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

Abstract

OBJECTIVE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Daniel Lewis, Carmine A Donofrio, Claire O'Leary, Ka-Loh Li, Xiaoping Zhu, Ricky Williams, Ibrahim Djoukhadar, Erjon Agushi, Cathal J Hannan, Emma Stapleton, Simon K Lloyd, Simon R Freeman, Andrea Wadeson, Scott A Rutherford, Charlotte Hammerbeck-Ward, D Gareth Evans, Alan Jackson, Omar N Pathmanaban, Federico Roncaroli, Andrew T King, David J Coope
• Journal: Journal of neurosurgery (J Neurosurg) Vol. 134 Issue 5 Pg. 1419-1429 (May 29 2020) ISSN: 1933-0693 [Electronic] United States
• PMID: 32470937 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Neoplasm Proteins
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factor Receptor-1

Topics

• Adult
• Anisotropy
• Body Water
• Diffusion Magnetic Resonance Imaging
• Female
• Humans
• Inflammation
• Magnetic Resonance Imaging (methods)
• Male
• Microcirculation
• Middle Aged
• Neoplasm Proteins (analysis)
• Neovascularization, Pathologic (diagnostic imaging, pathology)
• Neurofibromatosis 2 (diagnostic imaging, pathology)
• Neuroma, Acoustic (chemistry, diagnostic imaging, genetics, pathology)
• Tumor Microenvironment
• Tumor-Associated Macrophages (metabolism)
• Vascular Endothelial Growth Factor A (analysis)
• Vascular Endothelial Growth Factor Receptor-1 (analysis)
• Young Adult