Lymphangiogenesis in Regional Lymph Nodes Is an Independent Prognostic Marker in Rectal Cancer Patients after Neoadjuvant Treatment

Abstract

One of the major prognostic factors in rectal cancer is lymph node metastasis. The formation of lymph node metastases is dependent on the existence of a premetastatic niche. An important factor preceding metastasis are lymph vessels which are located in the lymph node. Accordingly, the occurrence of intranodal lymphangiogenesis is thought to indicate distant metastasis and worse prognosis. To evaluate the significance of lymph node lymphangiogenesis, we studied formalin fixed, paraffin embedded adenocarcinomas and regional lymph nodes of 203 rectal cancer patients who were treated with neoadjuvant radiochemotherapy and consecutive curative surgery with cancer free surgical margins (R0). Regional lymph node lymph vessels were detected by immunohistochemistry for podoplanin (D2-40). Our results show that the presence of lymphatic vessels in regional lymph nodes significantly affects the disease-free survival in univariate and multivariate analyses. In contrast, there was no correlation between peritumoral or intratumoral lymph vessel density and prognosis. Indeed, our study demonstrates the importance of lymphangiogenesis in regional lymph nodes after neoadjuvant radiochemotherapy and consecutive surgery as an independent prognostic marker. Staining for intranodal lymphangiogenesis and methods of intravital imaging of lymphangiogenesis and lymphatic flow may be a useful strategy to predict long-term outcome in rectal cancer patients. Furthermore, addition of VEGF-blocking agents to standardized neoadjuvant treatment schemes might be indicated in advanced rectal cancer.

Increased Angiogenesis and Lymphangiogenesis in Metastatic Sentinel Lymph Nodes Is Associated With Nonsentinel Lymph Node Involvement and Distant Metastasis in Patients With Melanoma

“…11 In human samples, the biological and prognostic role of SLN lymphangiogenesis was investigated in breast 14,21 and rectal cancers. 25 The induction of lymphangiogenesis in metastatic SLN was also documented in patients with melanoma; 15 however, to the best of our knowledge, this is the first study evaluating the prognostic significance of this process in patients with melanoma. Our observation about the association between increased intratumoral SLN blood vessel proliferation rate and the presence of distant metastasis in patients with melanoma, might be of interest in terms of tumor biology of lymph node metastasis and further progression of melanoma disease, because SLN angiogenesis could represent a connecting element between lymphatic and hematogeneous systems, facilitating melanoma cells dissemination.…”

Metastatic and non-metastatic sentinel inguinofemoral lymph nodes in vulvar cancer show an increased lymphangiogenesis

“…The findings of Ishii et al suggest that, in oral squamous cell carcinoma, the primary tumour actively induces lymphangiogenesis in SLNs prior to the onset of metastases, and that tumour-derived VEGF-C is important in this process [24]. Lymphangiogenesis in the regional lymph nodes is an independent prognostic marker in rectal cancer patients after neoadjuvant chemotherapy, as determined by Jacob et al [25]. Increased SLN metastasis and lymphangiogenesis is associated with metastatic involvement of non-sentinel axillary lymph nodes in breast cancer [26].…”

Immunology of the Lymphatic System

“…One of the primary reasons a tumor might want to communicate with distant tissues is in order to prepare the new environment for metastasizing cells, otherwise known as the pre-metastatic niche (reviewed by Peinado et al 2011 ;Psaila and Lyden 2009 ). Changes to lymph nodes immediately downstream of tumor-bearing sites prior to arrival of metastasizing cells have frequently been recorded in experimental models (Harrell et al 2007 ;Hirakawa et al 2005Hirakawa et al , 2007Mumprecht et al 2010 ;Ruddell et al 2008 ), and similar changes in clinical samples are showing prognostic potential (Kurahara et al 2010 ;Jakob et al 2011 ). In mouse models of lymph node metastasis, tumor-draining lymph nodes present with greatly enlarged and supernumerary lymphatic sinuses before metastasis occurs, whereas lymph node metastases are not observed in the absence of LN lymphatic expansion (Hirakawa et al 2007 ).…”