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.

希佩尔-林道病 (VHL)。 为了深入了解 VHL 相关中枢神经系统 (CNS) 血管母细胞瘤的自然史，我们正在进行一项针对 VHL 患者的自然史研究。 对 VHL 患者的一系列临床和影像学结果的回顾表明，血管母细胞瘤具有多个肿瘤生长期，中间有生长停滞期，许多未经治疗的肿瘤可能在数年内保持相同的大小，不需要治疗。此外，瘤周囊肿常见于中枢神经系统血管母细胞瘤，且囊肿增大的速度比血管母细胞瘤本身快得多。事实上，当症状出现时，产生症状的大部分占位效应源自囊肿，而不是相关的血管母细胞瘤。 纵向成像和囊液分析表明，瘤周囊肿形成的机制是血浆通过可渗透的肿瘤血管外渗。 随后，导致肿瘤血管通透性增加的因素（例如辐射）可能会加剧水肿和/或囊肿增殖，而降低肿瘤血管通透性的靶向治疗药物可能会减少水肿/囊肿形成并延迟或预防症状发展。 这项研究的未来结果应该能够确定血管母细胞瘤的特性，从而预测症状的形成，从而允许治疗较小的肿瘤，从而减少等待治疗较大的、有症状的血管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停滞的成血管细胞。 我们对 VHL 患者切除的中枢神经系统血管母细胞瘤中的肿瘤细胞进行了表征和扩增。 与胚胎来源的成血管细胞一致，肿瘤细胞表现出中胚层标志物 brachyury、Flk-1 和 Scl 的共表达。 肿瘤细胞还表达造血干细胞抗原和受体，包括CD133、CD34、c-kit、Scl、促红细胞生成素和促红细胞生成素受体。 肿瘤细胞（成血管细胞）扩增并分化为红细胞、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，来自VHL患者中枢神经系统血管母细胞瘤的肿瘤细胞是源自胚胎停滞中胚层的成血管细胞，并为人类肿瘤发生作为发育现象提供了证据。 正在探索基于血管母细胞瘤的肿瘤发生的治疗策略。 VHL 中的内淋巴囊肿瘤 (ELST) 与听力损失、耳鸣、眩晕、耳闷感和/或面神经功能障碍有关。在 VHL 中，ELST 经常发生在双侧，并经常导致严重的神经功能障碍，包括耳聋。尽管 ELST 具有破坏性作用及其与 VHL 的关联，但与 ELST 相关的听前庭功能障碍的潜在病理生理机制以及 ELST 治疗的最佳时机尚未确定。我们分析了 35 名接受 38 次 ELST 的 VHL 患者的系列影像学、临床和手术结果。我们发现 ELST 大小与感音神经性听力损失或前庭病无关。 ELST 相关的感音神经性听力损失和前庭病常常由于肿瘤相关的迷路内出血而突然发生，或者与内淋巴积水一致地隐匿地发生。这两种病理生理机制都是在与耳囊侵入无关的非常小的肿瘤中发现的。 这些研究结果表明，VHL 中不明原因的听觉前庭功能障碍的高发生率可能部分可以用显微镜下的 ELST 来解释。 由于听前庭发病率与肿瘤大小无关且不可预测，因此早期发现 ELST 并进行手术治疗可以降低听前庭发病率。 2 型神经纤维瘤病 (NF2)。 NF2 中枢神经系统肿瘤的多变性质、缺乏对其自然史的了解以及对导致症状形成的潜在机制的理解不足，导致治疗被保留到出现神经功能缺损时。 基于这种治疗模式，治疗时的肿瘤通常很大，并且与不可逆的神经功能衰退和治疗引起的发病风险增加相关。随后，了解这些与 NF2 相关的肿瘤的自然史对于确定患有这些病变的患者的最佳治疗方法并深入了解这些肿瘤的发展至关重要。 为了深入了解这种抑癌综合征对肿瘤发生和进展的影响，并确定与症状演变相关的因素，我们今年启动了一项针对 NF2 患者的前瞻性自然史研究。 这项前瞻性自然史研究应该有助于确定决定肿瘤生物学和行为的随机因素，因为它与症状形成和最终的最佳治疗有关。