Neuro-oncology of Familial Neoplasia Syndromes

家族性肿瘤综合征的神经肿瘤学

• 批准号: 8158236
• 负责人: Russell Lonser
• 金额: $ 144.12万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8158236
• 关键词: Neoplasms; Syndrome; neuro-oncology

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.

von Hippel-Lindau病（VHL）。 为了洞悉与VHL相关的中枢神经系统（CNS）血管细胞瘤的自然史，我们对VHL患者进行了持续的自然史研究。 VHL患者中连续的临床和成像发现的综述，并显示血管群的肿瘤生长多个时期，被阻塞生长的时期分离，许多未经治疗的肿瘤可能保持相同的大小数年，并且不需要治疗。此外，通常在CNS血管群中发现周围囊肿，囊肿的肿瘤效果比血管蛋白细胞瘤本身大得多。实际上，到出现症状时，产生囊肿症状的大部分质量作用，而不是相关的血管母细胞瘤。 纵向成像和囊肿流体分析表明，基础的周围肿瘤囊肿形成的机制是通过可渗透的肿瘤血管进行血浆渗出。 随后，导致肿瘤血管渗透性增加（例如辐射）的因素可能会加剧水肿和/或囊肿传播，而靶向的治疗剂可降低肿瘤血管渗透性，可能会潜在地减少水肿/囊肿的形成并延迟或阻止症状发育。 这项研究的未来发现应导致鉴定血管细胞瘤特性，该特性将预测症状形成允许治疗较小的肿瘤，这应减少与等待较大的症状性血管蛋白母细胞瘤相关的发病率。 先前的研究表明，血管母细胞瘤中的肿瘤细胞是发育中的血管细胞。 我们表征和扩大了VHL患者中CNS血管母细胞瘤的肿瘤细胞。 与胚胎学衍生的血管细胞一致，肿瘤细胞表现出中胚层标志物的共表达，FLK-1和SCL。 肿瘤细胞还表达造血干细胞抗原和受体，包括CD133，CD34，C-KIT，SCL，SCL，促红细胞生成素和促红细胞生成素受体。 肿瘤细胞（血管细胞）扩展并分化为红细胞，粒细胞和内皮祖细胞。 造血和内皮后代中野生型VHL等位基因的缺失证实了它们的肿瘤起源。 这些发现表明，VHL患者中枢神经系统血管群的肿瘤细胞是源自胚胎学上的中胚层的血管细胞，并为人类肿瘤发生为发育现象提供了证据。 正在探索基于血管细胞瘤的肿瘤发生的治疗策略。 VHL中的内晶囊囊肿瘤（ELSTS）与听力损失，耳鸣，眩晕，听觉饱满度和/或面神经功能障碍有关。在VHL中，ELST经常发生双侧发生，并且经常导致明显的神经疾病，包括耳聋。尽管ELSTS及其与VHL的关联造成了破坏性的影响，但尚未定义与ELSTS相关的有声伏植物功能障碍的潜在病理生理机制以及ELSTS治疗的最佳时机。我们分析了35例38例ELST的VHL患者的串行成像，临床和外科手术发现。我们发现Elst大小与感觉神经性听力损失或前庭病无关。 ELST相关的感觉神经性听力丧失和前庭病通常是由于肿瘤相关的丙氨酸内出血，或阴险地与内淋巴水滴一致的。发现这两种病理生理机制都是与耳胶囊浸润无关的很小的肿瘤。 这些发现表明，在VHL中无法解释的视听功能障碍的高发生率可能部分解释了微观ELSTS。 因为有声尾腹发病与肿瘤的大小无关，并且是不可预测的，因此对ELSTS的早期检测和手术治疗可以降低视听的发病率。 神经纤维瘤病2型（NF2）。 NF2中枢神经系统肿瘤的多重蛋白质性质，缺乏对其自然历史的理解以及理解引起症状形成的基本机制的缺陷导致治疗被保留在神经系统缺陷中。 基于这种治疗范式，治疗时的肿瘤通常很大，并且与不可逆的神经系统下降和治疗风险增加有关。随后，对与NF2相关的这些肿瘤的自然史的了解对于确定这些病变患者的最佳治疗并深入了解这些肿瘤的发展至关重要。 为了获得对该肿瘤抑制综合征对肿瘤发育和进展的影响的临床和分子见解，并确定与症状进化有关的因素，我们启动了今年NF2患者的前瞻性自然史研究。 这项前瞻性自然史研究对于确定决定肿瘤生物学和行为的随机因素应该很有用，因为它与症状形成有关，最终是最佳治疗。