The Presence of Small Nerve Fibers in the Tumor Microenvironment as Predictive Biomarker of Oncological Outcome Following Partial Hepatectomy for Intrahepatic Cholangiocarcinoma

SIMPLE SUMMARY: Nerve fibers in the microenvironment of malignant tumors have been shown to be an important prognostic factor for long-term survival in various cancer types; however, their role in intrahepatic cholangiocarcinoma remains to be determined. Therefore, the impact of nerve fibers on long-term survival was investigated in a large European cohort of patients with intrahepatic cholangiocarcinoma who were treated by curative-intent surgical resection. By univariate and multivariate statistics, the absence of nerve fibers was determined to be an independent predictor of impaired long-term survival. A group comparison between patients with and without nerve fibers showed a statically significant difference with a cancer-specific 5-year-survival of 47% in patients with nerve fibers compared to 21% in patients without nerve fibers. Thus, the presence of nerve fibers in the microenvironment of intrahepatic cholangiocarcinoma is revealed as a novel and important prognostic biomarker in these patients. ABSTRACT: The oncological role of the density of nerve fibers (NFs) in the tumor microenvironment (TME) in intrahepatic cholangiocarcinoma (iCCA) remains to be determined. Therefore, data of 95 iCCA patients who underwent hepatectomy between 2010 and 2019 was analyzed regarding NFs and long-term outcome. Extensive group comparisons were carried out and the association of cancer-specific survival (CSS) and recurrence-free survival (RFS) with NFs were assessed using Cox regression models. Patients with iCCA and NFs showed a median CSS of 51 months (5-year-CSS = 47%) compared to 27 months (5-year-CSS = 21%) in patients without NFs (p = 0.043 log rank). Further, NFs (hazard ratio (HR) = 0.39, p = 0.002) and N-category (HR = 2.36, p = 0.010) were identified as independent predictors of CSS. Patients with NFs and without nodal metastases displayed a mean CSS of 89 months (5-year-CSS = 62%), while patients without NFs or with nodal metastases but not both showed a median CCS of 27 months (5-year-CSS = 25%) and patients with both positive lymph nodes and without NFs showed a median CCS of 10 months (5-year-CSS = 0%, p = 0.001 log rank). NFs in the TME are, therefore, a novel and important prognostic biomarker in iCCA patients. NFs alone and in combination with nodal status is suitable to identify iCCA patients at risk of poor oncological outcomes following curative-intent surgery.