Viral vs non-viral combined hepatocellular–cholangiocarcinoma: Distinct genomic landscapes and survival outcomes.

Abstract

e16292 Background: Combined hepatocellular–cholangiocarcinoma (cHCC-CCA) is a rare and biologically heterogeneous primary liver cancer. Prior literature has reported conflicting clinical outcomes and treatment responses. Given the established prognostic influence of viral hepatitis in hepatocellular carcinoma, understanding whether similar effects exist in cHCC-CCA may have therapeutic implications. We evaluated published clinical outcomes and genomic datasets to explore differences between viral and non-viral cHCC-CCA. Methods: A structured PubMed and Embase search identified case reports and series reporting viral status, demographics, treatment details, and overall survival (OS) in patients with cHCC-CCA. Studies lacking OS attribution or viral status were excluded. Due to heterogeneous follow-up and absence of standardized censoring, survival data were analyzed descriptively; differences in OS distributions between viral and non-viral etiologies were compared using a nonparametric Mann–Whitney U test. A complementary genomic cohort of annotated cHCC-CCA cases was identified in cBioPortal. Differences in OS were compared using Student’s t-test. Mutation frequency differences were evaluated to identify putative biologic distinctions. Results: Across published cases, median OS was 49.5 months in the viral cohort and 20.0 months in the non-viral cohort, with mean OS of 47.7 ± 18.5 and 29.6 ± 16.2 months, respectively. This difference was statistically significant by Mann–Whitney U testing (U = 14.5, Z = −2.27, p = 0.023). A crude hazard approximation derived from median OS ratios suggested lower mortality risk in viral cHCC-CCA (HR = 0.40), although formal time-to-event analyses were not feasible. In the cBioPortal cohort, viral cases similarly demonstrated longer OS compared with non-viral cases (mean 23.1 vs 13.0 months; p = 0.02). Genomic analysis identified 367 differentially mutated genes, with significantly enriched alterations in non-viral tumors including IDH , SLC16A1 , CLDN18 , HMCN1 , ADAMTS8 , BNC1 , YES1 , and TGFBR1 (all p < 0.05). Although not statistically significant, viral cases demonstrated higher frequencies of CTNNB1 , TERT , MYCT1 , and MYCBPAP alterations. Conclusions: Across published clinical series and genomic datasets, viral etiology in cHCC-CCA was associated with longer OS compared with non-viral disease. Non-viral tumors demonstrated enrichment of mutations associated with metabolic reprogramming, proliferative signaling, pathway escape, and metastatic biology, potentially contributing to poorer outcomes. These findings are hypothesis-generating and limited by retrospective reporting, selection bias, and absence of true time-to-event datasets. Larger prospective cohorts and standardized genomic annotation will be essential to validate whether viral and non-viral cHCC-CCA represent distinct disease subsets.