What are the Milan criteria for liver transplantation in patients with liver cancer?

Milan Criteria for Liver Transplantation in Hepatocellular Carcinoma

Patients with hepatocellular carcinoma (HCC) are eligible for liver transplantation if they have a single tumor ≤5 cm OR up to three nodules with none exceeding 3 cm, with no macrovascular invasion and no extrahepatic spread. 1

Core Criteria Definition

The Milan criteria, established in 1996, remain the international benchmark for selecting HCC patients for liver transplantation 2. These criteria specifically require:

• Single tumor ≤5 cm in diameter, OR
• Up to 3 nodules, each ≤3 cm in diameter
• No macrovascular invasion
• No extrahepatic disease 2, 1

Expected Outcomes

Patients meeting Milan criteria achieve:

• 5-year survival of 65-78%, comparable to non-HCC transplant indications 2
• 10-year survival around 50% 2
• Recurrence rates below 15% 2
• Perioperative mortality of 3% 2

These outcomes match or exceed the 65-87% 5-year survival seen in non-HCC transplant recipients across major registries (ELTR, OPTN, ANZLTR) 2.

Diagnostic Requirements

Preoperative assessment must use dynamic CT or dynamic MRI showing arterial enhancement followed by washout in portal venous or delayed phases 1. The size of the largest tumor or total tumor diameter should be the primary consideration in patient selection 2.

Staging must include:

• Chest CT for pulmonary metastases
• Abdominal and pelvic CT or MRI 1

Critical Biomarker Considerations

Alpha-fetoprotein (AFP) levels provide essential prognostic information and must be incorporated into transplant decisions 1:

• AFP >1,000 ng/mL is an absolute contraindication to transplantation, regardless of tumor burden 1
• AFP <400 ng/mL predicts significantly better outcomes in patients beyond Milan criteria (86.2% vs 0% 3-year survival) 3

Downstaging Protocols

Patients initially beyond Milan criteria may be considered for transplantation after successful downstaging to within Milan criteria 1, 4. Requirements include:

• AFP must remain <1,000 ng/mL for at least 3 months after downstaging 1
• Locoregional therapies (TACE, RFA, percutaneous ethanol injection) are used for downstaging 4
• Wait at least 3 months after locoregional therapy before listing to assess tumor biology 4
• Assessment should follow modified RECIST criteria 2

Waitlist Management

For patients with anticipated waiting times >6 months, bridging locoregional therapy is appropriate to prevent dropout 1. Monitoring requires:

• Periodic imaging (dynamic CT, dynamic MRI, or contrast-enhanced ultrasound)
• Serial AFP measurements 1

The dropout rate reaches 20% when waiting times are prolonged 2.

Priority Allocation

The MELD score inadequately predicts dropout risk in HCC patients 2. High-risk patients for dropout include those with:

• Multinodular tumors
• Neoadjuvant treatment failures
• Baseline AFP ≥200 ng/mL or increases >15 ng/mL/month 2

Expanded Criteria Considerations

While Milan criteria remain the standard, modest expansion may be considered in centers with low waitlist mortality 2. The most validated expansion is the UCSF criteria (single tumor ≤6.5 cm, ≤3 nodules with largest ≤4.5 cm, total diameter ≤8 cm) 2.

The "Up-to-seven" rule (sum of largest tumor size in cm plus number of tumors ≤7) achieved 71.2% 5-year survival in patients without microvascular invasion 5, though this was based on explant pathology rather than preoperative imaging, limiting clinical applicability 2.

Any expansion beyond Milan criteria requires 5-year survival ≥60% to avoid compromising outcomes for non-HCC candidates 2. Centers must consider their specific waitlist mortality before expanding criteria 2.

Living Donor Transplantation

Living donor liver transplantation is an appropriate alternative when waiting lists exceed 6-7 months 2. This setting provides opportunity to explore expanded indications within research protocols 2.

Common Pitfalls

• Do not rely on Milan criteria alone—incorporate AFP levels, as elevated AFP predicts poor outcomes even within Milan criteria 1, 3
• Avoid transplanting patients with AFP >1,000 ng/mL regardless of tumor size 1
• Do not list patients immediately after downstaging—the mandatory 3-month observation period identifies aggressive tumor biology 1, 4
• Microvascular invasion doubles mortality risk but cannot be reliably assessed preoperatively 5