Abstract
Male sex, age, cirrhosis, and HBsAg are the major risk factors for hepatocellular carcinoma (HCC). The geographic distribution of HCC is highly uneven, such that three distinct incidence areas are recognized. To clarify the reason(s) for this geographic variability of HCC, the risk factors in earch incidence area were assessed. In parallel with the geographic distribution of HCC, HBsAg prevalence was highest in both HCC patients and in general population in Africa and Asia, where mothers of HCC patients are frequently HBsAg-positive, suggesting that hepatitis B virus hyperendemicity and perinatal infection account for the high HCC incidence in these areas. Cirrhosis, which is found on autopsy in 80% of the cases of HCC patients worldwide, is the most prevalent risk factor for HCC in areas where hepatitis B virus infection is less common. However, HBsAg carriage adds to the HCC risk carried by cirrhosis and explains the higher incidence of HCC in cirrhotics from Africa and Asia as well as elsewhere. Available data suggest that chronic HCV infection is a risk factor for cirrhosis and HCC. HBV vaccination should decrease HCC incidence rates worldwide; however, HCC prevention in regions where HBsAg carriage is infrequent may also require prevention of the other causes of cirrhosis in order for HCC rates to decline.
References
Muir C, Waterhouse J, Mack T, Dowell J, Whelan S (eds): Cancer Incidence in Five Continents, Vol V. World Health Organization, IARC Scientific Publications No. 88, 1987
Waterhouse J, Muir C, Shanmugaratnam K, Powell J (eds): Cancer Incidence in Five Continents, Vol IV. World Health Organization, IARC Scientific Publications No. 42, 1982, pp 714–715
Waterhouse J, Muir C, Correa P, Powell J (eds): Cancer Incidence in Five Continents, Vol III. World Health Organization, IARC Scientific Publications No. 15, 1976, pp 500–501
Cancer Incidence in Five Continents, Vol II. World Health Organization, IARC Scientific Publications, 1970, pp 350–351
World Health Statistics Annual 1988. World Health Organization.
Williams DF, Parker RA, Kendrick JS: The box plot: A simple visual method to interpret data. Ann Intern Med 110:916–921, 1989
Rustgi VK: Epidemiology of hepatocellular carcinoma. Gastroenterol Clin North Am 16:545–551, 1987
London WT: Primary hepatocellular carcinoma—etiology, pathogenesis and prevention. Hum Pathol 12:1085–1097, 1981
Lai CL, Gregory PB, Wu PC, Lok ASF, Wong KP, Ng MMT: Hepatocellular carcinoma in chinese males and females, possible causes for the male predominance. Cancer 60:1107–1110, 1987
Heyward WL, Lanier AP, Bender TR, Hardison HH, Dohan PH, McMahon BJ, Francis DP: Primary hepatocellular carcinoma in Alaskan natives, 1969–1979. Int J Cancer 28:47–50, 1981
Hadziyannis SJ: Hepatocellular carcinoma and type B hepatitis. Clin Gastroenterol 9:117–134, 1980
Denoix P: Epidemiologie generale du cancer primitif du foie.In Les Cancers Primitifis du Foie. 40° Congres Français de Medicine, Dakar, Paris, Masson, 1976, pp 33–42
Beasley RP, Hwang LY, Lin CC, Chien CS: Hepatocellular carcinoma and hepatitis B virus: A prospective study of 22,707 men in Taiwan. Lancet 2:1129–1133, 1981
Di Bisceglie AM, Rustgi VK, Hoofnagle JH, Dusheiko GM, Lotze MT: Hepatocellular carcinoma. Ann Intern Med 108:390–401, 1988
Thrichopoulos D, Violacki M, Xirouchaki E: Epidemiology of hepatitis B and primary hepatic carcinoma. Lancet 2:1038–1039, 1975
Szmuness W: Hepatocellular carcinoma and the hepatitis B virus: Evidence for a causal association. Prog Med Virol 24:40–69, 1978
Sagebiel RW, McFarland RB, Taft EB: Primary carcinoma of the liver in relation to cirrhosis. Am J Clin Pathol 40:516–520, 1963
Peters RL: Pathology of hepatocellular carcinoma.In Hepatocellular Carcinoma. K Okuda, RL Peters (eds). New York, Wiley Medical, 1976, pp 107–168
Pequignot H, Etienne JP, Delavierre Ph, Petite JP: Cancers primitifs du foie sur cirrhose. Presse Med 75:2595–2600, 1967
Ottolenghi A: Rilievi statitici su carcinomi primitivi e cirrosi del fegato. Cancro 19:559–567, 1966
Crocè SL, Sodde M, Polo S, Melato M, Tiribelli C: Primary liver cancer and liver cirrhosis in the Trieste area: A study on 16,245 autopsies. Ital J Gastroenterol 20:25, 1988 (abstract)
Bartoloni F, Giannini A, Napoli P: Hepatocellular carcinoma and cirrhosis: A review of their relative incidence in a 25-year period in the Florence area. Hepato-Gastroenterol 31:215–217, 1984
Nakashima T, Okuda K, Masamichi K: Pathology of hepatocellular carcinoma in Japan 232 consecutive cases autopsied in ten years. Cancer 51:863–877, 1983
Akagi GO, Furuya K, Otsuka H: Hepatitis B antigen in the liver in hepatocelluar carcinoma in Shikoku, Japan, Cancer 49:678–682, 1982
Lin WSJ: Hepatoma in Taiwan: A pathological study. Trans Gastroenterol Soc ROC 9:3–5, 1980
Saracci R, Repetto F: Time trends of PLC: Indication of increased incidence in selected cancer registry populations. J Natl Cancer Inst 65:241–297, 1980
Macnab GM, Alexander JJ, Lecatsas G, Bey EM, Urbanowicz JM: Hepatitis B surface antigen produced by a human hepatoma cell line. Br J Cancer 34:509–515, 1976
Okuda K: Primary liver cancer. Dig Dis Sci 31: 133S-145S, 1986
Zeitlhofer J: Zur frage der haurigkeit und form der primaren leberkrebse. Krebsartz 6:154–160, 1951
Lutwick LI: Relation between aflatoxin, hepatitis B, and hepatocellular carcinoma. Lancet 1:755–757, 1979
Edmondson HA, Craig JR: Neoplasms of the liver In. Diseases of the Liver. L Schiff, ER Schiff (eds). Philadelphia, JB Lippincott 1987, pp 1109–1158
Zaman SN, Johnson RD, Johnson PG, Melia VM, Portmann BC, Williams R: Risk factors in development of hepatocellular carcinoma in cirrhosis: prospective study of 613 patients. Lancet 1:1357–1359, 1985
Pirovino M, Heer M, Joller-Jemelka HP, Altorfer J, Akovbiantz A, Schmid M: Hepatocellular carcinoma and hepatitis B virus infection. Analysis of 75 cases from Switzerland. Liver 3:398–402, 1983
Ferenci P, Dragosics B, Marosi L, Kiss F: Relative incidence of primary liver cancer in cirrhosis in Austria. Etiological considerations. Liver 4:7–14, 1984
Bartok I, Remenar E, Toth J, Duschanek P, Kanyar B: Clinicopathological studies of liver cirrhosis and hepatocellular carcinoma in a general hospital. Hum Pathol 12:794–803, 1981
Hide DC, Sherlock S, Winawer SJ: Clinical manifestations of hepatoma. Am J Med 56:83–91, 1974
The Liver Cancer Study Group of Japan: Primary liver cancer in Japan. Cancer 60:1400–1401, 1987
Kishi K, Shikata T, Hirohashi S, Hasegawa H, Yamazaki S, Makuuchi M: Hepatocellular carcinoma. A clinical and pathologic analysis of 57 hepatectomy cases. Cancer 51:542–548, 1983
Villa E, Baldini GM, Pasquinelli C, Melegari M, Cariani E, Di Chirico G, Manenti F: Risk factors for hepatocellular carcinoma in Italy. Male sex; hepatitis B virus, non-A, non-B infection, and alcohol. Cancer 62:611–615, 1988
Okuda K, Ohtsuki T, Obata H, Tomimatsu M, Okazaki N, Hasegawa H, Nakajima Y, Ohnishi K: Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Cancer 56:918–928, 1985
Amuso M, Cottone M, Craxì A, D'Amico G, Di Piazza S, Filippazzo G Le Moli S, Maniscalco GE, Oliva L, Palazzo U, Pasta L, Pinzello G, Rinaldi F, Pagliaro L, Guli V, La Rosa G, Dardanoni L, Genova G: Serologic markers of hepatitis B infection in primary liver cancer. A comparison with matched cases of cirrhosis. Rendic Gastroenterol 8:167–171, 1976
Pagliaro L, Simonetti RG, Craxì A, Spanò C, Filippazzo MG, Palazzo U, Patti S, Giannuoli G, Marraffa A, Colombo M, Tommasini M, Bellentani S, Villa E, Manenti F, Caporaso N, Coltorti M, Del Vecchio-Blanco C, Farsi P, Smedile A, Verme G: Alcohol and HBV infection as risk factors for hepatocellular carcinoma in Italy: A multicentric, controlled study. Hepato-Gastroenterol 30:48–50, 1983
Trichopoulos D, MacMahon B, Sparros L, Merikas G: Smoking and hepatitis B negative primary hepatocellular carcinoma. J Natl Cancer Inst 65:111–114, 1980
Pagliaro L, Saracci R, Bardelli D, Filippazzo G, and a Group of the Italian Association for the Study of the Liver (AISF): Chronic liver disease, alcohol consumption and HBsAg antigen in Italy: A multiregional case-control study. Ital J Gastroenterol 14:90–95, 1982
Filippazzo MG, Aragona E, Cottone M, Dardanoni G, Lanzarone F, Maringhini A, Patti C, Sciarrino E, Simonetti R, Tiné F, Pagliaro L: Assessment of some risk factors for hepatocellular carcinoma: A case-control study. Stat Med 4:345–351, 1985
Simonetti RG, Lojacono F, Cammà C, Fiorello F, Pagliaro L: Etiological and clinical features in 369 consecutive patients with HCC (in preparation)
Trichopoulos D, Gerety RJ, Sparros L, Tabor E, Xirouchaki E, Munoz N, Linsell CA: Hepatitis B and primary hepatocellular carcinoma in a european population. Lancet 2:1217–1219, 1978
Kew MC: Clinical, pathologic, and etiologic heterogeneity in hepatocellular carcinoma: Evidence from southern Africa. Hepatology 1:366–369, 1981
Lu SN, Lin TM, Chen CJ, Chen JS, Liaw YF, Chang WY, Hsu ST: A case-control study of primary hepatocellular carcinoma in Taiwan. Cancer 62:2051–2055, 1988
Coursaget P, Maupas P, Goudeau A, Chiron JP, Druker J, Dennis F, Diop-Mar I: Primary hepatocellular carcinoma in intertropical Africa: Relationship between age and hepatitis B virus etiology. J Natl Cancer Inst 65:687–690, 1980
Kew MC, Kassianides C, Hodkinson J, Coppin A, Peterson AC: Hepatocellular carcinoma in urban born blacks: Frequency and relation to hepatitis B virus infection. Br Med J 293:1339–1341, 1986
Zhou XD, Detolla L, Custer P, London T: Iron, ferritin, hepatitis surface and core antigens in the livers of Chinese patients with hepatocellular carcinoma. Cancer 59:1430–1437, 1987
Lin DY, Liaw YF, Chu CM, Chang-Chien CS, Wu CS, Chen PC, Sheen IS: Hepatocellular carcinoma in noncirrhotic patients. A laparoscopy study of 92 cases in Taiwan. Cancer 54:1466–1468, 1984
Kew MC, Di Bisceglie AM, Paterson AC: Smoking as a risk factor in hepatocellular carcinoma. A case-control study in southern African Blacks. Cancer 56:2315–2317, 1985
Hsu HC, Wu TT, Wu MZ, Wu CY, Chiou TJ, Sheu JC, Lee CS, Chen DS: evolution of expression of hepatitis B surface and core antigens (HBsAg, HBcAg) in resected primary and recurrent hepatocellular carcinoma in HBsAg carriers in Taiwan. Correlation with local host immune response. Cancer 62:915–921, 1988
Tabor E, Gerety R, Vogel CL, Bayley AC, Anthony PP, Chan CH, Barker LF: Hepatitis B virus infection and primary hepatocellular carcinoma. J Natl Cancer Inst 58:1197–1200, 1977
Kew MC, Desmyter J, Bradburne AF, Macnab GM: Hepatitis B virus infection in southern African Blacks with hepatocellular cancer. J Natl Cancer Inst 62:517–520, 1979
Sjogren MH, Lemon SM, Chung WK, Sun HS, Hoofnagle JH: IgM antibody to hepatitis B core antigen in korean patients with hepatocellular carcinoma. Hepatology 4:615–618, 1984
Chung WK, Sun HS, Park DH, Minuk GY, Hoofnagle JH: Primary hepatocellular carcinoma and hepatitis B virus infection in Korea. J Med Virol 11:99–104, 1983
Joishy SK, Bennett JM, Balasegaram M, McIntyre JM, Falkson G, Moertel C, Carbole PP: Clinical and chemotherapeutic study of hepatocellular carcinoma in Malaysia. Cancer 50:1065–1069, 1982
Okuda K, Nakashima T, Sakamoto K, Ikari T, Hidaka H, Kubo Y, Sakuma K, Motoike Y, Okuda H, Obata H: Hepatocellular carcinoma arising in non-cirrhotic and highly cirrhotic livers: A comparative study of histopathology and frequency of hepatitis B markers. Cancer 49:450–455, 1982
Benhamou JP, Fauvert R: Le cancer primitif du foie en France. Sem Hop 34:121–134, 1958
Ilardi CF, Ying YY, Ackerman LV, Elias J: Hepatitis B surface antigen and hepatocellular carcinoma in the People's Republic of China. Cancer 46:1612–1616, 1980
Kew MC, Rossouw E, Paterson A, Hodkinson J, Whitcutt M, Dusheiko G: Hepatitis B virus status of black women with hepatocellular carcinoma. Gastroenterology 84:693–696, 1983
Kew MC, Geddes EW: Hepatocellular carcinoma in rural southern African Blacks. Medicine 61:98–108, 1982
Maupas P, Goudeau A, Coursaget P, Chiron JP, Drucker J, Barin F, Perrin J, Denis F, Diop Mar I: Hepatitis B virus infection and primary hepatocellular carcinoma: Epidemiological, clinical and virological studies in Senegal from the perspective of prevention by active immunization.In Liver Cancer. Amsterdam, Elsevier, 1981, pp 481–506
Hsu HC, Lin WSJ, Tsai MJ: Hepatitis B surface antigen and hepatocellular carcinoma in Taiwan. Cancer 52:1825–1832, 1983
Okuda K, Peters R, Simson IW: Gross anatomic features of hepatocellular carcinoma from three disparate geographic areas. Cancer 54:2165–2173, 1984
Johnson PJ, Williams R: Cirrhosis and aetiology of hepatocellular carcinoma. J Hepatol 4:140–147, 1987
Shikata T: Primary liver carcinoma and liver cirrhosis. In: Hepatocellular carcinoma. K Okuda, RL Peters (Eds). New York, Wiley Medical, 1976, pp 53–71
Tiribelli C, Melato M, Crocé L, Giarelli L, Okuda K, Ohnishi K: Prevalence of hepatocellular carcinoma relation to cirrhosis: Comparison of two different cities of the world—Trieste Italy, and Chiba, Japan. Hepatology 10:998–1002, 1989
Okuda K, Nakashima T, Masamichi K, Kondo Y, Wada K: Hepatocellular carcinoma without cirrhosis in Japanese patients. Gastroenterology 97:140–146, 1989
Kew MC: Hepatocellular carcinoma with and without cirrhosis: A comparison in southern African Blacks. Gastroenterology 97:136–139, 1989
Johnson PJ, Krasner N, Portmann B, Eddleston ALWF, Williams R: Hepatocellular carcinoma in Great Britain: Influence of age, sex, HBsAg status, and aetiology of underlying cirrhosis. Gut 19:1022–1026, 1978
Smalley SR, Moertel CG, Hilton JF, Weiland LH, Wieand HS, Adson MA, Melton LJ, Batts K: Hepatoma in the non-cirrhotic liver. Cancer 62:1414–1424, 1988
Jakobovits AW, Gibson PR, Dudley FY: Primary liver cell carcinoma complicating autoimmune chronic active hepatitis. Dig Dis Sci 26:694–699, 1981
Sumithran E, Looi LM: Race-related morphologic variations in hepatocellular carcinoma. Cancer 56:1124–1127, 1985
Paterson AC, Kew MC, Duskeiko GM, Isacson C: Liver cell dysplasia accompanying hepatocellular carcinoma in southern Africa. J Hepatol 8:241–248, 1989
Zamann SN, Johnson PJ, Williams R: Silent cirrhosis in patients with hepatocellular carcinoma. Cancer 65:1607–1610, 1990
Hallen J, Linne I: Cirrhosis of the liver in one community.In Alcoholic Cirrhosis and Other Toxic Hepatopatias. A Engel, T Larsson (eds), Stockholm, Nordinska Bokhandelus Forlag, 1970, pp 336–355
Martini A, Bode C: The epidemiology of cirrhosis of the liver.In Alcoholic Cirrhosis and Other Toxic Hepatopatias. A Engel, T Larsson (eds), Stockholm, Nordinska Bokhandelus Forlag, 1970, pp 315–335
Ringertz O: Epidemiologia della epatite da siero.In Epatite Virale. N Tygstrup (ed). Il Pansiero Scientifico. Rome, 1974, pp 80–95
Payet M, Sankale M, Saimot G, Larouze B, Brochard C: Facteurs etiologiques du cancer primitif du foie.In Les Cancers primitifs du foie. Congres Français de Medicine, Paris, Masson, 1976, pp 7–32
Colombo M, Donato MF, Tommasini MA, De Fazio C, Del Minno E, Di Carlo CB, Dioguardi N: Prospective study of hepatocellular carcinoma in patients with cirrhosis. Proceedings of International Meeting June 21–24, 1989. Pugnochiuso (Italy). Normal and neoplastic Growth in Hepatology: Interface between basic and clinical science.
Nakanuma Y, Ohta G: Morphology of cirrhosis and occurrence of hepatocellular carcinoma in alcoholics with and without HBsAg and in non-alcoholic HBsAg positive patients. A comparative autopsy study. Liver 3:231–237, 1983
Kew MC, Rossouw E, Hodkinson J, Paterson A, Dusheiko GM, Whitcutt M: Hepatitis B virus status of southern African Blacks with hepatocellular carcinoma: Comparison between rural and urban patients. Hepatology 3:65–68, 1983
Coursaget P, Maupas P, Goudeau A, Chiron JP, Raynaud 8, Druker J, Barin F, Denis F, Mar ID, Diop B: A case control study of hepatitis B virus serological markers in Senegal patients suffering from primary hepatocellular carcinoma. Prog Med Virol 27:49–59, 1981
Cohen C, Path MRC, Berson SD, Path D, Geddes EW: Hepatitis B antigen in black patients with hepatocellular carcinoma. Cancer 41:245–249, 1978
Roggendorf M, Hwang LY, Beasley RF, Chen PH, Chen TC, Lo YR, Dienhardt F: Anti-HBc IgM in cases of hepatocellular carcinoma and cirrhosis in Taiwan. J Hepatol 5:268–273, 1987
Tong MJ, Chien MC, Lo KJ, Tsai YT, Lee JK: Hepatitis B viral markers in patients with chronic hepatitis and with primary hepatocellular in Taiwan. Prog Med Virol 27:60–65, 1985
Otu AA: Hepatocellular carcinoma, hepatic cirrhosis, and hepatitis virus infection in Nigeria. Cancer 60:2581–2585, 1987
Sakuma K, Saitoh N, Kasai M, Jitsukawa H, Yoshino I, Yamaguchi, Nobutomo K, Yamumi M, Tsuda F, Komazawa T, Nakamura T, Yoshida Y, Okuda K: Relative risks of death due to liver disease among Japanese male adults having various status for hepatitis B s and e antigen/ antibody in serum: A prospective study. Hepatology 8:1642–1646, 1988
Beasley RP: Hepatitis B virus. The major etiology of hepatocellular carcinoma. Cancer 61:1942–1956, 1988
Obata H, Hayashi N, Motoike Y, Hisamizu T, Okuda H, Kobayashi S, Nishioka K: A prospective study on the development of hepatocellular carcinoma from liver cirrhosis with persistent hepatitis B virus infection. Int J Cancer 25:741–747, 1980
D'Amico G, Morabito A, Pagliaro L, Marubini E, Liver Study Group of V. Cervello Hospital: Survival and prognostic indicators in compensated and decompensated cirrhosis. Dig Dis Sci 31:468–475, 1986
D'Amico, G, Pasta L, Vizzini G, Caltagirone M, Politi F, Traina M, Pagliaro L, Liver Study Group of V. Cervello Hospital: Natural history of cirrhosis. A prospective study (in preparation)
Kew MC, Popper H: Relationship between hepatocellular carcinoma and cirrhosis. Sem Liver Dis 4:136–146, 1984
Bruix J, Calvet X, Josep C, Ventura N, Bruguera M, Castillo R, Barrera JM, Ercilla G, Sanchez-Tapias JM, Vall M, Bru C, Rodes J: Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet 2:1004–1005, 1989
Colombo M, Kuo G, Choo QL, Donato MF, Del Ninno E, Tommasini MA, Dioguardi N, Houghton M: Prevalence of antibodies to hepatitis C virus in Italian patients with hepatocellular carcinoma. Lancet 2:1006–1008, 1989
Simonetti RG, Cottone M, Craxì A, Pagliaro L, Rapicetta M, Chionne P, Costantino A: Prevalence of antibodies to hepatitis C virus in hepatocellular carcinoma. Lancet 2:1338, 1989
Simonetti RG, Cammà, C, Fiorello F, Cottone M, Craxi A, Rapicetta M, Marino L, Fiorentino G, Magrin S, Giuseppetti R, Costantino A, Stroffolini T, Pagliaro L: Hepatitis C virus infection and hepatocellular carcinoma. A casecontrol study. Proceedings of the autumn meeting AISF 1990. Ital J Gastroenterol 22:329, 1990
Saito I, Miyamura T, Ohbayashi A, Harada H, Katayama T, Kikuchi S, Watanabe Y, Koi S, Onji M, Ohta Y, Choo QL, Houghton M, Kuo G: Hepatitis C virus infection is associated with the development of hepatocellular carcinoma. Proc Natl Acad Sci USA 97:6547–6549, 1990
Kew MC, Houghton M, Choo QL, Kuo G: Hepatitis C virus antibodies in southern African Blacks with hepatocellular carcinoma. Lancet 1:873–874, 1990
Dazza MC, Meneses LV, Girard, PM, Villaroel C, Brechot C, Larouse B: Hepatitis C virus antibody and hepatocellular carcinoma. Lancet 1:1216, 1990
Yoo JY, Shien HK, Park CK, Chung KW, Sun HS, Chung WK, Di Bisceglie AM, Waggoner JJ, Hoofnagle JH: Prevalence of anti-HCV in patients with various liver diseases in Korea. Proceedings of the 41st annual meeting the AASLD 1990. Hepatology 12:975, 1990
Yu MC, Tong MJ, Coursaget P, Ross RK, Govindarajan S, Henderson BE: 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
Hasan F, Jeffers LJ, De Medina M, Redy KR, Parker T, Shiff ER, Houghton M, Choo Q, Kuo G: Hepatitis C associated hepatocellular carcinoma. Hepatology 12:589–591, 1990
Larouze B, London WT, Saimot G, Werner BG, Lustbader ED, Payet M, Blumberg BS: Host responses to hepatitis B infection in patients with primary hepatic carcinoma and their families: A case control study in Senegal, West Africa. Lancet 2:534–538, 1976
Chang MH, Chen DS, Hsu HC, Wu MZ, Hsu HY, Lee CY: Childhood hepatocellular carcinoma in Taiwan. The prominent of perinatally transmitted hepatitis B virus infections.In Viral Hepatitis and Liver Disease. Alan R. Liss, New York, 1988, pp. 726–727
Ishak KG: Hepatic lesions caused by anabolic and contraceptive steroids. Sem Liver Dis 1:116–128, 1981
Johnson FL: Androgenic-anabolic steroids and hepatocellular carcinoma.In Hepatocellular Carcinoma. K Okuda, RL Peters (eds). New York, John Wiley & Sons, 1976, pp 95–103
Klatskim G: Hepatic tumors: Possible relation to use of oral contraceptive. Gastroenterology 73:386–394, 1977
Neuberger J, Forman D, Doll R, Williams R: Oral contraceptives and hepatocellular carcinoma. Br Med J 292:1355–1357, 1986
Forman D, Vincent TJ, Doll R: Cancer of the liver and the use of oral contraceptives. Br Med J 292:1357–1361, 1986
Newberne PM: Chemical carcinogenesis: Mycotoxins and other chemicals to which humans are exposed. Sem Liver Dis 4:122–135, 1984
Higginson J: The epidemiology of primary carcinoma of the liver.In Tumors of the Liver. GT Pack, AH Islami (eds). New York, Springer Verlag 1970, pp 38–52
Ohnishi S, Murakami T, Moriyama T, Mitamura K, Imawari M: Androgen and estrogen receptors in hepatocellular carcinoma and in the surrounding noncancerous liver tissue. Hepatology 6:440–443, 1986
Johnson FL, Feagler JR, Lerner KG: Association of androgenic-anabolic steroid therapy with development of hepatocellular carcinoma. Lancet 2:1273–1276, 1972
Ikbal MJ, Wilkinson ML, Johnson PJ: Sex steroid receptors proteins in foetal, adult and malignant liver tissue. Br J Cancer 48:791–796, 1983
Nagasue N, Ito A, Yukaya H: Androgen receptors in hepatocellular carcinoma and surrounding parenchyma. Gastroenterology 89:643–647, 1985
Brechot C, Nalpas B, Couroucé AM, Duhamel G, Callard P, Carnot F, Tiollais P, Berthelot P: Evidence that hepatitis B virus has a role in liver-cell carcinoma in alcoholic liver disease. Engl J Med 306:1384–1387, 1982
Brechot C, Degos F, Lugassy C, Thiers V, Zafrani S, Franco D, Bismuth H, Trepo C, Benhamou JO, Wands J, Isselbacher K, Tiollais P, 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
Pontisso P, Stenico D, Diodati G, Marin G, Caldironi MV, Giacchino R, Realdi G: HBV-DNA sequences are rarely detected in the liver of patients with HBsAg negative chronic active liver disease and with hepatocellular carcinoma in Italy. Liver 7:211–215, 1987
Fowler MJF, Greenfield C, Chu CM: Integration of HBV-DNA may not be a prerequisite for the maintenance of the state of malignant transformation. An analysis of 110 liver biopsies. J Hepatol 2:218–229, 1986
Walter E, Blum HE, Meier P, Huonker M, Schmid MI, Maier KP, Offensperger WB, Offensperger S, Gerok W: Hepatocellular carcinoma in alcoholic liver disease: No evidence for a pathogenetic role of hepatitis virus infection. Hepatology 8:745–748, 1988
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Simonetti, R.G., Cammà, C., Fiorello, F. et al. Hepatocellular carcinoma. Digest Dis Sci 36, 962–972 (1991). https://doi.org/10.1007/BF01297149
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DOI: https://doi.org/10.1007/BF01297149