Hepatitis Viruses, Alcohol, and Tobacco in the Etiology of Hepatocellular Carcinoma in Italy Silvia Franceschi, 1 Maurizio Montella, 3 Jerry Polesel, 5 Carlo La Vecchia, 6,7 Anna Crispo, 3 Luigino Dal Maso, 5 Pietro Casarin, 8 Francesco Izzo, 4 Luigi G. Tommasi, 5 Isabelle Chemin, 2 Christian Tre ´po, 2 Marina Crovatto, 9 and Renato Talamini 5 1 International Agency for Research on Cancer; 2 Institut National de la Sante et de la Recherche Medicale Unite ´ 271, Lyons, France; 3 Servizio di Epidemiologia, Istituto Tumori ‘‘Fondazione Pascale,’’ Cappella dei Cangiani; 4 Divisione di Chirurgia D, Istituto Tumori ‘‘Fondazione Pascale,’’ Cappella dei Cangiani, Naples, Italy; 5 Unita ` di Epidemiologia e Biostatistica, Centro di Riferimento Oncologico, Istituto Nazionale Tumori, Aviano, Italy; 6 Istituto di Ricerche Farmacologiche ‘‘Mario Negri’’; 7 Istituto di Statistica Medica e Biometria, Universita ` degli Studi di Milano, Milan, Italy; 8 Divisione di Medicina 3, Ospedale ‘‘S. Maria degli Angeli’’; and 9 Divisione di Microbiologia e Immunologia, Ospedale ‘‘S. Maria degli Angeli,’’ Pordenone, Italy Abstract Mortality rates of hepatocellular carcinoma (HCC) are high in Italy compared with other Western countries. To elucidate further the role of hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol drinking, and tobacco smoking in the etiology of HCC, we carried out a hospital-based case-control study in two areas of Italy: the province of Pordenone in the Northeast and the town of Naples in the South. A total of 229 HCC cases (median age, 66 years) and 431 controls (median age, 65 years) answered a questionnaire and provided blood samples between 1999 and 2002. Odds ratios (OR), percent attributable risks, and corresponding 95% confidence inter- vals were computed using unconditional multiple logistic regression. ORs for hepatitis B surface antigen (HBsAg) positive versus HBsAg negative and for anti-HCV antibody positive versus anti-HCV antibody negative were 20.2 and 15.6, respectively. Positivity for both markers was associated with an OR of 51.6. Sensitive molecular techniques applied to sera in a subset of HCC cases disclosed a very small number of occult hepatites. Maximal lifetime alcohol intake of z35 versus <7 drinks/wk was associated with an HBV/ HCV adjusted OR of 5.9. Tobacco smoking was unrelated to HCC risk overall but seemed to enhance HCC risk among virus carriers. Overall, 61% of HCC were attributable to HCV, 13% to HBV, and 18% to heavy alcohol drinking. In conclusion, our study confirms the importance of HCV in HCC etiology in Italy where the widespread dissemination of the virus dates back four or five decades. (Cancer Epidemiol Biomarkers Prev 2006;15(4):683–9) Introduction Upward trends in incidence or mortality of hepatocellular carcinoma (HCC) have been reported in the United States (1), Japan (2), and in several European countries, including Italy (3), over the last two or three decades. These increases have been chieflyattributedtothespreadofhepatitisCvirus(HCV;ref.1), whichoccurredearlierinJapanandSouthernEuropethaninthe United States (3, 4) and has been mainly sustained by i.v. drug use and the use of contaminated needles in medical procedures (5). Although the role of heavy alcohol drinking has long been recognized (6-9), the contribution of cigarette smoking to HCC has been established only recently (10, 11). To elucidate further the interplay of viruses and lifestyle, we have conducted a case-control study of HCC in two areas of Italy, characterized by different levels of alcohol consumption (12) and HCV prevalence (13, 14). Sensitive molecular techni- ques for viral genomes were added to serologic assays to obtain a more accurate figure of the proportion of HCC attributable to hepatitis B virus (HBV) or HCV. Materials and Methods Between January 1999 and July 2002, we conducted a case- control study on the association of HBV and HCV with HCC in theprovinceofPordenoneintheNortheastofItalyandthetown ofNaplesintheSouth.Theoriginalstudyincludedanothercase group (lymphohematopoietic neoplasms) whose relationship with HBV and HCV has already been reported (15, 16). Cases. Cases in the present report included patients <85 years of age with incident HCC, who had not yet received any cancer treatment at study entry. They were admitted to the National Cancer Institute in Aviano, the ‘‘Santa Maria degli Angeli’’ General Hospital in Pordenone, and the ‘‘Pascale’’ National Cancer Institute, plus four General Hospitals in Naples (i.e., the hospitals to which the majority of HCC patients from the two study areas were referred). A total of 261 HCC cases were identified. Three cases refused to participate in the study and 29 HCC cases were interviewed but could not give a blood sample, thus leaving 229 cases (median age, 66 years; range, 43-84 years) for whom both questionnaire and blood sample were available. Histologic or cytologic confir- mation was available from the majority (78.2%) of HCC cases whereas diagnosis was based on ultrasound, tomography, and elevated a-fetoprotein levels in the remaining HCC cases. According to the Child-Pugh classification, 59.0% of HCC cases were classified as class A, 31.7% as class B, and 18.4% as class C. All medical and histocytologic records were reviewed by two authors (F.I. and L.G.T.). Controls. The comparison group included patients <85 years of age admitted to the same hospitals where HCC cases had been interviewed for a wide spectrum of acute conditions. Patients whose hospital admission was due to diseases related to alcohol and tobacco use (e.g., respiratory diseases, peptic ulcer, lung cancer, head and neck cancer, etc.) or hepatitis viruses (e.g., hepatitis, cirrhosis, esophageal varices, etc.) were specifically excluded from the control group, as were those 683 Cancer Epidemiol Biomarkers Prev 2006;15(4). April 2006 Received 9/7/05; revised 1/11/06; accepted 1/30/06. Grant support: Associazione Italiana per la Ricerca sul Cancro, Lega Italiana per la Lotta contro i Tumori, and Compagnia San Paolo grant 11582/23719. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Silvia Franceschi, IARC, 150 cours Albert Thomas, 69372 Lyon cedex 08, France. Phone: 33-4-72-73-84-02; Fax: 33-4-72-73-83-45. E-mail: franceschi@iarc.fr Copyright D 2006 American Association for Cancer Research. doi:10.1158/1055-9965.EPI-05-0702 on June 12, 2020. © 2006 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from