Neuro-oncology of Familial Neoplasia Syndromes

National Institute Of Neurological Disorders And Stroke

Investigators

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Abstract

von Hippel-Lindau Disease (VHL): We are continuing to follow VHL patients in a natural history study of 250 VHL patients (Lonser et al. 2014) to gain further insights into the natural history of VHL-associated central nervous system (CNS) hemangioblastomas. So far, our findings confirm that most hemangioblastomas grow in a saltatory pattern characterized by periods of growth and quiescence. Quiescent tumors do not need treatment. Hemangioblastomas are more likely to cause symptoms and need surgical treatment if they are associated with enlarging tumor cysts. Plasma extravasation through permeable tumor vessels underlies the formation of peritumoral cysts and syringes. Embryologic hemangioblasts are the cells of origin of VHL-associated CNS hemangioblastomas. New, noninvasive treatments for VHL-associated CNS hemangioblastoma are needed. Our laboratory has documented that mutant VHL protein expressed by a germline missense VHL gene mutation retains some biochemical function, but this function is lost through accelerated breakdown of the mutant protein. Vorinostat, a histone deacetylase inhibitor approved for the treatment of refractory cutaneous T-cell lymphoma (CTCL), experimentally slows the intracellular breakdown of the mutant VHL protein. To test this hypothesis, we enrolled seven germline missense VHL patients with symptomatic central nervous system hemangioblastomas. The subjects received 400 mg/day of vorinostat for seven days and surgical resection hemangioblastomas. Hemangioblastomas were analyzed using Western blot, immunohistochemistry and real-time qPCR. We found that short-duration treatment with vorinostat increased pVHL levels and suppressed tumor progression signaling in VHL-associated hemangioblastomas. These results indicate that HDACi treatment can rescue tumor pVHL in germline missense mutated VHL patients and treatment could arrest tumor growth. We also analyzed the natural history of retrobulbar hemangioblastomas in a large cohort of VHL patients in order to define presentation, progression and management. Eighteen patients with retrobulbar hemangioblastoma on surveillance MR imaging met the inclusion criteria for this study. We found that retrobulbar hemangioblastomas may remain stable and clinically asymptomatic for long durations. Recent growth and larger tumor volume were associated with symptom occurrence. Surgical treatment of symptomatic retrobulbar hemangioblastomas can be safe and may reverse the associated symptoms. Neurofibromatosis Type 2 (NF2): The protean nature of central nervous system tumors in NF2 and incomplete understanding of their natural history and underlying mechanisms of symptom formation have resulted in treatment being delayed until after the development of neurologic deficits. Based on this treatment paradigm, tumors at the time of treatment are typically large and associated with irreversible neurologic deficits and increased risk of treatment-induced morbidity. Subsequently, knowledge of the natural history of tumors associated with NF2 is critical for predicting the future growth of a tumor and deciding on the best treatment of affected patients. To gain clinical and molecular insights into the effects of NF2 gene mutations on tumor development/progression and to identify features associated with symptom evolution in NF2-associated tumors, we are performing an ongoing natural history study of 269 NF2 patients. Analysis of this study data will allow us to gain a better understanding of the natural history of CNS tumors in NF2. So far, variable patterns of tumor growth, including a stuttering pattern, have been observed in many subjects. Preliminary studies suggest that genetic factors beyond the NF2 gene mutation are associated with increased disease severity in patients with NF2. This prospective natural history study should be useful in identifying the factors that affect tumor biology, symptom formation, and optimal timing of treatment in NF2. We are completing a longitudinal analysis (submitted, Oral Presentation at AANS Annual Meeting 2017). We sought to prospectively analyze the utility of FLAIR MRI to predict hearing loss in patients with NF2. We tested the hypothesis in a cohort of patients with small, untreated VS (<500mm3) to avoid the effects of surgery or large tumor size on labyrinthine FLAIR signal. We confirmed that no patients with hearing loss had normal labyrinthine FLAIR signal. We then found that a change in labyrinthine FLAIR signal preceded hearing loss in that ear by 2.7 years. In no case did a FLAIR signal change reverse from elevated to normal. These interesting findings offer clinicians an opportunity to monitor patients with NF2 with a non-invasive predictive biomarker of hearing loss. Patients with neurofibromatosis type 2 (NF2) have a predisposition to develop peripheral neuropathic symptoms due to focal compression from tumors as well as due to NF2 haploinsufficiency mediated axonal neuropathy. We recently analyzed the prevalence of compressive and generalized peripheral neuropathies in patients with NF2, and evaluate the role of surgery in alleviating neuropathic symptoms. We found that patients with NF2 present with peripheral neuropathic symptoms due to compression from tumors and due to axonal neuropathy. In instances of distinct tumor compression, nerve fascicle sparing surgical resection leads to resolution of neuropathic symptoms. EMG/NCS studies help guide management of NF2 patients with peripheral neuropathic symptoms.