Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: A multicenter prospective study

107noNonalcoholic fatty liver disease (NAFLD) represents the hepatic manifestation of metabolic syndrome and may evolve into hepatocellular carcinoma (HCC). Only scanty clinical information is available on HCC in NAFLD. The aim of this multicenter observational prospective study was to assess the clinical features of patients with NAFLD-related HCC (NAFLD-HCC) and to compare them to those of hepatitis C virus (HCV)-related HCC. A total of 756 patients with either NAFLD (145) or HCV-related chronic liver disease (611) were enrolled in secondary care Italian centers. Survival was modeled according to clinical parameters, lead-time bias, and propensity analysis. Compared to HCV, HCC in NAFLD patients had a larger volume, showed more often an infiltrative pattern, and was detected outside specific surveillance. Cirrhosis was present in only about 50% of NAFLD-HCC patients, in contrast to the near totality of HCV-HCC. Regardless of tumor stage, survival was significantly shorter (P = 0.017) in patients with NAFLD-HCC, 25.5 months (95% confidence interval 21.9-29.1), than in those with HCV-HCC, 33.7 months (95% confidence interval 31.9-35.4). To eliminate possible confounders, a propensity score analysis was performed, which showed no more significant difference between the two groups. Additionally, analysis of patients within Milan criteria submitted to curative treatments did not show any difference in survival between NAFLD-HCC and HCV-HCC (respectively, 38.6 versus 41.0 months, P = nonsignificant) Conclusions: NAFLD-HCC is more often detected at a later tumor stage and could arise also in the absence of cirrhosis, but after patient matching, it has a similar survival rate compared to HCV infection; a future challenge will be to identify patients with NAFLD who require more stringent surveillance in order to offer the most timely and effective treatment. (Hepatology 2016;63:827-838)openopenPiscaglia F.; Svegliati-Baroni G.; Barchetti A.; Pecorelli A.; Marinelli S.; Tiribelli C.; Bellentani S.; Bernardi M.; Biselli M.; Caraceni P.; Domenicali M.; Garuti F.; Gramenzi A.; Lenzi B.; Magalotti D.; Cescon M.; Ravaioli M.; Del Poggio P.; Olmi S.; Rapaccini G.L.; Balsamo C.; Di Nolfo M.A.; Vavassori E.; Alberti A.; Benvegnau L.; Gatta A.; Giacomin A.; Vanin V.; Pozzan C.; Maddalo G.; Giampalma E.; Cappelli A.; Golfieri R.; Mosconi C.; Renzulli M.; Roselli P.; Dell'isola S.; Ialungo A.M.; Risso D.; Marenco S.; Sammito G.; Bruzzone L.; Bosco G.; Grieco A.; Pompili M.; Rinninella E.; Siciliano M.; Chiaramonte M.; Guarino M.; Camma C.; Maida M.; Costantino A.; Barcellona M.R.; Schiada L.; Gemini S.; Lanzi A.; Stefanini G.F.; Dall'aglio A.C.; Cappa F.M.; Suzzi A.; Mussetto A.; Treossi O.; Missale G.; Porro E.; Mismas V.; Vivaldi C.; Bolondi L.; Zoli M.; Granito A.; Malagotti D.; Tovoli F.; Trevisani F.; Venerandi L.; Brandi G.; Cucchetti A.; Bugianesi E.; Vanni E.; Mezzabotta L.; Cabibbo G.; Petta S.; Fracanzani A.; Fargion S.; Marra F.; Fani B.; Biasini E.; Sacco R.; Morisco F.; Caporaso N.; Colombo M.; D'ambrosio R.; Croce L.S.; Patti R.; Giannini E.G.; Loria P.; Lonardo A.; Baldelli E.; Miele L.; Farinati F.; Borzio M.; Dionigi E.; Soardo G.; Caturelli E.; Ciccarese F.; Virdone R.; Affronti A.; Foschi F.G.; Borzio F.Piscaglia, F.; Svegliati-Baroni, G.; Barchetti, A.; Pecorelli, A.; Marinelli, S.; Tiribelli, C.; Bellentani, S.; Bernardi, M.; Biselli, M.; Caraceni, P.; Domenicali, M.; Garuti, F.; Gramenzi, A.; Lenzi, B.; Magalotti, D.; Cescon, M.; Ravaioli, M.; Del Poggio, P.; Olmi, S.; Rapaccini, G. L.; Balsamo, C.; Di Nolfo, M. A.; Vavassori, E.; Alberti, A.; Benvegnau, L.; Gatta, A.; Giacomin, A.; Vanin, V.; Pozzan, C.; Maddalo, G.; Giampalma, E.; Cappelli, A.; Golfieri, R.; Mosconi, C.; Renzulli, M.; Roselli, P.; Dell'Isola, S.; Ialungo, A. M.; Risso, D.; Marenco, S.; Sammito, G.; Bruzzone, L.; Bosco, G.; Grieco, A.; Pompili, M.; Rinninella, E.; Siciliano, M.; Chiaramonte, M.; Guarino, M.; Camma, C.; Maida, M.; Costantino, A.; Barcellona, M. R.; Schiada, L.; Gemini, S.; Lanzi, A.; Stefanini, G. F.; Dall'Aglio, A. C.; Cappa, F. M.; Suzzi, A.; Mussetto, A.; Treossi, O.; Missale, G.; Porro, E.; Mismas, V.; Vivaldi, C.; Bolondi, L.; Zoli, M.; Granito, A.; Malagotti, D.; Tovoli, F.; Trevisani, F.; Venerandi, L.; Brandi, G.; Cucchetti, A.; Bugianesi, E.; Vanni, E.; Mezzabotta, L.; Cabibbo, G.; Petta, S.; Fracanzani, A.; Fargion, S.; Marra, F.; Fani, B.; Biasini, E.; Sacco, R.; Morisco, F.; Caporaso, N.; Colombo, M.; D'Ambrosio, R.; Croce, L. S.; Patti, R.; Giannini, E. G.; Loria, P.; Lonardo, A.; Baldelli, E.; Miele, L.; Farinati, F.; Borzio, M.; Dionigi, E.; Soardo, G.; Caturelli, E.; Ciccarese, F.; Virdone, R.; Affronti, A.; Foschi, F. G.; Borzio, F

Changing aetiological factors of hepatocellular carcinoma and their potential impact on the effectiveness of surveillance

Background: The aetiological factors of hepatocellular carcinoma may vary over time. Aims: The study assessed the potential impact of the aetiological factors on the effectiveness of surveillance in real-world patients. Methods: Multicentre, cross-sectional study enrolling consecutive hepatocellular carcinoma cases during a six month period. Results: 1733 cases (1311 prevalent and 422 incident) were recruited (mean age 68.6 years; 46.1% cases over 70 years; 73.9% males; 95.3% with cirrhosis); 63.0% were hepatitis C virus positive and 23.7% were virus negative. Amongst incident HCCs, 34.5% were single <= 3 cm and 54.4% met the Milan criteria; 61.6% were diagnosed during surveillance; virus negative patients showed the lowest rate of surveillance (51.0%). Surveillance was an independent predictor of detecting single HCCs <= 2 cm (O.R. = 5.4; 95% C.I. = 2.4-12.4) or HCCs meeting the Milan criteria (O.R. = 3.1; 95% C.I. = 1.9-5.2). Compared with an earlier Italian survey, there was a higher proportion of elderly subjects (P < 0.01), Child-Pugh class A cases (P < 0.01), of virus-negative patients (P < 0.01) and with single tumours <= 3 cm (P < 0.01) and a lower prevalence of hepatitis C virus positive individuals (P < 0.01). Conclusion: HCC is characterised by a growing prevalence of elderly patients and cases unrelated to hepatitis virus infections. The application of surveillance must be implemented, particularly amongst non-viral patients. (C) 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved

Prevalence and prognostic significance of the presence of esophageal varices in patients with hepatocellular carcinoma

BACKGROUND &#38; AIMS: It has been suggested that clinically relevant portal hypertension may affect the therapeutic management and prognosis of cirrhotic patients with hepatocellular carcinoma (HCC). Nevertheless, the importance of the presence of esophageal varices in these patients has not yet been addressed formally. In this study our aim was to evaluate the prevalence and prognostic relevance of the presence of esophageal varices in a large series of patients with HCC. METHODS: The prevalence of esophageal varices was evaluated in 1153 HCC patients who were consecutively referred to 10 Italian centers (the Italian Liver Cancer group). Survival was calculated from the time of HCC diagnosis until death or until the most recent follow-up visit, and was evaluated according to the presence or absence of esophageal varices. The independent prognostic meaning of the presence of esophageal varices was evaluated further in a multivariate regression analysis. RESULTS: Esophageal varices were found in 730 patients (63.3%). Patients with varices showed significantly shorter survival times (P < .0001) as compared with patients without varices. Death as a result of bleeding was more common in patients with varices (P = .0127). In multivariate analysis, the presence of esophageal varices was associated independently with poorer survival (adjusted relative risk, 1.25; 95% confidence interval, 1.06-1.48; P = .0095). CONCLUSIONS: More than half of the patients with HCC have esophageal varices. The presence of esophageal varices is associated with a higher risk of death from bleeding, and is an independent determinant of the patient's prognosis. This variable should be taken into account in the diagnostic and therapeutic work-up of HCC patients

Relative decrease in the role played by hepatitis B virus infection in the aetiology of hepatocellular carcinoma during a 20-year period: a multicentre Italian study

Abstract BACKGROUND: Chronic hepatitis B virus (HBV) infection is one of the most frequent aetiological factors associated with the development of hepatocellular carcinoma (HCC). AIM: This study evaluated the temporal trend in the aetiological role played by HBV infection alone in patients diagnosed with HCC during the last 20 years in Italy. METHODS: Among the 2042 HCC patients included in the Italian Liver Cancer (ITA.LI.CA.) database, 346 had chronic HBV infection alone. We assessed the proportion of HCC patients with HBV infection in four quinquennia (1987-1991, 1992-1996, 1997-2001, 2002-2006) and evaluated their main clinical, virological and oncological characteristics across these periods. RESULTS: Although the absolute number increased, the proportion of HBV-related HCC relatively decreased over time from 26.7% (47/176 patients) in 1987-1991 to 14.7% (127/862 patients) in 2002-2006 (P=0.0005). Patients' demographical, clinical and virological characteristics were similar across the four quinquennia. A greater proportion of patients was diagnosed with non-advanced HCC in more recent years (from 26% in 1987-1991 to 48% in 2002-2006, P=0.025), likely owing to a growing use of semiannual surveillance (from 63% in 1987-1991 to 80% in 2002-2006). CONCLUSIONS: We observed a significant, relative decrease in the role played by chronic HBV infection alone in the determinism of HCC during the last 20 years. In recent years, more patients are diagnosed with non-advanced HCC probably owing to improvements in HCC detection

Early and very early hepatocellular carcinoma: when and how much do staging and choice of treatment really matter? A multi-center study.

BACKGROUND: A consensus on the most reliable staging system for hepatocellular carcinoma (HCC) is still lacking but the most used is a revised Barcelona Clinic Liver Cancer (BCLC) system, adopted by the American Association for the Study of Liver Diseases (AASLD). We investigated how many patients are diagnosed in "very early" and "early" stage, follow the AASLD guidelines for treatment and whether their survival depends on treatment. METHODS: Data were collected in 530 "very early" and "early" HCC patients recruited by a multicentric Italian collaborative group (ITA.LI.CA). The Kaplan-Meier method was used to estimate overall survival and the log rank to test the statistical significance of difference between groups. Cox's multivariate stepwise regression analysis was used to pinpoint independent prognostic factors and the adjusted relative risks (hazard ratios) were calculated as well. A statistical analysis based on the chi-square test was used to identify significant differences in clinical or pathological features between patients. A P-value < 0.05 was considered statistically significant. RESULTS: "Very early" HCC were 3%; Cox multivariate analysis did not identify variables independently associated with survival. The patients following AASLD recommendations (20%) did not show longer survival. In "early" HCC patients (25%), treatment significantly modulated survival (p = 0.0001); the 28% patients treated according to the AASLD criteria survived longer (p = 0,004). The Cox analysis however identified only age, gender, number of lesions and Child class as independent predictors of survival. CONCLUSION: patients with very early" HCC were very few in this analysis. In most instances they were not treated with the treatment suggested as the most appropriate by the AASLD guidelines and the type of treatment had no impact on survival, even though the number of patients was relatively low and part of the patients were diagnosed before the introduction of the guidelines: this analysis, therefore, might not be considered as conclusive and should be validated. The "early" stage group involved more patients, rarely treated according to the guidelines, both overall and also in those diagnosed after their publication; the survival was in part predicted by the type of treatment, with better results in those treated according to AASLD indications

Effect of the etiology of viral cirrhosis on the survival of patients with hepatocellular carcinoma.

OBJECTIVES: The aim of this study was to assess whether hepatocellular carcinoma occurring in the setting of hepatitis B or C virus infection has different prognosis. METHODS: We performed a multicentric case-control study comparing 102 pairs of patients affected by hepatitis B virus- or hepatitis C virus-related hepatocellular carcinoma. Patients were matched for sex (male/female: 84/18 pairs), age, center, and period of enrollment, underlying chronic liver disease (cirrhosis/chronic hepatitis: 97/5 pairs), Child-Pugh class (A/B/C: 70/25/7 pairs), hepatocellular carcinoma stage (nonadvanced/advanced: 50/52 pairs) and, when possible, modality of cancer diagnosis (75 pairs: 47 during and 28 outside surveillance). RESULTS: In the whole population, patients with hepatitis B tended to have a poor prognosis than those with hepatitis C (p = 0.160), and this difference became statistically significant among the patients with an advanced hepatocellular carcinoma (p = 0.025). Etiology, Child-Pugh class, gross pathology, and alpha-fetoprotein were the significant independent prognostic factors in the whole population. The distribution of these prognostic factors did not differ between patients with hepatitis B or hepatitis C, both in the whole population and in the subgroup of advanced hepatocellular carcinomas. CONCLUSION: Hepatitis B virus-related hepatocellular carcinomas have a greater aggressiveness than hepatitis C virus-related tumors, which becomes clinically manifest once they have reached an advanced stage

Hepatocellular carcinoma in patients without cirrhosis in Italy.

BACKGROUND: In the Western world, hepatocellular carcinoma seldom develops in patients without cirrhosis, and reports describing the characteristics of non-cirrhotic patients with hepatocellular carcinoma are rather infrequent. METHODS: We evaluated the main clinical characteristics, treatment options, and survival of patients with hepatocellular carcinoma developed in non-cirrhotic liver among the 3027 consecutive cases of hepatocellular carcinoma accrued in the Italian Liver Cancer database during the last 20 years. RESULTS: We identified 52 patients with hepatocellular carcinoma in non-cirrhotic livers (1.7% of all hepatocellular carcinomas), 42 with (80.8%) and 10 without (19.2%) chronic liver disease. In patients without chronic liver disease, median tumour diameter was greater compared to patients with chronic liver disease (7.8 versus 4.0cm, P=0.046). Curative treatment was feasible in 20 patients (38.5%). Median overall survival was 26 months and 5-year survival rate was 23.7%. Detection of hepatocellular carcinoma outside surveillance (P=0.036), advanced hepatocellular carcinoma stage (P<0.0001), and non-curative treatment (P=0.007) were associated with worse prognosis, but tumour stage was the only independent predictor of survival. CONCLUSIONS: In Italy, less than 2% of hepatocellular carcinomas develop in a non-cirrhotic liver, and almost never in a normal liver. These patients frequently present with advanced tumours, have low eligibility rates for curative treatment, and have a dismal prognosis despite their preserved liver function

Semiannual and annual surveillance of cirrhotic patients for hepatocellular carcinoma: effects on cancer stage and patient survival (Italian experience)

OBJECTIVES: Surveillance of cirrhotic patients for early detection of hepatocellular carcinoma, based on ultrasonography and α1-fetoprotein determination, is a recommended practice. However, it has not been proved that this procedure can improve patient survival. METHODS: We conducted a multicenter retrospective study on 1051 consecutive patients with hepatocellular carcinoma. The criteria for eligibility were presence of underlying cirrhosis, and description of cancer stage and modalities of its diagnosis. Among 821 patients fulfilling these criteria, the tumor was detected during semiannual surveillance in 215 individuals (group 1), during annual surveillance in 155 (group 2), and as a result of symptoms or incidentally in 451 (group 3). Survival of patients under surveillance was corrected for lead time. RESULTS: Cancer stage was similar in groups 1 and 2 and was less advanced than in group 3 (p &lt; 0.001). The frequency of ablative treatments or chemoembolization was similar in groups 1 and 2 and was greater than in group 3 (p &lt; 0.001). Both surveillance programs doubled the prevalence of potential candidates for liver transplantation (68.5% and 62.5%) with respect to group 3 (32.3%, p &lt; 0.001). However, only 15 patients underwent transplantation. In groups 1 and 2, the 5-yr survival was equivalent and was greater than in group 3 (p &lt; 0.001). By segregating patients according to severity of cirrhosis, the benefit was confined to compensated cirrhosis (adjusted relative risk of death for patients under surveillance: 0.59 [95% CI = 0.450.78]). CONCLUSIONS: Semiannual and annual surveillance equally improve the survival of cirrhotic patients with hepatocellular carcinoma and greatly increase the amenability rate to liver transplantation. When access to liver transplantation is limited, this benefit is restricted to patients with a good cirrhosis-related prognosis. © 2002 by Am. Coll. of Gastroenterology