Patient selection and organ allocation for liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) relies predominantly on clinical parameters, such as tumor burden (i.e., radiologic imaging). Patients transplanted within Milan criteria have outstanding outcomes with a 5- and 10-year survival of 70% and 55%, respectively. Tumor recurrence after transplant is rare in these patients (10%) but treatment options upon recurrence are generally limited and outcomes are poor. There are also several studies showing how a subgroup of patients with tumors outside the Milan criteria might achieve comparable outcomes to patients within Milan criteria. In other words, the size and number of tumor nodules not always reflects tumor biology, which could be better captured using molecular proxis for cancer aggressiveness. Over the last decade, we have significantly improved our understanding of the molecular landscape of early stage HCC. This includes the development of molecular classification, identification of prognostic and mutational signatures, and potential mechanisms of hepatocarcinogenesis. Some of them have already proven useful to predict tumor-related outcomes in HCC patients after LT. Most of these analyses are limited to tissue-derived biomarkers, which limits their implementation in clinical practice as tissue biopsy is not required for HCC diagnosis. Minimally-invasive alternative tools, such as liquid biopsy, are being increasingly explored and could help to individualize risk stratification for patients with HCC who will benefit from LT despite being outside accepted clinical criteria.
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