Liver transplantation for hepatocellular carcinoma arising in non-cirrhotic liver: a national-wide retrospective cohort study with propensity score matching analysis in China

Introduction

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death and ranks sixth in terms of new cases worldwide (1). Majority of HCC develop in cirrhotic liver caused by inflammatory disease, such as hepatitis B or C virus infection, which is called cirrhotic hepatocellular carcinoma (C-HCC). However, the incidence of non-cirrhotic hepatocellular carcinoma (NC-HCC) has risen from less than 10% to more than 20% in the past two decades (2-8). Due to the absence of liver hepatitis, unclear early symptoms and unconventional surveillance, most NC-HCC patients appear in a relatively advanced stage, when the tumor has reached a considerable size or (intrahepatic) metastasis has developed (9,10). Liver transplantation (LT) remains the optimal therapy for patients with HCC (11,12). Different from C-HCC, LT for NC-HCC remains controversial due to lack of clinical experiences with detailed long-term follow-up. Some early small sample reports have suggested that outcomes after LT for NC-HCC are poor (13,14). However, a single center study from the United States suggested that outcome after LT for NC-HCC is similar as C-HCC (15). Two reports from Europe found that there is no difference in survival between NC-HCC and C-HCC patients after LT (10,16). So far, there have been lack of reports from East Asia with long-term follow-up. China Liver Transplant Registry (CLTR), which is one of the largest liver transplants databases worldwide, is also the national scientific LT registration system in China and all LT centers in Mainland China should submit transplant data to CLTR in a timely, accurate, true and complete manner. The database comprises information on donor, recipient, immunosuppression, pathology from explanted liver, underlying liver disease, cirrhosis, time of death, and cause of death. Therefore, based on CLTR, we designed this largest sample retrospective analysis, and aimed to determine outcome after LT for NC-HCC and to identify variables that are associated with survival. In our study, we applied propensity score matching (PSM), a statistical method for analyzing intervention effects using non-experimental or observational data, which offers advantages in controlling confounding variables in observational studies. We present this article in accordance with the STROBE reporting checklist (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-402/rc).

Methods

Study patients

The details of 24,230 liver transplants, performed from January 2015 to December 2020, were collected by the CLTR. This study was performed according to the Declaration of Helsinki (and its subsequent amendments) and approved by the CLTR (No. 20230029). Informed consent was obtained from all the patients for the use of their data for research purposes. Voluntarily donated organs from citizens have become the sole legitimate source of transplantable organs from deceased donors in China science January 2015 (17,18). It is important to note that all deceased organ donations in China are nondirected donations. Additionally, to ensure fair, just, open, and traceable allocation, all organs from deceased donors are automatically allocated through the China Organ Transplant Response System in accordance with national policies (19).

All patients in this study did not receive liver grafts from prisoners. A total of 16,757 recipients were excluded from this study according to following exclusion criteria: pediatric LT; LT for non-tumor lesions; LT for other malignant tumors (cholangiocarcinoma, carcinoma of gallbladder, mixed carcinoma, and secondary tumors); re-transplantation or combined liver-kidney transplantation; incomplete laboratory or clinical data; death within 1 week due to post-operative hemorrhage after LT. The remaining 7,473 patients were enrolled, and their data were used for analysis. Eight hundred and forty-five NC-HCC recipients were enrolled (NC group, n=845), which were matched using propensity score at a 1:2 ratio with C-HCC recipients (C group, n=1,690). Diagnosis of liver cirrhosis and HCC was confirmed by liver biopsy or pathology after LT. The parameters for matching included sex, serum alpha fetoprotein (AFP), Model for End-stage Liver Disease (MELD) score, donor type, recipients’ age, vascular invasion, tumor diameter, tumor number, within or beyond Milan or Hangzhou criteria. By using PSM calibration, underlying liver diseases in HCC patients were eliminated, making cirrhotic and non-cirrhotic patients more comparable.

Data collection

Patient baseline characteristics and clinical variables were collected in this study. Data extracted from the medical records included sex, age, operation year, MELD score, size of largest HCC tumor, number of HCC tumors, vascular invasion, AFP level, within or beyond Milan criteria, within or beyond Hangzhou criteria and pre-transplant treatment were collected. The follow-up data extracted included death, cause of death, HCC recurrence or date of last follow-up.

Statistical analysis

Continuous variables with a normal distribution are expressed as the mean ± standard deviation (SD) or medians and interquartile ranges (IQRs). Categorical variables are expressed as numbers (n) or proportions (%). The Kolmogorov-Smirnov test was used to evaluate the normality of the data distribution. Normally distributed data were compared using Student’s t-tests, while non-normally distributed continuous variables were compared using Mann-Whitney U-tests. Using the Kaplan-Meier method generated by the log-rank test, the graft survival (GS), tumor-free survival (TFS) and overall survival (OS) rates were compared among patients with LT for cirrhotic HCC or non-cirrhotic HCC. Cox proportional hazard models were used to estimate hazard ratios (HRs) for OS and TFS, and to determine independent risk factors. The HR and its 95% confidence interval (CI) were estimated in the univariable and multivariable Cox regression analyses. Statistical analysis was performed using SAS software, version 9.2 (SAS institute, Cary, NC, USA). P value <0.05 was considered statistically significant.

Results

Baseline characteristics of the cohorts

The recipients and donors’ demographic characteristics are presented in Tables 1,2. Before PSM, among all 7,473 HCC recipients, non-cirrhotic liver accounted for 11.4% (855/7,473). After PSM, there was no difference in recipients’ age, sex, MELD score, pre-transplant AFP or operation year between the two groups after PSM. The tumor characteristics including size, number, histological differentiation and vascular invasion did not differ between the two groups. Meanwhile, except for liver resection, there are no differences in pre-transplant treatment including transcatheter arterial chemoembolization (TACE), radio frequency ablation (RFA), and RFA + TACE between NC group and C group.

HCC recurrence

The HCC recurrence rate was 11.1% (94/845) in NC group and 15.3% (258/1,690) in C group (P=0.005). The interval for the development of HCC recurrence was 11.5±11.9 months in NC group and 11.0±11.3 months in C group (P=0.76) (Table 2). The 1-, 3- and 5-year HCC recurrence rates were higher in C group than these in NC group (11.83% vs. 10.53%, 19.47% vs. 15.86% and 23.31% vs. 20.59%, P=0.004) (Table 3).

Other post-LT complications

Compared with C group, NC group was associated with lower incidences of new-onset diabetes mellitus (8.28% vs. 13.67%, P<0.001) and pleural effusion (34.08% vs. 50.21%, P<0.001), and higher incidences of intra-abdominal bleeding (5.92% vs. 2.43%, P<0.001) and graft versus host disease (GVHD) (2.72% vs. 0.53%, P<0.001) (Table 3) and urinary tract infection (0.36% vs. 0, P=0.03).

Survival

We analyzed the survival of cirrhotic and non-cirrhotic recipients before PSM,and found that compared with cirrhotic recipients, non-cirrhotic recipients showed lower OS (1-, 3- and 5-year: 79.55%, 69.42% and 59.21 % vs. 85.45%, 71.13% and 64.36%), TFS (1-, 3- and 5-year: 73.05%, 60.18% and 51.90% vs. 79.20%, 65.61% and 58.36%) and GS (1-, 3- and 5-year: 78.96%, 64.07% and 58.72% vs. 84.61%, 69.92% and 63.22%) (Figure 1, P<0.001 for all).

Figure 1 The comparison of survival between non-cirrhotic and cirrhotic HCC recipients before PSM. (A) According to the cumulative survival curve, non-cirrhotic recipients (n=855) showed lower OS than cirrhotic recipients (n=6,618) (1-, 3- and 5-year OS: 79.55%, 69.42% and 59.21% vs. 85.45%, 71.13% and 64.36%; P<0.001). (B) Compared with cirrhotic recipients, non-cirrhotic recipients showed lower TFS (1-, 3- and 5-year TFS: 73.05%, 60.18% and 51.90% vs. 79.20%, 65.61% and 58.36%; P<0.001). (C) Similarly, difference of GS was observed between two groups (1-, 3- and 5-year GS: 78.96%, 64.07% and 58.72% vs. 84.61%, 69.92% and 63.22%; P<0.001). HCC, hepatocellular carcinoma; PSM, propensity score matching; OS, overall survival; TFS, tumor-free survival; GS, graft survival; NC, non-cirrhotic; C, cirrhotic.

After PSM, we found that compared with C group, NC group showed lower OS (1-, 3- and 5-year: 79.4%, 65.1% and 59.3% vs. 85.6%, 70.4% and 63.1%; P=0.003), TFS (1-, 3- and 5-year: 73.0%, 60.3% and 51.9% vs. 78.8%, 63.7% and 54.2%; P=0.03) and GS (1-, 3- and 5-year: 78.8%, 64.2% and 58.8% vs. 84.7%, 68.9% and 61.9%; P=0.007) (Figure 2).

Figure 2 The comparison of survival between non-cirrhotic and cirrhotic HCC recipients after PSM. (A) According to the cumulative survival curve, recipients in NC group (n=845) showed lower OS than those in C group (n=1,690) (1-, 3- and 5-year OS: 79.44%, 65.08% and 59.28% vs. 85.56%, 70.41% and 63.07%; P=0.003). (B) Compared with C group, NC group showed lower TFS (1-, 3- and 5-year TFS: 73.00%, 60.26% and 51.86% vs. 78.77%, 63.70% and 54.23%; P=0.03). (C) Similarly, difference of GS was observed between two groups (1-, 3- and 5-year GS: 78.84%, 64.22% and 58.79% vs. 84.67%, 68.94% and 61.91%; P=0.007). HCC, hepatocellular carcinoma; PSM, propensity score matching; OS, overall survival; TFS, tumor-free survival; GS, graft survival; NC, non-cirrhotic; C, cirrhotic.

For HCC recipients from CLTR database, according to the cumulative survival curve, NC-HCC recipients within Hangzhou criteria showed lower OS (1-, 3- and 5-year: 85.7%, 73.1% and 67.7% vs. 90.9%, 80.8% and 75.3%; P=0.001), TFS (1-, 3- and 5-year: 82.6%, 70.4% and 61.2% vs. 87.0%, 75.8% and 68.1%; P=0.02) and GS (1-, 3- and 5-year: 84.9%, 71.7% and 66.9% vs. 89.9%, 79.6% and 73.8%; P=0.002) than C-HCC recipients within Hangzhou Criteria (Figure 3). For recipients from CLTR exceeding the Hangzhou criteria, the OS, TFS and GS showed no differences between non cirrhotic and cirrhotic HCC recipients (P=0.14, P=0.20 and P=0.21, respectively) (Figure 4).

Figure 3 The comparison of survival between non-cirrhotic and cirrhotic HCC recipients within Hangzhou criteria. (A) According to the cumulative survival curve, non-cirrhotic recipients within Hangzhou criteria (n=557) showed lower OS than cirrhotic HCC recipients within Hangzhou criteria (n=1,097) (1-, 3- and 5-year OS: 85.69%, 73.11% and 67.67% vs. 90.91%, 80.80% and 75.32%; P=0.001). (B) Compared with cirrhotic HCC recipients within Hangzhou criteria, non-cirrhotic recipients within Hangzhou criteria showed lower TFS (1-, 3- and 5-year TFS: 82.60%, 70.39% and 61.15% vs. 86.97%, 75.78% and 68.06%; P=0.02). (C) Similarly, difference of GS was observed between these two groups (1-, 3- and 5-year GS: 84.93%, 71.74% and 66.86% vs. 89.93%, 79.55% and 73.79%; P=0.002). HCC, hepatocellular carcinoma; OS, overall survival; TFS, tumor-free survival; GS, graft survival.

Figure 4 The comparison of survival between non-cirrhotic and cirrhotic HCC recipients beyond Hangzhou criteria. (A) According to the cumulative survival curve, there was no difference of OS between non-cirrhotic (n=288) and cirrhotic HCC recipients (n=593) (1-, 3- and 5-year OS: 67.40%, 49.23% and 42.07% vs. 76.04%, 52.26% and 41.22%; P=0.14). (B) Compared with cirrhotic HCC recipients beyond Hangzhou criteria, non-cirrhotic recipients beyond Hangzhou criteria showed no difference of TFS (1-, 3- and 5-year TFS: 54.59%, 40.26% and 33.24% vs. 64.12%, 42.56% and 29.11%; P=0.20). (C) Similarly, no difference of GS was observed between these two groups (1-, 3- and 5-year GS: 67.11%, 49.39% and 42.21% vs. 75.32%, 50.40% and 40.37%; P=0.21). HCC, hepatocellular carcinoma; OS, overall survival; TFS, tumor-free survival; GS, graft survival.

We evaluated factors that influenced the OS and TFS in NC-HCC recipients from CLTR (Table 4). Factors associated with a P<0.05 in the univariate analysis were entered into a multivariate analysis. The analysis revealed that beyond Hangzhou criteria (HR =2.079, P<0.001), MELD score ≥25 (HR =1.502, P=0.01) and early allograft dysfunction (EAD) (HR =2.139, P<0.001) were independent risk factors for OS, while recipient age ≥50 years (HR =1.423, P=0.02), beyond Hangzhou criteria (HR =2.188, P<0.001) and EAD (HR =1.918, P<0.001) were independent risk factors for TFS.

Discussion

Here, we present the world’s largest sample of NC-HCC patients for LT, sourced from a national database. To control for confounding indicators as much as possible, we matched basic recipient characteristics, tumor morphological features and biological features using PSM. This research identified that the outcomes of non-cirrhotic recipients were poorer than those of cirrhotic recipients from China. The postoperative recurrence rate of NC-HCC recipients was higher than that of C-HCC recipients. Furthermore, we analyzed HCC recipients from CLTR within Hangzhou criteria, a commonly criteria used in mainland China, and found that the prognosis of NC-HCC recipients was also worse than that of C-HCC recipients. These finding differ from some previous large sample retrospective cohort study (5,6,15).

Existing evidence suggests that HCC caused by different etiologies may exhibit clinical, pathological, and therapeutic differences (20). Consequently, the survival of patients with HCC after LT primarily depends on etiology, tumor biological characteristics, viral infection and other sophisticated regulatory mechanisms (21). As we know, cirrhosis related to chronic hepatitis B virus (HBV) infection is a major risk factor for HCC. However, some patients with chronic HBV do not progress to cirrhosis when diagnosed with HCC (22). In our research, preoperative HBV infection accounts for about 80% in NC-HCC recipients, which also indicates that HBV is still a main risk factor for NC-HCC in Chinese population. Which is different from that in the American population, where non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome are the main risk factors HCC in the absence of cirrhosis (23). As accounted for 11.4% in this study, NC-HCC often receives less attention compared to C-HCC due to its relatively small proportion in HCC cases (2-7). Patients with cirrhosis typically receive regular surveillance and timely treatment throughout all stages, from cirrhosis to HCC. In contrast, NC-HCC tends to progress more rapidly, with unclear early symptoms, fewer tumors, larger tumor volumes, lower differentiation, and increased vascular invasion and intrahepatic metastasis (15,24). These factors may contribute to the poor prognosis of NC-HCC patients. Some researchers propose that multicenter carcinogenesis or circulating tumor cells could also account for the poor prognosis in NC-HCC (25). Additionally, NC-HCC appears to be more dependent on the regulation of miRNA networks than C-HCC (26). A bioinformatics analysis based on miRNA-seq data from 135 non-cirrhotic and 80 cirrhotic patients identified two miRNAs critically correlated with clinical features of NC-HCC patients. Another study investigating genetic alterations in HCC through comparative genomic hybridization found that NC-HCC exhibited more genomic alterations, particularly increased copy number on chromosome 8q, which may contribute to the specific tumor biology of NC-HCC (27). One prospective study reported that C-HCC and NC-HCC have distinct clinical and imaging features, and that the time of contrast agent clearance is related to the histopathological grade of HCC (28). Therefore, we predict numerous intrinsic factors may contribute to the poor prognosis of NC-HCC after LT, necessitating further investigations.

In addition, we also found that the average age of NC-HCC recipients is generally younger than that of C-HCC recipients. Due to the absence of cirrhosis, NC-HCC patients’ liver function is usually well protected, resulting in relatively lower pre-transplant MELD scores (29). This observation is confirmed in the unmatched CLTR data of this study. Consequently, NC-HCC patients experience longer waiting list times and have a lower likelihood of receiving a donor liver compared to C-HCC patients.

In this study, the CLTR NC-HCC recipients represent independent sample, and all the CLTR cirrhotic HCC recipients were matched with them, rendering a dependent sample. This is why multivariate analysis was conducted only on NC-HCC recipients. The results indicate that Hangzhou criteria, recipient’s MELD score and EAD were identified as the major risk factors associated with OS in NC-HCC recipients after LT. Furthermore, Hangzhou criteria, recipient age and EAD were independent risk factors influencing TFS of NC-HCC recipients.

In the present study, the tumor recurrence rate in C-HCC recipients was higher than that in NC-HCC recipients. We found that, among patients within the Hangzhou criteria, both OS and TFS rates were higher in NC-HCC recipients compared to C-HCC recipients. Conversely, there were no differences in OS and TFS between patients beyond the Hangzhou criteria, regardless of the presence of liver cirrhosis. As we know, Hangzhou criteria is considered as an important factor that affecting C-HCC recipient’s prognosis and is traditionally used as selection criteria for LT in patients with cirrhotic HCC (30,31). Our multivariate analysis firstly indicated Hangzhou criteria was an independent prognostic factor for NC-HCC recipients.

Although there is a general consensus that pre-LT MELD score is an excellent predictor of post-LT mortality, it remains controversial that whether MELD score could be a predictor of post-transplant survival (32). Some reports showed MELD score cannot predict patient or graft survival in LT recipients (33-35). While in another large cohort national study, MELD has been proven to be a valid predictor of short-term survival after LT in patients with HBV-induced cirrhosis (36). In our study, the prognosis of HCC in non-cirrhotic liver may be influenced by the limitations of operation and is unrelated to MELD scores associated with HCC in cirrhotic livers.

As for EAD, our previous studies showed that grafts or recipients who experienced EAD had a worse survival prognosis, thus EAD can serve as a predictor of post-LT prognosis (37,38), which is consistent with our current research. Although EAD is not related initially to tumor size or histology, it implies longer cold ischemia time and heavy ischemia-reperfusion injury, which are closely related to tumor recurrence and non-cirrhotic HCC prognosis (39,40).

Age is a significant clinical concern in the field of surgery. Oncologic outcomes and survival data for older transplant recipients are conflicting. In the context of HCC, the concerns about tumor spread and recurrence create an additional challenge when LT is considered, as both tend to affect older patients (41). Age is a marker of surgical risk. Frailty and declines in physiologic reserves may increase perioperative complications in older surgical patients, particularly in complex hepatic operations (42). Research compared 3 groups of LT recipients and showed satisfactory post-transplantation outcomes in the first 5 years were achievable in the cohort older than 65 years when accompanied by comprehensive recipient screening (43). In marked contrast, research from US of LT for early-stage HCC patients showed elderly recipients had worse 5-year OS than non-elderly recipients (44). With the increase of experience and the improvement of results, we see a shift in the age limit from around 50 years to the current situation, where most transplant centers do not have strict age limit when wait-listing the patients for LT (45,46). Although age over 50 years in NC-HCC recipients was associated with worse tumor free survival in our cohort, LT provides a survival benefit for NC-HCC recipients over 50 years of age. In the first 5 years after LT, more than 50 years old is not a risk factor affecting OS. When considering LT for HCC patients, age itself should not be a prohibitive factor.

Of course, this study has some limitations. This is a retrospective study based on multiple centers, reflecting the perioperative management strategies adopted by different transplant centers. Furthermore, some multicenter clinical studies of LT for non-cirrhotic HCC should be performed.

Conclusions

In conclusion, LT for NC-HCC is associated with a poor prognosis. This finding suggests that NC-HCC may exhibit more aggressive characteristics and warrants greater clinical attention.

Acknowledgments

We thank the CLTR for providing a qualified public database, and the local administrative staff who contributed to the quality control of the data in China.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-402/rc

Data Sharing Statement: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-402/dss

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-402/prf

Funding: This work was supported by grants from National Key Research and Development Program of China (2021YFA1100500), National Natural Science Foundation of China (92159202) and Key Research & Development Plan of Zhejiang Province (2022C03108).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-402/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was performed according to the Declaration of Helsinki (and its subsequent amendments) and approved by the CLTR (No. 20230029). Informed consent was obtained from all the patients for the use of their data for research purposes. No organs from executed prisoners were used.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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