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Outcome of Patients With Recurrent Hepatocellular Carcinoma in Liver Transplantation
Outcome of Patients With Recurrent Hepatocellular Carcinoma in Liver Transplantation J.W. Park, K.W. Lee, S.J. Kim, S.H. Choi, J.S. Heo, C.H.D. Kwon, D.J. Kim, Y.S. Han, S.K. Lee, and J.W. Joh ABSTRACT Liver transplantation (OLT) is the treatment of choice for patients with hepatic cirrhosis related hepatocellular carcinoma (HCC). Among 156 liver transplant patients for HCC from June 1996 to February 2005, 23 had recurrent HCC. To evaluate risk factors that affect early recurrence of HCC after OLT, we divided the 23 patients into two groups: early (ⱕ12 months) and late (⬎12 months) recurrences. Among them, 15 patients were dead and eight alive patients had been followed to 31 July 2005. The most common recurrence site was the grafted liver (n ⫽ 15), next was bone (n ⫽ 11), lung (n ⫽ 8), lymph node (n ⫽ 6), brain (n ⫽ 4), skin (n ⫽ 2), adrenal gland (n ⫽ 1). There were no significant differences between the two groups in age or tumor size, number of tumors, cell differentiation, alpha-feto protein levels, tumor staging, number of patients within Milan criteria, steroid pulse therapy, infectious diseases, and immunostaining of tumor. In our study, there were no risk factors that predict early tumor recurrence. We noticed that more patients in the early recurrence group were excluded by Milan criteria due to a more progressed tumor staging with higher mean levels of serum alpha-feto protein.
T
HE COMMON CAUSE of hepatocellular carcinoma (HCC) in Korea is hepatitis B virus (HBV)-related liver cirrhosis; liver transplantation (OLT) is the treatment of choice for these patients. With the help of immunosuppressive agents and developments in surgical technique, patient outcomes after OLT are improving, but there is still a risk of recurrence of underlying causes, including viral hepatitis or HCC. Risk factors that predicted the recurrence of HCC after OLT included tumor size, number of tumors, and vascular invasion. The aim of this study was to investigate the characteristics of patients with recurrent HCC to discover risk factors that affect early recurrence of HCC after OLT.
PATIENTS AND METHODS Among 156 liver transplant patients for HCC from June 1996 to February 2005, 23 had recurrent HCC. We studied the characteristics of 23 patients divided into two groups, according to the time of recurrence, namely, an early recurrence group (ⱕ12 months) versus a late recurrence group (⬎12 months). Continuous variables were compared using Student t test and categorical variables using Fisher Exact Test. Statistical analysis was performed using SPSS 11.5 for Windows.
RESULTS
Of 156 adult patients who received OLT for HCC from June 1996 to February 2005, 23 patients (14.7%) showed recurrences. They had received four cadaveric and 19 living donor liver transplantations due to HBV-related liver cirrhosis (n ⫽ 19), hepatitis C virus (HCV)-related liver cirrhosis (n ⫽ 2), HBV-related hepatitis (n ⫽ 1), HCVrelated hepatitis (n ⫽ 1). The pathological stage according to the 6th AJCC/UICC was stage II in 12; stage IIIA in nine; stage IIIB in one; and stage IIIC in one. There was significant difference in cumulative survival time between stage II versus stage IIIB and stage IIIC (P ⫽ .0338 in log-rank test). The male/female ratio was 22:1. The mean age of patients was 50.1 years (35 to 68 years). At July 31, 2005, 15 patients were dead and eight alive. The most common site of recurrence was the grafted liver (n ⫽ 15), bone (n ⫽ 11), lung (n ⫽ 8), lymph node (n ⫽ 6), brain (n ⫽ From the Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Address reprint requests to J.W. Joh, MD, PhD, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Gangnam-gu, Seoul, Korea, 135-710. E-mail: [email protected]
© 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.06.030
Transplantation Proceedings, 38, 2121–2122 (2006)
2121
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4), skin (n ⫽ 2), and adrenal gland (n ⫽ 1). Viral hepatitis recurred in nine patients (HBV: 7; HCV: 2). Five patients had received steroid pulse therapy for rejection. The mean levels of elevated alpha-feto protein before and after tumor recurrence were 8284 ng/mL (2 to 171,792 ng/mL) and 7,594,009 ng/mL (2 to 1,000,000 ng/mL). The mean duration of tumor recurrence after OLT was 12.5 months (1.2 to 46.8). The mean duration of death after tumor recurrence was 9.1 months (0.8 to 27.9) and mean survival duration was 20.9 months (2.9 to 69.5). Among 23 recurrence patients, 14 were in the early and nine in the late recurrence groups. The mean age between two groups was 50.4 ⫾ 5.9 years versus 49.6 ⫾ 9.3 years. The mean tumor size was 5.7 ⫾ 4.4 cm versus 3.7 ⫾ 1.3 cm (P ⬎ .05). Three of the 14 patients (21.4%) in the early recurrence group, and four of nine patients (44.4%) in the late recurrence group were within the Milan criteria (P ⬎ .05). The mean levels of alpha-feto protein before and after recurrence were 13487 ng/mL versus 191 ng/mL and 116576 ng/mL versus 12730 ng/mL (P ⬎ .05). The mean duration to death after tumor recurrence between two groups was 5.3 ⫾ 6.1 months versus 13.2 ⫾ 11.0 months (P ⬎ .05). The stage II patients in each group were six and six stage IIIA were six and three. There was one patient in stage IIIB and IIIC (P ⬎ .05), respectively, who were both in the early recurrence group. The mean duration of recurrence-free survival between two groups was 3.9 ⫾ 2.3 months and 25.9 ⫾ 10.9 months (P ⫽ .000). The mean duration of overall survival was 9.2 ⫾ 6.0 months and 39.1 ⫾ 16.2 months (P ⫽ .000). Edmondson tumor grade II and III in the early group were 11 and 3; in the late group, seven and two (P ⬎ .05). In a study of immunohistochemical staining for p53, cyclin D1, and cyclin E, there was no significant statistical difference between the two groups. Recurrence of viral hepatitis (four vs five) and steroid pulse therapy (two vs three), biliary infection (three vs two), cytomegalovirus infection (two vs one) showed also no significant statistical differences between the two groups.
PARK, LEE, KIM ET AL
DISCUSSION
Tumor features that predict recurrence and poor prognosis after OLT for HCC include tumor size, number of tumors, micro/macrovascular invasion, high serum alpha-feto protein,1 and Milan criteria, which is one of the well-known predictors. In current studies, it has been suggested that immunostainings of the tumor, including p53, Ki-67,2 p-27, cyclin E, cyclin A,3 and cyclin D14 predict more rapid recurrence and poorer prognosis. In addition to these tumor features, we must consider the role of immunosuppression in tumor recurrence. Evaluating the key role of immunosuppression in tumor recurrence, Vivarelli et al reported that high exposure to immunosuppression agents favored tumor recurrence.5 In our study, even though there were no risk factors that predicted early tumor recurrence, we noted that more patients were excluded from Milan criteria and that the mean level of serum alpha-feto protein was higher. Tumor staging was more progressive among the early than the late recurrence group.
REFERENCES 1. Shetty K, Timmins K, Brensinger C, et al: Liver transplantation for hepatocellular carcinoma validation of present selection criteria in predicting outcome. Liver Transpl 10:911, 2004 2. Guzman G, Alagiozian-Angelova V, Layden-Almer JE, et al: p53, Ki-67, and serum alpha feto-protein as predictors of hepatocellular carcinoma recurrence in liver transplantation patients. Mod Pathol 18:1498, 2005 3. Zhou Q, He Q, Liang LJ: Expression of p27, cyclin E and cyclin A in hepatocellular carcinoma and its clinical significance. World J Gastroenterol 9:2450, 2003 4. Zhang YJ, Chen SY, Chen CJ, et al: Polymorphism in cyclin D1 gene and hepatocellular carcinoma. Mol Carcinog 33:125, 2002 5. 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 11:497, 2005
T
HE COMMON CAUSE of hepatocellular carcinoma (HCC) in Korea is hepatitis B virus (HBV)-related liver cirrhosis; liver transplantation (OLT) is the treatment of choice for these patients. With the help of immunosuppressive agents and developments in surgical technique, patient outcomes after OLT are improving, but there is still a risk of recurrence of underlying causes, including viral hepatitis or HCC. Risk factors that predicted the recurrence of HCC after OLT included tumor size, number of tumors, and vascular invasion. The aim of this study was to investigate the characteristics of patients with recurrent HCC to discover risk factors that affect early recurrence of HCC after OLT.
PATIENTS AND METHODS Among 156 liver transplant patients for HCC from June 1996 to February 2005, 23 had recurrent HCC. We studied the characteristics of 23 patients divided into two groups, according to the time of recurrence, namely, an early recurrence group (ⱕ12 months) versus a late recurrence group (⬎12 months). Continuous variables were compared using Student t test and categorical variables using Fisher Exact Test. Statistical analysis was performed using SPSS 11.5 for Windows.
RESULTS
Of 156 adult patients who received OLT for HCC from June 1996 to February 2005, 23 patients (14.7%) showed recurrences. They had received four cadaveric and 19 living donor liver transplantations due to HBV-related liver cirrhosis (n ⫽ 19), hepatitis C virus (HCV)-related liver cirrhosis (n ⫽ 2), HBV-related hepatitis (n ⫽ 1), HCVrelated hepatitis (n ⫽ 1). The pathological stage according to the 6th AJCC/UICC was stage II in 12; stage IIIA in nine; stage IIIB in one; and stage IIIC in one. There was significant difference in cumulative survival time between stage II versus stage IIIB and stage IIIC (P ⫽ .0338 in log-rank test). The male/female ratio was 22:1. The mean age of patients was 50.1 years (35 to 68 years). At July 31, 2005, 15 patients were dead and eight alive. The most common site of recurrence was the grafted liver (n ⫽ 15), bone (n ⫽ 11), lung (n ⫽ 8), lymph node (n ⫽ 6), brain (n ⫽ From the Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Address reprint requests to J.W. Joh, MD, PhD, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Gangnam-gu, Seoul, Korea, 135-710. E-mail: [email protected]
© 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.06.030
Transplantation Proceedings, 38, 2121–2122 (2006)
2121
2122
4), skin (n ⫽ 2), and adrenal gland (n ⫽ 1). Viral hepatitis recurred in nine patients (HBV: 7; HCV: 2). Five patients had received steroid pulse therapy for rejection. The mean levels of elevated alpha-feto protein before and after tumor recurrence were 8284 ng/mL (2 to 171,792 ng/mL) and 7,594,009 ng/mL (2 to 1,000,000 ng/mL). The mean duration of tumor recurrence after OLT was 12.5 months (1.2 to 46.8). The mean duration of death after tumor recurrence was 9.1 months (0.8 to 27.9) and mean survival duration was 20.9 months (2.9 to 69.5). Among 23 recurrence patients, 14 were in the early and nine in the late recurrence groups. The mean age between two groups was 50.4 ⫾ 5.9 years versus 49.6 ⫾ 9.3 years. The mean tumor size was 5.7 ⫾ 4.4 cm versus 3.7 ⫾ 1.3 cm (P ⬎ .05). Three of the 14 patients (21.4%) in the early recurrence group, and four of nine patients (44.4%) in the late recurrence group were within the Milan criteria (P ⬎ .05). The mean levels of alpha-feto protein before and after recurrence were 13487 ng/mL versus 191 ng/mL and 116576 ng/mL versus 12730 ng/mL (P ⬎ .05). The mean duration to death after tumor recurrence between two groups was 5.3 ⫾ 6.1 months versus 13.2 ⫾ 11.0 months (P ⬎ .05). The stage II patients in each group were six and six stage IIIA were six and three. There was one patient in stage IIIB and IIIC (P ⬎ .05), respectively, who were both in the early recurrence group. The mean duration of recurrence-free survival between two groups was 3.9 ⫾ 2.3 months and 25.9 ⫾ 10.9 months (P ⫽ .000). The mean duration of overall survival was 9.2 ⫾ 6.0 months and 39.1 ⫾ 16.2 months (P ⫽ .000). Edmondson tumor grade II and III in the early group were 11 and 3; in the late group, seven and two (P ⬎ .05). In a study of immunohistochemical staining for p53, cyclin D1, and cyclin E, there was no significant statistical difference between the two groups. Recurrence of viral hepatitis (four vs five) and steroid pulse therapy (two vs three), biliary infection (three vs two), cytomegalovirus infection (two vs one) showed also no significant statistical differences between the two groups.
PARK, LEE, KIM ET AL
DISCUSSION
Tumor features that predict recurrence and poor prognosis after OLT for HCC include tumor size, number of tumors, micro/macrovascular invasion, high serum alpha-feto protein,1 and Milan criteria, which is one of the well-known predictors. In current studies, it has been suggested that immunostainings of the tumor, including p53, Ki-67,2 p-27, cyclin E, cyclin A,3 and cyclin D14 predict more rapid recurrence and poorer prognosis. In addition to these tumor features, we must consider the role of immunosuppression in tumor recurrence. Evaluating the key role of immunosuppression in tumor recurrence, Vivarelli et al reported that high exposure to immunosuppression agents favored tumor recurrence.5 In our study, even though there were no risk factors that predicted early tumor recurrence, we noted that more patients were excluded from Milan criteria and that the mean level of serum alpha-feto protein was higher. Tumor staging was more progressive among the early than the late recurrence group.
REFERENCES 1. Shetty K, Timmins K, Brensinger C, et al: Liver transplantation for hepatocellular carcinoma validation of present selection criteria in predicting outcome. Liver Transpl 10:911, 2004 2. Guzman G, Alagiozian-Angelova V, Layden-Almer JE, et al: p53, Ki-67, and serum alpha feto-protein as predictors of hepatocellular carcinoma recurrence in liver transplantation patients. Mod Pathol 18:1498, 2005 3. Zhou Q, He Q, Liang LJ: Expression of p27, cyclin E and cyclin A in hepatocellular carcinoma and its clinical significance. World J Gastroenterol 9:2450, 2003 4. Zhang YJ, Chen SY, Chen CJ, et al: Polymorphism in cyclin D1 gene and hepatocellular carcinoma. Mol Carcinog 33:125, 2002 5. 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 11:497, 2005