Abstract
PURPOSE: The impact of first recurrence site on outcome after resection of intrahepatic cholangiocarcinoma (IHC) is ill-defined, as are the genomic underpinnings of recurrence and outcomes. METHODS: Resected patients with IHC at two institutions with genomic data were included. Sites of first recurrence (SOFR) were classified as liver only (LO), extrahepatic (EH) only, or simultaneous liver and extrahepatic (SIM). Overall survival (OS) was calculated from the time of recurrence. RESULTS: Between 1993 and 2021, 318 patients met inclusion criteria; 232 (73%) recurred. SOFR were LO = 93 (40%), EH = 80 (34%), and SIM = 59 (26%). Median OS from recurrence was similar in the LO (33 [26, 42] months) and EH groups (33 [23, 46] months) but much lower in SIM (12 [9.8, 18] months; P < .001). Moderate/poor tumor differentiation, lymphovascular invasion, N1 disease, perineural invasion, and time to recurrence (all P < .05) were associated with SIM; only positive resection margin predicted LO (P = .007). No individual genomic or pathway alterations predicted SOFR; however, for all recurrers, TP53mut (n = 51, 22%; hazard ratio [HR], 2.0 [1.4 to 2.9]; P = .002), CDKN2Adel (n = 34, 15%; HR, 3.4 [95% CI, 2.2 to 5.3]; P < .001), CDKN2B (n = 25, 11%; HR, 3.2 [95% CI, 2.0 to 5.0]; P < .001), and KRASmut (n = 25, 11%; HR, 2.5 [95% CI, 1.6 to 4.0]; P = .002) were associated with worse OS. On multivariable analysis, SIM (HR, 2.5 [95% CI, 1.7 to 3.5]; P < .001), N1 status (HR, 1.8 [95% CI, 1.2 to 2.6]; P = .004), and alterations in the high-risk genotype (TP53mut, CDKN2Adel or KRASmut; n = 84, 36%; HR, 2.4 [95% CI, 1.7 to 3.3]; P < .001) were independent predictors of poor OS. CONCLUSION: Recurrence after resection of IHC is common, and the liver was the most common site (66%). Clinicopathologic and genomic factors had limited ability to predict SOFR. Although LO and EH were associated with similar OS, SIM recurrences had dramatically worse OS. Adjuvant strategies targeting liver recurrence may improve outcomes after resection of IHC.