Liver metastases of intrahepatic cholangiocarcinoma: implications for a potential new staging system

Abstract

Background: Intrahepatic cholangiocarcinoma (iCCA) with liver metastases (LM) are perceived to have a poor prognosis but the American Joint Committee on Cancer (AJCC) classifies them as early stage in the absence of lymph nodes or extrahepatic spread. Methods: Patients with iCCA from the European Network for the Study of Cholangiocarcinoma (ENS-CCA) and Surveillance, Epidemiology, and End Results (SEER) registries with survival/staging (AJCCv.7) data were eligible. Modified staging was used (mAJCCv.7): Group-A: stages-I-III (excluding T2bN0); Group-B: stage-IVa (excluding T2bN1M0); Group-C: LM (T2bN0/1) and Group-D: stage-IVb (extra-hepatic metastases). Survival analysis (Kaplan Meier and Cox Regression) was performed in an ENS-CCA training cohort (TC) and findings internally [ENS-CCA (iVC)] and externally [SEER] validated. The aim was to assess if LM (Group-C) had a shorter survival compared to other early stages (Group-A). A modified version of AJCCv.8 (mAJCCv.8) is proposed. Results: Total of 574 and 4,171 patients from the ENS-CCA and SEER registries were included. Following the new classification, 19.86% and 17.31% of patients from the ENS-CCA and SEER registries were reclassified into the Group-C, respectively. In the ENS-CCA TC, multivariable Cox Regression was adjusted for obesity (p-value 0.026) and performance status (p-value <0.001); patients in Group-C (HR 2.53 (95%CI 1.18-5.42); p-value 0.017) had a higher risk of death (vs Group-A). Findings were validated in the ENS-CCA iVC (HR 2.93 (95%CI 2.04-4.19); p-value <0.001) and in the SEER registry (HR of 1.88 (95%CI 1.68-2.09); p-value <0.001). Conclusions: iCCA LM have a worse outcome than other early stages. As AJCCv.8 does not take this into consideration, a modification of AJCC v.8 (mAJCCv.8) including "liver metastases: multiple liver lesions, with or without vascular invasion" as a novel "M1a stage" is suggested.