Introduction. Hepatocellular carcinoma is now known to arise in association with nonalcoholic steatohepatitis. The aim of this study is to examine the clinicopathological features of this entity using liver resection cases at a large Western center. Methods. We retrospectively reviewed all cases of partial liver resection for hepatocellular carcinoma over a 10-year period. We included for the purpose of this study patients with histological evidence of nonalcoholic steatohepatitis and excluded patients with other chronic liver diseases such as viral hepatitis and alcoholic liver disease. Results. We identified 9 cases in which malignancy developed against a parenchymal background of histologically-active nonalcoholic steatohepatitis. The median age at diagnosis was 58 (52–82) years, and 8 of the patients were male. Median body mass index was 30.2 (22.7–39.4)？kg/m2. Hypertension was present in 77.8% of the patients and diabetes mellitus, obesity, and hyperlipidemia in 66.7%, respectively. The background liver parenchyma was noncirrhotic in 44% of the cases. Average tumor diameter was 7 . 0 ± 4 . 8 ？cm. Three-fourths of the patients developed recurrence within two years of resection, and 5-year survival was 44%. Conclusion. Hepatocellular carcinoma may arise in the context of nonalcoholic steatohepatitis, often before cirrhosis has developed. Locally advanced tumors are typical, and long-term failure rate following resection is high. 1. Introduction Nonalcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the West today [1]. NAFLD is associated with the diseases of diabetes mellitus (DM) and obesity and has come to be considered a hepatic manifestation of the metabolic syndrome [2–4]. The most severe form of NAFLD is an inflammatory and fibrosing parenchymal lesion known as nonalcoholic steatohepatitis (NASH) [5]. NASH affects roughly 3% of adults in Western countries [1] and approximately 25–30% of the morbidly obese [6]. A subset of NASH patients will ultimately develop frank cirrhosis, with its potential end-points of liver failure and hepatocellular carcinoma (HCC) [7]. DM and obesity have each been shown to increase risk for liver cancer occurrence or liver cancer-related mortality in large-scale prospective cohort studies [8–11]. It is logical to assume that NASH is the connecting link between these metabolic diseases and liver malignancy. Surprisingly, however, few clinical studies have been devoted to investigating NASH-associated HCC [1, 12–14] (Table 1). Similarly, few surgical series have been published
References
[1]
J. Ertle, A. Dechêne, J. P. Sowa et al., “Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis,” International Journal of Cancer, vol. 128, no. 10, pp. 2436–2443, 2011.
[2]
G. Marchesini, M. Brizi, G. Blanchi et al., “Nonalcoholic fatty liver disease: a feature of the metabolic syndrome,” Diabetes, vol. 50, no. 8, pp. 1844–1850, 2001.
[3]
E. Bugianesi, N. Leone, E. Vanni et al., “Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma,” Gastroenterology, vol. 123, no. 1, pp. 134–140, 2002.
[4]
G. Marchesini, E. Bugianesi, G. Forlani et al., “Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome,” Hepatology, vol. 37, no. 4, pp. 917–923, 2003.
[5]
E. M. Brunt, C. G. Janney, A. M. Di Bisceglie, B. A. Neuschwander-Tetri, and B. R. Bacon, “Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions,” American Journal of Gastroenterology, vol. 94, no. 9, pp. 2467–2474, 1999.
[6]
S. H. Caldwell, D. M. Crespo, H. S. Kang, and A. M. S. Al-Osaimi, “Obesity and hepatocellular carcinoma,” Gastroenterology, vol. 127, pp. S97–S103, 2004.
[7]
M. S. Ascha, I. A. Hanouneh, R. Lopez, T. A. R. Tamimi, A. F. Feldstein, and N. N. Zein, “The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis,” Hepatology, vol. 51, no. 6, pp. 1972–1978, 2010.
[8]
E. E. Calle, C. Rodriguez, K. Walker-Thurmond, and M. J. Thun, “Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. Adults,” The New England Journal of Medicine, vol. 348, no. 17, pp. 1625–1638, 2003.
[9]
H. O. Adami, W. H. Chow, O. Nyrén et al., “Excess risk of primary liver cancer in patients with diabetes mellitus,” Journal of the National Cancer Institute, vol. 88, no. 20, pp. 1472–1477, 1996.
[10]
L. Wideroff, G. Gridley, L. Mellemkjaer et al., “Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in denmark,” Journal of the National Cancer Institute, vol. 89, no. 18, pp. 1360–1365, 1997.
[11]
H. B. El-Serag, T. Tran, and J. E. Everhart, “Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma,” Gastroenterology, vol. 126, no. 2, pp. 460–468, 2004.
[12]
M. Shimada, E. Hashimoto, M. Taniai et al., “Hepatocellular carcinoma in patients with non-alcoholic steatohepatitis,” Journal of Hepatology, vol. 37, no. 1, pp. 154–160, 2002.
[13]
A. L. Chagas, L. O. O. Kikuchi, C. P. M. S. Oliveira et al., “Does hepatocellular carcinoma in non-alcoholic steatohepatitis exist in cirrhotic and non-cirrhotic patients?” Brazilian Journal of Medical and Biological Research, vol. 42, no. 10, pp. 958–962, 2009.
[14]
E. Hashimoto, S. Yatsuji, M. Tobari et al., “Hepatocellular carcinoma in patients with nonalcoholic steatohepatitis,” Journal of Gastroenterology, vol. 44, no. 19, supplement, pp. 89–95, 2009.
[15]
H. Hashizume, K. Sato, H. Takagi et al., “Primary liver cancers with nonalcoholic steatohepatitis,” European Journal of Gastroenterology and Hepatology, vol. 19, no. 10, pp. 827–834, 2007.
[16]
N. Kawada, K. Imanaka, T. Kawaguchi et al., “Hepatocellular carcinoma arising from non-cirrhotic nonalcoholic steatohepatitis,” Journal of Gastroenterology, vol. 44, no. 12, pp. 1190–1194, 2009.
[17]
S. M. Malik, P. A. Gupte, M. E. de Vera, and J. Ahmad, “Liver transplantation in patients with nonalcoholic steatohepatitis-related hepatocellular carcinoma,” Clinical Gastroenterology and Hepatology, vol. 7, no. 7, pp. 800–806, 2009.
[18]
K. Tokushige, E. Hashimoto, S. Yatsuji et al., “Prospective study of hepatocellular carcinoma in nonalcoholic steatohepatitis in comparison with hepatocellular carcinoma caused by chronic hepatitis C,” Journal of Gastroenterology, vol. 45, no. 9, pp. 960–967, 2010.
[19]
Y. Takuma and K. Nouso, “Nonalcoholic steatohepatitis-associated hepatocellular carcinoma: our case series and literature review,” World Journal of Gastroenterology, vol. 16, no. 12, pp. 1436–1441, 2010.
[20]
World Health Organization, Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications, World Health Organization, Department of Noncommunicable Disease Surveillance, 1999.
[21]
J. I. Cleeman, “Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III),” Journal of the American Medical Association, vol. 285, no. 19, pp. 2486–2497, 2001.
[22]
N. Sattar, A. Gaw, O. Scherbakova et al., “Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study,” Circulation, vol. 108, no. 4, pp. 414–419, 2003.
[23]
J. Bruix, M. Sherman, J. M. Llovet et al., “Clinical management of hepatocellular carcinoma. Conclusions of the barcelona-2000 EASL conference,” Journal of Hepatology, vol. 35, no. 3, pp. 421–430, 2001.
[24]
H. A. Edmonson and P. E. Steiner, “Primary carcinoma of the liver: a study of 100 cases among 48,900,” Cancer, vol. 7, no. 3, pp. 462–503, 1954.
[25]
E. G. Giannini, E. Marabotto, V. Savarino et al., “Hepatocellular carcinoma in patients with cryptogenic cirrhosis,” Clinical Gastroenterology and Hepatology, vol. 7, no. 5, pp. 580–585, 2009.
[26]
B. Q. Starley, C. J. Calcagno, and S. A. Harrison, “Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection,” Hepatology, vol. 51, no. 5, pp. 1820–1832, 2010.
[27]
J. M. Regimbeau, M. Columbat, P. Mognol et al., “Obesity and diabetes as a risk factor for hepatocellular carcinoma,” Liver Transplantation, vol. 10, no. 2, pp. S69–S73, 2004.
[28]
V. Paradis, S. Zalisnski, E. Chelbi et al., “Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liverfibrosis: a pathological analysis,” Hepatology, vol. 49, no. 3, pp. 851–859, 2009.
[29]
Y. Komorizono, T. Shibatou, K. Sako, et al., “Cryptogenic hepatocellular carcinoma and nonalcoholic steatohepatitis: a review of ten Japanese cases [AASLD abstract 1221],” Hepatology, vol. 44, no. 4, supplement 1, pp. 644A–645A, 2006.
[30]
G. Guzman, E. M. Brunt, L. M. Petrovic, G. Chejfec, T. J. Layden, and S. J. Cotler, “Does nonalcoholic fatty liver disease predispose patients to hepatocellular carcinoma in the absence of cirrhosis?” Archives of Pathology and Laboratory Medicine, vol. 132, no. 11, pp. 1761–1766, 2008.
[31]
C. Weyer, R. L. Hanson, P. A. Tataranni, C. Bogardus, and R. E. Pratley, “A high fasting plasma insulin concentration predicts type 2 diabetes independent of insulin resistance: evidence for a pathogenic role of relative hyperinsulinemia,” Diabetes, vol. 49, no. 12, pp. 2094–2101, 2000.
[32]
K. Saito, S. Inoue, T. Saito et al., “Augmentation effect of postprandial hyperinsulinaemia on growth of human hepatocellular carcinoma,” Gut, vol. 51, no. 1, pp. 100–104, 2002.
[33]
J. A. Price, S. J. Kovach, T. Johnson et al., “Insulin-like growth factor I is a comitogen for hepatocyte growth factor in a rat model of hepatocellular carcinoma,” Hepatology, vol. 36, no. 5, pp. 1089–1097, 2002.
[34]
L. J. Marnett, “Oxyradicals and DNA damage,” Carcinogenesis, vol. 21, no. 3, pp. 361–370, 2000.
[35]
W. Hu, Z. Feng, J. Eveleigh et al., “The major lipid peroxidation product, trans-4-hydroxy-2-nonenal, preferentially forms DNA adducts at codon 249 of human p53 gene, a unique mutational hotspot in hepatocellular carcinoma,” Carcinogenesis, vol. 23, no. 11, pp. 1781–1789, 2002.
[36]
S. Yang, H. Z. Lin, J. Hwang, V. P. Chacko, and A. M. Diehl, “Hepatic hyperplasia in noncirrhotic fatty livers: is obesity-related hepatic steatosis a premalignant condition?” Cancer Research, vol. 61, no. 13, pp. 5016–5023, 2001.
[37]
T. Roskams, S. Q. Yang, A. Koteish et al., “Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease,” American Journal of Pathology, vol. 163, no. 4, pp. 1301–1311, 2003.
[38]
A. Sánchez, V. M. Factor, I. S. Schroeder, P. Nagy, and S. S. Thorgeirsson, “Activation of NF-κB and STAT3 in rat oval cells during 2-acetylaminofluorene/partial hepatectomy-induced liver regeneration,” Hepatology, vol. 39, no. 2, pp. 376–385, 2004.
