The Role of Angiogenesis in the Transformation of Plexiform Neurofibroma into Malignant Peripheral Nerve Sheath Tumors in Children With Neurofibromatosis Type 1

Purpose: The role of angiogenesis in the transformation of peripheral neurofibroma (PNF) to malignant peripheral nerve sheath tumor (MPNST) in neurofibromatosis type 1 (NF1) remains elusive and forms the objective of this study. Experimental Design: Archival tissue from 5 children with NF1 and PNF, who developed MPNST between the ages of 8 and 15 years were analyzed for differences in microvasculature. The role of proangiogenic growth factors such as Vascular Endothelial Growth Factor (VEGF), and its receptors Flk-1 and Flt-1, and vessel maturity, defined as von Willebrand factor (vWf), alpha-smooth muscle actin(+) (SMA(+)), were evaluated by immuno-histochemistry. Results: A qualitative evaluation of the vasculature showed predominantly alpha-SMA+/vWf+ more stable vessels in PNF, and an irregular meshwork of alpha-SMA-/vWf+ endothelial cells structures in MPNST. In NF and PNF tumor cells were VEGF(-), in contrast to VEGF(+) tumor cells in MPNST. If present, the VEGF stain was confined mainly to the perivascular spaces in PNF, unlike the mainly stromal VEGF stain in MPNST. VEGF receptors also manifested a tumor stage-specific pattern. Flk-1 and Flt-1 were restricted to the mature, well-formed vasculature in PNF, but exhibited a diffuse pattern in MPNST. Conclusion: Our study provides a rare opportunity to document consistent and histologically detectable differences in the vascular organization of PNF and MPNST. It permits a pair-wise evaluation of the malignant conversion of benign PNF into its malignant counterpart, in the same patients. The phenotypic variations and characteristics of the vessels in these tumors are consistent with the idea that a strong proangiogenic drive contributes to the progressive growth in MPNST.