Inflammation and vascular permeability correlate with growth in sporadic vestibular schwannoma

Abstract

BackgroundInflammation is hypothesized to be a key event in the growth of sporadic vestibular schwannoma (VS). In this study we sought to investigate the relationship between inflammation and tumor growth in vivo using the PET tracer 11C-(R)-PK11195 and dynamic contrast enhanced (DCE) MRI derived vascular biomarkers.MethodsNineteen patients with sporadic VS (8 static, 7 growing, and 4 shrinking tumors) underwent prospective imaging with dynamic 11C-(R)-PK11195 PET and a comprehensive MR protocol, including high temporal resolution DCE-MRI in 15 patients. An intertumor comparison of 11C-(R)-PK11195 binding potential (BPND) and DCE-MRI derived vascular biomarkers (Ktrans, vp, ve) across the 3 different tumor growth cohorts was undertaken. Tissue of 8 tumors was examined with immunohistochemistry markers for inflammation (Iba1), neoplastic cells (S-100 protein), vessels (CD31), the PK11195 target translocator protein (TSPO), fibrinogen for vascular permeability, and proliferation (Ki-67). Results were correlated with PET and DCE-MRI data.ResultsCompared with static tumors, growing VS displayed significantly higher mean 11C-(R)-PK11195 BPND (−0.07 vs 0.47, P = 0.020), and higher mean tumor Ktrans (0.06 vs 0.14, P = 0.004). Immunohistochemistry confirmed the imaging findings and demonstrated that TSPO is predominantly expressed in macrophages. Within growing VS, macrophages rather than tumor cells accounted for the majority of proliferating cells.ConclusionWe present the first in vivo imaging evidence of increased inflammation within growing sporadic VS. Our results demonstrate that 11C-(R)-PK11195 specific binding and DCE-MRI derived parameters can be used as imaging biomarkers of inflammation and vascular permeability in this tumor group.

Gamma Knife Radiosurgery does not alter the copy number aberration profile in sporadic vestibular schwannoma

“…Considering the bias of ASCAT only calling heterogeneity in tumors with large aberration and the variant allele frequencies reported in our WES study, it seems likely that most or all VSs consists of more than one major genetic clone. A recent study by Lewis et al found that tumor-associated macrophages constituted 50-60% of the cells in eight growing VSs [33]. Hence, infiltrating macrophages might constitute the clone coexisting with the neoplastic cells.…”

The impact of the MIB-1 index on facial nerve outcomes in vestibular schwannoma surgery

“…Concerning pathophysiology, it can be assumed that local residual cells with higher mitotic activity driven by inflammation will disturb the local function of the facial nerve by contributing to the formation of scars. Lewis et al [27] suggested that inflammation is a relevant parameter when evaluating the growth of vestibular schwannomas. Positive correlations between higher MIB-1 index values and the presence of CD68positive macrophages and CD45-positive lymphocytes were also observed in our study.…”

“…Positive correlations between higher MIB-1 index values and the presence of CD68positive macrophages and CD45-positive lymphocytes were also observed in our study. In an investigation by Lewis et al [27], tumour tissues obtained from 8 sporadic VSs were immunohistochemically analysed, and the growing tumours were found to exhibit significantly higher proportions of Ki-67/Iba1 (ionised calcium-binding adapter molecule)-positive cells. Additionally, programmed cell death 1 ligand 1 (PD-L1) expression was recently described in VSs [5], and it was suggested that PD-L1 expression, tumour-associated macrophages, and rapid tumour growth could be correlated with each other.…”

“…It has been proposed that in a VS, a MIB-1 index > 2% indicates a shorter tumour doubling time [46]. In addition, it has been suggested that the mean MIB-1 or Ki-67 labelling index will be higher in growing tumours than in static tumours, demonstrating that in VS, relative to growth, there are fewer inflammatory cells [27]. However, the clinical impact of the MIB-1 index on facial nerve outcomes is unknown.…”

Progression of Contralateral Hearing Loss in Patients With Sporadic Vestibular Schwannoma

“…These clinical observations suggest additional explanations for the pathophysiology of SNHL, beyond only mechanical compression of adjacent structures. Recent studies have revealed new insights about the capacity of secreted factors, such as tumor necrosis factor alpha (TNFα), and extracellular vesicles (EVs) from human VSs to cause cochlear damage (11)(12)(13)(14)(15)(16). The greater the severity of SNHL associated with a VS tumor, the greater the degree of hair cell loss and neuronal fiber disorganization seen in cochlear explants exposed to tumor secretions (11,13).…”