Original Article/Transplantation
Hepatocellular carcinoma recurrence after acute liver allograft rejection treatment: A multicenter European experience

https://doi.org/10.1016/j.hbpd.2019.05.006Get rights and content

Abstract

Background

During the last decades, several risk factors for the recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) have been investigated. However, the impact of two important drivers of oncogenesis, namely the immunosuppression and the treatment of acute cellular rejection (ACR) have been marginally addressed. This study aimed at investigating the impact of ACR treatment on the incidence of tumor recurrence in a large European HCC-LT population.

Methods

Seven hundred and eighty-one adult patients transplanted between February 1, 1985 and June 30, 2016 were retrospectively analyzed. After propensity score match, 116 patients treated for ACR using steroid boluses were compared with 115 patients who did not present any ACR or a histologic but clinical irrelevant ACR.

Results

Steroid boluses treated patients had a 18-fold higher overall incidence of HCC recurrence than those non-treated patients (16.4% vs. 0.9%; P<0.0001). At multivariate Cox regression analysis, steroid boluses used to treat ACR were an independent risk factor for HCC recurrence (HR=14.2; 95% CI: 1.8–110.4; P = 0.010).

Conclusions

The decision to treat ACR as well as to reinforce immunosuppression load should be cautiously taken in view of the presented results. Prospective studies are needed to further elucidate the clinical impact of immunosuppression on HCC recurrence after transplantation.

Introduction

Liver transplantation (LT) is the best curative treatment of hepatocellular carcinoma (HCC) developed in a cirrhotic liver [1]. Unfortunately, about 15%–20% of LT patients experience HCC recurrence [2]. During the last two decades, multiple pre- and post-LT risk factors for recurrence have been investigated [3], [4], [5]. Although HCC development and recurrence had already been linked to immunosuppression (IS) more than 30 years ago both in the experimental and clinical settings, the “tumor risk factor IS” has shown controversial results [6], [7], [8], [9], [10]. The inconsistency of the studies regarding IS with HCC recurrence is explained by the fact that most investigated cohorts were heterogeneous, receiving very different IS schemes. Moreover, almost all attention in this field of transplant oncology has been given to the morphologic (numbers and diameter of tumor) and biologic (tumor markers and PET-scan tumor uptake) behavior of cancer [11].

Clinical research on HCC recurrence has been primarily done in relation to the detrimental role of the IS load in form of continued steroid use or higher dosage of calcineurin inhibitors (CNI) and the protective role of mammalian target of rapamycin inhibitors (mTORi), with these latter drugs exhibiting both immunosuppressive and anti-angiogenic/proliferative properties [12], [13], [14], [15], [16], [17]. The impact of the treatment of acute cellular rejection (ACR) as a possible risk factor for HCC recurrence has never been reported.

The study aimed to investigate the effect of ACR treatment with steroids on HCC recurrence in a broader European population of LT patients using a rigorous statistical approach based on a propensity score matching (PSM).

Section snippets

Methods

A retrospective analysis was performed including 781 adult patients transplanted between February 1, 1985 and June 30, 2016, and having a pre-LT radiological/pathological diagnosis of HCC. Data were obtained from the prospectively collected databases of three collaborative centers: Brussels (n = 309), Innsbruck (n = 296), and Mainz (n = 176). In order to create two homogeneous and comparable groups, the following exclusion criteria were used: (a) follow-up shorter than two years after LT in

Results

Patient- and tumor-related characteristics before and after PSM are displayed in Tables 1 and 2. After PSM, 116 patients with one or more episodes of ACR treated with steroid boluses were identified and compared to 115 patients consisting of 75 (65.2%) patients who did not present ACR and 40 (34.8%) patients who presented a documented but clinically irrelevant rejection not deserving treatment. When comparing these two groups, no differences were observed concerning patient characteristics,

Discussion

The majority of studies dealing with HCC recurrence focus on the well-established tumor-related variables morphology (number and diameter), biology (evolution of tumor and inflammatory markers in the absence or presence of LRT and tumor uptake at PET-scan) [23], [24] and pathology (microvascular invasion, tumor differentiation, satellite lesions) of the hepatectomy specimen.

Conversely, the role of IS has been less extensively clarified, although several studies have been published on this

Contributors

LQ, IS, FA and LJ were responsible for the conception, design and analysis of the study and for writing the paper. LQ, IS, FA, HLM, FM, and LK were involved with the collection and interpretation of data. FA, HLM and OG participated in data management and manuscript review. All authors contributed to the design and interpretation of the study and to further drafts. LQ is the guarantor.

Funding

None.

Ethical approval

Not needed.

Competing interest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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