Hearing loss affects 95% of patients with vestibular schwannoma (VS), either because of the disease or its treatment. In untreated tumors, hearing loss is usually progressive but can be sudden and profound in up to 10%. In neurofibromatosis type 2-related schwannomatosis (NF2), where bilateral VS are almost universal, bilateral hearing loss has a greater impact on quality of life than any other factor. Hearing loss may result from vascular compromise of the cochlea, direct damage to the cochlear nerve by the tumor, direct growth of tumor into the cochlea, distortion of the cochlear nucleus by larger tumors, or the buildup of toxic metabolites in CSF, particularly at the fundus of the internal auditory canal. There are numerous means by which hearing can be rehabilitated. Hearing aids are helpful for those who have reasonable residual hearing although hearing distortion is common in VS patients and may limit the amount of benefit. If treatment of a tumor is required, then hearing preservation options such as stereotactic radiosurgery or hearing preservation surgery may be considered if the tumor is small- or medium-sized. However, hearing loss often progresses more quickly following stereotactic radiosurgery and the risk of losing hearing following hearing preservation surgery is as high as 60% depending on tumor size and the approach used. Patients with profound hearing loss often benefit from cochlear implantation as long as the cochlear nerve is intact and open-set speech discrimination is not uncommon. In patients in whom the cochlear nerve is no longer intact (usually following surgery for VS in NF2), auditory brainstem implantation is a viable option although auditory benefit is limited, mainly providing an aid to lip reading.

Vestibular schwannoma surgery demands much of the surgeon, both in preparation and execution of a surgical plan. We review preoperative aspects, including decision-making and setting up the necessary equipment and surgical environment. The ergonomics of microsurgery and strategies to deal with the surgical burden are reviewed. The steps in tumor resection are described in detail, with the authors' perspective on how each of these stages is best achieved. This incorporates techniques for effective tumor removal while identifying and preserving key structures. We expand upon methods to dissect blood vessels, cranial nerves, and the brainstem, with a focus on tips for facial nerve dissection. A variety of surgical challenges are dealt with, specifically their avoidance as well as how to deal with them should they arise. Scenarios that are covered are venous sinus injury, brain swelling, bleeding, and encountering unexpected pathology. Facial nerve issues discussed are severe tumor adherence, conduction block, and nerve division. Recognition that this is a highly variable pathology and equipping oneself with surgical techniques to deal with the range of challenges encountered are key to mastering this surgery.

OBJECTIVE:Translabyrinthine excision of a vestibular schwannoma is associated with acute vestibular failure. Preoperative intratympanic gentamicin (ITG) injections can improve objective balance function after surgery but its clinical benefits remain to be established. METHODS:Adult patients undergoing translabyrinthine removal of a vestibular schwannoma between January 2014 and February 2018 underwent preoperative vestibular function testing. Patients were divided in to 3 groups, those with vestibular function (VF) who received ITG injections, those with VF but did not receive ITG and those with no VF. Groups were compared according to degree of vertigo, length of stay, time to unassisted mobilization, and postoperative anti-emetic consumption. RESULTS:Forty six patients had ITG injections (Group 1), 7 had residual VF but refused treatment (Group 2), 21 had no VF (Group 3). Group 1 had a significant improvement in vertigo over time whereas groups 2 and 3 did not. There was a statistically significant 70% decrease in time to independent mobilization between Group 1 and other groups and a 19% decrease in length of stay in Group 1 compared to other groups although this did not reach statistical significance. Two patients had injection-related complications. Group 1 used less anti-emetics than other groups but this was not statistically significant. CONCLUSION:Preoperative intratympanic gentamicin injection with vestibular rehabilitation exercises is associated with less postoperative vertigo and earlier postoperative mobilization. There was reduced duration of hospitalization and decreased consumption of anti-emetic but not significantly so possibly because of low numbers of patients in the no treatment group. LEVEL OF EVIDENCE:2 Laryngoscope, 134:3316-3322, 2024.

Introduction:Surgery for skull base epidermoid cysts (SBECs) has several inherent risks including aseptic meningitis and cerebrospinal fluid (CSF) malabsorption. Perioperative measures to reduce the likelihood of such complications have not been evaluated, and this study sought to compare outcomes before and after implementation of an institutional perioperative protocol in the management of SBECs. Methods:Review of a prospective database of surgically managed SBECs. Outcomes were compared before (2003-2008) and after (2010-2021) implementation of a perioperative protocol including intraoperative hyper-irrigation, prolonged course of postoperative steroids, and aggressive management of CSF malabsorption. Results:A total of 39 patients were included: 12 before and 27 after implementation of the protocol. The groups were similar with respect to mean age ( p  = 0.99), gender ( p  = 0.29), surgical approach-most commonly retrosigmoid ( p  > 0.99)-and extent of resection-most commonly total or near total ( p  = 0.64). The post-protocol implementation group had a significantly lower rate of CSF diversion ( p  = 0.04). The overall rates of hydrocephalus (7 vs. 30%), CSF leak (19 vs. 33%), bacterial meningitis (15 vs. 33%), and mean length of stay (12 vs. 49 days) were lower in the post-implementation group, although differences did not reach statistical significance. Rates of aseptic meningitis and cranial nerve palsies were similar. Conclusion:Our additional perioperative measures resulted in more favorable CSF dynamics with reduced need for CSF diversion and secondary consequences such as wound leaks and infective meningitis.

Objective:Skull base chordoma and chondrosarcoma are distinct sarcomas of the skull base but share significant therapeutic challenges due to their proximity to critical neurovascular structures, making surgical resection difficult. We sought to establish factors associated with outcome predictors in a national cohort of patients. Methods and analysis:Data for all patients referred with a diagnosis of skull base chordoma or chondrosarcoma from April 2017 to December 2022 were obtained. We performed analyses of data pertaining to the first cohort of patients treated in the UK with proton beam therapy (PBT) to determine factors associated with obtaining gross total resection (GTR) and adequate clearance of the brainstem and optic apparatus. Results:Of 230 patients with skull base chordoma or chondrosarcoma referred for PBT, 71% were accepted for PBT, with a wide regional variation between referring neurosurgical units (29%-93%). Of the first 75 consecutive patients treated with PBT, the only factor predictive of obtaining GTR was surgical resection at a unit with higher volumes of patients accepted for PBT (OR 1.32, 95% CI 1.11 to 1.63, p=0.004). Use of intraoperative MRI (OR 4.84, 95% CI 1.21 to 27.83, p=0.04) and resection at a higher volume unit (OR 1.29, 95% CI 1.07 to 1.64, p=0.013) were associated with increased rates of tumour clearance from the brainstem/optic apparatus. Conclusions:Treatment at a higher volume centre was a key determinant of the optimal surgical outcome in this cohort. These data support the management of skull base chordomas and chondrosarcomas in higher volume centres where multidisciplinary experience can be accumulated.

OBJECTIVES:Radiation treatment, particularly at a young age, creates theoretical risk for long-term adverse radiation effects, including the development of malignancy. The literature is sparse on radiation-induced vestibular schwannomas (VSs). METHODS:A retrospective review was performed for cases of suspected radiation-induced VS at 2 high-volume centers. Only cases where radiation included coverage of the posterior fossa were included with those diagnosed within 3 years of radiation treatment being excluded. Patient and tumor characteristics were collected. A systematic literature review was also performed for any previously published series on radiation-induced VS. RESULTS:Eight cases of radiation-induced VS were identified with a median follow-up 125 months (range 7-131). The median age at incident radiation was 15 years (range 2-46). The median age at VS diagnosis was 57 years (range 26-83) with median interval from radiation to diagnosis of 51-years (range 15-66). The median tumor size was 6 mm (range 3-21). Two patients underwent surgical resection. Lesions were described as soft and highly vascular, with medium to high adherence to the facial nerve. Five articles with a total of 52 patients were identified, median age at VS diagnosis was 42-years (range 23-73) with a median interval from radiation to diagnosis of 19 years (range 15-23). CONCLUSIONS:The development of VS following radiation exposure appears rare and our understanding of the condition remains incomplete. Further studies are required to determine the best management of these patients and determine whether there is a causative relationship between radiation exposure and the development of VS.

[This corrects the article DOI: 10.1093/noajnl/vdad089.].

Skull base chordomas and chondrosarcomas are distinct types of rare, locally aggressive mesenchymal tumors that share key principles of imaging investigation and multidisciplinary care. Maximal safe surgical resection is the treatment choice for each, often via an expanded endoscopic endonasal approach, with or without multi- layer skull base repair. Postoperative adjuvant radiation therapy is frequently administered, usually with particle therapy such as proton beam therapy (PBT). Compared with photon therapy, PBT enables dose escalation while limiting damage to dose-limiting neurologic structures, particularly the brainstem and optic apparatus, due to energy deposition being delivered at a high maximum with a rapid decrease at the end of the penetration range (Bragg peak phenomenon). Essential requirements for PBT following gross total or maximal safe resection are tissue diagnosis, minimal residual tumor after resection, and adequate clearance from PBT dose-limiting structures. The radiologist should understand surgical approaches and surgical techniques, including multilayer skull base repair, and be aware of evolution of postsurgical imaging appearances over time. Accurate radiologic review of all relevant preoperative imaging examinations and of intraoperative and postoperative MRI examinations plays a key role in management. The radiology report should reflect what the skull base surgeon and radiation oncologist need to know, including distance between the tumor and PBT dose-limiting structures, tumor sites that may be difficult to access via the endoscopic endonasal route, the relationship between intradural tumor and neurovascular structures, and tumor sites with implications for postresection stability.

Introduction Skull base meningiomas (SBMs) are often subtotally resected and there is a paucity of evidence regarding the long-term rates of postoperative tumor progression. We aimed to investigate the factors that influence tumor recurrence in patients with an extended period of follow-up. Methods Surgically resected tumors with long-term radiological follow-up were included for analysis. Data were collected on patient demographics, anatomical location, Simpson grade, World Health Organization (WHO) grade, modality of reintervention, and functional status. Recurrence was defined as tumor progression requiring intervention. Kaplan-Meier method and log-rank test were used to calculate recurrence-free probability. Cox regression analysis was used to determine factors associated with tumor progression. Results Sixty-one patients were identified. Median radiological follow-up was 11.25 (IQR 4.3) years. Median age at first surgery was 50 (IQR 17) years. A total of 55/61(90%) tumors were WHO grade I and 6/61(10%) were grade II. Gross total resection (GTR) was achieved in 37/61 (60.7%) patients with subtotal resection (STR) in 24/61 (39.3%). In total, 28/61(45.9%) demonstrated recurrence/regrowth with a median time to recurrence of 2.8 (IQR 5) years. Also, 15/37 (40.5%) and 13/24 (54.2%) patients with GTR and STR, respectively, had tumor recurrence. Of the 28 recurrences, 4/28 (14.3%) underwent reresection, 9/28 (32.1%) were managed with radiotherapy, and 15/28 (53.6%) received both reresection and radiotherapy. Tumor grade was the only significant predictor of tumor recurrence (p = 0.033). Neurological function at last follow-up was significantly worse (modified Rankin scale >2) in patients with recurrence (p = 0.035). Conclusion Surgically resected SBMs are associated with a significant recurrence rate during prolonged follow-up, irrespective of the extent of resection achieved. We recommend a prolonged period of radiological surveillance for SBM following surgical resection.

There is no guidance surrounding postoperative venous thromboembolism (VTE) prophylaxis using pharmacological agents (chemoprophylaxis) in patients undergoing skull base surgery. The aim of this study was to compare VTE and intracranial haematoma rates after skull base surgery in patients treated with/without chemoprophylaxis. Review of prospective quaternary centre database including adults undergoing first-time skull base surgery (2009–2020). VTE was defined as deep vein thrombosis (DVT) and pulmonary embolism (PE) within 6 months of surgery. Multivariate logistic regression was used to determine factors predictive of postoperative intracranial haematoma/VTE. Propensity score matching (PSM) was used in group comparisons. One thousand five hundred fifty-one patients were included with a median age of 52 years (range 16–89 years) and female predominance (62

OBJECTIVE:The aim of this study was to describe the natural history of incidental benign-appearing notochordal lesions of the skull base with specific attention to features that can make differentiation from low-grade chordoma more difficult, namely contrast uptake and bone erosion. METHODS:In this retrospective case series, the authors describe the clinical outcomes of 58 patients with incidental benign-appearing notochordal lesions of the clivus, including those with minor radiological features of bone erosion or contrast uptake. RESULTS:All lesions remained stable during a median follow-up of almost 3 years. Thirty-seven (64%) patients underwent contrast-enhanced MRI; lesions in 14 (38%) of these patients exhibited minimal contrast enhancement. Twenty-seven (47%) patients underwent CT; lesions in 6 (22%) of these patients exhibited minimal bone erosion. CONCLUSIONS:These data make the case for monitoring selected cases of benign-appearing notochordal lesions of the clivus in the first instance even when there is minor contrast uptake or minimal bone erosion.

ObjectivesNew diagnostic criteria for NF2-related schwannomatosis (NF2) were published in 2022. An updated UK prevalence was generated in accordance with these, with an emphasis on the rate of de novo NF2 (a 50% frequency is widely quoted in genetic counselling). The distribution of variant types among de novo and familial NF2 cases was also assessed.MethodsThe UK National NF2 database identifies patients meeting updated NF2 criteria from a highly ascertained population cared for by England’s specialised service. Diagnostic prevalence was assessed on 1 February 2023. Molecular analysis of blood and, where possible, tumour specimens forNF2, LZTR1andSMARCB1was performed.Results1084 living NF2 patients were identified on prevalence day (equivalent to 1 in 61 332). The proportion with NF2 inherited from an affected parent was only 23% in England. If people without a confirmed molecular diagnosis or bilateral vestibular schwannoma are excluded, the frequency of de novo NF2 remains high (72%). Of the identified de novo cases, almost half were mosaic. The most common variant type was nonsense variants, accounting for 173/697 (24.8%) of people with an established variant, but only 18/235 (7.7%) with an inheritedNF2pathogenic variant (p<0.0001). Missense variants had the highest proportion of familial association (56%). The prevalence ofLZTR1-related schwannomatosis andSMARCB1-related schwannomatosis was 1 in 527 000 and 1 in 1.1M, respectively, 8.4–18.4 times lower than NF2.ConclusionsThis work confirms a much higher rate of de novo NF2 than previously reported and highlights the benefits of maintaining patient databases for accurate counselling.

Background Most schwannomas are isolated tumours occurring in otherwise healthy people. However, bilateral vestibular schwannomas (BVS) or multiple non-vestibular schwannomas indicate an underlying genetic predisposition. This is most commonly NF2 -related schwannomatosis (SWN), but when BVS are absent, this can also indicate SMARCB1 -related or LZTR1 -related SWN. Methods We assessed the variant detection rates for the three major SWN genes ( NF2 , LZTR1 and SMARCB1 ) in 154 people, from 150 families, who had at least one non-vestibular schwannoma, but who did not meet clinical criteria for NF2 -related SWN at the time of genetic testing. Results We found that 17 (11%) people from 13 families had a germline SMARCB1 variant and 19 (12%) unrelated individuals had a germline LZTR1 variant. 19 people had an NF2 variant, but 18 of these were mosaic and 17 were only detected when 2 tumours were available for testing. The overall detection rate was 25% using blood alone, but increased to 36% when tumour analysis was included. Another 12 people had a germline variant of uncertain significance (VUS). Conclusions There were similar proportions of LZTR1 , SMARCB1 or mosaic NF2 . However, since an NF2 variant was detected in tumours from 103 people, it is likely that further cases of mosaicism would be detected if more people had additional tumours available for analysis. In addition, if further evidence becomes available to show that the VUSs are pathogenic, this would significantly increase the proportion of people with a genetic diagnosis. Our results indicate the importance of comprehensive genetic testing and improved variant classification.

Objective:Surveillance plays a crucial role in managing patients with vestibular schwannomas (VSs). Consensus is lacking on the optimal duration, frequency, and modality of imaging. Standardizing this approach would ensure safe and effective care, reduce patient distress, and promote consistency in management decisions among clinicians. Methods:In July 2022, a multi-disciplinary Delphi consensus was conducted at the British Skull Base Society Meeting. Expert United Kingdom-based skull-base surgeons and neuroradiologists were presented semi-systematic literature reviews summarizing current evidence on VS management. Anonymized opinions were collated and discussed to reach a majority vote, which was deemed the final consensus opinion. Results:Recommendations for VS managed by surveillance are: (1) surveillance frequency should decrease over time; (2) surveillance may be discontinued when the remaining lifetime risk of VS growth is <0.5% (∼8.5 years); (3) factors such as age, VS size, VS location, and cystic components should be considered. Surveillance after surgery or radiotherapy has limited evidence but recommendations are: (4) surveillance should be adjusted based on residual tumor size or nodular enhancement. Imaging modality and sequences are recommended to be (5) high-resolution magnetic resonance imaging with T1, T2, FIESTA/CISS multiplanar sequences, contrast is not required in untreated cases, and linear reporting of measurements is pragmatically sufficient. Conclusion:This consensus and literature review provides an evidence and expert opinion-based guide to help clinicians with the surveillance of patients with VS. Further research should focus on better understanding the dynamic nature of growth risks and the growth characteristics of postintervention VS to enable personalized growth risk stratification.

Background Nonauditory symptoms can be a prominent feature in patients with sporadic vestibular schwannoma (VS), but the cause of these symptoms is unknown. Inflammation is hypothesized to play a key role in the growth and symptomatic presentation of sporadic VS, and in this study, we investigated through translocator protein (TSPO) positron emission tomography (PET) whether inflammation occurred within the "normal appearing" brain of such patients and its association with tumor growth.Methods Dynamic PET datasets from 15 patients with sporadic VS (8 static and 7 growing) who had been previously imaged using the TSPO tracer [11C](R)-PK11195 were included. Parametric images of [11C](R)-PK11195 binding potential (BPND) and the distribution volume ratio (DVR) were derived and compared across VS growth groups within both contralateral and ipsilateral gray (GM) and white matter (WM) regions. Voxel-wise cluster analysis was additionally performed to identify anatomical regions of increased [11C](R)-PK11195 binding.Results Compared with static tumors, growing VS demonstrated significantly higher cortical (GM, 1.070 vs. 1.031, P = .03) and whole brain (GM & WM, 1.045 vs. 1.006, P = .03) [11C](R)-PK11195 DVR values. The voxel-wise analysis supported the region-based analysis and revealed clusters of high TSPO binding within the precentral, postcentral, and prefrontal cortex in patients with growing VS.Conclusions We present the first in vivo evidence of increased TSPO expression and inflammation within the brains of patients with growing sporadic VS. These results provide a potential mechanistic insight into the development of nonauditory symptoms in these patients and highlight the need for further studies interrogating the role of neuroinflammation in driving VS symptomatology.

Objective This study aimed to assess degree of audiovestibular handicap in patients with vestibular schwannoma. Methods Audiovestibular handicap was assessed using the Hearing Handicap Inventory, Tinnitus Handicap Inventory and Dizziness Handicap Inventory. Patients completed questionnaires at presentation and at least one year following treatment with microsurgery, stereotactic radiosurgery or observation. Changes in audiovestibular handicap and factors affecting audiovestibular handicap were assessed. Results All handicap scores increased at follow up, but not significantly. The Tinnitus Handicap Inventory and Dizziness Handicap Inventory scores predicted tinnitus and dizziness respectively. The Hearing Handicap Inventory was not predictive of hearing loss. Age predicted Tinnitus Handicap Inventory score and microsurgery was associated with a deterioration in Dizziness Handicap Inventory score. Conclusion Audiovestibular handicap is common in patients with vestibular schwannoma, with 75 per cent having some degree of handicap in at least one inventory. The overall burden of handicap was, however, low. The increased audiovestibular handicap over time was not statistically significant, irrespective of treatment modality.

OBJECTIVE:Skull base meningiomas (SBMs) involving the cavernous sinus encase the internal carotid artery (ICA) and may lead to stenosis of the vessel. Although ischemic stroke has been reported in the literature, there are to the authors' knowledge no reported studies quantifying the risk of stroke in these patients. The authors aimed to determine the frequency of arterial stenosis in patients with SBMs that encase the cavernous ICA and to estimate the risk of ischemic stroke in these patients.METHODS:Records of all patients with SBM encasing the ICA whose cases were managed by the skull base multidisciplinary team at Salford Royal Hospital between 2011 and 2017 were reviewed using a two-stage approach: 1) clinical and radiological strokes were identified from electronic patient records, and 2) cases were reviewed to examine the correlation between ICA stenosis associated with SBM encasement and anatomically related stroke. Strokes that were caused by another pathology or did not occur in the perfusion territory were excluded.RESULTS:In the review of patient records the authors identified 118 patients with SBMs encasing the ICA. Of these, 62 SBMs caused stenosis. The median age at diagnosis was 70 (IQR 24) years, and 70% of the patients were female. The median follow-up was 97 (IQR 101) months. A total of 13 strokes were identified in these patients; however, only 1 case of stroke was associated with SBM encasement, which occurred in the perfusion territory of a patient without stenosis. Risk of acute stroke during the follow-up period for the entire cohort was 0.85%.CONCLUSIONS:Acute stroke in patients with ICA encasement by SBMs is rare despite the propensity of these tumors to stenose the ICA. Patients with ICA stenosis secondary to their SBM did not have a higher incidence of stroke than those with ICA encasement without stenosis. The results of this study demonstrate that prophylactic intervention to prevent stroke is not necessary in ICA stenosis secondary to SBM.

NF2-schwannomatosis is the most common genetic predisposition syndrome associated with meningioma. Meningioma in NF2-schwannomatosis is a major source of morbidity and mortality. This is due to accumulative tumor burden in patients with synchronous schwannomas and ependymomas, sometimes including complex collision tumors. Balancing the impact of multiple interventions against the natural history of various index tumors, and the ongoing risk of de novo tumors over an individual's lifetime makes decision-making complex. The management of any given individual meningioma is often different from a comparable sporadic tumor. There is typically a greater emphasis on conservative management and tolerating growth until a risk boundary is reached, whereby symptomatic deterioration or higher risk from anticipated future treatment is threatened. Management by high-volume multidisciplinary teams improves quality of life and life expectancy. Surgery remains the mainstay treatment for symptomatic and rapidly enlarging meningioma. Radiotherapy has an important role but carries a higher risk compared to its use in sporadic disease. Whilst bevacizumab is effective in NF2-associated schwannoma and cystic ependymoma, it has no value in the management of meningioma. In this review, we describe the natural history of the disease, underlying genetic, molecular, and immune microenvironment changes, current management paradigms, and potential therapeutic targets.

OBJECTIVE:Preoperative differentiation of facial nerve schwannoma (FNS) from vestibular schwannoma (VS) can be challenging, and failure to differentiate between these two pathologies can result in potentially avoidable facial nerve injury. This study presents the combined experience of two high-volume centers in the management of intraoperatively diagnosed FNSs. The authors highlight clinical and imaging features that can distinguish FNS from VS and provide an algorithm to help manage intraoperatively diagnosed FNS.METHODS:Operative records of 1484 presumed sporadic VS resections between January 2012 and December 2021 were reviewed, and patients with intraoperatively diagnosed FNSs were identified. Clinical data and preoperative imaging were retrospectively reviewed for features suggestive of FNS, and factors associated with good postoperative facial nerve function (House-Brackmann [HB] grade ≤ 2) were identified. A preoperative imaging protocol for suspected VS and recommendations for surgical decision-making following an intraoperative FNS diagnosis were created.RESULTS:Nineteen patients (1.3%) with FNSs were identified. All patients had normal facial motor function preoperatively. In 12 patients (63%), preoperative imaging demonstrated no features suggestive of FNS, with the remainder showing subtle enhancement of the geniculate/labyrinthine facial segment, widening/erosion of the fallopian canal, or multiple tumor nodules in retrospect. Eleven (57.9%) of the 19 patients underwent a retrosigmoid craniotomy, and in the remaining patients, a translabyrinthine (n = 6) or transotic (n = 2) approach was used. Following FNS diagnosis, 6 (32%) of the tumors underwent gross-total resection (GTR) and cable nerve grafting, 6 (32%) underwent subtotal resection (STR) and bony decompression of the meatal facial nerve segment, and 7 (36%) underwent bony decompression only. All patients undergoing subtotal debulking or bony decompression exhibited normal postoperative facial function (HB grade I). At the last clinical follow-up, patients who underwent GTR with a facial nerve graft had HB grade III (3 of 6 patients) or IV facial function. Tumor recurrence/regrowth occurred in 3 patients (16%), all of whom had been treated with either bony decompression or STR.CONCLUSIONS:Intraoperative diagnosis of an FNS during a presumed VS resection is rare, but its incidence can be reduced further by maintaining a high index of suspicion and undertaking further imaging in patients with atypical clinical or imaging features. If an intraoperative diagnosis does occur, conservative surgical management with bony decompression of the facial nerve only is recommended, unless there is significant mass effect on surrounding structures.

Vestibular schwannomas are benign nerve sheath tumours that arise on the vestibulocochlear nerves. Vestibular schwannomas are known to occur in the context of tumour predisposition syndromes NF2-related and LZTR1-related schwannomatosis. However, the majority of vestibular schwannomas present sporadically without identification of germline pathogenic variants. To identify novel genetic associations with risk of vestibular schwannoma development, we conducted a genome-wide association study in a cohort of 911 sporadic vestibular schwannoma cases collated from the neurofibromatosis type 2 genetic testing service in the north-west of England, UK and 5500 control samples from the UK Biobank resource. One risk locus reached genome-wide significance in our association analysis (9p21.3, rs1556516, P = 1.47 × 10-13, odds ratio = 0.67, allele frequency = 0.52). 9p21.3 is a genome-wide association study association hotspot, and a number of genes are localized to this region, notably CDKN2B-AS1 and CDKN2A/B, also referred to as the INK4 locus. Dysregulation of gene products within the INK4 locus have been associated with multiple pathologies and the genes in this region have been observed to directly impact the expression of one another. Recurrent associations of the INK4 locus with components of well-described oncogenic pathways provides compelling evidence that the 9p21.3 region is truly associated with risk of vestibular schwannoma tumorigenesis.