Ramita Dewan1, Alex Pemov1, H Jeffrey Kim1, Keaton L Morgan1, Raul A Vasquez1, Prashant Chittiboina1, Xiang Wang1, Settara C Chandrasekharappa1, Abhik Ray-Chaudhury1, John A Butman1, Douglas R Stewart1, Ashok R Asthagiri1. 1. Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.D., K.L.M., R.A.V., P.C., X.W., A.R.-C., A.R.A.); Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland (A.P., D.R.S.); Office of the Clinical Director, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland (H.J.K.); Radiology and Imaging Sciences, The Clinical Center at the National Institutes of Health, National Institutes of Health, Bethesda, Maryland (J.A.B.); Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland (S.C.C.); Department of Neurosurgery, University of Virginia, CDW, Charlottesville, Virginia (A.R.A.).
Abstract
BACKGROUND: Neurofibromatosis type 2 (NF2) is a tumor syndrome that results from mutation of the NF2 tumor suppressor gene. The hallmark of NF2 is the presence of bilateral vestibular schwannoma (VS). Though NF2-associated and sporadic VS share identical histopathologic findings and cytogenetic alterations, NF2-associated VS often appears multilobulated, is less responsive to radiosurgery, and has worse surgical outcomes. Temporal bone autopsy specimens and MRI of the inner ear performed on NF2 patients suggest that multiple discrete tumors may be present within the labyrinth and cerebellopontine angle. METHODS: Treatment-naïve ears in patients enrolled in a prospective NF2 natural history study (NIH#08-N-0044) were included for MRI analysis. T2-weighted and postcontrast T1-weighted MRIs were evaluated for the presence of multiple discrete tumors or a multilobulated mass. Peripheral blood (germline) and regional samples of tumor tissue were procured from consecutive patients enrolled in this study undergoing resection of a multilobulated VS (MVS). Histopathologic evaluation and genetic analysis (single nucleotide polymorphism array analysis, NF2 sequencing) were performed on each specimen. RESULTS: Over half of NF2 ears harbored either an MVS (60/139 ears) or multiple discrete masses (19/139 ears). For 4 successive MVSs, genetic analysis revealed an admixture of cell populations, each with its own somatic NF2 mutation or deletion. CONCLUSIONS: These findings suggest that the majority of NF2-associated VSs are polyclonal, such that the tumor mass represents a collision of multiple, distinct tumor clones. This explains the characteristic lobulated gross appearance of NF2-associated VS, and may also explain the substantially different treatment outcomes compared with sporadic VS. Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.
BACKGROUND:Neurofibromatosis type 2 (NF2) is a tumor syndrome that results from mutation of the NF2tumor suppressor gene. The hallmark of NF2 is the presence of bilateral vestibular schwannoma (VS). Though NF2-associated and sporadic VS share identical histopathologic findings and cytogenetic alterations, NF2-associated VS often appears multilobulated, is less responsive to radiosurgery, and has worse surgical outcomes. Temporal bone autopsy specimens and MRI of the inner ear performed on NF2patients suggest that multiple discrete tumors may be present within the labyrinth and cerebellopontine angle. METHODS: Treatment-naïve ears in patients enrolled in a prospective NF2 natural history study (NIH#08-N-0044) were included for MRI analysis. T2-weighted and postcontrast T1-weighted MRIs were evaluated for the presence of multiple discrete tumors or a multilobulated mass. Peripheral blood (germline) and regional samples of tumor tissue were procured from consecutive patients enrolled in this study undergoing resection of a multilobulated VS (MVS). Histopathologic evaluation and genetic analysis (single nucleotide polymorphism array analysis, NF2 sequencing) were performed on each specimen. RESULTS: Over half of NF2 ears harbored either an MVS (60/139 ears) or multiple discrete masses (19/139 ears). For 4 successive MVSs, genetic analysis revealed an admixture of cell populations, each with its own somatic NF2 mutation or deletion. CONCLUSIONS: These findings suggest that the majority of NF2-associated VSs are polyclonal, such that the tumor mass represents a collision of multiple, distinct tumor clones. This explains the characteristic lobulated gross appearance of NF2-associated VS, and may also explain the substantially different treatment outcomes compared with sporadic VS. Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.
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