The microenvironment in sporadic and neurofibromatosis type II-related vestibular schwannoma: the same tumor or different? A comparative imaging and neuropathology study.

Daniel Lewis,Claire O’Leary,Alan Jackson,Federico Roncaroli,Ibrahim Djoukhadar,Charlotte Hammerbeck-Ward,Scott A Rutherford,Andrea Wadeson,Ricky Williams,D Gareth Evans,Andrew T King,Xiaoping Zhu,Erjon Agushi,Emma Stapleton,Cathal John Hannan ,Simon Freeman ,Carmine Antonio Donofrio ,Omar Pathmanaban ,Simon Lloyd ,Ka‐Loh Li ,David Coope

doi:10.3171/2020.3.jns193230

Abstract

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.

Highlights

The imaging and tissue analysis results indicate that inflammation is a key contributor to tumor microenvironment (TME) and should be viewed as a therapeutic target in both vestibular schwannoma (VS) groups
Sporadic and neurofibromatosis type 2 (NF2)-related VSs share biallelic inactivation of the NF2 gene,[2,3,4] but they present with phenotypic differences.[5,6]
NF2-related VSs develop as multifocal tumors along cranial nerve VIII5,6 and are difficult to remove

Summary

Methods

Study Design and Patient Population DCE-MRI data sets from two separate patient cohorts were used in this study. The study MRI scan and the results of previous MRI were reviewed collectively by the multidisciplinary team and tumors were classified as static/shrinking, growing, or sufficiently large to preclude monitoring of growth and mandate early resection. This classification was based upon clinical decision, with patients with growing VSs recommended to undergo either microsurgery or stereotactic radiosurgery (SRS), and patients with static or shrinking tumors offered a period of observation. Voxel-wise maps of microvascular kinetic parameters and absolute cerebral blood flow (CBFET) estimates were derived from the low-dose, high-temporal-resolution DCE-MRI data sets using the extended Tofts model[21] and a previously developed T1-weighted early time points method,[26] respectively.

Results

Discussion

Conclusion