Milan Criteria for Liver Transplantation in Hepatocellular Carcinoma
Patients with hepatocellular carcinoma 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, 2
Core Eligibility Requirements
The Milan criteria define transplant candidacy based on three essential components:
- Tumor size and number: Either a solitary lesion measuring 5 cm or less, OR up to three separate nodules with the largest not exceeding 3 cm 1, 2
- Vascular status: Complete absence of macrovascular invasion on imaging 1, 2
- Disease extent: No evidence of extrahepatic metastatic spread 1, 2
Expected Outcomes When Meeting Milan Criteria
Patients who satisfy these criteria achieve excellent transplant outcomes:
- 5-year survival: 65-78%, which is comparable to patients transplanted for non-malignant indications 1
- 10-year survival: Approximately 50% 1
- Recurrence rates: Below 15% 1
- Perioperative mortality: Around 3% 1
Required Diagnostic Workup
Before determining Milan criteria eligibility, complete staging must include:
- Hepatic imaging: Dynamic CT or dynamic MRI demonstrating arterial enhancement followed by washout in portal venous or delayed phases 1, 2
- Extrahepatic staging: Chest CT for pulmonary metastases, plus abdominal and pelvic CT or MRI 1, 2
Critical Biomarker Consideration
Alpha-fetoprotein (AFP) >1,000 ng/mL represents an absolute contraindication to transplantation, regardless of whether tumor burden meets Milan criteria. 1, 2
This is a crucial pitfall to avoid—even if imaging shows a patient within Milan criteria, an AFP exceeding 1,000 ng/mL predicts poor outcomes and disqualifies the candidate. AFP provides essential prognostic information that must be incorporated into all transplant decisions 1, 2.
Waitlist Management
For patients meeting Milan criteria with anticipated waiting times exceeding 6 months:
- Bridging locoregional therapy is appropriate to prevent tumor progression and waitlist dropout 1, 2
- Monitoring requirements: Periodic imaging (dynamic CT, dynamic MRI, or contrast-enhanced ultrasound) plus serial AFP measurements 1, 2
- High-risk dropout patients: Those with multinodular tumors, neoadjuvant treatment failures, baseline AFP ≥200 ng/mL, or AFP increases >15 ng/mL/month 1
Downstaging to Milan Criteria
Patients initially beyond Milan criteria may be considered after successful downstaging:
- Requirement: Tumor reduction to within Milan criteria using locoregional therapies 2, 3
- AFP threshold: Must maintain AFP <1,000 ng/mL for at least 3 months before listing 2
- Observation period: At least 3 months after locoregional therapy to assess tumor biology and response 2, 3
- Outcomes: Successfully downstaged patients achieve survival comparable to those always within Milan criteria 4
Expanded Criteria Considerations
While Milan criteria remain the gold standard, modest expansions may be considered in specific circumstances:
- UCSF criteria (University of California, San Francisco) represent the most validated expansion 1
- Up-to-seven criteria (sum of largest tumor diameter in cm plus number of tumors ≤7) achieved 71.2% 5-year survival in patients without microvascular invasion 5
- Living donor transplantation provides opportunity to explore expanded indications when waiting lists exceed 6-7 months, particularly within research protocols 1
The evidence shows that tumor size and number alone tell only a partial story—incorporating AFP levels, response to locoregional therapy, and absence of microvascular invasion can identify patients beyond strict Milan criteria who may still achieve acceptable outcomes 5, 4. However, expansion should only occur in centers with low waitlist mortality to avoid harming non-HCC patients awaiting transplantation 1.