The choice of candidates with hepatocellular carcinoma (HCC) for liver transplantation (LT) has historically depended on morphological criteria, particularly the Milan criteria (MC) [
1]. MC has served as a strong and consistent framework for many years, but its shortcomings in accurately representing tumor biology have become more apparent. In this context, Yu et al. [
2] offer a thorough network meta-analysis (NMA) that compares both established and new transplant selection criteria, along with validation in a large independent cohort.
By combining data from 35 studies, the authors compare the performance of morphologic criteria (MC, University of California San Francisco [UCSF], Up-to-Seven, and Hangzhou) to alpha-fetoprotein (AFP)-based models [
3-
5]. Their analysis indicates that AFP-inclusive criteria exhibit enhanced post-transplant outcomes regarding overall and recurrence-free survival in comparison to exclusively morphologic frameworks. These results support the increasing agreement that biological markers offer additional prognostic significance beyond mere tumor size and quantity.
A significant strength of this study is its dual methodology. The NMA gives a wide-ranging comparison, and the external validation cohort of more than 1,000 patients confirms the main findings in the real world. The validation cohort is especially important because it uses standardized imaging assessments, competing-risk methodology, and represents a high-volume transplant setting. These things together make the analysis more consistent and useful in the medical setting.
Nonetheless, various methodological factors warrant consideration. The star-shaped structure of the network makes it hard to formally check for inconsistencies, which is a common but important problem in NMAs of transplant criteria. Moreover, heterogeneity among studies, encompassing variations in locoregional therapy, imaging protocols, waiting time, donor type, and underlying liver disease, unavoidably leads to residual confounding. Although meta-regression was employed in addressing certain factors, the presumption of transitivity continues to pose difficulties in a domain characterized by significant regional and temporal variations in patient selection and treatment methodologies.
The validation cohort, although a distinct advantage, also delineates the limits of generalizability. Its predominance of hepatitis B-related HCC and living donor LT correlates with clinical practices in numerous Asian centers, contrasting with the deceased-donor-dominant, etiologically diverse Western contexts. The consistent performance of AFP-based criteria across various contexts is promising; however, additional validation in diverse transplant settings is essential.
The focus on AFP is important because it shows a bigger change in how candidates are chosen based on biology. AFP is easy to find and understand, but its limits should not be ignored. AFP-nonsecretory tumors, differing cutoff values, and the impact of pre-transplant therapies on AFP dynamics all make it difficult to use AFP in all cases. These factors underscore the necessity for ongoing enhancement of composite models that amalgamate biomarkers with radiological and clinical characteristics.
In conclusion, the research conducted by Yu et al.2 offers powerful comparative evidence endorsing AFP-based selection criteria as a significant improvement over conventional morphologic methods. The data, though not conclusive, support a trend toward biologically driven transplant decision-making. Future prospective studies and region-specific validations will be crucial to establish the optimal integration of such criteria into allocation policies, ensuring equity and maximizing long-term transplant benefits.
FOOTNOTES
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Authors’ contribution
Conception or design of the work and writing the article: J Kim.
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Conflicts of Interest
The author discloses no conflict.
Abbreviations
University of California San Francisco
REFERENCES
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- 2. Yu D, Hwang Y, Ju JS, Heo S, Kim SO, Choi SH, et al. Network meta-analysis and validation study of expanded liver transplantation criteria for hepatocellular carcinoma: significant role of alpha-fetoprotein. Clin Mol Hepatol 2026;32:751-771.
- 3. Lee HW, Suh KS. Liver transplantation for advanced hepatocellular carcinoma. Clin Mol Hepatol 2016;22:309-318.
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