Lymphatic Vessel Density and Vascular Endothelial Growth Factor-C Expression Correlate with Malignant Behavior in Human Pancreatic Endocrine Tumors

Abstract

Metastatic dissemination of tumor cells to regional lymph nodes is a common early feature of many human cancers including pancreatic adenocarcinoma. In contrast, lymph node metastasis is more variably observed in pancreatic endocrine tumors. The objective of this study was to assess the lymphatic system of human pancreatic endocrine tumors and correlate this to clinical behavior. Immunohistochemistry was performed using antibodies to two recently identified markers of lymphatic endothelium, namely, LYVE-1 and podoplanin, and to the lymphangiogenic factor vascular endothelial growth factor (VEGF)-C. As has been reported previously, we observed that in the normal pancreas, islets of Langerhans are devoid of intra-islet lymphatics, but that lymphatics are present in connective tissue in association with ducts and blood vessels. We found that both benign and malignant pancreatic endocrine tumors contain intratumoral lymphatic vessels. Lymphatic vessel density was related to the size of the tumor in benign tumors and to the presence of liver metastasis but not to lymph node metastasis in malignant tumors. VEGF-C was expressed in tumor cells: 4 of 19 (21%) benign tumors were positive, whereas 6 of 9 (67%) borderline tumors and 9 of 11 (82%) carcinomas were positive. These findings strongly suggest that lymphangiogenesis occurs in pancreatic endocrine tumors and that lymphatic invasion and the development of metastases are associated with VEGF-C expression.

Fluorescent LYVE-1 Antibody to Image Dynamically Lymphatic Trafficking of Cancer Cells In Vivo

“…In some cases tumor cells appear to influence the host lymphatic architecture, possibly paving the way for their own metastasis [18], although this influence varies with different tumor types. [19][20][21] These findings underscore the importance of a thorough understanding of the interaction of host lymphatic tissue with invading cancer cells. A clear comprehension of the in vivo realtime interactions of tumor cells with their surrounding environment, including the host lymphatic system, would greatly contribute to our ability to understand tumor invasion and metastasis.…”

Lateral peritumoral lymphatic vessel invasion can predict lymph node metastasis in esophageal squamous cell carcinoma

“…14,15 Indeed, several reports have shown that increased peritumoral lymphatic vessel density is positively associated with lymph node metastasis and malignant aggressiveness in patients with head and neck squamous cell carcinoma, melanoma and cervical and pancreas cancer. 5,[7][8][9] However, contrary to these results, several other investigators reported that increased peritumoral lymphangiogenesis is associated with favorable biological behavior and good survival. 16,17 Likewise, there exists a diversity of opinions as to the clinical significance of lymphangiogenesis.…”

“…[3][4][5][6] Lymphangiogenesis detected by antibodies specific for lymphatic endothelial cells has been associated with regional lymph node metastasis and a poor prognosis in head and neck squamous cell carcinoma, melanoma and cervical and pancreas cancer; however, recent studies on breast and prostate cancer seem to contradict this finding. 5,[7][8][9][10][11] The object of our study was to confirm the occurrence of lymphangiogenesis in esophageal squamous cell carcinoma by comparing the lymphatic vessel density in intratumoral, peritumoral and normal compartment; to verify the correlation of lymphatic vessel density and other pathological parameters; and to assess whether nodal metastasis is dependent on tumor-induced lymphangiogenesis or invasion of pre-existing lymphatic vessels.…”

First international consensus on the methodology of lymphangiogenesis quantification in solid human tumours

“…head and neck squamous cell carcinoma (Beasley et al, 2002;Maula et al, 2003), cutaneous melanoma (Dadras et al, 2003;Straume et al, 2003) and carcinomas of the thyroid (Hall et al, 2003), lung (Koukourakis et al, 2005), pancreas (Von Marschall et al, 2005), breast (Williams et al, 2003;Bono et al, 2004), cervix (Van Trappen et al, 2003) and prostate (Trojan et al, 2004)), as well as normal tissues in both adult and foetus. Nevertheless, the observation that expression of LYVE-1 can be downmodulated in some tissues, for example, in response to inflammation (Johnson L and Jackson DG, unpublished), and is absent in some tumour-associated lymphatics (Rubbia-Brandt et al, 2004;Stessels et al, 2004;Van der Auwera et al, 2004) underlines the importance of utilising multiple markers (e.g. LYVE-1/podoplanin, LYVE-1/Prox-1, etc.)…”