Imaging as an early biomarker to predict sensitivity to everolimus for progressive NF2-related vestibular schwannoma.

PURPOSE: NF2-related schwannomatosis (NF2) is characterized by bilateral vestibular schwannomas (VS) often causing hearing and neurologic deficits, with currently no FDA-approved drug treatment. Pre-clinical studies highlighted the potential of mTORC1 inhibition in delaying schwannoma progression. We conducted a prospective open-label, phase II study of everolimus for progressive VS in NF2 patients and investigated imaging as a potential biomarker predicting effects on growth trajectory. METHODS: The trial enrolled 12 NF2 patients with progressive VS. Participants received oral everolimus daily for 52 weeks. Brain imaging was obtained quarterly. As primary endpoint, radiographic response (RR) was defined as ≥ 20% decrease in target VS volume. Secondary endpoints included other tumors RR, hearing outcomes, drug safety and quality of life (QOL). RESULTS: Eight participants completed the trial and four discontinued the drug early due to significant volumetric VS progression. After 52 weeks of treatment, the median annual VS growth rate decreased from 77.2% at baseline to 29.4%. There was no VS RR and 3 of 8 (37.5%) participants had stable disease. Decreased or unchanged VS volume after 3 months of treatment was predictive of stabilization at 12 months. Seven of eight participants had stable hearing during treatment except one with a decline in word recognition score. Ten of twelve participants reported only minimal changes to their QOL scores. CONCLUSIONS: Volumetric imaging at 3 months can serve as an early biomarker to predict long-term sensitivity to everolimus treatment. Everolimus may represent a safe treatment option to decrease the growth of NF2-related VS in patients who have stable hearing and neurological condition. TRN: NCT01345136 (April 29, 2011).

Radiogenomics in NF2-Associated Schwannomatosis (Neurofibromatosis Type II): Exploratory Data Analysis.

Our pilot study aimed at exploratory radiogenomic data analysis in patients with NF2-associated schwannomatosis (formerly neurofibromatosis type II) to assume the potential of image biomarkers in this pathology. Fifty-three unrelated patients (37 (69.8%) women, avg. age 30.2 ± 11.2 y.o.) were enrolled in the study. First-order, gray-level co-occurrence matrix (GLCM), gray-level run length matrix (GLRLM), and geometry-based statistics were calculated (3718 features per region of interest). We demonstrated imaging patterns and statistically significant differences in radiomic features potentially related to the genotype and clinical phenotype of the disease. However, the clinical utility of these patterns should be further evaluated. The study was supported by the Russian Science Foundation grant 21-15-00262.

Surgical Management of Peripheral Nerve Pathology in Patients With Neurofibromatosis Type 2.

BACKGROUND: Neurofibromatosis type 2 (NF2) is rare genetic disorder mainly characterized by the development of central nervous system lesions, but peripheral nerve pathology may also cause high morbidity including pain, motor, and sensory loss. OBJECTIVE: To describe the tumor burden of patients with peripheral nerve pathology in NF2 including peripheral neuropathies and schwannomas and the results of surgery in the latter group. METHODS: We conducted a retrospective chart review of all patients with NF2 followed up at our NF2 Reference Center to include all patients suffering from peripheral nerve pathology. Tumor detection relied on focal MRIs based on symptoms. RESULTS: Thirty-four patients harboring 105 peripheral nerve schwannomas and 1 perineurioma were included. Schwannomas were mainly located in major nerves (n = 74, 71%) compared with subcutaneous (n = 23, 22%) and intramuscular (n = 8, 7%) cases. Most schwannomas (81/90-90%) were classical discrete tumors while multinodular cases represented only 9 cases (10%). During follow-up, 63 (60%) tumors were operated in 24 patients, including 39 schwannomas of major nerves. A complete resection was achieved in most of the cases (52/63, 83%) with a complete relief of preoperative pain in most patients (57/60, 95%). Persistent motor deficits (5/39, 13%) were mostly encountered in patients operated from multinodular schwannomas (4/5, 80%). Six patients had an associated peripheral neuropathy with 5 cases of pseudo-Charcot-Marie-Tooth-associated amyotrophy. CONCLUSION: Surgery remains a safe and effective method of treating peripheral nerve schwannoma-associated pain in NF2, with the exception of rare multinodular tumors. Special attention should be drawn to patients harboring severely debilitating neuropathies and perineuriomas.

Neurofibromatosis Type 2: Multiple Meningiomatosis and Vestibular Schwannomas on 68 Ga-DOTATATE PET/CT.

ABSTRACT: Neurofibromatosis type 2 (NF2) is an autosomal-dominant tumor predisposing syndrome that results from mutations in the NF2 tumor suppressor gene on chromosome 22. The development of bilateral vestibular schwannomas is the characteristic feature of the disease. However, other nervous system tumors, including meningiomas, ependymomas, and schwannomas, can be seen frequently. Herein, we present 68 Ga-DOTATATE PET/CT findings of 2 siblings with NF2.

Natural history and volumetric analysis of meningiomas in neurofibromatosis type 2.

OBJECTIVE: The objective of this paper was to describe the volumetric natural history of meningiomas in patients with neurofibromatosis type 2 (NF2). METHODS: The authors performed a retrospective descriptive study by reviewing NF2 patients with meningiomas at their institution between 2000 and 2019. Demographic data were collected from the electronic medical records. Tumor volume was collected using volumetric segmentation software. Imaging characteristics including peritumoral brain edema (PTBE) and tumor calcification were collected for each patient from their first to most recent MRI at the authors' institution. An increase of 15% or more per year from original tumor size was used as the cutoff to define growth. RESULTS: A total of 137 meningiomas from 48 patients were included in the analysis. The average number of tumors per person was 2.9. Ninety-nine (72.3%) tumors were in female patients. The median length of follow-up from first imaging to last imaging was 32 months (IQR 10.9, 68.3 months). Most tumors were located in the cerebral convexity (24.8%), followed by the falcine region (18.2%) and spine (10.2%). The median tumor growth was 0.12 cm3/yr (IQR 0.03, 0.52 cm3/yr). At the time of first imaging, 21.9% of tumors had calcifications, while 13.9% of meningiomas had PTBE. Of 137 tumors, 52 showed growth. Characteristics associated with tumor growth included PTBE (OR 9.12, 95% CI 1.48-56.4), tumor volume (per cm3) at first imaging (OR 0.91, 95% CI 0.83-0.99), and 10-year increased age at first imaging (OR 0.57, 95% CI 0.43-0.74). PTBE had the shortest median time to growth at 9.2 months. CONCLUSIONS: Although the majority of NF2-associated meningiomas do not grow in the short term, a wide range of growth patterns can be seen. Younger age at first imaging and presence of PTBE are associated with growth. Patients with these characteristics likely benefit from closer follow-up.

Neurofibromatosis type 2 versus sporadic vestibular schwannoma: The utility of MR diffusion and dynamic contrast-enhanced imaging.

BACKGROUND AND PURPOSE: The goal of this study was to assess the utility of diffusion-weighted imaging (DWI) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to distinguish sporadic vestibular schwannomas (VSs) from those related to neurofibromatosis type 2 (NF2). METHODS: We retrospectively reviewed 265 patients pathologically diagnosed with VSs between January 2015 and October 2020 in a single institution. There were 28 patients (male: 19, female: 9; age 11-67 years) including 23 sporadic and five NF2-related VSs, who had pretreatment DWI and DCE-MRI. Normalized mean apparent diffusion coefficient (nADCmean) and DCE-MRI parameters along with tumor characteristics were compared between sporadic and NF2-related VSs as appropriate. The diagnostic performances were calculated based on the receiver operating characteristic curve analysis for the values that showed significant differences. To identify significant modalities, multivariate logistic regression analysis was performed using nADCmean and the combination of statistically significant DCE-MRI parameters. RESULTS: NADCmean, fractional volume of extracellular space (Ve), and forward volume transfer constant (Ktrans) were significantly different between sporadic and NF2-related VSs (nADCmean: median 1.62 vs. 1.16, P = .002; Ve: median 0.40 vs. 0.66, P = .007; Ktrans: median 0.17 vs. 0.33, P = .007), whereas fractional plasma volume (Vp), reverse reflux rate constant (Kep), and tumor characteristics were not. The diagnostic performances of nADCmean, Ve, and Ktrans were 0.93, 0.90, and 0.90 area under the curves with cutoffs of 1.46, 0.51, and 0.29, respectively. nADCmean and the combination of Ve and Ktrans were both chosen as significant differentiators by multivariate logistic regression analysis (P = .027). CONCLUSIONS: DWI and DCE-MRI are both promising modalities to distinguish sporadic and NF2-related VSs.

Long-term Follow-up and Histological Correlation of Peripheral Nervous System Alterations in Neurofibromatosis Type 2.

PURPOSE: To examine long-term alterations of the dorsal root ganglia (DRG) and the peripheral nerve in patients with neurofibromatosis type 2 (NF2) by in vivo high-resolution magnetic resonance neurography (MRN) and their correlation to histology. METHODS: In this prospective study the lumbosacral DRG, the right sciatic, tibial, and peroneal nerves were examined in 6 patients diagnosed with NF2 and associated polyneuropathy (PNP) by a standardized MRN protocol at 3 T. Volumes of DRG L3-S2 as well as peripheral nerve lesions were assessed and compared to follow-up examinations after 14-100 months. In one patient, imaging findings were further correlated to histology. RESULTS: Follow-up MRN examination showed a non-significant increase of volume for the DRG L3: +0.41% (p = 0.10), L4: +22.41% (p = 0.23), L5: +3.38% (p = 0.09), S1: +10.63% (p = 0.05) and S2: +1.17% (p = 0.57). Likewise, peripheral nerve lesions were not significantly increased regarding size (2.18 mm2 vs. 2.15 mm2, p = 0.89) and number (9.00 vs. 9.33, p = 0.36). Histological analyses identified schwannomas as the major correlate of both DRG hyperplasia and peripheral nerve lesions. For peripheral nerve microlesions additionally clusters of onion-bulb formations were identified. CONCLUSION: Peripheral nervous system alterations seem to be constant or show only a minor increase in adult NF2. Thus, symptoms of PNP may not primarily attributed to the initial schwannoma growth but to secondary long-term processes, with symptoms only occurring if a certain threshold is exceeded. Histology identified grouped areas of Schwann cell proliferations as the correlate of DRG hyperplasia, while for peripheral nerve lesions different patterns could be found.

Variations and natural history of primary intraparenchymal lesions associated with neurofibromatosis type 2.

The study aimed to investigate the clinical implications and natural history of primary intraparenchymal lesions in patients with neurofibromatosis type 2. Radiological findings of 15 neurofibromatosis type 2 cases were retrospectively collected. Twenty-seven primary intraparenchymal lesions were observed in 7 out of 15 patients (47%). Cortical/subcortical T2 hyperintense lesions and enlarged Virchow-Robin spaces were the most common findings in five and four patients, respectively. During the follow-up period (median 84 months), one new primary intraparenchymal lesion was identified and increased lesions were observed in two cases on contrast-enhanced MRI. Surgical resection was performed in one case pathologically diagnosed with atypical meningioma. Twenty-five other lesions without contrast enhancement presented no apparent growth during follow-up. Although most primary intraparenchymal lesions are benign, a subset of cases would present newly developed or increased lesions on contrast-enhanced MRI. Careful monitoring is necessary for such cases, and pathological confirmation should be considered.

Safety of 3 Tesla Magnetic Resonance Imaging in Patients With Auditory Brainstem Implants.

OBJECTIVE: To evaluate the safety of 3 Tesla (T) magnetic resonance imaging (MRI) in patients with auditory brainstem implants (ABI) with the magnet removed at implantation and report incidence of complications. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary neurotology ambulatory practice. PATIENTS: Patients with diagnosis of Neurofibromatosis, type 2 (NF2) with functional ABIs. INTERVENTIONS: Observational recordings. MAIN OUTCOME MEASURES: Of the 89 patients meeting inclusion criteria, 7 patients underwent 3T MRI, with a total of 39 scans done. Three patients had 1 scan each, one patient had 4 scans, one patient had 5 scans, one patient had 6 scans, and one patient had 21 scans. The mean time between ABI placement and first 3 T scan was 118 ±â€Š73 months. The most common indication for imaging was surveillance of NF2 lesions. The most frequent scans were MRI brain (25.6%), followed by MRI of cervical (15%), thoracic (15%) and lumbar (15%) spine, and MRI IAC (8%). There were no reported complications for any of the scans. No scans were interrupted due to patient discomfort. There were no device malfunctions. CONCLUSIONS: 3 T MRIs are safe in patients with ABIs as long as the magnet is removed. It is recommended that the magnet be removed at the time of implantation in all NF2 patients, who require frequent surveillance.

Reliability and toxicity of bevacizumab for neurofibromatosis type 2-related vestibular schwannomas: A systematic review and meta-analysis.

BACKGROUND: The anti-angiogenic agent bevacizumab is currently the only drug used clinically for neurofibromatosis type 2-related vestibular schwannomas (NF2-VS). Though benefits have been demonstrated in several cases, the standardized dosage remains unclear. OBJECTIVE: Our meta-analysis was performed to systematically and comprehensively investigate the reliability and toxicity of bevacizumab in the treatment of NF2-VS, with particular emphasis on the impact of dosage. METHODS: The literature search was conducted for studies providing data on patients treated with bevacizumab for NF2-VS across PubMed, Embase, and Cochrane Library until December 31, 2020. Two reviewers extracted the incidence rate of results independently. Then we calculated and pooled unadjusted incidence rate with 95% CIs for each study. The subgroups analyzed were conducted. RESULTS: Fourteen citations (prospective or retrospective observational cohort studies) were eligible based on data from a total of 247 patients with NF2 and 332 related VSs. The pooled results showed that the radiographic response rate (RRR) was 30% [95% CI (20%-42%)], the hearing response rate (HRR) was 32% [95% CI (21%-45%)]. The incidence of major complications was: hypertension 29% [95% CI (23%-35%)], proteinuria 30% [95% CI (18%-44%)], menstrual disorders 44% [95% CI (16%-73%)], hemorrhage 14% [95% CI (4%-26%)], grade3/4 events 12% [95% CI (4%-22%)]. CONCLUSIONS: Nearly one-third of NF2-VS patients may benefit significantly from bevacizumab due to hearing improvement and tumor reduction. Menstrual disorders were the most common adverse events. The high-dose regimen didn't show better efficacy, but results varied considerably according to age.

Adult Auditory Brainstem Implant Outcomes and Three-Dimensional Electrode Array Position on Computed Tomography.

OBJECTIVES: Factors contributing to auditory brainstem implant (ABI) outcomes are poorly understood. The aims of this study are to (1) characterize ABI electrode array position on postoperative imaging and (2) determine if variability in position is related to perceptual outcomes. DESIGN: Retrospective cohort study. Subjects were selected from the adult ABI recipient population at Massachusetts Eye and Ear. Postoperative three-dimensional (3D) computed tomography (CT) reconstruction of the head was used to measure ABI array position in 20 adult ABI recipients (17 with Neurofibromatosis Type 2 (NF2) and three non-NF2 recipients). Three-dimensional electrode array position was determined based on angles from the horizontal using posterior and lateral views and on distances between the proximal array tip superiorly from the basion (D1), laterally (D2P) and posteriorly (D2L) from the midline. Array position was correlated with perceptual data (in 15 of the 20 recipients who used their ABI). Perceptual data included the number of electrodes that provided auditory sensation, location and type of side effects, level of speech perception (from no sound to open-set word recognition of monosyllables) and the amount of charge required for auditory perception. RESULTS: Although the 3D orientation of the ABI array exhibited a variety of angles, all arrays were posteriorly tilted from the lateral view and most were medially tilted from the posterior view. ABI position relative to the basion from posterior showed mean distances of 1.71 ± 0.42 and 1.1 ± 0.29 cm for D1 and D2, respectively, and a mean D2 of 1.30 ± 0.45 cm from the lateral view. A strong linear negative correlation was found between the number of active electrodes and the distance of the proximal array tip laterally from the basion (D2P; rs = -0.73, p = 0.006) when measured in the posterior view. Although side effects were experienced in all recipients and varied in type and location across the array, electrodes in the middle part of the array tended to elicit auditory sensations while the proximal and distal tips of the array tended to elicit nonauditory side effects. Arrays with and without low charge thresholds appeared to generally overlap in position. However, the two recipients with the best (open-set) speech perception had low charge thresholds and had arrays that were tilted superiorly in the posterior view. CONCLUSION: ABI recipients with better speech perception appear to share a profile of arrays that are tilted superiorly as compared to recipients with lower speech perception levels. These ABI recipients have a high number of active electrodes (10 or more) and require less electrical charge on individual electrodes to achieve optimal stimulation.

Peptide Receptor Radionuclide Therapy in Patients With Neurofibromatosis Type 2: Initial Experience.

PURPOSE: Neurofibromatosis type 2 (NF2) is a genetic disorder that is associated with multiple tumors of the nervous system, and approximately one half of patients present with meningiomas. For patients with multifocal disease, somatostatin receptor-targeted peptide receptor radionuclide therapy (PRRT) might be a suitable systemic treatment option. PATIENTS AND METHODS: Between March 2015 and August 2017, 11 NF2 patients (7 females and 4 males; mean age, 39 ± 12 years) with multifocal, progressive meningiomas underwent a median of 4 cycles of PRRT (range, 2-6 cycles). Acute and chronic adverse events were recorded according to National Institutes of Health's Common Toxicity Criteria (CTC) version 5.0. Follow-up MRIs (every 3 to 6 months), using the Response Assessment in Neuro-Oncology response criteria for meningiomas, were used to assess treatment responses. RESULTS: Peptide receptor radionuclide therapy was well tolerated in all patients without any relevant acute adverse effects. Transient hematologic toxicity (CTC grade 3) was observed in 2 subjects. Somatostatin receptor-directed radiopeptide therapy resulted in radiological disease stabilization in 6 of 11 patients. Median progression-free survival was 12 months (range, 1-55 months), and overall survival was 37 months (range, 5-61 months). CONCLUSIONS: Based on our retrospective pilot data, PRRT is feasible and well-tolerated in NF2 patients. It might offer a suitable treatment option in subjects with multiple, recurrent, or treatment-refractory meningiomas.

Bevacizumab as a surgery-sparing agent for spinal ependymoma in patients with neurofibromatosis type II: Systematic review and case.

Neurofibromatosis type 2 (NF2) is a rare, hereditary tumor syndrome, often requiring repeated surgeries for multiple lesions with significant cumulative morbidity. As such, non-operative management should be considered when possible for this patient population. The aim of this study is to provide a systematic review of the literature regarding this treatment strategy. A descriptive case of a patient in whom bevacizumab treatments enabled over 15 years of surgical postponement for a symptomatic spinal cord ependymoma is also provided. Evidence suggests that bevacizumab is a reasonable surgery-deferring option for cystic lesions, and it may be especially useful in NF2 patients to reduce cumulative morbidity.

Bilateral Vestibular Schwannomas in a Patient with Ring Chromosome 22: Case Report and Review of the Literature.

INTRODUCTION: Ring chromosome 22 (r[22]) can lead to the development of intracranial tumors such as meningiomas, neurofibromas, and schwannomas similar to neurofibromatosis 2 (NF2). CASE PRESENTATION: An 18-year-old female with r(22) and a history of global development delay and cognitive impairment presented with sudden hearing loss. MRI revealed bilateral vestibular schwannomas. Given documented audiologic decline in the patient's hearing, the larger tumor was treated with CyberKnife fractionated stereotactic radiosurgery, and the smaller tumor is being monitored. CONCLUSION: This case provides further evidence that patients with r(22) can develop clinical features of NF2, including the development of bilateral vestibular schwannomas, and should be monitored for hearing disturbances starting in puberty as a warning sign for these tumors.

Neurofibromatosis type 2: A nationwide population-based study focused on survival after meningioma surgery.

BACKGROUND: There is no dedicated study on outcome after meningioma surgery in neurofibromatosis type 2 (NF2) patients. METHODS: We processed the French Système National des Données de Santé (SNDS) database using an algorithm combining the type of surgical procedure and the International Classification of Diseases to retrieve cases of meningioma operated in NF2 patients between 2007 and 2017. Descriptive and survival analyses were performed. RESULTS: This nationwide study found 184 patients who were operated on for 315 meningiomas over a 10-year period. 57.6 % were female, median age at first surgery was 40 years IQR[24.8-50.2] and 10.9 % were under 18 years. Cranial convexity (23.4 %) and posterior skull base (16.8 %) were the most common locations. 89.7 % of the tumours were benign and 3.3 % malignant. 16.3 % of the patient received radiotherapy and 13.6 % stereotactic radiosurgery. Median follow-up was 6.3 years, IQR[5.3-7]. At data collection, 28 patients were dead (15.2 %) and median age at death was 41.7 years, IQR [32.7-50.4]. 5 patients died within the year of meningioma surgery. OS rates at 5 and 10 years were: 87.8 %, 95 %CI[82.6-93.3] and 73.2 %, 95 %CI[63.7-84.1] respectively. In univariable Cox regression analysis, Mortality-Related Morbidity Index (MRMI) (HR = 1.57, 95 %CI[1.3-1.9], p < 0.001) Expenditure-Related Morbidity Index (HR1.16, 95 %CI[1.09-1.24], p < 0.001), a malignant meningioma (HR=8.15, 95 %CI[2.78-23.85], p < 0.001), and a diagnosis of deafness or vestibular schwannoma (HR=2.52, 95 %CI[1.02-6.23], p = 0.0447), were associated to the outcome. In multivariable analysis, solely the MRMI and a malignant meningioma remained significant predictors of reduce OS. CONCLUSION: Using this unique database, we found that outcome of NF2 patients after meningioma surgery is impaired, especially for those with significant co-morbidities and affected by a malignant meningioma.

Neurofibromatosis type 2 in Phelan-McDermid syndrome: Institutional experience and review of the literature.

Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by rearrangements on chromosome 22q13.3 or sequence variants in SHANK3. Individuals with PMS caused by a 22q terminal deletion and a ring chromosome are at increased risk for Neurofibromatosis type 2 (NF2). However, the prevalence of NF2 in individuals with PMS and a r (22) is unknown. Individuals with PMS and a r (22) chromosome evaluated at the Greenwood Genetic Center (GGC) or by international collaborators, or identified through the PMS International Registry (PMSIR) were contacted and participated in a clinical questionnaire. Forty-four families completed the questionnaire and consented for the study. Of the individuals with a r (22), 7 (16%) carried a diagnosis of NF2. The average age of diagnosis of r (22) was 18 years old in individuals with NF2 and three years old in individuals without NF2 (p-value <0.001). Clinical findings were similar among all individuals in our sample with the exception of hearing loss, present in 57% of individuals with NF2 and 8% of individuals without NF2 (p-value <0.01). This is the largest clinical report of individuals with PMS and a r (22) chromosome. We show a diagnosis of NF2 in individuals with r (22) is not uncommon and may be under ascertained. Moreover, the presentation of NF2 in this cohort is variable and lifelong routine screening for features of NF2 in this population should be considered.

MRI based volumetric measurements of vestibular schwannomas in patients with neurofibromatosis type 2: comparison of three different software tools.

Neurofibromatosis type 2 is a neurogenetic disorder with an incidence of about 1:33.000. Hallmarks are bilateral benign vestibular schwannomas, which can lead to deafness or brainstem compression. Volumetric tumor measurements are essential to assess the efficacy of new therapies. We present a statistical and methodical comparison of three volumetric image analysis tools. We performed volumetric measurements on phantoms with predefined volumes (0.1 to 8.0 ml) and tumors seen on 32 head MRI scans from eight NF2 patients with BrainLab, ITK-Snap, or OsiriX. The software was compared with regard to accuracy and reproducibility of the measurements and time required for analysis. The mean volume estimated by all three software programs differed significantly from the true volume of the phantoms, but OsiriX and BrainLab gave estimates that were not significantly different from each other. For the actual tumors, the estimated volumes with all three software tools showed a low coefficient of variability, but the mean volume estimates differed among the tools. OsiriX showed the shortest analysis time. Volumetric assessment of MRI images is associated to an intrinsic risk of miscalculation. For precise volumes it is mandatory to use the same volumetric tools for all measurements.

Neurofibromatosis type 2 initially presenting as a preauricular mass: a case report.

Neurofibromatosis type 2 (NF2) is a rare genetic disease involving multiple tumors of the central and peripheral nervous systems. Most patients with NF2 have bilateral vestibular schwannomas; nonvestibular schwannomas may also develop. While the majority of patients may present with hearing impairment, tinnitus, dizziness and balance disorders, some may present with cutaneous manifestations. We describe the case of a 20-year-old man who initially presented with a solitary subcutaneous painless nodule in the left preauricular area without any other symptoms. He received excisional biopsy for the preauricular mass and the pathologic diagnosis was schwannoma. Magnetic resonance imaging of brain and neck revealed multiple mass lesions over the bilateral cerebellopontine angle cisterns, extending to the bilateral internal auditory canals, bilateral cervical neuroforamens, cervical and upper thoracic spinal canals, and left posterior neck. The patient was diagnosed with NF2 according to the clinical criteria. He underwent gamma knife stereotactic radiosurgery for bilateral vestibular schwannomas and is now under regular monitoring. CONCLUSION: NF2 patients may present with an isolated solitary cutaneous schwannoma with no other associated clinical findings. Further assessment is thus warranted in young patients presenting with a peripheral schwannoma despite absence of other clinical findings.

The microenvironment in sporadic and neurofibromatosis type II-related vestibular schwannoma: the same tumor or different? A comparative imaging and neuropathology study.

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.