title: Characterization of hepatocellular carcinoma (HCC) in non-alcoholic fatty liver disease (NAFLD) patients without cirrhosis.
abstract: BACKGROUND
  The incidence of hepatocellular carcinoma (HCC) has increased significantly in United States over the last few decades in parallel with the epidemic of nonalcoholic fatty liver disease (NAFLD). Limited data suggests that HCC could arise in steatotic liver without the presence of cirrhosis. The present study was conducted to characterize patients with NAFLD presenting with HCC in non-cirrhotic liver (NCL) compared to the NAFLD- HCC patients in association with cirrhotic liver (CL).
  
  
  METHODS
  A retrospective analysis of all patients diagnosed with HCC and NAFLD diagnosis seen at our institution between 2003 and 2012 was done. The patients were characterized based on demographic and clinical variables as well as histological and tumor features. Comparisons between the NCL and CL groups were done using analysis of variance (ANOVA) or the non-parametric Kruskal-Wallis tests and Pearson's chi-square tests or Fisher's Exact tests as appropriate. P value of <0.05 was considered statistically significant.
  
  
  RESULTS
  Thirty-six patients with NAFLD and HCC in NCL (HCC-NCL group) were identified and compared to 47 patients with NAFLD-HCC and Liver Cirrhosis (HCC-LC group). Liver fibrosis was not present in 55.9 % of patients in the HCC-NCL group (F0), stage 1 was present in 17.6 %, stage 2 in 8.8 % and stage 3 in 17.6 %. Lobular inflammation was present in 63.6 % of non-cirrhotic patients. Patients in the HCC-NCL were older (67.5 ± 12.3 vs. 62.7 ± 8.1 years), and less likely to be obese (52 % vs. 83 %) or have type 2 diabetes (38 % vs. 83 %), with p value <0.05 for all. More importantly, compared with the HCC-CL group, those in the HCC-NCL group were more likely to present with a single nodule (80.6 % vs. 52.2 %), larger nodule size (>5 cm) (77.8 % vs. 10.6 %), and receive hepatic resection as the modality of HCC treatment (66.7 % vs. 17 %); and were less likely to receive loco-regional therapy (22.3 % vs. 61.7 %) or orthotopic liver transplantation (OLT) (0 % vs. 72.3 %), with p value <0.001 for all. Furthermore, 86 % of patients without cirrhosis had HCC recurrence compared to only 14 % in patients with cirrhosis (p < 0.001). Unadjusted analysis indicates that non-cirrhotics had worse survival with mortality rate of 47 % vs. 28 % in CL group (p = 0.03); however this difference in survival between two groups was not significant after adjusting for age or OLT (p > 0.05).
  
  
  CONCLUSIONS
  Patients with HCC in the absence of liver cirrhosis are more likely to present at an older age with larger tumor and have higher rates of tumor recurrence. Studies to assess the cost-effectiveness of HCC surveillance in this group should be conducted.
authors.affiliation: Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
authors.forename: Bashar
authors.initials: B
authors.lastname: Mohamad
authors.affiliation: Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
authors.forename: Vaishal
authors.initials: V
authors.lastname: Shah
authors.affiliation: Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
authors.forename: Mykola
authors.initials: M
authors.lastname: Onyshchenko
authors.affiliation: Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Elshamy
authors.affiliation: Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
authors.forename: Federico
authors.initials: F
authors.lastname: Aucejo
authors.affiliation: Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Rocio
authors.initials: R
authors.lastname: Lopez
authors.affiliation: Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
authors.forename: Ibrahim A
authors.initials: IA
authors.lastname: Hanouneh
authors.affiliation: Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
authors.forename: Razan
authors.initials: R
authors.lastname: Alhaddad
authors.affiliation: Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195, USA. alkhoun@ccf.org.
authors.forename: Naim
authors.initials: N
authors.lastname: Alkhouri
mesh_terms: D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000473:pathology*; D008113:Liver Neoplasms / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000473:pathology; D065626:Non-alcoholic Fatty Liver Disease / Q000473:pathology*; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D016019:Survival Analysis
keywords: Non-alcoholic fatty liver disease; Non-cirrhotic non-alcoholic fatty liver disease; Primary hepatocellular carcinoma