Tumor-associated Lymphangiogenesis Correlates with Lymph Node Metastases and Prognosis in Hilar Cholangiocarcinoma

Background: Tumor-associated lymphangiogenesis has been shown to promote nodal spread and is of prognostic significance in some tumor entities. Currently, nothing is known about the impact of lymphangiogenesis on progression and prognosis in hilar cholangiocarcinoma.

Methods: We analyzed tissue specimens of normal liver and hilar cholangiocarcinoma (n = 60) by immunohistochemistry using the lymphendothelial-specific antibody D2-40 and subsequently quantified lymphatic microvessel density (LVD). The LVD was correlated with clinicopathological characteristics and recurrence pattern of the tumors as well as patients' survival.

Results: In contrast to the low abundance of lymphatic vessels in nontransformed liver tissue, we found an induction of lymphangiogenesis in hilar cholangiocarcinoma. Tumors with a high LVD (34 out of 60) had a significant higher incidence of lymph node involvement (p < 0.001), perivascular (p = 0.017), and perineural (p = 0.033) lymphangiosis and local recurrence (p < 0.001). Furthermore, a high LVD was identified to be a significant overall (three-year: 24.4% versus 90.5%; five-year: 7.0% versus 76.4%; p < 0.001) and disease-free (three-year: 8.3% versus 76.6%; five-year: 5.9% versus 61.4%; p < 0.001) survival disadvantage, with LVD representing an independent prognostic factor for survival (p < 0.001) in the multivariate analysis.

Conclusions: Lymphangiogenesis is associated with increased frequency of tumor cells in lymphatics and lymph nodes in hilar cholangiocarcinoma. The prognostic importance of tumor-associated lymphangiogenesis was reflected by LVD serving as an independent prognostic factor. In addition, lymphangiogenesis may represent a potential target in the development of new therapeutic approaches in hilar cholangiocarcinoma.