| Summary: | Neurofibromatosis 1 (NF1) is an autosomal dominant disease. Neurofibromas, benign tumours that develop from peripheral nerves, are a hallmark feature of NF1. Malignant peripheral nerve sheath tumours (MPNSTs) are one of the leading causes of death in people with NF1. Clinical evidence suggests that most MPNSTs develop from pre-existing plexiform neurofibromas. Most studies treat all NF1-associated neurofibromas as a single entity, ignoring important differences between pathological details, clinical presentation and natural history. I analysed clinical information on 476 probands with NF1 from the Henri Mondor database and found that individuals with subcutaneous neurofibromas were 3 times more likely to have internal plexiform neurofibromas and that individuals with internal plexiform neurofibromas were 20 times more likely to have MPNSTs than individuals without such tumours. These findings suggest that pathogenic differences in some neurofibromas may lead to different risks of progressing to malignancy. I collected formalin-fixed paraffin-embedded samples from NF1 patients and classified them histologically as nodular or diffuse neurofibromas. By using histochemistry, I found that mast cells were absent in MPNSTs and significantly more abundant in diffuse neurofibromas than in nodular neurofibromas. Mast cells were located at the periphery of nodular neurofibromas but were evenly distributed throughout diffuse neurofibromas. Double immunofluorescent staining of S100 (a marker of Schwann cells, the presumed tumour progenitor cell type) and neurofibromin (the protein product of NF1 gene) (Nf) showed that diffuse neurofibromas had significantly more S100+/Nf+ cells and fewer S100-/Nf- cells than nodular neurofibromas. Using laser microdissection of immunofluorescently stained slides, I found that some neurofibromas show evidence of clonal (presumably neoplastic) proliferation of S100+/Nf- cells while other neurofibromas appear to be neurofibromin haploinsufficient and polyclonal, and thus may be hyperplastic rather than neoplastic lesions. The results presented in this thesis support the hypothesis that neurofibromas in people with NF1 are pathogenically heterogeneous and that some kinds of neurofibromas are associated with the development of MPNSTs. These findings have important implications for the surveillance and treatment of people with NF1. === Medicine, Faculty of === Medical Genetics, Department of === Graduate
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