FGFR2/3-Altered Intrahepatic Cholangiocarcinoma: A Distinct Clinicopathologic and Molecular Subtype Associated with...

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive neoplasm with a poor prognosis. Fibroblast Growth Factor Receptor (FGFR) has emerged as a therapeutic target; however, the clinicopathologic, molecular, and prognostic features of FGFR-altered iCCAs remain incompletely defined. Thus, a 5-year retrospective study of genomically profiled iCCAs using dual whole-exome and whole-transcriptome sequencing, stratified by FGFR2/3 alteration status, to examine their clinicopathologic characteristics, biomarker expression, molecular profile, and prognostic significance on overall (OS), metastasis-free (MFS), progression-free (PFS), and disease-specific survival (DSS) was performed. Ninety iCCAs (25 [27.8%] FGFR2/3-altered and 65 [72.2%] FGFR2/3-wild-type) were identified. FGFR2/3-altered iCCAs encompassed FGFR2 fusions (BICC1, AHCYL1, CREB5, NOL4, NRAP, PAH, POC1B, SH3GLB1, BAIAP2L1, FKBP15, LRRFIP2, and TNS3), FGFR3::TACC3 fusion, and FGFR2 mutations (C382R and Y375C). FGFR2/3-altered iCCA patients were significantly younger (median = 61.0 vs. 68.0 years; p = 0.014), with larger (median = 9.6 vs. 6.4 cm; p = 0.002), well-differentiated (24.0% vs. 1.5%; p < 0.001), non-mucin-producing (84.0% vs. 3.1%; p < 0.001), and small duct tumors (100% vs. 32.3%; p < 0.001), harboring higher BAP1 (36.0% vs. 12.3%; p = 0.016), lower TP53 mutations (4.0% vs. 26.2%; p = 0.019), and ARID1A/KRAS wild-type (0.0% and 0.0% vs. 20% and 13.8%; p = 0.016 and 0.058). FGFR2/3-wild-type iCCAs were TP53/KRAS-enriched and harbored rare fusions (ST7::MET, NRG1::RBPMS, and RAB3GAP2::BRAF). FGFR2/3-altered iCCA patients had significantly higher 1-, 2-, and 3-year DSS (95.8%, 79.1%, and 79.1% vs. 68.4%, 48.2%, and 43.8%; univariate analysis: HR 0.29; 95% CI 0.09-0.95; p = 0.041) but not on multivariate analysis (HR 2.52; 95% CI 0.14-45.07; p = 0.530). In small duct iCCAs, FGFR2/3-altered iCCAs maintained significantly higher DSS versus their wild-type counterparts (95.8%, 79.1%, and 79.1% vs. 60.5%, 32.3%, and 32.3%; HR 0.24; 95% CI 0.06-0.90; p = 0.022), indicating improved survival is attributed to factors beyond small duct subtype. Independent prognostic factors included tumor multifocality (lower MFS), CEA > 2.5 ng/mL (lower PFS), TP53 mutation (lower OS), KRAS mutation (lower OS and DSS), radiotherapy (higher OS), and surgical resection (higher OS, MFS, and DSS). FGFR2/3-altered iCCAs represent a distinct subtype associated with improved DSS, driven by inherent clinicopathologic and co-molecular characteristics rather than FGFR2/3 alteration status alone. Genomic profiling expands the molecular landscape of iCCAs, refines prognostication, and informs patient selection for targeted therapy.