Skip to main content

Recurrence Patterns and Prognostic Factors in Patients with Hepatocellular Carcinoma in Noncirrhotic Liver: A Multi-Institutional Analysis

Annals of Surgical Oncology volume 21, pages 147–154 (2014)Cite this article

Abstract

Background

Hepatocellular carcinoma (HCC) primarily affects patients with a cirrhotic liver. Reports on the characteristics of patients with HCC in noncirrhotic liver, as well as predictors of recurrence and survival, are scarce.

Methods

Between 1992 and 2011, 334 patients treated for HCC in noncirrhotic liver were identified from three major hepatobiliary centers. Clinicopathological characteristics were analyzed and independent predictors of recurrence and overall survival were identified using Cox proportional hazards models.

Results

Median patient age was 58 years and 77 % were male. Most patients had a solitary (81 %) and poorly or undifferentiated tumor (56 %); median size was 6.5 cm. The majority of patients (96 %) underwent liver resection (microscopically negative margins in 94 %), whereas a few had transarterial chemoembolization or transplantation (4 %). Median recurrence-free survival (RFS) was 2.5 years, and 1- and 5-year RFS was 71.1, and 35 %, respectively. Elevated alkaline phosphatase levels [hazards ratio (HR) = 1.82], poor tumor differentiation (HR = 1.4), macrovascular invasion (HR = 2.18), and the presence of satellite lesions (HR = 1.9), or intrahepatic metastases (HR = 2.59) were independently associated with shorter RFS; in contrast, an intact tumor capsule independently prolonged RFS (HR = 0.46). Median overall survival was 5.9 years, and 1- and 5-year overall survival was 86.9, and 54.5 %, respectively. Tumor size ≥5 cm (HR = 2.27), macrovascular (HR = 2.72) or adjacent organ invasion (HR = 3.34), and satellite lesions (HR = 2.18) were independently associated with shorter overall survival, whereas an intact tumor capsule showed a protective effect (HR = 0.51).

Conclusions

Following resection of HCC in the setting of no cirrhosis, more than one-half of patients were alive after 5 years. However, even among patients with no cirrhosis, recurrence was common. Factors associated with RFS and overall survival included tumor characteristics, such as tumor capsule, satellite lesions, and vascular invasion.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.

    PubMed  Article  Google Scholar 

  2. Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 2006;45(4):529–38.

    PubMed  Article  Google Scholar 

  3. Bosetti C, Levi F, Boffetta P, Lucchini F, Negri E, La Vecchia C. Trends in mortality from hepatocellular carcinoma in Europe, 1980–2004. Hepatology. 2008;48(1):137–45.

    PubMed  Article  Google Scholar 

  4. Cabibbo G, Craxi A. Hepatocellular cancer: optimal strategies for screening and surveillance. Dig Dis. 2009;27(2):142–7.

    PubMed  Article  Google Scholar 

  5. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334(11):693–9.

    CAS  PubMed  Article  Google Scholar 

  6. Alkofer B, Lepennec V, Chiche L. Hepatocellular cancer in the non-cirrhotic liver. J Visc Surg. 2011;148(1):3-11.

    CAS  PubMed  Article  Google Scholar 

  7. Trevisani F, Frigerio M, Santi V, Grignaschi A, Bernardi M. Hepatocellular carcinoma in non-cirrhotic liver: a reappraisal. Dig Liver Dis. 2010;42(5):341–7.

    PubMed  Article  Google Scholar 

  8. Mayo SC, Shore AD, Nathan H, et al. Refining the definition of perioperative mortality following hepatectomy using death within 90 days as the standard criterion. HPB (Oxford). 2011;13(7):473–82.

    PubMed Central  PubMed  Article  Google Scholar 

  9. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240(2):205–13.

    PubMed  Article  Google Scholar 

  10. Tretiakova MS, Shabani-Rad MT, Guggisberg K, Hart J, Anders RA, Gao ZH. Genomic and immunophenotypical differences between hepatocellular carcinoma with and without cirrhosis. Histopathology. 2010;56(6):683–93.

    PubMed  Article  Google Scholar 

  11. Tannapfel A, Wittekind C. Genes involved in hepatocellular carcinoma: deregulation in cell cycling and apoptosis. Virchows Arch. 2002;440(4):345–52.

    CAS  PubMed  Article  Google Scholar 

  12. Ferrell LD, Crawford JM, Dhillon AP, Scheuer PJ, Nakanuma Y. Proposal for standardized criteria for the diagnosis of benign, borderline, and malignant hepatocellular lesions arising in chronic advanced liver disease. Am J Surg Pathol. 1993;17(11):1113–23.

    CAS  PubMed  Article  Google Scholar 

  13. Asiyanbola B, Chang D, Gleisner AL, et al. Operative mortality after hepatic resection: are literature-based rates broadly applicable? J Gastrointest Surg. 2008;12(5):842–51.

    PubMed  Article  Google Scholar 

  14. Grazi GL, Cescon M, Ravaioli M, et al. Liver resection for hepatocellular carcinoma in cirrhotics and noncirrhotics. Evaluation of clinicopathologic features and comparison of risk factors for long-term survival and tumour recurrence in a single centre. Aliment Pharmacol Ther. 2003;17(Suppl 2):119–29.

    PubMed  Article  Google Scholar 

  15. Shimada M, Rikimaru T, Sugimachi K, et al. The importance of hepatic resection for hepatocellular carcinoma originating from nonfibrotic liver. J Am Coll Surg. 2000;191(5):531–7.

    CAS  PubMed  Article  Google Scholar 

  16. Wu TH, Yu MC, Chen TC, et al. Encapsulation is a significant prognostic factor for better outcome in large hepatocellular carcinoma. J Surg Oncol. 2012;105(1):85–90.

    PubMed  Article  Google Scholar 

  17. Iguchi T, Aishima S, Sanefuji K, et al. Both fibrous capsule formation and extracapsular penetration are powerful predictors of poor survival in human hepatocellular carcinoma: a histological assessment of 365 patients in Japan. Ann Surg Oncol. 2009;16(9):2539–46.

    PubMed  Article  Google Scholar 

  18. Zavaglia C, De Carlis L, Alberti AB, et al. Predictors of long-term survival after liver transplantation for hepatocellular carcinoma. Am J Gastroenterol. 2005;100(12):2708–16.

    PubMed  Article  Google Scholar 

  19. Lee WC, Jeng LB, Chen MF. Estimation of prognosis after hepatectomy for hepatocellular carcinoma. Br J Surg. Mar 2002;89(3):311–6.

    PubMed  Article  Google Scholar 

  20. Lee JI, Lee JW, Kim YS, Choi YA, Jeon YS, Cho SG. Analysis of survival in very early hepatocellular carcinoma after resection. J Clin Gastroenterol. 2011;45(4):366–71.

    CAS  PubMed  Article  Google Scholar 

  21. Ng IO, Lai EC, Ng MM, Fan ST. Tumor encapsulation in hepatocellular carcinoma. A pathologic study of 189 cases. Cancer. Jul 1 1992;70(1):45–49.

    CAS  PubMed  Article  Google Scholar 

  22. Chen MF, Tsai HP, Jeng LB, et al. Prognostic factors after resection for hepatocellular carcinoma in noncirrhotic livers: univariate and multivariate analysis. World J Surg. 2003;27(4):443–7.

    PubMed  Article  Google Scholar 

  23. Bismuth H, Chiche L, Castaing D. Surgical treatment of hepatocellular carcinomas in noncirrhotic liver: experience with 68 liver resections. World J Surg. 1995;19(1):35–41.

    CAS  PubMed  Article  Google Scholar 

  24. Worns MA, Bosslet T, Victor A, et al. Prognostic factors and outcomes of patients with hepatocellular carcinoma in non-cirrhotic liver. Scand J Gastroenterol. 2012;47(6):718–28.

    PubMed  Article  Google Scholar 

  25. Dupont-Bierre E, Compagnon P, Raoul JL, Fayet G, de Lajarte-Thirouard AS, Boudjema K. Resection of hepatocellular carcinoma in noncirrhotic liver: analysis of risk factors for survival. J Am Coll Surg. 2005;201(5):663–70.

    PubMed  Article  Google Scholar 

  26. Laurent C, Blanc JF, Nobili S, et al. Prognostic factors and long-term survival after hepatic resection for hepatocellular carcinoma originating from noncirrhotic liver. J Am Coll Surg. 2005;201(5):656–62.

    PubMed  Article  Google Scholar 

  27. Young AL, Adair R, Prasad KR, Toogood GJ, Lodge JP. Hepatocellular carcinoma within a noncirrhotic, nonfibrotic, seronegative liver: surgical approaches and outcomes. J Am Coll Surg. 2012;214(2):174–83.

    PubMed  Article  Google Scholar 

  28. Lubrano J, Huet E, Tsilividis B, et al. Long-term outcome of liver resection for hepatocellular carcinoma in noncirrhotic nonfibrotic liver with no viral hepatitis or alcohol abuse. World J Surg. 2008;32(1):104–9.

    PubMed  Article  Google Scholar 

  29. Mavros MN, Mayo SC, Hyder O, Pawlik TM. A systematic review: treatment and prognosis of patients with fibrolamellar hepatocellular carcinoma. J Am Coll Surg. 2012;215(6):820–30.

    PubMed  Article  Google Scholar 

  30. Yu MC, Chan KM, Lee CF, et al. Alkaline phosphatase: does it have a role in predicting hepatocellular carcinoma recurrence? J Gastrointest Surg. 2011;15(8):1440–9.

    PubMed  Article  Google Scholar 

  31. Kondo K, Chijiiwa K, Funagayama M, Kai M, Otani K, Ohuchida J. Differences in long-term outcome and prognostic factors according to viral status in patients with hepatocellular carcinoma treated by surgery. J Gastrointest Surg. 2008;12(3):468–76.

    PubMed  Article  Google Scholar 

  32. Yeh CN, Chen MF, Lee WC, Jeng LB. Prognostic factors of hepatic resection for hepatocellular carcinoma with cirrhosis: univariate and multivariate analysis. J Surg Oncol. 2002;81(4):195–202.

    PubMed  Article  Google Scholar 

  33. Tan A, Yeh SH, Liu CJ, Cheung C, Chen PJ. Viral hepatocarcinogenesis: from infection to cancer. Liver Int. 2008;28(2):175–88.

    CAS  PubMed  Article  Google Scholar 

  34. Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 2006;6(9):674–87.

    CAS  PubMed  Article  Google Scholar 

Download references

Author information

Affiliations

  1. Division of Surgical Oncology, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Dean J. Arnaoutakis MD, Michael N. Mavros MD, Amin Firoozmand MD, Matthew Weiss MD, Christopher L. Wolfgang MD, Michael A. Choti MD & Timothy M. Pawlik MD, MPH, PhD

  2. Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China

    Feng Shen MD

  3. Institute for Digestive Diseases and Liver Transplantation Fundeni, Bucharest, Romania

    Sorin Alexandrescu MD & Irinel Popescu MD

Authors
  1. Dean J. Arnaoutakis MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael N. Mavros MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Feng Shen MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sorin Alexandrescu MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Amin Firoozmand MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Irinel Popescu MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Matthew Weiss MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Christopher L. Wolfgang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michael A. Choti MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Timothy M. Pawlik MD, MPH, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Timothy M. Pawlik MD, MPH, PhD.

Additional information

Dean J. Arnaoutakis and Michael N. Mavros contributed equally to the production of this manuscript.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Arnaoutakis, D.J., Mavros, M.N., Shen, F. et al. Recurrence Patterns and Prognostic Factors in Patients with Hepatocellular Carcinoma in Noncirrhotic Liver: A Multi-Institutional Analysis. Ann Surg Oncol 21, 147–154 (2014). https://doi.org/10.1245/s10434-013-3211-3

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-013-3211-3

Keywords

  • Tace
  • Vascular Invasion
  • Cirrhotic Liver
  • Intrahepatic Metastasis
  • Satellite Lesion