肝移植是治疗肝细胞肝癌(Hepatocellular carcinoma, HCC)的重要方法,但移植后的HCC复发影响了治疗效果,尽管有严格的纳入标准,但移植术后仍有较高的复发率。随着分子生物学的发展,HCC移植术后复发相关的分子标志物被不断提出并进行分析研究。在这篇综述中,我们重点关注肿瘤标志物和炎症标志物与HCC移植术后的相关性。HCC相关的肿瘤标志物主要有甲胎蛋白(Alpha-fetoprotein, AFP)、脱-γ-羧基凝血酶原(Des-gamma-carboxyprothrombin, DCP)等,相关的炎症标志物主要有C反应蛋白(C-reactive protein, CRP)、中性粒细胞淋巴细胞比值(Neutrophil lymphocyte ratio, NLR)、血小板淋巴细胞比值(Platelet lymphocyte ratio, PLR)等。但这些标志物都存在一定的缺陷,希望能通过更多的多中心的前瞻性研究,找着更好的分子标志物组合,从而更好地预测移植后复发,以希望获得更好的移植效果。
Liver transplantation is a potentially curative treatment for hepatocellular carcinoma (HCC). But, the recurrence of HCC after transplantation has seriously affected the treatment effect. Despite stringent selection criteria, recurrence occurs in a high proportion of patients transplanted for HCC. With the development of molecular biology, there are more and more molecular markers related to the recurrence after liver transplantation. In this review, we focus on the tumor markers and inflammatory markers. Tumor markers mainly include Alpha-fetoprotein (AFP), Des-gamma-carboxyprothrombin (DCP), etc. Inflammatory markers include C-reactive protein (CRP), Neutrophil lymphocyte ratio (NLR) and Platelet lymphocyte ratio (PLR), etc. However, taking into account the limitations of these markers, multicenter prospective studies are essential to find a better combination of molecular markers, which means better prediction of recurrence and better transplant treatment effect.
章文燕,郑树森. 肝癌移植术后复发相关标志物的研究进展 Molecular Markers and Recurrence of Hepatocellular Carcinoma after Liver Transplantation[J]. 临床医学进展, 2019, 09(03): 310-318. https://doi.org/10.12677/ACM.2019.93047
参考文献ReferencesBray, F., Ferlay, J., Soerjomataram, I., et al. (2018) Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 68, 394-424.
<br>https://doi.org/10.3322/caac.21492郑荣寿, 孙可欣, 张思维, 等. 2015年中国恶性肿瘤流行情况分析[J]. 中华肿瘤杂志, 2019, 41(1): 19-28.中华人民共和国卫生和计划生育委员会医政医管局. 原发性肝癌诊疗规范(2017年版) [J]. 中华肝脏病杂志, 2017, 25(12): 886-895.Couri, T. and Pillai, A. (2019) Goals and Targets for Personalized Therapy for HCC. Hepatology International, 2, 1-13.
<br>https://doi.org/10.1007/s12072-018-9919-1Wang, L.Y. and Zheng, S.S. (2018) Advances in Predicting the Prognosis of Hepatocellular Carcinoma Recipients after Liver Transplantation. Journal of Zheijang University SCIENCE B, 19, 497-504.
<br>https://doi.org/10.1631/jzus.B1700156Meirelles Junior, R.F., Salvalaggio, P., Rezende, M.B., et al. (2015) Liver Transplantation: History, Outcomes and Perspectives. Einstein (Sao Paulo), 13, 149-152. <br>https://doi.org/10.1590/S1679-45082015RW3164Agopian, V.G., Harlander-Locke, M., Zarrinpar, A., et al. (2015) A Novel Prognostic Nomogram Accurately Predicts Hepatocellular Carcinoma Recurrence after Liver Trans-plantation: Analysis of 865 Consecutive Liver Transplant Recipients. Journal of the American College of Surgeons, 220, 416-427.
<br>https://doi.org/10.1016/j.jamcollsurg.2014.12.025Chapman, W.C., Garcia-Aroz, S., Vachharajani, N., et al. (2017) Liver Transplantation for Advanced Hepatocellular Carcinoma after Downstaging without Up-Front Stage Re-strictions. Journal of the American College of Surgeons, 224, 610-621. <br>https://doi.org/10.1016/j.jamcollsurg.2016.12.020Rudnick, S.R. and Russo, M.W. (2018) Liver Transplan-tation beyond or Downstaging within the Milan Criteria for Hepatocellular Carcinoma. Expert Review of Gastroenter-ology & Hepatology, 12, 265-275.
<br>https://doi.org/10.1080/17474124.2018.1417035Akoad, M.E. and Pomfret, E.A. (2015) Surgical Resection and Liver Transplantation for Hepatocellular Carcinoma. Clinical Liver Disease, 19, 381-399. <br>https://doi.org/10.1016/j.cld.2015.01.007Hirokawa, F., Hayashi, M., Miyamoto, Y., et al. (2015) Predictors of Poor Prognosis by Recurrence Patterns after Curative Hepatectomy for Hepatocellular Carcinoma in Child-Pugh Classification A. Hepatogastroenterology, 62, 164-168.Au, K.P. and Chok, K.S.H. (2018) Multidisciplinary Ap-proach for Post-Liver Transplant Recurrence of Hepatocellular Carcinoma: A Proposed Management Algorithm. World Journal of Gastroenterology, 24, 5081-5094.
<br>https://doi.org/10.3748/wjg.v24.i45.5081Regalia, E., Fassati, L.R., Valente, U., et al. (1998) Pattern and Management of Recurrent Hepatocellular Carcinoma after Liver Transplantation. Journal of Hepato-Biliary-Pancreatic Surgery, 5, 29-34.
<br>https://doi.org/10.1007/PL00009947Roayaie, S., Schwartz, J.D., Sung, M.W., et al. (2004) Recurrence of Hepatocellular Carcinoma after Liver Transplant: Patterns and Prognosis. Liver Transplantation, 10, 534-540. <br>https://doi.org/10.1002/lt.20128Zimmerman, M.A., Ghobrial, R.M., Tong, M.J., et al. (2008) Recurrence of Hepatocellular Carcinoma Following Liver Transplantation: A Review of Preoperative and Postoperative Prognostic Indicators. Archives of Surgery, 143, 182-188; Discussion 188. <br>https://doi.org/10.1001/archsurg.2007.39De’angelis, N., Landi, F., Carra, M.C., et al. (2015) Managements of Recurrent Hepatocellular Carcinoma after Liver Transplantation: A Systematic Review. World Journal of Gastro-enterology, 21, 11185-11198.
<br>https://doi.org/10.3748/wjg.v21.i39.11185关智芬, 陈伟强. 肝移植术后复发性肝细胞癌的多学科治疗[J]. 岭南现代临床外科, 2018, 18(5): 589-592.Mazzaferro, V., Regalia, E., Doci, R., et al. (1996) Liver Trans-plantation for the Treatment of Small Hepatocellular Carcinomas in Patients with Cirrhosis. The New England Journal of Medicine, 334, 693-699.
<br>https://doi.org/10.1056/NEJM199603143341104Yao, F.Y., Ferrell, L., Bass, N.M., et al. (2001) Liver Transplantation for Hepatocellular Carcinoma: Expansion of the Tumor Size Limits Does Not Adversely Impact Survival. Hepatology, 33, 1394-1403.
<br>https://doi.org/10.1053/jhep.2001.24563Zheng, S.S., Xu, X., Wu, J., et al. (2008) Liver Transplantation for Hepatocellular Carcinoma: Hangzhou Experiences. Transplantation, 85, 1726-1732. <br>https://doi.org/10.1097/TP.0b013e31816b67e4Marsh, J.W., Dvorchik, I., Bonham, C.A., et al. (2000) Is the Pathologic TNM Staging System for Patients with Hepatoma Predictive of Outcome. Cancer, 88, 538-543.
<br>https://doi.org/10.1002/(SICI)1097-0142(20000201)88:3<538::AID-CNCR7>3.0.CO;2-HJonas, S., Mittler, J., Pascher, A., et al. (2007) Living Donor Liver Transplantation of the Right Lobe for Hepatocellular Carcinoma in Cirrhosis in a European Center. Liver Transplantation, 13, 896-903. <br>https://doi.org/10.1002/lt.21189Sugawara, Y., Tamura, S. and Makuuchi, M. (2007) Living Donor Liver Transplantation for Hepatocellular Carcinoma: Tokyo University Series. Digestive Diseases, 25, 310-312. <br>https://doi.org/10.1159/000106910Lee, S.G., Hwang, S., Moon, D.B., et al. (2008) Expanded Indication Criteria of Living Donor Liver Transplantation for Hepatocellular Carcinoma at One Large-Volume Center. Liver Transplantation, 14, 935-945.
<br>https://doi.org/10.1002/lt.21445Mazzaferro, V., Llovet, J.M., Miceli, R., et al. (2009) Predicting Survival after Liver Transplantation in Patients with Hepatocellular Carcinoma beyond the Milan Criteria: A Retrospective, Exploratory Analysis. The Lancet Oncology, 10, 35-43. <br>https://doi.org/10.1016/S1470-2045(08)70284-5Fan, J., Yang, G.S., Fu, Z.R., et al. (2009) Liver Transplantation Outcomes in 1,078 Hepatocellular Carcinoma Patients: A Multi-Center Experience in Shanghai, China. Journal of Cancer Research and Clinical Oncology, 135, 1403-1412.
<br>https://doi.org/10.1007/s00432-009-0584-6Li, J., Yan, L.N., Yang, J., et al. (2009) Indicators of Prognosis after Liver Transplantation in Chinese Hepatocellular Carcinoma Patients. World Journal of Gastroenterology, 15, 4170-4176. <br>https://doi.org/10.3748/wjg.15.4170Kim, J.H., Sinn, D.H., Gwak, G.Y., et al. (2016) Factors Determining Long-Term Outcomes of Hepatocellular Carcinoma within the Milan Criteria: Liver Transplantation versus Locoregional Therapy: A Retrospective Cohort Study. Medicine (Baltimore), 95, e4735. <br>https://doi.org/10.1097/MD.0000000000004735Yao, F.Y., Mehta, N., Flemming, J., et al. (2015) Down-staging of Hepatocellular Cancer before Liver Transplant: Long-Term Outcome Compared to Tumors within Milan Criteria. Hepatology, 61, 1968-1977.
<br>https://doi.org/10.1002/hep.27752Xu, X., Lu, D., Ling, Q., et al. (2016) Liver Transplantation for Hepato-cellular Carcinoma beyond the Milan Criteria. Gut, 65, 1035-1041. <br>https://doi.org/10.1136/gutjnl-2014-308513Levi Sandri, G.B., Rayar, M., Qi, X., et al. (2018) Liver Trans-plant for Patients outside Milan Criteria. Translational Gastroenterology and Hepatology, 3, 81. <br>https://doi.org/10.21037/tgh.2018.10.03Shimamura, T., Akamatsu, N., et al. (2018) Expanded Living-Donor Liver Transplantation Criteria for Patients with Hepatocellular Carcinoma Based on the Japanese Nationwide Survey: The 5-5-500 Rule—A Retrospective Study. Transplant International.Chen, J., Xu, X., Wu, J., et al. (2014) The Stratifying Value of Hangzhou Criteria in Liver Transplantation for Hepatocellular Carcinoma. PLoS ONE, 9, e93128. <br>https://doi.org/10.1371/journal.pone.0093128Qu, Z., Ling, Q., Gwiasda, J., et al. (2018) Hangzhou Criteria Are More Accurate than Milan Criteria in Predicting Long-Term Survival after Liver Transplantation for HCC in Germany. Langenbeck’s Archives of Surgery, 403, 643-654. <br>https://doi.org/10.1007/s00423-018-1696-8Audet, M., Panaro, F., Piardi, T., et al. (2009) Are the Hangzhou Criteria Adaptable to Hepatocellular Carcinoma Patients for Liver Transplantation in Western Countries? Liver Trans-plantation, 15, 822-823.
<br>https://doi.org/10.1002/lt.21765Fan, S.T. (2008) Selection of HCC Patients for Liver Transplantation: The Milan Criteria, Hangzhou Criteria and beyond. Hepatobiliary & Pancreatic Diseases International, 7, 233-234.Duvoux, C., Roudot-Thoraval, F., Decaens, T., et al. (2012) Liver Transplantation for Hepatocellular Carcinoma: A Model Including Alpha-Fetoprotein Improves the Performance of Milan Criteria. Gastroenterology, 143, 986-994.
<br>https://doi.org/10.1053/j.gastro.2012.05.052Toso, C., Asthana, S., Bigam, D.L., et al. (2009) Reassessing Selection Criteria Prior to Liver Transplantation for Hepatocellular Carcinoma Utilizing the Scientific Registry of Transplant Recipients Database. Hepatology, 49, 832-838.
<br>https://doi.org/10.1002/hep.22693Toso, C., Meeberg, G., Hernandez-Alejandro, R., et al. (2015) Total Tumor Volume and Alpha-Fetoprotein for Selection of Transplant Candidates with Hepatocellular Carcinoma: A Prospective Validation. Hepatology, 62, 158-165.
<br>https://doi.org/10.1002/hep.27787Han, K., Tzimas, G.N., Barkun, J.S., et al. (2007) Preoperative Alpha-Fetoprotein Slope Is Predictive of Hepatocellular Carcinoma Recurrence after Liver Transplantation. Canadian Journal of Gastroenterology, 21, 39-45.
<br>https://doi.org/10.1155/2007/206383Dumitra, T.C., Dumitra, S., Metrakos, P.P., et al. (2013) Pretransplantation Alpha-Fetoprotein Slope and Milan Criteria: Strong Predictors of Hepatocellular Carcinoma Recurrence after Transplantation. Transplantation, 95, 228-233.
<br>https://doi.org/10.1097/TP.0b013e31827743d7Citores, M.J., Lucena, J.L., De La Fuente, S., et al. (2019) Serum Biomarkers and Risk of Hepatocellular Carcinoma Recurrence after Liver Transplantation. World Journal of Hepatology, 11, 50-64. <br>https://doi.org/10.4254/wjh.v11.i1.50Yang, N., Li, Z., Yan, M., et al. (2019) Evaluation of Serum Alpha-Fetoprotein Level in Chronic Hepatitis C Patients. Clinical Laboratory, 65.Schieving, J.H., De Vries, M., Van Vugt, J.M., et al. (2014) Alpha-Fetoprotein, a Fascinating Protein and Biomarker in Neurology. European Journal of Paediatric Neurology, 18, 243-248. <br>https://doi.org/10.1016/j.ejpn.2013.09.003Bruix, J. and Sherman, M. (2011) Management of Hepatocellular Carcinoma: An Update. Hepatology, 53, 1020-1022.
<br>https://doi.org/10.1002/hep.24199European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer (2012) EASL-EORTC Clinical Practice Guidelines: Management of Hepatocellular Carcinoma. Journal of Hepatology, 4, 908-943.Benson, A.B., D’angelica, M.I., Abrams, T.A., et al. (2014) Hepatobiliary Cancers, Version 2.2014. Journal of the National Comprehensive Cancer Network, 12, 1152-1182. <br>https://doi.org/10.6004/jnccn.2014.0112Chaiteerakij, R., Zhang, X., Addissie, B.D., et al. (2015) Combinations of Biomarkers and Milan Criteria for Predicting Hepatocellular Carcinoma Recurrence after Liver Transplantation. Liver Transplantation, 21, 599-606.
<br>https://doi.org/10.1002/lt.24117Pote, N., Cauchy, F., Albuquerque, M., et al. (2015) Performance of PIVKA-II for Early Hepatocellular Carcinoma Diagnosis and Prediction of Microvascular Invasion. Journal of Hepatology, 62, 848-854.
<br>https://doi.org/10.1016/j.jhep.2014.11.005Hong, Y.M., Cho, M., Yoon, K.T., et al. (2017) Risk Factors of Early Recurrence after Curative Hepatectomy in Hepatocellular Carcinoma. Tumor Biology, 39, 1010428317720863. <br>https://doi.org/10.1177/1010428317720863Takada, Y., Ito, T., Ueda, M., et al. (2007) Living Donor Liver Transplantation for Patients with HCC Exceeding the Milan Criteria: A Proposal of Expanded Criteria. Digestive Diseases, 25, 299-302. <br>https://doi.org/10.1159/000106908Yang, K., Lee, T.B., Choi, B.H., et al. (2016) Development and Applicability of the A-P 200 Criteria for Liver Transplantation for Hepatocellular Carcinoma. Transplantation Proceedings, 48, 3317-3322.
<br>https://doi.org/10.1016/j.transproceed.2016.08.050Kim, S.H., Moon, D.B., Kim, W.J., et al. (2016) Preoperative Prognostic Values of Alpha-Fetoprotein (AFP) and Protein Induced by Vitamin K Absence or Antagonist-II (PIVKA-II) in Patients with Hepatocellular Carcinoma for Living Donor Liver Transplantation. Hepatobiliary Surgery and Nutrition, 5, 461-469.
<br>https://doi.org/10.21037/hbsn.2016.11.05De Stefano, F., Chacon, E., Turcios, L., et al. (2018) Novel Biomarkers in Hepatocellular Carcinoma. Digestive and Liver Disease, 50, 1115-1123. <br>https://doi.org/10.1016/j.dld.2018.08.019Kulik, L. and El-Serag, H.B. (2019) Epidemiology and Management of Hepatocellular Carcinoma. Gastroenterology, 156, 477-491.e471. <br>https://doi.org/10.1053/j.gastro.2018.08.065Kinoshita, A., Onoda, H., Imai, N., et al. (2015) C-Reactive Protein as a Prognostic Marker in Patients with Hepatocellular Carcinoma. Hepatogastroenterology, 62, 966-970.Chan, S.L. and Chan, A.W. (2017) Systematic Evaluation of Circulating Inflammatory Markers for Hepatocellular Carcinoma. Liver International, 37, 280-289.An, H.J., Jang, J.W., Bae, S.H., et al. (2012) Serum C-Reactive Protein Is a Useful Biomarker for Predicting Outcomes after Liver Transplantation in Patients with Hepatocellular Carcinoma. Liver Transplantation, 18, 1406-1414.
<br>https://doi.org/10.1002/lt.23512Kornberg, A., Witt, U., Kornberg, J., et al. (2016) Postoperative Peak Serum C-Reactive Protein Is a Predictor of Outcome Following Liver Transplantation for Hepatocellular Carcinoma. Biomarkers, 21, 152-159.
<br>https://doi.org/10.3109/1354750X.2015.1118548Halazun, K.J., Aldoori, A., Malik, H.Z., et al. (2008) Elevated Preoperative Neutrophil to Lymphocyte Ratio Predicts Survival Following Hepatic Resection for Colorectal Liver Metastases. European Journal of Surgical Oncology, 34, 55-60. <br>https://doi.org/10.1016/j.ejso.2007.02.014Halazun, K.J., Hardy, M.A., Rana, A.A., et al. (2009) Negative Impact of Neutrophil-Lymphocyte Ratio on Outcome after Liver Transplantation for Hepatocellular Carcinoma. Annals of Surgery, 250, 141-151.
<br>https://doi.org/10.1097/SLA.0b013e3181a77e59Yoshizumi, T., Ikegami, T., Yoshiya, S., et al. (2013) Impact of Tumor Size, Number of Tumors and Neutrophil-to-Lymphocyte Ratio in Liver Transplantation for Recurrent Hepatocellular Carcinoma. Hepatology Research, 43, 709-716. <br>https://doi.org/10.1111/hepr.12016Najjar, M., Agrawal, S., Emond, J.C., et al. (2018) Pretreatment Neutrophil-Lymphocyte Ratio: Useful Prognostic Biomarker in Hepatocellular Carcinoma. Journal of Hepatocellular Carcinoma, 5, 17-28.
<br>https://doi.org/10.2147/JHC.S86792Xu, Z.G., Ye, C.J., Liu, L.X., et al. (2018) The Pretransplant Neutrophil-Lymphocyte Ratio as a New Prognostic Predictor after Liver Transplantation for Hepatocellular Cancer: A Systematic Review and Meta-Analysis. Biomarkers in Medicine, 12, 189-199. <br>https://doi.org/10.2217/bmm-2017-0307Xia, W., Ke, Q., Wang, Y., et al. (2015) Predictive Value of Pre-Transplant Platelet to Lymphocyte Ratio for Hepatocellular Carcinoma Recurrence after Liver Transplantation. World Journal of Surgical Oncology, 13, 60.
<br>https://doi.org/10.1186/s12957-015-0472-2Pinato, D.J., Stebbing, J., Ishizuka, M., et al. (2012) A Novel and Validated Prognostic Index in Hepatocellular Carcinoma: The Inflammation Based Index (IBI). Journal of Hepatology, 57, 1013-1020.
<br>https://doi.org/10.1016/j.jhep.2012.06.022Lai, Q., Melandro, F., Larghi Laureiro, Z., et al. (2018) Platelet-to-Lymphocyte Ratio in the Setting of Liver Transplantation for Hepatocellular Cancer: A Systematic Review and Meta-Analysis. World Journal of Gastroenterology, 24, 1658-1665. <br>https://doi.org/10.3748/wjg.v24.i15.1658Han, S., Lee, S., Yang, J.D., et al. (2018) Risk of Posttransplant Hepatocellular Carcinoma Recurrence Is Greater in Recipients with Higher Platelet Counts in Living Donor Liver Transplantation. Liver Transplantation, 24, 44-55.
<br>https://doi.org/10.1002/lt.24961Xia, W., Ke, Q., Guo, H., et al. (2017) Expansion of the Milan Criteria without Any Sacrifice: Combination of the Hangzhou Criteria with the Pre-Transplant Platelet-to-Lymphocyte Ratio. BMC Cancer, 17, 14.
<br>https://doi.org/10.1186/s12885-016-3028-0