Nerve Fibers in the Tumor Microenvironment as a Novel Biomarker for Oncological Outcome in Patients Undergoing Surgery for Perihilar Cholangiocarcinoma

Jan Bednarsch; Jakob Kather; Xiuxiang Tan; Shivan Sivakumar; Claudio Cacchi; Georg Wiltberger; Zoltan Czigany; Florian Ulmer; Ulf Peter Neumann; Lara Rosaline Heij

doi:10.1159/000515303

Nerve Fibers in the Tumor Microenvironment as a Novel Biomarker for Oncological Outcome in Patients Undergoing Surgery for Perihilar Cholangiocarcinoma

Liver Cancer. 2021 Jun;10(3):260-274. doi: 10.1159/000515303. Epub 2021 May 6.

Authors

Jan Bednarsch¹, Jakob Kather², Xiuxiang Tan^{1

3

4}, Shivan Sivakumar^{5

6}, Claudio Cacchi⁷, Georg Wiltberger¹, Zoltan Czigany¹, Florian Ulmer¹, Ulf Peter Neumann^{1

3}, Lara Rosaline Heij^{1

4

7}

Affiliations

¹ Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany.
² Division of Gastroenterology and Hepatology, Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
³ Department of Surgery, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands.
⁴ NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.
⁵ Department of Oncology, University of Oxford, Oxford, United Kingdom.
⁶ Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom.
⁷ Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany.

Abstract

Introduction: Perihilar cholangiocarcinoma (pCCA) is a biliary tract cancer with a dismal prognosis, with surgery being the only chance of cure. A characteristic aggressive biological feature of pCCA is perineural growth which is defined by the invasion of cancer cells to nerves and nerve fibers. Recently, nerve fiber density (NFD) was linked to oncological outcomes in various malignancies; however, its prognostic role in pCCA remains to be elucidated.

Materials and methods: Data of 101 pCCA patients who underwent curative-intent surgery between 2010 and 2019 were included in this study. Extensive group comparisons between patients with high and low NFD were carried out, and the association of cancer-specific survival (CSS) and recurrence-free survival with NFD and other clinicopathological characteristics was assessed using univariate and multivariable cox regression models.

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 with 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).

Conclusion: NFD has been identified as an important novel prognostic biomarker in pCCA patients. NFD alone and in combination with nodal status in particular allows to stratify pCCA patients based on their risk for inferior oncological outcomes after curative-intent surgery.

Keywords: Biomarker; Cholangiocarcinoma; Nerve fiber density; Oncological outcome.