hereditary hemochromatosis in comparison to matched control patients with non-iron-related chronic liver disease.  Hepatology. 2001;  33 647-651
    CrossrefPubMedGoogle Scholar
  • 49 Caballeria L, Pares A, Castells A, Gines A, Bru C, Rodes J. Hepatocellular carcinoma in primary biliary cirrhosis: similar incidence to that in hepatitis C virus-related cirrhosis.  Am J Gastroenterol. 2001;  96 1160-1163
    PubMedGoogle Scholar
  • 50 Elzouki A N, Eriksson S. Risk of hepatobiliary disease in adults with severe alpha 1-antitrypsin deficiency (PiZZ): is chronic viral hepatitis B or C an additional risk factor for cirrhosis and hepatocellular carcinoma?.  Eur J Gastroenterol Hepatol. 1996;  8 989-994
    PubMedGoogle Scholar
  • 51 Eriksson S, Carlson J, Velez R. Risk of cirrhosis and primary liver cancer in alpha 1-antitrypsin deficiency.  N Engl J Med. 1986;  314 736-739
    CrossrefPubMedGoogle Scholar
  • 52 Giordano T P, Kramer J R, Souchek J, Richardson P, El-Serag H B. Cirrhosis and hepatocellular carcinoma in HIV-infected veterans with and without the hepatitis C virus: a cohort study, 1992-2001.  Arch Intern Med. 2004;  164 2349-2354
    CrossrefPubMedGoogle Scholar
  • 53 Rosenthal E, Poiree M, Pradier C et al.. Mortality due to hepatitis C-related liver disease in HIV-infected patients in France (Mortavic 2001 study).  AIDS. 2003;  17 1803-1809
    CrossrefPubMedGoogle Scholar
  • 54 Niederau C, Heintges T, Lange S et al.. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B.  N Engl J Med. 1996;  334 1422-1427
    CrossrefPubMedGoogle Scholar
  • 55 Fattovich G, Giustina G, Realdi G, Corrocher R, Schalm S W. Long-term outcome of hepatitis B e antigen-positive patients with compensated cirrhosis treated with interferon alfa. European Concerted Action on Viral Hepatitis (EUROHEP).  Hepatology. 1997;  26 1338-1342
    CrossrefPubMedGoogle Scholar
  • 56 Fattovich G, Giustina G, Sanchez-Tapias J et al.. Delayed clearance of serum HBsAg in compensated cirrhosis B: relation to interferon alpha therapy and disease prognosis. European Concerted Action on Viral Hepatitis (EUROHEP).  Am J Gastroenterol. 1998;  93 896-900
    CrossrefPubMedGoogle Scholar
  • 57 Lin S M, Sheen I S, Chien R N, Chu C M, Liaw Y F. Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection.  Hepatology. 1999;  29 971-975
    CrossrefPubMedGoogle Scholar
  • 58 Yuen M F, Hui C K, Cheng C C, Wu C H, Lai Y P, Lai C L. Long-term follow-up of interferon alfa treatment in Chinese patients with chronic hepatitis B infection: the effect on hepatitis B e antigen seroconversion and the development of cirrhosis-related complications.  Hepatology. 2001;  34 139-145
    CrossrefPubMedGoogle Scholar
  • 59 Liaw Y F, Sung J J, Chow W C et al.. Lamivudine for patients with chronic hepatitis B and advanced liver disease.  N Engl J Med. 2004;  351 1521-1531
    CrossrefPubMedGoogle Scholar
  • 60 Nishiguchi S, Shiomi S, Nakatani S et al.. Prevention of hepatocellular carcinoma in patients with chronic active hepatitis C and cirrhosis.  Lancet. 2001;  357 196-197
    CrossrefPubMedGoogle Scholar
  • 61 Valla D C, Chevallier M, Marcellin P et al.. Treatment of hepatitis C virus-related cirrhosis: a randomized, controlled trial of interferon alfa-2b versus no treatment.  Hepatology. 1999;  29 1870-1875
    CrossrefPubMedGoogle Scholar
  • 62 Camma C, Giunta M, Andreone P, Craxi A. Interferon and prevention of hepatocellular carcinoma in viral cirrhosis: an evidence-based approach.  J Hepatol. 2001;  34 593-602
    CrossrefPubMedGoogle Scholar
  • 63 Hayashi K, Kumada T, Nakano S et al.. Incidence of hepatocellular carcinoma in chronic hepatitis C after interferon therapy.  Hepatogastroenterology. 2002;  49 508-512
    PubMedGoogle Scholar
  • 64 Ikeda K, Saitoh S, Kobayashi M et al.. Long-term interferon therapy for 1 year or longer reduces the hepatocellular carcinogenesis rate in patients with liver cirrhosis caused by hepatitis C virus: a pilot study.  J Gastroenterol Hepatol. 2001;  16 406-415
    CrossrefPubMedGoogle Scholar
  • 65 Tanaka H, Tsukuma H, Kasahara A et al.. Effect of interferon therapy on the incidence of hepatocellular carcinoma and mortality of patients with chronic hepatitis C: a retrospective cohort study of 738 patients.  Int J Cancer. 2000;  87 741-749
    CrossrefPubMedGoogle Scholar
  • 66 Okanoue T, Itoh Y, Minami M et al.. Interferon therapy lowers the rate of progression to hepatocellular carcinoma in chronic hepatitis C but not significantly in an advanced stage: a retrospective study in 1148 patients. Viral Hepatitis Therapy Study Group.  J Hepatol. 1999;  30 653-659
    CrossrefPubMedGoogle Scholar
  • 67 Yoshida H, Shiratori Y, Moriyama M et al.. Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. IHIT Study Group. Inhibition of Hepatocarcinogenesis by Interferon Therapy.  Ann Intern Med. 1999;  131 174-181
    PubMedGoogle Scholar
  • 68 Toyoda H, Kumada T, Nakano S et al.. Effect of the dose and duration of interferon-alpha therapy on the incidence of hepatocellular carcinoma in noncirrhotic patients with a nonsustained response to interferon for chronic hepatitis C.  Oncology. 2001;  61 134-142
    CrossrefPubMedGoogle Scholar
  • 69 Valla D C, Degos F. Chemoprevention of hepatocellular carcinoma in hepatitis C virus-related cirrhosis: first, eliminate the virus.  J Hepatol. 2001;  34 606-609
    CrossrefPubMedGoogle Scholar
  • 70 Oka H, Tamori A, Kuroki T et al.. Prospective study of alpha-foetoprotein in cirrhotic patients monitored for development of hepatocellular carcinoma.  Hepatology. 1994;  19 61-66
    CrossrefPubMedGoogle Scholar
  • 71 Zhang J Y, Wang X, Han S G, Zhuang H. A case-control study of risk factors for hepatocellular carcinoma in Henan, China.  Am J Trop Med Hyg. 1998;  59 947-951
    PubMedGoogle Scholar
  • 72 Hytiroglou P, Theise N D, Schwartz M et al.. Macroregenerative nodules in a series of adult cirrhotic liver explants: issues of classification and nomenclature.  Hepatology. 1995;  21 703-708
    CrossrefPubMedGoogle Scholar
  • 73 Donato M F, Arosio E, Del Ninno E et al.. High rates of hepatocellular carcinoma in cirrhotic patients with high liver cell proliferative activity.  Hepatology. 2001;  34 523-528
    CrossrefPubMedGoogle Scholar
  • 74 Tiniakos D G, Brunt E M. Proliferating cell nuclear antigen and Ki-67 labeling in hepatocellular nodules: a comparative study.  Liver. 1999;  19 58-68
    PubMedGoogle Scholar
  • 75 Ballardini G, Groff P, Zoli M et al.. Increased risk of hepatocellular carcinoma development in patients with cirrhosis and with high hepatocellular proliferation.  J Hepatol. 1994;  20 218-222
    CrossrefPubMedGoogle Scholar
  • 76 Borzio M, Trere D, Borzio F et al.. Hepatocyte proliferation rate is a powerful parameter for predicting hepatocellular carcinoma development in liver cirrhosis.  Mol Pathol. 1998;  51 96-101
    PubMedGoogle Scholar
  • 77 Welch H G, Schwartz L M, Woloshin S. Do increased 5-year survival rates in prostate cancer indicate better outcomes?.  JAMA. 2000;  284 2053-2055
    CrossrefPubMedGoogle Scholar
  • 78 McMahon B J, Bulkow L, Harpster A et al.. Screening for hepatocellular carcinoma in Alaska natives infected with chronic hepatitis B: a 16-year population-based study.  Hepatology. 2000;  32 842-846
    CrossrefPubMedGoogle Scholar
  • 79 Wong L L, Limm W M, Severino R, Wong L M. Improved survival with screening for hepatocellular carcinoma.  Liver Transpl. 2000;  6 320-325
    CrossrefPubMedGoogle Scholar
  • 80 Oka H, Kurioka N, Kim K et al.. Prospective study of early detection of hepatocellular carcinoma in patients with cirrhosis.  Hepatology. 1990;  12 680-687
    PubMedGoogle Scholar
  • 81 Bolondi L, Sofia S, Siringo S et al.. Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma: a cost-effectiveness analysis.  Gut. 2001;  48 251-259
    CrossrefPubMedGoogle Scholar
  • 82 Liu J H, Chen P W, Asch S M et al.. Surgery for hepatocellular carcinoma: does it improve survival?.  Ann Surg Oncol. 2004;  11 298-303
    CrossrefPubMedGoogle Scholar
  • 83 Llovet J M, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification.  Semin Liver Dis. 1999;  19 329-338
    Article in Thieme ConnectPubMedGoogle Scholar
  • 84 Yamamoto J, Iwatsuki S, Kosuge T et al.. Should hepatomas be treated with hepatic resection or transplantation?.  Cancer. 1999;  86 1151-1158
    CrossrefPubMedGoogle Scholar
  • 85 Molmenti E P, Marsh J W, Dvorchik I et al.. Hepatobiliary malignancies. Primary hepatic malignant neoplasms.  Surg Clin North Am. 1999;  79 43-57 , viii
    CrossrefPubMedGoogle Scholar
  • 86 Llovet J M, Burroughs A, Bruix J. Hepatocellular carcinoma.  Lancet. 2003;  362 1907-1917
    CrossrefPubMedGoogle Scholar
  • 87 Bismuth H, Majno P E, Adam R. Liver transplantation for hepatocellular carcinoma.  Semin Liver Dis. 1999;  19 311-322
    Article in Thieme ConnectPubMedGoogle Scholar
  • 88 Michel J, Suc B, Montpeyroux F et al.. Liver resection or transplantation for hepatocellular carcinoma? Retrospective analysis of 215 patients with cirrhosis.  J Hepatol. 1997;  26 1274-1280
    PubMedGoogle Scholar
  • 89 Llovet J M, Bruix J, Gores G J. Surgical resection versus transplantation for early hepatocellular carcinoma: clues for the best strategy.  Hepatology. 2000;  31 1019-1021
    CrossrefPubMedGoogle Scholar
  • 90 Yao F Y, Ferrell L, Bass N M et al.. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival.  Hepatology. 2001;  33 1394-1403
    CrossrefPubMedGoogle Scholar
  • 91 Fletcher R H. Carcinoembryonic antigen.  Ann Intern Med. 1986;  104 66-73
    CrossrefPubMedGoogle Scholar
  • 92 Sullivan-Pepe M, Etzioni R, Feng Z et al.. Phases of biomarker development for early detection of cancer.  J Natl Cancer Inst. 2001;  93 1054-1061
    CrossrefPubMedGoogle Scholar
  • 93 Sherman M, Peltekian K M, Lee C. Screening for hepatocellular carcinoma in chronic carriers of hepatitis B virus: incidence and prevalence of hepatocellular carcinoma in a North American urban population.  Hepatology. 1995;  22 432-438
    CrossrefPubMedGoogle Scholar
  • 94 Trevisani F, D'Intino P E, Morselli-Labate A M et al.. Serum alpha-fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: influence of HBsAg and anti-HCV status.  J Hepatol. 2001;  34 570-575
    CrossrefPubMedGoogle Scholar
  • 95 Pateron D, Ganne N, Trinchet J C et al.. Prospective study of screening for hepatocellular carcinoma in Caucasian patients with cirrhosis.  J Hepatol. 1994;  20 65-71
    CrossrefPubMedGoogle Scholar
  • 96 Zoli M, Magalotti D, Bianchi G, Gueli C, Marchesini G, Pisi E. Efficacy of a surveillance program for early detection of hepatocellular carcinoma.  Cancer. 1996;  78 977-985
    CrossrefPubMedGoogle Scholar
  • 97 Izuno K, Fujiyama S, Yamasaki K, Sato M, Sato T. Early detection of hepatocellular carcinoma associated with cirrhosis by combined assay of des-gamma-carboxy prothrombin and alpha-fetoprotein: a prospective study.  Hepatogastroenterology. 1995;  42 387-393
    PubMedGoogle Scholar
  • 98 Sherman M. Alphafetoprotein: an obituary.  J Hepatol. 2001;  34 603-605
    CrossrefPubMedGoogle Scholar
  • 99 Grazi G L, Mazziotti A, Legnani C et al.. The role of tumor markers in the diagnosis of hepatocellular carcinoma, with special reference to the des-gamma-carboxy prothrombin.  Liver Transpl Surg. 1995;  1 249-255
    CrossrefPubMedGoogle Scholar
  • 100 Tsai S L, Huang G T, Yang P M, Sheu J C, Sung J L, Chen D S. Plasma des-gamma-carboxyprothrombin in the early stage of hepatocellular carcinoma.  Hepatology. 1990;  11 481-488
    PubMedGoogle Scholar
  • 101 Suehiro T, Sugimachi K, Matsumata T, Itasaka H, Taketomi A, Maeda T. Protein induced by vitamin K absence or antagonist II as a prognostic marker in hepatocellular carcinoma. Comparison with alpha-fetoprotein.  Cancer. 1994;  73 2464-2471
    PubMedGoogle Scholar
  • 102 Marrero J A, Su G L, Wei W et al.. Des-gamma carboxyprothrombin can differentiate hepatocellular carcinoma from nonmalignant chronic liver disease in American patients.  Hepatology. 2003;  37 1114-1121
    CrossrefPubMedGoogle Scholar
  • 103 Koike Y, Shiratori Y, Sato S et al.. Des-gamma-carboxy prothrombin as a useful predisposing factor for the development of portal venous invasion in patients with hepatocellular carcinoma: a prospective analysis of 227 patients.  Cancer. 2001;  91 561-569
    CrossrefPubMedGoogle Scholar
  • 104 Sato Y, Nakata K, Kato Y et al.. Early recognition of hepatocellular carcinoma based on altered profiles of alpha-foetoprotein.  N Engl J Med. 1993;  328 1802-1806
    CrossrefPubMedGoogle Scholar
  • 105 Kumada T, Nakano S, Takeda I et al.. Clinical utility of Lens culinaris agglutinin-reactive alpha-foetoprotein in small hepatocellular carcinoma: special reference to imaging diagnosis.  J Hepatol. 1999;  30 125-130
    CrossrefPubMedGoogle Scholar
  • 106 Shiraki K, Takase K, Tameda Y et al.. A clinical study of lectin-reactive alpha-foetoprotein as an early indicator of hepatocellular carcinoma in the follow-up of cirrhotic patients.  Hepatology. 1995;  22 802-807
    CrossrefPubMedGoogle Scholar
  • 107 Taketa K, Endo Y, Sekiya C et al.. A collaborative study for the evaluation of lectin-reactive alpha-foetoproteins in early detection of hepatocellular carcinoma.  Cancer Res. 1993;  53 5419-5423
    PubMedGoogle Scholar
  • 108 Hayashi K, Kumada T, Nakano S et al.. Usefulness of measurement of Lens culinaris agglutinin-reactive fraction of alpha-foetoprotein as a marker of prognosis and recurrence of small hepatocellular carcinoma.  Am J Gastroenterol. 1999;  94 3028-3033
    PubMedGoogle Scholar
  • 109 Okuda K, Tanaka M, Kanazawa N et al.. Evaluation of curability and prediction of prognosis after surgical treatment for hepatocellular carcinoma by Lens culinaris agglutinin-reactive alpha-foetoprotein.  Int J Oncol. 1999;  14 265-271
    PubMedGoogle Scholar
  • 110 Chen T H, Chen C J, Yen M F et al.. Ultrasound screening and risk factors for death from hepatocellular carcinoma in a high risk group in Taiwan.  Int J Cancer. 2002;  98 257-261
    CrossrefPubMedGoogle Scholar
  • 111 Larcos G, Sorokopud H, Berry G, Farrell G C. Sonographic screening for hepatocellular carcinoma in patients with chronic hepatitis or cirrhosis: an evaluation.  AJR Am J Roentgenol. 1998;  171 433-435
    PubMedGoogle Scholar
  • 112 Bartolozzi C, Lencioni R. In: Bartolozzi C, Lencioni R Liver Malignancies. Diagnostic and Interventional Radiology Berlin; Springer-Verlag 1999
    Google Scholar
  • 113 Takayasu K, Moriyama N, Muramatsu Y et al.. The diagnosis of small hepatocellular carcinomas: efficacy of various imaging procedures in 100 patients.  AJR Am J Roentgenol. 1990;  155 49-54
    PubMedGoogle Scholar
  • 114 Zhang B, Yang B. Combined alpha fetoprotein testing and ultrasonography as a screening test for primary liver cancer.  J Med Screen. 1999;  6 108-110
    PubMedGoogle Scholar
  • 115 Miller W J, Baron R L, Dodd III G D, Federle M P. Malignancies in patients with cirrhosis: CT sensitivity and specificity in 200 consecutive transplant patients.  Radiology. 1994;  193 645-650
    PubMedGoogle Scholar
  • 116 Kobayashi K, Sugimoto T, Makino H et al.. Screening methods for early detection of hepatocellular carcinoma.  Hepatology. 1985;  5 1100-1105
    PubMedGoogle Scholar
  • 117 Sangiovanni A, Del Ninno E, Fasani P et al.. Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance.  Gastroenterology. 2004;  126 1005-1014
    CrossrefPubMedGoogle Scholar
  • 118 Santagostino E, Colombo M, Rivi M et al.. A 6-month versus a 12-month surveillance for hepatocellular carcinoma in 559 hemophiliacs infected with the hepatitis C virus.  Blood. 2003;  102 78-82
    CrossrefPubMedGoogle Scholar

 Dr.
Morris Sherman

Toronto General Hospital, 200 Elizabeth Street, Toronto

Ont M5G 2C4 Canada

Email: morris.sherman@uhn.on.ca

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