title: Steatotic hepatocellular carcinoma: a variant associated with metabolic factors and late tumour relapse.
abstract: OBJECTIVE
  Steatosis in hepatocellular carcinoma (HCC) has been recognized for decades and found most commonly in small, well-differentiated HCC. However, the clinicopathological features and pathogenesis of HCC with steatosis is not well characterized. There are few data concerning whether HCC with steatosis should be regarded a distinct histological variant, steatotic HCC.
  
  
  RESULTS
  A retrospective cohort of 516 patients undergoing curative surgery for primary HCC was recruited. The median follow-up was 45.5 (range: 0.2-166.0) months. Steatotic HCC was defined as HCC with significant steatosis (≥5% of tumour cells). Associations with immunohistochemical expression of fatty acid binding protein-1 (FABP1), sonic hedgehog (SHH) and gene polymorphism of patatin-like phospholipase 3 (PNPLA3) were analysed. Steatotic HCC was found in 21.1% of patients and was associated with higher metabolic risks [diabetes mellitus (36.7% versus 18.2%) and hypertension (44.0% versus 28.7%)], underlying fatty liver (60.6% versus 37.8%), steatohepatitis (30.3% versus 13.0%), smaller tumour size, lower frequency of major vessel (1.8% versus 11.3%) and microvascular invasion (20.2% versus 32.4%), earlier tumour stages and lower serum alpha-fetoprotein. It was associated with developing late tumour relapse (hazard ratio 2.15, P = 0.002) independently of underlying cirrhosis and non-anatomical excision. Steatotic HCC did not differ from HCC without significant steatosis in immunohistochemical expression of FABP1 and SHH and PNPLA3 gene polymorphism.
  
  
  CONCLUSIONS
  Steatotic HCC is a common histological variant of HCC with distinct association with underlying fatty liver, steatohepatitis and metabolic risks. Despite more favourable baseline tumour features, it was associated with late tumour relapse.
authors.affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Anthony W H
authors.identifier: http://orcid.org/0000-0002-1771-163X
authors.initials: AW
authors.lastname: Chan
authors.affiliation: Department of Pathology, Peking Union Medical College Hospital, Beijing, China.
authors.forename: Shuangni
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Yau-Hei
authors.initials: YH
authors.lastname: Yu
authors.affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong.|Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.|Li Ka Shing Institute of Health Science, Sir Y. K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Joanna H M
authors.initials: JH
authors.lastname: Tong
authors.affiliation: Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Edith K Y
authors.initials: EK
authors.lastname: Tin
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Charing C N
authors.initials: CC
authors.lastname: Chong
authors.affiliation: Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.|Department of Clinical Oncology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Chan
authors.affiliation: Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.|Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Grace L H
authors.initials: GL
authors.lastname: Wong
authors.affiliation: Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.|Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Vincent W S
authors.initials: VW
authors.lastname: Wong
authors.affiliation: Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.|Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Henry L Y
authors.initials: HL
authors.lastname: Chan
authors.affiliation: Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.|Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Paul B S
authors.initials: PB
authors.lastname: Lai
authors.affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong.|Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.|Li Ka Shing Institute of Health Science, Sir Y. K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Ka-Fai
authors.initials: KF
authors.lastname: To
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D006528:Carcinoma, Hepatocellular / Q000150:complications / Q000401:mortality / Q000473:pathology*; D003920:Diabetes Mellitus / Q000453:epidemiology; D005234:Fatty Liver / Q000473:pathology*; D005260:Female; D006801:Humans; D006949:Hyperlipidemias / Q000453:epidemiology; D006973:Hypertension / Q000453:epidemiology; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008049:Lipase / Q000235:genetics; D008113:Liver Neoplasms / Q000150:complications / Q000401:mortality / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000401:mortality / Q000473:pathology; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D046888:Tissue Array Analysis; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D014408:Biomarkers, Tumor; D008049:Lipase; D008565:Membrane Proteins; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
keywords: fatty liver; hepatocellular carcinoma; relapse; steatohepatitis; steatosis