Combined hepatocellular-cholangiocarcinoma shows distinct recurrence patterns and poorer postoperative outcomes compared to hepatocellular carcinoma

Abstract

Combined hepatocellular–cholangiocarcinoma (cHCC-CCA) is an uncommon primary liver cancer with distinct histology but overlapping clinical features with hepatocellular carcinoma (HCC). This study compared postoperative outcomes between cHCC-CCA and HCC in patients with very-early or early-stage tumors. We retrospectively analyzed 137 patients with cHCC-CCA and 3637 with HCC, all of which were pathologically confirmed at Barcelona Clinic Liver Cancer stage 0–A and treated with curative-intent resection at a high-volume tertiary center between 2010 and 2018. Tumors were reclassified according to the 2019 World Health Organization criteria. To minimize baseline imbalances, 1:4 propensity score matching was performed, yielding 137 patients with cHCC-CCA and 532 matched patients with HCC. Overall survival (OS) and recurrence-free survival (RFS) were compared using Cox regression and subgroup analyses. In the matched cohort, baseline characteristics – including tumor stage – were well balanced; nevertheless, 5-year RFS and OS were significantly lower in cHCC-CCA [RFS, 46.8% vs. 56.8%; hazard ratio (HR), 1.41; 95% confidence interval (CI), 1.10–1.81; P = 0.007; and OS, 70.8% vs. 86.1%; HR, 2.02; 95% CI, 1.47–2.78; P < 0.001]. Subgroup analyses consistently demonstrated inferior outcomes for cHCC-CCA across clinical strata. Notably, OS was comparable between groups among patients without recurrence; however, in those with recurrence, cHCC-CCA was associated with significantly worse OS and a higher incidence of extrahepatic relapse (24.1% vs. 7.7%; P < 0.001), most frequently in the lungs and lymph nodes. cHCC-CCA is associated with significantly poorer postoperative outcomes than HCC, particularly in the setting of recurrence. Intensified surveillance and strategies to reduce extrahepatic recurrence may be warranted in this population.