Nonvestibular Schwannomas Research Articles

Gamma-knife radiosurgery for jugular foramen schwannomas. A systematic review and meta-analysis

IntroductionJugular Foramen Schwannomas (JFS) have been traditionally treated with surgical resection with an associated significant post-operative morbidity. Stereotactic radiosurgery has been investigated as potentially minimally invasive alternative to microsurgery. The aim of this study was to provide a systematic review and meta-analysis of the available literature regarding the outcomes of cases of JFS treated with radiosurgery. MethodsA literature review until 28th of March 2023 was performed. All studies looking at the outcomes of radiosurgery for the treatment of JFS were included. Studies including non-vestibular schwannomas without clear distinction of the tumour type were excluded. Risk of bias was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) scale. ResultsEight (8) studies with a total of 375 patients met the inclusion and exclusion criteria and were included in the analysis. Pooled overall tumour control rate was 93.2 % (95 % CI 89.8–96.6) after a weighted mean follow-up of 54.07 months (95 % CI 46.8–61.3). Patient free survival was reported only in 4 studies and ranged from 87 % to 97 % and 76.9–93.8 % in 5 and 10 years respectively. The radiation induced cranial nerve deficits rates after GKRS were 3.6 % (95%CI 1.7, 5.5 %). ConclusionAccording to our findings, radiosurgery for JFS has favourable clinical outcomes with a high rate of long-term tumour control and low complication rates.

Genetic findings in people with schwannomas who do not meet clinical diagnostic criteria for NF2-related schwannomatosis

BackgroundMost 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...

Brigatinib in NF2-Related Schwannomatosis with Progressive Tumors

BackgroundNF2-related schwannomatosis (NF2-SWN, formerly called neurofibromatosis type 2) is a tumor predisposition syndrome that is manifested by multiple vestibular schwannomas, nonvestibular schwannomas, meningiomas, and ependymomas. The condition is relentlessly progressive with no approved therapies. On the basis of preclinical activity of brigatinib (an inhibitor of multiple tyrosine kinases) in NF2-driven nonvestibular schwannoma and meningioma, data were needed on the use of brigatinib in patients with multiple types of progressive NF2-SWN tumors.MethodsIn this phase 2 platform trial with a basket design, patients who were 12 years of age or older with NF2-SWN and progressive tumors were treated with oral brigatinib at a dose of 180 mg daily. A central review committee evaluated one target tumor and up to five nontarget tumors in each patient. The primary outcome was radiographic response in target tumors. Key secondary outcomes were safety, response rate in all tumors, hearing response, and patient-reported outcomes.ResultsA total of 40 patients (median age, 26 years) with progressive target tumors (10 vestibular schwannomas, 8 nonvestibular schwannomas, 20 meningiomas, and 2 ependymomas) received treatment with brigatinib. After a median follow-up of 10.4 months, the percentage of tumors with a radiographic response was 10% (95% confidence interval [CI], 3 to 24) for target tumors and 23% (95% CI, 16 to 30) for all tumors; meningiomas and nonvestibular schwannomas had the greatest benefit. Annualized growth rates decreased for all tumor types during treatment. Hearing improvement occurred in 35% (95% CI, 20 to 53) of eligible ears. Exploratory analyses suggested a decrease in self-reported pain severity during treatment (−0.013 units per month; 95% CI, −0.002 to −0.029) on a scale from 0 (no pain) to 3 (severe pain). No grade 4 or 5 treatment-related adverse events were reported.ConclusionsBrigatinib treatment resulted in radiographic responses in multiple tumor types and clinical benefit in a heavily pretreated cohort of patients with NF2-SWN. (Funded by the Children’s Tumor Foundation and others; INTUITT-NF2 ClinicalTrials.gov number, NCT04374305.)

Multiple Intracranial Schwannomas of the Vestibular and Trigeminal Nerves: A Technical Note

BackgroundA schwannoma is a nerve sheath tumor that is formed by Schwann cells. Vestibular schwannomas are thought to account for the majority of intracranial schwannomas. Non-vestibular schwannomas account for about 10%, about half of which are trigeminal schwannomas. Multiple intracranial schwannomas originating from different cranial nerves are extremely rare. Observation(s)We describe the clinical case of a 42-year-old female patient with vestibular schwannoma and multiple trigeminal schwannomas. That case shows how multiple trigeminal schwannomas were identified intraoperatively during elective surgery for vestibular schwannoma removal, most of which were resected. No new neurological deficits were observed in the patient. LessonsThe presence of multiple intracranial schwannomas is extremely rare in neurosurgical practice and can change the intraoperative strategy and the course of the surgery.

CTNI-80. INTUITT-NF2, AN ADAPTIVE PLATFORM-BASKET TRIAL FOR NF2-RELATED SCHWANNOMATOSIS PATIENTS WITH PROGRESSIVE SCHWANNOMAS, MENINGIOMAS, AND EPENDYMOMAS: PRIMARY OUTCOME OF THE BRIGATINIB TREATMENT ARM

Abstract INTRODUCTION NF2-related schwannomatosis (NF2-SWN) predisposes affected individuals to vestibular schwannomas (VS), non-vestibular schwannomas (NVS), meningiomas, and ependymomas. The rarity of NF2-SWN and the presence of multiple tumor types has impeded clinical trials. We conducted a multi-center, adaptive, platform-basket trial to screen multiple drugs against progressive NF2-SWN tumors. We report the final analysis of the first treatment arm with brigatinib, an oral ALK inhibitor that inhibits multiple tyrosine kinases. METHODS This study enrolled participants ≥ 12 years with NF2-SWN and progressive target tumors (baskets: VS, NVS, meningioma, or ependymoma Radiographic response (RR) was defined as ≥ 20% decrease in target tumor volume from baseline. The primary outcome was RR rate. Secondary outcomes included safety, hearing response, and RR in non-target tumors. Tumor response was evaluated by MRI every 3 months in year 1 and every 6 months thereafter. In stage 1, 20 participants received brigatinib 180 mg daily. Interim analysis suggested activity in NVS and meningioma. Thus, an additional 20 participants with progressive meningioma or NVS were enrolled in stage 2. RESULTS Forty participants (median age 26 years, 12 pediatric, 28 female) were treated. Prior treatment included surgery (90%), radiation therapy (20%) and chemotherapy (55%). Target tumors included 10 VS, 9 NVS, 19 meningiomas, and 2 ependymomas. Overall RR rate was 10% for all target tumors (22% for non-VS, 11% for meningioma, 0% for VS, and 0% for ependymomas). There were no grade 4 or 5 treatment-related adverse events (AEs). The most common AEs were diarrhea (63%), nausea (40%), muscle cramps (33%), increased LDH (35%), increased AST (33%), and increased ALT (23%). CONCLUSION Brigatinib treatment was associated with RR in NVS and meningiomas in a heavily pretreated cohort of participants with progressing NF2-SWN tumors. This novel design provides unique ability to assess treatments for hereditary syndromes with multiple primary tumors.

NIMG-07. LONG-TERM FOLLOW-UP OF SCHWANNOMA GROWTH BEHAVIOR IN ADULT SCHWANNOMATOSIS PATIENTS USING WHOLE-BODY MRI

Abstract BACKGROUND The schwannomatoses include NF2-related schwannomatosis (NF2-SWN, formerly known as “NF2”) and non-NF2-related schwannomatosis (e.g. SMARCB1- and LZTR1-related schwannomatosis) and are caused by distinct germline pathogenic variants on chromosome 22. Patients may develop cranial, peripheral, and/or spinal nerve schwannomas. Except for vestibular schwannomas, the long-term growth behavior of schwannomas is unknown but this is important to guide patient surveillance and selection for treatment. Whole-body MRI (WBMRI) can detect whole-body schwannoma burden. METHODS 16 NF2-SWN and 12 non-NF2-SWN patients with WBMRI acquired between 2007-2010 underwent a repeat WBMRI between 2018-2022. Non-vestibular schwannomas were segmented on short tau inversion recovery (STIR) sequences. Tumor volume was calculated using a 3D tumor quantification software (3DQI). Tumor growth and shrinkage were defined as a volume change ³20% over the entire study period. RESULTS Median time between scans was 10.3 years. Median age was 43.5 years at baseline and 54 years at follow-up. Excluding resected tumors, 102 schwannomas (49 NF2-SWN, 53 non-NF2-SWN) were analyzed. 62/102 (61%) tumors grew >20% (65% NF2-SWN, 57% non-NF2-SWN); median growth was 96% in NF2-SWN and 94% in non-NF2-SWN. 24/102 (24%) tumors shrank >20% (20% NF2-SWN, 26% non-NF2-SWN); median shrinkage was 49% in NF2-SWN and 40% in non-NF2-SWN. 29 new tumors developed between scans (16 NF2-SWN, 13 non-NF2-SWN). Of 32 NF2-SWN tumors exposed to systemic or radiation therapy, 63% grew and 31% shrank. Of 7 non-NF2-SWN tumors exposed to treatment, 29% grew and 42% shrank. 11 non-NF2-SWN tumors shrank spontaneously without treatment. Spontaneous tumor shrinkage was not observed in NF2-SWN. CONCLUSIONS About 60% of SWN-associated schwannomas grow significantly over a decade. Spontaneous shrinkage is only observed in non-NF2-SWN tumors whereas, in NF2-SWN patients, about 60% of tumors grow despite treatment, suggesting a more aggressive tumor phenotype in NF2-SWN. Correlation of MRI findings with patient-reported outcomes and hormone exposure history are ongoing.

Vestibulocochlear Delineation for Vestibular Schwannoma Treated With Radiation Therapy

To develop a specialist-based consensus of cochlear contouring to be used in patients undergoing stereotactic radiosurgery (SRS) treatment for vestibular schwannoma. Representative computed tomography (CT) and magnetic resonance imaging (MRI) were used for cochlear contouring. The semicircles, cochlea, vestibule, and internal acoustic meatus were delineated by 7 radiation oncology department physicians and reviewed by neuroradiologists. A total of 12 cases accrued from a single academic institution were studied for a similarity analysis by the Dice coefficient. The suggested guideline is an easily reproductive tool that allows radiation oncologists to accurately contour the vestibulocochlear system to avoid toxicity due to inadequate dosimetry of organs at risk. This could be a useful tool even for non-vestibular schwannoma radiation therapy. The Dice coefficient suggests reproducible results as long as the following contouring recommendations are observed. The template for vestibulocochlear delineation may be useful for an adequate organs at risk definition. Future studies are required to find specific constraints for each segment of the vestibulocochlear system, and to mitigate interobserver variations.

CTNI-65. INTUITT-NF2, AN ADAPTIVE PLATFORM-BASKET TRIAL FOR NEUROFIBROMATOSIS 2 PATIENTS WITH PROGRESSIVE TUMORS: INTERIM RESULTS OF THE BRIGATINIB TREATMENT ARM

Abstract Neurofibromatosis type 2 (NF2) predisposes affected individuals to vestibular schwannomas (VS), non-vestibular schwannomas (NVS), meningiomas, and ependymomas. We developed an adaptive platform-basket trial to screen multiple drugs against any type of progressive NF2-related tumor. We report the interim analysis of the first treatment arm with brigatinib, an ALK inhibitor that inhibits multiple tyrosine kinases. We conducted a multicenter, phase II, open-label study for subjects ≥12 years old with NF2 and progressive target tumors (baskets: VS, NVS, meningioma, or ependymoma). Up to 5 non-target tumors were followed in each participant. In stage 1, 20 participants (minimum of 2 participants per basket) were treated with brigatinib 180 mg daily. Tumor response was evaluated by MRI every 3 months in year 1 and every 6 months thereafter. Radiographic response (RR) was defined as ≥20% decrease in target tumor volume from baseline. The primary outcome was RR rate. Per protocol, the brigatinib arm would be discontinued if no target tumor achieved a RR at interim analysis. Twenty subjects (median age=25 years, 7 pediatric, 12 females) were treated. Target tumors included 10 VS, 3 NVS, 5 meningiomas, and 2 ependymomas; non-target tumors included 18 VS, 36 NVS, and 14 meningiomas. RR rate for target and non-target tumors was 5% and 22%, respectively. By tumor basket, RR was 28% for meningioma, 26% for non-VS, 4% for VS, and 0% for ependymomas. Annualized tumor growth rates decreased for VS, NVS, and meningioma during treatment. Brigatinib was well tolerated with one dose reduction and one discontinuation due to grade 2 diarrhea. Brigatinib treatment was associated with RR in meningiomas, VS, and NVS. In stage 2, the study will enroll 20 participants in the two most promising baskets (meningioma and NVS). This novel design provides unique ability to assess treatments for hereditary syndromes with multiple primary tumors.

The Treatment Outcome of CyberKnife-Based Stereotactic Radiotherapy for Intracranial and Extracranial Nonvestibular Schwannomas: A Single-Center Experience

Data on the outcomes of CyberKnife-based hypofractionated stereotactic radiosurgery (hSRS) for intracranial and extracranial nonvestibular schwannomas (nVSs) are not sufficient. Patients who underwent hSRS for nVSs between 2010 and 2019 were retrospectively reviewed. A total of 39 patients with 39 nVSs were identified. The mean age was 53 (±18) years, and 20 patients (51%) were women. Twenty-five patients (64%) had previous surgeries. Seventeen patients (44%) had nVSs extending outside the cranium. The mean prescribed dose covering 95% of the planning target volume was 22Gy (±3.7 Gy), the mean fractionation was 4 (±2), and the mean target volume was 13cm3 (±16cm3). The radiological tumor control rate was 100% during the mean follow-up period of 67months (±37months). Thirty-seven patients (95%) were clinically stable during the mean follow-up period of 72months (±35months). Nine patients (23%) suffered from transient adverse radiation effects (AREs), including transient tumor expansion, and 2 (5%) suffered from permanent AREs. We summarized the treatment outcomes of hSRS for nVSs. Although all patients achieved radiological tumor control, the risk of either transient or permanent ARE was high. Therefore, it is necessary to monitor patients for clinical deterioration due to AREs.

Management of non-vestibular schwannomas in adult patients: a systematic review and consensus statement on behalf of the EANS skull base section Part II: Trigeminal and facial nerve schwannomas (CN V, VII).

Non-vestibular schwannomas are relatively rare, with trigeminal and jugular foramen schwannomas being the most common. This is a heterogenous group which requires detailed investigation and careful consideration to management strategy. The optimal management for these tumours remains unclear and there are several controversies. The aim of this paper is to provide insight into the main principles defining management and surgical strategy, in order to formulate a series of recommendations. A task force was created by the EANS skull base section committee along with its members and other renowned experts in the field to generate recommendations for the surgical management of these tumours on a European perspective. To achieve this, the task force performed an extensive systematic review in this field and had discussions within the group. This article is the second of a three-part series describing non-vestibular schwannomas (V, VII). A summary of literature evidence was proposed after discussion within the EANS skull base section. The constituted task force dealt with the practice patterns that exist with respect to pre-operative radiological investigations, ophthalmological assessments, optimal surgical and radiotherapy strategies, and follow-up management. This article represents the consensually derived opinion of the task force with respect to the treatment of trigeminal and facial schwannoma. The aim of treatment is maximal safe resection with preservation of function. Careful thought is required to select the appropriate surgical approach. Most middle fossa trigeminal schwannoma tumours can be safely accessed by a subtemporal extradural middle fossa approach. The treatment of facial nerve schwannoma remains controversial.

Clinical outcomes of benign brain tumors treated with single fraction LINAC-based stereotactic radiosurgery: Experience of a single institute.

Accelerator-based stereotactic radiosurgery (SRS) is a noninvasive and effective treatment modality widely used for benign brain tumors. This study aims to report 20-year treatment outcomes in our institute. From May 2001 to December 2020, 127 patients treated with LINAC-based single-fraction SRS for their benign brain lesions were included. A neurosurgeon and two radiation oncologists retrospectively reviewed all data. Computed tomography (CT) simulation was performed after head-frame fixation under local anesthesia. All planning CT images were co-registered and fused with gadolinium-enhanced magnetic resonance imaging taken within 3 months for lesions targeting and critical organs delineation. The marginal dose was prescribed at 60%-90% isodose lines, respectively, to cover ≥95% planning target volume. Outcome evaluations included clinical tumor control rate (TCR), defined as the need for salvage therapy, and radiological response, defined as no enlargement of >2 cm in the maximal diameter. Overall survival (OS) and adverse reaction (defined according to CTCAE 5.0) were also analyzed. The present study included 76 female and 51 male patients for analysis. The median age was 59 years (range, 20-88 years). Their diagnoses were vestibular schwannoma (VS, n = 54), nonvestibular cranial nerve schwannoma (n = 6), meningioma (n = 50), and pituitary adenoma (n = 17). Totally 136 lesions were treated in a single fraction, predominantly skull base tumors, accounting for 69.1%. Median and mean follow-up duration was 49 and 61 months (range, 1-214 months), Overall TCR was 92.9%. The 5-year disease-specific TCR for VS, nonvestibular schwannoma, meningioma, and pituitary adenoma were 97.4%, 91.7%, 93.8%, and 83.3%. Salvage therapy was indicated for eight patients at 4-110 months after SRS. Among symptomatic patients, post-SRS symptom(s) was improved, stable, and worse in 68.2%, 24.3%, and 3.6%, respectively. Radiological response rate for 111 evaluable patients was 94.6% (shrinkage, 28.8%; stable, 65.8%). OS was 96.1% without treatment-related mortality. One patient with post-SRS cranial nerve injury (0.8%, involving the trigeminal nerve, grade 2 toxicities). No grade 3-4 acute or late toxicity was found. Our results suggested that LINAC-based SRS effectively controls tumor growth and tumor-related neurological symptoms for patients with benign brain tumors. SRS is less aggressive, associated with low neurological morbidity and no mortality. Continuous follow-up is indicated to conclude longer outcomes.

Nonvestibular Schwannomas of the Head and Neck

Schwannomas are benign peripheral nerve sheath tumors, of which almost half occur in the head and neck. Schwannomas may arise from any cranial, autonomic, or peripheral nerve. It is crucial to recognize the imaging features suggestive of schwannoma because the management decisions are unique due to the generally benign nature of this disease. While most nonvestibular schwannomas will be asymptomatic until they are large, tumors within or adjacent to bony structures are often associated with neurologic symptoms. This article provides a multimodality imaging review of the varied appearance of nonvestibular schwannomas in the head and neck as well as correlative discussion of the clinical presentation and management.Learning Objective: To describe the imaging appearance, critical clinical features, and management implications of nonvestibular schwannomas of the head and neck

Endoscopic endonasal transmaxillary-pterygoid approach for skull-base non-vestibular schwannomas in 10 consecutive patients.

Non-vestibular schwannomas (NVSs) of the skull base occur in several sites, and few previous studies have evaluated the usefulness of the endoscopic endonasal transmaxillary-pterygoid approach (EETMPA) to resect these lesions. We aimed to evaluate the characteristics and clinical outcomes of patients who underwent EETMPA for skull-base NVSs and to investigate the efficacy, safety, and indications for the procedure. We retrospectively reviewed the clinical data of 10 consecutive patients (mean age, 45 ± 17) who underwent EETMPA for skull-base NVSs at the University of Tsukuba hospital between 2013 and 2020. We also calculated the total tumor volume and the size of the corridor to the tumor for EEA (SCEEA) in nine patients who underwent EEA for NVSs adjacent to the Meckel's cave or cavernous sinus. Nine patients (9/10), including five women (5/10), underwent primary surgery. Gross total resection and subtotal resection were achieved in five patients each (5/10). Postoperatively, one patient showed a new and mild cranial nerve V sensory deficit and one patient showed slight worsening of abducens nerve palsy. The greater palatine nerve was amputated in two patients; however, permanent perception loss in the soft palate was observed in one patient. The Vidian nerve was sacrificed in four patients, and new dry eye occurred in one patient. None of the patients experienced postoperative tumor recurrence or regrowth during the follow-up period of 40 ± 28months. EETMPA is safe and effective for excising skull-base NVSs which are not eligible for radiosurgery leading to a high rate of successful resection and a high rate of but mild neurological sequela. The EEA is appropriate when the tumor extends to the paranasal sinus with sufficient SCEEA.

Management of non-vestibular schwannomas in adult patients: a systematic review and consensus statement on behalf of the EANS skull base section. Part I: oculomotor and other rare non-vestibular schwannomas (I, II, III, IV, VI).

Non-vestibular schwannomas are relatively rare, with trigeminal and jugular foramen schwannomas being the most common. This is a heterogeneous group which requires detailed investigation and careful consideration to management strategy. The optimal management for these tumours remains unclear, and there are several controversies. The aim of this paper is to provide insight into the main principles defining management and surgical strategy, in order to formulate a series of recommendations. A task force was created by the EANS skull base section along with its members and other renowned experts in the field to generate recommendations for the surgical management of these tumours on a European perspective. To achieve this, the task force performed an extensive systematic review in this field and had discussions within the group. This article is the first of a three-part series describing non-vestibular schwannomas (I, II, III, IV, VI). A summary of literature evidence was proposed after discussion within the EANS skull base section. The constituted task force dealt with the practice patterns that exist with respect to pre-operative radiological investigations, ophthalmological assessments, optimal surgical and radiotherapy strategies and follow-up management. This article represents the consensually derived opinion of the task force with respect to the treatment of non-vestibular schwannomas. For each of these tumours, the management of these patients is complex, and for those which are symptomatic tumours, the paradigm is shifting towards the compromise between function preservation and progression-free survival.

Hearing recovery after surgical resection of non-vestibular schwannoma cerebellopontine angle tumors.

Post-operative outcomes for hearing after resection surgery to remove cerebellopontine angle (CPA) tumors other than vestibular schwannomas (VS) are not well understood. This study presents a series of patients with significant post-operative hearing recovery, trying to define the incidence among all patients operated on for removal of non-VS CPA tumors. This is a retrospective observational case series of 8 patients among 69 operated on for removal of non-VS CPA tumors between 2012 and 2020. All patients had pre- and post-operative hearing measurement with pure-tone average (PTA) and speech discrimination score (SDS), according to the American Academy of Otolaryngology-Head and Neck Surgery recommendations, auditory brainstem response (ABR) measurements and imaging. Six meningiomas and two lower cranial nerve schwannomas operated on with a retrosigmoid approach were included for analysis. The mean pre-operative PTA and SDS were 58 ± 20.7dB and 13 ± 17.5%, respectively. All patients had pre-operative class D hearing and asynchronous ABRs. They all showed significant hearing recovery, with an improvement of 36 ± 22.2dB (p = 0.0025) and 85 ± 16.9% (p = 0.0001) in PTA and SDS, respectively, with mean follow-up of 21 ± 23.5months. Seven patients recovered to a class A hearing level and one patient to class B. The ABRs became synchronous for three patients. The incidence of auditory recovery was 13% for patients operated on with a conservative approach (n = 60). A significant post-operative improvement in hearing could be a reasonable expectation in non-VS tumors extending into the CPA and a retrosigmoid approach should always be considered regardless of pre-operative hearing status.

Extracranial non-vestibular head and neck schwannomas: a case series with the review of literature

IntroductionSchwannomas are tumous that arise from Schwann cells. Schwannoma is one of the differential diagnosis for lateral neck swelling. ObjectiveIn this study, we aim to describe the incidence, presenting clinical features and management of extracranial, non-vestibular schwannomas of head and neck region, along with the review of the literature. MethodsPatients treated at our tertiary care hospital for head and neck schwannomas for the past 15 years were included in the study. A review of literature on the extracranial head and neck schwannoma was also done. ResultsTwenty-five cases were assessed in this study. Nineteen cases presented as a neck swelling during the initial evaluation. Vagus nerve was the most common nerve of origin, followed by the cervical sympathetic plexus. A rare presentation arising from brachial plexus C5 nerve root was also encountered. A few rare cases of schwannomas arose from the nasal cavity, paranasal sinuses, and oral cavity. Surgical excision was done in all the cases with histopathology suggestive of schwannoma. The nerve of origin of the tumor was identified in nineteen patients. Among them, 11 (58%) were from the vagus nerve, 7 (37%) from the cervical sympathetic chain, and 1 (4%) from the brachial plexus C5 nerve root. ConclusionA long-standing unilateral neck mass is the most common presenting complaint in head and neck schwannoma. The diagnosis is mainly based on clinical features and investigations such as imaging. The mainstay of treatment is complete surgical excision. The diagnosis is confirmed on the histopathological study after excision of the lesion. Due to the proximity of the tumor with the involved nerve, palsy may occur. Hence, an accurate preoperative diagnosis of schwannoma is essential.

Proteomic Imaging of Vestibular Schwannomas and Normal Nerves. Histopathologic Correlations.

Proteomic analysis of vestibular schwannoma (VS), non-vestibular schwannoma (NVS), and normal nerve (NN) using mass spectrometry and imaging of matrix assisted laser desorption ionization-time of flight (MALDI-TOF). Retrospective, qualitative, and descriptive study on VS, NVS, and NN. Samples were provided by our Tumor Bank. They were analyzed histologically then sprayed by acid matrix. The laser beam of MALDI performed desorption-ionization of the sample. A mass spectrogram (MS) was drawn depending on time of flight of ionized peptides, and MALDI-imaging was obtained which is a summation color spectrum depending on sample's peptide content. The slice was reexamined histologically and results compared with MALDI-imaging. Fifty schwannomas were sampled, of which 27 exploitable: 22 VS (17 Antoni type A and five type B) and five NVS (all Antoni type B). Eleven NN were analyzed. Among the 22 VS, near-total correlation between MALDI-imaging and pathology was found in two cases (9.1%), partial correlation in four (18.2%), and no correlation in 16 (72.7%); correlations were more frequent in VS of the Antoni type B. MS showed a peptide spike at 2,000 m/z in 7 (31.8%) and 5,000 m/z in 21 (95.5%). Among the five NVS, near-total correlation was found in three cases (60%), partial correlation in one (20%), and no correlation in one (20%). MS showed a peptide spike at 2,000 m/z in two (40%) and 5,000 m/z in all (100%). Among the 11 NN, near-total correlation was found in nine cases (81.8%), partial correlation in one (9.1%), and no correlation in one (9.1%). MS showed no peptide spike at 2,000 or 5,000 m/z. Behind homogeneous areas on histology, there was great heterogeneity on MALDI-imaging and MS, regarding VS and NVS, but not NN. There was a lack of correlation between MALDI-imaging and pathology in VS (except Antoni type B) as compared with NVS and NN. The lack of correlation in VS of the type A as compared with type B VS and NVS could be attributed to the overexpression of degeneration-associated proteins/peptides in VS of the type B as well as NVS that are better correlated with histologic findings. The two peptide spikes detected in schwannoma and not in NN opens up the prospect of tumor biomarkers identifiable by sequencing. The proteomic polymorphism found in VS and NVS was absent on histology which is a new morphologic characteristic of schwannoma. Further studies should be performed in the future to confirm the benefit and usefulness of the MALDI in the analysis of VS and NVS.

Germline Mutations for Novel Candidate Predisposition Genes in Sporadic Schwannomatosis.

Germline Mutations for Novel Candidate Predisposition Genes in Sporadic Schwannomatosis.

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.ConclusionNF2 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.

INNV-06. TREATMENT RESPONSE TO BEVACIZUMAB OVER TWO YEARS IN A PATIENT WITH GENETICALLY PROVEN SOMATIC NEUROFIBROMATOSIS TYPE 2 MOSAICISM

Abstract Neurofibromatosis type 2 (NF2) is a tumor predisposition syndrome characterized by the development of schwannomas, especially bilateral vestibular schwannomas (VS), and meningiomas. Heterozygous pathogenic variants in the NF2 gene are known to cause NF2, whereby somatic mosaicism is present in ~25% of simplex patients. In schwannomatosis, a disorder phenotypically similar to NF2, heterozygous SMARCB1 or LZTR1 variants may be causative. Recently, bevacizumab has shown efficiency as therapy for VS in some NF2 patients. We report on a thirty-three-year-old patient with bilateral VS, fourteen additional schwannomas and one intracranial meningioma. Next generation sequencing using a cancer gene panel and Sanger sequencing of LZTR1 on blood and oral mucosa DNA revealed no pathogenic variants in NF2, SMARCB1 or LZTR1. Sanger sequencing on DNA from three schwannomas identified the known NF2 nonsense variant c.784C >T;p.(R262*) (NM_000268.3, GRCh37/hg19) in all tumors, leading to the diagnosis of somatic NF2 mosaicism. Because of hearing impairment and tumor progression the patient underwent an off-label therapy with 5mg/kg bevacizumab. To determine treatment response, we evaluated MRI scans from five pre-therapeutic and two therapeutic years as well as pure-tone audiometry. After 25 months of treatment, (i) the pure-tone average improved by 11.2 dB indicating a hearing benefit, (ii) four of seven non-vestibular schwannomas showed a volume reduction of ≥ 20%, (iii) the volume of three of seven schwannomas stabilized, and (iv) the growth rate of the meningioma decreased. In conclusion, in a patient with somatic NF2 mosaicism, an off-label therapy with bevacizumab was efficient with respect to hearing improvement and tumor shrinkage in over half of non-vestibular schwannomas over a period of two years.