Parasympathetic Nerve Fibers in the Tumor Microenvironment as a Novel Biomarker Predicting Oncological Outcome in Perihilar Cholangiocarcinoma

Abstract

Introduction: Perineural growth defined by the invasion of cancers cells to nerves and nerve fibers is a characteristic biological feature in perihilar cholangiocarcinoma (pCCA). Recently, nerve fiber density (NFD) was linked to oncological outcomes in various malignancies, however, its prognostic role in pCCA remains to be elucidated. Method: Data of 101 pCCA patients who underwent curative intent surgery between 2010 and 2019 were included in this study. Extensive group comparisons and univariate and multivariable cox regression models were carried out to determine the association of cancer-specific survival (CSS), recurrence-free survival (RFS) with NFD and other clinico-pathological characteristics. Results: Patients with high NFD showed a median CSS of 90 months (95% CI: 48-132, 3-year-CSS=77%, 5-year-CSS=72%) compared to 33 months (95% CI: 19-47, 3-year-CSS=46%, 5-year-CSS=32%) in patients with low NFD (p=0.006 log rank). Further, N1 category (HR=2.84, p=0.001) and high NFD (HR=0.41, p=0.024) were identified as independent predictors of CSS in multivariable analysis. Patients with high NFD and negative lymph nodes, showed a median CSS of 90 months (3-year-CSS=88%, 5-year-CSS=80%), while patients either positive lymph nodes or low NFD displayed a median CSS of 51 months (3-year-CSS=59%, 5-year-CSS=45%) and patients with both positive lymph nodes and low NFD a median CSS of 24 months (3-year-CSS=26%, 5-year-CSS=16%, p=0.001 log rank). Conclusions: This study identifies NFD as an important novel prognostic biomarker in pCCA patients. NFD alone and in combination with nodal status in particular, allow to stratify patients based on their oncological risk after curative-intent surgery.