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Ann Liver Transplant 2024; 4(2): 71-79
Published online November 30, 2024 https://doi.org/10.52604/alt.24.0008
Copyright © The Korean Liver Transplantation Society.
Saran Ochir Gongor1 
, Kwang-Woong Lee1,2 , Nam-Joon Yi1,2 , YoungRok Choi1,2 , Suk Kyun Hong1,2 , Jeong-Moo Lee2 , Jae-Yoon Kim2 , Kyung-Suk Suh1,2
Correspondence to:Kwang-Woong Lee
Department of Surgery, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
E-mail: kwleegs@gmail.com
https://orcid.org/0000-0001-6412-1926
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background: Challenging clinical circumstances and high demand for liver transplantation have led to a refinement in the recipient selection criteria. This study aims to investigate the hypothesis that surgical outcomes in living donor liver transplantation (LDLT) for hepatocellular carcinoma (HCC) have improved over time with the shift from morphological to biological criteria.
Methods: A retrospective analysis was conducted on 942 adult HCC patients underwent LDLT at Seoul National University Hospital between 2000 and 2022. Study populations were divided into Group A (2000.01.01–2011.06.30, n=314) and Group B (2011.07.01–2022.06.30, n=628). Baseline characteristics, perioperative factors, and survival outcomes were compared.
Results: Group B demonstrated higher recurrence-free survival (RFS) compared to Group A (p=0.03). Additionally, Group B exhibited superior overall survival rates at the 1-, 3-, and 5-year intervals (95.9%, 87.9%, 84.6%, p<0.01). Moreover, Group B had a significantly lower recurrence rate (p=0.02) and mortality rate (p<0.01). The median time to recurrence was 9.1 months (interquartile range [IQR] 3.9–21.8) for Group A and 11.4 months (IQR 6.6–18.5) for Group B (p=0.92). Furthermore, Group A’s median tumor-bearing survival was 12.3 months (IQR 5.2–26.1), which was significantly shorter than Group B’s 20.0 months (IQR 5.4–25.7) (p<0.01).
Conclusion: The use of biological tumor markers in patient selection criteria has significantly improved the effectiveness of HCC treatment in LDLT and should be encouraged for pervasive use.
Keywords: Hepatocellular carcinoma, Liver transplantation, Mortality, Recurrence, Survival after recurrence
Hepatocellular carcinoma (HCC) is the most common indication for living donor liver transplantation (LDLT) globally [1,2] and liver transplantation (LT) is widely considered the best treatment for HCC [3]. Our center is no exception, where HCC accounts for over 50% of all adult LDLT cases annually (Fig. 1). It is projected that HCC cases will continue to increase in the future [4,5], leading to a higher demand for LT [6,7]. Moreover, paucity of deceased donors and regional trends have also contributed to the increase in the number of LDLTs for treating HCC [7-9]. To meet this demand, a significant progress has been made in surgical techniques [10], perioperative management, and immunosuppression regimens for LT [11,12].
Figure 1.Annual proportion of adult LDLT for HCC (n=942, 55%) vs. non-HCC (n=749, 45%). HCC became a major indication of adult LDLT over the years. LDLT, living donor liver transplantation; HCC, hepatocellular carcinoma.
Various selection criteria have been proposed to expand the eligibility and enhance the outcomes of LT in HCC, based on the tumor’s morphology [13-15]. However, there are still limitations to the morphological criteria, such as high recurrence of HCC and advanced tumor stages, and further increasing demand have led to a shift in transplantation eligibility criteria from morphology to biological markers in HCC treatments [16-20].
Post-LT immune suppression regimens have evolved, and the use of mammalian target of rapamycin (mTOR) inhibitors has become more common due to the adverse effects of calcineurin inhibitors (CNIs) [21,22]. Moreover, meta-analyses and numerous studies have shown that mTOR inhibitors are effective in LT and lead to improved survival outcomes [23-26]. Additionally, our recent study revealed that using pure laparoscopic donor hepatectomy led to better outcomes in 556 patients [10].
Therefore, we hypothesized that changes in selection criteria, surgical methods and post-operative management have led to better outcomes over the years. However, there is still a lack of long-term outcome data on LDLT in HCC, including a decade of follow-up, a large number of patients, and real-world evidence. Therefore, we aimed to evaluate the differences in outcomes between two distinct periods of HCC LDLT cohorts. The earlier decade focused on morphological criteria, while the recent decade prioritized additional biological tumor markers in HCC LDLT. Our primary measures include overall survival (OS), recurrence-free survival (RFS), and mortality rate.
A retrospective analysis was conducted on patients who were diagnosed with HCC and underwent LDLT at Seoul National University Hospital (SNUH) between January 2000 and June 2022. The study population was divided into two groups: Group A (January 1, 2000 to June 30, 2011) and Group B (July 1, 2011 to June 30, 2022). Patients with intra-hepatic cholangiocarcinoma (IHC) or combined IHC-HCC were excluded. The latest follow-up date for the study was January 1, 2024.
The study inclusion criteria were as follows: (i) age ≥18 years with written consent, (ii) histologically proven HCC with a degree of necrosis from 0 to 99 percent, (iii) unviable tumor or total necrotic nodules with a prior history of surgical resection resulting in HCC pathological confirmation, (iv) unviable tumor or total necrotic nodules with a prior history of locoregional therapies (LRT) such as transarterial chemoembolization, radio frequency ablation, and percutaneous ethanol injection therapy (PEIT).
The baseline characteristics, such as age, sex, and underlying disease, were reviewed. Preoperative model for end-stage liver disease (MELD) score, Child-Turcot-Pugh class, alpha-fetoprotein (AFP), protein-induced vitamin K absence (PIVKA-II), and prior history of surgical or LRT were investigated. LRT was defined based on type of interventions either single method or combined methods. Transarterial radioembolization was not included. Perioperative total operation time and graft liver volume were also analyzed. The graft-recipient-weight ratio (GRWR) calculation was based on the post-surgical graft volume (grams).
The Milan criteria were determined based on the extent of explant pathology reports. Unviable tumors or total necrotic nodules were considered within the Milan criteria. Far-advanced HCC was defined by tumor numbers greater than 10 or larger than 10 cm or the presence of macrovascular invasion. In explant histologic variables, explant tumor differentiation was assessed according to either WHO tumor differentiation grade (well to undifferentiated) or Edmondson-Steiner’s grade (I–IV). The largest viable tumor size, number of total viable tumors, and extent of microvascular invasion were also scrutinized. The OS rates and RFSs were shown at 1, 3, and 5 years, as there was a difference in the total follow-up periods between the two different time points.
Statistical analysis was performed using SPSS software version 29 (IBM Corp., Armonk, NY, USA). Student’s t-test or Kruskal–Wallis’s test were used on the continuous variables and results are shown as a median value with an interquartile range (IQR). Chi-square test and Fisher’s exact tests were used on the categorical variables, and results are shown as observed numbers with percentages. OS and RFS curves were calculated using Kaplan–Meier method, and comparisons were made using a Log-rank test. A p-value less than 0.05 was considered significant.
The Institutional Review Board of Seoul National University Hospital approved this study (IRB No. H-2024-052-1527). The board exempted informed consent for this retrospective study of prospectively collected data.
A total of 942 patients were included in this study. Table 1. presents the baseline characteristics of the study population, divided into Group A (n=314, 2000.01.01–2011.06.30) and Group B (n=628, 2011.07.01–2022.06.30). The median age was similar in both groups, with Group A at 56.0 (IQR 52.0–63.0) and Group B at 57.0 (IQR 52.0–62.0) (p=0.85). Males accounted for 83.4% of Group A and 80.6% of Group B (p=0.32).
Table 1 Baseline characteristics of study population
| Variable | Group A (n=314) | Group B (n=628) | p-value |
|---|---|---|---|
| Age (yr) | 56.0 (52.0–63.0) | 57.0 (52.0–62.0) | 0.85 |
| Sex | 0.32 | ||
| Male | 262 (83.4) | 506 (80.6) | |
| Female | 52 (16.6) | 122 (19.4) | |
| Underlying disease | <0.01 | ||
| Hepatitis B virus infection | 244 (77.7) | 467 (74.4) | |
| Hepatitis C virus infection | 21 (6.7) | 61 (9.7) | |
| Alcoholic liver disease | 6 (1.9) | 56 (8.9) | |
| Othersa) | 43 (13.7) | 44 (7.0) | |
| Child-Turcot-Pugh classification | <0.01 | ||
| A | 54 (17.2) | 392 (62.4) | |
| B | 56 (17.8) | 154 (24.5) | |
| C | 35 (10.8) | 82 (13.1) | |
| MELD score | 17.4 (12.7–23.3) | 9.0 (7.2–12.9) | 0.01 |
| Pre-operative liver resection | 9 (2.9) | 111 (17.7) | <0.01 |
| Pre-operative locoregional therapy | <0.01 | ||
| Single methods (TACE/TAE or RFA or PEIT) | 141 (44.9) | 349 (55.6) | |
| Double methods (TACE+RFA/PEIT or RFA+PEIT) | 56 (17.8) | 158 (25.2) | |
| Triple methods (TACE+RFA+PEIT) | 8 (2.5) | 31 (4.9) | |
| None | 109 (34.7) | 90 (14.3) |
Values are presented as median (interquartile range) or number (%).
MELD, model for end-stage liver disease; TACE, transarterial chemoembolization; TAE, transarterial embolization; RFA, radio frequency ablation; PEIT, percutaneous ethanol injection therapy.
a)Autoimmune hepatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson’s disease, cryptogenic hepatitis, non-B non-C liver cirrhosis, glycogen storage disease, membranous obstruction of inferior vena cava associated liver cirrhosis, Budd–Chiari syndrome, unknown causes.
Regarding underlying disease, a larger percentage of both Group A and Group B were affected by hepatitis B virus Infection (77.7% vs. 74.4% in Group B, Table 1, p<0.01). The number of resections and LRT has significantly increased in recent periods (Group B). Moreover, in Group B, preoperative liver resection was performed on more patients (17.7% vs. 2.9% in Group A, p<0.01).
We assessed the liver function and disease status of patients prior to surgery by utilizing LRT status, the MELD score, and the Child-Turcot-Pugh score. Group B had a considerably higher percentage of patients in Class A (62.4%) than Group A (37.2%), signifying a significant difference (p<0.01). The median MELD Score was significantly higher in Group A (17.4 [IQR 12.7–23.3]) compared to Group B (9.0 [IQR 7.2–12.9]), with a p-value of <0.01.
Single type LRT like trans-arterial chemoembolization (TACE) or radiofrequency ablation (RFA) or PEIT were undergone by 55.6% of patients in Group B, which was significantly higher than the 44.9% in Group A (p<0.01). Double LRT, such as TACE with RFA or PEIT, were more commonly used in Group B at 25.2% compared to 17.8% in Group A (p<0.01). The usage of Triple methods, TACE+RFA+PEIT, was also higher in Group B (4.9%) compared to Group A (2.5%), with a significant difference (p<0.01). Importantly, the proportion of patients who didn’t receive any LRT was significantly lower in Group B (14.3%) compared to Group A (34.7%), with a p-value of <0.01, indicating a statistically significant increase in the use of LRT in Group B.
Regarding the tumor’s biological characteristics before surgery, Group A had a significantly higher median AFP level of 15.0 ng/mL (IQR 5.5–84.5) than Group B’s median of 5.4 ng/mL (IQR 2.9–16.6), with a p-value of less than 0.01. However, there were no significant differences in PIVKA-II levels. Group A recorded a median level of 30.0 mAU/mL (IQR 16.0–90.5) compared to Group B’s 27.0 mAU/mL (IQR 18.0–67.0) (p=0.31). Before the surgery, Group B showed significant improvement in liver function and a decrease in preoperative AFP levels. Based on these findings, it can be concluded that Group B had a better preoperative status compared to Group A.
According to the Milan criteria, the analysis of the explant pathology showed that 72.6% of patients in Group A met the criteria, which was slightly lower than the 75.5% in Group B (p=0.50). The percentage of patients who were classified as far advanced and beyond the Milan criteria was similar in both groups, with minor differences between them. In Group A, 21.3% and 6.1% of patients were classified as far advanced and beyond the Milan criteria, respectively, while Group B had 18.2% and 6.4% in the same categories, respectively (p=0.50). Fig. 2 shows the annual proportion of cases that exceed the Milan criteria, including those that are beyond Milan and Far advanced at SNUH.
Figure 2.Annual proportion of beyond Milan criteria LDLT for HCC (beyond Milan and far advanced). Milan criteria were based on explant pathology, far advanced defined by tumor size larger than 10 cm or number over 10 or extrahepatic metastasis. LDLT, living donor liver transplantation; HCC, hepatocellular carcinoma.
Moreover, there was a significant difference in operation times, with Group A having a longer median time of 470.0 minutes (IQR 420.0–540.0) compared to 385.0 minutes in Group B (IQR 330.0–454.7; p<0.01). Graft liver volume was slightly higher in Group A, with a median of 715.0 mL (IQR 645.0–823.5), vs. 702.0 mL in Group B (IQR 612.0–803.0; p=0.03). The GRWR also showed a significant difference, with Group A having a higher median GRWR of 1.16 (IQR 0.97–1.16) compared to 1.05 in Group B (IQR 0.89–1.05; p<0.01). Tumor differentiation showed significant differences, with Group A showing poorer differentiation. Total necrosis was significantly higher in Group B (28.0% vs. 13.4%; p<0.01). Group A had larger tumors compared to Group B (2.4 cm vs. 2.2 cm; p=0.01) (Table 2).
Table 2 Tumor characteristics and post-surgical outcomes of study population
| Variable | Group A (n=314) | Group B (n=628) | p-value |
|---|---|---|---|
| Pre-operative AFP (ng/mL) | 15.0 (5.5–84.5) | 5.4 (2.9–16.6) | <0.01 |
| Pre-operative PIVKA-II (mAU/mL) | 30.0 (16.0–90.5) | 27.0 (18.0–67.0) | 0.31 |
| Missing value | 69 (22.0) | 13 (2.1) | |
| Explant-based Milan criteria | 0.50 | ||
| Within Milan | 228 (72.6) | 474 (75.5) | |
| Beyond Milan | 67 (21.3) | 114 (18.2) | |
| Far advanceda) | 19 (6.1) | 40 (6.4) | |
| Operation time (min) | 470.0 (420.0–540.0) | 385.0 (330.0–454.7) | <0.01 |
| Graft liver volume (mL) | 715.0 (645.0–823.5) | 702.0 (612.0–803.0) | 0.03 |
| GRWR | 1.16 (0.97–1.16) | 1.05 (0.89–1.05) | <0.01 |
| Largest tumor size (cm) | 2.4 (1.6–3.5) | 2.2 (1.4–3.5) | 0.01 |
| Number of tumors | 2 (1.0–2.0) | 2 (1.0–3.0) | 0.33 |
| Microvascular invasion | 41 (13.1) | 83 (13.2) | 0.10 |
| Tumor differentiationb) | <0.01 | ||
| Total necrosis | 42 (13.4) | 176 (28.0) | |
| E-S grade I–II | 130 (41.4) | 239 (38.0) | |
| E-S grade III–IV | 142 (45.3) | 213 (33.9) | |
| Recurrence | 74 (23.6) | 107 (17.0) | 0.02 |
| Time to recurrence (mon) | 9.1 (3.9–21.8) | 11.4 (6.6–18.5) | 0.92 |
| Tumor bearing survival (mon) | 12.3 (5.2–26.1) | 20.0 (5.4–25.7) | <0.01 |
| Overall mortality | 109 (34.7) | 101 (16.1) | <0.01 |
Values are presented as median (interquartile range) or number (%).
AFP, alpha-fetoprotein; PIVKA, protein induced vitamin K absence; GRWR, graft-recipient-weight ratio; E-S grade, Edmondson-Steiner’s grade.
a)Tumor size over 10 cm or number more than 10 or presence of extrahepatic metastasis. b)Tumor differentiation was either evaluated by World Health Organization well to undifferentiated grade or E-S grade I–IV.
Both Group A and Group B were compared in terms of post-surgical RFS, and the results were as follows: at 1 year, Group B had a significantly higher RFS rate of 90.6% compared to Group A’s rate of 86.3% (p=0.03) (Fig. 3A). However, after 3 years, both groups experienced a decline in their RFS rates to 84.4% and 80.0% for Group B and Group A, respectively. Finally, at the 5-year mark, the RFS rate for Group B was slightly higher than that of Group A at 82.8% and 78%, respectively.
Figure 3.Five-year recurrence-free survival (RFS) and overall survival (OS) rate. (A) Five-year RFS of Group A and B. Group A (n=314) shows a 1-year RFS of 86.3%, dropping to 80.0% at 3 years, and 78.0% at 5 years. In contrast, Group B (n=628) presents RFS of 90.6% at 1 year, 84.4% at 3 years, and 82.8% at 5 years (p=0.03). (B) Five-year OS of Group A and B. One-year survival rates were 95.9% for Group B and 91.7% for Group A. At 3 years, survival decreased to 87.9% for Group B and 80.6% for Group A. At 5-year, Group B survival rate was 84.6%, while Group A further declined to 77.4% (p<0.01). LT, liver transplantation.
Additionally, Group B exhibited better OS rates than Group A. Specifically, Group B demonstrated a 1-year OS rate of 95.9%, whereas Group A had a rate of 91.7%. At 3 years, Group B’s OS rate was 87.9%, and Group A’s was 80.6%. Finally, at the 5-year mark, Group B had an OS rate of 84.6%, which was significantly higher than Group A’s rate of 77.4% (p<0.01) (Fig. 3B).
Furthermore, the recurrence rate was higher in Group A (23.6%) compared to Group B (17.0%, p=0.02), but there was no significant difference in the median time to recurrence between the two groups. The median time to recurrence was 9.1 months (IQR 3.9–21.8) for Group A and 11.4 months (IQR 6.6–18.5) for Group B (p=0.92). Moreover, Group B had a longer median tumor-bearing survival time (20.0 months [IQR 5.4–25.7]) compared to Group A’s median tumor-bearing survival time (12.3 months [IQR 5.2–26.1], p<0.01). Additionally, the overall mortality rate was significantly higher in Group A (34.7%) compared to Group B (16.1%, p<0.01).
In summary, Group B had better OS rates, RFS rates, and median tumor-bearing survival time than Group A. Conversely, Group A had a higher recurrence rate and overall mortality rate.
Our study compared the long-term results of LDLT in HCC between two time periods. We observed a significant decrease in the median MELD score (Group A: 17.4, Group B: 9.0, p=0.01) and AFP levels (Group A: 15.0 ng/mL, Group B: 5.4 ng/mL, p<0.01) from the past to the recent period. The higher median AFP level in Group A may indicate more aggressive or advanced disease before transplantation. On the other hand, the lower AFP in the recent cohort can be attributed to the improved selection process for LT candidates, based on their tumor characteristics (e.g., AFP and PIVKA-II). Previous studies have suggested that a low AFP can lead to better survival and serve as an important prognostic predictor for HCC recurrence [27,28]. Our study also validates this hypothesis, as Group B, representing the most recent decade, achieved superior outcomes in RFS and 1-to-5-year OS rates of 95.9% and 84.6%, p<0.01. Although median time to recurrence did not show statistical significance, Group B had slightly longer median time to recurrence, indicating improved outcomes. Additionally, the overall mortality rate decreased in Group B (Group A: 34.7%, Group B: 16.1%, p<0.01). This may be related to the lower RFS and recurrence rate in Group B (Group A: 22.6%, Group B: 17.0%, p=0.02), as high tumor recurrence is associated with high mortality rate and recurrence is the major cause of post-surgical mortality.
At our center, every stage of the LT process follows a standardized routine protocol, and most living donor hepatectomies have been performed through pure 3D laparoscopy since 2015 [10]. These factors have likely contributed to the decreased total operation time and improved surgical outcomes in Group B, along with decreased cold and warm ischemic times for the graft liver. The implementation of standardized protocols and advancements in laparoscopic surgery technology have reduced operation time and improved outcomes in recent Group B.
The proportion of LRT was higher in Group B, where most patients received a single method of TACE, RFA, or PEIT (Group A: 44.9%, Group B: 55.6%). No LRT received patients were higher in Group A (Table 1). These results suggest that the majority of patients in Group B either exceeded the Milan criteria or were ineligible for surgery, thus requiring downstaging therapy to reduce tumor burden or bridging therapy for LT. As a result of these downstaging and bridging therapies, analysis of the tumors upon removal showed that more than 70% of patients in both groups met the Milan criteria (Table 2). Moreover, the percentage of completely necrotic nodules was higher in Group B (28.0%) compared to Group A (13.4%), indicating a greater use of LRT and a more successful therapeutic effect of LRT in Group B. This ultimately contributed to a higher survival rate and a lower recurrence rate in Group B.
CNIs, such as tacrolimus, have long been established as the standard immune suppression regimen after organ transplantation. However, CNIs have a limited range of therapeutic effectiveness: inadequate levels can lead to acute rejection, while excessive levels can result in toxic effects associated with CNIs [21,22]. Because of narrow trough level and adverse effects, there has been a shift in the use of immune suppression drugs. Since 2014, mTOR inhibitor drugs, such as sirolimus and everolimus, have been widely accepted as an alternative long-term (over 3 months) immunosuppression regimen. These drugs have demonstrated tumor suppressive effects and protection for the kidneys, resulting in improved long-term survival outcomes for liver transplant patients [25]. With this change, our center has regularly implemented mTOR inhibitors for advanced HCCs [29]. Specifically, in Group B, mTOR inhibitors were more commonly used as maintenance therapy and long-term immune suppression one month after transplantation, aiming to achieve clinical tolerance. Therefore, it is reasonable to assume that the increased use of mTOR inhibitors as a maintenance regimen in the recent decade has resulted in improved survival rates.
There are limitations to our study, as is typical of retrospective studies. Our analysis relied on the completeness of the medical records, which may introduce potential biases. Additionally, our findings may not be applicable to patients who underwent deceased donor liver transplantation (DDLT) as our study only included patients who underwent LDLT, not DDLT.
Nevertheless, our findings suggest that Group B, recent period, demonstrated superior survial results and decreased mortality rates than Group A, past period. Enhanced use of mTOR inhibitors and improved patient selection criteria, particularly focusing on tumor biological characteristics, have contributed significantly to these chronological improvements. Further pervasive use of biological tumor marker based patient selection criteria should be encouraged.
Figure 4.Time to recurrence and tumor bearing survival rate. (A) Time to recurrence rate of Group A and B. Group A showed a median time to recurrence of 9.1 months (n=74), while Group B had a median of 11.4 months (n=107), p=0.92. (B) Tumor bearing survival rate of Group A and B. Group A had a median survival of 12.3 months (n=65) and Group B (red) had a median of 20.0 months (n=64), p<0.01. LT, liver transplantation.
There was no funding related to this study.
Suk Kyun Hong is an editorial member of the journal but was not involved in the review process of this manuscript. Any other authors have no conflict of interest.
Conceptualization: KWL, SOG. Data curation: KWL, SOG, NJY, YRC, SKH, JML, KSS. Formal analysis: KWL, SOG. Investigation: KWL, SOG. Methodology: KWL, SOG, NJY, YRC, SKH, JML, KSS. Project administration: KWL. Resources: KWL, SOG, NJY, YRC, SKH, JML, KSS. Supervision: KWL, NJY, YRC, SKH, JML, KSS. Validation: KWL, SOG. Visualization: KWL, SOG. Writing – original draft: All. Writing – review & editing: KWL, SOG, NJY, YRC, SKH, JML, KSS.
Ann Liver Transplant 2024; 4(2): 71-79
Published online November 30, 2024 https://doi.org/10.52604/alt.24.0008
Copyright © The Korean Liver Transplantation Society.
Saran Ochir Gongor1 , Kwang-Woong Lee1,2 , Nam-Joon Yi1,2 , YoungRok Choi1,2 , Suk Kyun Hong1,2 , Jeong-Moo Lee2 , Jae-Yoon Kim2 , Kyung-Suk Suh1,2
1Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
2Department of Surgery, Seoul National University Hospital, Seoul, Korea
Correspondence to:Kwang-Woong Lee
Department of Surgery, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
E-mail: kwleegs@gmail.com
https://orcid.org/0000-0001-6412-1926
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background: Challenging clinical circumstances and high demand for liver transplantation have led to a refinement in the recipient selection criteria. This study aims to investigate the hypothesis that surgical outcomes in living donor liver transplantation (LDLT) for hepatocellular carcinoma (HCC) have improved over time with the shift from morphological to biological criteria.
Methods: A retrospective analysis was conducted on 942 adult HCC patients underwent LDLT at Seoul National University Hospital between 2000 and 2022. Study populations were divided into Group A (2000.01.01–2011.06.30, n=314) and Group B (2011.07.01–2022.06.30, n=628). Baseline characteristics, perioperative factors, and survival outcomes were compared.
Results: Group B demonstrated higher recurrence-free survival (RFS) compared to Group A (p=0.03). Additionally, Group B exhibited superior overall survival rates at the 1-, 3-, and 5-year intervals (95.9%, 87.9%, 84.6%, p<0.01). Moreover, Group B had a significantly lower recurrence rate (p=0.02) and mortality rate (p<0.01). The median time to recurrence was 9.1 months (interquartile range [IQR] 3.9–21.8) for Group A and 11.4 months (IQR 6.6–18.5) for Group B (p=0.92). Furthermore, Group A’s median tumor-bearing survival was 12.3 months (IQR 5.2–26.1), which was significantly shorter than Group B’s 20.0 months (IQR 5.4–25.7) (p<0.01).
Conclusion: The use of biological tumor markers in patient selection criteria has significantly improved the effectiveness of HCC treatment in LDLT and should be encouraged for pervasive use.
Keywords: Hepatocellular carcinoma, Liver transplantation, Mortality, Recurrence, Survival after recurrence
Hepatocellular carcinoma (HCC) is the most common indication for living donor liver transplantation (LDLT) globally [1,2] and liver transplantation (LT) is widely considered the best treatment for HCC [3]. Our center is no exception, where HCC accounts for over 50% of all adult LDLT cases annually (Fig. 1). It is projected that HCC cases will continue to increase in the future [4,5], leading to a higher demand for LT [6,7]. Moreover, paucity of deceased donors and regional trends have also contributed to the increase in the number of LDLTs for treating HCC [7-9]. To meet this demand, a significant progress has been made in surgical techniques [10], perioperative management, and immunosuppression regimens for LT [11,12].
Figure 1. Annual proportion of adult LDLT for HCC (n=942, 55%) vs. non-HCC (n=749, 45%). HCC became a major indication of adult LDLT over the years. LDLT, living donor liver transplantation; HCC, hepatocellular carcinoma.
Various selection criteria have been proposed to expand the eligibility and enhance the outcomes of LT in HCC, based on the tumor’s morphology [13-15]. However, there are still limitations to the morphological criteria, such as high recurrence of HCC and advanced tumor stages, and further increasing demand have led to a shift in transplantation eligibility criteria from morphology to biological markers in HCC treatments [16-20].
Post-LT immune suppression regimens have evolved, and the use of mammalian target of rapamycin (mTOR) inhibitors has become more common due to the adverse effects of calcineurin inhibitors (CNIs) [21,22]. Moreover, meta-analyses and numerous studies have shown that mTOR inhibitors are effective in LT and lead to improved survival outcomes [23-26]. Additionally, our recent study revealed that using pure laparoscopic donor hepatectomy led to better outcomes in 556 patients [10].
Therefore, we hypothesized that changes in selection criteria, surgical methods and post-operative management have led to better outcomes over the years. However, there is still a lack of long-term outcome data on LDLT in HCC, including a decade of follow-up, a large number of patients, and real-world evidence. Therefore, we aimed to evaluate the differences in outcomes between two distinct periods of HCC LDLT cohorts. The earlier decade focused on morphological criteria, while the recent decade prioritized additional biological tumor markers in HCC LDLT. Our primary measures include overall survival (OS), recurrence-free survival (RFS), and mortality rate.
A retrospective analysis was conducted on patients who were diagnosed with HCC and underwent LDLT at Seoul National University Hospital (SNUH) between January 2000 and June 2022. The study population was divided into two groups: Group A (January 1, 2000 to June 30, 2011) and Group B (July 1, 2011 to June 30, 2022). Patients with intra-hepatic cholangiocarcinoma (IHC) or combined IHC-HCC were excluded. The latest follow-up date for the study was January 1, 2024.
The study inclusion criteria were as follows: (i) age ≥18 years with written consent, (ii) histologically proven HCC with a degree of necrosis from 0 to 99 percent, (iii) unviable tumor or total necrotic nodules with a prior history of surgical resection resulting in HCC pathological confirmation, (iv) unviable tumor or total necrotic nodules with a prior history of locoregional therapies (LRT) such as transarterial chemoembolization, radio frequency ablation, and percutaneous ethanol injection therapy (PEIT).
The baseline characteristics, such as age, sex, and underlying disease, were reviewed. Preoperative model for end-stage liver disease (MELD) score, Child-Turcot-Pugh class, alpha-fetoprotein (AFP), protein-induced vitamin K absence (PIVKA-II), and prior history of surgical or LRT were investigated. LRT was defined based on type of interventions either single method or combined methods. Transarterial radioembolization was not included. Perioperative total operation time and graft liver volume were also analyzed. The graft-recipient-weight ratio (GRWR) calculation was based on the post-surgical graft volume (grams).
The Milan criteria were determined based on the extent of explant pathology reports. Unviable tumors or total necrotic nodules were considered within the Milan criteria. Far-advanced HCC was defined by tumor numbers greater than 10 or larger than 10 cm or the presence of macrovascular invasion. In explant histologic variables, explant tumor differentiation was assessed according to either WHO tumor differentiation grade (well to undifferentiated) or Edmondson-Steiner’s grade (I–IV). The largest viable tumor size, number of total viable tumors, and extent of microvascular invasion were also scrutinized. The OS rates and RFSs were shown at 1, 3, and 5 years, as there was a difference in the total follow-up periods between the two different time points.
Statistical analysis was performed using SPSS software version 29 (IBM Corp., Armonk, NY, USA). Student’s t-test or Kruskal–Wallis’s test were used on the continuous variables and results are shown as a median value with an interquartile range (IQR). Chi-square test and Fisher’s exact tests were used on the categorical variables, and results are shown as observed numbers with percentages. OS and RFS curves were calculated using Kaplan–Meier method, and comparisons were made using a Log-rank test. A p-value less than 0.05 was considered significant.
The Institutional Review Board of Seoul National University Hospital approved this study (IRB No. H-2024-052-1527). The board exempted informed consent for this retrospective study of prospectively collected data.
A total of 942 patients were included in this study. Table 1. presents the baseline characteristics of the study population, divided into Group A (n=314, 2000.01.01–2011.06.30) and Group B (n=628, 2011.07.01–2022.06.30). The median age was similar in both groups, with Group A at 56.0 (IQR 52.0–63.0) and Group B at 57.0 (IQR 52.0–62.0) (p=0.85). Males accounted for 83.4% of Group A and 80.6% of Group B (p=0.32).
Table 1 . Baseline characteristics of study population.
| Variable | Group A (n=314) | Group B (n=628) | p-value |
|---|---|---|---|
| Age (yr) | 56.0 (52.0–63.0) | 57.0 (52.0–62.0) | 0.85 |
| Sex | 0.32 | ||
| Male | 262 (83.4) | 506 (80.6) | |
| Female | 52 (16.6) | 122 (19.4) | |
| Underlying disease | <0.01 | ||
| Hepatitis B virus infection | 244 (77.7) | 467 (74.4) | |
| Hepatitis C virus infection | 21 (6.7) | 61 (9.7) | |
| Alcoholic liver disease | 6 (1.9) | 56 (8.9) | |
| Othersa) | 43 (13.7) | 44 (7.0) | |
| Child-Turcot-Pugh classification | <0.01 | ||
| A | 54 (17.2) | 392 (62.4) | |
| B | 56 (17.8) | 154 (24.5) | |
| C | 35 (10.8) | 82 (13.1) | |
| MELD score | 17.4 (12.7–23.3) | 9.0 (7.2–12.9) | 0.01 |
| Pre-operative liver resection | 9 (2.9) | 111 (17.7) | <0.01 |
| Pre-operative locoregional therapy | <0.01 | ||
| Single methods (TACE/TAE or RFA or PEIT) | 141 (44.9) | 349 (55.6) | |
| Double methods (TACE+RFA/PEIT or RFA+PEIT) | 56 (17.8) | 158 (25.2) | |
| Triple methods (TACE+RFA+PEIT) | 8 (2.5) | 31 (4.9) | |
| None | 109 (34.7) | 90 (14.3) |
Values are presented as median (interquartile range) or number (%)..
MELD, model for end-stage liver disease; TACE, transarterial chemoembolization; TAE, transarterial embolization; RFA, radio frequency ablation; PEIT, percutaneous ethanol injection therapy..
a)Autoimmune hepatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson’s disease, cryptogenic hepatitis, non-B non-C liver cirrhosis, glycogen storage disease, membranous obstruction of inferior vena cava associated liver cirrhosis, Budd–Chiari syndrome, unknown causes..
Regarding underlying disease, a larger percentage of both Group A and Group B were affected by hepatitis B virus Infection (77.7% vs. 74.4% in Group B, Table 1, p<0.01). The number of resections and LRT has significantly increased in recent periods (Group B). Moreover, in Group B, preoperative liver resection was performed on more patients (17.7% vs. 2.9% in Group A, p<0.01).
We assessed the liver function and disease status of patients prior to surgery by utilizing LRT status, the MELD score, and the Child-Turcot-Pugh score. Group B had a considerably higher percentage of patients in Class A (62.4%) than Group A (37.2%), signifying a significant difference (p<0.01). The median MELD Score was significantly higher in Group A (17.4 [IQR 12.7–23.3]) compared to Group B (9.0 [IQR 7.2–12.9]), with a p-value of <0.01.
Single type LRT like trans-arterial chemoembolization (TACE) or radiofrequency ablation (RFA) or PEIT were undergone by 55.6% of patients in Group B, which was significantly higher than the 44.9% in Group A (p<0.01). Double LRT, such as TACE with RFA or PEIT, were more commonly used in Group B at 25.2% compared to 17.8% in Group A (p<0.01). The usage of Triple methods, TACE+RFA+PEIT, was also higher in Group B (4.9%) compared to Group A (2.5%), with a significant difference (p<0.01). Importantly, the proportion of patients who didn’t receive any LRT was significantly lower in Group B (14.3%) compared to Group A (34.7%), with a p-value of <0.01, indicating a statistically significant increase in the use of LRT in Group B.
Regarding the tumor’s biological characteristics before surgery, Group A had a significantly higher median AFP level of 15.0 ng/mL (IQR 5.5–84.5) than Group B’s median of 5.4 ng/mL (IQR 2.9–16.6), with a p-value of less than 0.01. However, there were no significant differences in PIVKA-II levels. Group A recorded a median level of 30.0 mAU/mL (IQR 16.0–90.5) compared to Group B’s 27.0 mAU/mL (IQR 18.0–67.0) (p=0.31). Before the surgery, Group B showed significant improvement in liver function and a decrease in preoperative AFP levels. Based on these findings, it can be concluded that Group B had a better preoperative status compared to Group A.
According to the Milan criteria, the analysis of the explant pathology showed that 72.6% of patients in Group A met the criteria, which was slightly lower than the 75.5% in Group B (p=0.50). The percentage of patients who were classified as far advanced and beyond the Milan criteria was similar in both groups, with minor differences between them. In Group A, 21.3% and 6.1% of patients were classified as far advanced and beyond the Milan criteria, respectively, while Group B had 18.2% and 6.4% in the same categories, respectively (p=0.50). Fig. 2 shows the annual proportion of cases that exceed the Milan criteria, including those that are beyond Milan and Far advanced at SNUH.
Figure 2. Annual proportion of beyond Milan criteria LDLT for HCC (beyond Milan and far advanced). Milan criteria were based on explant pathology, far advanced defined by tumor size larger than 10 cm or number over 10 or extrahepatic metastasis. LDLT, living donor liver transplantation; HCC, hepatocellular carcinoma.
Moreover, there was a significant difference in operation times, with Group A having a longer median time of 470.0 minutes (IQR 420.0–540.0) compared to 385.0 minutes in Group B (IQR 330.0–454.7; p<0.01). Graft liver volume was slightly higher in Group A, with a median of 715.0 mL (IQR 645.0–823.5), vs. 702.0 mL in Group B (IQR 612.0–803.0; p=0.03). The GRWR also showed a significant difference, with Group A having a higher median GRWR of 1.16 (IQR 0.97–1.16) compared to 1.05 in Group B (IQR 0.89–1.05; p<0.01). Tumor differentiation showed significant differences, with Group A showing poorer differentiation. Total necrosis was significantly higher in Group B (28.0% vs. 13.4%; p<0.01). Group A had larger tumors compared to Group B (2.4 cm vs. 2.2 cm; p=0.01) (Table 2).
Table 2 . Tumor characteristics and post-surgical outcomes of study population.
| Variable | Group A (n=314) | Group B (n=628) | p-value |
|---|---|---|---|
| Pre-operative AFP (ng/mL) | 15.0 (5.5–84.5) | 5.4 (2.9–16.6) | <0.01 |
| Pre-operative PIVKA-II (mAU/mL) | 30.0 (16.0–90.5) | 27.0 (18.0–67.0) | 0.31 |
| Missing value | 69 (22.0) | 13 (2.1) | |
| Explant-based Milan criteria | 0.50 | ||
| Within Milan | 228 (72.6) | 474 (75.5) | |
| Beyond Milan | 67 (21.3) | 114 (18.2) | |
| Far advanceda) | 19 (6.1) | 40 (6.4) | |
| Operation time (min) | 470.0 (420.0–540.0) | 385.0 (330.0–454.7) | <0.01 |
| Graft liver volume (mL) | 715.0 (645.0–823.5) | 702.0 (612.0–803.0) | 0.03 |
| GRWR | 1.16 (0.97–1.16) | 1.05 (0.89–1.05) | <0.01 |
| Largest tumor size (cm) | 2.4 (1.6–3.5) | 2.2 (1.4–3.5) | 0.01 |
| Number of tumors | 2 (1.0–2.0) | 2 (1.0–3.0) | 0.33 |
| Microvascular invasion | 41 (13.1) | 83 (13.2) | 0.10 |
| Tumor differentiationb) | <0.01 | ||
| Total necrosis | 42 (13.4) | 176 (28.0) | |
| E-S grade I–II | 130 (41.4) | 239 (38.0) | |
| E-S grade III–IV | 142 (45.3) | 213 (33.9) | |
| Recurrence | 74 (23.6) | 107 (17.0) | 0.02 |
| Time to recurrence (mon) | 9.1 (3.9–21.8) | 11.4 (6.6–18.5) | 0.92 |
| Tumor bearing survival (mon) | 12.3 (5.2–26.1) | 20.0 (5.4–25.7) | <0.01 |
| Overall mortality | 109 (34.7) | 101 (16.1) | <0.01 |
Values are presented as median (interquartile range) or number (%)..
AFP, alpha-fetoprotein; PIVKA, protein induced vitamin K absence; GRWR, graft-recipient-weight ratio; E-S grade, Edmondson-Steiner’s grade..
a)Tumor size over 10 cm or number more than 10 or presence of extrahepatic metastasis. b)Tumor differentiation was either evaluated by World Health Organization well to undifferentiated grade or E-S grade I–IV..
Both Group A and Group B were compared in terms of post-surgical RFS, and the results were as follows: at 1 year, Group B had a significantly higher RFS rate of 90.6% compared to Group A’s rate of 86.3% (p=0.03) (Fig. 3A). However, after 3 years, both groups experienced a decline in their RFS rates to 84.4% and 80.0% for Group B and Group A, respectively. Finally, at the 5-year mark, the RFS rate for Group B was slightly higher than that of Group A at 82.8% and 78%, respectively.
Figure 3. Five-year recurrence-free survival (RFS) and overall survival (OS) rate. (A) Five-year RFS of Group A and B. Group A (n=314) shows a 1-year RFS of 86.3%, dropping to 80.0% at 3 years, and 78.0% at 5 years. In contrast, Group B (n=628) presents RFS of 90.6% at 1 year, 84.4% at 3 years, and 82.8% at 5 years (p=0.03). (B) Five-year OS of Group A and B. One-year survival rates were 95.9% for Group B and 91.7% for Group A. At 3 years, survival decreased to 87.9% for Group B and 80.6% for Group A. At 5-year, Group B survival rate was 84.6%, while Group A further declined to 77.4% (p<0.01). LT, liver transplantation.
Additionally, Group B exhibited better OS rates than Group A. Specifically, Group B demonstrated a 1-year OS rate of 95.9%, whereas Group A had a rate of 91.7%. At 3 years, Group B’s OS rate was 87.9%, and Group A’s was 80.6%. Finally, at the 5-year mark, Group B had an OS rate of 84.6%, which was significantly higher than Group A’s rate of 77.4% (p<0.01) (Fig. 3B).
Furthermore, the recurrence rate was higher in Group A (23.6%) compared to Group B (17.0%, p=0.02), but there was no significant difference in the median time to recurrence between the two groups. The median time to recurrence was 9.1 months (IQR 3.9–21.8) for Group A and 11.4 months (IQR 6.6–18.5) for Group B (p=0.92). Moreover, Group B had a longer median tumor-bearing survival time (20.0 months [IQR 5.4–25.7]) compared to Group A’s median tumor-bearing survival time (12.3 months [IQR 5.2–26.1], p<0.01). Additionally, the overall mortality rate was significantly higher in Group A (34.7%) compared to Group B (16.1%, p<0.01).
In summary, Group B had better OS rates, RFS rates, and median tumor-bearing survival time than Group A. Conversely, Group A had a higher recurrence rate and overall mortality rate.
Our study compared the long-term results of LDLT in HCC between two time periods. We observed a significant decrease in the median MELD score (Group A: 17.4, Group B: 9.0, p=0.01) and AFP levels (Group A: 15.0 ng/mL, Group B: 5.4 ng/mL, p<0.01) from the past to the recent period. The higher median AFP level in Group A may indicate more aggressive or advanced disease before transplantation. On the other hand, the lower AFP in the recent cohort can be attributed to the improved selection process for LT candidates, based on their tumor characteristics (e.g., AFP and PIVKA-II). Previous studies have suggested that a low AFP can lead to better survival and serve as an important prognostic predictor for HCC recurrence [27,28]. Our study also validates this hypothesis, as Group B, representing the most recent decade, achieved superior outcomes in RFS and 1-to-5-year OS rates of 95.9% and 84.6%, p<0.01. Although median time to recurrence did not show statistical significance, Group B had slightly longer median time to recurrence, indicating improved outcomes. Additionally, the overall mortality rate decreased in Group B (Group A: 34.7%, Group B: 16.1%, p<0.01). This may be related to the lower RFS and recurrence rate in Group B (Group A: 22.6%, Group B: 17.0%, p=0.02), as high tumor recurrence is associated with high mortality rate and recurrence is the major cause of post-surgical mortality.
At our center, every stage of the LT process follows a standardized routine protocol, and most living donor hepatectomies have been performed through pure 3D laparoscopy since 2015 [10]. These factors have likely contributed to the decreased total operation time and improved surgical outcomes in Group B, along with decreased cold and warm ischemic times for the graft liver. The implementation of standardized protocols and advancements in laparoscopic surgery technology have reduced operation time and improved outcomes in recent Group B.
The proportion of LRT was higher in Group B, where most patients received a single method of TACE, RFA, or PEIT (Group A: 44.9%, Group B: 55.6%). No LRT received patients were higher in Group A (Table 1). These results suggest that the majority of patients in Group B either exceeded the Milan criteria or were ineligible for surgery, thus requiring downstaging therapy to reduce tumor burden or bridging therapy for LT. As a result of these downstaging and bridging therapies, analysis of the tumors upon removal showed that more than 70% of patients in both groups met the Milan criteria (Table 2). Moreover, the percentage of completely necrotic nodules was higher in Group B (28.0%) compared to Group A (13.4%), indicating a greater use of LRT and a more successful therapeutic effect of LRT in Group B. This ultimately contributed to a higher survival rate and a lower recurrence rate in Group B.
CNIs, such as tacrolimus, have long been established as the standard immune suppression regimen after organ transplantation. However, CNIs have a limited range of therapeutic effectiveness: inadequate levels can lead to acute rejection, while excessive levels can result in toxic effects associated with CNIs [21,22]. Because of narrow trough level and adverse effects, there has been a shift in the use of immune suppression drugs. Since 2014, mTOR inhibitor drugs, such as sirolimus and everolimus, have been widely accepted as an alternative long-term (over 3 months) immunosuppression regimen. These drugs have demonstrated tumor suppressive effects and protection for the kidneys, resulting in improved long-term survival outcomes for liver transplant patients [25]. With this change, our center has regularly implemented mTOR inhibitors for advanced HCCs [29]. Specifically, in Group B, mTOR inhibitors were more commonly used as maintenance therapy and long-term immune suppression one month after transplantation, aiming to achieve clinical tolerance. Therefore, it is reasonable to assume that the increased use of mTOR inhibitors as a maintenance regimen in the recent decade has resulted in improved survival rates.
There are limitations to our study, as is typical of retrospective studies. Our analysis relied on the completeness of the medical records, which may introduce potential biases. Additionally, our findings may not be applicable to patients who underwent deceased donor liver transplantation (DDLT) as our study only included patients who underwent LDLT, not DDLT.
Nevertheless, our findings suggest that Group B, recent period, demonstrated superior survial results and decreased mortality rates than Group A, past period. Enhanced use of mTOR inhibitors and improved patient selection criteria, particularly focusing on tumor biological characteristics, have contributed significantly to these chronological improvements. Further pervasive use of biological tumor marker based patient selection criteria should be encouraged.
Figure 4. Time to recurrence and tumor bearing survival rate. (A) Time to recurrence rate of Group A and B. Group A showed a median time to recurrence of 9.1 months (n=74), while Group B had a median of 11.4 months (n=107), p=0.92. (B) Tumor bearing survival rate of Group A and B. Group A had a median survival of 12.3 months (n=65) and Group B (red) had a median of 20.0 months (n=64), p<0.01. LT, liver transplantation.
There was no funding related to this study.
Suk Kyun Hong is an editorial member of the journal but was not involved in the review process of this manuscript. Any other authors have no conflict of interest.
Conceptualization: KWL, SOG. Data curation: KWL, SOG, NJY, YRC, SKH, JML, KSS. Formal analysis: KWL, SOG. Investigation: KWL, SOG. Methodology: KWL, SOG, NJY, YRC, SKH, JML, KSS. Project administration: KWL. Resources: KWL, SOG, NJY, YRC, SKH, JML, KSS. Supervision: KWL, NJY, YRC, SKH, JML, KSS. Validation: KWL, SOG. Visualization: KWL, SOG. Writing – original draft: All. Writing – review & editing: KWL, SOG, NJY, YRC, SKH, JML, KSS.
Table 1 Baseline characteristics of study population
| Variable | Group A (n=314) | Group B (n=628) | p-value |
|---|---|---|---|
| Age (yr) | 56.0 (52.0–63.0) | 57.0 (52.0–62.0) | 0.85 |
| Sex | 0.32 | ||
| Male | 262 (83.4) | 506 (80.6) | |
| Female | 52 (16.6) | 122 (19.4) | |
| Underlying disease | <0.01 | ||
| Hepatitis B virus infection | 244 (77.7) | 467 (74.4) | |
| Hepatitis C virus infection | 21 (6.7) | 61 (9.7) | |
| Alcoholic liver disease | 6 (1.9) | 56 (8.9) | |
| Othersa) | 43 (13.7) | 44 (7.0) | |
| Child-Turcot-Pugh classification | <0.01 | ||
| A | 54 (17.2) | 392 (62.4) | |
| B | 56 (17.8) | 154 (24.5) | |
| C | 35 (10.8) | 82 (13.1) | |
| MELD score | 17.4 (12.7–23.3) | 9.0 (7.2–12.9) | 0.01 |
| Pre-operative liver resection | 9 (2.9) | 111 (17.7) | <0.01 |
| Pre-operative locoregional therapy | <0.01 | ||
| Single methods (TACE/TAE or RFA or PEIT) | 141 (44.9) | 349 (55.6) | |
| Double methods (TACE+RFA/PEIT or RFA+PEIT) | 56 (17.8) | 158 (25.2) | |
| Triple methods (TACE+RFA+PEIT) | 8 (2.5) | 31 (4.9) | |
| None | 109 (34.7) | 90 (14.3) |
Values are presented as median (interquartile range) or number (%).
MELD, model for end-stage liver disease; TACE, transarterial chemoembolization; TAE, transarterial embolization; RFA, radio frequency ablation; PEIT, percutaneous ethanol injection therapy.
a)Autoimmune hepatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson’s disease, cryptogenic hepatitis, non-B non-C liver cirrhosis, glycogen storage disease, membranous obstruction of inferior vena cava associated liver cirrhosis, Budd–Chiari syndrome, unknown causes.
Table 2 Tumor characteristics and post-surgical outcomes of study population
| Variable | Group A (n=314) | Group B (n=628) | p-value |
|---|---|---|---|
| Pre-operative AFP (ng/mL) | 15.0 (5.5–84.5) | 5.4 (2.9–16.6) | <0.01 |
| Pre-operative PIVKA-II (mAU/mL) | 30.0 (16.0–90.5) | 27.0 (18.0–67.0) | 0.31 |
| Missing value | 69 (22.0) | 13 (2.1) | |
| Explant-based Milan criteria | 0.50 | ||
| Within Milan | 228 (72.6) | 474 (75.5) | |
| Beyond Milan | 67 (21.3) | 114 (18.2) | |
| Far advanceda) | 19 (6.1) | 40 (6.4) | |
| Operation time (min) | 470.0 (420.0–540.0) | 385.0 (330.0–454.7) | <0.01 |
| Graft liver volume (mL) | 715.0 (645.0–823.5) | 702.0 (612.0–803.0) | 0.03 |
| GRWR | 1.16 (0.97–1.16) | 1.05 (0.89–1.05) | <0.01 |
| Largest tumor size (cm) | 2.4 (1.6–3.5) | 2.2 (1.4–3.5) | 0.01 |
| Number of tumors | 2 (1.0–2.0) | 2 (1.0–3.0) | 0.33 |
| Microvascular invasion | 41 (13.1) | 83 (13.2) | 0.10 |
| Tumor differentiationb) | <0.01 | ||
| Total necrosis | 42 (13.4) | 176 (28.0) | |
| E-S grade I–II | 130 (41.4) | 239 (38.0) | |
| E-S grade III–IV | 142 (45.3) | 213 (33.9) | |
| Recurrence | 74 (23.6) | 107 (17.0) | 0.02 |
| Time to recurrence (mon) | 9.1 (3.9–21.8) | 11.4 (6.6–18.5) | 0.92 |
| Tumor bearing survival (mon) | 12.3 (5.2–26.1) | 20.0 (5.4–25.7) | <0.01 |
| Overall mortality | 109 (34.7) | 101 (16.1) | <0.01 |
Values are presented as median (interquartile range) or number (%).
AFP, alpha-fetoprotein; PIVKA, protein induced vitamin K absence; GRWR, graft-recipient-weight ratio; E-S grade, Edmondson-Steiner’s grade.
a)Tumor size over 10 cm or number more than 10 or presence of extrahepatic metastasis. b)Tumor differentiation was either evaluated by World Health Organization well to undifferentiated grade or E-S grade I–IV.
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