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We investigated the expression of SOX9, a transcription factor linked to the hedgehog pathways, and desert hedgehog, previously shown to be expressed in a malignant peripheral nerve sheath tumor cell line, in neurofibromatosis 1 tumors (neurofibromas and malignant peripheral nerve sheath tumor), and in a group of sporadic spindle cell sarcomas. We found that SOX9 was expressed in Schwann cells from neurofibromatosis 1 tumors, and was significantly up-regulated in malignant peripheral nerve sheath tumor versus neurofibromas at the protein level (P<.0001) and in malignant peripheral nerve sheath tumor and plexiform neurofibroma as compared to diffuse tumors at the mRNA level (P = .002 and P = .009, respectively). SOX9, however, was not a specific feature of malignant peripheral nerve sheath tumor because a significant proportion of spindle cell sarcomas unrelated to neurofibromatosis 1 were also positive. Interestingly, within neurofibromas, SOX9 expression correlated to the histology mostly found in plexiform areas, whereas it was negative or weak in diffuse neurofibroma (P < .0001). In sporadic sarcomas, the proportion of positive cells was actually heterogeneous among cases. Desert hedgehog expression was mostly found in sarcomas (P = .0002), but diffuse staining was only seen in non neurofibromatosis I tumors, whereas malignant peripheral nerve sheath tumor displayed only focal expression. Finally, we found no significant correlation between the expression of SOX9 and desert hedgehog, and neither SOX9 nor desert hedgehog expression was correlated to the histoprognostic grade in sarcomas. Altogether, these results indicate that, although not a specific feature of neurofibromatosis I tumors, SOX9 may play a role in the development of malignant peripheral nerve sheath tumor in patients with neurofibromatosis I and does not appear to be linked to autocrine stimulation by the desert hedgehog signaling pathway. (C) 2011 Elsevier Inc. All rights reserved.