1Department of Neurosurgery, Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre.
2Division of Informatics, Imaging and Data Sciences, Wolfson Molecular Imaging Centre (WMIC), University of Manchester.
J Neurosurg. 2020 May 29;134(5):1419-1429. doi: 10.3171/2020.3.JNS193230. Print 2021 May 1.
Inflammation and angiogenesis may play a role in the growth of sporadic and neurofibromatosis type 2 (NF2)-related vestibular schwannoma (VS). The similarities in microvascular and inflammatory microenvironment have not been investigated. The authors sought to compare the tumor microenvironment (TME) in sporadic and NF2-related VSs using a combined imaging and tissue analysis approach.
Diffusion MRI and high-temporal-resolution dynamic contrast-enhanced (DCE) MRI data sets were prospectively acquired in 20 NF2-related and 24 size-matched sporadic VSs. Diffusion metrics (mean diffusivity, fractional anisotropy) and DCE-MRI-derived microvascular biomarkers (transfer constant [Ktrans], fractional plasma volume, tissue extravascular-extracellular space [ve], longitudinal relaxation rate, tumoral blood flow) were compared across both VS groups, and regression analysis was used to evaluate the effect of tumor size, pretreatment tumor growth rate, and tumor NF2 status (sporadic vs NF2-related) on each imaging parameter. Tissues from 17 imaged sporadic VSs and a separate cohort of 12 NF2-related VSs were examined with immunohistochemistry markers for vessels (CD31), vessel permeability (fibrinogen), and macrophage density (Iba1). The expression of vascular endothelial growth factor (VEGF) and VEGF receptor 1 was evaluated using immunohistochemistry, Western blotting, and double immunofluorescence.
Imaging data demonstrated that DCE-MRI-derived microvascular characteristics were similar in sporadic and NF2-related VSs. Ktrans (p < 0.001), ve (p ≤ 0.004), and tumoral free water content (p ≤ 0.003) increased with increasing tumor size and pretreatment tumor growth rate. Regression analysis demonstrated that with the exception of mean diffusivity (p < 0.001), NF2 status had no statistically significant effect on any of the imaging parameters or the observed relationship between the imaging parameters and tumor size (p > 0.05). Tissue analysis confirmed the imaging metrics among resected sporadic VSs and demonstrated that across all VSs studied, there was a close association between vascularity and Iba1+ macrophage density (r = 0.55, p = 0.002). VEGF was expressed by Iba1+ macrophages.
The authors present the first in vivo comparative study of microvascular and inflammatory characteristics in sporadic and NF2-related VSs. The imaging and tissue analysis results indicate that inflammation is a key contributor to TME and should be viewed as a therapeutic target in both VS groups.
炎症和血管生成可能在散发和神经纤维瘤病 2 型（NF2）相关前庭神经鞘瘤（VS）的生长中发挥作用。微血管和炎症微环境之间的相似性尚未得到研究。作者试图使用联合成像和组织分析方法比较散发和 NF2 相关 VS 的肿瘤微环境（TME）。
前瞻性地在 20 例 NF2 相关和 24 例大小匹配的散发 VS 中采集扩散 MRI 和高时间分辨率动态对比增强（DCE）MRI 数据集。比较两组 VS 的扩散指标（平均弥散度、各向异性分数）和 DCE-MRI 衍生的微血管生物标志物（转运常数[Ktrans]、血浆分数、组织血管外细胞外空间[ve]、纵向弛豫率、肿瘤血流），并进行回归分析以评估肿瘤大小、预处理肿瘤生长率和肿瘤 NF2 状态（散发与 NF2 相关）对每个成像参数的影响。对 17 例成像的散发 VS 组织和单独的 12 例 NF2 相关 VS 组织进行免疫组织化学标记血管（CD31）、血管通透性（纤维蛋白原）和巨噬细胞密度（Iba1）检测。使用免疫组织化学、Western 印迹和双重免疫荧光评估血管内皮生长因子（VEGF）和 VEGF 受体 1 的表达。
影像学数据表明，散发和 NF2 相关 VS 的 DCE-MRI 衍生微血管特征相似。Ktrans（p<0.001）、ve（p≤0.004）和肿瘤游离水含量（p≤0.003）随肿瘤大小和预处理肿瘤生长率的增加而增加。回归分析表明，除平均弥散度（p<0.001）外，NF2 状态对任何成像参数或观察到的成像参数与肿瘤大小之间的关系均无统计学意义（p>0.05）。组织分析证实了切除的散发 VS 中的影像学指标，并表明在所研究的所有 VS 中，血管生成与 Iba1+巨噬细胞密度之间存在密切关联（r=0.55，p=0.002）。Iba1+巨噬细胞表达 VEGF。
作者首次进行了散发和 NF2 相关 VS 微血管和炎症特征的体内比较研究。影像学和组织分析结果表明，炎症是 TME 的关键贡献者，应被视为两组 VS 的治疗靶点。
