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Recurrence of Hepatocellular Carcinoma Following Liver Transplantation Within Milan Criteria

  • Chapter
Disease Recurrence After Liver Transplantation

Abstract

The optimal curative options for the management of hepatocellular carcinoma (HCC) are surgical resection and/or liver transplantation (LT). Recent data suggest that ablative treatment such as radio frequency ablation (RFA) may be comparable to surgical resection for small tumors. The 5-year tumor-free survival after surgical resection (or RFA) is less than LT irrespective of the risk factor for HCC. LT is considered the best option in people with HCC and portal hypertension, or those with advanced cirrhosis because of lower surgical mortality rates. Prior to the introduction of Milan criteria, the long-term results of liver transplantation in patients with hepatocellular carcinoma have been variable and disappointing, with an overall 5-year survival rate ranging from 30 to 40 %. Application of Milan criteria has reduced tumor recurrence rates to ~10 % and has improved 5-year tumor-free survival (~70 %). The UNOS data also suggested that the survival improved after the publication of Milan criteria in the United States. There is an ongoing debate whether Milan criteria could be expanded without having an adverse effect on tumor-free survival. Published studies suggest that HCC patients transplanted outside the Milan criteria have 5-year survival rates between 46 and 60 %. One of the major criticisms of Milan criteria is that it is based on pre-LT imaging findings, and only 70 % of explant pathology findings correlate with imaging. Moreover, imaging techniques, protocols, and interpretations of images are not uniform, and additionally, Milan criteria do not take into consideration the variability of tumor biology. As we understand the variability of HCC tumor biology better and develop reliable molecular markers, we may be able to redefine the LT selection criteria for patients with HCC without any negative effects of outcomes. Until then, Milan criteria appear to be a reasonable benchmark for selecting HCC patients for LT.

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Abbreviations

AFP:

Alpha fetoprotein

HCC:

Hepatocellular carcinoma

LT:

Liver transplantation

RFA:

Radio frequency ablation

TACE:

Trans Arterial Chemo Embolization

UNOS:

United Network for Organ Sharing

References

  1. Parkin DM, Bray F, Ferlay J, et al. Estimating the world cancer burden: Globocan 2000. Int J Cancer. 2001;94:153–6.

    Article  CAS  PubMed  Google Scholar 

  2. Surveillance, Epidemiology, and End Results (SEER) Program. SEER*Stat database: incidence—SEER 9 Regs research data, Nov 2009 Sub (1973–2007). Bethesda: National Cancer Institute; 2010.

    Google Scholar 

  3. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142(6):1264–73.e1.

    Article  PubMed Central  PubMed  Google Scholar 

  4. Llovet JM, Schwartz M, Mazzaferro V. Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis. 2005;25:181–200.

    Article  PubMed  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;334:693–9.

    Article  CAS  PubMed  Google Scholar 

  6. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology. 2001;33:1394–403.

    Article  CAS  PubMed  Google Scholar 

  7. Mazzaferro V, Llovet JM, Miceli R, et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol. 2009;10:35–43.

    Article  PubMed  Google Scholar 

  8. Zheng SS, Xu X, Wu J, et al. Liver transplantation for hepatocellular carcinoma: Hangzhou experiences. Transplantation. 2008;85:1726–32.

    Article  CAS  PubMed  Google Scholar 

  9. Iwatsuki S, Gordon RD, Shaw BW, et al. Role of liver transplantation in cancer therapy. Ann Surg. 1985;202(4):401–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. O’Grady JG, Polson RJ, Rolles K, et al. Liver transplantation for malignant disease. Results in 93 consecutive patients. Ann Surg. 1988;207(4):373–9.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Ringe B, Wittekind C, Bechstein WO, et al. The role of liver transplantation in hepatobiliary malignancy: a retrospective analysis of 95 patients with particular regard to tumor stage and recurrence. Ann Surg. 1989;209:88–98.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Olthoff KM, Millis JM, Rosove MH, et al. Is liver transplantation justified for the treatment of hepatic malignancies? Arch Surg. 1990;125:1261–8.

    Article  CAS  PubMed  Google Scholar 

  13. Ismail T, Angrisani L, Gunson BK, et al. Primary hepatic malignancy: the role of liver transplantation. Br J Surg. 1990;77:983–7.

    Article  CAS  PubMed  Google Scholar 

  14. Penn I. Hepatic transplantation for primary and metastatic cancer of the liver. Surgery. 1991;110:726–35.

    CAS  PubMed  Google Scholar 

  15. Haug CE, Jenkins RL, Rohrer RJ, et al. Liver transplantation for primary hepatic cancer. Transplantation. 1992;53:376–82.

    Article  CAS  PubMed  Google Scholar 

  16. Moreno-Gonzalez E, Gomez R, Garcia I, et al. Liver transplantation in malignant primary hepatic neoplasms. Am J Surg. 1992;163:395–400.

    Article  CAS  PubMed  Google Scholar 

  17. Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology. 1999;30:1434–40.

    Article  CAS  PubMed  Google Scholar 

  18. Bismuth H, Majno PE, Adam R. Liver transplantation for hepatocellular carcinoma. Semin Liver Dis. 1999;19:311–22.

    Article  CAS  PubMed  Google Scholar 

  19. Jonas S, Bechstein WO, Steinmüller T, et al. Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology. 2001;33(5):1080–6.

    Article  CAS  PubMed  Google Scholar 

  20. Hemming AW, Cattral MS, Reed AI, et al. Liver transplantation for hepatocellular carcinoma. Ann Surg. 2001;233(5):652–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Yoo HY, Patt CH, Geschwind JF, et al. The outcome of liver transplantation in patients with hepatocellular carcinoma in the United States between 1988 and 2001: 5-year survival has improved significantly with time. J Clin Oncol. 2003;21:4329–35.

    Article  PubMed  Google Scholar 

  22. Decaens T, Roudot-Thoraval F, Hadni-Bresson S, et al. Impact of UCSF criteria according to pre- and post-OLT tumor features: analysis of 479 patients listed for HCC with a short waiting time. Liver Transpl. 2006;12:1761–9.

    Article  PubMed  Google Scholar 

  23. Duffy JP, Vardanian A, Benjamin E, et al. Liver transplantation criteria for hepatocellular carcinoma should be expanded: a 22-year experience with 467 patients at UCLA. Ann Surg. 2007;246(3):502–11.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Adler M, De Pauw F, Vereerstraeten P, et al. Outcome of patients with hepatocellular carcinoma listed for liver transplantation within the Eurotransplant allocation system. Liver Transpl. 2008;14:526–33.

    Article  PubMed  Google Scholar 

  25. Herrero JI, Sangro B, Pardo F, et al. Liver transplantation in patients with hepatocellular carcinoma across Milan criteria. Liver Transpl. 2008;14:272–8.

    Article  PubMed  Google Scholar 

  26. Pelletier SJ, Fu S, Thyagarajan V, et al. An intention-to-treat analysis of liver transplantation for hepatocellular carcinoma using organ procurement transplant network data. Liver Transpl. 2009;15:859–68.

    Article  PubMed  Google Scholar 

  27. Mazzaferro V, Bhoori S, Sposito C, et al. Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence-based analysis of 15 years of experience. Liver Transpl. 2011;17:S44–57.

    Article  PubMed  Google Scholar 

  28. Freeman RB, Mithoefer A, Ruthazer R, et al. Optimizing staging for hepatocellular carcinoma before liver transplantation: a retrospective analysis of the UNOS/OPTN database. Liver Transpl. 2006;12:1504–11.

    Article  PubMed  Google Scholar 

  29. Macdonald B, Sewell JL, Harper AM, et al. Liver transplantation for hepatocellular carcinoma: analysis of factors predicting outcome in 1074 patients in OPTN Region 5. Clin Transplant. 2015;29:506–12.

    Article  CAS  PubMed  Google Scholar 

  30. Chaiteerakij R, Zhang X, Addissie BD, et al. Combinations of biomarkers and Milan criteria for predicting hepatocellular carcinoma recurrence after liver transplantation. Liver Transpl. 2014;21:599–606.

    Article  Google Scholar 

  31. 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.

    Article  PubMed  Google Scholar 

  32. Klintmalm GB. Liver transplantation for hepatocellular carcinoma. A registry report of the impact of tumor characteristics on outcome. Ann Surg. 1998;228:479–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Tamura S, Kato T, Berho M, et al. Impact of histological grade of hepatocellular carcinoma on the outcome of liver transplantation. Arch Surg. 2001;136:25–30.

    Article  CAS  PubMed  Google Scholar 

  34. Takamori R, Wong LL, Dang C, et al. Needle-tract implantation from hepatocellular cancer: is needle biopsy of the liver always necessary? Liver Transpl. 2000;6:67–72.

    CAS  PubMed  Google Scholar 

  35. Chapoutot C, Perney P, Fabre D, et al. Needle-tract seeding after ultrasound-guided puncture of hepatocellular carcinoma. A study of 150 patients. Gastroenterol Clin Biol. 1999;23:552–6.

    CAS  PubMed  Google Scholar 

  36. Tarhan NC, Hatipoğlu T, Ercan E, et al. Correlation of dynamic multidetector CT findings with pathological grades of hepatocellular carcinoma. Diagn Interv Radiol. 2011;17:328–33.

    PubMed  Google Scholar 

  37. Yoon SH, Lee JM, So YH, et al. Multiphasic MDCT enhancement pattern of hepatocellular carcinoma smaller than 3 cm in diameter: tumor size and cellular differentiation. Am J Roentgenol. 2009;193:W482–9.

    Article  Google Scholar 

  38. Asayama Y, Yoshimitsu K, Nishihara Y, et al. Arterial blood supply of hepatocellular carcinoma and histologic grading: radiologic-pathologic correlation. Am J Roentgenol. 2008;190:W28–34.

    Article  Google Scholar 

  39. Jang HJ, Kim TK, Burns PN, et al. Enhancement patterns of hepatocellular carcinoma at contrast-enhanced US: comparison with histologic differentiation. Radiology. 2007;244:898–906.

    Article  PubMed  Google Scholar 

  40. Lee JH, Lee JM, Kim SJ, et al. Enhancement patterns of hepatocellular carcinomas on multiphasicmultidetector row CT: comparison with pathological differentiation. Br J Radiol. 2012;85:e573–83.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Pecchi A, Besutti G, Besutti G, et al. Post-transplantation hepatocellular carcinoma recurrence: patterns and relation between vascularity and differentiation degree. World J Hepatol. 2015;7(2):276–84.

    Article  PubMed Central  PubMed  Google Scholar 

  42. Vagefi PA, Dodge JL, Yao FY, et al. Potential role of the donor in hepatocellular carcinoma recurrence after liver transplantation. Liver Transpl. 2015;21(2):187–94.

    Article  PubMed Central  PubMed  Google Scholar 

  43. Detry O, Govaerts L, Deroover A, et al. Prognostic value of 18F-FDG PET/CT in liver transplantation for hepatocarcinoma. World J Gastroenterol. 2015;21(10):3049–54.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Xia W, Ke Q, Wang Y, et al. Predictive value of pre-transplant platelet to lymphocyte ratio for hepatocellular carcinoma recurrence after liver transplantation. World J Surg Oncol. 2015;13(1):472.

    Article  Google Scholar 

  45. Xiao GQ, Liu C, Liu DL, et al. Neutrophil-lymphocyte ratio predicts the prognosis of patients with hepatocellular carcinoma after liver transplantation. World J Gastroenterol. 2013;19(45):8398–407.

    Article  PubMed Central  PubMed  Google Scholar 

  46. Roberts JP. Tumor surveillance-what can and should be done? Screening for recurrence of hepatocellular carcinoma after liver transplantation. Liver Transpl. 2005;11:S45–6.

    Article  PubMed  Google Scholar 

  47. Yokoyama I, Carr B, Saitu H, et al. Accelerated growth rates of recurrent hepatocellular carcinoma after liver transplantation. Cancer. 1991;68:2095–100.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Penn I. The effect of immunosuppression on pre-existing cancers. Transplantation. 1993;55:742–7.

    Article  CAS  PubMed  Google Scholar 

  49. Freise CE, Ferrell L, Liu T, et al. Effect of systemic cyclosporine on tumor recurrence after liver transplantation in a model of hepatocellular carcinoma. Transplantation. 1999;67:510–3.

    Article  CAS  PubMed  Google Scholar 

  50. Vivarelli M, Cucchetti A, Piscaglia F, et al. Analysis of risk factors for tumor recurrence after liver transplantation for hepatocellular carcinoma: key role of immunosuppression. Liver Transpl. 2005;11:497–503.

    Article  PubMed  Google Scholar 

  51. Vivarelli M, Bellusci R, Cucchetti A, et al. Low recurrence rate of hepatocellular carcinoma after liver transplantation: better patient selection or lower immunosuppression? Transplantation. 2002;74:1746–51.

    Article  PubMed  Google Scholar 

  52. Schumacher G, Oidtmann M, Rueggeberg A, et al. Sirolimus inhibits growth of human hepatoma cells alone or combined with tacrolimus, while tacrolimus promotes cell growth. World J Gastroenterol. 2005;11:1420–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Guba M, von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med. 2002;8:128–35.

    Article  CAS  PubMed  Google Scholar 

  54. Zhou J, Fan J, Wang Z, et al. Conversion to sirolimus immunosuppression in liver transplantation recipients with hepatocellular carcinoma: report of an initial experience. World J Gastroenterol. 2006;12:3114–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  55. Zimmerman MA, Trotter JF, Wachs M, et al. Sirolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma. Liver Transpl. 2008;14:633–8.

    Article  PubMed  Google Scholar 

  56. Chinnakotla S, Davis GL, Vasani S, et al. Impact of sirolimus on the recurrence of hepatocellular carcinoma after liver transplantation. Liver Transpl. 2009;15:1834–42.

    Article  PubMed  Google Scholar 

  57. Taketomi A, Fukuhara T, Morita K, et al. Improved results of a surgical resection for the recurrence of hepatocellular carcinoma after living donor liver transplantation. Ann Surg Oncol. 2010;17(9):2283–9.

    Article  PubMed  Google Scholar 

  58. Lachenmayer A, Alsinet C, Chang CY, et al. Molecular approaches to treatment of hepatocellular carcinoma. Dig Liver Dis. 2010;42 suppl 3:S264–72.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.

    Article  CAS  PubMed  Google Scholar 

  60. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomized, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25–34.

    Article  CAS  PubMed  Google Scholar 

  61. Weinmann A, Niederle IM, Koch S, et al. Sorafenib for recurrence of hepatocellular carcinoma after liver transplantation. Dig Liver Dis. 2012;44(5):432–7.

    Article  CAS  PubMed  Google Scholar 

  62. De Simone P, Crocetti L, Pezzati D, et al. Efficacy and safety of combination therapy with everolimus and sorafenib for recurrence of hepatocellular carcinoma after liver transplantation. Transplant Proc. 2014;46(1):241–4.

    Article  PubMed  Google Scholar 

  63. Bruix J, Takayama T, Mazzaferro V, et al. STORM: a phase III randomized, double-blind, placebo-controlled trial of adjuvant sorafenib after resection or ablation to prevent recurrence of hepatocellular carcinoma (HCC). J Clin Oncol. 2009;32:5s (suppl; abstr- 4006).

    Google Scholar 

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Authors and Affiliations

  1. Institute for Digestive Health and Liver Disease, Mercy Medical Center, Baltimore, MD, 21202, USA

    Anantha K. Nuthalapati M.D.

  2. Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, 21202, USA

    Steven I. Hanish M.D.

  3. Institute for Digestive Health and Liver Disease, Mercy Medical Center & University of Maryland School of Medicine, Baltimore, MD, 21202, USA

    Paul J. Thuluvath MD, AGAF, FACG, FAASLD, FRCP

Authors
  1. Anantha K. Nuthalapati M.D.
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  2. Steven I. Hanish M.D.
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  3. Paul J. Thuluvath MD, AGAF, FACG, FAASLD, FRCP
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Correspondence to Paul J. Thuluvath MD, AGAF, FACG, FAASLD, FRCP .

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  1. Institute for Digestive Health & Liver Disease, Mercy Medical Center & University of Maryland School of Medicine, Baltimore, Maryland, USA

    Paul J. Thuluvath

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Nuthalapati, A.K., Hanish, S.I., Thuluvath, P.J. (2016). Recurrence of Hepatocellular Carcinoma Following Liver Transplantation Within Milan Criteria. In: Thuluvath, P. (eds) Disease Recurrence After Liver Transplantation. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-2947-4_11

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  • DOI: https://doi.org/10.1007/978-1-4939-2947-4_11

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