Progenitor cell markers predict outcome of patients with hepatocellular carcinoma beyond Milan criteria undergoing liver transplantation

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• 作者：Oriana Miltiadous¹ ; Daniela Sia¹ ; ² ; Yujin Hoshida¹ ; Maria Isabel Fiel¹ ; Andrew N. Harrington¹ ; Swan N. Thung¹ ; Poh Seng Tan¹ ; ³ ; Hui Dong⁴ ; Kate Revill¹ ; Charissa Y. Chang¹ ; Sasan Roayaie⁵ ; Thomas J. Byrne⁶ ; Vincenzo Mazzaferro² ; Jorge Rakela⁶ ; Sander Florman¹ ; Myron Schwartz¹ ; Josep M. Llovet¹ ; ⁷ ; ⁸ ; ^{Josep.Llovet@mssm.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：HCC ; hepatocellular carcinoma ; LT ; liver transplantation ; CK19 ; cytokeratin protein 19 ; HR ; hazard Ratio ; EpCAM ; epithelial cell adhesion molecule ; OS ; overall survival ; miVI ; microvascular invasion ; TGFb ; transforming growth factor-beta ; CT ; computed tomography ; MRI ; magnetic resonance imaging ; AFP ; alpha-fetoprotein ; IHC ; immunohistochemical ; RPS6 ; ribosomal protein S6 ; FDR ; false discovery rate ; H&E ; hematoxylin and eosin ; PPV ; positive predictive value ; NPV ; negative predictive value ; HCV ; h
• 刊名：Journal of Hepatology
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：63
• 期：6
• 页码：1368-1377
• 全文大小：1028 K

文摘

In patients with hepatocellular carcinoma (HCC), liver transplantation (LT) is an excellent therapy if tumor characteristics are within the Milan criteria. We aimed to define genomic features enabling to identify HCC patients beyond Milan criteria who have acceptable transplant outcomes.

Methods

Among 770 consecutive HCC patients transplanted between 1990 and 2013, 132 had tumors exceeding Milan criteria on pathology and were enrolled in the study; 44% of the patients satisfied the ‘up-to-7 rule’ [7 = sum of the size of the largest tumor and the number of tumors]. Explant tumors were assessed for genomic signatures and immunohistochemical markers associated with poor outcome.

Results

At a median follow-up of 88 months, 64 patients had died and 45 recurred; the 5-year overall survival (OS) and recurrence rates were 57% and 35%, respectively. Cytokeratin 19 (CK19) gene signature was independently associated with recurrence [Hazard ratio (HR) = 2.95, m>pm> <0.001], along with tumor size (HR = 3.37, m>pm> = 0.023) and presence of satellites (HR = 2.98, m>pm> = 0.001). S2 subclass signature was independently associated with poor OS (HR = 3.18, m>pm> = 0.001), along with tumor size (HR = 5.06, m>pm> <0.001) and up-to-7 rule (HR = 2.50, m>pm> = 0.002). Using the presence of progenitor cell markers (either CK19 or S2 signatures) patients were classified into poor prognosis (n = 58; 5-year recurrence 53%, survival 45%) and good prognosis (n = 74; 5-year recurrence 19%, survival 67%) (HR = 3.16, m>pm> <0.001 for recurrence, and HR = 1.72, m>pm> = 0.04 for OS).

Conclusions

HCC patients transplanted beyond Milan criteria without gene signatures of progenitor markers (CK19 and S2) achieved survival rates similar as those within Milan criteria. Once prospectively validated, these markers may support a limited expansion of LT indications.