Vestibular schwannomas are tumors arising from the vestibulocochlear nerve at the cerebellopontine angle. Their proximity to eloquent brainstem structures means that the pathology itself and the treatment thereof can be associated with significant morbidity. The vast majority of these tumors are sporadic, with the remainder arising as a result of the genetic syndrome Neurofibromatosis Type 2 or, more rarely, LZTR1-related schwannomatosis. The natural history of these tumors is extremely variable, with some tumors not displaying any evidence of growth, others demonstrating early, persistent growth and a small number growing following an extended period of indolence. Emerging evidence now suggests that far from representing Schwann cell proliferation only, the tumor microenvironment is complex, with inflammation proposed to play a key role in their growth. In this review, we provide an overview of this new evidence, including the role played by immune cell infiltration, the underlying molecular pathways involved, and biomarkers for detecting this inflammation in vivo. Given the limitations of current treatments, there is a pressing need for novel therapies to aid in the management of this condition, and we conclude by proposing areas for future research that could lead to the development of therapies targeted toward inflammation in vestibular schwannoma.

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 [K ^trans ], fractional plasma volume, tissue extravascular-extracellular space [v _e ], 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. K ^trans (p < 0.001), v _e (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.

Objective: Few data are available on the surgical results in patients with incidentally discovered nonfunctioning pituitary adenoma (NFPA). We investigated the efficacy and safety of surgery in patients with incidentally discovered NFPA.Design: Retrospective analysis of prospectively recorded outcomes.Methods: From 1990 to 2011, of 804 consecutive patients undergoing surgery for NFPA, 212 cases had an incidentally discovered tumor (26.4%). Among them, 117 patients were asymptomatic, while 95 had some visual and/or hormonal deficit. The main outcome of the study was to evaluate the frequency of radical resection as judged on the first postoperative neuroimaging study and detection of recurring disease during long-term follow-up.Results: Postoperative residual tumor was detected in 8.9% of patients with asymptomatic incidentalomas as compared with 31.2% of patients with symptomatic incidentalomas (P<0.001) and 41.2% of patients in the control group (P<0.001). Multivariate analysis confirmed that having an asymptomatic incidentaloma was independently associated with a better outcome. The 5-year recurrence-free survival in patients with incidentaloma was 86.8% (95% CI 80.2–92.4%) as compared with 77.9% (95% CI 73.6–82.2%; P<0.01) in the control group. This difference was almost completely due to a lower frequency of relapse in asymptomatic patients. Multivariate analysis confirmed the independent lower risk of tumor recurrence in asymptomatic NFPA.Conclusion: Our study shows for the first time that surgically treated patients with asymptomatic NFPA have a better early and long-term outcome that is independent from all the other demographic, clinical, and morphologic characteristics of the patients.

With the advent of immunotherapies, the field of cancer therapy has been revived with new hope, especially for cancers with dismal prognoses, such as the glioblastoma multiforme (GBM). Currently, immunotherapies should potentiate the host’s own antitumor immune response against cancer cells, but it has been documented that they are effective only in small subsets of patients. Therefore, accurate predictors of response are urgently needed to identify who will benefit from immune-modulatory therapies. Brain tumors are challenging in terms of treatments. The immune response in the brain is highly regulated, and the immune microenvironment in brain metastases is active with a high density of tumor-infiltrating lymphocytes (TILs, CD3+ T cells) in certain patients and, therefore, may serve as a potential treatment target. In our study, we performed immunohistochemistry for CD3 and PD-L1 along the routine assessment of the O6-methylguanine-methyltransferase (MGMT) promoter methylation status and the IDH1 and 2 status in a single center cohort of 69 patients with GBM (58 primary tumors and 11 recurrences) who underwent standard multimodal therapies (surgery/radiotherapy/adjuvant temozolamide). We analyzed the association of PD-L1 tumor expression and TILs with overall survival (OS). The PD-L1 expression was observed in 25 of 58 (43%) newly diagnosed primary glioblastoma specimens. The sparse-to-moderate density of TILs, identified with CD3+ expression, was found in 48 of 58 (83%) specimens. Neither PD-L1 expression nor TILs were associated with overall survival. In conclusion, TILs and/or PD-L1 expression are detectable in the majority of glioblastoma samples, and even if they slightly relate to the outcome, they do not show a statistically significant correlation.