The protean nature of the central nervous system tumors in NF2, incomplete understanding of their natural history, and undefined mechanism of symptom formation have resulted in treatment only of patients with neurologic deficits. Based on this treatment paradigm, tumors at the time of treatment are typically large and have produced irreversible neurologic deficit. Surgical removal of large tumors often causes addition deficits. Better knowledge of NF2 natural history and tumor growth patterns could improve surgical timing and outcomes. We started a natural history study of NF2 patients 9 years ago, to gain clinical and molecular insights into the effects of the type (missense, nonsense, deletion) of NF2 gene mutation on tumor development/progression and to identify features associated with symptom evolution in patients with NF2-associated tumors. This prospective natural history study should find factors that influence tumor biology, symptom formation, and treatment outcome. The natural history study of NF2 enrolled 169 subjects. So far, 104 subjects have competed the 5-year study. The final subjects will complete the study by November 20, 2018. Previous work in the study showed that elevated intralabyrinthine protein and larger tumor size by MRI-scanning correlated with hearing loss. The saltatory growth pattern, in which the tumor periodically grows, was more often seen (59%), than linear (30%) or exponential growth (11%). Because tumor growth and symptom production are unpredictable and new tumors develop in NF2 patients over their lifetime, we have not discovered a better method for timing of tumor resection than the present practice of resecting only symptom-producing tumors. This year our study of NF2 resulted in 2 published manuscripts. The first publication reported the first comprehensive whole exome sequencing study of NF2-related meningiomas. Sequencing of 2 adjacent intracranial meningiomas removed from the same patient showed that the second copy of the NF2 gene was inactivated in both tumors. The faster growing tumor, a Grade II meningioma, had a higher level of genomic instability than the slower-growing, Grade I meningioma. The second manuscript examined the histological findings of 43 surgically-removed peripheral nerve tumors from patients in the NF2 natural history study. Eleven benign nerve sheath tumors (26%) showed hybrid features of both neurofibroma and schwannoma. Immunohistochemical studies showed the schwannoma component to be S100+, CD 34- while the neurofibroma component was CD34+, variable S100+. Our findings show that the schwannoma/neurofibroma hybrid tumor should be included in the differential diagnosis of nerve sheath tumors in NF2 patients and that the relationship between neurofibroma and schwannoma appears to be closer than previously thought.
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