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. Review of serial clinical and imaging findings in VHL patients and have revealed that hemangioblastomas have multiple periods of tumor growth separated by periods of arrested growth and many untreated tumors may remain the same size for several years and will not require treatment. Furthermore, peritumoral cysts were commonly found with CNS hemangioblastomas and the pace of enlargement for the cysts was much greater than for the hemangioblastoma itself. In fact, by the time symptoms appeared, the majority of the mass effect that produced the symptoms derived from the cyst, rather than 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 cells in hemangioblastomas are developmentally-arrested hemangioblasts. We characterized and expanded tumor cells from resected CNS hemangioblastomas in VHL patients. Consistent with an embryologically-derived hemangioblast, the neoplastic cells demonstrated co-expression of mesodermal markers brachyury, Flk-1 and Scl. The neoplastic cells also expressed hematopoietic stem cell antigens and receptors including CD133, CD34, c-kit, Scl, erythropoietin and erythropoietin receptor. Neoplastic cells (hemangioblasts) were expanded and differentiated into erythrocytic, granulocytic and endothelial progenitors. Deletion of the wild-type VHL allele in the hematopoietic and endothelial progeny confirmed their neoplastic origin. These findings indicate that the neoplastic cells from CNS hemangioblastomas in VHL patients are hemangioblasts derived from embryologically-arrested mesoderm and provide evidence for human tumourigenesis as developmental phenomenon. Treatment strategies based on the tumorigenesis of hemangioblastomas are being explored. Endolymphatic sac tumors (ELSTs) in VHL are associated with hearing loss, tinnitus, vertigo, aural fullness, and/or facial nerve dysfunction. In VHL, ELSTs frequently occur bilaterally and often result in significant neurologic disability, including deafness. Despite the devastating effects of ELSTs and their association with VHL, the underlying pathophysiologic mechanisms of audiovestibular dysfunction associated with ELSTs and the optimal timing of treatment of ELSTs had not been defined. We analyzed the serial imaging, clinical and surgical findings in 35 VHL patients with 38 ELSTs. We found that ELST size was not related to sensorineural hearing loss or vestibulopathy. ELST-associated sensorineural hearing loss and vestibulopathy often occurred suddenly due to tumor-associated intralabyrinthine hemorrhage, or insidiously, consistent with endolymphatic hydrops. Both of these pathophysiologic mechanisms were found with very small tumors that are not associated with otic capsule invasion. These findings suggest that the high incidence of unexplained audiovestibular dysfunction in VHL may in part be explained microscopic ELSTs. Because audiovestibular morbidity is not related to tumor size and is unpredictable, early detection and surgical treatment of ELSTs can reduce audiovestibular morbidity. Neurofibromatosis Type 2 (NF2). The multiple protean nature of the central nervous system tumors in NF2, lack in understanding of their natural history, and deficiencies in comprehension of underlying mechanisms that cause symptom formation have resulted in treatment being reserved until the time neurologic deficits develop. Based on this treatment paradigm, tumors at the time of treatment are typically large and associated with irreversible neurologic decline and increased risk of treatment induced morbidity. Subsequently, knowledge of the natural history of these tumors associated with NF2 is critical to determine the optimal treatment of patients with these lesions and to gain insight into the development of these tumors. To gain clinical and molecular insights into the effects of this tumor suppressor syndrome on tumor development and progression and to identify factors linked to symptom evolution, we have initiated a prospective natural history study of NF2 patients this year. 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.
Showing the most recent 10 out of 54 publications
