Key words : Immunosuppression, Metastasis, Survival

Introduction
Hepatocellular carcinoma (HCC) accounts for 80% of primary liver cancers; incidence and mortality of HCC are still increasing globally, making it the fourth leading cause of cancer-related deaths worldwide.¹ At the time of diagnosis, <25% of HCC cases are resectable, often because of underlying liver disease and inadequate hepatic reserve.² Liver transplant (LT) is the most effective treatment option for nonmetastatic or unresectable HCC, particularly in the presence of cirrhosis. In the late 1990s, Mazzaferro and colleagues developed the first transplant criteria, which is now known as the Milan criteria. Criteria include patients with cirrhosis having a single tumor of 5 cm or less, those with no more than 3 tumors, each no larger than 3 cm in diameter, and those without extrahepatic manifestations and gross vascular invasion.³

As use of LT for HCC treatment has increased, criteria have expanded and indications have been extended through less restrictive requirements for the size and number of tumors. Despite the application of updated criteria, recurrence of HCC has been reported to occur in about 10% to 15% of LT recipients and most commonly in the first 2 years after LT. Recurrence typically is accompanied by significant mortality and limited potential for a cure.⁴ The prognosis of patients with recurrent HCC after LT remains poor, and there are several areas of uncertainty in the management of these patients. Improving the understanding of the contributing factors of HCC recurrence after LT remains urgent. In this study, we evaluated tumor recurrence charac-teristics of HCC patients after LT, the treatments given, and the survival outcomes of this patient group in our center.

Materials and Methods
From January 2003 to December 2023, 512 LTs were performed in our center (Baskent University Ankara Hospital, Ankara, Türkiye). Among patients who underwent LT, 63 received transplants because of HCC. Patient follow-up was done by a multidis-ciplinary team. We obtained details of patient transplant procedures, demographic characteristics, and laboratory and radiologic reports from hospital records. We retrospectively assessed the patient tumor status at the time of diagnosis, tumor recurrence patterns, time to recurrence, treatment strategies used, and survival outcomes. Posttransplant recurrence was diagnosed by alpha-fetoprotein (AFP) levels and imaging studies with or without histologic confirmation. Overall survival was defined as the time from the date of surgery to death (from any cause) or last follow-up. We used the Kaplan-Meier method to generate survival curves and calculate 3- and 5-year overall survival rates for recurrent and nonrecurrent groups, Survival periods were compared between recurrent and nonrecurrent groups. P < .05 was considered statistically significant.

Results
Between 2003 and 2023, 512 patients underwent LT. Among 204 adult patients, 63 underwent LT because of HCC. Median age was 55 years (range, 30-68 y), and 57 patients (90%) were men. In 32 patients (51%), LT was performed in accordance with expanded criteria developed by our center. Of 63 patients, 35 (55%) had living donors and 20 (45%) had deceased donors. The most common etiology was hepatitis B virus (HBV) infection (n = 26); in 23 patients, the etiology for HCC was unknown. Hepatitis C virus (HCV) infection was detected in 5 patients, HBV and hepatitis D virus in 3, HBV and HCV in 2, alcohol-induced cirrhosis in 1, and autoimmune hepatitis in 1 patient.

Of 63 patients, 16 (25%) developed HCC recurrence after LT. Fifteen patients (94%) who developed recurrence were men. Only 1 of the patients who developed recurrence was still alive at the time of this report. Of 16 patients with recurrence, 50% had local and distant recurrence, 31% (n = 5) had distant metastasis, and 19% (n = 3) developed only locoregional recurrence. The most frequent sites of distant metastasis were lungs and bones. Inter-ventional procedures like radiofrequency ablation, transarterial radioembolization, and transcatheter arterial chemoembolization were performed in 8 patients with recurrence. Only 4 patients received systemic treatment. Median overall survival was 65 months for all 63 LT patients (Figure 1). Median time to recurrence was 11.6 months.

Median survival was significantly lower in the recurrent group than in the nonrecurrent group (33 vs 149 mo; P = .001) (Figure 2). The 3- and 5-year survival rates for the nonrecurrent group were 74% and 63%, respectively. However, for the recurrent group, the 3- and 5-year survival rates were 43% and 31%, respectively. During follow-up, 8 patients (12.6%) developed secondary malignancies (skin, lung, and hematological cancers).

Discussion
Liver transplant is the best treatment option for HCC in patients with cirrhosis. The criterium for transplant is still a subject of discussion worldwide. The Milan and other expanded criteria consider morphologic features like tumor number and size but not histopathologic characteristics, such as grade and differentiation of the tumor. Despite adherence to the criteria for LT in HCC patients, up to 20% to 30% of transplanted HCC patients may develop tumor recurrence that negatively affects their survival.⁵

In our center, we use the expanded Baskent University transplant criteria for patients with nonmetastatic HCC. Regardless of tumor number and size, these criteria include patients without major vascular invasion and without distant metastases.

In the previous report from our center of 49 adult patients who had LT, 17 patients (26.5%) had HCC recurrence during follow-up. Median overall survival was 64.3 months for all included patients. Median time to recurrence was 12.6 months. The 3- and 5-year survival rates were 80% and 68% in the nonrecurrent group and 52% and 17% in the recurrent group, respectively.⁶ In the present study, the recurrence rate of HCC was 25% after LT and the median survival rates were significantly lower for the recurrent patient group compared with the nonrecurrent group. The recurrence rate obtained in our study was consistent with the literature, and this reflects that transplant criteria are mainly based on tumor burden characteristics (size and number) and do not necessarily reflect the biological behavior of HCC.

Several studies have reported and correlated the added value of AFP level as a useful predictor of HCC recurrence. In patients, high AFP levels before LT were found to be associated with worse survival rate after transplant.^7,8

In our study, the median time to posttransplant recurrence was 11.6 months. This result aligns with other studies in the literature that reported a median time to recurrence ranging from 7 to 36 months. In the report from Fernandez-Sevilla and colleagues of 493 patients transplanted for HCC, 70 patients (14.2%) developed recurrence after a median disease-free interval of 17 months.⁹ Among patients with recurrence, 70% of recurrences were diagnosed within the 2 years after LT. As shown in our study, most recurrences were extrahepatic (lung, lymph nodes, and bone); intrahepatic recurrences were observed in only 2 patients (2.8%).⁹

Timing of HCC recurrence is variable; in most cases, timing is 1 to 3 years after LT. Early recurrence, defined as those occurring less than 1 year after LT, is frequently associated with significantly worse prognosis, possibly the result of HCC micrometastasis engraftment.¹⁰ Considered the timing of HCC recurrence reported in the literature, post-LT surveillance should be more intense for the first 3 years after LT. As shown in our study, lung and bones are the most frequent metastatic sites of recurrence.¹¹ This indicates the need for close follow-up of these sites by radiologic imaging techniques, especially during the first 2 to 3 years after LT.

We found that median survival was significantly lower in the recurrent group than in the nonrecurrent group (33 vs 149 mo, respectively; P = .001). In other words, survival was almost 5 times better in the nonrecurrent group than in patients who developed recurrence. Recurrence of HCC after LT leads to poor survival outcomes, as already reported, with a median survival of less than 2 years.^12,13 Survival after recurrence observed in our study was one of the longest reported, showing that a multidisciplinary approach, including local therapies, is effective in this group of patients.

In our study, 3- and 5-year survival rates were 43% and 31%, respectively. Kim and colleagues reported 1-year, 3-year, and 5-year survival rates of 65.2%, 34.0%, and 20.5%, respectively, in the 151 patients who had HCC recurrence after LT. In that study, multivariable Cox analysis showed that grafts from living donors, recurrence-free interval of more than 9 months, AFP levels of ≥100 ng/mL at the time of recurrence, recurrence in bone, and everolimus treatment within 3 months after recurrence were related with improved survival after recurrence.¹⁴

The immune system is the primary defense mechanism against cancer, and the role of immuno-suppressive regimens in the risk of HCC recurrence after LT has been previously examined. However, the optimal immunosuppression regimen to reduce the frequency of HCC recurrence and improve survival has not yet been determined and still represents a matter of debate. Calcineurin inhibitors, such as tacrolimus and cyclosporine, create a permissive environment for the growth of cancer cells because of impairment of the recipient’s immune system.¹⁵ Calcineurin inhibitors have been shown to be associated with increased recurrence rates of posttransplant HCC, whereas mammalian target of rapamycin inhibitors have been shown to inhibit HCC growth in vitro and in animal models.¹⁶

Among our included study patients, 25% received systemic treatment, with the most commonly used agent being sorafenib. Recurrence of HCC can be considered as a systemic disease because of persistence of malignant cells after resection of the affected liver. Therefore, HCC recurrence after LT often requires systemic therapy.

In the past few years, the combination of the anti-programmed cell death ligand 1 (PD-L1) antibody atezolizumab and the anti-vascular endothelial growth factor antibody bevacizumab and the combination of the anti-PD-L1 antibody durvalumab with a single “priming” dose of the anticytotoxic T-lymphocyte-associated protein 4 antibody tremelimumab showed prolonged overall survival compared with sorafenib and became the first-line treatment option in patients with advanced HCC. Despite these promising results with immunotherapy, the use of immune checkpoint inhibitors after transplant may expose liver recipients to the risk of allograft rejection and graft loss.¹⁷ Therefore, tyrosine kinase inhibitors such as sorafenib and lenvatinib remain the optimal choice in systemic first-line therapy.

Conclusions
Advances in interventional radiology, surgery, and medical oncology treatments have led to prolonged survival in patients with HCC. Despite these developments, HCC recurrence is still associated with poor prognosis. Although immune checkpoint inhibitors have become the first-line treatment for advanced HCC worldwide, the use of these agents in the treatment of posttransplant HCC remains controversial. At the same time, the choice of immunosuppressive regimens is still a matter of debate. Management of HCC recurrence remains a big issue, and few data and no single guideline for management of HCC recurrence management in immunosuppressed recipients remain as limitations.

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