Predictive Immunohistochemistry in Cholangiocarcinoma: Current Clinical Utility, Practical Limitations, and Emerging Directions

Cholangiocarcinoma (CCA) remains a difficult-to-treat biliary malignancy in which therapeutic stratification increasingly depends on predictive biomarkers. Although next-generation sequencing is essential for the detection of targetable genomic alterations, immunohistochemistry (IHC) retains a practical role because it is widely available, rapid, and tissue-sparing. This narrative review summarizes the current and emerging role of predictive IHC in CCA, with emphasis on its clinical utility, interpretative pitfalls, and integration with molecular testing. HER2 and mismatch repair proteins currently represent the most relevant IHC-based markers in routine practice, albeit in selected subsets of patients. By contrast, PD-L1 has clear biological relevance but limited value as a stand-alone treatment selector in CCA, whereas Claudin 18.2 is promising but still investigational. Additional lines of research, including tumor microenvironment profiling, integrin-related pathways, and other theragnostic targets, may further refine patient selection, but these approaches are not yet standardized. Digital image analysis, radiomics, and machine learning are likely to improve quantification and may support future biomarker integration. A practical pathology-oriented approach should prioritize tissue stewardship, conservative interpretation of IHC results, and close coordination with molecular methods.