Donor sex and donor-recipient sex disparity do not affect hepatocellular carcinoma recurrence after living donor liver transplantation

Rak Kyun Oh; Shin Hwang; Gi-Won Song; Chul-Soo Ahn; Deok-Bog Moon; Tae-Yong Ha; Dong-Hwan Jung; Gil-Chun Park; Young-In Yoon; Woo-Hyoung Kang

doi:10.4174/astr.2023.105.3.133

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Oh, Hwang, Song, Ahn, Moon, Ha, Jung, Park, Yoon, and Kang: Donor sex and donor-recipient sex disparity do not affect hepatocellular carcinoma recurrence after living donor liver transplantation

Original Article

Annals of Surgical Treatment and Research 2023; 105(3): 133-140.

Published online: 1 September 2023

DOI: https://doi.org/10.4174/astr.2023.105.3.133

Donor sex and donor-recipient sex disparity do not affect hepatocellular carcinoma recurrence after living donor liver transplantation

Rak Kyun Oh

, Shin Hwang

, Gi-Won Song

, Chul-Soo Ahn

, Deok-Bog Moon

, Tae-Yong Ha

, Dong-Hwan Jung

, Gil-Chun Park

, Young-In Yoon

, Woo-Hyoung Kang

Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Corresponding Author: Shin Hwang. Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea. Tel: +82-2-3010-3930, Fax: +82-2-3010-6701, shwang@amc.seoul.kr

Received 30 May 2023 Revised 11 July 2023 Accepted 1 August 2023

The Korean Surgical Society

https://creativecommons.org/licenses/by-nc/4.0/

Annals of Surgical Treatment and Research is an Open Access Journal. All articles are distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose

Studies have yielded contradictory results on whether donor sex and donor-recipient sex disparity affect hepatocellular carcinoma (HCC) recurrence after living donor liver transplantation (LDLT). The present study assessed whether donor sex or donor-recipient sex disparity affects HCC recurrence after LDLT at a high-volume center.

Methods

This study included 772 HCC patients who underwent LDLT between January 2006 and December 2015 at Asan Medical Center. Patients were divided into 4 groups based on the sex of the donor and recipient: male-to-male (n = 490, 63.5%), male-to-female (n = 75, 9.7%), female-to-male (n = 170, 22.0%), and female-to-female (n = 37, 4.8%).

Results

Disease-free survival (DFS; P = 0.372) and overall survival (OS; P = 0.591) did not differ significantly among the 4 groups. DFS also did not differ significantly between LDLT recipients with male and female donors (P = 0.792) or between male and female recipients (P = 0.084). After patient matching with an α-FP/des-γ-carboxy prothrombin/tumor volume score cutoff of 5logs, donor-recipient sex disparity did not significantly affect DFS (P = 0.598) or OS (P = 0.777). There were also no differences in DFS in matched LDLT recipients with male and female donors (P = 0.312) or between male and female recipients (P = 0.374).

Conclusion

Neither donor sex nor donor-recipient sex disparity significantly affected posttransplant HCC recurrence.

Keywords: Androgens, Donor selection, Donor sex, Hepatocellular carcinoma, Sex disparity

INTRODUCTION

Hepatocellular carcinoma (HCC) is an established indication for liver transplantation (LT) and a major indication for living donor LT (LDLT) in Asian countries [1]. Posttransplant HCC recurrence, however, is associated with shortened patient survival, despite active treatment of recurrent tumors. Thus, LT candidates are carefully selected to reduce the risk of HCC recurrence.

The incidence of HCC incidence is higher in men than in women [2]. Sex disparities have also been observed in the prognosis of untreated patients and in recurrence rates after liver resection [3 4]. Three recent studies have analyzed the effect of donor sex on posttransplant HCC recurrence [5 6 7]. A Korean single-center study reported that the recurrence rate was higher after LT from male than from female donors [5]. An analysis of patients in the United Network for Organ Sharing (UNOS) database revealed that, compared with LT from female donors, LT from male donors was significantly associated with lower HCC recurrence in female, but not in male, recipients [6]. By contrast, an analysis of the Japanese Liver Transplantation Society database found that donor sex did not affect post-LT recurrence of HCC [7].

To attempt to resolve these contradictory results, this retrospective, single-center observational study assessed whether donor sex could affect the incidence of HCC recurrence after LDLT using data from a high-volume transplant center in South Korea.

METHODS

Patient selection

The LT database of the Asan Medical Center was searched to identify adult patients who underwent primary LDLT for HCC during the 10-year period from January 2006 to December 2015. Patients were included if they were aged ≥18 years at the time of LDLT and had been diagnosed with HCC prior to LT. Patients were excluded if they were incidentally diagnosed with HCC by examination of the explanted liver, if they had undergone retransplantation, if they had combined HCC-cholangiocarcinoma, and if they had died <3 months after LT. Patients who underwent dual-donor LT were also excluded to avoid bias from 2 donors regardless of donor sex disparity. Patients were also excluded if serum concentrations of α-FP and des-γ-carboxy prothrombin (DCP) were not measured within 2 weeks prior to LDLT because patients were matched by α-FP/DCP/tumor volume (TV) scores (ADV scores) rather than by propensity scores [8 9 10 11]. A total of 772 patients were included in this study.

The study patients were followed-up until April 2021 or patient death through review of institutional medical records and with the assistance of the National Health Insurance Service in Korea. The study protocol was approved by the Institutional Review Board of Asan Medical Center (No. 2021-1508), which waived the requirement for informed consent due to the retrospective nature of this study. This study was performed in accordance with the ethical guidelines of the World Medical Association Declaration of Helsinki 2013.

Calculation of ADV scores

ADV scores were calculated as the log of the product of α-FP concentration (ng/mL), DCP concentration (mAU/mL), and TV (mL) [8 9 10 11]. The α-FP and DCP concentrations were measured within 2 weeks prior to the LDLT operation, and explanted TV was calculated using the 3-dimensional size information in the pathology report. If there were multiple tumors, the total TV was calculated by multiplying the TV of the largest tumor by the number of tumors. For patient matching, an ADV score cutoff of 5log was used to exclude patients with high risk of HCC recurrence [10 11].

Statistical analysis

Numerical data are presented as medians with ranges or means and standard deviations. Continuous variables were compared using the Student t-test or analysis of variance, and categorical variables were compared using chi-square tests. Survival curves were generated using the Kaplan-Meier method and compared using log-rank tests. Statistical analyses were performed using IBM SPSS Statistics ver. 22 (IBM Corp.), with P-values of <0.05 considered statistically significant.

RESULTS

Patient demographics

The 772 patients in this study were classified into 4 groups according to the sex of the LT donor and recipient. Of the 772 recipients, 490 (63.5%) underwent male-to-male (MM), 75 (9.7%) underwent male-to-female (MF), 170 (22.0%) underwent female-to-male (FM), and 37 (4.8%) underwent female-to-female (FF) LT. The clinicopathologic features of the 4 groups were similar, except for graft-to-recipient weight ratio (P < 0.001) and graft type (P < 0.001), primarily due to smaller-sized grafts from female donors, as well as donor age (P < 0.001) (Table 1).

Disease-free and overall patient survival

Of the 772 patients, 171 (22.2%) experienced HCC recurrence and 120 (15.5%) died of all causes over a median follow-up period of 72 months. Of the 120 patients who died, 94 died of HCC recurrence-related causes and 26 died of other causes. The 1-, 3-, 5-, and 10-year disease-free survival (DFS) rates were 87.2%, 80.8%, 78.0%, and 76.5%, respectively, whereas the 1-, 3-, 5-, and 10-year overall survival (OS) rates were 96.4%, 87.8%, 85.7%, and 83.3%, respectively (Fig. 1).

Disease-free and overall patient survival according to donor-recipient sex disparity

The 5-year DFS and OS rates were 77.2% and 85.1%, respectively, in the MM group; 83.9% and 90.1%, respectively, in the MF group; 76.4% and 85.2%, respectively, in the FM group; and 83.8% and 86.5%, respectively, in the FF group. These results indicated that neither DFS (P = 0.372) nor OS (P = 0.591) differed significantly in these 4 groups (Fig. 2).

Disease-free and overall patient survival according to donor and recipient sex

The 5-year DFS and OS rates did not differ significantly in LDLT recipients with male and female donors (DFS: 78.1% vs. 77.7%, P = 0.792 [Fig. 3A]; OS: 85.8% vs. 85.4%, P = 0.534 [Fig. 3B]). The 5-year DFS and OS rates also did not differ in male and female recipients (DFS: 77.0% vs. 83.7%, P = 0.084 [Fig. 3C]; OS: 85.1% vs. 88.9%, P = 0.271 [Fig. 3D]).

Disease-free and overall patient survival according to donor-recipient sex disparity in selected patients with ADV scores of <5log

Of the 772 patients, 590 (76.4%) had ADV scores of <5log; of the latter, 389 (65.9%) underwent MM, 54 (9.2%) underwent MF, 120 (20.3%) underwent FM, and 27 (4.6%) underwent FF LT. The 5-year DFS rates in these 4 groups were 84.7%, 88.8%, 88.6%, and 88.9%, respectively, whereas their 5-year OS rates were 89.9%, 92.1%, 94.2%, and 92.6%, respectively. These results indicated that neither DFS (P = 0.598) nor OS (P = 0.777) differed significantly in these 4 groups (Fig. 4).

Disease-free and overall patient survival according to donor and recipient sex in the selected patients with ADV score of <5log

Evaluation of the 590 patients with ADV scores of <5log showed that the 5-year DFS and OS rates did not differ significantly in LDLT recipients with male and female donors (DFS: 85.2% vs. 88.6%, P = 0.312 [Fig. 5A]; OS: 90.1% vs. 93.3%, P = 0.748 [Fig. 5B]). The 5-year DFS and OS rates also did not differ in male and female recipients (DFS: 85.6% vs. 88.8%, P = 0.374 [Fig. 5C]; OS: 90.7% vs. 92.3%, P = 0.561 [Fig. 5D]).

DISCUSSION

Predicting the posttransplant prognosis in patients who have undergone LT for treatment of HCC is difficult because the tumor burden at LT is highly variable, HCC tumor biology is heterogeneous, and immunosuppression may alter outcomes. Factors investigated for their ability to predict posttransplant HCC recurrence have included tumor size, tumor number, vascular invasion, tumor differentiation, and α-FP and DCP concentrations [12 13 14 15 16]. The risk of posttransplant HCC recurrence may be reduced by careful selection of patients for LT [17 18 19 20 21 22], but, to date, donor sex and donor-recipient sex disparity has not been considered a selection criterion for LT.

Recently, a few studies have analyzed the effect of donor sex on posttransplant HCC recurrence. A male donor was reported to be associated with higher HCC recurrence in analysis of a Korean single-center LT cohort [5]. A male donor was also reported to be associated with lower HCC recurrence in female recipients in analysis of the UNOS data [6]. However, no difference was identified in HCC recurrence according to donor sex in analysis of the Japanese Liver Transplantation Society database [7]. Thus, the present study was intended to elucidate these contradictory outcomes. The present study demonstrated that donor sex and donor-recipient sex disparity did not affect HCC recurrence after LT, with no difference in HCC recurrence rates in recipients of male and female donor livers. Evaluation of the entire study cohort of 772 patients showed that HCC recurrence appeared marginally higher in male recipients, but this difference disappeared after patient selection with an ADV score cutoff of 5log.

Abovementioned 2 studies showing risk of donor sex-associated HCC recurrence in LT recipients had casted an important issue on donor selection [5 6], especially in LDLT. If a male donor had been a proven risk factor for HCC recurrence, it would be seriously considered when selecting a living donor among potential donors. Contrarily, 2 high-volume studies—analysis of the Japanese Liver Transplantation Society database [7] and the present study—demonstrated that donor sex was not associated with posttransplant HCC recurrence. The present study also revealed that donor-recipient sex disparity did not affect posttransplant HCC recurrence. These results suggest that there is no need to consider donor sex or donor sex disparity in selecting a living donor for LDLT.

Sex hormone receptors in the liver have been reported to mediate most sex disparities in HCC in the non-LT setting [23 24 25 26 27], although other studies have suggested that sex hormones themselves can mediate these disparities [28 29]. A study assessing the prognostic values of androgen receptor (AR) expression and activity in patients with HCC showed that higher AR expression was associated with a higher median OS [24]. Two AR scores showed a relative increase of upregulated to downregulated androgen-responsive genes in high-grade HCC, with higher AR activity being associated with poorer patient outcomes. The possible intrahepatic presence of sex hormone receptors suggests that any possible differences in overall recurrence rates after LT were likely due to differences in graft recurrence rate. The present study found that donor-recipient sex disparity did not affect the rate of HCC recurrence, suggesting that intrahepatic sex hormone receptors were unrelated to recurrence.

ADV score has been reported to be closely associated with the prognosis of patients with HCC after LT or hepatic resection [8 9 10 11]. Therefore, the present study selected eligible patients as those with an ADV score cutoff of 5log rather than using the usual propensity score matching method. After ADV score-based patient matching, neither donor-recipient sex disparity nor donor or recipient sex per se affected the rate of HCC recurrence after LT.

This study had several limitations. This study was retrospective in nature and included patients at a single center in an HBV-endemic country. Most of the HCCs included in this study had developed in HBV-infected livers.

In conclusion, the present study demonstrated that neither donor sex nor donor-recipient sex disparity affected posttransplant HCC recurrence.

Notes

Fund/Grant Support: None.

Conflict of Interest: No potential conflict of interest relevant to this article was reported.

Author Contribution:

Conceptualization, Project Administration: SH.
Formal Analysis: RKO, GWS. CSA.
Investigation: DBM, TYH, DHJ.
Methodology: GCP, YIY, WHK.
Writing – Original Draft: SH, RKO.
Writing – Review & Editing: All authors.

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Fig. 1

Kaplan-Meier analysis of (A) disease-free survival (DFS) and (B) overall survival (OS) in all 772 patients who underwent living donor liver transplantation for hepatocellular carcinoma. Comparisons by log-rank tests.

Fig. 2

Kaplan-Meier analysis of (A) disease-free survival (DFS) and (B) overall survival (OS) curves in all 772 patients according to sex matching of the donor and recipient. Comparisons by log-rank tests. MM, male-to-male; MF, male-to-female; FM, female-to-male; FF, female-to-female.

Fig. 3

Kaplan-Meier analysis of disease-free survival (DFS) and overall survival (OS) in all 772 patients according to the sex of the donor (A and B) and recipient (C and D). Comparisons by log-rank tests.

Fig. 4

Kaplan-Meier analysis of (A) disease-free survival (DFS) and (B) overall survival (OS) in the 590 patients with ADV scores of <5log according to sex matching of the donor and recipient. Comparisons by log-rank tests. MM, male-to-male; MF, male-to-female; FM, female-to-male; FF, female-to-female; ADV, multiplication of α-FP, des-γ-carboxy prothrombin, and tumor volume.

Fig. 5

Kaplan-Meier analysis of disease-free survival (DFS) and overall survival (OS) in the 590 patients with ADV score of <5log according to the sex of the donor (A and B) and recipient (C and D). Comparisons by log-rank tests. ADV, multiplication of α-FP, des-γ-carboxy prothrombin, and tumor volume.

Table 1

Clinicopathological features of the recipients according to the sex of the donor and recipient

Values are presented as number only, mean ± standard deviation, median, or number (%).

LT, liver transplantation; ALD, alcoholic liver disease; MELD, model for end-stage liver disease; HCC, hepatocellular carcinoma; DCP, des-γ-carboxy prothrombin; ADV, multiplication of α-FP, DCP, and tumor volume.

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