Outcomes of liver transplantation in hepatocellular carcinoma: a single-center experience

Aim. To evaluate the long-term results of liver transplantation for hepatocellular carcinoma. To perform an analysis of risk factors for tumor recurrence.

Materials and methods. A retrospective analysis of 63 deceased donor liver transplantations, which were performed from January 2010 to February 2020. Patients were divided into three groups according to the Milan and California criteria – within the Milan criteria, outside the Milan criteria, but within the California criteria, outside the California criteria.

Results. There were 33 recipients within the Milan criteria, 5 within the California criteria, and 25 outside the California criteria. The 5-years recurrence rate was 9.1%, 40% and 52%, respectively (p = 0.002), five-year survival rate of – 93.2%, 66.7% and 54.7% (p = 0.041). Factors associated with an increased risk of recurrence: five and more tumor nodes (OR = 3.675; 95% CI (1.35–9.97); p = 0.011), macroscopic vascular invasion (OR = 5.97; 95% CI (2.06–17.31); p = 0.001) and inconsistency with California criteria (OR = 4.00; 95% CI (1.49–10.74); p = 0.006). The factors associated with a lower recurrence rate: one or two tumor nodes (p = 0.014 and 0.042, respectively), a high grade of histological differentiation (RR = 0.24; 95% CI (0.06–0.93); p = 0.039), compliance with Milanese criteria (RR = 0.18; 95% CI (0.06–0.58); p = 0.004).

Conclusion. Liver transplantation can be performed in a number of patients beyond the Milan and California criteria. The morphological and biological characteristics of the tumor and a multidisciplinary differentiated approach to treatment have an important role in the success of treatment.

1. Waller L.P., Deshpande V., Pyrsopoulos N. Hepato cellular carcinoma: A comprehensive review. World J. Hepatol. 2015; 7 (26): 2648–2663. https://doi.org/10.4254/wjh.v7.i26.2648

2. Breder V.V., Kosyrev V.Y., Kudashkin N.E., Laktionov K.K. Hepatocellular carcinoma as a social and medical problem in the Russian Federation. Meditsinskiy sovet = Medical Council. 2016; 10: 10–18. https://doi.org/10.21518/2079-701X-2016-10-10-18 (In Russian)

3. Perini M.V., Starkey G., Fink M.A., Bhandari R., Muralid haran V., Jones R., Christophi C. From minimal to maximal surgery in the treatment of hepatocarcinoma: A review. World J. Hepatol. 2015; 7 (1): 93–100. https://doi.org/10.4254/wjh.v7.i1.93

4. Llovet J.M., Bru C., Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin. Liver Dis. 1999; 19 (3): 329–338. https://doi.org/10.1055/s-2007-1007122

5. Yang J.D., Hainaut P., Gores G.J., Amadou A., Plymoth A., Roberts L.R. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat. Rev. Gastroenterol. Hepatol. 2019; 16 (10): 589–604. https://doi.org/10.1038/s41575-019-0186-y.

6. Raza A., Sood G.K. Hepatocellular carcinoma review: Current treatment, and evidence-based medicine. World J. Gastroenterol. 2014; 20 (15): 4115–4127. https://doi.org/10.3748/wjg.v20.i15.4115

7. Kow A.W.C. Transplantation versus liver resection in patients with hepatocellular carcinoma. Transl. Gastroenterol. Hepatol. 2019; 4: 33. https://doi.org/10.21037/tgh.2019.05.06

8. Kumari R., Sahu M.K., Tripathy A., Uthansingh K., Behera M. Hepatocellular carcinoma treatment: hurdles, advances and prospects. Hepat. Oncol. 2018; 5 (2): HEP08. Published 2018 Sep 28. https://doi.org/10.2217/hep-2018-0002

9. Xu D.W., Wan P., Xia Q. Liver transplantation for hepatocellular carcinoma beyond the Milan criteria: A review. World J. Gastroenterol. 2016; 22 (12): 3325–3334. https://doi.org/10.3748/wjg.v22.i12.

10. Ferrer-Fàbrega J., Forner A., Liccioni A., Miquel R., Molina V., Navasa M., Fondevila C., García-Valdecasas J.C., Bruix J., Fuster J. Prospective validation of ab initio liver transplantation in hepatocellular carcinoma upon detection of risk factors for recurrence after resection. Hepatology. 2016; 63 (3): 839– 849. https://doi.org/10.1002/hep.28339

11. Kakodkar R., Soin A.S. Liver Transplantation for HCC: A Review. Indian J. Surg. 2012; 74 (1): 100–117. https://doi.org/10.1007/s12262-011-0387-2

12. Charrière B., Maulat C., Suc B., Muscari F. Contribution of alpha-fetoprotein in liver transplantation for hepatocellular carcinoma. World J. Hepatol. 2016; 8 (21): 881–890. https://doi.org/10.4254/wjh.v8.i21.881

13. Wang Y., Shen Z., Zhu Z., Han R., Huai M. Clinical values of AFP, GPC3 mRNA in peripheral blood for prediction of hepatocellular carcinoma recurrence following OLT: AFP, GPC3 mRNA for prediction of HCC. Hepat. Mon. 2011; 11 (3): 195–199. PMCID: PMC3206678.

14. Choi H.J., Kim D.G., Na G.H., Han J.H., Hong T.H., You Y.K. Clinical outcome in patients with hepatocellular carcinoma after living-donor liver transplantation. World J. Gastroenterol. 2013; 19 (29): 4737–4744. https://doi.org/10.3748/wjg.v19.i29.4737

15. Colhoun E.D. 5th, Forsberg C.G., Chavin K.D., Baliga P.K., Taber D.J. Incidence and risk factors of hepatocellular carcinoma after orthotopic liver transplantation. Surgery. 2017; 161 (3): 830–836. https://doi.org/10.1016/j.surg.2016.08.049

16. Schraiber Ldos. S., de Mattos A.A., Zanotelli M.L., Cantisani G.P., Brandão A.B., Marroni C.A., Kiss G., Ernani L., MarconPdos. S. Alpha-fetoprotein level predicts recurrence after transplantation in hepatocellular carcinoma. Medicine (Baltimore). 2016; 95 (3): e2478. https://doi.org/10.1097/MD.0000000000002478

17. Saitta C., Raffa G., Alibrandi A., Brancatelli S., Lombardo D., Tripodi G., Raimondo G., Pollicino T. PIVKA-II is a useful tool for diagnostic characterization of ultrasound-detected liver nodules in cirrhotic patients. Medicine (Baltimore). 2017; 96 (26): e7266. https://doi.org/10.1097/MD.0000000000007266

18. Johnson P.J. The BALAD-2 and GALAD Biomarker models for hepatocellular carcinoma. Gastroenterol. Hepatol. (NY). 2017; 13 (4): 231–233. PMID: 28546794; PMCID: PMC5441024.

19. Akateh C., Black S.M., Conteh L., Miller E.D., Noonan A., Elliott E., Pawlik T.M., Tsung A., Cloyd J.M. Neoadjuvant and adjuvant treatment strategies for hepatocellular carcinoma. World J. Gastroenterol. 2019; 25 (28): 3704–3721. https://doi.org/10.3748/wjg.v25.i28.3704

20. Massarollo P.C., Coppini A.Z., Salzedas-Netto A.A., Coelho F.F., Minami T., Gonzalez A.M. Favorable long-term outcome in patients submitted to liver transplantation after downstaging of hepatocellular carcinoma according to a Brazilian selection protocol. Transplant. Proc. 2016; 48 (7): 2338–2340. https://doi.org/10.1016/j.transproceed.2016.06.029.

21. Yu C.Y., Ou H.Y., Huang T.L., Chen T.Y., Tsang L.L., Chen C.L., Cheng Y.F. Hepatocellular carcinoma downstaging in liver transplantation. Transplant. Proc. 2012; 44 (2): 412–414. https://doi.org/10.1016/j.transproceed.2012.01.043.

22. Cescon M., Cucchetti A., Ravaioli M., Pinna A.D. Hepatocellular carcinoma locoregional therapies for patients in the waiting list. Impact on transplantability and recurrence rate. J. Hepatol. 2013; 58 (3): 609–618. Epub 2012 Oct 4. https://doi.org/10.1016/j.jhep.2012.09.021.

23. Finkenstedt A., Vikoler A., Portenkirchner M., Mülleder K., Maglione M., Margreiter C., Moser P., Vogel W., Bale R., Freund M., Luger A., Tilg H., Petersen J., Schneeberger S., Graziadei I., Zoller H., Glodny B. Excellent post-transplant survival in patients with intermediate stage hepatocellular carcinoma responding to neoadjuvant therapy. Liver Int. 2016; 36 (5): 688–695. Epub 2015 Oct 12. https://doi.org/10.1111/liv.12966.

24. Park H.W., Hwang S., Ahn C.S., Kim K.H., Moon D.B., Ha T.Y., Song G.W., Jung D.H., Park G.C., Namgoong J.M., Park C.S., Park Y.H., Kang S.H., Jung B.H., Lee S.G. Longterm survival outcomes for living donor liver transplant recipients with pathologically nonviable hepatocellular carcinoma. Transplant. Proc. 2013; 45 (8): 3032–3034. https://doi.org/10.1016/j.transproceed.2013.08.027.

25. Beal E.W., Dittmar K.M., Hanje A.J., Michaels A.J., Conteh L., Davidson G., Black S.M., Bloomston P.M., Dillhoff M.E., Schmidt C.R. Pretransplant Locoregional Therapy for Hepatocellular Carcinoma: Evaluation of Explant Pathology and Overall Survival. Front. Oncol. 2016; 6: 143. https://doi.org/10.3389/fonc.2016.00143

26. Jung E.S., Kim J.H., Yoon E.L., Lee H.J., Lee S.J., Suh S.J., Lee B.J., Seo Y.S., Yim H.J., Seo T.S., Lee C.H., Yeon J.E., Park J.J., Kim J.S., Bak Y.T., Byun K.S. Comparison of the methods for tumor response assessment in patients with hepatocellular carcinoma undergoing transarterial chemoembolization. J. Hepatol. 2013; 58 (6): 1181–1187. https://doi.org/10.1016/j.jhep.2013.01.039.

27. Victor D.W. 3rd, Monsour H.P. Jr., Boktour M., Lunsford K., Balogh J., Graviss E.A., Nguyen D.T., McFadden R., Divatia M.K., Heyne K., Ankoma-Sey V., Egwim C., Galati J., Duchini A., Saharia A., Mobley C., Gaber A.O., Ghobrial R.M. Outcomes of liver transplantation for hepatocellular carcinoma beyond the university of California San Francisco criteria: a single-center experience. Transplantation. 2020; 104 (1): 113– 121. https://doi.org/10.1097/TP.0000000000002835.

28. Mazzaferro V., Llovet J.M., Miceli R., Bhoori S., Schiavo M., Mariani L., Camerini T., Roayaie S., Schwartz M.E., Grazi G.L., Adam R., Neuhaus P., Salizzoni M., Bruix J., Forner A., De Carlis L., Cillo U., Burroughs A.K., Troisi R., Rossi M., Gerunda G.E., Lerut J., Belghiti J., Boin I., Gugenheim J., Rochling F., Van Hoek B., Majno P. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol. 2009; 10 (1): 35–43. https://doi.org/10.1016/S1470-2045(08)70284-5.

29. Mazzaferro V., Sposito C., Zhou J., Pinna A.D., De Carlis L., Fan J., Cescon M., Di Sandro S., Yi-Feng H., Lauterio A., Bongini M., Cucchetti A. Metroticket 2.0 model for analysis of competing risks of death after liver transplantation for hepatocellular carcinoma. Gastroenterology. 2018; 154 (1): 128–139. Epub 2017 Oct 5. https://doi.org/10.1053/j.gastro.2017.09.025.

30. Castroagudín J.F., Molina-Pérez E., Ferreiro-Iglesias R., Abdulkader I., Otero-Antón E., Tomé S., Varo-Pérez E. Late recur rence of hepatocellular carcinoma after liver transplantation: is an active surveillance for recurrence needed? Transplant. Proc. 2012; 44 (6): 1565–1567. https://doi.org/10.1016/j.transproceed.2012.05.007.

31. Bittermann T., Hoteit M.A., Abt P.L., Forde K.A., Goldberg D. Waiting time and explant pathology in transplant recipients with hepatocellular carcinoma: A Novel Study Using National Data. Am. J. Transplant. 2014; 14 (7): 1657–1663. https://doi.org/10.1111/ajt.12774. Epub 2014 Jun 5.

32. Nissen N.N., Menon V., Bresee C., Tran T.T., Annamalai A., Poordad F., Fair J.H., Klein A.S., Boland B., Colquhoun S.D. Recurrent hepatocellular carcinoma after liver transplant: identifying the high-risk patient. HPB (Oxford). 2011; 13 (9): 626–632. https://doi.org/10.1111/j.1477-2574.2011.00342.x

33. Patel S.S., Arrington A.K., McKenzie S., Mailey B., Ding M., Lee W., Artinyan A., Nissen N., Colquhoun S.D., Kim J. Milan criteria and UCSF criteria: a preliminary comparative study of liver transplantation outcomes in the United States. Int. J. Hepatol. 2012; 2012: 253517. https://doi.org/10.1155/2012/253517

34. Unek T., Karademir S., Arslan N.C., Egeli T., Atasoy G., Sagol O., Obuz F., Akarsu M., Astarcioglu I. Comparison of Milan and UCSF criteria for liver transplantation to treat hepatocellular carcinoma. World J. Gastroenterol. 2011; 17 (37): 4206–4212. https://doi.org/10.3748/wjg.v17.i37.4206

35. Baccarani U., Adani G.L., Avellini C., Lorenzin D., Currò G., Beltrami A., Pasqualucci A., Bresadola V., Risaliti A., Viale P.L., Beltrami C.A., Bresadola F. Comparison of clinical and pathological staging and long-term results of liver transplantation for hepatocellular carcinoma in a single transplant center. Transplant. Proc. 2006; 38 (4): 1111–1113. https://doi.org/10.1016/j.transproceed.2006.02.015

36. Abdelfattah M.R., Abaalkhail F., Al-Manea H. Misdiagnosed or incidentally detected hepatocellular carcinoma in explanted livers: lessons learned. Ann. Transplant. 2015; 20: 366–372. https://doi.org/10.12659/AOT.893782.

37. Mehta N. Hepatocellular carcinoma—how to determine therapeutic options. Hepatol. Commun. 2020; 4 (3): 342–354. https://doi.org/10.1002/hep4.1481

38. Zeair S., Rajchert J., Stasiuk R., Cyprys S., Miętkiewski J., Zasada-Cedro K., Karpińska E., Duczkowska M., Parc zewski M., Wawrzynowicz-Syczewska M. Recurrence of hepatocellular carcinoma after liver transplantation: a single-center experience. Ann. Transplant. 2019; 24: 499–505. https://doi.org/10.12659/AOT.918150