Objectives: Schwannomatosis is a dominantly inherited condition predisposing to schwannomas of mainly spinal and peripheral nerves with some diagnostic overlap with neurofibromatosis-2 (NF2), but the underlying epidemiology is poorly understood. We present the birth incidence and prevalence allowing for overlap with NF2.Methods: Schwannomatosis and NF2 cases were ascertained from the Manchester region of England (population=4.8 million) and from across the UK. Point prevalence and birth incidence were calculated from regional birth statistics. Genetic analysis was also performed on NF2, LZTR1 and SMARCB1 on blood and tumour DNA samples when available.Results: Regional prevalence for schwannomatosis and NF2 were 1 in 126 315 and 50 500, respectively, with calculated birth incidences of 1 in 68 956 and 1 in 27 956. Mosaic NF2 causes a substantial overlap with schwannomatosis resulting in the misdiagnosis of at least 9% of schwannomatosis cases. LZTR1-associated schwannomatosis also causes a small number of cases that are misdiagnosed with NF2 (1%–2%), due to the occurrence of a unilateral vestibular schwannoma. Patients with schwannomatosis had lower numbers of non-vestibular cranial schwannomas, but more peripheral and spinal nerve schwannomas with pain as a predominant presenting symptom. Life expectancy was significantly better in schwannomatosis (mean age at death 76.9) compared with NF2 (mean age at death 66.2; p=0.004).Conclusions: Within the highly ascertained North-West England population, schwannomatosis has less than half the birth incidence and prevalence of NF2.

Inflammation 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. Nineteen 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 (BP_ND) and DCE-MRI derived vascular biomarkers (K^trans, v_p, v_e) 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. Compared with static tumors, growing VS displayed significantly higher mean ¹¹C-(R)-PK11195 BP_ND (−0.07 vs 0.47, P = 0.020), and higher mean tumor K^trans (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. We 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.

Meningiomas are tumors that develop from the arachnoid layer of the meningeal membrane covering the brain and spinal cord. Schwannomas arise from Schwann cells surrounding nerves. Meningiomas and schwannomas are normally isolated and sporadic but account for almost half of all primary brain and central nervous system tumors in adults.¹ They are rare in children and young adults, with meningiomas accounting for approximately 3% of brain tumors in the pediatric population and schwannomas accounting for approximately 5%. Ninety-four percent of schwannomas are vestibular schwannomas (VSs).¹ The occurrence of multiple meningiomas and/or schwannomas in patients who have not received radiotherapy is unusual and often associated with the tumor suppressor syndrome neurofibromatosis type 2 (NF2) or, less frequently, schwannomatosis.² Consequently, the occurrence of multiple meningiomas or schwannomas, unlike solitary tumors, usually triggers genetic evaluation. It is not standard practice to test patients with solitary tumors, but testing in young patients sometimes heralds genetic syndromes with multiple subsequent tumors. Indeed, previous work³ has shown that 14% of children with isolated meningiomas and 13% with schwannomas will later fulfill the diagnostic criteria for NF2.⁴

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.