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

Abstract

<jats:sec><jats:title>OBJECTIVE</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>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 [K<jats:sup>trans</jats:sup>], fractional plasma volume, tissue extravascular-extracellular space [v<jats:sub>e</jats:sub>], 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.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>Imaging data demonstrated that DCE-MRI–derived microvascular characteristics were similar in sporadic and NF2-related VSs. K<jats:sup>trans</jats:sup> (p &lt; 0.001), v<jats:sub>e</jats:sub> (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 &lt; 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 &gt; 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<jats:sup>+</jats:sup> macrophage density (r = 0.55, p = 0.002). VEGF was expressed by Iba1<jats:sup>+</jats:sup> macrophages.</jats:p></jats:sec><jats:sec><jats:title>CONCLUSIONS</jats:title><jats:p>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.</jats:p></jats:sec>

Macrophage and Lymphocyte Infiltration Is Associated with Volumetric Tumor Size but Not with Volumetric Growth in the Tübingen Schwannoma Cohort

“…On the contrary, when the infiltration of lymphocyte and macrophage marker expression was taken together as an inflammatory score, a higher score was associated with slower tumor growth. This is in direct contradiction to the current literature that suggests that immune cell infiltration leads to faster tumor growth [ 6 , 8 , 17 ]. However, our study is the largest so far in regard to the description of immune cell infiltration and volumetric growth.…”

“…Based on the current literature, the observation of decreased tumor growth with increased inflammatory infiltration was unexpected. Until now, the contrary has been advocated, that immune cell infiltration may be an expression of tumor-associated macrophages driving schwannoma growth [ 6 , 8 , 17 ]. Only one study that assessed PET imaging with specific tracers for inflammation in a small group of vestibular schwannomas shown a higher cell density in non-growing tumors compared to growing VS [ 9 ].…”

The LEGATOS technique: A new tissue‐validated dynamic contrast‐enhanced MRI method for whole‐brain, high‐spatial resolution parametric mapping

“…Previous in vivo studies in sporadic VS have demonstrated that kinetic parameter estimates derived through use of the ETM with low‐spatial, HT resolution DCE‐MRI accurately reflect inter‐tumor differences in tissue vascularity metrics and correlate with differences in macrophage content and tumor growth rate 5,30 . However, the inherent low‐spatial resolution in derived parameter maps limited accurate assessment of intratumoral heterogeneity, especially within smaller lesions.…”

“…The ETM has been adopted in this study as previous application of this model with low‐spatial resolution HT data sets derived from DTR DCE‐MRI was found to give both tissue‐validated and clinically relevant kinetic parameter estimates 4,5,30 . Recent studies have also shown through a model selection process using the Akaike information criteria, that the ETM was one of the optimal models in pharmacokinetic analysis of DCE‐MRI data in brain tumors 42 and papillary thyroid carcinoma 43 .…”

Cellular mechanisms of heterogeneity inNF2-mutant schwannoma

“…5H). Recent studies of schwannomas highlight the presence and clinical influence of macrophages, which can be important paracrine sources of both HGF and PDGF 12,59 . Thus, Nf2-deficiency may also enable macropinocytic scavenging in response to paracrine factors from the microenvironment, which could further drive schwannoma heterogeneity by activating additional signaling pathways.…”