Impact of Tumor Multifocality on Outcomes Following Resection of Intrahepatic Cholangiocarcinoma: Implications for Future Staging Systems

BACKGROUND: The AJCC staging system has assigned variable prognostic weight to multifocal disease across versions for intrahepatic cholangiocarcinoma (iCCA). We aimed to better delineate how multifocality influences survival in patients with resectable iCCA to refine clinical staging and better inform treatment sequencing. PATIENTS AND METHODS: We retrospectively identified patients undergoing curative-intent hepatectomy for iCCA between 2000 and 2024 from 6 international, high-volume hepatobiliary centers. Patients were stratified by multifocality, T classification, and N classification. Overall survival (OS) was evaluated using Kaplan-Meier and Cox regression analyses, and a novel modified system was proposed based on current AJCC groupings. RESULTS: A total of 731 patients met the study inclusion criteria. Multifocal disease was present in 36% of patients with T2-T4 tumors and was independently associated with worse OS (hazard ratio, 1.64; 95% CI, 1.21-2.22; P=.002) compared with solitary tumors on multivariable analysis. This survival disadvantage persisted across T2 classification (28.8 vs 44.8 months; P=.001) and T3 classification (21.2 vs 36.5 months; P=.003), and remained significant after adjustment for nodal status (P=.003 and P=.017, respectively). Compared with solitary disease, multifocality also conferred worse OS in patients with node-negative (36.0 vs 58.9 months; P=.003) and regionally node-positive disease (19.2 vs 23.8 months; P=.016). Current AJCC staging failed to distinguish prognostic differences between stage II and stage IIIA disease (48.3 vs 46.9 months; P=.190). However, our proposed modifications, which classify multifocal tumors as T3 and upstage multifocality from stage II to stage IIIA in node-negative disease and from stage IIIB to a newly defined stage IIIC in node-positive disease, better stratified overall risk (P<.001). CONCLUSIONS: Multifocality independently predicts poor prognosis in resectable iCCA. Refining the current staging system by reclassifying multifocal tumors as T3 may improve prognostic stratification and better inform treatment sequencing.