Expression of lymphangiogenic factors and evidence of intratumoral lymphangiogenesis in pancreatic endocrine tumors

Bence Sipos, Wolfram Klapper, Marie Luise Kruse, Holger Kalthoff, Dontscho Kerjaschki, Günter Klöppel

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68 Scopus citations


Lymphangiogenesis is thought to promote the progression of malignant tumors. Because the lymphangiogenic factors vascular endothelial factor (VEGF)-C and -D are expressed in endocrine cells, we investigated their expression in pancreatic endocrine tumors (PETs) and correlated these data and intratumoral lymph vessel density (iLVD) with clinicopathological features. Lymph vessels were identified with anti-podoplanin antiserum and with podoplanin/proliferating cell nuclear antigen double labeling. PETs (n = 104) were investigated by immunohistochemical staining for VEGF, basic fibroblast growth factor, and VEGF-C expression. VEGF-C and VEGF-D mRNA were quantified by real-time reverse transcriptase-polymerase chain reaction. PETs showed higher iLVD than normal pancreata, bet iLVD did not discriminate between benign and malignant PETs. In PETs proliferating lymph vessels were identified. High DLVD was associated with lymph vessel invasion and it was more frequent in angioinvasive/metastatic tumors than in grossly invasive tumors. VEGF-C expression correlated with iLVD as well as with glucagon and pancreatic polypeptide expression. PETs show intratumoral lymphangiogenesis, which is associated with VEGF-C expression in tumor cells. The association between iLVD and lymph vessel invasion and angioinvasive/metastatic features in PETs suggests that lymphangiogenesis may promote malignant progression of PETs. PET is the first human tumor entity in which VEGF-C-related intratumoral lympliangiogenesis has been demonstrated.

Original languageEnglish
Pages (from-to)1187-1197
Number of pages11
JournalAmerican Journal of Pathology
Issue number4
StatePublished - Oct 2004
Externally publishedYes


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