The inflammatory microenvironment in vestibular schwannoma

Hannan, Cathal John; Lewis, Daniel; O’Leary, Claire; Donofrio, Carmine Antonio; Evans, D Gareth; Roncaroli, Federico; Brough, David; King, Andrew T.; Coope, David; Pathmanaban, Omar

doi:10.1093/noajnl/vdaa023

Cited by 48 publications

(77 citation statements)

References 96 publications

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“…Within the last years, the role of inflammatory processes in the development and progression of vestibular schwannoma has been described [ 5 , 6 , 7 ]. Especially the infiltration of vs. tissue with inflammatory cells has been reported to be associated with tumor growth in small cohorts [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

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

Gonçalves

Suhm

Ries

et al. 2021

Cancers

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Most patients with vestibular schwannomas can be cured with microsurgical resection, or tumor growth can be stabilized by radiotherapy in certain cases. Recurrence is rare but usually difficult to treat. Treatment alternatives to local therapies are not established. There is growing evidence of the role of inflammatory processes in schwannomas, which may be exploitable by targeted innovative therapies. To further define the impact of inflammation with tumor growth in vestibular schwannoma, we performed immunohistochemical analyses of CD3, CD8, CD68 and CD163 to assess lymphocyte and macrophage infiltration in 923 tumor tissue samples of surgically resected vestibular schwannomas. An inflammatory score was compared with tumor size and volumetric growth. We observed a significantly larger preoperative tumor size with increased expression rates of CD3, CD8, CD68 and CD163 (p < 0.0001, p < 0.0001, p = 0.0015 and p < 0.0001, respectively), but no differences in percentual volumetric tumor growth. When all four markers were combined as an inflammatory score, tumors with high inflammatory infiltration showed slower percentual growth in a multivariate analysis, including MIB1 expression (p = 0.0249). We conclude that inflammatory cell infiltration increases with larger tumor size but is associated with slower percentual volumetric tumor growth.

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Section: Introductionmentioning

confidence: 99%

“…First insights into the role of inflammatory processes have been gained. For example, the differentiation of infiltrating macrophages into M2 macrophages has been described [ 6 , 10 ]. These cells are believed to act as tumor-associated macrophages, a concept that has been developed in other cancer types.…”

Section: Introductionmentioning

confidence: 99%

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

Gonçalves

Suhm

Ries

et al. 2021

Cancers

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“…It is also possible that an immune mediated mechanism could play a role in the pathophysiology of hearing loss progression, as immune and inflammatory mechanisms have previously been found to occur in other inner ear pathologies such as Ménière's disease, DFNA34 hearing loss and related autoimmune and autoinflammatory diseases of the inner ear ( 24 – 26 ). A growing field of evidence suggests that inflammation is a key feature of the VS microenvironment as well, such as excessive activation of the NLRP3 inflammasome leading to upregulation of associated proteins NLRP3 and IL-1β, which have been preferentially upregulated in tumors associated with increased hearing loss ( 12 , 27 ). The relative impact on thresholds vs. word understanding in contralateral ears can provide clues to the nature of which VS-secreted factors or immune mediated responses may be responsible for causing hearing loss in the VS-ipsilateral ear, and can guide further research in this direction.…”

Section: Discussionmentioning

confidence: 99%

Progression of Contralateral Hearing Loss in Patients With Sporadic Vestibular Schwannoma

et al. 2020

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Background and Introduction: Vestibular schwannomas (VSs) are the most common tumors of the cerebellopontine angle, typically presenting unilaterally with ipsilateral sensorineural hearing loss (SNHL). The mechanism of tumor-induced hearing loss has recently been shown to be related to secreted tumor factors, in addition to mechanical compression of the adjacent auditory nerve, and these factors may percolate through CSF or blood to affect contralateral hearing as well. Methods: This is a retrospective study of medical records for patients treated for VS at Mass Eye and Ear from January 1994 through October 2018. Included patients had unilateral VS and sequential audiometry allowing for longitudinal assessment of hearing over time. Mass Eye and Ear's audiology database was used to select age-and sex-matched case controls, also with sequential audiometry, from the non-VS population. Subgroup analysis was performed by age, sex, baseline hearing, and tumor size at initial diagnosis. Hearing loss progression was performed using Kaplan-Meier analysis to account for variable follow-up times. Results: A total of 661 patients were identified with VS and sequential audiometry. The population was predominantly female vs. male (368 vs. 293, p = 0.0035), driven primarily by younger patients with Koos 4 tumors (76 female vs. 49 male, p = 0.016). Patients with normal baseline hearing bilaterally (N = 241) demonstrated no significant difference in hearing loss progression in VS-contralateral vs. control ears. Patients with abnormal baseline VS-ipsilateral hearing (N = 190), however, demonstrated significantly higher likelihood of reaching moderate SNHL in VS-contralateral ears. Subgroup analysis by age, sex, and baseline tumor size did not yield any subgroup-specific trends for hearing loss progression. Discussion and Conclusion: This is the largest study to date tracking long-term bilateral hearing outcomes in patients with VS, and demonstrates that, in patients with abnormal hearing in the VS-ipsilateral ear, there exists a long-term risk of progression to moderate hearing loss in the contralateral ear as well. Combined with the absence Early et al. Vestibular Schwannoma Contralateral Hearing Loss of significant changes in word understanding in the affected ears, these findings may provide clues to the nature of tumor-secreted factors involved in VS-associated hearing loss. Female predominance within the VS patient population is confirmed, driven mostly by younger female patients with Koos 4 tumors.

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“…[4][5][6] Previously, VS were considered to be a largely homogenous proliferation of Schwann's cells with bland intervening stroma, but it is now understood that there is a complex microenvironment characterized by an inflammatory cell infiltrate that may correlate with tumor progression. [7][8][9] Analyses of VS tissue have demonstrated greater levels of inflammatory cell infiltration in growing as opposed to static VS and there is evidence that inflammatory cells account for a substantial proportion of cells in growing VS. 6,10 This has led to the suggestion that tumor inflammation promotes growth, although we are yet to determine if immune infiltrates are fueling tumor cell proliferation or eliminating tumor cells and maintaining growth control in more active tumors. These developments in VS pathobiology create new avenues for translational research, both in terms of the early identification of growing tumors, and the development of targeted therapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

Beyond Antoni: A Surgeon's Guide to the Vestibular Schwannoma Microenvironment

Hannan

Lewis

O’Leary

et al. 2020

J Neurol Surg B Skull Base

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Introduction Vestibular schwannomas (VS) are histologically benign tumors arising from cranial nerve VIII. Far from a homogenous proliferation of Schwann cells, mounting evidence has highlighted the complex nature of the inflammatory microenvironment in these tumors. Methods A review of the literature pertaining to inflammation, inflammatory molecular pathways, and immune-related therapeutic targets in VS was performed. Relevant studies published up to June 2020 were identified based on a literature search in the PubMed and MEDLINE databases and the findings were synthesized into a concise narrative review of the topic. Results The VS microenvironment is characterized by a dense infiltrate of inflammatory cells, particularly macrophages. Significantly higher levels of immune cell infiltration are observed in growing versus static tumors, and there is a demonstrable interplay between inflammation and angiogenesis in growing VS. While further mechanistic studies are required to ascertain the exact role of inflammation in angiogenesis, tumor growth, and Schwann cell control, we are beginning to understand the key molecular pathways driving this inflammatory microenvironment, and how these processes can be monitored and targeted in vivo. Conclusion Observational research has revealed a complex and heterogeneous tumor microenvironment in VS. The functional landscape and roles of macrophages and other immune cells in the VS inflammatory infiltrate are, however, yet to be established. The antiangiogenic drug bevacizumab has shown the efficacy of targeted molecular therapies in VS and there is hope that agents targeting another major component of the VS microenvironment, inflammation, will also find a place in their future management.

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The inflammatory microenvironment in vestibular schwannoma

Cited by 48 publications

References 96 publications

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

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

Progression of Contralateral Hearing Loss in Patients With Sporadic Vestibular Schwannoma

Beyond Antoni: A Surgeon's Guide to the Vestibular Schwannoma Microenvironment

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