Viral vs. Non-Viral Combined Hepatocellular-Cholangiocarcinoma: Distinct Genomic Landscapes and Survival Outcomes

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare, biologically heterogeneous primary liver cancer with conflicting reported outcomes. The prognostic impact of viral hepatitis in cHCC-CCA remains unclear. Given its established influence in hepatocellular carcinoma, we evaluated whether viral etiology is associated with distinct clinical and genomic features in cHCC-CCA.

A structured PubMed and Embase search identified case reports and series describing viral status, treatment, and overall survival (OS) in cHCC-CCA. Studies lacking OS attribution or viral status were excluded. Due to heterogeneous follow-up and absence of standardized censoring, survival was analyzed descriptively, with viral versus non-viral OS compared using Mann-Whitney U testing. A complementary genomic cohort from cBioPortal was analyzed to compare mutation frequencies between viral and non-viral cases.

Median OS was 49.5 months for viral versus 20.0 months for non-viral disease (mean 47.7 ± 18.5 vs 29.6 ± 16.2 months; p = 0.023). A crude hazard approximation suggested lower mortality risk in viral cases (HR ≈ 0.40), though formal time-to-event analysis was not feasible. In the genomic cohort, viral cases similarly demonstrated longer mean OS (23.1 vs 13.0 months; p < 0.05). Non-viral tumors showed enrichment of mutations including IDH, SLC16A1, CLDN18, HMCN1, ADAMTS8, BNC1, YES1, and TGFBR1.

Viral cHCC-CCA was associated with longer observed survival across clinical and genomic datasets. Non-viral tumors demonstrated enrichment of mutations associated with metabolic reprogramming, proliferative signaling, pathway escape, and metastatic biology, potentially contributing to poorer outcomes. These hypothesis-generating findings require validation in prospective cohorts with standardized genomic annotation.