- Email: [email protected]
Small-Sized Liver Graft Does Not Increase the Risk of Hepatocellular Carcinoma Recurrence After Living Donor Liver Transplantation
Small-Sized Liver Graft Does Not Increase the Risk of Hepatocellular Carcinoma Recurrence After Living Donor Liver Transplantation S. Hwang, S.G. Lee, C.S. Ahn, K.H. Kim, D.B. Moon, T.Y. Ha, K.M. Park, G.W. Song, D.H. Jung, B.S. Kim, and K.M. Moon ABSTRACT Purpose. Following implantation into adult recipients, living donor liver grafts usually undergo liver regeneration. This regeneration process may provoke the growth of occult hepatocellular carcinoma (HCC) cells in the recipient body. To assess the risk of HCC recurrence, we analyzed the influence of graft–recipient weight ratio (GRWR). Methods. The 181 recipients with HCC within the University of California at San Francisco (UCSF) criteria were divided into four groups according to GRWR: low GRWR (⬍0.8; n ⫽ 30), mid GRWR (0.8 –1.0; n ⫽ 65), high GRWR (⬎1.0; n ⫽ 64), and whole liver graft group (⬎1.5; n ⫽ 22). Results. There were no differences in overall patient survival (P ⫽ .105) and recurrencefree survival (P ⫽ .406) among these four groups. GRWR ⬍0.8 was not a significant risk factor for HCC recurrence. Similar outcomes were obtained in HCC patients who met the Milan criteria (n ⫽ 170). Conclusions. We think that small living donor liver graft and subsequent liver regeneration do not increase the risk of posttransplant HCC recurrence when HCC is within the Milan or UCSF criteria.
L
IVING DONOR liver transplantation (LDLT) has been replacing deceased donor liver transplantation (DDLT) in countries where there is an extreme shortage of deceased donors. Following technical improvements, the outcome of LDLT has become comparable to that of DDLT.1–5 However, due to early graft regeneration following implantation of partial liver graft, adult LDLT may have potential risk of hepatocellular carcinoma (HCC) recurrence. Theoretically, there should be no biological or oncologic difference between LDLT and DDLT after full regeneration of a partial liver graft. A partial liver graft undergoes a complex process of liver regeneration through hypertrophy and hyperplasia of the hepatocytes.6,7 This regeneration process, however, can provoke the growth of occult HCC cells within the recipient body. At the same time, especially during the early posttransplant period, replication of HCC cells can also be accelerated by strong immunosuppression. These possible associations between graft regeneration and HCC recurrence suggest that small liver grafts should be avoided in HCC patients undergoing liver transplantation because rapid regeneration following implantation of such liver graft is an inevitable and natural process.
It has been hypothesized that rapid liver regeneration process during early posttransplant period can affect the growth of HCC cells within or outside the liver.8,9 Because the native liver would have been removed, there should be no HCC cells in the new liver graft, in the absence of new implantation from the circulation. Systematic verification of this hypothesis would require large-volume basic and clinical studies to disclose the possible underlying mechanisms. In this clinical study, to assess the influence of living donor liver graft size on HCC recurrence, we analyzed the effect of graft–recipient weight ratio (GRWR) on HCC recurrence in 181 recipients who met the University of California San Francisco (UCSF) criteria. MATERIALS AND METHODS In our institution, 932 adult liver transplantations (787 LDLTs and 145 DDLTs) were performed from August 1992 to December From the Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Address reprint requests to Dr Sung-Gyu Lee, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, 388-1 Poongnap-Dong, Seoul 138-736, Republic of Korea. E-mail: [email protected]
0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.03.066
© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1526
Transplantation Proceedings, 39, 1526 –1529 (2007)
SMALL LIVER GRAFTS
1527
2004.10,11 Of these patients, 282 (30.3%) were diagnosed as having HCC before transplantation or from the explanted liver specimens. Our eligibility criteria for HCC patients were primarily the UCSF criteria with preoperative imaging studies, but some more advanced HCC patients were accepted on case-by-case basis, especially for LDLT. Because the incidence of deceased organ donors was very low in Korea, only a small number of HCC patients were allocated to DDLT through the Korean Network for Organ Sharing. To determine whether GRWR had an influence on HCC recurrence, we performed a case-controlled study. To avoid bias from various factors related to the surgery or tumor, we excluded 101 recipients from this analysis, 19 perioperative mortality patients within 3 months, 16 who underwent salvage transplantation, 2 who underwent retransplantation, 1 who underwent split DDLT, 51 with pathologically advanced HCC beyond the UCSF criteria, and 34 with incidentally detected HCC.12–14 Some of the recipients had overlapping exclusion criteria. The reason why the HCC patients beyond the UCSF criteria were excluded was to match the HCC recurrence rate for reasonable comparison because such patients showed definitely high incidence of HCC recurrence. In contrast, there was no HCC recurrence in recipients who were incidentally diagnosed as HCC only at the explanted livers.1,15 The remaining 181 patients were stratified into four groups according to GRWR, ⬍0.8 (low GRWR group, n ⫽ 30), 0.8 to 1.0 (mid GRWR group, n ⫽ 65), ⬎1.0 (high GRWR group, n ⫽ 64), and whole liver graft group after DDLT (n ⫽ 22). We arbitrarily regarded the low GRWR group as the small-for-size graft group. The weight of whole liver graft was not available in all DDLT cases, but no whole liver graft was smaller than 1.5 of GRWR. Patient and tumor profiles are summarized in Tables 1 and 2. Of the 181 patients, 139 (76.8%) underwent pretransplant treatments, including transarterial chemoembolization (n ⫽ 111, 61.3%), radiofrequency ablation (n ⫽ 20, 11.1%) and percutaneous ethanol injection (n ⫽ 8, 4.4%). Liver transplantation was planned due to progressive deterioration of liver function or failure of HCC treatment. Mean values with standard deviation and median values with range were used for numeric data. The significance of differences was assessed by analysis of variance. Survival curves were estimated by the Kaplan-Meier method and compared with the log-rank test. Multivariate analysis was carried out using the Cox proportional hazard model. Patient death unrelated to HCC recurrence was regarded as a censored case during the statistical analysis of HCC recurrence. Statistical significance was defined as P-value ⬍ .05.
RESULTS Patient Survival
Of the 181 recipients, HCC recurred in 24 (13.3%), and 22 died from HCC recurrence during a median follow-up of 38 months (range, 3–116 months). Another 10 recipients died from causes other than HCC recurrence. There were no differences in overall patient survival among the four GRWR groups (P ⫽ .105; Fig 1). Similar outcomes were obtained when the HCC patients were confined to the Milan criteria (n ⫽ 170; P ⫽ .132). HCC Recurrence
We observed no differences in recurrence-free survival according to GRWR (P ⫽ .406; Fig 2). Similar outcomes were also obtained after application of the Milan criteria (n ⫽ 170; P ⫽ .256). The most common sites of initial HCC recurrence were the engrafted liver itself (n ⫽ 13), the lungs (n ⫽ 4), liver and lungs (n ⫽ 1), peritoneum and abdomen (n ⫽ 6), abdominal wall (n ⫽ 1), and adrenal glands (n ⫽ 1). These recurrent HCC lesions were initially treated by transarterial chemoembolization (n ⫽ 13), systemic chemotherapy (n ⫽ 5), and surgical resections (n ⫽ 6), including lung metastasectomy (n ⫽ 3), liver resection (n ⫽ 1), adrenalectomy (n ⫽ 1), and abdominal wall excision (n ⫽ 1). According to the progression of recurrent tumors, aggressive multimodality treatments with minimal immunosuppression were concurrently carried out. However, the median survival period after tumor recurrence was 7 months in the low GRWR group, 5 months in the mid GRWR group, 19 months in the high GRWR group, and 10 months in the whole liver graft group (P ⫽ .431). Risk Factor Analysis for Posttransplant HCC Recurrence
Univariate analysis revealed that significant risk factors for posttransplant HCC recurrence included preoperative serum ␣-fetoprotein concentration, tumor size, microvascular invasion, and histologic differentiation (Table 2). Multivariate analysis showed that moderate/poor
Table 1. Demographic and Graft Profiles of HCC Patients Who Underwent Liver Transplantation Parameters/GRWR Group
GRWR range No. of patients Age (yrs) Male gender, n (%) MELD score Viral hepatitis B, n (%) Within Milan criteria, n (%) Living donor graft type, n (%) Right lobe graft Left lobe graft Dual grafts Median follow-up period, mos
Low
Mid
High
Whole Liver
P-Value
⬍0.8 30 50.3 ⫾ 6.8 23 (76.7) 16.5 ⫾ 6.4 27 (90) 28 (93.3)
0.8–1.0 65 51.8 ⫾ 6.2 53 (81.5) 17.7 ⫾ 8.8 60 (92.3) 64 (98.5)
⬎1.0 64 51.3 ⫾ 7.0 51 (79.7) 17.8 ⫾ 8.5 61 (95.3) 58 (90.6)
⬎1.5 22 49.1 ⫾ 6.5 17 (77.3) 20.1 ⫾ 6.4 19 (86.4) 20 (90.9)
.377 .945 .489 .553 .272
7 (23.3) 20 (66.7) 3 (10.0) 43.5 ⫾ 24.6
35 (53.8) 13 (20.0) 17 (26.2) 34.4 ⫾ 19.7
50 (78.1) 2 (3.1) 12 (18.8) 46.2 ⫾ 22.1
54.8 ⫾ 33.1
.002
GRWR, graft-recipient weight ratio; HCC, hepatocellular carcinoma; MELD, Model for End-Stage Liver Disease.
1528
HWANG, LEE, AHN ET AL Table 2. Univariate Analysis of Risk Factors for HCC Recurrence in 181 HCC Patients Within the UCSF Criteria Disease-Free Survival Rate Parameter
GRWR ⬍0.8 0.8–1.0 ⬎1.0 Whole liver Pretransplant ␣-fetoprotein (ng/mL) ⱕ20 ⬎20 and ⱕ200 ⬎200 and ⱕ1000 ⬎1000 Tumor size (cm) ⱕ2 ⬎2 and ⱕ5 ⬎5 No. of tumors 1 2 3 Microvascular invasion No Yes Tumor distribution Unilobar Bilobar Histologic differentiation Well Moderate/poor
Patients (n)
1 Year
3 Year
5 Year
30 65 64 22
93.3% 90.8% 95.3% 100%
89.7% 80.7% 89.1% 88.9%
89.7% 80.7% 89.1% 72.7%
91 56 16 14
96.7% 94.6% 81.3% 85.7%
94.1% 86.1% 73.9% 55.6%
94.1% 86.1% 73.9% 55.6%
79 97 5
97.4% 92.7% 60.0%
95.9% 80.6% 40.0%
91.7% 76.6% 40.0%
119 38 24
95.8% 94.4% 95.5%
88.0% 85.2% 90.7%
82.5% 85.2% 90.7%
173 8
94.7% 75.0%
88.0% 50.0%
83.8% 50.0%
160 21
94.9% 85.7%
87.0% 80.7%
82.6% 80.7%
78 66
97.4% 87.8%
94.0% 73.4%
85.8% 73.4%
P-Value
.406
.002
⬍.001
.806
.002
.222
.006
HCC, hepatocellular carcinoma.
histologic differentiation was the only significant risk factor (relative risk, 3.71; 95% confidence interval, 1.18 – 11.73; P ⫽ .025).1,16,17 GRWR ⬍ 0.8 was not a significant risk factor on univariate analysis.
When we compared HCC recurrence in recipients of LDLT and DDLT, we observed no prognostic difference.1 However, the influence of graft size was not investigated,
Fig 1. Cumulative survival curves of the patients with HCC within the UCSF criteria according to GRWR. The overall 5-year survival rates were 89.5% in the low GRWR group, 73.7% in the mid GRWR group, 84.8% in the high GRWR group and 54.8% in the whole liver graft group (P ⫽ .105).
Fig 2. Recurrence-free survival curves of the patients with HCC within the UCSF criteria after censoring of HCC-unrelated mortalities. The 5-year recurrence-free survival rates were 89.7% in the low GRWR group, 80.7% in the mid GRWR group, 89.1% in the high GRWR group, and 72.7% in the whole liver graft group (P ⫽ .406).
DISCUSSION
SMALL LIVER GRAFTS
necessitating a complementary study to assess the prognostic significance of small-for-size grafts on HCC recurrence. The results presented here show that small graft and subsequent rapid liver regeneration did not increase the risk of posttransplant HCC recurrence when the HCC lesions were within the Milan or UCSF criteria. This study was primarily focused on the patterns of HCC recurrence among different GRWR groups rather than LDLT versus DDLT because the number of DDLT patient appeared disproportionately small in our series. Three LDLT groups showed similar outcomes on both HCC recurrence and overall survival. In contrast, DDLT group had two patients with late HCC recurrence around 5 years, which made both overall and recurrence-free survival rates rather low. An animal experiment showed accelerated growth of tumor cells during liver graft regeneration, suggesting that significant activation of cell signaling pathways related to tumor invasion, migration, and angiogenesis occurring in small-for-size liver grafts promoted early and invasive tumor growth after liver transplantation.18 Although this animal study suggested that the low GRWR group may have had a higher risk of HCC recurrence when compared with the higher GRWR groups, we did not find that to be consistent with the result of this study. Rather, we found that histologic differentiation was the only significant risk factor for HCC recurrence in patients within the UCSF criteria. There is a possibility that the inconsistency between our clinical findings and the animal study is due to the differences in tumor load relative to the transplanted liver graft. According to both Milan and UCSF criteria, there must be no or really small number of HCC cells in the circulation.19,20 Because the process of graft regeneration occurs only in the transplanted liver graft, absence or presence of extremely small number of HCC cells indicates that there should be no significant HCC growth in the engrafted liver. We found that the 1-year recurrence rate was low in all study groups, and only 56% of all recurrent HCC lesions were detected in the liver at the time of initial HCC recurrence. Thus, the triggering hypothesis, that rapid liver regeneration is associated with the intra- and extrahepatic growth of HCC cells, is not proven to be true in this study. Further studies should be followed to assess the influence of graft size in HCC patients. In conclusion, we think that small living donor liver graft and subsequent liver regeneration do not increase the risk of posttransplant HCC recurrence when HCC is within the Milan or UCSF criteria.
REFERENCES 1. Hwang S, Lee SG, Joh JW, et al: Liver transplantation for adult patients with hepatocellular carcinoma in Korea: comparison
1529 between cadaveric donor and living donor liver transplantations. Liver Transpl 11:1265, 2005 2. Todo S, Furukawa H: Living donor liver transplantation for adult patients with hepatocellular carcinoma: experience in Japan. Ann Surg 240:451, 2004 3. Yokoi H, Isaji S, Yamagiwa K, et al: The role of living-donor liver transplantation in surgical treatment for hepatocellular carcinoma. J Hepatobiliary Pancreat Surg 13:123, 2006 4. Malago M, Sotiropoulos GC, Nadalin S, et al: Living donor liver transplantation for hepatocellular carcinoma: a single-center preliminary report. Liver Transpl 12:934, 2006 5. Takada Y, Ueda M, Ito T, et al: Living donor liver transplantation as a second-line therapeutic strategy for patients with hepatocellular carcinoma. Liver Transpl 12:912, 2006 6. Lee SG, Hwang S, Lee YJ, et al: Regeneration of graft liver in adult-to-adult living donor liver transplantation using a left lobe graft. J Korean Med Sci 13:350, 1998 7. Yokoi H, Isaji S, Yamagiwa K, et al: Donor outcome and liver regeneration after right-lobe graft donation. Transpl Int 18:915, 2005 8. Efimova EA, Glanemann M, Liu L, et al: Effects of human hepatocyte growth factor on the proliferation of human hepatocytes and hepatocellular carcinoma cell lines. Eur Surg Res 36:300, 2004 9. von Schweinitz D, Faundez A, Teichmann B, et al: Hepatocyte growth-factor-scatter factor can stimulate post-operative tumor-cell proliferation in childhood hepatoblastoma. Int J Cancer 85:151, 2000 10. Moon DB, Lee SG: Adult-to-adult living donor liver transplantation at the Asan Medical Center. Yonsei Med J 45:1162, 2004 11. Hwang S, Lee SG, Lee YJ, et al: Lessons learned from 1000 living donor liver transplantations in a single center: how to make living donations safe. Liver Transpl 12:920, 2006 12. Mazzaferro V, Regalia E, Doci R, et al: Liver transplantation for the treatment of small hepatocellular carcinoma in patients with cirrhosis. New Engl J Med 334:693, 1996 13. 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 33:1394, 2001 14. Yao FY, Ferrell L, Bass NM, et al: Liver transplantation for hepatocellular carcinoma: comparison of the proposed UCSF criteria with the Milan criteria and the Pittsburgh modified TNM criteria. Liver Transpl 8:765, 2002 15. Choi SH, Lee HH, Lee DS, et al: Clinicopathological features of incidental hepatocellular carcinoma in liver transplantation. Transplant Proc 36:2293, 2004 16. Tamura S, Kato T, Berho M, et al: Impact of histological grade of hepatocellular carcinoma on the outcome of liver transplantation. Arch Surg 136:25, 2001 17. Jonas S, Bechstein WO, Steinmuller T, et al: Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology 33:1080, 2001 18. Man K, Lo CM, Xiao JW, et al: The significance of graft size on tumor recurrence/metastases after liver transplantation—activation of cell invasion and migration pathways. Liver Transpl 12:C-30 [abstract], 2006 19. Witzigmann H, Geissler F, Benedix F, et al: Prospective evaluation of circulating hepatocytes by alpha-fetoprotein messenger RNA in patients with hepatocellular carcinoma. Surgery 131: 34, 2002 20. Sutcliffe R, Maguire D, Murphy P, et al: Detection and clinical significance of bone marrow micrometastases in patients undergoing liver transplantation for hepatocellular carcinoma. Transplantation 80:88, 2005
L
IVING DONOR liver transplantation (LDLT) has been replacing deceased donor liver transplantation (DDLT) in countries where there is an extreme shortage of deceased donors. Following technical improvements, the outcome of LDLT has become comparable to that of DDLT.1–5 However, due to early graft regeneration following implantation of partial liver graft, adult LDLT may have potential risk of hepatocellular carcinoma (HCC) recurrence. Theoretically, there should be no biological or oncologic difference between LDLT and DDLT after full regeneration of a partial liver graft. A partial liver graft undergoes a complex process of liver regeneration through hypertrophy and hyperplasia of the hepatocytes.6,7 This regeneration process, however, can provoke the growth of occult HCC cells within the recipient body. At the same time, especially during the early posttransplant period, replication of HCC cells can also be accelerated by strong immunosuppression. These possible associations between graft regeneration and HCC recurrence suggest that small liver grafts should be avoided in HCC patients undergoing liver transplantation because rapid regeneration following implantation of such liver graft is an inevitable and natural process.
It has been hypothesized that rapid liver regeneration process during early posttransplant period can affect the growth of HCC cells within or outside the liver.8,9 Because the native liver would have been removed, there should be no HCC cells in the new liver graft, in the absence of new implantation from the circulation. Systematic verification of this hypothesis would require large-volume basic and clinical studies to disclose the possible underlying mechanisms. In this clinical study, to assess the influence of living donor liver graft size on HCC recurrence, we analyzed the effect of graft–recipient weight ratio (GRWR) on HCC recurrence in 181 recipients who met the University of California San Francisco (UCSF) criteria. MATERIALS AND METHODS In our institution, 932 adult liver transplantations (787 LDLTs and 145 DDLTs) were performed from August 1992 to December From the Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Address reprint requests to Dr Sung-Gyu Lee, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, 388-1 Poongnap-Dong, Seoul 138-736, Republic of Korea. E-mail: [email protected]
0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.03.066
© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1526
Transplantation Proceedings, 39, 1526 –1529 (2007)
SMALL LIVER GRAFTS
1527
2004.10,11 Of these patients, 282 (30.3%) were diagnosed as having HCC before transplantation or from the explanted liver specimens. Our eligibility criteria for HCC patients were primarily the UCSF criteria with preoperative imaging studies, but some more advanced HCC patients were accepted on case-by-case basis, especially for LDLT. Because the incidence of deceased organ donors was very low in Korea, only a small number of HCC patients were allocated to DDLT through the Korean Network for Organ Sharing. To determine whether GRWR had an influence on HCC recurrence, we performed a case-controlled study. To avoid bias from various factors related to the surgery or tumor, we excluded 101 recipients from this analysis, 19 perioperative mortality patients within 3 months, 16 who underwent salvage transplantation, 2 who underwent retransplantation, 1 who underwent split DDLT, 51 with pathologically advanced HCC beyond the UCSF criteria, and 34 with incidentally detected HCC.12–14 Some of the recipients had overlapping exclusion criteria. The reason why the HCC patients beyond the UCSF criteria were excluded was to match the HCC recurrence rate for reasonable comparison because such patients showed definitely high incidence of HCC recurrence. In contrast, there was no HCC recurrence in recipients who were incidentally diagnosed as HCC only at the explanted livers.1,15 The remaining 181 patients were stratified into four groups according to GRWR, ⬍0.8 (low GRWR group, n ⫽ 30), 0.8 to 1.0 (mid GRWR group, n ⫽ 65), ⬎1.0 (high GRWR group, n ⫽ 64), and whole liver graft group after DDLT (n ⫽ 22). We arbitrarily regarded the low GRWR group as the small-for-size graft group. The weight of whole liver graft was not available in all DDLT cases, but no whole liver graft was smaller than 1.5 of GRWR. Patient and tumor profiles are summarized in Tables 1 and 2. Of the 181 patients, 139 (76.8%) underwent pretransplant treatments, including transarterial chemoembolization (n ⫽ 111, 61.3%), radiofrequency ablation (n ⫽ 20, 11.1%) and percutaneous ethanol injection (n ⫽ 8, 4.4%). Liver transplantation was planned due to progressive deterioration of liver function or failure of HCC treatment. Mean values with standard deviation and median values with range were used for numeric data. The significance of differences was assessed by analysis of variance. Survival curves were estimated by the Kaplan-Meier method and compared with the log-rank test. Multivariate analysis was carried out using the Cox proportional hazard model. Patient death unrelated to HCC recurrence was regarded as a censored case during the statistical analysis of HCC recurrence. Statistical significance was defined as P-value ⬍ .05.
RESULTS Patient Survival
Of the 181 recipients, HCC recurred in 24 (13.3%), and 22 died from HCC recurrence during a median follow-up of 38 months (range, 3–116 months). Another 10 recipients died from causes other than HCC recurrence. There were no differences in overall patient survival among the four GRWR groups (P ⫽ .105; Fig 1). Similar outcomes were obtained when the HCC patients were confined to the Milan criteria (n ⫽ 170; P ⫽ .132). HCC Recurrence
We observed no differences in recurrence-free survival according to GRWR (P ⫽ .406; Fig 2). Similar outcomes were also obtained after application of the Milan criteria (n ⫽ 170; P ⫽ .256). The most common sites of initial HCC recurrence were the engrafted liver itself (n ⫽ 13), the lungs (n ⫽ 4), liver and lungs (n ⫽ 1), peritoneum and abdomen (n ⫽ 6), abdominal wall (n ⫽ 1), and adrenal glands (n ⫽ 1). These recurrent HCC lesions were initially treated by transarterial chemoembolization (n ⫽ 13), systemic chemotherapy (n ⫽ 5), and surgical resections (n ⫽ 6), including lung metastasectomy (n ⫽ 3), liver resection (n ⫽ 1), adrenalectomy (n ⫽ 1), and abdominal wall excision (n ⫽ 1). According to the progression of recurrent tumors, aggressive multimodality treatments with minimal immunosuppression were concurrently carried out. However, the median survival period after tumor recurrence was 7 months in the low GRWR group, 5 months in the mid GRWR group, 19 months in the high GRWR group, and 10 months in the whole liver graft group (P ⫽ .431). Risk Factor Analysis for Posttransplant HCC Recurrence
Univariate analysis revealed that significant risk factors for posttransplant HCC recurrence included preoperative serum ␣-fetoprotein concentration, tumor size, microvascular invasion, and histologic differentiation (Table 2). Multivariate analysis showed that moderate/poor
Table 1. Demographic and Graft Profiles of HCC Patients Who Underwent Liver Transplantation Parameters/GRWR Group
GRWR range No. of patients Age (yrs) Male gender, n (%) MELD score Viral hepatitis B, n (%) Within Milan criteria, n (%) Living donor graft type, n (%) Right lobe graft Left lobe graft Dual grafts Median follow-up period, mos
Low
Mid
High
Whole Liver
P-Value
⬍0.8 30 50.3 ⫾ 6.8 23 (76.7) 16.5 ⫾ 6.4 27 (90) 28 (93.3)
0.8–1.0 65 51.8 ⫾ 6.2 53 (81.5) 17.7 ⫾ 8.8 60 (92.3) 64 (98.5)
⬎1.0 64 51.3 ⫾ 7.0 51 (79.7) 17.8 ⫾ 8.5 61 (95.3) 58 (90.6)
⬎1.5 22 49.1 ⫾ 6.5 17 (77.3) 20.1 ⫾ 6.4 19 (86.4) 20 (90.9)
.377 .945 .489 .553 .272
7 (23.3) 20 (66.7) 3 (10.0) 43.5 ⫾ 24.6
35 (53.8) 13 (20.0) 17 (26.2) 34.4 ⫾ 19.7
50 (78.1) 2 (3.1) 12 (18.8) 46.2 ⫾ 22.1
54.8 ⫾ 33.1
.002
GRWR, graft-recipient weight ratio; HCC, hepatocellular carcinoma; MELD, Model for End-Stage Liver Disease.
1528
HWANG, LEE, AHN ET AL Table 2. Univariate Analysis of Risk Factors for HCC Recurrence in 181 HCC Patients Within the UCSF Criteria Disease-Free Survival Rate Parameter
GRWR ⬍0.8 0.8–1.0 ⬎1.0 Whole liver Pretransplant ␣-fetoprotein (ng/mL) ⱕ20 ⬎20 and ⱕ200 ⬎200 and ⱕ1000 ⬎1000 Tumor size (cm) ⱕ2 ⬎2 and ⱕ5 ⬎5 No. of tumors 1 2 3 Microvascular invasion No Yes Tumor distribution Unilobar Bilobar Histologic differentiation Well Moderate/poor
Patients (n)
1 Year
3 Year
5 Year
30 65 64 22
93.3% 90.8% 95.3% 100%
89.7% 80.7% 89.1% 88.9%
89.7% 80.7% 89.1% 72.7%
91 56 16 14
96.7% 94.6% 81.3% 85.7%
94.1% 86.1% 73.9% 55.6%
94.1% 86.1% 73.9% 55.6%
79 97 5
97.4% 92.7% 60.0%
95.9% 80.6% 40.0%
91.7% 76.6% 40.0%
119 38 24
95.8% 94.4% 95.5%
88.0% 85.2% 90.7%
82.5% 85.2% 90.7%
173 8
94.7% 75.0%
88.0% 50.0%
83.8% 50.0%
160 21
94.9% 85.7%
87.0% 80.7%
82.6% 80.7%
78 66
97.4% 87.8%
94.0% 73.4%
85.8% 73.4%
P-Value
.406
.002
⬍.001
.806
.002
.222
.006
HCC, hepatocellular carcinoma.
histologic differentiation was the only significant risk factor (relative risk, 3.71; 95% confidence interval, 1.18 – 11.73; P ⫽ .025).1,16,17 GRWR ⬍ 0.8 was not a significant risk factor on univariate analysis.
When we compared HCC recurrence in recipients of LDLT and DDLT, we observed no prognostic difference.1 However, the influence of graft size was not investigated,
Fig 1. Cumulative survival curves of the patients with HCC within the UCSF criteria according to GRWR. The overall 5-year survival rates were 89.5% in the low GRWR group, 73.7% in the mid GRWR group, 84.8% in the high GRWR group and 54.8% in the whole liver graft group (P ⫽ .105).
Fig 2. Recurrence-free survival curves of the patients with HCC within the UCSF criteria after censoring of HCC-unrelated mortalities. The 5-year recurrence-free survival rates were 89.7% in the low GRWR group, 80.7% in the mid GRWR group, 89.1% in the high GRWR group, and 72.7% in the whole liver graft group (P ⫽ .406).
DISCUSSION
SMALL LIVER GRAFTS
necessitating a complementary study to assess the prognostic significance of small-for-size grafts on HCC recurrence. The results presented here show that small graft and subsequent rapid liver regeneration did not increase the risk of posttransplant HCC recurrence when the HCC lesions were within the Milan or UCSF criteria. This study was primarily focused on the patterns of HCC recurrence among different GRWR groups rather than LDLT versus DDLT because the number of DDLT patient appeared disproportionately small in our series. Three LDLT groups showed similar outcomes on both HCC recurrence and overall survival. In contrast, DDLT group had two patients with late HCC recurrence around 5 years, which made both overall and recurrence-free survival rates rather low. An animal experiment showed accelerated growth of tumor cells during liver graft regeneration, suggesting that significant activation of cell signaling pathways related to tumor invasion, migration, and angiogenesis occurring in small-for-size liver grafts promoted early and invasive tumor growth after liver transplantation.18 Although this animal study suggested that the low GRWR group may have had a higher risk of HCC recurrence when compared with the higher GRWR groups, we did not find that to be consistent with the result of this study. Rather, we found that histologic differentiation was the only significant risk factor for HCC recurrence in patients within the UCSF criteria. There is a possibility that the inconsistency between our clinical findings and the animal study is due to the differences in tumor load relative to the transplanted liver graft. According to both Milan and UCSF criteria, there must be no or really small number of HCC cells in the circulation.19,20 Because the process of graft regeneration occurs only in the transplanted liver graft, absence or presence of extremely small number of HCC cells indicates that there should be no significant HCC growth in the engrafted liver. We found that the 1-year recurrence rate was low in all study groups, and only 56% of all recurrent HCC lesions were detected in the liver at the time of initial HCC recurrence. Thus, the triggering hypothesis, that rapid liver regeneration is associated with the intra- and extrahepatic growth of HCC cells, is not proven to be true in this study. Further studies should be followed to assess the influence of graft size in HCC patients. In conclusion, we think that small living donor liver graft and subsequent liver regeneration do not increase the risk of posttransplant HCC recurrence when HCC is within the Milan or UCSF criteria.
REFERENCES 1. Hwang S, Lee SG, Joh JW, et al: Liver transplantation for adult patients with hepatocellular carcinoma in Korea: comparison
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