Risk of recurrence in hepatitis B-related hepatocellular carcinoma: Impact of viral load in late recurrence
Authors: Yujin Hoshida
Journal: Journal of Hepatology (2009)

Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinomaJournal of HepatologyVol. 51Issue 5PreviewHepatitis B virus (HBV) levels correlate with the development of hepatocellular carcinoma (HCC), but the role of viral load in HCC recurrence after tumor resection remains unclear. Herein we aimed to investigate the role of viral load in HCC recurrence following tumor resection. Full-Text PDF Hepatocellular carcinoma (HCC) is a highly prevalent and lethal cancer type being the third leading cause of cancer-related death worldwide [[1]Llovet J.M. Burroughs A. Bruix J. Hepatocellular carcinoma.Lancet. 2003; 362: 1907-1917Abstract Full Text Full Text PDF PubMed Scopus (3858) Google Scholar]. More than 80% of cases occur in developing countries particularly in Eastern Asia and sub-Saharan Africa mainly due to chronic infection with hepatitis B virus (HBV) [1Llovet J.M. Burroughs A. Bruix J. Hepatocellular carcinoma.Lancet. 2003; 362: 1907-1917Abstract Full Text Full Text PDF PubMed Scopus (3858) Google Scholar, 2El-Serag H.B. Rudolph K.L. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.Gastroenterology. 2007; 132: 2557-2576Abstract Full Text Full Text PDF PubMed Scopus (4616) Google Scholar]. Hence, HBV is the most common cause of HCC in the world. Although population-based universal infant vaccination is shown to be effective in preventing new neonatal HBV infection and related HCC [[3]Chang M.H. Shau W.Y. Chen C.J. et al.Hepatitis B vaccination and hepatocellular carcinoma rates in boys and girls.Jama. 2000; 284: 3040-3042Crossref PubMed Scopus (181) Google Scholar], there are still over 350 million individuals with chronic infection, and the prevalence reaches 10–20% of the population in the endemic areas. Once chronic infection is established, complete eradication of the virus is still not possible, and these patients are facing the risk of HCC development [[4]Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22,707 men in Taiwan. Lancet 1981;2:1129–1133.Google Scholar]. HCC usually develops on a background of chronic liver damage, i.e., sustained hepatic inflammation, regeneration, and fibrogenesis, owing to hepatitis virus infection, alcohol abuse, metabolic disorders, or exposure to environmental carcinogens [[2]El-Serag H.B. Rudolph K.L. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.Gastroenterology. 2007; 132: 2557-2576Abstract Full Text Full Text PDF PubMed Scopus (4616) Google Scholar]. In fact, cirrhosis is observed in 80% of HCC patients. These risk factors are thought to indirectly promote HCC development by generating a carcinogenic microenvironment in the liver, known as the “field effect”, which is assumed to cause accumulated genetic hits inducing cellular transformation [[2]El-Serag H.B. Rudolph K.L. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.Gastroenterology. 2007; 132: 2557-2576Abstract Full Text Full Text PDF PubMed Scopus (4616) Google Scholar]. However, in contrast to hepatitis C and other risk factors, it is known that HBV-related HCC is less associated with the presence of cirrhosis, and this trend becomes more obvious in younger patients whose duration of infection is not long enough to develop full-blown cirrhosis [1Llovet J.M. Burroughs A. Bruix J. Hepatocellular carcinoma.Lancet. 2003; 362: 1907-1917Abstract Full Text Full Text PDF PubMed Scopus (3858) Google Scholar, 2El-Serag H.B. Rudolph K.L. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.Gastroenterology. 2007; 132: 2557-2576Abstract Full Text Full Text PDF PubMed Scopus (4616) Google Scholar, 5Di Bisceglie A.M. Hepatitis B and hepatocellular carcinoma.Hepatology. 2009; 49: S56-S60Crossref PubMed Scopus (244) Google Scholar]. This observation has prompted the suggestion that HBV itself has direct carcinogenic potential, and studies have shown that HBV might directly activate oncogenic signaling: cis-activation through integration of viral genetic material into host cellular genomic DNA and trans-activation by viral products such as HBx protein [2El-Serag H.B. Rudolph K.L. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.Gastroenterology. 2007; 132: 2557-2576Abstract Full Text Full Text PDF PubMed Scopus (4616) Google Scholar, 5Di Bisceglie A.M. Hepatitis B and hepatocellular carcinoma.Hepatology. 2009; 49: S56-S60Crossref PubMed Scopus (244) Google Scholar, 6Kremsdorf D. Soussan P. Paterlini-Brechot P. Brechot C. Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis.Oncogene. 2006; 25: 3823-3833Crossref PubMed Scopus (239) Google Scholar, 7Chan H.L. Sung J.J. Hepatocellular carcinoma and hepatitis B virus.Semin Liver Dis. 2006; 26: 153-161Crossref PubMed Scopus (196) Google Scholar]. Other lines of evidence suggest that increased risk of HCC is associated with certain HBV genotypes, e.g., genotype C in Asian population [8Chan H.L. Tse C.H. Mo F. et al.High viral load and hepatitis B virus subgenotype ce are associated with increased risk of hepatocellular carcinoma.J Clin Oncol. 2008; 26: 177-182Crossref PubMed Scopus (265) Google Scholar, 9Yang H.I. Yeh S.H. Chen P.J. et al.Associations between hepatitis B virus genotype and mutants and the risk of hepatocellular carcinoma.J Natl Cancer Inst. 2008; 100: 1134-1143Crossref PubMed Scopus (514) Google Scholar] and genotype F in the Alaskan population [[10]Livingston S.E. Simonetti J.P. McMahon B.J. et al.Hepatitis B virus genotypes in Alaska Native people with hepatocellular carcinoma: preponderance of genotype F.J Infect Dis. 2007; 195: 5-11Crossref PubMed Scopus (217) Google Scholar]. In addition, precore and basal core promoter mutations in the HBV genome have been reported as risk factors of HCC development [9Yang H.I. Yeh S.H. Chen P.J. et al.Associations between hepatitis B virus genotype and mutants and the risk of hepatocellular carcinoma.J Natl Cancer Inst. 2008; 100: 1134-1143Crossref PubMed Scopus (514) Google Scholar, 11Llovet J.M. Lok A. Hepatitis B virus genotype and mutants: risk factors for hepatocellular carcinoma.J Natl Cancer Inst. 2008; 100: 1121-1123Crossref PubMed Scopus (15) Google Scholar, 12Baptista M. Kramvis A. Kew M.C. High prevalence of 1762(T) 1764(A) mutations in the basic core promoter of hepatitis B virus isolated from black Africans with hepatocellular carcinoma compared with asymptomatic carriers.Hepatology. 1999; 29: 946-9353Crossref PubMed Scopus (237) Google Scholar, 13Kao J.H. Chen P.J. Lai M.Y. Chen D.S. Basal core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers.Gastroenterology. 2003; 124: 327-334Abstract Full Text PDF PubMed Scopus (485) Google Scholar]. These findings suggest that there is a certain variation in the carcinogenic potential according to the viral strains. Consistent with the hypothesis of direct carcinogenic effect of HBV, accumulating evidence has shown that a high serum HBV DNA level, indicative of increased viral replication, is a risk factor for de novo HCC development in HBV carriers irrespective of hepatitis activity [14Chen G. Lin W. Shen F. Iloeje U.H. London W.T. Evans A.A. Past HBV viral load as predictor of mortality and morbidity from HCC and chronic liver disease in a prospective study.Am J Gastroenterol. 2006; 101: 1797-1803Crossref PubMed Scopus (234) Google Scholar, 15Chen C.J. Yang H.I. Su J. et al.Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.JAMA. 2006; 295: 65-73Crossref PubMed Scopus (2643) Google Scholar, 16Sherman M. Risk of hepatocellular carcinoma in hepatitis B and prevention through treatment.Cleve Clin J Med. 2009; 76: S6-S9Crossref PubMed Scopus (42) Google Scholar]. In addition, a recent study suggested that prolonged suppression of HBV replication with nucleoside or nucleotide analogs may reduce the risk of HBV-related HCC development [[17]Liaw Y.F. Sung J.J. Chow W.C. et al.Lamivudine for patients with chronic hepatitis B and advanced liver disease.N Engl J Med. 2004; 351: 1521-1531Crossref PubMed Scopus (2044) Google Scholar], suggesting that antiviral treatment is a promising strategy to prevent hepatocarcinogenesis. Localized HCC tumors can be subjected to potentially curative treatments such as surgical resection and percutaneous ablation. However, even after such radical therapies, more than 70% of patients have recurrence at 5 years, which still limits survival of the patients [[1]Llovet J.M. Burroughs A. Bruix J. Hepatocellular carcinoma.Lancet. 2003; 362: 1907-1917Abstract Full Text Full Text PDF PubMed Scopus (3858) Google Scholar]. It is known that there are two distinct types of HCC recurrence: tumors grown from dissemination of the primary tumor and de novo tumors arising from the “field effect” in diseased liver [1Llovet J.M. Burroughs A. Bruix J. Hepatocellular carcinoma.Lancet. 2003; 362: 1907-1917Abstract Full Text Full Text PDF PubMed Scopus (3858) Google Scholar, 18Bruix J. Sherman M. Management of hepatocellular carcinoma.Hepatology. 2005; 42: 1208-1236Crossref PubMed Scopus (5208) Google Scholar, 19Sherman M. Recurrence of hepatocellular carcinoma.N Engl J Med. 2008; 359: 2045-2047Crossref PubMed Scopus (179) Google Scholar, 20Llovet J.M. Schwartz M. Mazzaferro V. Resection and liver transplantation for hepatocellular carcinoma.Semin Liver Dis. 2005; 25: 181-200Crossref PubMed Scopus (774) Google Scholar]. That is, the latter is clonally independent from the primary tumor. Discrimination of these types of recurrence is clinically important because the biological basis producing each recurrence is different and the following therapeutic intervention should be considered accordingly [[21]Hoshida Y. Villanueva A. Llovet J.M. Molecular profiling to predict hepatocellular carcinoma outcome.Expert Rev Gastroenterol Hepatol. 2009; 3: 101-103Crossref PubMed Scopus (32) Google Scholar]. However, it is difficult to examine the clonal difference from a practical point of view in the clinical setting because of the lack of reliable and clinically applicable markers. Imamura et al. proposed a convenient framework to clinically differentiate each type of recurrence as “early” or “late” recurrence based on a cut-off of 2 years after surgery [[22]Imamura H. Matsuyama Y. Tanaka E. et al.Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy.J Hepatol. 2003; 38: 200-207Abstract Full Text Full Text PDF PubMed Scopus (1234) Google Scholar]. This framework has made it possible to assess risk factors for each type of recurrence [18Bruix J. Sherman M. Management of hepatocellular carcinoma.Hepatology. 2005; 42: 1208-1236Crossref PubMed Scopus (5208) Google Scholar, 23Hoshida Y. Villanueva A. Kobayashi M. et al.Gene expression in fixed tissues and outcome in hepatocellular carcinoma.N Engl J Med. 2008; 359: 1995-2004Crossref PubMed Scopus (1063) Google Scholar]. Early recurrence, which appears within 2 years after surgery, is associated with tumor-related factors including the presence of vascular invasion and additional tumor sites besides the primary lesion (satellite lesion), which is consistent with the notion that this type of recurrence is tumor dissemination as a consequence of malignant characteristic of the primary tumor. On the other hand, late recurrence, which appears more than 2 years after surgery, is considered to be associated with the severity of hepatic inflammation and liver damage closely linked to the “field effect”. With the successful implementation of HCC surveillance programs, increasing number of HCC tumors are diagnosed at an early stage, where the tumor has less likelihood of dissemination and thus removed more effectively without residual tumor cells [[24]Llovet J.M. Bruix J. Novel advancements in the management of hepatocellular carcinoma in 2008.J Hepatol. 2008; 48: S20-S37Abstract Full Text Full Text PDF PubMed Scopus (796) Google Scholar]. This means that more patients avoid the risk of early recurrence and thus survive longer enough to acquire late recurrence. This shift of recurrence pattern highlights increasing necessity to focus on late recurrence, which cannot be treated with early detection and resection of the primary tumor. In theory, late recurrence is assumed to arise from the same biology associated with the initial HCC development in cirrhosis [[19]Sherman M. Recurrence of hepatocellular carcinoma.N Engl J Med. 2008; 359: 2045-2047Crossref PubMed Scopus (179) Google Scholar], and thus in HBV-related HCC, both of the direct carcinogenic effect of HBV and the “field effect” are assumed to be responsible for late recurrence. Recently, Kim et al. reported that persistent viremia is associated with disease-free survival after 12 months of surgery, suggesting its association with late recurrence [[25]Kim B.K. Park J.Y. Kim do Y. et al.Persistent hepatitis B viral replication affects recurrence of hepatocellular carcinoma after curative resection.Liver Int. 2008; 28: 393-401Crossref PubMed Scopus (110) Google Scholar]. In this issue of the Journal, Wu et al. evaluated clinical variables together with HBV-related factors including viral load, genotype, and recurrent mutations, for their prognostic implication with respect to early and late recurrence in 193 HBV-related HCC patients [[26]Wu J.-C. Huang Y.-H. Chau G.-Y. Su C.-W. Lai C.-R. Lee P.-C. et al.Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma.J Hepatol. 2009; 51: 890-897Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar]. During the median follow-up of 5 years, 134 patients (69%) had HCC recurrence, which is comparable to the figures in the literature [[18]Bruix J. Sherman M. Management of hepatocellular carcinoma.Hepatology. 2005; 42: 1208-1236Crossref PubMed Scopus (5208) Google Scholar]. Consistent with the notion of the pattern of HCC recurrence, the study clearly showed that tumor-related factors (microvascular invasion, positive cut margin, and high serum AFP level) were associated with the risk of early recurrence, whereas liver inflammation/damage-related factors (histological inflammation and ICG-15 retention rate) were independently associated with the risk of late recurrence [[26]Wu J.-C. Huang Y.-H. Chau G.-Y. Su C.-W. Lai C.-R. Lee P.-C. et al.Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma.J Hepatol. 2009; 51: 890-897Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar]. Of note, high HBV viral load was found to be associated with the risk of late, but not early, recurrence. The frequency of genotype C in HCC patients was higher compared to HBV carriers and correlated with high HBV viral load and more severe histological inflammation, consistent with previous observations [8Chan H.L. Tse C.H. Mo F. et al.High viral load and hepatitis B virus subgenotype ce are associated with increased risk of hepatocellular carcinoma.J Clin Oncol. 2008; 26: 177-182Crossref PubMed Scopus (265) Google Scholar, 9Yang H.I. Yeh S.H. Chen P.J. et al.Associations between hepatitis B virus genotype and mutants and the risk of hepatocellular carcinoma.J Natl Cancer Inst. 2008; 100: 1134-1143Crossref PubMed Scopus (514) Google Scholar]. The recurrent mutations were also correlated with genotype C to some extent. However, the viral load was the only significant variable independently associated with late recurrence, probably because the high HBV DNA level is the most functional measure reflecting the exposure to the direct carcinogenic effect of HBV. In the multivariate analysis, tumor multinodularity appeared to be associated with both early and late recurrences, which assumingly indicates the presence of satellite tumors due to the dissemination as well as the “field effect”-related multicentric metachronous tumors. In conclusion, these findings confirmed that late recurrence mostly corresponds to de novo carcinogenesis associated with HBV viremia as well as the “field effect” in HBV-related HCC. This may support prioritized use of anti-HBV treatment as adjuvant therapy after the resection or ablation of HCC for the patients with a high HBV DNA level to prevent late recurrence. This scenario may prompt the design of more powered clinical trials compared to the setting of chemoprevention targeting cirrhosis to prevent initial HCC development, given that the incidence rate of recurrence is higher than that of initial HCC development [[27]Ikeda K. Arase Y. Kobayashi M. et al.Significance of multicentric cancer recurrence after potentially curative ablation of hepatocellular carcinoma: a longterm cohort study of 892 patients with viral cirrhosis.J Gastroenterol. 2003; 38: 865-876Crossref PubMed Scopus (40) Google Scholar]. Furthermore, investigation of the molecular mechanism of the direct carcinogenic effect of HBV may help clarify additional therapeutic targets in terms of HCC prevention. Currently available evidence, mostly obtained from PCR-based assays with limited scale, have identified a handful of the genomic integrations potentially affecting function of genes, e.g., cyclin A and telomerase reverse transcriptase, in a sporadic manner [6Kremsdorf D. Soussan P. Paterlini-Brechot P. Brechot C. Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis.Oncogene. 2006; 25: 3823-3833Crossref PubMed Scopus (239) Google Scholar, 7Chan H.L. Sung J.J. Hepatocellular carcinoma and hepatitis B virus.Semin Liver Dis. 2006; 26: 153-161Crossref PubMed Scopus (196) Google Scholar]. Recently emerging genomics technology like high-throughput sequencing [28Maher C.A. Kumar-Sinha C. Cao X. et al.Transcriptome sequencing to detect gene fusions in cancer.Nature. 2009; 458: 97-101Crossref PubMed Scopus (707) Google Scholar, 29Gnirke A. Melnikov A. Maguire J. et al.Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing.Nat Biotechnol. 2009; 27: 182-189Crossref PubMed Scopus (1071) Google Scholar] may provide a more comprehensive view of critical recurrent oncogenic integration events. Combination of the new sequencing assay with chromatin immunoprecipitation (ChIP-Seq) [[30]Mikkelsen T.S. Ku M. Jaffe D.B. et al.Genome-wide maps of chromatin state in pluripotent and lineage-committed cells.Nature. 2007; 448: 553-560Crossref PubMed Scopus (3316) Google Scholar], may help to identify oncogenic transactivation by HBV proteins to obtain complementary information of the direct carcinogenic effect caused by HBV.