Early Fibrosis but Late Tumor Stage and Worse Outcomes in Hepatocellular Carcinoma Patients Without Hepatitis B or Hepatitis C

Abstract

Background and Aims

The features of non-viral, nonalcohol hepatocellular carcinoma (NBNC-HCC) remain elusive. The aim of this study was to investigate this clinical characteristics and overall survival of NBNC-HCC compared to hepatitis B- (HBV-HCC) and hepatitis C-related (HCV-HCC) HCC.

Methods

We analyzed the etiologies, fibrosis stages, clinical data, and outcomes of newly diagnosed patients with HCC.

Results

A total of 1777 HCC patients were recruited, including 332 patients with NBNC-HCC, 682 patients with HBV-HCC, 680 patients with HCV-HCC, and 83 patients with HBV/HCV HCC. Patients with NBNC-HCC were older (69.9 ± 11.9 years). Patients with NBNC-HCC exhibited a higher prevalence of diabetes (43.9%) compared to the HBV-HCC (27.1%, p < 0.05) and HCV-HCC (30.2%, p < 0.05) groups. Compared to patients from the viral-related HCC groups, patients with NBNC-HCC exhibited a significantly lower fibrosis stage. NBNC-HCC patients exhibited a higher proportion of Barcelona Clinic Liver Cancer (BCLC) classification stage C and stage D compared to patients from the HBV-HCC and HCV-HCC groups. With a mean of 2.33 ± 2.31 years of follow-up, the median survival of patients with NBNC-HCC was 1.75 (95% CI 1.33–2.17) years, which was significantly lower than that of patients with HBV-HCC (p = 0.041) and HCV-HCC (p < 0.001).

Conclusions

Patients with NBNC-HCC have a higher risk of diabetes than patients with HCC of viral etiologies. Although patients with NBNC-HCC exhibited a milder fibrosis stage, their more advanced HCC stages and worse overall survival should be taken into consideration in clinical care.

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References

  1. 1.

    Nishikawa H, Osaki Y. Non-B, non-C hepatocellular carcinoma (Review). Intern J Oncol. 2013;43:1333–1342.

    CAS  Article  Google Scholar 

  2. 2.

    Cho EJ, Kwack MS, Jang ES, et al. Relative etiological role of prior hepatitis B virus infection and nonalcoholic fatty liver disease in the development of non-B non-C hepatocellular carcinoma in a hepatitis B-endemic area. Digestion. 2011;84:17–22.

    Article  Google Scholar 

  3. 3.

    Utsunomiya T, Shimada M. Molecular characteristics of non-cancerous liver tissue in non-B non-C hepatocellular carcinoma. Hepatol Res. 2011;41:711–721.

    Article  Google Scholar 

  4. 4.

    Lu SN, Su WW, Yang SS, et al. Secular trends and geographic variations of hepatitis B virus and hepatitis C virus-associated hepatocellular carcinoma in Taiwan. Intern J Cancer. 2006;119:1946–1952.

    CAS  Article  Google Scholar 

  5. 5.

    Kimura T, Kobayashi A, Tanaka N, et al. Clinicopathological characteristics of non-B non-C hepatocellular carcinoma without past hepatitis B virus infection. Hepatol Res. 2017;47:405–418.

    CAS  Article  Google Scholar 

  6. 6.

    Tateishi R, Okanoue T, Fujiwara N, et al. Clinical characteristics, treatment, and prognosis of non-B, non-C hepatocellular carcinoma: a large retrospective multicenter cohort study. J Gastroenterol. 2015;50:350–360.

    CAS  Article  Google Scholar 

  7. 7.

    Suzuki Y, Ohtake T, Nishiguchi S, et al. Survey of non-B, non-C liver cirrhosis in Japan. Hepatol Res. 2013;43:1020–1031.

    PubMed  Google Scholar 

  8. 8.

    Kim SK, Marusawa H, Eso Y, et al. Clinical characteristics of non-B non-C hepatocellular carcinoma: a single-center retrospective study. Digestion. 2011;84:43–49.

    Article  Google Scholar 

  9. 9.

    Nakagawa S, Wei L, Song WM, et al. Molecular liver cancer prevention in cirrhosis by organ transcriptome analysis and lysophosphatidic acid pathway inhibition. Cancer Cell. 2016;30:879–890.

    CAS  Article  Google Scholar 

  10. 10.

    Wakiyama S, Matsumoto M, Haruki K, et al. Clinical features and outcome of surgical patients with non-B non-C hepatocellular carcinoma. Anticancer Res. 2017;37:3207–3213.

    CAS  PubMed  Google Scholar 

  11. 11.

    Nishio T, Hatano E, Sakurai T, et al. Impact of hepatic steatosis on disease-free survival in patients with non-B non-C hepatocellular carcinoma undergoing hepatic resection. Ann Surg Oncol. 2015;22:2226–2234.

    Article  Google Scholar 

  12. 12.

    Imura S, Shimada M, Utsunomiya T, et al. Clinicopathological characteristics of patients with non-B non-C hepatocellular carcinoma: a special reference to metabolic syndrome. Hepato-gastroenterology. 2014;61:129–135.

    CAS  PubMed  Google Scholar 

  13. 13.

    Okuda Y, Mizuno S, Shiraishi T, et al. Clinicopathological factors affecting survival and recurrence after initial hepatectomy in non-B non-C hepatocellular carcinoma patients with comparison to hepatitis B or C virus. BioMed Res Intern. 2014;2014:975380.

    Article  Google Scholar 

  14. 14.

    Nishikawa H, Arimoto A, Wakasa T, Kita R, Kimura T, Osaki Y. Comparison of clinical characteristics and survival after surgery in patients with non-B and non-C hepatocellular carcinoma and hepatitis virus-related hepatocellular carcinoma. J Cancer. 2013;4:502–513.

    Article  Google Scholar 

  15. 15.

    Kaneda K, Kubo S, Tanaka H, et al. Features and outcome after liver resection for non-B non-C hepatocellular carcinoma. Hepato-gastroenterology. 2012;59:1889–1892.

    PubMed  Google Scholar 

  16. 16.

    Chang IC, Huang SF, Chen PJ, et al. The hepatitis viral status in patients with hepatocellular carcinoma: a study of 3843 patients from Taiwan liver cancer network. Medicine. 2016;95:e3284.

    CAS  Article  Google Scholar 

  17. 17.

    Yeh ML, Huang CI, Huang CF, et al. The impact of an additional extra-hepatic primary malignancy on the outcomes of patients with hepatocellular carcinoma. PLoS ONE. 2017;12:e0184878.

    Article  Google Scholar 

  18. 18.

    Kuo YH, Kee KM, Wang JH, et al. Association between chronic viral hepatitis and metabolic syndrome in southern Taiwan: a large population-based study. Aliment Pharmacol Ther. 2018;48:993–1002.

    CAS  Article  Google Scholar 

  19. 19.

    Kwak HW, Park JW, Koh YH, Lee JH, Yu A, Nam BH. Clinical characteristics of patients with cryptogenic hepatocellular carcinoma in a hepatitis B virus-endemic area. Liver Cancer. 2016;5:21–36.

    CAS  Article  Google Scholar 

  20. 20.

    Tokushige K, Hashimoto E, Horie Y, Taniai M, Higuchi S. Hepatocellular carcinoma in Japanese patients with nonalcoholic fatty liver disease, alcoholic liver disease, and chronic liver disease of unknown etiology: report of the nationwide survey. J Gastroenterol. 2011;46:1230–1237.

    Article  Google Scholar 

  21. 21.

    Nagaoki Y, Hyogo H, Aikata H, et al. Recent trend of clinical features in patients with hepatocellular carcinoma. Hepatol Res. 2012;42:368–375.

    CAS  Article  Google Scholar 

  22. 22.

    Chen CH, Huang GT, Yang PM, et al. Hepatitis B- and C-related hepatocellular carcinomas yield different clinical features and prognosis. Euro J Cancer. 2006;42:2524–2529.

    Article  Google Scholar 

  23. 23.

    Oh KC, Park SH, Park JC, et al. Is the prevalence of cryptogenic hepatocellular carcinoma increasing in Korea? Korean J Gastroenterol. 2005;45:45–51.

    PubMed  Google Scholar 

  24. 24.

    Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84.

    Article  Google Scholar 

  25. 25.

    Ma WL, Lai HC, Yeh S, Cai X, Chang C. Androgen receptor roles in hepatocellular carcinoma, fatty liver, cirrhosis and hepatitis. Endocr Relat Cancer. 2014;21:R165–R182.

    CAS  Article  Google Scholar 

  26. 26.

    Jun TW, Yeh ML, Yang JD, et al. More advanced disease and worse survival in cryptogenic compared to viral hepatocellular carcinoma. Liver Intern. 2018;38:895–902.

    Article  Google Scholar 

  27. 27.

    Karagozian R, Derdak Z, Baffy G. Obesity-associated mechanisms of hepatocarcinogenesis. Metabolism. 2014;63:607–617.

    CAS  Article  Google Scholar 

  28. 28.

    Mittal S, Sada YH, El-Serag HB, et al. Temporal trends of nonalcoholic fatty liver disease-related hepatocellular carcinoma in the veteran affairs population. Clin Gastroenterol Hepatol. 2015;13:594-601.e1.

    Article  Google Scholar 

  29. 29.

    Piscaglia F, Svegliati-Baroni G, Barchetti A, et al. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study. Hepatology. 2016;63:827–838.

    Article  Google Scholar 

  30. 30.

    Ohkura Y, Sasaki K, Matsuda M, Hashimoto M, Watanabe G. Long-term prognosis after resection of cryptogenic hepatocellular carcinoma. BMC Surg. 2015;15:115.

    Article  Google Scholar 

  31. 31.

    Takeishi K, Maeda T, Shirabe K, et al. Clinicopathologic features and outcomes of non-B, non-C hepatocellular carcinoma after hepatectomy. Ann Surg Oncol. 2015;22:S1116–S1124.

    Article  Google Scholar 

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Acknowledgments

This study was supported partly by grants from The Ministry of Science and Technology, Taiwan (MOST104-2314-B-037-078-MY3, 107-2314-B-037-082-MY3), and Kaohsiung Medical University Hospital (S10606, S10709, KMUH106-6R07). The authors thank secretary help from Taiwan Liver Research Foundation (TLRF). The foundation did not influence how the study was conducted or the approval of the manuscript. The authors also thank Dr. Tyng-Yuan Jang and Dr. Ta-Ya Lin for their active contribution in revising the manuscript.

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Correspondence to Jee-Fu Huang.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of Institutional Review Board of Kaohsiung Medical University Chung-Ho Memorial Hospital (IRB Number: KMUHIRB-E(II)-20180281) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Hsu, PY., Hsu, CT., Yeh, ML. et al. Early Fibrosis but Late Tumor Stage and Worse Outcomes in Hepatocellular Carcinoma Patients Without Hepatitis B or Hepatitis C. Dig Dis Sci 65, 2120–2129 (2020). https://doi.org/10.1007/s10620-019-05938-3

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Keywords

  • Hepatocellular carcinoma
  • Liver fibrosis
  • Cancer staging
  • Nonalcoholic fatty liver disease