Familial schwannomatosis carrying LZTR1 variant p.R340X with brain tumor: A case report.

Schwannomatosis (SWN) is a rare genetic condition characterized by the risk of developing multiple benign peripheral nerve sheath tumors; however, the risk of developing malignant tumors in patients with SWN remains unclear. This study described the case of a 57-year-old Japanese man diagnosed with SWN whose older brother also had SWN. Whole-exome sequencing identified a heterozygous mutation [c.1018C > T (p.Arg340X)] in the LZTR1 gene, linked to the RAS/MAPK pathway, in the patient and his brother. Moreover, the patient had aphasia and right-sided paralysis because of a brain tumor. RNA sequencing revealed the remarkable upregulation of several genes associated with oxidative stress, such as the reactive oxygen species pathway and oxidative phosphorylation, a downstream effector of the RAS/MAPK pathway, in the the patient and his brother compared with healthy volunteers. The final diagnosis was LZTR1-related familial SWN, and the dysregulated RAS/MAPK pathway in this patient might be associated with brain tumorigenesis.

NF2-Related Schwannomatosis (NF2): Molecular Insights and Therapeutic Avenues.

NF2-related schwannomatosis (NF2) is a genetic syndrome characterized by the growth of benign tumors in the nervous system, particularly bilateral vestibular schwannomas, meningiomas, and ependymomas. This review consolidates the current knowledge on NF2 syndrome, emphasizing the molecular pathology associated with the mutations in the gene of the same name, the NF2 gene, and the subsequent dysfunction of its product, the Merlin protein. Merlin, a tumor suppressor, integrates multiple signaling pathways that regulate cell contact, proliferation, and motility, thereby influencing tumor growth. The loss of Merlin disrupts these pathways, leading to tumorigenesis. We discuss the roles of another two proteins potentially associated with NF2 deficiency as well as Merlin: Yes-associated protein 1 (YAP), which may promote tumor growth, and Raf kinase inhibitory protein (RKIP), which appears to suppress tumor development. Additionally, this review discusses the efficacy of various treatments, such as molecular therapies that target specific pathways or inhibit neomorphic protein-protein interaction caused by NF2 deficiency. This overview not only expands on the fundamental understanding of NF2 pathophysiology but also explores the potential of novel therapeutic targets that affect the clinical approach to NF2 syndrome.

Historical Development of Diagnostic Criteria for NF2-related Schwannomatosis.

NF2-related schwannomatosis (NF2; previously termed neurofibromatosis type 2) is a tumor-prone disorder characterized by development of multiple schwannomas and meningiomas. The diagnostic criteria of NF2 have been regularly revised. Clinical criteria for NF2 were first formulated at the National Institutes of Health Consensus Conference in 1987 and revised in 1990. Revised criteria were also proposed by the Manchester group in 1992 and by the National Neurofibromatosis Foundation (NNFF) in 1997. The 2011 Baser criteria improved the sensitivity of diagnostic criteria, particularly for patients without bilateral vestibular schwannomas. Revisions to the Manchester criteria were published in 2019, with replacement of "glioma" by "ependymoma," removal of "neurofibroma," addition of an age limit of 70 years for development of vestibular schwannomas, and introduction of molecular criteria, which led to the most widely used criteria. In 2022, the criteria were reviewed and updated by the international committee of NF experts. In addition to changes in diagnostic criteria, the committee recommended the use of "schwannomatosis" as an umbrella term for conditions that predispose to schwannomas. Each type of schwannomatosis was classified by the gene containing the disease-causing pathogenic variant. Molecular data from NF2 patients led to further clarification of the diagnostic criteria for NF2 mosaic phenotypes. Given all these changes, the diagnostic criteria of NF2 may be confusing. Herein, to help healthcare professionals who diagnose NF2 conditions in the clinical setting, we review the historical development of diagnostic criteria.

Gene Therapy for Neurofibromatosis Type 2-Related Schwannomatosis: Recent Progress, Challenges, and Future Directions.

Neurofibromatosis type 2 (NF2)-related schwannomatosis is a rare autosomal dominant monogenic disorder caused by mutations in the NF2 gene. The hallmarks of NF2-related schwannomatosis are bilateral vestibular schwannomas (VS). The current treatment options for NF2-related schwannomatosis, such as observation with serial imaging, surgery, radiotherapy, and pharmacotherapies, have shown limited effectiveness and serious complications. Therefore, there is a critical demand for novel effective treatments. Gene therapy, which has made significant advancements in treating genetic diseases, holds promise for the treatment of this disease. This review covers the genetic pathogenesis of NF2-related schwannomatosis, the latest progress in gene therapy strategies, current challenges, and future directions of gene therapy for NF2-related schwannomatosis.

Multiple intracranial schwannomas of the vestibular and trigeminal nerves: Technical note.

BACKGROUND: A 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. LESSONS: The presence of multiple intracranial schwannomas is extremely rare in neurosurgical practice and can change the intraoperative strategy and the course of the surgery.

18F-FDG PET/CT revealed sporadic schwannomatosis involving the lumbar spinal canal and both lower limbs: a case report.

Schwannomatosis is a rare autosomal dominant hereditary syndrome disease characterized by multiple schwannomas throughout the body, without bilateral vestibular schwannoma or dermal schwannoma. The most common location of schwannomatosis is the head and neck, as well as the limbs, while multiple schwannomas in the lumbosacral canal and lower extremities are relatively rare. In this study, we report a 79-year-old woman diagnosed with schwannomatosis. MRI and contrast-enhanced imaging revealed multiple schwannomas in both lower extremities. An 18F-FDG PET/CT examination revealed that in addition to multiple tumors with increased 18F-FDG uptake in both lower extremities, there was also an increased 18F-FDG uptake in a mass in the lumbosacral canal. These masses were confirmed to be schwannomas by pathology after surgery or biopsy. 18F-FDG PET/CT findings of schwannomas were correlated with MRI and pathological components. Antoni A area rich in tumor cells showed significant enhancement on contrast-enhanced T1WI, and PET/CT showed increased uptake of 18F-FDG in the corresponding area, while Antoni B region rich in mucus showed low enhancement on contrast-enhanced T1WI, accompanied by a mildly increased 18F-FDG uptake.

Bevacizumab Treatment for Patients with NF2-Related Schwannomatosis: A Single Center Experience.

(1) Background: NF2-related schwannomatosis, characterized by the development of bilateral vestibular schwannomas, often necessitates varied treatment approaches. Bevacizumab, though widely utilized, demonstrates variable effectiveness on hearing and tumor growth. At the same time, (serious) adverse events have been frequently reported. (2) Methods: A single center retrospective study was conducted, on NF2-related schwannomatosis patients treated with bevacizumab from 2013 to 2023, with the aim to assess treatment-related and clinical outcomes. Outcomes of interest comprised hearing, radiologic response, symptoms, and adverse events. (3) Results: Seventeen patients received 7.5 mg/kg bevacizumab for 7.1 months. Following treatment, 40% of the patients experienced hearing improvement, 53%, stable hearing, and 7%, hearing loss. Vestibular schwannoma regression occurred in 31%, and 69% remained stable. Further symptomatic improvement was reported by 41%, stable symptoms by 47%, and worsened symptoms by 12%. Treatment discontinuation due to adverse events was observed in 29% of cases. Hypertension (82%) and fatigue (29%) were most frequently reported, with no occurrences of grade 4/5 toxicities. (4) Conclusion: Supporting previous studies, bevacizumab demonstrated positive effects on hearing, tumor control, and symptoms in NF2-related schwannomatosis, albeit with common adverse events. Therefore, careful consideration of an appropriate management strategy is warranted.

A Curious Case of Common Peroneal Nerve Schwannoma.

Schwannoma or neurilemmoma is a slow-growing tumor that develops from nerve sheaths. It is mostly benign and only rarely transforms into malignancy. The incidence of schwannoma is very low in the lower limbs. Schwannomas developing from the common peroneal nerve is unlikely. A middle-aged male presented with complaints of left knee pain, which was radiating to the left foot, and a painful swelling at the back of the knee. An intralesional excision was done, and the patient made a full recovery with no postoperative complications. The excised specimen was found to be a schwannoma of the common peroneal nerve of the left leg. At the one-month, three-month, and one-year postoperative follow-ups, the patient had no complaints of pain on passive and active dorsiflexion of the foot. There was complete recovery from paresthesia and intact sensation was present. This report shows that asymptomatic schwannomas can sometimes present with symptoms of pain. In such cases, careful and complete excision of the schwannoma can lead to full recovery.

A rare case of schwannomatosis with meningioma: a case report.

Introduction: Schwannomatosis is characterized by multiple schwannomas without vestibular schwannomas or any other stigmata of neurofibromatosis type 2 (NF2). Schwannomatosis is a rare disorder, with a reported incidence ranging from 1 in 40 000 to 1 in 1.7 million. Meningioma is also associated with schwannomatosis in around 5% of cases. Case presentation: We describe a case of a 20-year-old female presenting with progressive weakness of the right lower limb for 7 months with a tingling sensation and numbness of the same limb for 6 months and was found to have schwannomatosis with multiple spinal and right cerebellopontine angle (CPA) (9th/10th cranial nerve) schwannomas and left anterior cranial fossa meningioma. Discussion: Schwannomas in schwannomatosis are seen along the cranial, spinal, and peripheral nerves but not along the vestibular nerve, as is characteristically seen in NF2. The occurrence of meningiomas is about 5% in individuals with schwannomatosis, and the patient in our case also had an associated meningioma. The tumor was confirmed to be a schwannoma based on features on an MRI examination and histological examination. Conclusion: It is of great significance to identify the entire spectrum of the disease in a patient with schwannomatosis, and to differentiate it from related conditions in order to track and surgically manage the patient appropriately based on symptomatology and imaging findings.

High-frequency ultrasound imaging findings in the diagnosis of segmental schwannomatosis of the ulnar nerve: case report and literature review.

Schwannomatosis is characterized by the development of multiple schwannomas without evidence of vestibular tumors. Segmental schwannomatosis is defined as being limited to one limb or five or fewer contiguous segments of the spine. We report a case of a 20-year-old male with the painful masses of the left upper extremity with associated numbness and paresthesia in the ulnar nerve distribution. The high-frequency ultrasound showed that the ulnar nerve fascicles were enlarged and expanded with beadlike growth. The patient underwent surgery twice and all the tumors were pathologically confirmed to be schwannomas. Together, the medical history, imaging, and pathology findings indicated the diagnosis of segmental schwannomatosis. By the imaging diagnostic tools, MRI is the most commonly used in assistance with diagnosis of segmental schwannomatosis while high-frequency ultrasonography is rare. In this paper, we discuss the value of high-frequency ultrasonography in the diagnosis of this rare disease. This case report provides a deeper understanding of segmental schwannomatosis and may help improve the accuracy of preoperative diagnosis.

Auditory brainstem implants for hearing rehabilitation in NF2-schwannomatosis: A systematic review and single-arm meta-analysis.

BACKGROUND: NF2-schwannomatosis (NF2) is an autosomal dominant disorder prone to hearing loss. Auditory brainstem implants (ABIs) offer a promising solution for hearing rehabilitation in NF2. OBJECTIVE: To synthesize existing literature on ABI implantation in NF2, focusing on audiological outcomes and ABI-related complications. METHODS: The systematic review followed PRISMA guidelines and was registered in the PROSPERO database (CRD42022362155). Relevant studies were identified by searching PubMed, EMBASE, CENTRAL, CMB, and CNKI from inception to August 2023. Data on environmental sound discrimination, open-set discrimination, closed-set discrimination, and ABI-related complications were extracted and subjected to meta-analysis. Publication bias was evaluated using funnel plots and Egger's test. RESULTS: Thirty-three studies were included. The pooled estimate was 58% (95% CI 49-66%) for environmental sound discrimination and 55% (95% CI 40-69%) for closed-set discrimination. Regarding open-set discrimination, the pooled estimates were 30% (95% CI 19-42%) for sound only, 46% (95% CI 37-54%) for lip-reading only, and 63% (95% CI 55-70%) for sound plus lip-reading. The pooled occurrence of ABI-related complications was 33% (95% CI 15-52%). CONCLUSION: This meta-analysis underscores the effectiveness and safety of ABIs in NF2, providing valuable insights for evidence-based decision-making and hearing rehabilitation strategies.

An unusual finding of an anaplastic meningioma in NF2-related schwannomatosis.

NF2-related schwannomatosis (NF2) is a rare autosomal-dominant genetic disorder characterized by bilateral vestibular schwannomas and multiple meningiomas. This case report presents the extremely rare occurrence of an anaplastic meningioma in a 12-year-old male with previously undiagnosed NF2. The patient presented with a history of abdominal pain and episodic emesis, gait unsteadiness, right upper and lower extremity weakness, and facial weakness. He had sensorineural hearing loss and wore bilateral hearing aids. MR imaging revealed a sizable left frontoparietal, dural-based meningioma with heterogeneous enhancement with mass effect on the brain and midline shift. Multiple additional CNS lesions were noted including a homogenous lesion at the level of T5 indicative of compression of the spinal cord. The patient underwent a frontotemporoparietal craniotomy for the removal of his large dural-based meningioma, utilizing neuronavigation and transdural ultrasonography for precise en bloc resection of the mass. Histopathology revealed an anaplastic meningioma, WHO grade 3, characterized by brisk mitotic activity, small-cell changes, high Ki-67 proliferation rate, and significant loss of P16. We report an anaplastic meningioma associated with an underlying diagnosis of NF2 for which we describe clinical and histopathological features.

Four distinct ipsilateral vestibular schwannomas: A case of mosaic NF2-related schwannomatosis.

OBJECTIVES: Distinguishing between sporadic and germline/mosaic NF2-related schwannomatosis is important to ensure that patients have appropriate long-term care. With this report, we describe a unique case of a patient with 4 ipsilateral schwannomas and identify a combination of sequencing modalities that can accurately diagnose mosaic NF2-related schwannomatosis. METHODS: We present a 32-year-old woman with a familial history of vestibular schwannoma in her father and right-sided schwannomas involving the apical and basal turns of cochlea, lateral semicircular canal, and internal auditory canal (IAC). Genetic analysis of blood and frozen tissue from 2 tumors (intralabyrinthine and IAC tumors) was performed using next-generation sequencing (NGS), multiplex ligation-dependent probe amplification (MLPA), and optical genome mapping (OGM). RESULTS: Germline testing for NF2, LZTR1, and SMARCB1 was negative. Tumor genetic testing revealed a shared NF2 pathogenic variant between the 2 tumors ("first hit") but distinct "second hit" NF2 variants, including mosaic loss of chromosome 22 in the IAC tumor seen only with OGM, consistent with mosaic NF2-related schwannomatosis. CONCLUSIONS: Multimodality sequencing, including NGS, MLPA, and OGM, was required to ensure appropriate diagnosis of mosaic NF2-related schwannomatosis in this patient. A similar approach can be used for other patients with multiple ipsilateral tumors and suspected tumor predisposition.

The impact of mental health on health-related quality of life in patients with NF2-related Schwannomatosis.

NF2-related schwannomatosis (NF2-SWN) is a rare genetic disorder and is associated with progressive morbidities. This study aimed to investigate the relationship between NF2-SWN disease severity, health-related Quality of Life (QoL), and mental health aspects of patients. Standardised questionnaires assessing mental health problems (symptoms of depression, anxiety, and somatic burden), psychological factors (resilience, loneliness, and personality functioning), and health-related QoL were administered to 97 patients with NF2-SWN. The results of these questionnaires were compared with physician-rated disease severity. Questionnaires were completed by 77 patients. Physician-rated disease severity scores were available for 55 patients. NF2-SWN patients showed a high prevalence of clinically relevant symptoms of depression (30%), anxiety (16%), and somatic burden (32%). Almost all variables showed moderate to high correlations with NF2-SWN-related QoL. NF2-SWN-related QoL was associated with physician-reported disease severity (r = 0.614). In the stepwise hierarchical linear regression analysis, a significant model with four predictors (disease severity type, depression symptoms, personality functioning, and gender) explained 64% of the variance in NF2-SWN-related QoL. Our results showed a strong association between NF2-SWN-related QoL and depression symptoms. Moreover, personality functioning is an important influencing factor, representing a modifiable construct that can be targeted by prevention programs or psychotherapy.

A Rare Case of Hepatic Schwannoma in the Setting of Schwannomatosis.

Schwannomas are benign nerve sheath tumors commonly found in the head, neck, vestibular system, and extremities. Primary hepatic schwannomas are exceptionally rare, with 34 cases reported to date according to our review of the literature. This case report describes a 79-year-old man with a medical history of skin and thyroid cancer, who presented with no clinical symptoms and underwent a follow-up MRI due to an initial scan indicating a suspicious hepatic mass resembling an atypical hemangioma. The MRI revealed a 3.6 cm left hepatic mass concerning for an intrahepatic cholangiocarcinoma. Histopathological and immunohistochemical studies of a biopsy of the liver mass confirmed the presence of a benign hepatic schwannoma. Further evaluation revealed multiple spinal schwannomas, leading to the diagnosis of schwannomatosis. The diagnosis of hepatic schwannomas poses challenges through imaging alone. This case underscores the importance of microscopic evaluation in accurately diagnosing hepatic masses. Additionally, the presence of concurrent schwannomas should be considered in patients initially diagnosed with isolated schwannomas.

Transcriptomic and epigenetic dissection of spinal ependymoma (SP-EPN) identifies clinically relevant subtypes enriched for tumors with and without NF2 mutation.

Ependymomas encompass multiple clinically relevant tumor types based on localization and molecular profiles. Tumors of the methylation class "spinal ependymoma" (SP-EPN) represent the most common intramedullary neoplasms in children and adults. However, their developmental origin is ill-defined, molecular data are scarce, and the potential heterogeneity within SP-EPN remains unexplored. The only known recurrent genetic events in SP-EPN are loss of chromosome 22q and NF2 mutations, but neither types and frequency of these alterations nor their clinical relevance have been described in a large, epigenetically defined series. Transcriptomic (n = 72), epigenetic (n = 225), genetic (n = 134), and clinical data (n = 112) were integrated for a detailed molecular overview on SP-EPN. Additionally, we mapped SP-EPN transcriptomes to developmental atlases of the developing and adult spinal cord to uncover potential developmental origins of these tumors. The integration of transcriptomic ependymoma data with single-cell atlases of the spinal cord revealed that SP-EPN display the highest similarities to mature adult ependymal cells. Unsupervised hierarchical clustering of transcriptomic data together with integrated analysis of methylation profiles identified two molecular SP-EPN subtypes. Subtype A tumors primarily carried previously known germline or sporadic NF2 mutations together with 22q loss (bi-allelic NF2 loss), resulting in decreased NF2 expression. Furthermore, they more often presented as multilocular disease and demonstrated a significantly reduced progression-free survival as compared to SP-EP subtype B. In contrast, subtype B predominantly contained samples without NF2 mutation detected in sequencing together with 22q loss (monoallelic NF2 loss). These tumors showed regular NF2 expression but more extensive global copy number alterations. Based on integrated molecular profiling of a large multi-center cohort, we identified two distinct SP-EPN subtypes with important implications for genetic counseling, patient surveillance, and drug development priorities.

Perspectives of adults with neurofibromatosis regarding the design of psychosocial trials: Results from an anonymous online survey.

BACKGROUND/AIMS: Individuals with neurofibromatosis, including neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2)-related schwannomatosis (SWN), and other forms of SWN, often experience disease manifestations and mental health difficulties for which psychosocial interventions may help. An anonymous online survey of adults with neurofibromatosis assessed their physical, social, and emotional well-being and preferences about psychosocial interventions to inform clinical trial design. METHODS: Neurofibromatosis clinical researchers and patient representatives from the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration developed the survey. Eligibility criteria included age ≥ 18 years, self-reported diagnosis of NF1, NF2, or SWN, and ability to read and understand English. The online survey was distributed internationally by the Neurofibromatosis Registry and other neurofibromatosis foundations from June to August 2020. RESULTS: Surveys were completed by 630 adults (18-81 years of age; M = 45.5) with NF1 (78%), NF2 (14%), and SWN (8%) who were mostly White, not Hispanic/Latino, female, and from the United States. The majority (91%) reported that their neurofibromatosis symptoms had at least some impact on daily life. In the total sample, 51% endorsed a mental health diagnosis, and 27% without a diagnosis believed they had an undiagnosed mental health condition. Participants indicated that neurofibromatosis affected their emotional (44%), physical (38%), and social (35%) functioning to a high degree. Few reported ever having participated in a drug (6%) or psychosocial (7%) clinical trial, yet 68% reported they "probably" or "definitely" would want to participate in a psychosocial trial if it targeted a relevant concern. Top treatment targets were anxiety, healthier lifestyle, and daily stress. Top barriers to participating in psychosocial trials were distance to clinic, costs, and time commitment. Respondents preferred interventions delivered by clinicians via individual sessions or a combination of group and individual sessions, with limited in-person and mostly remote participation. There were no significant group differences by neurofibromatosis type in willingness to participate in psychosocial trials (p = 0.27). Regarding interest in intervention targets, adults with SWN were more likely to prefer psychosocial trials for pain support compared to those with NF1 (p < 0.001) and NF2 (p < 0.001). CONCLUSION: This study conducted the largest survey assessing physical symptoms, mental health needs, and preferences for psychosocial trials in adults with neurofibromatosis. Results indicate a high prevalence of disease manifestations, psychosocial difficulties, and untreated mental health problems in adults with neurofibromatosis and a high degree of willingness to participate in psychosocial clinical trials. Patient preferences should be considered when designing and implementing psychosocial interventions to develop the most feasible and meaningful studies.

Multidisciplinary neurofibromatosis conference in the management of patients with neurofibromatosis type 1 and schwannomatosis in a single tertiary care institution.

OBJECTIVE: To evaluate the role of weekly neurofibromatosis (NF) multi-disciplinary conferences (MDC) on the diagnostic and therapeutic plan for patients with NF type 1 (NF1) and schwannomatosis (SWN). MATERIALS AND METHODS: This retrospective study reviewed patients with confirmed or suspected NF1 and SWN discussed in weekly MDC from March to July 2021. Demographic data collected included patient age, sex, pre-conference and post-conference diagnosis, radiological studies reviewed, and provider specialties in attendance. Outcomes reported included changes in imaging interpretation and treatment plans, changes in post-conference diagnosis relative to pre-conference diagnosis, and time to completion of the recommended change in treatment. RESULTS: Data from 17 MDC "pre-conference" lists included 75 patients (38 female, 37 males, mean age (years): 38 (range: 6-80)) with NF1 (52%, 39/75) and SWN (36%, 27/75) discussed over a total of 91 case reviews. 18.7% (14/75) of all patients had NF2-related SWN, and 17.3% (13/75) of all patients had non-NF2 SWN. The MDC led to changes in imaging interpretation in 18.7% and changes in patient management in 74.7% (diagnostic testing (n = 52), surgical plan (n = 24), medical treatment (n = 9), clinical trial status (n = 4), and radiation treatment (n = 1)) of cases. Among patients for whom a change in management was recorded, 91% (62/68) completed at least one recommendation (mean time to completion (days): 41.4 (range: 0-278)). CONCLUSION: Weekly MDC changes the diagnostic and therapeutic management of the majority of patients discussed (74.7%) and promotes a high adherence rate to recommendations (91%).

Recommendations for the collection and annotation of biosamples for analysis of biomarkers in neurofibromatosis and schwannomatosis clinical trials.

INTRODUCTION: Neurofibromatosis 1 and schwannomatosis are characterized by potential lifelong morbidity and life-threatening complications. To date, however, diagnostic and predictive biomarkers are an unmet need in this patient population. The inclusion of biomarker discovery correlatives in neurofibromatosis 1/schwannomatosis clinical trials enables study of low-incidence disease. The implementation of a common data model would further enhance biomarker discovery by enabling effective concatenation of data from multiple studies. METHODS: The Response Evaluation in Neurofibromatosis and Schwannomatosis biomarker working group reviewed published data on emerging trends in neurofibromatosis 1 and schwannomatosis biomarker research and developed recommendations in a series of consensus meetings. RESULTS: Liquid biopsy has emerged as a promising assay for neurofibromatosis 1/schwannomatosis biomarker discovery and validation. In addition, we review recommendations for a range of biomarkers in clinical trials, neurofibromatosis 1/schwannomatosis-specific data annotations, and common data models for data integration. CONCLUSION: These Response Evaluation in Neurofibromatosis and Schwannomatosis consensus guidelines are intended to provide best practices for the inclusion of biomarker studies in neurofibromatosis 1/schwannomatosis clinical trials, data, and sample annotation and to lay a framework for data harmonization and concatenation between trials.

MRI features of benign peripheral nerve sheath tumors: how do sporadic and syndromic tumors differ?

OBJECTIVES: To compare MRI features of sporadic and neurofibromatosis syndrome-related localized schwannomas and neurofibromas. METHODS: In this retrospective study, our pathology database was searched for "neurofibroma" or "schwannoma" from 2014 to 2019. Exclusion criteria were lack of available MRI and intradural or plexiform tumors. Qualitative and quantitative anatomic (location, size, relationship to nerve, signal, muscle denervation) and functional (arterial enhancement, apparent diffusion-weighted coefficient) MRI features of sporadic and syndrome-related tumors were compared. Statistical significance was assumed for p < 0.05. RESULTS: A total of 80 patients with 64 schwannomas (sporadic: 42 (65.6%) v. syndrome-related: 22 (34.4%)) and 19 neurofibromas (sporadic: 7 (36.8%) v. syndrome-related: 12 (41.7%)) were included. Only signal heterogeneity (T2W p=0.001, post-contrast p=0.03) and a diffused-weighted imaging target sign (p=0.04) were more frequent with schwannomas than neurofibromas. Sporadic schwannomas were similar in size to syndrome-related schwannomas (2.9±1.2cm vs. 3.7±3.2 cm, p = 0.6), but with greater heterogeneity (T2W p = 0.02, post-contrast p = 0.01). Sporadic neurofibromas were larger (4.6±1.5cm vs. 3.4±2.4 cm, p = 0.03) than syndrome-related neurofibromas, also with greater heterogeneity (T2W p=0.03, post-contrast p=0.04). Additional tumors along an affected nerve were only observed with syndrome-related tumors). There was no difference in apparent diffusion coefficient values or presence of early perfusion between sporadic and syndrome-related tumors (p > 0.05). CONCLUSIONS: Although syndrome-related and sporadic schwannomas and neurofibromas overlap in their anatomic, diffusion and perfusion features, signal heterogeneity and presence of multiple lesions along a nerve are differentiating characteristics of syndrome-related tumors.