ABSTRACT
Liver transplantation (LT) is a curative therapy for selected patients with hepatocellular carcinoma (HCC) and cirrhosis, simultaneously treating tumors and underlying liver disease. This review provides an up-to-date overview of LT for HCC, focusing on key considerations for hepatobiliary surgeons. We discuss established selection criteria (Milan and University of California, San Francisco) and the evolution of expanded eligibility models incorporating tumor biology (e.g., “up-to-7” criteria, alpha-fetoprotein–based models). Outcomes of LT for HCC are excellent in appropriately selected patients, with 5-year survival >70% and low recurrence rates when within criteria. We examine strategies for downstaging advanced HCC to transplantable disease, which have enabled curative LT in patients initially beyond criteria with acceptable 10-year outcomes. We compare living donor and deceased donor LT, highlighting the role of living donor transplantation in expanding access and its comparable survival. Immunosuppression protocols are reviewed, with an emphasis on striking a balance between preventing rejection and minimizing the risk of tumor recurrence. We also address global trends and challenges, including organ shortages and ethical considerations, and survey recent innovations from clinical trials and translational research—such as machine perfusion organ preservation, novel biomarkers, and immunotherapy—for their potential impact on HCC transplant practice.
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KEYWORDS: Hepatocellular carcinoma; Liver transplantation; Neoadjuvant therapy; Immunosuppression; Biomarkers
INTRODUCTION
Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the fourth leading cause of cancer-related death, with over 800,000 new cases and 900,000 deaths annually [
1]. For early-stage HCC in the setting of cirrhosis, liver transplantation (LT) offers the best chance of long-term survival by removing both the tumor and the diseased liver, thereby reducing the risk of recurrence in the remnant liver. The seminal introduction of the Milan criteria in 1996 defined a subgroup of HCC patients (a single tumor ≤5 cm, or up to 3 tumors ≤3 cm, without vascular invasion or metastasis) who could achieve excellent post-LT outcomes [
2]. This led to the broad adoption of LT for HCC within these limits, with 5-year survival rates exceeding 70% and recurrence-free survival rates around 83% in the initial series [
2,
3]. LT has since become an established curative treatment for selected HCC patients and now comprises a significant proportion of transplant caseloads globally.
Over the past two decades, the increasing incidence of HCC and organ shortages has driven a refinement of selection criteria and policies to balance the benefits of transplant and equity [
4,
5]. Expanded criteria, such as the UCSF (University of California, San Francisco) criteria (one tumor ≤6.5 cm or up to 3 tumors with the largest ≤4.5 cm, total diameter ≤ 8 cm), demonstrated that carefully selected patients slightly beyond Milan can achieve similar outcomes (5-year survival 75%) [
6,
7]. Additionally, tumor biology markers (especially alpha-fetoprotein, AFP) were recognized as critical predictors of recurrence. For instance, patients beyond Milan but with low AFP may fare better than those within Milan with very high AFP [
8]. An AFP >1,000 ng/mL is associated with poor prognosis and has become an exclusion criterion for transplant in many programs [
9]. These insights spurred the development of composite selection models and downstaging protocols to expand transplant eligibility for HCC safely.
This review provides a comprehensive overview of LT for HCC, with an emphasis on topics relevant to hepatobiliary surgeons. We examine patient selection criteria and predictive models, outcomes and recurrence data, and approaches to downstage advanced tumors. The roles of living donor vs. deceased donor LT are compared, and immunosuppression strategies are discussed in the context of tumor control. We also highlight global trends and challenges, and summarize emerging innovations—including novel biomarkers, immune-based therapies, and organ preservation techniques—that are shaping the future of transplant oncology for HCC. By synthesizing current evidence and clinical practice, we aim to guide optimal management of HCC patients being considered for liver transplantation.
PATIENT SELECTION CRITERIA AND ELIGIBILITY MODELS
Milan and UCSF Criteria (Conventional Selection)
The Milan criteria have been the cornerstone of HCC transplant selection since 1996, offering a benchmark for excellent outcomes. Patients meeting Milan criteria (≤3 tumors up to 3 cm or a single tumor ≤5 cm, with no macrovascular invasion) have 5-year post-LT survival rates above 70% and a recurrence rate of 15% [
10]. These stringent limits minimize the risk of post-transplant tumor recurrence by excluding patients with high tumor burden. In 2001, the UCSF criteria were proposed to modestly extend the size limits (one lesion ≤6.5 cm or up to 3 lesions ≤4.5 cm, total diameter ≤8 cm) [
11]. UCSF’s experience demonstrated that expanding the tumor size allowance did not compromise outcomes, achieving a 5-year survival rate of 75%, comparable to Milan [
12]. Both Milan and UCSF criteria rely on static morphological features (tumor size, number, and the absence of macrovascular invasion) as surrogates for favorable tumor biology. They have been widely used to guide transplant eligibility, especially in regions with limited organ supply where strict selection is necessary to ensure optimal use of grafts.
BEYOND MILAN: EXPANDED CRITERIA AND TUMOR BIOLOGY MODELS
Many centers observed that some patients with tumors exceeding the Milan/UCSF criteria could still achieve good outcomes if the tumors were biologically indolent. This led to proposals of expanded criteria that push the envelope of tumor size/number. Notably, the “up-to-7” rule (proposed by Mazzaferro et al.) permits tumors where the sum of the number of lesions and the diameter of the largest lesion is ≤7 [
7,
13]. In a study of over 1,000 explanted livers, patients beyond Milan but within the up-to-7 parameters had 5-year survival equivalent to those meeting Milan criteria [
14]. However, as tumor burden increases, outcomes gradually worsen (“the Metroticket model”), implying an upper limit beyond which the benefit of LT drops off [
15]. Mazzaferro et al. quantified this with the Metroticket 2.0 model, incorporating AFP levels: for instance, to achieve excellent survival, patients with AFP <200 can have tumors meeting up-to-7 criteria, whereas if AFP is 400–1,000, only up to 4 total tumor burden is acceptable [
15,
16]. This model illustrates how higher AFP (a marker of aggressive biology) necessitates stricter size limits to maintain outcomes.
In fact, AFP has emerged as a key predictor of post-LT HCC recurrence and survival [
17]. An AFP >1,000 ng/mL is one of the strongest indicators of poor outcome and is often considered a contraindication to transplant [
18]. The French AFP model (Duvoux et al., 2012) was an early example that combined tumor size/number with AFP cutoffs, showing that patients beyond Milan could achieve acceptable survival if their AFP level was ≤100 ng/mL, whereas higher AFP levels or large tumors portended worse outcomes [
7]. Dynamic changes in AFP (such as responses to therapy or rapid rises) also carry prognostic significance [
19]. The New York/California (NYCA) score (2018) further integrates AFP response over time with tumor size/number to stratify risk groups; it outperformed Milan and French models in predicting recurrence [
14,
16]. Patients whose AFP decreases with therapy and who meet certain tumor size/number thresholds can be considered for LT beyond standard criteria with outcomes similar to traditional candidates [
20]. Overall, selection paradigms have shifted from rigid morphologic criteria toward a more nuanced assessment of tumor biology. Many programs now use a combination of tumor burden limits and biomarkers (such as AFP) to identify “low-risk” HCC, even if slightly beyond the Milan criteria, while excluding “high-risk” HCC, even within Milan, if the biology is unfavorable [
20,
21]. This approach aims to maximize transplant benefit by expanding access to those who will derive long-term cure, without significantly increasing post-LT recurrence (
Table 1).
DOWNSTAGING ADVANCED HCC TO TRANSPLANT CRITERIA
Downstaging refers to the use of therapeutic interventions to shrink or control HCC that initially exceeds transplant criteria, thereby reducing the tumor burden to within acceptable limits (typically Milan) and qualifying the patient for LT [
22]. This is distinct from “bridging” therapy, which is treatment given to patients already within criteria to prevent tumor progression while awaiting transplant. Downstaging has become an established strategy to expand the pool of transplant candidates, given the recognition that some larger or more numerous tumors respond to therapy and behave indolently thereafter.
Common downstaging treatments include locoregional therapies such as transarterial chemoembolization (TACE), transarterial radioembolization (TARE with yttrium-90), radiofrequency ablation, percutaneous ethanol injection, and, more recently, stereotactic body radiotherapy (SBRT). These modalities can achieve partial or complete tumor necrosis in a significant subset of patients. Typical criteria for attempting downstaging (as adopted in United Network for Organ Sharing [UNOS]) include tumor burdens just beyond Milan, for example: a single tumor up to 6–8 cm, 2–3 tumors up to 5 cm (with total diameter 8–10 cm), or, in some protocols, even 4–5 small tumors [
23]. Patients are treated and then re-evaluated; if tumor burden is successfully reduced to meet transplant criteria (and stable for a period of time), they become eligible for LT listing with a standardized Model for End Stage Liver Disease (MELD) exception. Current UNOS downstaging criteria allow inclusion of tumors initially beyond Milan within defined limits, and this approach has been implemented nationally [
24]. An international consensus conference in 2012 supported downstaging as a selection tool, noting that patients who could be downstaged to the Milan criteria had outcomes comparable to those initially within the criteria [
25]. Bridging therapy is generally recommended for patients who meet the criteria if the anticipated waitlist time exceeds 6 months, particularly for intermediate tumor stages (UNOS T2) [
26], to reduce the risk of progression beyond the transplantable stage.
Not all tumors can be successfully downstaged; reported success rates vary, but roughly 50–70% of patients within downstaging protocols achieve sufficient tumor control to meet criteria and proceed to transplant [
26]. The outcomes among those who are downstaged and transplanted are critically important. A landmark multi-center study, reported by Tabrizian et al. (2022), has provided 10-year outcome data validating downstaging. In this cohort of 341 downstaged patients (initially beyond Milan) compared to 2,122 standard criteria patients [
22], the 10-year post-LT survival in downstaged patients was 52.1%, not far from the 61.5% in those always within criteria [
27]. Recurrence rates at 10 years were 20.6% in the downstaged group versus 13.3% in the standard group [
26]. By contrast, patients whose tumors exceeded criteria and could not be downstaged had much poorer outcomes (10-year survival 43% and recurrence 41%) [
24]. These data underscore that downstaging can select a subset of initially advanced HCC that attains long-term survival approaching conventional HCC transplant results, whereas proceeding with transplant without successful downstaging leads to unacceptably high recurrence. The study authors noted that this finding validates current national policy and supports the adoption of downstaging worldwide to expand transplant access safely and effectively [
23]. Importantly, the process of downstaging itself may serve as a “test of biology”—tumors responsive to therapy are more likely to be biologically favorable, whereas aggressive tumors that progress despite therapy are filtered out and avoided for transplant [
6,
12].
In the United States, downstaging to within Milan has been formally incorporated into allocation policy. Candidates must demonstrate a tumor response within standard criteria for a specified period (e.g., maintaining response for ≥3–6 months) before they can receive HCC exception points. AFP levels must also be below a threshold (e.g., <500 ng/mL) to gain an exception, reflecting the exclusion of very high AFP cases. This policy took effect after accumulating evidence of favorable outcomes in downstaged patients, and it has increased the opportunities for transplant in patients who would have been initially turned down. As of UNOS’s recent update, downstaging success, followed by a 6-month observation period, is required prior to exception approval to ensure tumor stability and mitigate the risk of aggressive disease slipping through [
23,
28].
Some centers have pushed the boundaries of downstaging in select situations. For example, HCC with portal vein tumor thrombosis (PVTT) has traditionally been an absolute contraindication to transplant due to dismal prognosis. However, an innovative report from India described 25 patients with PVTT who underwent aggressive downstaging with SBRT to the portal vein and locoregional therapy (TACE/TARE) to the tumor, followed by living donor LT. Remarkably, their 5-year overall survival rate was 57%, and their recurrence-free survival rate was 51%, comparable to outcomes in similar patients without PVTT [
29]. While this is a highly selected series, it highlights that even macrovascular invasion—long thought to be a transplant exclusion—might be overcome in carefully controlled circumstances using living donor grafts [
20,
30]. Such approaches are still experimental and warrant further study, but they suggest future potential to extend transplant to advanced HCC cases that respond dramatically to multimodal therapy.
In summary, downstaging has become a cornerstone of modern HCC transplant practice, allowing many patients with tumors initially beyond traditional criteria to achieve curative transplantation. Successful downstaging results in outcomes comparable to those of non-downstaged patients [
25]. Strict protocols and selection criteria are necessary, including limits on initial tumor burden, the use of effective bridging therapies, AFP monitoring, and observation of tumor stability, to ensure that only those with favorable biology proceed to transplant. For hepatobiliary surgeons, close collaboration with oncology and interventional radiology colleagues is essential to implement downstaging strategies and to assess response. When appropriately executed, downstaging increases the pool of transplant recipients without substantially worsening recurrence rates, thus addressing some of the unmet needs for curative therapy in intermediate-stage HCC.
OUTCOMES AND SURVIVAL AFTER TRANSPLANTATION FOR HCC
Survival Outcomes
Liver transplantation for HCC within accepted criteria yields survival outcomes comparable to transplantation for non-malignant indications. Historical series and registry data indicate a 5-year overall survival of approximately 70–80% for HCC patients meeting Milan criteria [
31]. For instance, Mazzaferro’s original cohort reported a 4-year survival rate of 75% [
32], and subsequent analyses have consistently shown 5-year survival rates of over 70% and 4-year recurrence-free survival rates of over 80% for patients meeting the Milan criteria [
32]. Patients with UCSF criteria have similar outcomes (75% at 5 years) when properly selected [
33]. These outcomes firmly establish LT as the optimal treatment for early-stage HCC, outperforming other therapies like resection or ablation in eligible patients (who have lower survival in the context of cirrhosis).
Patients who undergo successful downstaging and then undergo LT also enjoy excellent outcomes, although these are slightly inferior to those who continually meet the criteria. As noted, 5-year and 10-year survival rates in downstaged patients are approximately 60–70% and 50%, respectively [
34]. Notably, this is dramatically better than for patients with advanced HCC who are transplanted without downstaging or beyond criteria. Those cases have high recurrence and poor long-term survival (e.g., only 43% at 10 years) [
35]. Thus, strict selection and/or downstaging are critical to achieving good outcomes; transplantation of tumors with high-risk features results in frequent post-LT failure. It is generally accepted that if HCC recurs aggressively after transplant, median survival is limited (often <2 years), so prevention via selection is paramount.
The risk of HCC recurrence after LT is primarily determined by tumor biology characteristics. For patients within the Milan criteria, reported recurrence rates are in the range of 10–15% [
36]. As tumor burden or poor differentiation increases, the risk of recurrence rises. In the Tabrizian et al. series, recurrence at 10 years was 13.3% for Milan criteria patients, 20.6% for downstaged (initially beyond Milan) patients, and over 40% for those transplanted beyond criteria [
22]. Most recurrences occur within the first 2–3 years post-transplant and typically involve extrahepatic sites (such as the lungs or bones) or the graft liver. Pathological features associated with recurrence include microvascular invasion in the explant, poor tumor differentiation, large tumor size (>5 cm), multifocal disease, and high pre-transplant AFP or satellite lesions (
Table 2). Many of these factors are encapsulated in scoring systems, such as the RETREAT score (which includes AFP, largest tumor size, number of tumors, and microvascular invasion), to stratify recurrence risk post-LT [
37]. A high RETREAT score predicts higher recurrence probability and can inform surveillance intensity post-transplant.
To illustrate, microvascular invasion is found in approximately 15–20% of explants in Milan and significantly increases the likelihood of recurrence. AFP-L3 (an AFP isoform) and des-gamma-carboxy prothrombin (DCP, also known as Proteins Induced by Vitamin K Absence or Antagonist-II [PIVKA-II]) are novel biomarkers that can predict recurrence even when tumors meet morphological criteria for recurrence [
38]. A recent study has shown that high pre-transplant AFP-L3 or DCP levels strongly predict early post-LT recurrence [
39]. Incorporating such biomarkers into selection or post-LT monitoring may improve outcomes by identifying patients at elevated risk who might benefit from closer follow-up or adjunct therapies [
40].
Despite careful selection, a subset of patients will experience HCC recurrence after transplant. Management options depend on the location and extent of recurrence. Curative-intent treatments (surgical resection of isolated metastasis, or local ablation/radiation) can prolong survival in selected cases and are associated with the best outcomes [
41]. In one series, patients who could undergo surgical removal of recurrent disease had a 3-year survival rate of 60%, compared to 37% with combined treatments and only 11% with non-surgical therapy [
22]. Surgical treatment is typically feasible only for a minority of patients with solitary or oligometastatic recurrence and favorable tumor biology (e.g., low AFP at recurrence, long disease-free interval) [
42]. Occasionally, “salvage transplantation” can be considered if the patient initially underwent resection and then had recurrence; outcomes of salvage LT for recurrence after prior resection are reported to be comparable to primary LT in carefully selected patients [
43]. However, for patients whose HCC recurs widely, systemic therapy is often the main option. Tyrosine kinase inhibitors like sorafenib (and more recently lenvatinib) or second-line agents (regorafenib, cabozantinib) have been used, but survival benefits are modest (median survival 10–13 months on sorafenib vs. 2–5 months best supportive care) [
44,
45]. Tolerability in post-LT patients can be an issue due to immunosuppressive drug interactions and organ toxicity. Emerging systemic options include Immunotherapy, but this comes with a high risk of precipitating allograft rejection (reported in up to 25–50% of cases where checkpoint inhibitors were given) [
46]. Thus, the use of immune checkpoint inhibitors for recurrent HCC after transplantation is controversial and typically avoided, unless in a clinical trial, as graft loss can occur.
In summary, long-term survival after LT for HCC is excellent for those within the criteria or successfully downstaged, whereas outcomes deteriorate when high-risk tumors are transplanted. Recurrence is the leading cause of post-LT mortality in HCC patients, and its prevention through proper candidate selection is vital. For surgeons, achieving negative-margin resection of the native liver with careful explant examination provides important prognostic information (e.g., microvascular invasion status) that guides follow-up. Multidisciplinary management of any recurrence, with aggressive therapy for isolated lesions, can prolong survival in select patients [
42]. Ongoing research into adjuvant treatments to prevent recurrence (such as peri-transplant targeted therapy or Immunotherapy) is discussed later in this review.
LIVING DONOR VS. DECEASED DONOR LIVER TRANSPLANTATION
The use of living donor liver transplantation (LDLT) has significantly impacted the management of HCC, especially in regions with organ shortages and long wait times. In LDLT, a portion of liver from a healthy living donor is used, allowing the transplant to be performed without waiting for a deceased donor organ. This offers several potential advantages for HCC patients (
Table 3):
HCC patients on the deceased donor waiting list risk tumor progression leading to dropout (estimated 15–30% dropout rate, depending on wait time) [
47,
48]. With LDLT, the transplant can be performed electively once a donor is available, often much sooner than a deceased organ would arise. This mitigates the risk of the tumor growing beyond criteria or the patient’s liver decompensating. Studies have shown that LDLT can markedly lower dropout rates and improve intention-to-treat survival for HCC. For example, one analysis reported a 5-year intention-to-treat survival of 68% with LDLT versus 57% with deceased donor LT (DDLT) for eligible HCC patients, mainly due to avoidance of waitlist attrition [
37].
Because a living donor graft is allocated outside of the usual listing prioritization, centers have the discretion to use LDLT for patients who might not receive a deceased liver due to criteria restrictions or allocation policies. Some programs consider LDLT for HCC cases that are beyond conventional criteria (e.g., slightly larger tumors or after experimental downstaging). Ethically, this is balanced against donor risk, but it allows for the expansion of LT in countries or centers willing to push the limits for a potential cure. In fact, it is often stated that extended criteria LDLT more suitably addresses HCC (beyond the Milan criteria), whereas scarce deceased grafts are reserved for standard criteria patients to ensure optimal use [
37]. Countries like South Korea, Japan, and India, where LDLT is prevalent, have reported utilizing living donor grafts for HCC beyond the Milan criteria with acceptable outcomes, whereas such patients might not receive a deceased donor offer under strict allocation rules [
37].
Earlier single-center studies raised concern that HCC recurrence might be higher after LDLT compared to DDLT. One hypothesis was that the shorter wait time in LDLT bypasses the “natural selection” where aggressive tumors declare themselves by progressing on the waitlist (thus those patients would have dropped out in a DDLT scenario). A notable early study suggested a higher recurrence rate in LDLT recipients, sparking debate. However, more recent and larger analyses have found no significant difference in post-transplant HCC recurrence or survival between LDLT and DDLT when controlling for tumor characteristics [
49]. The initially observed disparity is now thought to be due to case selection and small sample sizes. In fact, a multi-center cohort (A2ALL study) in 2012 and subsequent reports have shown comparable recurrence rates for LDLT and DDLT in patients of similar risk. Some contemporary studies even suggest a survival benefit with LDLT due to the reduced dropout. A 2019 analysis from Toronto showed that LDLT for HCC offered increased overall survival compared to waiting for a deceased donor (likely reflecting the advantage of immediate transplantation) [
50]. Thus, with careful selection, LDLT achieves similar cancer outcomes to DDLT. The key is that LDLT should not be used to transplant biologically unfavorable tumors that would be excluded from DDLT—doing so would predictably yield poor results and unjustified donor risk. Instead, LDLT is best applied to expand access to transplant for appropriate HCC patients in the face of organ shortage.
There is wide regional variation in the use of LDLT for HCC. In East Asia, where deceased donation rates are low, LDLT is a primary means of transplantation—for example, in South Korea, over 70% of liver transplants are living donor, many for HCC [
1]. These programs have developed expertise that has led to excellent LDLT outcomes. In North America and Europe, LDLT constitutes a small minority of transplants (e.g., 4–5% in the U.S.) [
51], but its use is gradually increasing as centers gain experience and patients seek to avoid long waits. The ethical imperative is to ensure donor safety—donors must be meticulously evaluated and fully informed of risks (0.2–0.5% donor mortality and 30% risk of complications for right lobe donation). From the HCC standpoint, LDLT’s ability to circumvent wait time is its greatest benefit. It is particularly advantageous for patients who are early in their disease course but at risk of dropout due to wait times in certain regions.
In summary, living donor LT is a powerful tool in the management of HCC, offering timely transplantation and the possibility to treat patients beyond the constraints of deceased donor allocation. Current evidence indicates that, in experienced centers, HCC outcomes with LDLT are equivalent to DDLT. LDLT improves intention-to-treat survival by eliminating waitlist losses. Hepatobiliary surgeons involved in LDLT must balance the oncologic benefit to the recipient with the principle of “do no harm” to the healthy donor; as such, thorough donor evaluation and careful recipient selection (avoiding futile transplants in aggressive HCC) are paramount. LDLT will likely continue to play a growing role, particularly as demand for transplant for HCC increases globally.
IMMUNOSUPPRESSION PROTOCOLS AND ONCOLOGICAL IMPLICATIONS
Immunosuppression is a necessary facet of post-transplant management, but it has complex interactions with cancer outcomes. On one hand, inadequate immunosuppression risks graft rejection; on the other hand, excessive immunosuppression may promote tumor recurrence by impairing immune surveillance of residual cancer cells. Here we review standard immunosuppressive regimens in LT and their specific implications for HCC patients.
Standard Immunosuppression Regimens
Most liver transplant recipients, including those with HCC, receive a calcineurin inhibitor (CNI) such as tacrolimus (or cyclosporine in some cases) as the backbone of immunosuppression. CNIs are often combined with an antiproliferative agent like mycophenolate mofetil and corticosteroids (tapered off within months if possible). In HCC patients, some centers incorporate mTOR (mammalian target of rapamycin) inhibitors, such as sirolimus or everolimus, into the regimen. This is because mTOR inhibitors have dual utility: they are immunosuppressive but also have anti-neoplastic properties (anti- angiogenic and anti-proliferative effects), which could theoretically help reduce cancer recurrence [
22]. mTOR signaling is often upregulated in HCC, especially aggressive tumors, so mTOR inhibitors might counteract that pathway (
Table 4) [
52].
High levels of immunosuppression have been associated with increased HCC recurrence risk. CNI exposure in particular shows a dose-dependent relationship with recurrence – higher trough levels of tacrolimus or cyclosporine are linked to higher recurrence rates [
53]. The presumed mechanism is that strong immunosuppression blunts the patient’s anti-tumor immune response, allowing micrometastatic disease to grow unchecked. In contrast, mTOR inhibitors have shown promise in reducing recurrence. Several retrospective studies and meta-analyses have reported that incorporating an mTOR inhibitor is associated with lower HCC recurrence and improved survival, for example one meta-analysis noted recurrence rates of 13.8% vs. 8.0% (favoring mTOR inhibitor use) [
54]. The only randomized controlled trial to date (the SiLVER trial) compared sirolimus-based immunosuppression vs standard immunosuppression in HCC patients. It demonstrated a slight improvement in recurrence-free survival at 3–5 years with sirolimus, but this advantage diminished over longer follow-up. The long-term benefit remains uncertain, but early outcomes suggested an advantage. Based on such evidence, some transplant oncologists advocate using mTOR inhibitors (at least for the first 2–3 years post-LT) in HCC patients to potentially curb recurrence.
To balance efficacy and safety, expert consensus guidelines have recommended minimal effective CNI levels for HCC patients. The International Liver Transplantation Society (ILTS) Transplant Oncology Consensus conference advises target trough concentrations of tacrolimus <10 ng/mL (and cyclosporine <300 ng/mL) in HCC recipients [
55]. This is lower than what might be used in other high-risk immunologic settings, reflecting the desire to avoid over-immunosuppression. In practice, many centers attempt to wean steroids early and keep tacrolimus at the low end of the therapeutic range if the patient’s graft is stable, especially after the first 6–12 months.
An important development in the HCC-cirrhosis population has been the advent of direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV). Initially, there were fears that treating HCV with DAAs in transplant recipients might increase HCC recurrence or aggressiveness (some early observations suggested a possible association). Fortunately, larger studies debunked this concern—treating HCV either before or after LT does not increase HCC recurrence risk [
56]. In fact, curing HCV improves overall survival. A multi-center study of 800 patients found no difference in HCC recurrence between DAA-treated vs untreated groups (hazard ratio 0.96), and a follow-up showed significantly reduced mortality in those cured of HCV (HR 0.54) [
57]. Thus, antiviral therapy for hepatitis C should be utilized in transplant patients as indicated, without fear of promoting HCC (indeed, it likely benefits outcomes).
Another emerging issue is the use of immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab) in transplant recipients. As mentioned, such agents can precipitate lethal graft rejection by unleashing T-cell activity against the allograft. This risk (documented rejection rates 25–50% in reported cases) generally precludes routine use of checkpoint inhibitors in the post-transplant setting. However, if a patient develops recurrent HCC that is otherwise untreatable, some have attempted Immunotherapy as a last resort, with extreme caution. Each case requires weighing the substantial rejection risk against potential cancer control—currently, this is only done in experimental or compassionate use scenarios. No standard immunosuppressive regimen can fully prevent this rejection if checkpoint inhibitors are given; combination with high-dose steroids or other therapies has been tried, but the safety profile remains poor. Therefore, Immunotherapy for post-LT HCC recurrence is not standard and is the subject of ongoing research into how to modulate the immune system safely [
58].
For HCC patients, most centers tailor immunosuppression to mitigate recurrence risk: using the lowest necessary CNI dose, considering early switch or addition of an mTOR inhibitor, and avoiding prolonged high-dose steroids [
59]. If renal function allows, some will maintain sirolimus therapy for 2–5 years post-LT in HCC recipients, given its anti-tumor properties, although this must be balanced against its side effects (e.g., impaired wound healing, dyslipidemia). Close monitoring of AFP and imaging in the first years is warranted, and if any concerning rise in tumor markers occurs, some clinicians will further lower immunosuppression while investigating for recurrence. Overall, the influence of immunosuppression on HCC recurrence remains an area of active study. While it is intuitive and supported by some data that less immunosuppression and mTOR use are beneficial, no definitive protocol exists [
60]. Individualized therapy is recommended, and multidisciplinary discussion (transplant surgery, hepatology, oncology) is needed to balance graft health with cancer control on a case-by-case basis.
GLOBAL TRENDS, CHALLENGES, AND RECENT INNOVATIONS IN HCC TRANSPLANTATION
Global Epidemiology and Transplant Demand
The burden of HCC is rising in many parts of the world, particularly as risk factors like nonalcoholic fatty liver disease (NAFLD) and alcohol-related cirrhosis increase [
61]. While viral hepatitis (hepatitis B virus, HCV) remains a major cause of HCC in Asia and Africa, the successful treatment of HCV has led to a shift in the West, where NAFLD/ nonalcoholic steatohepatitis and alcohol are projected to become the dominant causes of HCC and cirrhosis-related deaths by 2040. This epidemiologic transition means more patients with metabolic syndrome-related HCC, often older and with comorbidities, are entering transplant evaluations. Globally, around 34,000 liver transplants were performed in 2021, a number that continues to grow modestly each year. However, there are stark disparities in access: transplant rates per capita are highest in developed regions (e.g., North America, Europe, East Asia) and very limited in low-income countries [
62]. South Korea, for example, performs the most LTs per million population worldwide (owing to a high rate of living donation) [
63]. HCC constitutes a significant indication for LT; in some high-endemic regions and specific centers, HCC accounts for 30–50% of liver transplants in adults. In the U.S., the proportion of transplants performed for HCC increased substantially after the adoption of the MELD exception policy in 2002, and HCC now accounts for roughly 20–25% of liver transplant cases [
64].
A critical challenge is the scarcity of donor organs relative to the number of patients who could benefit. This shortage necessitates careful allocation. One ethical question is prioritizing HCC patients (who are often less physiologically ill from liver failure) versus non-HCC patients who may die quickly without transplant. Most systems use a variant of the MELD score for organ allocation. Because MELD (based on labs like bilirubin, INR, and creatinine) underestimates risk in HCC (HCC patients can have low MELD scores despite harboring life-threatening cancer), special exception points are awarded. Ensuring equity between HCC and non-HCC candidates has been a moving target – policies have been tweaked (e.g., capping exception MELD, instituting a 6-month delay before granting exceptions, adjusting for AFP) [
35] to prevent HCC patients from having a disproportionate advantage in receiving organs. In the U.S., current policy grants a MELD exception, roughly equivalent to a 15-point MELD (and now a complex system of MMaT-3, etc.), after a 6-month waiting period if the criteria are met [
35]. This delay was introduced to allow aggressive tumors to declare themselves (if they progress beyond the criteria in 6 months, the patient will not be transplanted). Such policies aim to strike a balance between urgency and utility.
Similarly, South Korea's system, managed by the Korean Network for Organ Sharing (KONOS), also utilizes a MELD-based framework but has unique adaptations that reflect its healthcare landscape. Given the high prevalence of HCC and the world's leading rate of LDLT, the deceased donor allocation system for HCC in Korea faces different pressures. While MELD exception points are granted, the criteria and waitlist dynamics are influenced by the availability of LDLT as a viable alternative, which can reduce waitlist mortality for HCC patients compared to regions solely reliant on deceased donors. This presents an advantage in timely treatment but also raises complex ethical discussions about equity between those with and without access to a living donor.
Different countries have taken varying approaches: in some European systems, HCC exceptions are also used, but with regional differences in how points are assigned. Some countries have strict limits on AFP for listing (e.g., AFP >400 or 1,000 can disqualify in certain regions) [
65]. There is also debate on the upper age limit for HCC transplant, as many HCC patients are older; careful pre-transplant oncogeriatric assessment is needed rather than a fixed cutoff [
66].
A further challenge is waitlist dropout—in areas with low organ availability, many HCC patients will progress before transplant. Strategies such as sharing organs nationally, utilizing marginal donors, or living donation can mitigate this. In regions with active LDLT programs, patients have a “safety valve” if the deceased wait becomes too long. In places without LDLT, unfortunately, a significant fraction of HCC patients deteriorate or drop off the list (as mentioned, up to 20% in the U.S. and higher elsewhere). Early palliative care involvement is recommended for those on the waitlist, given the risk of dropout and high symptom burden if tumors progress.
Regional Differences in Criteria
Some centers and countries have adopted their own expanded criteria for diagnosis. For example, the University of Toronto proposed criteria without an upper limit on tumor size/number but emphasizing tumor behavior (no vascular invasion, no nodes/metastases, and response to therapy)—essentially, case-by-case selection beyond fixed limits. They found survival could be acceptable in selected patients outside Milan. China’s Hangzhou criteria allow either Milan or “total tumor diameter ≤8 cm with well-differentiated histology or AFP ≤400” and have reported good outcomes. Japan’s Kyoto criteria incorporate tumor biology (up to 10 tumors ≤5 cm if DCP ≤400 mAU/mL) to select patients with many small tumors but low malignant potential. These regional criteria reflect attempts to maximize the use of available donors and patient populations (e.g., hepatitis B-related HCC often presents with multiple small tumors, thus the Kyoto criteria) [
67]. They underscore that Milan is not a one-size-fits-all worldwide program; individual programs individualize based on their context, especially where living donation allows flexibility.
To combat organ shortage, efforts are underway to expand the donor pool and improve graft utilization: - Machine Perfusion: Normothermic machine perfusion and other perfusion technologies represent a significant innovation in organ preservation. Instead of preserving a liver on ice (static cold storage), machine perfusion maintains the organ in a functioning state ex vivo, perfused with warm oxygenated blood or solution. This technique can rejuvenate marginal livers, allow for viability assessment, and potentially reduce ischemia-reperfusion injury. For HCC patients, machine perfusion could increase organ availability by making previously unusable livers transplantable [
68]. It also may allow safe usage of organs from extended criteria donors (older age, fatty livers, donation after Circulatory Death donors), thereby expanding the pool. Recent active investigations have demonstrated improved early graft function and lower discard rates for machine-perfused livers in clinical trials [
69]. Machine perfusion devices (e.g., OrganOx, TransMedics OCS) are increasingly being adopted in transplant centers. As this technology matures, it is expected to help address donor shortages and benefit HCC patients by shortening wait times and providing better grafts.
1. Marginal donor use
Beyond perfusion, transplant teams are employing other strategies to expand the donor pool. Transplanting HCV-positive livers into HCV-negative recipients (followed by antiviral treatment) has become routine, effectively increasing the organ supply. Similarly, using donors with mild fibrosis, steatosis, or older donors can be acceptable to minimize patient dropout, although these require careful intraoperative management and adjustments to immunosuppression. For HCC patients, slightly higher risk grafts might be justified if the tumor is at risk of progression – the trade-off being between accepting a less-than-perfect liver now vs. waiting longer and risking the cancer worsening [
70].
2. Split liver and ABO-incompatible transplants
Splitting one deceased donor liver to help two recipients (usually an adult and a child) can indirectly free up organs, although for HCC, this is rarely applicable (adults with HCC typically need a full or large partial graft). ABO-incompatible transplants, enabled by desensitization protocols, are used in some LDLT cases in Asia, again to increase donor options.
Translational Research and Future Directions
There are exciting developments on the horizon that may further refine HCC transplant candidate selection and post-transplant management:
1. Molecular and Genetic Markers
Research is ongoing to identify genetic signatures or specific mutations in HCC that correlate with recurrence risk and could inform selection. For instance, specific mutations (such as those in TP53 or markers of aggressive biology) may indicate a tumor that is prone to recur, even if it is small. Genomic profiling of HCC tumors has revealed pathways associated with poor outcomes. In the coming years, it is conceivable that a molecular panel on biopsy or blood could supplement radiologic criteria in listing decisions, adding a layer of personalization [
71].
2. Liquid biopsy
Circulating tumor DNA (ctDNA) and circulating tumor cells are being studied as non-invasive biomarkers [
72]. Detecting ctDNA in the blood pre-transplant (or its persistence post-transplant) could signal the presence of microscopic residual disease. If validated, this could influence the urgency of transplant or the intensity of post-LT monitoring. A liquid biopsy may also detect early recurrence before it becomes radiologically visible, enabling earlier intervention.
3. Immune profiling
Given the interplay of HCC with the immune system (especially after transplant), profiling the immune status of patients is of interest. This could include assessing tumor-infiltrating lymphocytes or the patient’s immunogenetics. For example, an “immune active” tumor microenvironment might predict better response to immunotherapies (if they are used) but also higher risk of rejection if checkpoint inhibitors are given. This field is still in its infancy, but as Immunotherapy has become the frontline treatment for advanced HCC, understanding how to integrate it with transplant is crucial. Some early phase trials are testing neoadjuvant Immunotherapy (checkpoint inhibitors given before transplant to downstage/control HCC) [
58]. Initial experiences were worrisome due to reports of acute rejection when the transplant was performed shortly after Immunotherapy. However, more recent case series with careful timing (e.g., requiring a washout period of at least 3–6 months off Immunotherapy before transplant) have shown that some patients can be successfully transplanted with no immune complications and had complete pathological necrosis of their tumors. This is very promising, suggesting we may eventually develop protocols to safely combine immune checkpoint inhibitors in the pre-transplant setting to improve downstaging or eradicate HCC, then transplant the patient once the drug has sufficiently cleared. Ongoing trials are exploring this strategy, and if it proves safe, it could significantly improve outcomes for those with borderline HCC by reducing recurrence.
4. Adjuvant therapy
To date, no adjuvant (post-transplant) therapy is standard for HCC due to concerns of toxicity and rejection. Sorafenib was tested in the adjuvant setting, but the trial was negative (terminated early due to lack of benefit and side effects). Now, with newer agents, there is renewed interest in trials of adjuvant Immunotherapy or targeted therapy after transplant for very high-risk cases (e.g., those with vascular invasion in the explant). Any such approach must carefully balance immunosuppression. An example is a pilot study of low-dose immune checkpoint blockade after transplant under intensive monitoring; results are not yet precise, but this remains a frontier for research given the high stakes.
5. Radiomics and imaging
Another innovation is advanced imaging analysis (radiomics), where AI algorithms analyze CT/MRI characteristics of HCC lesions beyond what the naked eye sees [
73]. Radiomics can potentially predict tumor grade or the likelihood of microinvasion prior to surgery. If a radiomic signature strongly predicted “high-risk” HCC, that patient might be routed to other therapies or require downstaging before transplant. This technology could refine how we categorize “within criteria” beyond just size/count, by adding a qualitative assessment of tumor aggressiveness gleaned from imaging data.
As transplant oncology is a rapidly evolving field, global registries and collaborations (such as the Liver Cancer Network, ILTS Transplant Oncology group, and regional consortia) are crucial. They enable the pooling of data to answer questions such as how far the criteria can be expanded safely or what the outcomes are with new protocols. Policy changes, such as UNOS adopting downstaging, often stem from such shared data. A challenge remains in resource-limited settings where transplantation for HCC is not widely accessible—for example, in many parts of Africa and South America, liver transplant programs are scarce. Efforts by international societies aim to train surgeons and establish programs in these areas; however, cost and infrastructure are significant barriers.
In summary, the landscape of liver transplantation for HCC is one of continual progress. Innovative techniques, such as machine perfusion and the use of living donors, are helping to alleviate organ shortages. At the same time, advancements in biomarkers and an increased understanding of tumor biology are improving candidate selection. Immunotherapy and other systemic treatments, once thought incompatible with transplant, are being cautiously studied to improve cure rates further. The coming years are likely to see transplant criteria further refined using molecular data and enhanced by technology, to offer this life-saving treatment to more patients while maintaining excellent outcomes.
CONCLUSION
Liver transplantation is the optimal treatment for patients with early-stage HCC in the setting of cirrhosis, offering the chance of long-term survival and cure. Rigorous patient selection based on tumor burden and biology is essential to ensure low recurrence rates. The Milan criteria have provided a foundation for selecting appropriate candidates, and ongoing efforts have expanded these limits safely by incorporating factors like AFP and treatment response. Downstaging therapies allow patients with more advanced HCC to reach transplant with survival outcomes now validated as acceptable, especially under the structured criteria adopted by UNOS [
2]. Centers must remain judicious and highly selective when venturing beyond standard criteria, balancing the potential benefit of transplant against the risk of post-LT recurrence.
Post-transplant outcomes for HCC are excellent in well-selected patients, with a 5-year survival rate of around 70–80% and recurrence in only 10–20% of cases. The use of living donor transplantation has improved access to LT and reduced waitlist dropouts for HCC patients, without compromising oncologic outcomes. Optimal immunosuppressive management—such as maintaining low CNI levels and considering mTOR inhibitors—may further reduce recurrence, although this strategy continues to be refined.
Global trends indicate an increasing demand for liver transplants for HCC amid organ shortages. Innovative solutions, such as normothermic machine perfusion, are being explored to expand the donor pool. Meanwhile, research into biomarkers (AFP-L3, DCP, ctDNA) and advancements in imaging are paving the way for more precise risk stratification. The advent of Immunotherapy has revolutionized the treatment of advanced HCC. However, challenges remain in the transplant setting due to rejection. Early trials suggest that with proper timing and patient selection, immune therapies could be integrated to improve downstaging or serve as adjuvant treatments.
In conclusion, LT for HCC represents a successful paradigm of multidisciplinary cancer care, marrying oncology with transplant surgery. Continuous innovation in selection criteria, bridging treatments, donor utilization, and post-LT management is expanding its reach. The ultimate goal is to offer a cure to as many HCC patients as possible while ensuring the safety of graft outcomes. Ongoing clinical trials and translational studies are likely to inform future guidelines, potentially altering HCC transplant policies in the years to come. Hepatobiliary surgeons, as key players in this field, should stay abreast of these developments to provide cutting-edge, evidence-based care for patients with liver cancer.
NOTES
-
ACKNOWLEDGEMENTS
The authors thank the multidisciplinary liver tumor boards and transplant teams at their institutions for insights that informed this review.
-
FUND
None.
-
ETHICS STATEMENT
The consent for publication is not required as the submission does not include any images or information that may identify the person.
-
CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported
Table 1.Comparison of selection criteria for liver transplantation in HCC
Table 1.
|
Criteria |
Single tumor |
Multiple tumors |
Total tumor burden |
Biological markers |
5-year survival |
|
Milan criteria |
≤5 cm |
Up to 3 tumors, each ≤3 cm |
Not applicable |
Not considered |
>70% |
|
UCSF criteria |
≤6.5 cm |
Up to 3 tumors, largest ≤4.5 cm |
Total tumor diameter ≤8 cm |
Not considered |
~75% |
|
“Up-to-7” criteria |
None |
Not applicable |
(Sum of largest tumor diameter in cm) + (number of tumors) ≤7 |
Not considered |
~71% |
|
Metroticket 2.0 |
None |
Not applicable |
Scored based on tumor size and number |
Includes AFP level as a key variable |
Stratified by risk |
|
French AFP model |
Varies |
Varies |
Size/number criteria beyond Milan |
Acceptable only if AFP ≤100 ng/mL |
~75% |
|
NYCA score |
Varies |
Varies |
Size/number criteria beyond Milan |
Integrates AFP response over time |
Stratified by risk |
|
Toronto (UofT) criteria |
No upper size limit |
No upper number limit |
Focus on tumor behavior |
Emphasizes dynamic assessment of tumor behavior (e.g., response to therapy) over static size limits. Excludes vascular invasion and metastases. |
Case-by-case |
|
Kyoto criteria |
≤5 cm |
Up to 10 tumors |
Not applicable |
Acceptable only if DCP ≤400 mAU/mL |
>80% |
Table 2.High-risk factors for post-transplant HCC recurrence
Table 2.
|
Category |
Risk factor |
Key details & evidence |
|
Pathological factors |
Microvascular invasion (MVI) |
- One of the strongest predictors of recurrence when found in the explanted liver |
|
Poor tumor differentiation |
- Found in ~15–20% of explants within Milan criteria |
|
Satellite lesions/multifocality |
- A higher histological grade suggests more aggressive tumor biology |
|
- A higher number of tumors or the presence of satellites increases recurrence risk |
|
Biological markers |
High pre-transplant AFP |
- AFP >1,000 ng/mL is associated with a poor prognosis and is often a contraindication for transplant |
|
AFP-L3, DCP (PIVKA-II) |
- Novel biomarkers that can strongly predict early post-LT recurrence, even when morphological criteria are met |
|
Clinical factors |
RETREAT Score |
- A scoring system that incorporates AFP, tumor size/number, and MVI to stratify post-LT recurrence risk |
Table 3.Comparison of LDLT vs. DDLT for HCC
Table 3.
|
Feature |
Living donor LT (LDLT) |
Deceased donor LT (DDLT) |
|
Wait time & dropout risk |
Allows for timely transplantation, mitigating the risk of waitlist dropout due to tumor progression. |
Long wait times can lead to a significant risk of dropout (15–30%) as the tumor progresses beyond criteria. |
|
Intention-to-treat survival |
Can improve intention-to-treat survival by eliminating waitlist attrition. |
Overall survival can be lower due to waitlist dropout. |
|
Expansion of criteria |
Provides the flexibility for centers to transplant select patients who are beyond standard criteria. |
Generally adheres to strict national or regional allocation criteria to ensure equitable use of a scarce resource. |
|
Post-transplant recurrence |
Recent large-scale studies show that recurrence and survival rates are comparable to DDLT when controlling for tumor characteristics. |
Serves as the benchmark for post-transplant HCC outcomes. |
|
Key advantage |
Timely transplantation and expansion of the donor pool. |
No risk to a healthy donor. |
Table 4.Post-transplant immunosuppressant choice and tumor recurrence risk
Table 4.
|
Drug class |
Examples |
Key considerations |
|
Calcineurin inhibitors (CNIs) |
Tacrolimus, cyclosporine |
(Potential for increased risk) High trough levels have been linked to a higher risk of recurrence. |
|
mTOR inhibitors |
Sirolimus, everolimus |
(Potential for decreased risk) Possess anti-neoplastic properties; associated with lower recurrence and improved survival in many studies. |
|
Antiproliferative agents |
Mycophenolate mofetil (MMF) |
- Often used as part of a combination regimen to allow for lower CNI doses. |
|
Corticosteroids |
Prednisone |
(Potential for increased risk) Prolonged, high-dose therapy should be avoided. |
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