Neurooncology of Benign Central and Peripheral Nervous System Tumors

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This ongoing natural history study has resulted in significant improvements in the understanding how NF2 affects patients. We found that central nervous system tumors in NF2 demonstrate a stepwise growth pattern. We also found that these tumors are made of many different populations of tumor cells. These findings emphasize the need for long term follow up of patients with NF2 to evaluate disease progression. Patients with NF2 have symptoms that significantly affect their lives such as hearing loss and speech/swallowing dysfunction. This natural historya study has helped us understand how these symptoms arise even when the tumors are very small or quiescent. These findings will help clinicians find better ways to prevent hearing loss and to counsel patients about speech and swallowing problems. Using the current cohort of subjects with NF2, we confirmed the presence of increased protein within perilymph by MRI imaging as FLAIR hyperintensity. In this cross sectional study, a close correlation between increased protein and hearing loss was demonstrated. This study validated MRI imaging as a method to detect increased protein within perilymph, and as a marker for hearing loss. We now have a convenient, non-invasive tool for monitoring of perilymph protein content. MRI imaging can be performed repeatedly and over long periods to detect changes in perilymph protein with time and with changes in hearing. In another analysis, we found that a large proportion of patients with NF2 report speech and swallow deficits that are not evident on objective measurements. We also found hypoglossal neuropathy unrelated to prior surgical interventions. Our findings suggest that swallowing and speech in problems in NF2 are associated with lower cranial nerve neuropathy, some due to compressive effects of posterior fossa tumors. We found that patients with NF2 present with neuropathy related to peripheral nerve schwannomas as well as unexplained EMG/NCS findings. In instances of distinct schwannoma growth along peripheral nerves, nerve fascicle sparing surgical resection leads to resolution of neuropathic symptoms. EMG/NCS studies and imaging helps guide the management of NF2 patients with high degree of certainty. Neurofibromatosis type 2 (NF2) presents with central and peripheral nervous system tumors and non-neoplastic manifestations including peripheral neuropathy and a large variation in penetrance and severity. Although germline nonsense and frameshift NF2 mutations are hypothesized to confer severe disease, the relationship between mutation type and manifestations of this disease is not completely understood. In this study, our goal was to deeply investigate phenotypes of NF2 patients and examine relationships between the effects of germline genotype on disease severity. Deep phenotypic profiles were created (serially for 5 years) including clinical evaluations, self-reported functional measures, lifetime interventions (surgical, radiation and drug treatments), and imaging (tumor number, type and volume using volumetric MRI of the neuroaxis). Validated germline mutation data (n = 68) was used to examine relationships between genotype and phenotype with attention to NF2 mutation type (indel/large deletion), genomic effect (missense/nonsense/frameshift), predicted protein effect (truncating/non-truncating) and location (exonic/intronic/splice-site). We found that tumor burden varied greatly between patients (total tumors on MRI median 24, interquartile range 8-52). Tumor burden on initial MRI was associated with number of surgeries during the protocol period (p < 0.0001). We found that cranial meningiomas were a major determinant of total tumor burden. Total tumor burden (number and volume) was associated with worse Karnofsky Performance Scale (KPS) and decline in KPS over the study protocol (p < 0.0001). We found that truncating mutations in exons 11-12 were associated with more severe disease in terms of tumor number on MRI (p = 0.0439). We concluded that this is the first large scale study to deeply phenotype patients with NF2 including longitudinal analysis and demonstrates several previously unrecognized trends related to germline mutations type, imaging findings, and measures of disease severity.