title: Pure and mixed fibrolamellar hepatocellular carcinomas differ in natural history and prognosis after complete surgical resection.
abstract: BACKGROUND
  The purpose of the current study was to describe pure and mixed fibrolamellar hepatocellular carcinoma (FL-HCC).
  
  
  METHODS
  Consecutive patients with pure and mixed FL-HCC were identified from a central pathological review using Edmondson's criteria. Clinical, pathological, and epigenetic characteristics of patients who underwent curative surgery were evaluated. Overall and disease-free survival as well as patterns of disease recurrence were examined. Methylation levels of L1 retrotransposon (LINE-1) repetitive elements and Ras association domain family 1A gene (RASSF1) promoter were also assessed using pyrosequencing.
  
  
  RESULTS
  Forty of 53 patients with a median age of 22 years (range, 9 years-;65 years) met the criteria for analysis. Central pathological review found that 30 patients (75%) had pure and 10 patients (25%) had mixed FL-HCC. Pure FL-HCC typically occurred in patients aged < 30 years. These patients often presented with lymph node metastasis at the time of diagnosis and frequently experienced extrahepatic recurrences (n = 16). Conversely, mixed FL-HCC appeared to resemble to classic HCC, occurring in patients aged > 40 years and frequently involving the liver as the primary site of disease recurrence. With a median follow-up of 7.8 years, the median overall survival from the time of diagnosis in all patients was 6.4 years (range, 3.2 years-12 years). Multivariate analysis found that the risk of death was increased in patients with higher American Joint Committee on Cancer disease stages (P = .003) and those with mixed FL-HCC (P = .03). Methylation analysis of LINE-1 repetitive elements and RASSF1 promoter revealed different methylation levels between pure and mixed FL-HCC, suggesting a different epigenetic background.
  
  
  CONCLUSIONS
  Pure and mixed FL-HCC display distinct clinical presentations and epigenetic backgrounds leading to different prognoses and as such may be regarded as separate clinical entities.
authors.affiliation: Department of Medical Oncology, Beaujon University Hospital, Clichy, France.
authors.forename: Gabriel G
authors.initials: GG
authors.lastname: Malouf
authors.forename: Laurence
authors.initials: L
authors.lastname: Brugières
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Le Deley
authors.forename: Sandrine
authors.initials: S
authors.lastname: Faivre
authors.forename: Monique
authors.initials: M
authors.lastname: Fabre
authors.forename: Valérie
authors.initials: V
authors.lastname: Paradis
authors.forename: Isabelle
authors.initials: I
authors.lastname: Aerts
authors.forename: Christophe
authors.initials: C
authors.lastname: Le Tourneau
authors.forename: Chantal
authors.initials: C
authors.lastname: Dreyer
authors.forename: Sophie
authors.initials: S
authors.lastname: Branchereau
authors.forename: Jacques
authors.initials: J
authors.lastname: Belghiti
authors.forename: Eric
authors.initials: E
authors.lastname: Raymond
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D002648:Child; D019175:DNA Methylation; D018572:Disease-Free Survival; D005260:Female; D006498:Hepatectomy; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012008:Recurrence; D016896:Treatment Outcome; D055815:Young Adult