Schwannoma Research Articles

Scoring model to predict postoperative neurological deterioration in spinal schwannoma.

Spinal schwannomas (SSs) are benign tumors affecting the nerve sheath, accounting for 25% of spinal nerve root tumors. Surgery represents the mainstay of treatment for SS patients. Following surgery, approximately 30% of patients experienced developed new or worsening neurological deterioration, which probably represented an inevitable complication of nerve sheath tumor surgery. The objective of this study was to identify the rates of new or worsening neurological deterioration in our center and accurately predict the neurological outcomes of patients with SS by developing a new scoring model. A total of 203 patients were retrospectively enrolled at our center. Risk factors associated with postoperative neurological deterioration were identified by multivariate logistic regression analysis. β-coefficients for independent risk factors were used to define a numerical score to generate a scoring model. The validation cohort at our center was used to verify the accuracy and reliability of the scoring model. Receiver operating characteristic (ROC) curve analysis was used to evaluate the performance of the scoring model. In this study, five measured variables were selected for the scoring model: duration of preoperative symptoms (1 point), radiating pain (2 points), tumor size (2 points), tumor site (1 point), and dumbbell tumor (1 point). The scoring model divided the spinal schwannoma patients into three categories: low risk (0-2 points), intermediate risk (3-5 points), and high risk (6-7 points), with predicted risks of neurological deterioration of 8.7%, 36%, and 87.5%, respectively. And the validation cohort confirmed the model with the predicted risks of 8.6%, 46.4%, and 66.6%, respectively. The new scoring model might intuitively and individually predict the risk of neurological deterioration and may aid individualized treatment decision-making for SS patients.

A Two-Stage End-to-End Deep Learning Framework for Pathologic Examination in Skin Tumor Diagnosis

Neurofibromas (NF), Bowen's disease (BD), and Seborrheic Keratosis (SK) are common skin tumors. Pathological examination is the golden standard for diagnosis of these tumors. Current pathological diagnosis is mainly based on the observation of naked eyes under microscope, which is laborious and time-consuming. Digitization of pathology brings the opportunity for AI technology to improve the efficiency of diagnosis. This research aims to develop an end-to-end extendable framework for the diagnosis of skin tumor based on pathological slide image. NF, BD, SK were selected as target skin tumors. A two-stage skin cancer diagnosis framework (TSSD) is proposed in this paper, which consists of two parts: patches-wise diagnosis and slide-wise diagnosis. Patches-wise diagnosis compares different Convolutional Neural Networks (CNN) to extract features and distinguish categories from patches generated in whole slide images. Slide-wise diagnosis combines Attention Graph Gated Network (AGGN) model prediction with post-processing algorithm. This approach can fuse information from feature embedding learning and domain knowledge to draw a conclusion. Training, validation and testing were performed on NF, BD, SK and negative samples. Accuracy and ROC curves were used to evaluate the classification performance. This study investigated on the feasibility of skin tumor diagnosis in pathological image and may be the first time that deep learning is applied to address these three kinds of tumor diagnosis in skin pathology.

Vestibular dysfunction in neurofibromatosis type 2-related schwannomatosis.

Neurofibromatosis type 2-related schwannomatosis is a genetic disorder characterized by neurologic tumours, most typically vestibular schwannomas that originate on the vestibulo-cochlear nerve(s). Although vestibular symptoms can be disabling, vestibular function has never been carefully analysed in neurofibromatosis type 2-related schwannomatosis. Furthermore, chemotherapy (e.g. bevacizumab) can reduce tumour volume and improve hearing in neurofibromatosis type 2-related schwannomatosis, but nothing is known about its vestibular effects. In this report, we studied the three primary vestibular-mediated behaviours (eye movements, motion perception and balance), clinical vestibular disability (dizziness and ataxia), and imaging and hearing in eight untreated patients with neurofibromatosis type 2-related schwannomatosis and compared their results with normal subjects and patients with sporadic, unilateral vestibular schwannoma tumours. We also examined how bevacizumab affected two patients with neurofibromatosis type 2-related schwannomatosis. Vestibular schwannomas in neurofibromatosis type 2-related schwannomatosis degraded vestibular precision (inverse of variability, reflecting a reduced central signal-to-noise ratio) but not vestibular accuracy (amplitude relative to ideal amplitude, reflecting the central signal magnitude) and caused clinical disability. Bevacizumab improved vestibular precision and clinical disability in both patients with neurofibromatosis type 2-related schwannomatosis but did not affect vestibular accuracy. These results demonstrate that vestibular schwannoma tumours in our neurofibromatosis type 2-related schwannomatosis population degrade the central vestibular signal-to-noise ratio, while bevacizumab improves the signal-to-noise ratio, changes that can be explained mechanistically by the addition (schwannoma) and suppression (bevacizumab) of afferent neural noise.

Merlin tumor suppressor function is regulated by PIP2-mediated dimerization.

Neurofibromatosis Type 2 is an inherited disease characterized by Schwann cell tumors of cranial and peripheral nerves. The NF2 gene encodes Merlin, a member of the ERM family consisting of an N-terminal FERM domain, a central α-helical region, and a C-terminal domain. Changes in the intermolecular FERM-CTD interaction allow Merlin to transition between an open, FERM accessible conformation and a closed, FERM-inaccessible conformation, modulating Merlin activity. Merlin has been shown to dimerize, but the regulation and function Merlin dimerization is not clear. We used a nanobody based binding assay to show that Merlin dimerizes via a FERM-FERM interaction, orientated with each C-terminus close to each other. Patient derived and structural mutants show that dimerization controls interactions with specific binding partners, including HIPPO pathway components, and correlates with tumor suppressor activity. Gel filtration experiments showed that dimerization occurs after a PIP2 mediated transition from closed to open conformation monomers. This process requires the first 18 amino acids of the FERM domain and is inhibited by phosphorylation at serine 518. The discovery that active, open conformation Merlin is a dimer represents a new paradigm for Merlin function with implications for the development of therapies designed to compensate for Merlin loss.

Proteasomal pathway inhibition as a potential therapy for NF2-associated meningioma and schwannoma.

Neurofibromatosis 2 (NF2) is an inherited disorder caused by bi-allelic inactivation of the NF2 tumor suppressor gene. NF2-associated tumors, including schwannoma and meningioma, are resistant to chemotherapy, often recurring despite surgery and/or radiation, and have generally shown cytostatic response to signal transduction pathway inhibitors, highlighting the need for improved cytotoxic therapies. Leveraging data from our previous high-throughput drug screening in NF2 preclinical models, we identified a class of compounds targeting the ubiquitin-proteasome pathway (UPP), and undertook studies using candidate UPP inhibitors, ixazomib/MLN9708, pevonedistat/MLN4924, and TAK-243/MLN7243. Employing human primary and immortalized meningioma (MN) cell lines, CRISPR-modified Schwann cells (SCs), and mouse Nf2-/- SCs, we performed dose response testing, flow cytometry-based Annexin V and cell cycle analyses, and RNA-sequencing to identify potential underlying mechanisms of apoptosis. In vivo efficacy was also assessed in orthotopic NF2-deficient meningioma and schwannoma tumor models. Testing of three UPP inhibitors demonstrated potent reduction in cell viability and induction of apoptosis for ixazomib or TAK-243, but not pevonedistat. In vitro analyses revealed that ixazomib or TAK-243 downregulates expression of c-KIT and PDGFRα, as well as the E3 ubiquitin ligase SKP2 while upregulating genes associated with endoplasmic reticulum stress-mediated activation of the unfolded protein response (UPR). In vivo treatment of mouse models revealed delayed tumor growth, suggesting a therapeutic potential. This study demonstrates the efficacy of proteasomal pathway inhibitors in meningioma and schwannoma preclinical models and lays the groundwork for use of these drugs as a promising novel treatment strategy for NF2 patients.

Benign peripheral nerve tumors: Analysis of 89 FNA cases emphasizing diagnostic accuracy and their morphologic spectrum.

Benign peripheral nerve tumors (BPNTs) are a heterogenous group of soft tissue tumors that include a variety of nerve sheath tumors, granular cell tumor (GCT), and ganglioneuroma. Only a few large studies exist on cytopathology and diagnostic accuracy using fine-needle aspiration (FNA) biopsy for this set of neoplasms. Both surgical and cytopathology files were searched for cases of BPNT. FNA biopsy was performed using standard techniques. Eighty-nine cases from 88 patients (male:female=1:1; age range: 16-85years, mean age,51years) met inclusion criteria. FNA sites included extremities (58, 65%), head/neck (14, 16%), deep (9, 10%), and trunk (8, 10%). Aspirates were from primary neoplasms in all but one instance. There were 65 schwannomas, seven neurofibromas, seven perineuriomas, seven GCTs, and three ganglioneuromas/neuromas. Aspirates of schwannoma, GCT, neurofibroma (NF), and perineurioma (PN) were correctly diagnosed in 86%, 100%, 29%, and 0% of cases, respectively. Five tumors (6%) were interpreted as either a specific sarcoma or suspicious for sarcoma. Remaining aspirates were classified as spindle cell neoplasm, salivary gland neoplasm, and nondiagnostic. Cytologic features for schwannoma, NF, PN, and ganglioneuroma showed spindle cell-dominant smears arranged mainly in syncytial clusters. GCT aspirates contained a population of epithelioid cells harboring coarsely granular cytoplasm and bare nuclei. Immunohistochemical (IHC) staining in 55 (62%) cases showed S-100 expression in 95%. FNA biopsy coupled with IHC is reliable in correctly classifying schwannoma and GCT, but less so for NF. Perineurioma can be mistaken for sarcoma.

MRI Evaluation of Intradural Extramedullary Spinal Tumors with Histopathological Correlation - A Cross Sectional Study

Introduction: Tumors of nerve sheath, neurofibroma and schwannoma represent 30% of intradural extramedullary tumors. Schwannomas and neurofibromas are histologically composed of Schwann cells. Schwannomas almost always arise from the dorsal sensory roots and form well- encapsulated firm masses that compress adjacent tissue, without invading the involved nerve. Neurofibromas are more complex and are composed of Schwann cells mixed with fibroblast they involve the parent nerve. Meningiomas comprise approximately 25% of primary intraspinal tumors and are second only to nerve sheath tumors in frequency. Spinal cord meningiomas are originate from meningothelial cells near the distal root ganglia. Most menongiomas are intradural extramedullary, only 5% are extradural. Aim of the Study: The aim of this study was to evaluate the role of MRI in diagnosis of intradural extramedullary spinal tumors compared to histopathological findings. Methods: This was a cross sectional study and was conducted in the Department of Radiology and Imaging, Sylhet M.A.G. Osmani Medical College, Sylhet in collaboration with Department of Neurosurgery & Pathology of the same hospital, Sylhet, Bangladesh during the period from September, 2018 to August 2020. Result: In total 35 patients completed the study. In our study we found the Mean ± SD of age was 41.71±13.9 in years. Majority (54%) of our patients presented with spinal tumor were male compared to female (46%).We found schwannoma was diagnosed by (42.9%), meningioma (31.4%), neurofibroma (25.7%) respectively. Neurofibroma & schwannoma showed male predominance with 66.67% & 60% while meningioma showed female predominance with 63.6%. We found majority (55.6%, 60% & 72.7%) of neurofibroma, schwannoma & meningioma was in dorsal region respectively. Conclusion: In our study we found that MRI is a very sensitive and effective imaging procedure of suspected spinal schwannoma tumor of the spinal cord for accurate pre-operative diagnosis and ........

Characterization of Dental Pulp Stem Cell Populations in the Teeth of Patients With Neurofibromatosis Type 1 - Therapeutic Potential for Bone Tissue Engineering.

Neurofibromas (NF) are the most common benign nerve sheath tumors in the tongue, gingiva, major salivary glands, and jaw bones. Nowadays, tissue engineering is a revolutionary technique for reconstructing tissues. To explore the feasibility of using stem cells derived from NF teeth to treat orofacial bone defects, the differences in cell biological properties between an NF teeth group and Normal teeth group. The intra-dental pulp tissues from each tooth were extracted. The cell survival rates, morphology, proliferation rates, cell activity, and differentiation abilities were contrastively analyzed between the NF teeth group and Normal teeth group. Between the two groups, there were no differences in the primary generation (P0) cells (p>0.05), the cell yield, and the time required for the cells to grow out of the pulp tissue and attach to the culture plate. Furthermore, no differences were found at the first generation (passage) between the two groups in colony formation rate and cell survival rate. The proliferation capacity, cell growth curve, and surface marker expression of dental pulp cells was not altered in the third generation (p>0.05). Dental pulp stem cells from NF teeth were successfully obtained and were not different from normal dental pulp stem cells. Although, clinical research using tissue-engineered bone to repair bone defects is still in its infancy, it will eventually enter the clinic and become a routine means of bone defect reconstruction treatment as related disciplines and technologies develop.

Effect of Antibiotic Treatment on Attenuated Salmonella typhimurium VNP20009 Mediated Schwannoma Growth Control.

This study evaluated the effect of enrofloxacin antibiotic treatment on the ability of an attenuated Salmonella typhimurium (S. typhimurium) strain VNP20009 to control schwannoma growth in a preclinical mouse schwannoma tumor model. The antitumor efficacy of VNP20009 intratumoral (i.t.) injection was assessed in a syngeneic mouse-NF2 schwannoma model, with and without subcutaneous (s.c.) injection of enrofloxacin beginning on day-1 or day-8 post-VNP20009 injection. S. typhimurium colonization was assessed in excised tumor samples following antibiotic treatment. I.t. injection of the VNP20009 significantly decreased the growth of schwannoma tumors in mice compared to PBS-treated controls. Treatment of mice with enrofloxacin on day-1 post-VNP20009 injection resulted in abrogation of VNP20009-mediated tumor growth control. In contrast, tumor growth in i.t. VNP20009-injected mice infused with enrofloxacin beginning on day 8 was significantly decreased compared to i.t. PBS-injected controls. Enrofloxacin significantly reduced the number of viable VNP20009 bacteria in excised tumor samples within one day of antibiotic infusion. Viable bacteria were either few or essentially eliminated at the end of the experiment in antibiotic-treated animals compared to VNP20009-only. Viable VNP20009 can persist for as long as 2.5 weeks following intratumoral injection of schwannoma, during which time tumor growth is retarded. Antibiotic treatment starting 1-day following i.t. VNP20009 abrogated bacterial tumor growth control, whereas initiation of antibiotics 8-days following i.t. VNP20009 was associated with control of tumor growth, albeit less than seen in animals unexposed to antibiotics.

DDDR-06. NEUROFIBROMATOSIS TUMOR SUPPRESSORS COOPERATIVELY DRIVE TUMOR DE-DIFFERENTIATION AND MEK INHIBITOR RESISTANCE IN PERIPHERAL NERVOUS SYSTEM TUMORS

Abstract Schwann cell derived tumors comprising schwannomas, neurofibromas, and malignant peripheral nerve sheath tumors (MPNSTs) are the most common cancers of the peripheral nervous system and often arise in patients with neurofibromatosis type-1 (NF-1) or type-2 (NF-2). NF-1 is caused by loss of NF1, a negative regulator of Ras signaling, and NF-2 is caused by loss of NF2, a pleiotropic tumor suppressor with numerous functions including inhibition of PAK signaling. However, whether functional interactions exist between the NF1 and NF2 tumor suppressors remain unclear. More broadly, there are currently no effective molecular therapies for patients with Schwann cell tumors beyond the MEK inhibitor selumetinib to treat neurofibromas in patients with NF-1. Here, we integrate DNA methylation profiling, whole exome sequencing, bulk and single-cell RNA sequencing, biochemistry, and pharmacology across human samples, cell lines, and mouse xenografts to identify cellular de-differentiation as a driver of malignant transformation and selumetinib resistance. Single nuclear RNA-sequencing of human neurofibromas (n = 3) or MPNSTs (n = 3) revealed a total of 13 cell types with increased proliferating, de-differentiated tumor cell populations in MPNST samples. Single cell RNA-sequencing of MPNST mouse xenografts revealed persistence of de-differentiated cell populations in selumetinib treated samples compared to vehicle control, suggesting cellular de-differentiation underlies treatment resistance. A genome-wide CRISPRi screen for mediators of selumetinib response in NF1 deficient neurofibroma cells revealed NF2 loss drives selumetinib resistance. Consistently, NF2 suppression in NF1 deficient neurofibroma cells caused Schwann cell de-differentiation and activation of PAK, a serine threonine kinase. Translationally, a small molecule PAK inhibitor in combination with selumetinib formed an effective therapy in mouse MPNST xenografts. In sum, we elucidate a paradigm of de-differentiation driving malignant transformation and treatment resistance in Schwann cell tumors, uncovering a functional link between the NF1 and NF2 tumor suppressors that sheds light on a novel therapeutic vulnerability.

Single-cell multiomics identifies clinically relevant mesenchymal stem-like cells and key regulators for MPNST malignancy.

Malignant peripheral nerve sheath tumor (MPNST), a highly aggressive Schwann cell (SC)-derived soft tissue sarcoma, arises from benign neurofibroma (NF); however, the identity, heterogeneity and origins of tumor populations remain elusive. Nestin+ cells have been implicated as tumor stem cells in MPNST; unexpectedly, single-cell profiling of human NF and MPNST and their animal models reveal a broad range of nestin-expressing SC lineage cells and dynamic acquisition of discrete cancer states during malignant transformation. We uncover a nestin-negative mesenchymal neural crest-like subpopulation as a previously unknown malignant stem-like state common to murine and human MPNSTs, which correlates with clinical severity. Integrative multiomics profiling further identifies unique regulatory networks and druggable targets against the malignant subpopulations in MPNST. Targeting key epithelial-mesenchymal transition and stemness regulators including ZEB1 and ALDH1A1 impedes MPNST growth. Together, our studies reveal the underlying principles of tumor cell-state evolution and their regulatory circuitries during NF-to-MPNST transformation, highlighting a hitherto unrecognized mesenchymal stem-like subpopulation in MPNST disease progression.

Investigation of optimal planning strategy in gamma knife perfexion for vestibular schwannoma tumor using hybrid plan technique

Purpose. Stereotactic radiosurgery (SRS) for vestibular schwannoma (VS) is clinically challenging because of surrounding critical structures. We generated and compared the forward plan (FP), inverse plan (IP), and hybrid plan (HP) for the optimal planning strategy in Gamma Knife stereotactic radiosurgery (GKSRS) for vestibular schwannoma tumors (VS). Methods and materials. In this study, 51 planning scenarios of 17 patients with VS were planned for GKSRS using FP, IP, and HP in Leksell Gamma plan (LGP10.1) using the TMR10 algorithm. The planning images were obtained using the following MRI (GE, USA) scan parameters: T1W images-MPRAGE sequence, FOV-256 mm × 256 mm, matrix size-512 mm × 512 mm, and the slice thickness 1 mm. The total dose was prescribed12Gy and normalized at 50% isodose level. Results and discussion. The plan parameters were compared dosimetrically by maintaining FP as a base plan. The statistical analysis, including one-factor, repeated measures ANOVA and Bonferroni correction tests, were performed. The p-value for planning parameters such as brainstem dose, beam ON time, and gradient index significantly favored HP. Conclusion. Overall results show that HP is an efficient method for GKSRS of VS The p-value was less than 0.001 and statistically significant for various plan indices.

Single-cell sequencing reveals the cell map and transcriptional network of sporadic vestibular schwannoma.

In this study, based on three tumor samples obtained from patients with sporadic vestibular schwannoma, 32,011 cells were obtained by single-cell transcriptome sequencing, and 22,309 high-quality cells were obtained after quality control and double cells removal. Then, 18 cell clusters were obtained after cluster analysis, and each cluster was annotated as six types of cells. Afterward, an in-depth analysis was conducted based on the defined six cell clusters, including characterizing the functional characteristics of each cell subtype, describing the cell development and differentiation pathway, exploring the interaction between cells, and analyzing the transcriptional regulatory network within the clusters. Based on these four dimensions, various types of cells in sporadic vestibular schwannoma tumor tissues were described in detail. For the first time, we expanded on the functional state of cell clusters that have been reported and described Schwann cells in the peripheral nervous system, which have not been reported in previous studies. Combined with the data of sporadic vestibular schwannoma and normal tissues in the gene expression omnibus (GEO) database, the candidate biomarkers of sporadic vestibular schwannoma were explored. Overall, this study described the single-cell map of sporadic vestibular schwannoma for the first time, revealing the functional state and development trajectory of different cell types. Combined with the analysis of data in the GEO database and immunohistochemical verification, it was concluded that HLA-DPB1 and VSIG4 may be candidate biomarkers and potential therapeutic targets for patients with sporadic vestibular schwannoma.

Inhibition of YAP/TAZ-driven TEAD activity prevents growth of NF2-null schwannoma and meningioma.

Schwannoma tumours typically arise on the eighth cranial nerve and are mostly caused by loss of the tumour suppressor Merlin (NF2). There are no approved chemotherapies for these tumours and the surgical removal of the tumour carries a high risk of damage to the eighth or other close cranial nerve tissue. New treatments for schwannoma and other NF2-null tumours such as meningioma are urgently required. Using a combination of human primary tumour cells and mouse models of schwannoma, we have examined the role of the Hippo signalling pathway in driving tumour cell growth. Using both genetic ablation of the Hippo effectors YAP and TAZ as well as novel TEAD palmitoylation inhibitors, we show that Hippo signalling may be successfully targeted in vitro and in vivo to both block and, remarkably, regress schwannoma tumour growth. In particular, successful use of TEAD palmitoylation inhibitors in a preclinical mouse model of schwannoma points to their potential future clinical use. We also identify the cancer stem cell marker aldehyde dehydrogenase 1A1 (ALDH1A1) as a Hippo signalling target, driven by the TAZ protein in human and mouse NF2-null schwannoma cells, as well as in NF2-null meningioma cells, and examine the potential future role of this new target in halting schwannoma and meningioma tumour growth.

Machine Learning for Automated Calculation of Vestibular Schwannoma Volumes.

Machine learning-derived algorithms are capable of automated calculation of vestibular schwannoma tumor volumes without operator input. Volumetric measurements are most sensitive for detection of vestibular schwannoma growth and important for patient counseling and management decisions. Yet, manually measuring volume is logistically challenging and time-consuming. We developed a deep learning framework fusing transformers and convolutional neural networks to calculate vestibular schwannoma volumes without operator input. The algorithm was trained, validated, and tested on an external, publicly available data set consisting of magnetic resonance imaging images of medium and large tumors (178-9,598 mm 3 ) with uniform acquisition protocols. The algorithm was then trained, validated, and tested on an internal data set of variable size tumors (5-6,126 mm 3 ) with variable acquisition protocols. The externally trained algorithm yielded 87% voxel overlap (Dice score) with manually segmented tumors on the external data set. The same algorithm failed to translate to accurate tumor detection when tested on the internal data set, with Dice score of 36%. Retraining on the internal data set yielded Dice score of 82% when compared with manually segmented images, and 85% when only considering tumors of similar size as the external data set (>178 mm 3 ). Manual segmentation by two experts demonstrated high intraclass correlation coefficient (0.999). Sophisticated machine learning algorithms delineate vestibular schwannomas with an accuracy exceeding established norms of up to 20% error for repeated manual volumetric measurements-87% accuracy on a homogeneous data set, and 82% to 85% accuracy on a more varied data set mirroring real world neurotology practice. This technology has promise for clinical applicability and time savings.

Clinical presentation, management, and research progress of adrenal schwannoma.

ObjectiveThis study shares our experience in managing adrenal schwannoma (AS).MethodsThe clinical data of eight patients with AS in our hospital from April 2007 to April 2022 were analyzed retrospectively.ResultsA total of 1309 patients with adrenal lesions were treated in the affiliated hospital of Guizhou Medical University for 15 years, of which only 8 cases were diagnosed as AS, accounting for 0.61%. Among the eight patients with AS, there were five females and three males, with an average age of 48.63 ± 12.05 years, and the average maximum diameter of the tumor was 6.96 ± 1.83 cm. All patients underwent adrenalectomy and were pathologically diagnosed as AS after the operation. The average follow-up time of eight patients with AS was 60.13 ± 22.33 months, and there was no recurrence or metastasis.ConclusionThe retroperitoneum is an uncommon site for schwannoma tumors, and among adrenal incidentalomas, the schwannoma is rare. The disease lacks specific clinical and imaging features, but correct diagnosis before the pathological examination is very important for clinical management and surgical decision. When imaging examination indicates a slow-growing retroperitoneal mass, schwannoma should be considered. Surgical resection is the main treatment. Pathology is the gold standard for diagnosis. Most of the tumors are benign and have a good prognosis. There is a risk of recurrence after the operation, and it should be monitored actively.

Cellular schwannoma of the posterior tongue: a rare case report with a literature review

Introduction: Schwannoma is a gradually growing encapsulated benign tumor arising from the Schwan cells of the peripheral nerve sheath. This study aims to report a rare case of tongue cellular schwannoma. Case presentation: A 15-year-old boy presented with a swelling of the posterior part of the tongue that had started 2 years prior. On examination, a large mass was seen in the posterior part of the tongue. It was smooth, mobile, and nontender on palpation. A contrast computed tomography scan of the neck revealed an irregular, ill-defined, thick-walled cystic lesion. Magnetic resonance imaging demonstrated a well-circumscribed, enhancing mass measuring about 5×4.56×4.59 cm and causing compression upon the oropharyngeal airway. Histopathologic examination revealed a cellular schwannoma. Discussion: Histologically, all schwannoma tumors are encapsulated. Under the capsule, there are 2 specific patterns associated together, but they can be easily differentiated from each other. The first one is made up of firmly aggregated Schwan cells arranged in rows with palisade and enlarged nuclei which are known as Antoni type-A. The second one is the Antoni type-B that consists of weakly packed Schwann cells. Conclusion: Tongue schwannoma is regarded as a solitary encapsulated benign tumor that may cause complications like difficulty in phonation. The primary treatment modality usually is transoral excision.

Manajemen Anestesi Reseksi Tumor Cerebello-pontine Angle Vestibular Schwannoma dengan Posisi Lateral

Cerebellopontine angle (CPA) tumors are the most common neoplasms in the posterior fossa, accounting for 5-10% of intracranial tumors. Most CPA tumors are benign, with over 85% being vestibular schwannoma (acoustic neuromas). The preferred treatment for symptomatic vestibular schwannoma has been surgical excision. Craniotomy for vestibular schwannoma resections in lateral position gave better surgical field exposure, but also posed increased risk of ventilation-perfusion mismatch and atelectasis of the dependent lung in lengthy surgery. A 25 years old woman, with loss of hearing function, disturbed sense of balance, left hemiplegia, difficulties to swallow, on magnetic resonance imaging (MRI) examination had solid lesion in the cerebello-pontine angle size 5,6 cm x 5 cm x 4.5 cm which is diagnosed as Cerebello-pontine angle vestibular schwannoma sinistra. Patient underwent surgical resection in right lateral position under general anesthesia and the surgical resection performed in 6 hour 40 minutes. The goals of anesthetic management in vestibular schwannoma tumor resection are to facilitate ideal surgical condition and provide brain protection by maintaining cerebral perfusion pressure, avoid hemodynamic instability, enable intraoperative neuro-monitoring and ensure the early detection and prompt management of potential complications.

Sporadic diffuse neurofibroma of the retropharyngeal space.

Neurofibroma (NF) rarely arises in the retropharyngeal space (RPS) of patients with or without Neurofibromatosis type I (NF-I). The diffuse subtype of NF (DNF) is characterized by an infiltrative growth pattern and typically involves the skin and subcutaneous tissue of the head and neck. We describe the clinic-pathologic features of a DNF involving the RPS of an adult without NF-I. To date, this subtype of NF has never been reported at this site.

Abstract 1549: The tumorigenesis model in DGCR8 associated schwannomatosis

Abstract Purpose: Schwannomatosis is an inherited disorder that affects Schwann cells from peripheral nerves. It is diagnosed when multiple schwannomas occur in the absence of bilateral vestibular schwannomas. The two main genes associated with this disorder are SMARCB1 and LZTR1 both on chromosome 22q (Chrm22q). Somatic inactivation of NF2, downstream of SMARCB1, is observed in most schwannomas. The accepted model of schwannomatosis involves multiple hits over three steps to inactivate LZTR1 or SMARCB1 together with NF2. Following this pattern, most of the LZTR1/SMARCB1-schwannomas acquire a somatic loss of Chrm22 (thus deleting the three genes) and a somatic mutation affecting the remaining wild-type NF2 copy on the GPV allele. Several studies have postulated the plausible existence of other susceptibility genes predisposing to schwannomatosis and the likelihood of those being localized in Chrm22q. Last year we identified a GPV in the microprocessor DGCR8 (c.1552G>A; p.E518K) located in the Chrm22q11 region, as responsible for a familial form of schwannomatosis and multinodular goiter (Rivera et al JCI, 2020). Our goal is to clarify the role of DGCR8 as a novel tumor susceptibility gene and the tumorigenic mechanisms that lead to DGCR8-schwannomatosis. Methods: We searched for patients affected of schwannoma and thyroid tumors. By whole exome sequencing we identified the same DGCR8 (c.1552G>A; p.E518K) variant in one patient. We then collected a total of 13 DGCR8-schwannomas from carriers. Eleven tumors were subjected to WES and two tumors were subjected to a NGS targeted panel covering all known schwannoma genes in Chrm22q. Results: We report the second case of a patient with peripheral schwannomatosis and thyroid alterations caused by the germline pathogenic variant E518K in DGCR8. Loss of Chrm22q was seen in all 13 tumors analyzed. While all tumors had at least one alteration of NF2, 4 tumors had no somatic mutations on the retained (not deleted) allele (30.8%). Given that DGCR8 localizes 5’ of LZTR1, the second step (LOH) leads to the deletion of DGCR8 and the three bona fide schwannoma genes (LZTR1, SMARCB1 and NF2) adding up to a total of 6 hits in a 3-step model. Suggesting that the path to tumorigenesis driven by DGCR8 requires the loss of the wild type allele of Chrm22q and in more than two thirds of the tumors a complete inactivation of NF2 occurs. Conclusion: Our findings highlight DGCR8 as a schwannomatosis gene mapping to the Chrm22 cluster of tumor suppressors that cooperate to promote tumorigenesis in Schwann cell and pinpoints an important role of miRNA regulation in this process. Citation Format: Clara Nogué, Anne-Sophie Chong, Elia Grau, HyeRim Han, Eduard Dorca, Carla Roca, Jose Luis Mosquera, Conxi lazaro, William D. Foulkes, Joan Brunet, Bárbara Rivera Polo. The tumorigenesis model in DGCR8 associated schwannomatosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1549.