Surreal illustration of a liver tree with biomarker fruits in a hopeful desert landscape.

Beyond the Milan Criteria: How New Advances are Improving Liver Transplant Outcomes for HCC Patients

Author's portrait.
Beau Callahan in Health & Wellness December 2025 • 4 min read.

"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.

Expanding the Boundaries: UCSF and Metroticket Criteria

Surreal illustration of a liver tree with biomarker fruits in a hopeful desert landscape.

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.

The UCSF criteria, introduced in 2001, allowed for larger tumors and a greater number of nodules while maintaining comparable outcomes to the Milan criteria. Similarly, the Metroticket model, developed by Mazzaferro and colleagues in 2009, used an “up-to-seven” rule (the sum of tumor size and number up to seven) to expand eligibility.

  • 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.
Although these expanded criteria offered increased access to liver transplantation, they still relied primarily on tumor size and number, which have inherent limitations. It became clear that simply observing tumor size and number does not fully explain tumor behavior. Two separate analyses of the UNOS database demonstrated that longer waitlist time [11], or even LT for HCC in a longer waitlist region [12], improved overall survival (OS) and RFS.

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.

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.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1007/s40472-018-0212-y, Alternate LINK

Title: Liver Transplantation For Hcc Beyond Milan

Subject: Transplantation

Journal: Current Transplantation Reports

Publisher: Springer Science and Business Media LLC

Authors: Paolo Magistri, Russell Rosenblatt, Karim J. Halazun

Published: 2018-10-25

Everything You Need To Know

1

What were the **Milan criteria**, and why were they important in the context of liver transplantation for HCC?

The **Milan criteria**, established in 1996, were a pivotal development in liver transplantation (LT) for hepatocellular carcinoma (HCC). They defined specific limits on tumor size and number, such as a single tumor no larger than 5 cm or up to 3 tumors, each no larger than 3 cm. Patients meeting these criteria experienced a remarkable 83% recurrence-free survival (RFS) at 4 years. The importance lies in providing a benchmark to assess eligibility, which significantly improved outcomes compared to prior experiences. The implications are that it offered hope to patients previously deemed ineligible, marking a significant turning point in the treatment landscape.

2

How did the **Milan criteria** compare to the **UCSF criteria** and the **Metroticket model** in terms of patient eligibility?

The **Milan criteria** focused on the size and number of tumors to determine eligibility for liver transplantation. However, these criteria have limitations as they don't account for the tumor's biological behavior. The expanded criteria, such as the **UCSF criteria** and the **Metroticket model**, sought to broaden eligibility while maintaining comparable outcomes by allowing for larger tumors or a greater number of nodules. The **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. The **Metroticket Model** used an "up-to-seven" rule to expand the Milan criteria. This expansion addressed some of the restrictions of the Milan criteria, providing increased access to transplantation for more patients.

3

How do the **UCSF criteria** differ from the **Milan criteria**, and what is the significance of these differences?

The **UCSF criteria** expanded the eligibility criteria for liver transplantation, compared to the **Milan criteria**. Introduced in 2001, the **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. This expansion provided access to liver transplantation for patients with larger tumors or a greater number of nodules. The significance lies in the potential to include more patients, but its importance also means a need to maintain comparable transplant outcomes. This is important because it helps to avoid compromising patient survival. Both **UCSF criteria** and the **Milan criteria** are important to help physicians make informed decisions and improve patient survival rates.

4

What is the **Metroticket model**, and why is it important in the context of liver transplantation?

The **Metroticket model** broadened the scope of the **Milan criteria** by using an "up-to-seven" rule, increasing the number and size of tumors while aiming to maintain post-transplant survival. This model was developed by Mazzaferro and colleagues in 2009. The **Metroticket model** represents an effort to refine the criteria for patient selection in liver transplantation. This effort to expand the parameters of patient selection is important because it offers greater access to life-saving transplants. The implications are that it allows for more patients to potentially benefit from transplantation while maintaining acceptable outcomes. This makes it a significant advancement in the field.

5

What role do **biomarkers** play in the future of HCC treatment, and how do they relate to the **Milan criteria**?

The future of liver transplantation for HCC involves the use of **biomarkers** to better understand tumor biology and predict tumor behavior. While the **Milan criteria**, **UCSF criteria**, and the **Metroticket model** primarily rely on tumor size and number, **biomarkers** offer a deeper understanding of the disease. The significance of this shift lies in the potential for more accurate patient selection and personalized treatment strategies. By incorporating **biomarkers**, clinicians can better predict recurrence risk and tailor treatment plans accordingly. This is important because it can lead to improved patient outcomes and potentially expand the number of eligible patients.

Newsletter Subscribe

Subscribe to get the latest articles and insights directly in your inbox.