CHOLANGIOCARCINOMA: A COMPREHENSIVE OVERVIEW OF EPIDEMIOLOGY, PATHOGENESIS, DIAGNOSIS, AND TREATMENT

Background: Cholangiocarcinoma (CCA) is an uncommon yet highly aggressive malignancy of the biliary tract, typically diagnosed at advanced stages and associated with poor outcomes. Its incidence continues to rise worldwide, particularly for intrahepatic CCA. Progress in molecular profiling and precision oncology has enabled the introduction of targeted therapies, although inequalities in diagnostic and therapeutic access persist. Aim of the Study: The objective of this review is to integrate current evidence on the epidemiology, molecular pathogenesis, diagnostic strategies, and treatment of CCA, with particular attention to actionable molecular alterations, targeted therapies, and the role of personalized medicine. Materials and Methods: A narrative review of the English-language literature (2021–2025) was performed using PubMed, Scopus, PMC, and Google Scholar. Articles were selected if they addressed molecular biomarkers (e.g., FGFR2, IDH1), novel diagnostic tools, or systemic therapies. Priority was given to phase II/III clinical trials, real-world data, and emerging technologies such as liquid biopsy and AI-based histopathology. Results: Targetable alterations including FGFR2 fusions and IDH1 mutations have reshaped therapeutic strategies in intrahepatic CCA. Agents such as pemigatinib and ivosidenib have shown meaningful clinical activity, with real-world data confirming meaningful clinical benefit in patients with FGFR2 fusions. Advances in next-generation sequencing and liquid biopsy have enhanced diagnostic precision and disease monitoring. Nevertheless, major barriers remain, including delayed molecular testing, limited availability of clinical trials, and development of resistance mechanisms. Conclusions: Although treatment innovations have improved outcomes for selected patients, CCA continues to be a highly lethal malignancy with significant unmet needs. Broader implementation of molecular diagnostics, equitable access to targeted therapies, and earlier intervention are crucial. Future work must also address resistance pathways and promote inclusive research to fully realize the potential of precision oncology in cholangiocarcinoma.