Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. HCC is a major problem worldwide because of its high prevalence and severe natural history and it is the major cause of cancer-related mortality in sub-Saharan Africa and in the Far East (1). HCC is the seventh most prevalent cancer in men and the ninth most common in women, with an estimated total of one million cases occurring each year (2–6). It carries a dismal overall prognosis: 92% of affected individuals will die because of their disease (3). In general, tumor incidence increases with age and occurs most often between the third and fifth decades of life (2). The distribution pattern shows striking and pronounced geographic and racial variations. The biological characteristics of this tumor vary significantly in different geographical areas, from country to country and even from one part of a country to another. Because of the widely divergent rates of HCC worldwide, it is possible to identify high-, intermediate-, and low-incidence areas. In China and south-east and sub-Saharan Africa, as many as 10–30 new cases per 100,000 males in habitants are reported each year, whereas in northern Europe, North America, and Australia, the annual rates of HCC are less than 3 cases a year per 100,000 males.
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Kew, M. C. and Popper, H. (1984) Relationship between hepatocellular carcinoma and cirrhosis. Semin. Liver Dis. 4, 136–146.
Anon. (1987) Hepatocellular cancer: differences between high and low incidence regions. [Editorial] Lancet. 2, 1183–1184.
Rustgi, V. K. (1987) Epidemiology of hepatocellular carcinoma. Gastroenterol. Clin. North. Am. 16, 545–551.
Arya, S. C., Ashraf, S. J., Parande, C. M., Tobeiqi, M. S., and Ageel, A. R. (1988) Hepatitis B and delta markers in primary hepatocellular carcinoma patients in the Gizan area of Saudi Arabia. APMIS 3(Supp l), 30–34.
Di Bisceglie, A. M., Rustgi, V. K., Hoofnagle, J. H., Dusheiko, G. M., and Lotze, M. T. (1988) NIH conference. Hepatocellular carcinoma. Ann. Intern. Med. 108, 390–401.
Bridbord, K. (1989) Pathogenesis and prevention of hepatocellular carcinoma. Cancer Detect. Prev. 14, 191–192.
Curley, S. A., Levin, B., and Rich, T. A. (1995). Liver and bile ducts, in Clinical Oncology (Abeloff, M. D., Armitage, J. O., Lichter, A. S., Niederhuber, J. E., eds. ), Churchill Livingstone, London, pp.1305–1372.
Simonetti, R. G., Camma, C., Fiorello, F., Politi, F., D’Amico, G., and Pagliaro, L. (1991) Hepatocellular carcinoma. A worldwide problem and the major risk factors. Dig. Dis. Sci. 36, 962–972.
Tsai, J. F., Chang, W. Y., Jeng, J. E., Ho, M. S., Wang, L. Y., Hsieh, M. Y., et al. (1993) Hepatitis C virus infection as a risk factor for non-alcoholic liver cirrhosis in Taiwan. J. Med. Virol. 41, 296–300.
Colombo, M. (1995) Should patients with chronic viral hapatitis be screened for hepatocellular carcinoma? Viral Hepat. Rev. 1, 67–75.
Sherlock, S. and Dooley, J. (1997) Hepatic tumors, in Disease of the Liver and Biliary System, 10th ed., Blackwell Science, Oxford, pp. 531–559.
Kew, M. C. (1995) Cancer of the liver. Curr. Opin. Gastroenterol. 11, 202–206.
Kiyosawa, K., Sodeyama, T., Tanaka, E., Gibo, Y., Yoshizawa, K., Nakano, Y., et al. (1990) Interrelationship of blood transfusion, non-A, non-B hepatitis and hepatocellular carcinoma: analysis by detection of antibody to hepatitis C virus. Hepatology. 12, 671–675.
Tong, M. J., El-Farra, N. S., Reikes, A. R., and Co, R. L. (1995) Clinical outcomes after transfusion-associated hepatitis C. N. Engl. J. Med. 332, 1463–1466.
Tsai, J. F., Chang, W. Y., Jeng, J. E., Ho, M. S., Lin, Z. Y., and Tsai, J. H. (1994) Effects of hepatitis C and B viruses infection on the development of hepatocellular carcinoma. J. Med. Virol. 44, 92–95.
Tsai, J. F., Jeng, J. E., Ho, M. S., Chang, W. Y., Lin, Z. Y., and Tsai, J. H. (1994) Hepatitis B and C virus infection as risk factors for hepatocellular carcinoma in Chinese: a case-control study. Int. J. Cancer. 56, 619–621.
Tsai, J. F., Jeng, J. E., Ho, M. S., Chang, W. Y., Hsieh, M. Y., Lin, Z. Y., and Tsai, J. H. (1996) Additive effect modification of hepatitis B surface antigen and e antigen on the development of hepatocellular carcinoma. Br. J. Cancer. 73, 1498–1502.
Sheu, J. C., Sung, J. L., Chen, D. S., Lai, M. Y., Wang, T. H., Yu, J. Y., et al. (1985) Early detection of hepatocellular carcinoma by real-time ultrasonography. A prospective study. Cancer. 56, 660–666.
Takayama, T., Makuuchi, M., Hirohashi, S., Sakamoto, M., Okazaki, N., Takayasu, K., et al. (1990) Malignant transformation of adenomatous hyperplasia to hepatocellular carcinoma. Lancet. 2, 1150–1153.
Feitelson, M. A. (1986) HVB and cancer, in Concepts in Viral Pathogenesis II (Notkins, A. L. and Oldstone, M. B. A., eds. ), Springer-Verlag, New York, pp. 269–275.
Popper, H., Shafritz, D. A., and Hoofnagle, J. H. (1987) Relation of the hepatitis B virus carrier state to hepatocellular carcinoma. Hepatology. 7, 764–772.
Ganem, D. and Varmus, H. E. (1987) The molecular biology of the hepatitis B viruses. Annu. Rev. Biochem. 56, 651–693.
Harris, C. C. (1990) Hepatocellular carcinogenesis: recent advances and speculations. Cancer Cells. 2, 146–148.
Wogan, G. N. (1992) Aflatoxins as risk factors for hepatocellular carcinoma in humans. Cancer Res. 52, 2114s–2118s.
Ross, R. K., Yuan, J. M., Yu, M. C., Wogan, G. N., Qian, G. S., Tu, J. T., et al. (1992) Urinary aflatoxin biomarkers and risk of hepatocellular carcinoma. Lancet. 1, 943–946.
Kato, I., Tominaga, S., and Ikari, A. (1992) The risk and predictive factors for developing liver cancer among patients with decompensated liver cirrhosis. Jpn. J. Clin. Oncol. 22, 278–285.
Tsukuma, H., Hiyama, T., Tanaka, S., Nakao, M., Yabuuchi, T., Kitamura, T., et al. (1993) Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N. Engl. J. Med. 328, 1797–1801.
Ikeda, K., Saitoh, S., Koida, I., Arase, Y., Tsubota, A., Chayama, K., et al. (1993) A multivariate analysis of risk factors for hepatocellular carcinogenesis: a prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology. 18, 47–53.
Bolondi, L., Siringo, S., Rigamonti, A., Sofia, S., Gaiani, S., Zironi, G., et al. (1993) Multivariate analysis of risk factors for hepatocellular carcinoma in patients with cirrhosis. A prospective study. J. Hepatol. 18(Suppl. 1), S80.
Johnson, P. J. and Williams, R. (1987) Cirrhosis and the aetiology of hepatocellular carcinoma. J. Hepatol. 4, 140–147.
Anthony, P. P., Vogel, C. L., and Barker, L. F. (1973) Liver cell dysplasia: a premalignant condition. J. Clin. Pathol. 26, 217–223.
Borzio, M., Bruno, S., Roncalli, M., Mels, G. C., Ramella, G., Borzio, F., et al. (1991) Liver cell dysplasia and risk of hepatocellular carcinoma in cirrhosis: a preliminary report. Br. Med. J. 302, 1312.
Borzio, M., Bruno, S., Roncalli, M., Mels, G. C., Ramella, G., Borzio, F., et al. (1995) Liver cell dysplasia is a major risk factor for hepatocellular carcinoma in cirrhosis: a prospective study. Gastroenterology. 108, 812–817.
Watanabe, S., Okita, K., Harada, T., Kodama, T., Numa, Y., Takemoto, T., et al. (1983) Morphologic studies of the liver cell dysplasia. Cancer 51, 2197–2205.
Nakanuma, Y., Kanel, G. C., Doishita, K., Ohta, G., and Peters, R. L. (1989) Risk lesions in cirrhosis and development of hepatocellular carcinoma: an autopsy study. Biomed. Pharmacother. 43, 127–133.
Podda, M., Roncalli, M., Battezzati, P. M., Borzio, M., Bruno, S., Servida, E. et al. (1992) Liver-cell dysplasia and hepatocellular carcinoma. Ital. J. Gastroenterol. 24, 39–42.
Farber, E. (1976) Hyperplastic areas, hyperplastic nodules, and hyperbasophilic areas as putative precursor lesions. Cancer Res. 36, 2532–2533.
Farber, E. and Sarma, D. S. (1987) Hepatocarcinogenesis: a dynamic cellular perspective. Lab. Invest. 56, 4–22.
Schirmacher, P., Held, W. A., Yang, D., Biempica, L., and Rogler, C. E. (1991) Selective amplification of periportal transitional cells precedes formation of hepatocellular carcinoma in SV40 large tag transgenic mice. Am. J. Pathol. 139, 231–241.
Cullen, J. M., Sandgren, E. P., Brinster, R. L., and Maronpot, R. R. (1993) Histologic characterization of hepatic carcinogenesis in transgenic mice expressing SV40 T-antigens. Vet. Pathol. 30, 111–118.
Geller, S. A., Nichols, W. S., Kim, S., Tolmachoff, T., Lee, S., Dycaico, M. J., et al. (1994) Hepatocarcinogenesis is the sequel to hepatitis in Z#2 alpha 1-antitrypsin transgenic mice: histopathological and DNA ploidy studies. Hepatology. 19, 389–397.
Thorgeirsson, U. P., Gomez, D. E., Lindsay, C. K., Sinha, C. C., and Adamson, R. H. (1996) Liver tumors and possible preneoplastic lesions, induced by a food-derived heterocyclic amine in cynomolgus monkeys; a study of histology and cytokeratin expression. Liver. 16, 71–83.
Ho, J. C., Wu, P. C., and Mak, T. K. (1981) Liver cell dysplasia in association with hepatocellularcarcinoma, cirrhosis and hepatitis B surface antigen in Hong Kong. Int. J. Cancer. 28, 571–574.
Roncalli, M., Borzio, M., De Biagi, G., Ferrari, A. R., Macchi, R., Tombesi, V. M., et al. (1986) Liver cell dysplasia in cirrhosis. A serologic and immunohistochemical study. Cancer. 57, 1515–1521.
Cohen, C. and Berson, S. D. (1986) Liver cell dysplasia in normal, cirrhotic, and hepatocellular carcinoma patients. Cancer. 57, 1535–1538.
Omata, M., Mori, J., Yokosuka, O., Iwama, S., Ito, Y., and Okuda, K. (1982) Hepatitis B virus antigens in liver tissue in hepatocellular carcinoma and advanced chronic liver disease-relationship to liver cell dysplasia. Liver. 2, 125–132.
Nakashima, T., Okuda, K., Kojiro, M., Jimi, A., Yamaguchi, R., Sakamoto, K., et al. (1983) Pathology of hepatocellular carcinoma in Japan. 232 consecutive cases autopsied in ten years. Cancer. 51, 863–877.
Akagi, G., Furuya, K., Kanamura, A., Chihara, T., and Otsuka, H. (1984) Liver cell dysplasia and hepatitis B surface antigen in liver cirrhosis and hepatocellular carcinoma. Cancer 54, 315–318.
Henmi, A., Uchida, T., and Shikata, T. (1985) Karyometric analysis of liver cell dysplasia and hepatocellular carcinoma. Evidence against precancerous nature of liver cell dysplasia. Cancer. 55, 2594–2599.
Zhao, M. and Zimmermann, A. (1998) Liver cell dysplasia: reactivities for cmet protein, Rb protein, E-cadherin and transforming growth factor-beta 1 in comparison with hepatocellular carcinoma. Histol. Histopathol. 13, 657–670.
Ganne-Carrié, N., Chastang, C., Chapel, F., Munz, C., Paterton, D., Sibony, M., et al. (1996) Predictive score for the development on hepatocellular carcinoma and additional value of live large cell dysplasia in western patients with cirrhosis. Hepatology. 23, 1112–1118.
Sakurai, M. (1978) Liver cell dysplasia and hepatitis B surface and core antigens in cirrhosis and hepatocellular carcinoma of autopsy cases. Acta Pathol. Jpn. 28, 705–719.
Paterson, A. C., Kew, M. C., Duskeiko, G. M., and Isaacson, C. (1989) Liver cell dysplasia accompanying hepatocellular carcinoma in southern Africa. Differences between urban and rural populations. J. Hepatol. 8, 241–248.
Theise, N. D., Schwartz, M., Miller, C., and Thung, S. N. (1992) Macroregenerative nodules and hepatocellular carcinoma in forty-four sequential adult liver explants with cirrhosis. Hepatology. 16, 949–955.
Ojanguren, I., Castella, E., Ariza, A., Santos, J., Planas, R., and Bruguera, M. (1997) Liver cell atypias: a comparative study in cirrhosis with and without hepatocellular carcinoma. Histopathology. 30, 106–112.
Lee, R. G., Tsamandas, A. C. and Demetris, A. J. (1997) Large cell change (liver cell dysplasia) and hepatocellular carcinoma in cirrhosis: matched casecontrol study, pathological analysis, and pathogenetic hypothesis. Hepatology. 26, 1415–1422.
Vandelli, C., Renzo, F., Floridia, A., Pifferi, M., Di Marco, G., Piccinini, L., et al. (1998) Hepatocellular carcinoma: role of viruses and liver cell dysplasia. Ital. J. Gastroenterol. Hepatol. 30(Suppl. 1), A70.
Beasley, R. P., Hwang, L. Y., Lin, C. C., and Chien, C. S. (1981) Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22,707 men in Taiwan. Lancet. 2, 1129–1133.
Oshima, A., Tsukuma, H., Hiyama, T., Fujimoto, I., Yamano, H., and Tanaka, M. (1984) Follow-up study of HBsAg-positive blood donors with special reference to effect of drinking and smoking on development of liver cancer. Int. J. Cancer 34, 775–779.
Brechot, C., Pourcel, C., Louise, A., Rain, B., and Tiollais, P. (1980) Presence of integrated hepatitis B virus DNA sequences in cellular DNA of human hepatocellular carcinoma. Nature. 286, 533–535.
Scaglioni, P. P., Melegari, M., and Wands, J. R. (1996) Recent advances in the molecular biology of hepatitis B virus. Baillieres Clin. Gastroenterol. 10, 207–225.
Busuttil, R. W. and Farmer, D. G. (1996) The surgical treatment of primary hepatobiliary malignancy. Liver Transpl. Surg. 2, s114–s130.
Koike, K., Moriya, K., Iino, S., Yotsuyanagi, H., Endo, Y., Miyamura, T., et al. (1994) High-level expression of hepatitis B virus HBx gene and hepatocarcinogenesis in transgenic mice. Hepatology. 19, 810–819.
Kim, C. M., Koike, K., Saito, I., Miyamura, T., and Jay, G. (1991) HBx gene of hepatitis B virus induces liver cancer intransgenic mice. Nature 351, 317–320.
Diamantis, I. D., McGandy, C. E., Chen, T. J., Liaw, Y. F., Gudat, F., and Bianchi, L. (1992) Hepatitis B X-gene expression in hepatocellular carcinoma. J. Hepatol. 15, 400–403.
Takada, S., Tsuchida, N., Kobayashi, M., and Koike, K. (1995) Disruption of the function of tumor-suppressor gene p53 by the hepatitis B virus X protein and hepatocarcinogenesis. J. Cancer Res. Clin. Oncol. 12, 593–601.
Paterlini, P., Poussin, K. and De Mitri, S. (1994) Rate of persistence, structure, and expression of HBV genome in HCC developing in HBs-Ag negative patients, in Viral Hepatitis and Liver Disease (Nishioka, K. and Suzuki, H., eds. ), Springer-Verlag, Tokyo, pp.757–762.
Brechot, C. (1996) Hepatitis B and C viruses and primary liver cancer. Baillieres Clin Gastroenterol. 10, 335–373.
Brechot, C. (1987) Hepatitis B virus (HBV) and hepatocellular carcinoma. HBV DNA status and its implications. J. Hepatol. 4, 269–279.
Schimke, R. T. (1990) The search for early genetic events in tumorigenesis: an amplification paradigm. Cancer Cells. 2, 149–151.
Slagle, B. L., Zhou, Y. Z., and Butel, J. S. (1991) Hepatitis B virus integration event in human chromosome 17p near the p53 gene identifies the region of the chromosome commonly deleted in virus-positive hepatocellular carcinomas. Cancer Res. 51, 49–54.
Takahashi, K., Kudo, J., Ishibashi, H., Hirata, Y., and Niho, Y. (1993) Frequent loss of heterozygosity on chromosome 22 in hepatocellular carcinoma. Hepatology. 17, 794–799.
Bressac, B., Kew, M., Wands, J., and Ozturk, M. (1991) Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature. 350, 429–431.
Harris, C. C. (1993) p53: at the crossroads of molecular carcinogenesis and risk assessment. Science. 262, 1980–1981.
Solomon, E., Borrow, J., and Goddard, A. D. (1991) Chromosome aberrations and cancer. Science. 254, 1153–1160.
Derynck, R., Goeddel, D. V., Ullrich, A., Gutterman, J. U., Williams, R. D., Bringman, T. S., et al. (1987) Synthesis of messenger RNAs for transforming growth factors alpha and beta and the epidermal growth factor receptor by human tumors. Cancer Res. 47, 707–712.
Hsia, C. C., Axiotis, C. A., Di Bisceglie, A. M., and Tabor, E. (1992) Transforming growth factor-alpha in human hepatocellular carcinoma and co-expression with hepatitis B surface antigen in adjacent liver. Cancer. 70, 1049–1056.
Shirai, Y., Kawata, S., Ito, N., Tamura, S., Takaishi, K., Kiso, S., et al. (1992) Elevated levels of plasma transforming growth factor-beta in patients with hepatocellular carcinoma. Jpn. J. Cancer Res. 83, 676–679.
Mead, J. E. and Fausto, N. (1989) Transforming growth factor a may be a physiological regulator of liver regeneration by means of an autocrine mechanism. Proc. Natl. Acad. Sci. USA 86, 1558–1562.
Yeh, J. and Yeh, Y. C. (1989) Transforming growth factor-alpha and human cancer. Biomed. Pharmacother. 43, 651–659.
Sherlock, S. (1994) Viruses and hepatocellular carcinoma. Gut. 35, 828–832.
Terris, B., Ingster, O., Rubbia, L., Dubois, S., Belghiti, J., Feldmann, G., et al. (1997) Interphase cytogenetic analysis reveals numerical chromosome aberrations in large liver cell dysplasia. J. Hepatol. 27, 313–319.
Colombo, M., Kuo, G., Choo, Q. L., Donato, M. F., Del Ninno, E., Tommasini, M. A., et al. (1989) Prevalence of antibodies to hepatitis C virus in Italian patients with hepatocellular carcinoma. Lancet. 2, 1006–1008.
Simonetti, R. G., Cottone, M., Craxì, A., Pagliaro, L., Rapicetta, M., Chionne, P., et al. (1989) Prevalence of antibodies to hepatitis C virus in hepatocellular carcinoma. Lancet. 2, 1338.
Levrero, M., Tagger, A., Balsano, C., De Marzio, E., Avantaggiati, M. L., Natoli, G., et al. (1991) Antibodies to hepatitis C virus in patients with hepatocellular carcinoma. J. Hepatol. 12, 60–63.
Caporaso, N., Romano, M., Marmo, R., De Sio, I., Morisco, F., Minerva, A., et al. (1991) Hepatitis C virus infection is an additive risk factor for development of hepatocellular carcinoma in patients with cirrhosis. J. Hepatol. 12, 367–371.
Bruix, J., Barrera, J. M., Calvet, X., Ercilla, G., Costa, J., Sanchez-Tapias, J. M., et al. (1989) Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet. 2, 1004–1006.
Kew, M. C., Houghton, M., Choo, Q. L., and Kuo, G. (1990) Hepatitis C virus antibodies in southern African blacks with hepatocellular carcinoma. Lancet. 2, 873–874.
Kiyosawa, K. and Furuta, S. (1991) Review of hepatitis C in Japan. J. Gastroenterol. Hepatol. 6, 383–391.
Gentilini, P., Melani, L., Riccardi, D., Casini Raggi, V., and Romanelli, R. G. (1994) Hepatocellular carcinoma and viral cirrhosis. Hepatology. 20, 764–765.
Muchmore, E., Popper, H., Peterson, D. A., Miller, M. F., and Lieberman, H. M. (1988) Non-A, non-B hepatitis-related hepatocellular carcinoma in a chimpanzee. J. Med. Primatol. 17, 235–346.
Diamantis, I. D., McGandy, C. E., Chen, T. J., Liaw, Y. F., Gudat, F., and Bianchi, L. (1994) Detection of hepatitis B and C viruses in liver tissue with hepatocellular carcinoma. J. Hepatol. 20, 405–409.
De Mitri, M. S., Poussin, K., Baccarini, P., Pontisso, P., D’Errico, A., Simon, N., et al. (1995) HCV-associated liver cancer without cirrhosis. Lancet. 1, 413–415.
el-Refaie, A., Savage, K., Bhattacharya, S., Khakoo, S., Harrison, T. J., el-Batanony, M., et al. (1996) HCV-associated hepatocellular carcinoma without cirrhosis. J. Hepatol. 24, 277–285.
Moradpour, D. and Wand, J. R. (1996) Hepatic oncogenesis, in Hepatology a Textbook of Liver Disease, 3rd ed. (Zakim, D. and Boyer, T. D., eds. ), WB Saunders, Philadelphia, pp.1490–1512.
Ferrell, L., Wright, T., Lake, J., Roberts, J., and Ascher, N. (1992) Incidence and diagnostic features of macroregenerative nodules vs. small hepatocellular carcinoma in cirrhotic livers. Hepatology. 16, 1372–1381.
Orsatti, G., Theise, N. D., Thung, S. N., and Paronetto, F. (1993) DNA image cytometric analysis of macroregenerative nodules (adenomatous hyperplasia) of the liver: evidence in support of their preneoplastic nature. Hepatology. 17, 621–627.
Tanaka, S., Takenaka, K., Matsumata, T., Mori, R., and Sugimachi, K. (1996) Hepatitis C virus replication is associated with expression of transforming growth factor-alpha and insulin-like growth factor-II in cirrhotic livers. Dig. Dis. Sci. 41, 208–215.
Sakamuro, D., Furukawa, T., and Takegami, T. (1995) Hepatitis C virus nonstructural protein NS3 transforms NIH 3T3 cells. J. Virol. 69, 3893–3896.
Ray, R. B., Lagging, L. M., Meyer, K., and Ray, R. (1996) Hepatitis C virus core protein cooperates with ras and transforms primary rat embryo fibroblasts to tumorigenic phenotype. J. Virol. 70, 4438–4443.
Matsumoto, M., Zhu, N., and Hwang, S. B. (1995) Interactions of hepatitis C virus core protein with members of tumor necrosis factor receptor family: implication for HCV persistency and pathogenesis. Intl. Symposium on Hepatitis C Virus and Related Viruses, paper C48.
Hagiwara, H., Hayashi, N., Mita, E., Hiramatsu, N., Ueda, K., Takehara, T., et al. (1992) Detection of hepatitis C virus RNA in chronic non-A, non-B liver disease. Gastroenterology. 102, 692–694.
Ruiz, J., Sangro, B., Cuende, J. I., Beloqui, O., Riezu-Boj, J. I., Herrero, J. I., et al. (1992) Hepatitis B and C viral infections in patients with hepatocellular carcinoma. Hepatology. 16, 637–641.
Sheu, J. C., Huang, G. T., Shih, L. N., Lee, W. C., Chou, H. C., Wang, J. T., et al. (1992) Hepatitis C and B viruses in hepatitis B surface antigen-negative hepatocellular carcinoma. Gastroenterology. 103, 1322–1327.
Takeda, S., Shibata, M., Morishima, T., Harada, A., Nakao, A., Takagi, H., et al. (1992) Hepatitis C virus infection in hepatocellular carcinoma. Detection of plus-strand and minus-strand viral RNA. Cancer. 70, 2255–2259.
Thelu, M. A., Zarski, J. P., Dardelet, D., Lunel, F., and Seigneurin, J. M. (1992) Low prevalence of hepatitis C virus genome detected by PCR in serum of Caucasian patients with hepatocellular carcinoma. J. Hepatol. 14, 415–416.
Benvegnù, L., Fattovich, G., Diodati, G., Noventa, F., Pontisso, P., Tremolada, F., et al. (1993) Hepatitis C virus infection and replication in patient with hepatocellular carcinoma. In Viral Hepatitis and Liver Disease (Nishioka, K., Suzuki, H., Mishiro, S., and Oda, T. eds.), Springer-Verlag, Tokyo. pp. 706–709.
Bukh, J., Miller, R. H., Kew, M. C., and Purcell, R. H. 1993 Hepatitis C virus RNA in southern African blacks with hepatocellular carcinoma. Proc. Natl. Acad. Sci. USA 90, 1848–1851.
Mangia, A., Vallari, D. S., and Di Bisceglie, A. M. (1994) Use of confirmatory assays for diagnosis of hepatitis C viral infection in patients with hepatocellular carcinoma. J. Med. Virol. 43, 125–128.
Oka, H., Yamamoto, S., Kuroki, T., Harihara, S., Marumo, T., Kim, S. R., et al. (1995) Prospective study of chemoprevention of hepatocellular carcinoma with Sho-saiko-to (TJ-9). Cancer. 76, 743–749.
Vandelli, C., Piaggi, V., Palmisani, L., Renzo, F., Di Marco, G., Floridia, A., et al. (1992) Histological and morphological evolution of anti HCV correlated liver damage. J. Hepatol. 17(Suppl. 1), S31.
Oka, H., Kurioka, N., Kim, K., Kanno, T., Kuroki, T., Mizoguchi, Y., et al. (1990) Prospective study of early detection of hepatocellular carcinoma in patients with cirrhosis. Hepatology. 12, 680–687.
Sato, Y., Nakata, K., Kato, Y., Shima, M., Ishii, N., Koji, T., et al. (1993) Early recognition of hepatocellular carcinoma based on altered profiles of alpha-fetoprotein. N. Engl. J. Med. 328, 1802–1806.
Cottone, M., Turri, M., Caltagirone, M., Parisi, P., Orlando, A., Fiorentino, G., et al. (1994) Screening for hepatocellular carcinoma in patients with Child’s A cirrhosis: an 8-year prospective study by ultrasound and alphafetoprotein. J. Hepatol. 2, 1029–1034.
Pateron, D., Ganne, N., Trinchet, J. C., Aurousseau, M. H., Mal, F., Meicler, C., et al. (1994) Prospective study of screening for hepatocellular carcinoma in Caucasian patients with cirrhosis. J. Hepatol. 20, 65–71.
Kaklamani, E., Trichopoulos, D., Tzonou, A., Zavitsanos, X., Koumantaki, Y., Hatzakis, A., et al. (1991) Hepatitis B and C viruses and their interaction in the origin of hepatocellular carcinoma. JAMA 265, 1974–1976.
Simonetti, R. G., Camma, C., Fiorello, F., Cottone, M., Rapicetta, M., Marino, L., et al. (1992) Hepatitis C virus infection as a risk factor for hepatocellular carcinoma in patients with cirrhosis. A case-control study. Ann. Intern. Med. 116, 97–102.
Benvegnù, L., Fattovich, G., Noventa, F., Tremolada, F., Chemello, L., Cecchetto, A., et al. (1994) Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma in cirrhosis. A prospective study. Cancer 74, 2442–2448.
Szczepanski, W. (1997) Liver cell dysplasia in liver cirrhosis and hepatocellular carcinoma. Pol. J. Pathol. 48, 147–157.
Furuya, K., Nakamura, M., Yamamoto, Y., Togei, K., and Otsuka, H. (1988) Macroregenerative nodule of the liver. A clinicopathologic study of 345 autopsy cases of chronic liver disease. Cancer 61, 99–105.
Craig, J. R., Klatt, E. C., and Yu, M. (1991) Role of cirrhosis and the development of HCC, in Etiology, Patology, and Treatment of Hepatocellular Carcinoma in North America (Tabor, E., Di Bisceglie, A. M., and Purcell, R. H. eds.), The Woodlands, Portfollo Publishing, pp. 177–190.
Cohen, C. and Derose, P. B. (1994) Liver cell dysplasia in alpha-1-antitrypsin deficiency. Mod. Pathol. 7, 31–36.
Riegler, J. L. (1996) Preneoplastic conditions of the liver. Semin. Gastrointest. Dis. 7, 74–87.
Idilman, R., De Maria, N., Colantoni, A., and Van Thiel, D. H. (1998) Pathogenesis of hepatitis B and C-induced hepatocellular carcinoma. J. Viral. Hepat. 5, 285–299.
Kew, M. C. (1994) Hepatitis C virus and hepatocellular carcinoma. FEMS Microbiol. Rev. 14, 211–219.
Gerber, M. A., Shieh, Y. S., Shim, K. S., Thung, S. N., Demetris, A. J., Schwartz, M., et al. (1992) Detection of replicative hepatitis C virus sequences in hepatocellular carcinoma. Am. J. Pathol. 141, 1271–1277.
Horiike, N., Nonaka, T., Kumamoto, I., Kajino, K., Onji, M., and Ohta, Y. (1993) Hepatitis C virus plus-and minus-strand RNA in hepatocellular carcinoma and adjoining nontumorous liver. J. Med. Virol. 41, 312–315.
Takamizawa, A., Mori, C., Fuke, I., Manabe, S., Murakami, S., Fujita, J., et al. (1991) Structure and organization of the hepatitis C virus genome isolated from human carriers. J. Virol. 65, 1105–1113.
Teramoto, T., Satonaka, K., Kitazawa, S., Fujimori, T., Hayashi, K., and Maeda, S. (1994) p53 Gene abnormalities are closely related to hepatoviral infections and occur at a late stage of hepatocarcinogenesis. Cancer Res. 54, 231–235.
Adachi, E., Hashimoto, H., and Tsuneyoshi, M. (1993) Proliferating cell nuclear antigen in hepatocellular carcinoma and small cell liver dysplasia. Cancer. 72, 2902–2909.
Shibata, M., Morizane, T., Uchida, T., Yamagami, T., Onozuka, Y., Nakano, M., et al. (1998) Irregular regeneration of hepatocytes and risk of hepatocellular carcinoma in chronic hepatitis and cirrhosis with hepatitis-C-virus infection. Lancet. 1, 1773–1777.
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© 2000 Humana Press Inc., Totowa, NJ
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Vandelli, C., Renzo, F. (2000). Hepatocellular Carcinoma. In: Habib, N.A. (eds) Hepatocellular Carcinoma. Methods in Molecular Medicine™, vol 45. Humana Press. https://doi.org/10.1385/1-59259-079-9:71
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DOI: https://doi.org/10.1385/1-59259-079-9:71
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