Satellite lesions versus intrahepatic metastasis in multifocal intrahepatic cholangiocarcinoma: Prognostic impact and genomic profiling

Background and Aims: Multifocal intrahepatic cholangiocarcinoma (ICC) is typically categorized as satellite lesions (SL) or intrahepatic metastasis (IM). Clinical staging and prognostic significance of multifocal ICC are a topic of debate. Approach and Results: ICC patients with solitary or multifocal tumors undergoing curative-intent surgical resection were identified from an international multi-institutional database. SL and IM were classified according to distribution patterns. Among 1,064 patients included in the cohort, 358 had multifocal tumors that were defined as IM (n=95) or SL (n=263). Isolated AJCC Stage II of multifocal ICC disease was associated with shorter overall (OS)(median: 26.1 vs. 60.0 mo, p <0.001) and disease-free survival (DFS)(median DFS: 9.8 vs. 25.0 mo, p <0.01) than solitary tumors within Stage II, yet had a comparable prognosis as Stage III disease. Patients with IM or SL had comparable OS and DFS (both p >0.1), regardless of tumor number status. Genomic profiling demonstrated highly concordant mutational landscape of IM and SL in 24 multifocal ICC patients. Phylogenetic and evolutionary trajectory analysis supported that multifocal lesions with different distribution patterns were of the same origin derived from the corresponding primary tumors. Additionally, single-nucleus RNA sequencing revealed that both IM and SL harbored increased level of copy number variations compared with the primary lesion, indicative of malignant progression. Conclusions: Multifocal ICC should be categorized as AJCC Stage III disease regardless of IM and SL patterns. Both SL and IM are clonal origin derived from primary ICC tumor, and represent metastatic progression with poor long-term survival.