Beyond the Milan Criteria: How New Advances are Improving Liver Transplant Outcomes for HCC Patients
"Discover how evolving criteria and biomarkers are expanding eligibility and enhancing success in liver transplantation for hepatocellular carcinoma."
In 1996, the landscape of liver transplantation (LT) for hepatocellular carcinoma (HCC) transformed, thanks to the work of Mazzaferro and colleagues. Their research led to the development of the Milan criteria, offering a beacon of hope compared to the previously dismal outcomes associated with LT for HCC. Before this, liver transplantation for HCC had a poor success rate.
The Milan criteria established specific tumor size and number limits for transplant eligibility. Patients falling within these limits (a single tumor ≤5 cm or 3 tumors ≤3 cm) experienced a remarkable 83% recurrence-free survival (RFS) at 4 years. Building upon this success, the United Network for Organ Sharing (UNOS) began awarding Model for End-Stage Liver Disease (MELD) exception points for HCC in 2002, recognizing the disproportionate mortality risk that the MELD score alone didn't capture.
However, the Milan criteria are not without their limitations. They are confined by the accuracy of radiological measurements. More crucially, the criteria fail to account for the biological behavior of the tumor. Recent advancements incorporating biomarkers like alpha-fetoprotein and neutrophil-lymphocyte ratio are filling this gap, providing effective means of predicting tumor behavior.
Transplant Demand and Tumor Risk
Liver transplantation is a life-saving therapy for people with complications of cirrhosis and stage T2 hepatocellular carcinoma, but demand for organs far outstrips supply. The 2023 status report describes efforts to increase usable deceased-donor organs and develop alternative donor sources as major priorities. A study of liver transplantation for HCC found that alpha-fetoprotein (AFP) independently predicted tumor recurrence and correlated with vascular invasion and tumor differentiation.
From First Transplants to Evolving Criteria
Thomas Starzl performed the world's first liver transplantation for hepatocellular carcinoma in the United States in 1963; three of the first seven liver transplants were for HCC. One review describes transplantation as a potential three-part treatment: removing the tumor, preventing metachronous lesions in the cirrhotic liver, and restoring liver function. The broader history of liver transplantation also reflects how surgical advances alone were insufficient while understanding of immunology remained limited.
Expanding the Boundaries: UCSF and Metroticket Criteria
The Milan criteria, while groundbreaking, were seen by some as overly restrictive. Researchers sought to expand the criteria without compromising the success of liver transplantation. This led to the development of alternative criteria, such as those from the University of California-San Francisco (UCSF) and the Metroticket model.
- UCSF Criteria: Allowed for a single tumor up to 6.5 cm or up to 3 tumors with the largest lesion ≤4.5 cm, with a total tumor diameter ≤ 8 cm.
- Metroticket Model: Expanded the Milan criteria using the up-to-seven criteria to expand the tumor size and number allowable while maintaining non-inferior post-LT survival.
Expanding Beyond Milan
A review published February 10, 2025, describes liver transplantation as a cornerstone of HCC care for almost three decades and says its role is evolving to include patients beyond the widely used Milan criteria. It highlights combining dynamic biomarkers such as alpha-fetoprotein with downstaging approaches and assessment of tumor evolution. A 2024 review identifies organ shortages, better pre-transplant bridging and downstaging therapies, and post-transplant recurrence treatment as major challenges; it also discusses the emerging relevance of immune checkpoint inhibitors.
Limits of Broader Selection
Evidence supporting broader selection has important limitations. In one report, 283 patients without microvascular invasion who met Up-to-Seven criteria had 71.2% five-year overall survival, but the analysis relied on postoperative histology to determine outcomes. A preliminary U.S. comparison suggested that patients transplanted within UCSF criteria might have survival equivalent to those within Milan criteria, while noting that the UCSF group was small. Organ scarcity remains a major constraint on transplantation access.
Balancing Criteria and Tumor Risk
A network meta-analysis reported higher five-year recurrence-free survival for patients within both Milan and AFP criteria than for patients within AFP criteria but beyond Milan criteria: 89.2% versus 74.1% (P = 0.014). Another source reported microvascular invasion rates of 37.2% and 50.0% in two groups assessed with simple risk models, compared with 13.6% among patients within Milan criteria; both comparisons were statistically significant (P < 0.001). A separate reply describes an approach in which patients exceeding Milan criteria were downstaged and continuously treated with TACE during the waiting period under a strict protocol. Locoregional therapy has also been described as a way to distinguish potentially transplantable patients with advanced HCC.
The Future of HCC Treatment: Biomarkers and Personalized Approaches
The future of liver transplantation for HCC lies in refining patient selection through a deeper understanding of tumor biology. Biomarkers offer a powerful tool to predict tumor behavior and recurrence risk, enabling clinicians to move beyond simple size and number criteria.
Promising Therapies, Unresolved Questions
A 2025 review comparing liver resection and liver transplantation for HCC notes that conclusions across meta-analyses have been inconsistent, partly because of overlapping datasets and methodological heterogeneity. Another review explores immune checkpoint inhibitors as bridging or downstaging therapies for transplant-eligible HCC patients. It identifies graft rejection, immune-related toxicities, and gaps in evidence as clinical challenges to integrating these drugs into transplant protocols.
Access and Long-Term Outcomes
A 2025 article on global variation and systemic inequities in access describes liver transplantation as the only curative intervention for patients with decompensated cirrhosis. It also reports good long-term outcomes for patients with hepatocellular carcinoma. The article's framing highlights access inequities as an important systemic issue alongside clinical outcomes.
Selection with TTV and AFP
A prospective validation study proposed that, at centers with waiting times of at least eight months, HCC transplant candidate selection could be expanded using total tumor volume (TTV) of 115 cm³ or less and AFP of 400 ng/mL or less. Patients with AFP above 400 ng/mL were excluded from the study. The authors expected increased waiting-list dropout with this approach, alongside equivalent and satisfactory post-transplant survival.
Scoring systems that combine morphometric data with biomarkers, such as the MORAL score, AFP model, RETREAT score, and Metroticket 2.0, represent a significant step forward. These systems provide more accurate pre-LT assessments for HCC recurrence, ultimately leading to improved outcomes.
By integrating objective biological indices into allocation models, the liver transplant community can make more informed decisions, ensuring that life-saving therapies are offered to those who will truly benefit while avoiding futile transplants. With continued research and refinement, these personalized approaches promise to further improve the lives of patients with HCC.