Modified nodal staging for intrahepatic cholangiocarcinoma invading hilum and perihilar cholangiocarcinoma

Background: Intrahepatic cholangiocarcinoma (iCCA) encompasses a heterogenous group of malignancies. Hilar type iCCA (h-iCCA) may represent a distinct subtype characterized by invasion of the hepatic hilum. We sought to investigate the clinicopathological characteristics of h-iCCA with a focus on the prognostic impact of nodal status relative to peripheral iCCA and perihilar cholangiocarcinoma (pCCA). Methods: Patients with iCCA and pCCA undergoing curative-intent resection were identified from an international multi-institutional database. Prognostic impact of different lymph node metastasis (LNM) count in each subtype of iCCA and pCCA were examined, and a modified N category was proposed. Results: Among 1240 patients with iCCA, 291 (23.5%) had tumors with hilar invasion; h-iCCA was associated with more aggressive clinicopathological characteristics and worse prognosis. Patients with h-iCCA were more likely to undergo lymphadenectomy and had an increased likelihood of LNM. Among h-iCCA, patients with 1-2 LNM had worse OS versus individuals without nodal metastasis (median OS: 24.0 vs. 53.9 months; p < 0.001), yet better OS compared with individuals with ≥ 3 LNM (median OS: 24.0 vs. 15.0 months; p = 0.039). In contrast, patients with peripheral iCCA with 1-2 LNM and ≥ 3 LNM had comparable OS (median OS: 29.0 vs. 26.5 months, p = 0.472). Patients with h-iCCA and pCCA with no nodal metastasis, 1-2 LNM, and≥ 3 LNM had incrementally worse OS. h-iCCA demonstrated a divergent genomic landscape compared with peripheral iCCA, with a higher frequency of KRAS and TP53 mutations yet lower incidence of IDH mutation; genomic alterations were largely concordant between h-iCCA versus pCCA. Conclusions: iCCA with hilar invasion represented a distinct subgroup of CCA characterized by aggressive behavior and poor survival that had clinical and genetic features more consistent with pCCA than peripheral iCCA. A modified N category is proposed for h-iCCA and pCCA: mN0 (no nodal metastasis), mN1 (1-2 LNM), and mN2 (≥3 LNM), which provided better discrimination for patient prognosis.