Hepatitis B virus surface antigen-negative and hepatitis C virus antibody-negative hepatocellular carcinoma: clinical characteristics, outcome, and risk factors for early and late intrahepatic recurrence after resection

Cancer. 2013 Jan 1;119(1):126-35. doi: 10.1002/cncr.27697. Epub 2012 Jun 26.


Background: Although the incidence of hepatitis B virus surface antigen (HBsAg)-negative/hepatitis C virus antibody (HCVAb)-negative hepatocellular carcinoma (NBNC-HCC) is gradually increasing, it has been mostly ignored in previous studies. The objective of this exploratory study was to investigate the clinicopathologic characteristics and prognostic factors that influence recurrence and survival in patients with NBNC-HCC.

Methods: A retrospective analysis was performed of 675 patients with NBNC-HCC and 3529 patients with HBsAg-positive/HCVAb-negative HCC (BNC-HCC) who underwent curative resection between 1997 and 2009. Intrahepatic recurrences were classified into early (≤1 year) and late (>1 year) recurrences. Multivariate competing risks analyses with Bonferroni correction were used to evaluate independent prognostic factors.

Results: There were no significant differences between the NBNC-HCC and BNC-HCC groups regarding overall survival, cumulative incidence of HCC-specific death, and recurrence. However, the patients with NBNC-HCC were much older (P < .001), were associated less often with cirrhosis or elevated α-fetoprotein levels (P < .001), and had a much lower ratio of men to women (P < .001). NBNC-HCC tumors were larger (P < .001), but were involved less often with vascular invasion (P = .004). Women, serum γ-glutamyl transpeptidase level, tumor size, tumor capsule, and tumor differentiation were identified as independent risk factors for HCC-specific survival in patients with NBNC-HCC. The cumulative incidence of HCC-specific death for women with NBNC-HCC was significantly greater than for men with NBNC-HCC (P < .001).Tumor capsule and vascular invasion were identified as independent risk factors for early recurrence of NBNC-HCC, whereas tumor differentiation was identified as the only significant risk factor for late recurrence.

Conclusions: Patients who had NBNC-HCC had characteristics and prognostic factors that differed from those in patients who had BNC-HCC. Women with NBNC-HCC should be more closely monitored, and it may be worthwhile to evaluate estrogen administration for the maintenance of sex hormone balance and to improve these poor outcomes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Hepatocellular / immunology
  • Carcinoma, Hepatocellular / mortality
  • Carcinoma, Hepatocellular / surgery
  • Carcinoma, Hepatocellular / virology*
  • Female
  • Hepatectomy
  • Hepatitis B Surface Antigens / analysis*
  • Hepatitis C Antibodies / analysis*
  • Humans
  • Liver Cirrhosis / complications
  • Liver Neoplasms / immunology
  • Liver Neoplasms / mortality
  • Liver Neoplasms / surgery
  • Liver Neoplasms / virology*
  • Male
  • Middle Aged
  • Neoplasm Recurrence, Local / immunology
  • Prognosis
  • Retrospective Studies
  • Risk Factors


  • Hepatitis B Surface Antigens
  • Hepatitis C Antibodies