Occult multifocal and incidental hepatocellular carcinoma: An analysis of long-term survival and risk factors at a single liver transplant center

The clinical significance of occult HCC identified on explant pathology in liver transplantation (LT) remains unclear. Among recipients of LT, discordance between pre-LT radiographic assessment of HCC and explant tumor burden is common. Data regarding the association of incidental HCC (no pre-LT radiographic diagnosis) and occult multifocal hepatocellular carcinoma (omHCC, pre-LT radiology underestimates a number of explant tumors) with outcomes are scarce. Post-LT recurrence and survival were compared among recipients of LT (n=919, 2002-2019) with incidental HCC (n=129), omHCC (n=349), and non-omHCC (n=437). Multivariable analysis identified independent predictors of omHCC in the subset of patients with kHCC. Compared to kHCC, incidental HCC had similar 5-year overall (OS) and recurrence-free survival (RFS), lower post-LT recurrence (6.9% vs. 16.2%, p=0.0019), but higher non-HCC-related mortality (38.4% vs. 23.7%, p=0.0042). Of 790 kHCC, 349 (44.1%) had omHCC, who demonstrated greater radiographic number of lesions (p=0.049) and locoregional treatments (p<0.001) but similar maximum and pre-LT alphafetoprotein compared to non-omHCC. Compared to kHCC without omHCC, patients with omHCC had inferior 5-year OS (60.4% vs. 70.9%, p=0.010) and RFS (56.8% vs. 69.7%, p<0.001), higher recurrence (23.8% vs. 9.2%, p<0.001), and similar non-HCC-related mortality. These observations remained true within patients who remained within Milan throughout preoperative imaging (5-y OS: 62.1% vs. 72.6%, p=0.027; RFS: 58.6% vs. 71.7%, p=0.010; recurrence: 21.7% vs. 7.6%, p<0.001). Multivariable predictors of omHCC tumor included a number of pre-LT locoregional therapies (OR 1.62 for 2 treatments, 95% CI 1.15-2.28, p=0.005; OR 1.98 for 3+ treatments, 1.36-2.88, p<0.001). In patients with kHCC prior to LT, the presence of omHCC is common and associated with inferior post-LT survival and higher recurrence rates. The development of improved radiographic and serum biomarkers that more accurately reflect explant tumor burden may improve patient selection and post-LT outcomes.