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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, Pâ =â .03) and whole brain (GM & WM, 1.045 vs. 1.006, Pâ =â .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.
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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.
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Neoplasias Inducidas por Radiación , Neuroma Acústico , Humanos , Neuroma Acústico/radioterapia , Persona de Mediana Edad , Adulto , Femenino , Anciano , Masculino , Neoplasias Inducidas por Radiación/etiología , Estudios Retrospectivos , Anciano de 80 o más Años , Adulto Joven , Adolescente , Radioterapia/efectos adversosRESUMEN
PURPOSE: 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. METHODS: 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. RESULTS: One thousand five hundred fifty-one patients were included with a median age of 52 years (range 16-89 years) and female predominance (62%). Postoperative chemoprophylaxis was used in 81% of patients at a median of 1 day postoperatively. There were 12 VTE events (1.2%), and the use of chemoprophylaxis did not negate the risk of VTE entirely (p > 0.99) and was highest on/after postoperative day 6 (9/12 VTE events). There were 18 intracranial haematomas (0.8%), and after PSM, chemoprophylaxis did not significantly increase the risk of an intracranial haematoma (p > 0.99). Patients administered chemoprophylaxis from postoperative days 1 and 2 had similar rates of intracranial haematomas (p = 0.60) and VTE (p = 0.60), affirmed in PSM. CONCLUSION: Postoperative chemoprophylaxis represents a relatively safe strategy in patients undergoing skull base surgery. We advocate a personalised approach to chemoprophylaxis and recommend it on postoperative days 1 or 2 when indicated.
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Embolia Pulmonar , Tromboembolia Venosa , Adulto , Humanos , Femenino , Adolescente , Adulto Joven , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Masculino , Tromboembolia Venosa/prevención & control , Tromboembolia Venosa/inducido químicamente , Tromboembolia Venosa/tratamiento farmacológico , Estudios Prospectivos , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/tratamiento farmacológico , Factores de Riesgo , Anticoagulantes/uso terapéutico , Hemorragia Cerebral/tratamiento farmacológico , Estudios Retrospectivos , Hematoma , Base del Cráneo/cirugíaRESUMEN
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.
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Gentamicinas , Neuroma Acústico , Cuidados Preoperatorios , Humanos , Gentamicinas/administración & dosificación , Neuroma Acústico/cirugía , Masculino , Femenino , Persona de Mediana Edad , Anciano , Cuidados Preoperatorios/métodos , Adulto , Inyección Intratimpánica , Resultado del Tratamiento , Estudios Retrospectivos , Recuperación de la Función , Antibacterianos/administración & dosificación , Vértigo/etiología , Vértigo/prevención & control , Pruebas de Función Vestibular , Tiempo de Internación/estadística & datos numéricosRESUMEN
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.
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BACKGROUND: The occurrence of hyperostotic bilateral spheno-orbital meningiomas (BSOMs) is very rare. Patients present with bilateral symptoms and require bilateral treatment. This series describes 6 patients presenting to 2 UK neurosurgical units and includes a literature review. To the best of the authors' knowledge, this is the largest series documented. OBSERVATIONS: This is a retrospective review of patients with BSOMs presenting between 2006 and 2023. Six females, whose mean age was 43 (range: 36-64) years, presented with features of visual disturbance. Bilateral sphen-oorbital meningiomas were identified. All patients underwent bilateral staged resections. The patients had an initial improvement in their symptoms. Extensive genetic testing was performed in 4 patients, with no variants in the NF2, LZTR1, SMARCB1, SMARCE1, and SMARCA4 genes or other variants detected. The mean follow-up was 100.3 (range: 64-186) months. Sixty-seven percent of patients had good long-term visual acuity. The progression rate was 75% and was particularly aggressive in 1 patient. Four patients required radiation therapy, and 2 needed further surgery. LESSONS: Hyperostotic BSOMs are extensive, challenging tumors causing significant disability. They can recur, with significant patient impact. Multidisciplinary management and indefinite long-term follow-up are essential. The biology of these tumors remains unclear. As molecular testing expands, the understanding of BSOM oncogenesis and potential therapeutic targets is likely to improve.
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Neurofibromatosis 2 , Neuroma Acústico , Radiocirugia , Humanos , Neuroma Acústico/complicaciones , Neuroma Acústico/radioterapia , Neuroma Acústico/cirugía , Neurofibromatosis 2/complicaciones , Neurofibromatosis 2/cirugía , Transformación Celular Neoplásica/patología , Resultado del TratamientoRESUMEN
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.
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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.
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Estenosis Carotídea , Accidente Cerebrovascular Isquémico , Neoplasias Meníngeas , Meningioma , Neoplasias de la Base del Cráneo , Accidente Cerebrovascular , Humanos , Femenino , Masculino , Meningioma/complicaciones , Meningioma/diagnóstico por imagen , Meningioma/epidemiología , Estenosis Carotídea/complicaciones , Estenosis Carotídea/diagnóstico por imagen , Estenosis Carotídea/epidemiología , Constricción Patológica/diagnóstico por imagen , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Neoplasias de la Base del Cráneo/complicaciones , Neoplasias de la Base del Cráneo/diagnóstico por imagen , Neoplasias de la Base del Cráneo/patología , Neoplasias Meníngeas/complicaciones , Neoplasias Meníngeas/diagnóstico por imagen , Neoplasias Meníngeas/epidemiología , Arteria Carótida Interna/diagnóstico por imagen , Arteria Carótida Interna/patología , Estudios RetrospectivosRESUMEN
Background: Radiation treatment of benign tumors in tumor predisposition syndromes is controversial, but short-term studies from treatment centers suggest safety despite apparent radiation-associated malignancy being reported. We determined whether radiation treatment in NF2-related schwannomatosis patients is associated with increased rates of subsequent malignancy (M)/malignant progression (MP). Methods: All UK patients with NF2 were eligible if they had a clinical/molecular diagnosis. Cases were NF2 patients treated with radiation for benign tumors. Controls were matched for treatment location with surgical/medical treatments based on age and year of treatment. Prospective data collection began in 1990 with addition of retrospective cases in 1969. Kaplan-Meier analysis was performed for malignancy incidence and survival. Outcomes were central nervous system (CNS) M/MP (2cm annualized diameter growth) and survival from index tumor treatment. Results: In total, 1345 NF2 patients, 266 (133-Male) underwent radiation treatments between 1969 and 2021 with median first radiotherapy age of 32.9 (IQR = 22.4-46.0). Nine subsequent CNS malignancies/MPs were identified in cases with only 4 in 1079 untreated (P < .001). Lifetime and 20-year CNS M/MP was ~6% in all irradiated patients-(4.9% for vestibular schwannomas [VS] radiotherapy) versus <1% in the non-irradiated population (P < .001/.01). Controls were well matched for age at NF2 diagnosis and treatment (Males = 133%-50%) and had no M/MP in the CNS post-index tumor treatment (P = .0016). Thirty-year survival from index tumor treatment was 45.62% (95% CI = 34.0-56.5) for cases and 66.4% (57.3-74.0) for controls (P = .02), but was nonsignificantly worse for VS radiotherapy. Conclusion: NF2 patients should not be offered radiotherapy as first-line treatment of benign tumors and should be given a frank discussion of the potential 5% excess absolute risk of M/MP.
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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.
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Neoplasias de los Nervios Craneales , Neurilemoma , Neuroma Acústico , Humanos , Estudios Retrospectivos , Recurrencia Local de Neoplasia/patología , Neurilemoma/diagnóstico por imagen , Neurilemoma/cirugía , Neuroma Acústico/diagnóstico por imagen , Neuroma Acústico/cirugía , Neoplasias de los Nervios Craneales/diagnóstico por imagen , Neoplasias de los Nervios Craneales/cirugía , Nervio Facial/diagnóstico por imagen , Nervio Facial/cirugía , Nervio Facial/patología , Resultado del Tratamiento , Estudios Multicéntricos como AsuntoRESUMEN
BACKGROUND: There is evidence that macrophage infiltration in the tumor microenvironment promotes vestibular schwannoma (VS) growth. Efficacy of bevacizumab in NF2-associated VS demonstrates the value of therapies targeting the microvascular tumor microenvironment, and tumor-associated macrophages (TAMs) may represent another druggable target. OBJECTIVE: To characterize the relationship between growth, TAM infiltration, and circulating monocyte chemokines in a large cohort of patients with VS. METHODS: Immunostaining for Iba1 (macrophages), CD31 (endothelium), and fibrinogen (permeability) was performed on 101 growing and 19 static sporadic VS. The concentrations of monocyte-specific chemokines were measured in the plasma of 50 patients with growing VS and 25 patients with static VS. RESULTS: The Iba1 + cell count was significantly higher in growing as compared with static VS (592 vs 226/×20 HPF, P =<0.001). Similarly, the CD31 + % surface area was higher in growing VS (2.19% vs 1.32%, P = .01). There was a positive correlation between TAM infiltration and VS growth rate, which persisted after controlling for the effect of tumor volume (aR2 = 0.263, P =<0.001). The plasma concentrations of several monocytic chemokines were higher in patients with growing rather than static VS. CONCLUSION: There is a strong positive correlation between TAM infiltration and volumetric growth of VS, and this relationship is independent of tumor size. There is a colinear relationship between TAM infiltration and tumor vascularity, implying that inflammation and angiogenesis are interlinked in VS. Chemokines known to induce monocyte chemotaxis are found in higher concentrations in patients with growing VS, suggestive of a potential pathophysiological mechanism.
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Neuroma Acústico , Humanos , Neuroma Acústico/patología , Quimiocinas/metabolismo , Inflamación/metabolismo , Macrófagos/metabolismo , Macrófagos/patología , Microambiente TumoralRESUMEN
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.
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Neurilemoma , Neurofibromatosis , Neurofibromatosis 2 , Neuroma Acústico , Neoplasias Cutáneas , Humanos , Neuroma Acústico/genética , Estudio de Asociación del Genoma Completo , Neurilemoma/genética , Neurilemoma/patología , Neurofibromatosis/genética , Neoplasias Cutáneas/genética , Neurofibromatosis 2/genética , Factores de Transcripción/genéticaRESUMEN
Objective The study aimed to determine long-term outcomes in patients with intraoperative electrical conduction block in an anatomically intact facial nerve (FN). Methods Single center retrospective review of prospectively collected database of all vestibular schwannoma surgeries between January 1, 2008 and August 25, 2015. Operative notes were reviewed and patients with anatomically intact FNs, but complete conduction block at the end of surgery were included for analysis. Results In total, 371 patients had vestibular schwannoma surgery of which 18 met inclusion criteria. Mean follow-up was 34.28 months and average tumor size was 28.00 mm. Seventeen patients had House-Brackmann Grade VI facial palsy immediately postoperatively and one patient was grade V. At 1 year, three patients remained grade VI (17%), two improved to grade V (11%), seven to grade IV (39%), six to grade III (33%), and one patient to grade II (6%). On extended follow-up, five patients (28%) had additional 1 to 2 score improvement in facial function. Subset analysis revealed no correlation of tumor size, vascularity, adherence to nerve, operative approach, extent of resection, splaying of FN, and recurrent tumor or sporadic tumors to the extent of FN recovery. Conclusion Intraoperative conduction block does not condemn a patient to permanent FN palsy. There is potential for a degree of recovery comparable with those undergoing nerve grafting. Our data do not clearly support a policy of same-surgery or early-postoperative primary nerve grafting in the event of a complete conduction block, and instead we favor monitoring for recovery in an anatomically intact nerve.
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BACKGROUND: Bilateral vestibular schwannomas (VS) are pathognomonic of neurofibromatosis type 2 (NF2), but the diagnostic criteria also include unilateral VS (UVS) in combination with multiple meningiomas (MM) and other schwannomas, as well as MM without VS. OBJECTIVE: To investigate the diagnostic value of these criteria and establish the presence of other genetic conditions in patients presenting in this manner. METHODS: The Manchester International NF2 database was accessed to obtain information on patients presenting with a UVS and MM or ≥2 nonintradermal schwannomas (NIDS). We gathered data on patients diagnosed with NF2 due to MM without VS and on patients presenting with MM without meeting NF2 criteria. Analysis was performed for pathogenic variants (PVs) in NF2, SMARCE1, SMARCB1, and LZTR1. RESULTS: A total of 31 of 131 patients presenting with a UVS and MM had a nonrefuted diagnosis of NF2 after molecular studies, in comparison with 85 of 96 patients presenting with UVS and ≥2 NIDS (P ≤ .00001). Fifty percent of patients presenting with a UVS and ≥2 NIDS with NF2 developed bilateral VS, compared with only 26% of those who presented with a UVS and MM (P = .0046). In total, 11 of 152 patients presenting with MM without fulfilling NF2 criteria were found to have a PV in SMARCE1, and 7 of 152 were confirmed to have mosaic NF2. CONCLUSION: Patients presenting with UVS and MM are significantly more likely to have a nonrefuted diagnosis of NF2 than patients presenting with UVS and ≥2 NIDS, but significantly less likely to develop bilateral VS. Seven percent of those presenting with MM without meeting NF2 criteria had PV in SMARCE1, and 5% had mosaic NF2.
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Neoplasias Meníngeas , Meningioma , Neurilemoma , Neurofibromatosis 2 , Proteínas Cromosómicas no Histona , Proteínas de Unión al ADN , Humanos , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/genética , Meningioma/diagnóstico , Meningioma/genética , Neurilemoma/diagnóstico , Neurilemoma/genética , Neurilemoma/patología , Neurofibromatosis 2/diagnóstico , Neurofibromatosis 2/genética , Neurofibromatosis 2/patología , Síndrome , Factores de Transcripción/genéticaRESUMEN
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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BACKGROUND: Limited data exist on the disease course of neurofibromatosis type 2 (NF2) to guide clinical trial design. METHODS: A prospective database of patients meeting NF2 diagnostic criteria, reviewed between 1990 and 2020, was evaluated. Follow-up to first vestibular schwannoma (VS) intervention and death was assessed by univariate analysis and stratified by age at onset, era referred, and inheritance type. Interventions for NF2-related tumors were assessed. Cox regression was performed to determine the relationship between individual factors from time of diagnosis to NF2-related death. RESULTS: Three hundred and fifty-three patients were evaluated. During 4643.1 follow-up years from diagnosis to censoring, 60 patients (17.0%) died. The annual mean number of patients undergoing VS surgery or radiotherapy declined, from 4.66 and 1.65, respectively, per 100 NF2 patients in 1990-1999 to 2.11 and 1.01 in 2010-2020, as the number receiving bevacizumab increased (2.51 per 100 NF2 patients in 2010-2020). Five patients stopped bevacizumab to remove growing meningioma or spinal schwannoma. 153/353 (43.3%) had at least one neurosurgical intervention/radiation treatment within 5 years of diagnosis. Patients asymptomatic at diagnosis had longer time to intervention and better survival compared to those presenting with symptoms. Those symptomatically presenting <16 and >40 years had poorer overall survival than those presenting at 26-39 years (P = .03 and P = .02, respectively) but those presenting between 16 and 39 had shorter time to VS intervention. Individuals with de novo constitutional variants had worse survival than those with de novo mosaic or inherited disease (P = .004). CONCLUSION: Understanding disease course improves prognostication, allowing for better-informed decisions about care.
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Neoplasias Meníngeas , Meningioma , Neurofibromatosis 2 , Neuroma Acústico , Estudios de Seguimiento , Humanos , Neurofibromatosis 2/epidemiología , Neurofibromatosis 2/genética , Neurofibromatosis 2/terapiaRESUMEN
Clear cell meningioma (CCM) is a rare variant of meningioma. In recent years, an association between cranial and spinal CCMs and germline loss of function mutations in the SMARCE1 gene (SWI/SNF chromatin remodeling complex subunit gene) has been discovered. We report a family with an incidental large spinal clear cell meningioma in a young adult following reflex screening for a germline loss of function pathogenic variant (PV) in the SMARCE1 gene. The index patient's mother and maternal grandfather were both also tested positive presymptomatically for SMARCE1. His mother developed intracranial and spinal meningiomas and his maternal grandfather developed a spinal CCM 4 years following a clear spinal MRI scan which required surgical excision. In this report we particularly emphasize the importance of genetic counseling and screening in siblings, parents and offspring of patients who are diagnosed with intracranial or spinal CCM in the context of SMARCE1 PVs. We recommend brain and spine Imaging screening of asymptomatic SMARCE1 PV carriers at least every 3 years, even if the baseline scan did not show any tumors.
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Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad , Meningioma/genética , Neoplasias de la Columna Vertebral/genética , Adolescente , Niño , Preescolar , Femenino , Asesoramiento Genético , Pruebas Genéticas , Mutación de Línea Germinal/genética , Humanos , Masculino , Meningioma/diagnóstico , Meningioma/diagnóstico por imagen , Meningioma/patología , Linaje , Neoplasias de la Columna Vertebral/diagnóstico , Neoplasias de la Columna Vertebral/diagnóstico por imagen , Neoplasias de la Columna Vertebral/patología , Adulto JovenRESUMEN
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 [Ktrans], fractional plasma volume, tissue extravascular-extracellular space [ve], 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. Ktrans (p < 0.001), ve (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.
Asunto(s)
Imagen por Resonancia Magnética/métodos , Neurofibromatosis 2/patología , Neuroma Acústico/patología , Microambiente Tumoral , Adulto , Anisotropía , Agua Corporal , Imagen de Difusión por Resonancia Magnética , Femenino , Humanos , Inflamación , Masculino , Microcirculación , Persona de Mediana Edad , Proteínas de Neoplasias/análisis , Neovascularización Patológica/diagnóstico por imagen , Neovascularización Patológica/patología , Neurofibromatosis 2/diagnóstico por imagen , Neuroma Acústico/química , Neuroma Acústico/diagnóstico por imagen , Neuroma Acústico/genética , Macrófagos Asociados a Tumores/metabolismo , Factor A de Crecimiento Endotelial Vascular/análisis , Receptor 1 de Factores de Crecimiento Endotelial Vascular/análisis , Adulto JovenRESUMEN
PURPOSE: To evaluate the incidence of mosaicism in de novo neurofibromatosis 2 (NF2). METHODS: Patients fulfilling NF2 criteria, but with no known affected family member from a previous generation (n = 1055), were tested for NF2 variants in lymphocyte DNA and where available tumor DNA. The proportion of individuals with a proven or presumed mosaic NF2 variant was assessed and allele frequencies of identified variants evaluated using next-generation sequencing. RESULTS: The rate of proven/presumed mosaicism was 232/1055 (22.0%). However, nonmosaic heterozygous pathogenic variants were only identified in 387/1055 (36.7%). When variant detection rates in second generation nonmosaics were applied to de novo cases, we assessed the overall probable mosaicism rate to be 59.7%. This rate differed by age from 21.7% in those presenting with bilateral vestibular schwannoma <20 years to 80.7% in those aged ≥60 years. A mosaic variant was detected in all parents of affected children with a single-nucleotide pathogenic NF2 variant. CONCLUSION: This study has identified a very high probable mosaicism rate in de novo NF2, probably making NF2 the condition with the highest expressed rate of mosaicism in de novo dominant disease that is nonlethal in heterozygote form. Risks to offspring are small and probably correlate with variant allele frequency detected in blood.