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

Jan Bednarsch,Dong Liu,Mika Rosin,Simone Appinger,Lara Rosaline Heij,Mariëlle Coolsen,Marcel Den Dulk,Xiuxiang Tan,Zoltan Czigany,Nadine Therese Gaisa,Shiva Boroojerdi,Jakob Nikolas Kather,Ulf Peter Neumann,Sven Arke Lang,Edgar Dahl,Shivan Sivakumar,Tom Florian Ulmer

doi:10.3390/cancers13153661

Jan Bednarsch, Dong Liu + Show 15 more

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https://doi.org/10.3390/cancers13153661

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Abstract

Simple SummaryNerve 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.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.

Highlights

Based on the anatomical localization of the primary tumor, cholangiocellular carcinomas (CCA) can be devided into intrahepatic CCA, perihilar CCA and distal CCA [1]
The patient cohort consisted of 55 women (57%) and 41 men (43%) with a median age of 65 years and the majority being assessed as ASA (American Society of Anesthesiologists classification) III or higher (53%, 51/96)
The identification of novel prognosticmarkers may provide insight into the underlying tumor biology of the disease and has the potential to further improve individualized medical management of these complex patients [15]. In this translational retrospective study, we identified nerve fibers (NFs) as a powerful novel prognostic biomarker for longterm oncological outcome in intrahepatic cholangiocarcinoma (iCCA) patients

Summary

Introduction

Based on the anatomical localization of the primary tumor, cholangiocellular carcinomas (CCA) can be devided into intrahepatic CCA (iCCA), perihilar CCA (pCCA) and distal CCA (dCCA) [1]. Even though iCCA is the least common subtype of CCA, it still comprises about 15% of all primary liver tumors [2]. In some cases, the etiology of CCA remains unclear, cholestatic conditions and diseases associated with chronic inflammation are considered to be the major traditional risk factors in the oncogenesis of CCA [5]. In iCCA patients in particular, etiological factors such as parenchymal disease related to hepatic cirrhosis, viral hepatis or chronic alcohol consumption may play a pronounced role, illustrating distinct differences compared to the extrahepatic subtypes of CCA [5]. Irrespective of the CCA subentity, radical surgery with lymphadenectomy followed by adjuvant chemotherapy is considered as the current gold-standard approach as it provides improved long-term outcomes in comparison to merely medical or interventional treatment [6,7,8]

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