背景:2型神经纤维瘤病(NF2)是一种由NF2抑癌基因突变引起的肿瘤综合征。NF2的标志是存在双侧前庭神经鞘瘤(VS)。尽管NF2相关和零星的VS具有相同的组织病理学发现和细胞遗传学改变,NF2相关的VS通常出现多小叶,对放射外科的反应较差,并且手术效果较差。对NF2患者进行的颞骨尸检标本和内耳MRI显示,迷宫和小脑桥脑角内可能存在多个离散肿瘤。
方法:纳入前瞻性NF2自然史研究(NIH#08-N-0044)患者的初治耳朵进行MRI分析。评估T2加权和对比后T1加权MRI是否存在多个离散肿瘤或多小叶肿块。外周血(种系)和肿瘤组织的区域样本来自本研究中接受多小叶VS(MVS)切除的连续患者。组织病理学评估和遗传分析(单核苷酸多态性阵列分析,对每个样本进行NF2测序)。
结果:超过一半的NF2耳朵具有MVS(60/139耳)或多个离散质量(19/139耳)。对于4个连续的MVS,遗传分析揭示了细胞群的混合物,每个都有自己的体细胞NF2突变或缺失。
结论:这些发现表明,大多数NF2相关的VSs是多克隆的,这样肿瘤块代表了多重碰撞,不同的肿瘤克隆。这解释了NF2相关VS的特征性分叶状总体外观,也可以解释与散发性VS相比,治疗结果有很大不同。
BACKGROUND: Neurofibromatosis type 2 (NF2) is a tumor syndrome that results from mutation of the NF2 tumor suppressor gene. The hallmark of NF2 is the presence of bilateral vestibular schwannoma (VS). Though NF2-associated and sporadic VS share identical histopathologic findings and cytogenetic alterations, NF2-associated VS often appears multilobulated, is less responsive to radiosurgery, and has worse surgical outcomes. Temporal bone autopsy specimens and MRI of the inner ear performed on NF2 patients suggest that multiple discrete tumors may be present within the labyrinth and cerebellopontine angle.
METHODS: Treatment-naïve ears in patients enrolled in a prospective NF2 natural history study (NIH#08-N-0044) were included for MRI analysis. T2-weighted and postcontrast T1-weighted MRIs were evaluated for the presence of multiple discrete tumors or a multilobulated mass. Peripheral blood (germline) and regional samples of tumor tissue were procured from consecutive patients enrolled in this study undergoing resection of a multilobulated VS (MVS). Histopathologic evaluation and genetic analysis (single nucleotide polymorphism array analysis, NF2 sequencing) were performed on each specimen.
RESULTS: Over half of NF2 ears harbored either an MVS (60/139 ears) or multiple discrete masses (19/139 ears). For 4 successive MVSs, genetic analysis revealed an admixture of cell populations, each with its own somatic NF2 mutation or deletion.
CONCLUSIONS: These findings suggest that the majority of NF2-associated VSs are polyclonal, such that the tumor mass represents a collision of multiple, distinct tumor clones. This explains the characteristic lobulated gross appearance of NF2-associated VS, and may also explain the substantially different treatment outcomes compared with sporadic VS.