von Hippel-Lindau Disease (VHL). To gain insights into the natural history of VHL-associated central nervous system (CNS) hemangioblastomas, we have an ongoing natural history study of VHL patients. Analysis of serial clinical and imaging findings in VHL patients and have revealed that nearly all hemangioblastomas demonstrate a saltatory growth pattern characterized by periods of growth and quiescence. Because of this pattern of growth, many tumors will remain unchanged in size for years and asymptomatic not requiring treatment. Furthermore, peritumoral cysts were frequently found with CNS hemangioblastomas. The rate of enlargement of these peritumoral cysts was most often far greater than for the hemangioblastoma and, when symptoms appeared, most of the symptom-producing mass effect was from the cyst, not the associated hemangioblastoma. Longitudinal imaging and cyst fluid analyses demonstrated that the mechanism that underlies the formation of peritumoral cysts is plasma extravasation through permeable tumor vessels. Subsequently, factors that lead to increased tumor vessel permeability (e.g., radiation) may exacerbate edema and/or cyst propagation, while targeted therapeutic agents that reduce tumor vascular permeability could potentially reduce edema/cyst formation and delay or prevent symptom development. Future findings of this study should lead to the identification of hemangioblastoma properties that will predict symptom formation permitting the treatment of smaller tumors, which should reduce the morbidity associated with waiting to treat larger, symptomatic hemangioblastomas. Previous studies have suggested that the neoplastic cell of origin in hemangioblastomas are developmentally-arrested hemangioblasts. Characterized and cultured VHL-associated tumor cells from resected CNS hemangioblastomas were consistent with an embryologic hemangioblast (expressing mesodermal markers brachyury, Flk-1 and Scl). Further, the neoplastic cells could be expanded and differentiated in culture into blood and endothelial progenitors that had loss of heterozygosity of the VHL gene. Loss of heterozygosity analysis also demonstrated that mast cells in VHL are tumor-derived. These findings indicate the origin in VHL-associated CNS hemangioblastomas are derived from embryologic hemangioblasts. Treatment strategies based on the tumorigenesis of hemangioblastomas are being explored. Endolymphatic sac tumors (ELSTs) in VHL are frequently associated with hearing loss, tinnitus and vertigo. In VHL, bilateral ELSTs can occur bilaterally and can underlie significant neurologic disability, including binaural deafness. While sporadic and VHL-associated ELSTs can cause devastating audiovestibular dysfunction, the underlying pathophysiologic mechanisms of this dysfunction and the optimal timing of treatment of ELSTs had not been defined. Previously, we analyzed the serial imaging, clinical and surgical findings in VHL patients with ELSTs and found that ELST size was not related to audiovestibular morbidity. Further, it was revealed that ELST-associated audiovestibulopathy is due to tumor-associated intralabyrinthine hemorrhage, or endolymphatic hydrops. These pathophysiologic mechanisms of hearing loss and vestibulopathy can be found with very small tumors. These findings suggest that the frequent finding of unexplained VHL-associated audiovestibular dysfunction may in part be explained microscopic ELSTs. Because audiovestibular morbidity is not related to tumor size and is unpredictable, early detection via improved testing/imaging and surgical treatment of ELSTs can reduce audiovestibular morbidity. 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 in 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 NF-2 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 NF2 patients. This prospective natural history study should be useful in identifying the stochastic factors that determine tumor biology and behavior as it relates to symptom formation and ultimately, optimal treatment.

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Montgomery, Blake K; Alimchandani, Meghna; Mehta, Gautam U et al. (2016) Tumors displaying hybrid schwannoma and neurofibroma features in patients with neurofibromatosis type 2. Clin Neuropathol 35:78-83
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