Blurring the Anatomical Lines in Extrahepatic Cholangiocarcinoma: An Integrated Clinic-Oncological and Exploratory Proteomic Comparison of Perihilar and Distal Tumors.

Abstract

Extrahepatic cholangiocarcinoma (eCCA) includes perihilar cholangiocarcinoma (pCCA) and distal cholangiocarcinoma (dCCA), classified on the basis of tumor location. However, the oncological and molecular characteristics of these subtypes remain uncertain. We compared their oncological outcomes and investigated potential proteomic differences based on tumor location. A single-center retrospective study was conducted on 204 patients who underwent surgical resection for eCCA between 2007 and 2023. Clinicopathological data were collected, and overall survival (OS) and disease-free survival (DFS) were compared. Prognostic factors were identified using multivariate analyses with a stepwise Cox proportional hazards model. For molecular analysis, 60 proteomic assays were performed in triplicate using 20 resected eCCA samples. No significant differences were observed between pCCA (n = 113) and dCCA (n = 91) in terms of severe morbidity or postoperative mortality. Patients with dCCA had a higher R0 resection rate compared with those with pCCA (79.1% versus 48.7%, p < 0.001). Furthermore, lymph node positivity was more frequent in dCCA (61.5% versus 29.2%, p < 0.001), whereas microvascular and perineural invasion were more prevalent in pCCA. Despite these clinicopathological differences, no significant differences were observed in 5-year OS (43.1% versus 48.3%, p = 0.57) or 5-year DFS (37.6% versus 32.8%, p = 0.46). Tumor location was not identified as an independent prognostic factor. Proteomic analysis identified 686 proteins with significantly differential expression between the two subtypes. However, principal component analysis failed to clearly separate pCCA and dCCA samples. Our study reinforces the view that pCCA and dCCA, despite clinicopathological variations, exhibit comparable long-term oncological outcomes. Tumor location was not identified as an independent prognostic factor, emphasizing the need for an integrated approach in future studies of targeted therapies for eCCA.