A cohort study of CNS tumors in Multiple Endocrine Neoplasia Type 1.

PURPOSE: Multiple Endocrine Neoplasia Type-1 (MEN1) is thought to increase the risk of meningioma and ependymoma. Hereby, we aimed to describe the frequency, the incidence and specific clinical and histological features of CNS tumors in the MEN1 population (except pituitary tumors). EXPERIMENTAL DESIGN: The study population included patients harboring CNS tumors diagnosed with MEN1 syndrome after 1990 and followed-up in the French MEN1 national cohort. Standardized incidence rate (SIR) was calculated based on the French Gironde CNS tumors registry. Genomic analyses were performed on somatic DNA from 7 CNS tumors including meningiomas and ependymomas from MEN1 patients, then in 50 sporadic meningiomas and ependymomas. RESULTS: Twenty-nine CNS tumors were found among the 1498 symptomatic patients (2%) (incidence=47.4/100'000 person-years; SIR=4.5), including 12 meningiomas (0.8%) (incidence=16.2/100'000; SIR=2.5), 8 ependymomas (0.5%) (incidence=10.8/100'000; SIR=17.6), 5 astrocytomas (0.3%) (incidence=6.7/100'000; SIR=5.8), and 4 schwannomas (0.3%) (incidence=5.4/100'000; SIR=12.7). Meningiomas in MEN1 patients were benign, mostly meningothelial, with 11 years earlier onset compared to the sporadic population and an F/M ratio of 1/1. Spinal and cranial ependymomas were mostly classified WHO grade 2. A biallelic MEN1 inactivation was observed in 4/5 ependymomas and 1/2 meningiomas from the MEN1 patients, whereas MEN1 deletion in one allele was present in respectively 3/41 and 0/9 sporadic meningiomas and ependymomas. CONCLUSIONS: Incidence of each CNS tumor was higher in the MEN1 population than in the French general population. Meningiomas and ependymomas should be considered part of the MEN1 syndrome, but somatic molecular data are missing to conclude for astrocytomas and schwannomas.

Surgical management of sporadic and schwannomatosis-associated pelvic schwannomas.

Pelvic schwannomas are rare tumors that may occur either sporadically or in the context of schwannomatosis. We retrospectively reviewed the charts of patients harboring a pelvic schwannoma under conservative management or operated at our reference center between 2016 and 2023. All patients were operated by a multidisciplinary team, combining a vascular surgeon and a neurosurgeon. Twenty-four patients harboring 33 pelvic tumors were included in the cohort, including 12 patients with sporadic lesions, 2 patients with NF2-related schwannomatosis, and 10 patients with NF2-independent schwannomatosis. Multi-nodular tumors were more frequent in schwannomatosis compared to sporadic cases (p = 0.005). The mean age at diagnosis was 41 years old. Schwannomas were located on branches of the sciatic nerve (23/33, 70%), the femoral nerve (6/33, 18%), and the obturator nerve (4/33, 12%). Over the course of the study, 16 patients were operated, including 11 sporadic cases. The indication for surgery was pain (12/16, 75%) or tumor growth (4/16, 25%). Complete resection was achieved in 14 of 16 patients (87%). The mean post-operative follow-up was 37 months (range: 2-168 months). At last-follow-up, complete pain relief was achieved in all 12 patients with pre-operative pain. Post-operative morbidity included 3 long-term localized numbness and one MRC class 4 motor deficit in a multi-nodular tumor in a schwannomatosis patient. Despite its limited size, our series suggests that nerve-sparing resection of pelvic schwannomas offers satisfying rates of functional outcome both in sporadic and schwannomatosis cases, except for multi-nodular tumors.

Super-enhancer hijacking drives ectopic expression of hedgehog pathway ligands in meningiomas.

Hedgehog signaling mediates embryologic development of the central nervous system and other tissues and is frequently hijacked by neoplasia to facilitate uncontrolled cellular proliferation. Meningiomas, the most common primary brain tumor, exhibit Hedgehog signaling activation in 6.5% of cases, triggered by recurrent mutations in pathway mediators such as SMO. In this study, we find 35.6% of meningiomas that lack previously known drivers acquired various types of somatic structural variations affecting chromosomes 2q35 and 7q36.3. These cases exhibit ectopic expression of Hedgehog ligands, IHH and SHH, respectively, resulting in Hedgehog signaling activation. Recurrent tandem duplications involving IHH permit de novo chromatin interactions between super-enhancers within DIRC3 and a locus containing IHH. Our work expands the landscape of meningioma molecular drivers and demonstrates enhancer hijacking of Hedgehog ligands as a route to activate this pathway  in neoplasia.

Schwannomatosis: a Realm Reborn: year one.

PURPOSE OF REVIEW: In 2022, an international consensus recommendation revised the nomenclature for neurofibromatosis type 2 ( NF2 ) and Schwannomatosis (SWN), now grouped under the umbrella term Schwannomatosis, and defined new diagnostic criteria. RECENT FINDINGS: This review describes the molecular criteria for diagnosis of schwannomatosis and the subsequent diagnosis strategy, while setting out the most recent advances in our understanding of the natural history, pathology, molecular biology and treatment of schwannomatosis-associated tumors, including schwannomas, meningiomas and ependymomas. SUMMARY: Somatic mutation screening should become a new standard for the diagnosis of NF2 -, LTZTR1 -, SMARCB1 - and 22q-schwannomatosis to discriminate those conditions. Constitutional events in NF2 -Schwannomatosis have a major influence on disease severity and justifiably motivate ongoing efforts on gene replacement therapy research. On the other hand, underlying mechanisms of disease severity and associated pain remain largely unknown in non- NF2 -SWN and independent of germline mutation. Research efforts therefore focus on pain relief in ongoing trials and the discovery of new molecular mechanisms underlying schwannoma tumorigenesis/pain/neuropathies.

Target volume delineation for radiotherapy of meningiomas: an ANOCEF consensus guideline.

PURPOSE: Radiotherapy is, with surgery, one of the main therapeutic treatment strategies for meningiomas. No prospective study has defined a consensus for the delineation of target volumes for meningioma radiotherapy. Therefore, target volume definition is mainly based on information from retrospective studies that include heterogeneous patient populations. The aim is to describe delineation guidelines for meningioma radiotherapy as an adjuvant or definitive treatment with intensity-modulated radiation therapy and stereotactic radiation therapy techniques. This guideline is based on a consensus endorsed by a multidisciplinary group of brain tumor experts, members of the Association of French-speaking Neuro-oncologists (ANOCEF). MATERIALS AND METHODS: A 3-step procedure was used. First, the steering group carried out a comprehensive review to identify divergent issues on meningiomas target volume delineation. Second, an 84-item web-questionnaire has been developed to precisely define meningioma target volume delineation in the most common clinical situations. Third, experts members of the ANOCEF were requested to answer. The first two rounds were completed online. A third round was carried out by videoconference to allow experts to debate and discuss the remaining uncertain questions. All questions remained in a consensus. RESULTS: Limits of the target volume were defined using visible landmarks on computed tomography and magnetic resonance imaging, considering the pathways of tumor extension. The purpose was to develop clear and precise recommendations on meningiomas target volumes. CONCLUSION: New recommendations for meningiomas delineation based on simple anatomic boundaries are proposed by the ANOCEF. Improvement in uniformity in target volume definition is expected.

Respective roles of Pik3ca mutations and cyproterone acetate impregnation in mouse meningioma tumorigenesis.

Despite their rarity, PIK3CA mutations in meningiomas have raised interest as potentially targetable, ubiquitous mutations owing to their presence in sporadic benign and malignant tumors but also in hormone-related cases. Using new genetically engineered mouse models, we here demonstrate that Pik3ca mutations in postnatal meningeal cells are sufficient to promote meningioma formation but also tumor progression in mice. Conversely, hormone impregnation, whether alone or in association with Pik3ca and Nf2 mutations, fails to induce meningioma tumorigenesis while promoting breast tumor formation. We then confirm in vitro the effect of Pik3ca mutations but not hormone impregnation on the proliferation of primary cultures of mouse meningeal cells. Finally, we show by exome analysis of breast tumors and meninges that hormone impregnation promotes breast tumor formation without additional somatic oncogenic mutation but is associated with an increased mutational burden on Pik3ca-mutant background. Taken together, these results tend to suggest a prominent role of Pik3ca mutations over hormone impregnation in meningioma tumorigenesis, the exact effect of the latter is still to be discovered.

Intracranial Solitary Fibrous Tumour Management: A French Multicentre Retrospective Study.

BACKGROUND: Intracranial solitary fibrous tumour (iSFT) is an exceptional mesenchymal tumour with high recurrence rates. We aimed to analyse the clinical outcomes of newly diagnosed and recurrent iSFTs. METHODS: We carried out a French retrospective multicentre (n = 16) study of histologically proven iSFT cases. Univariate and multivariate Cox models were used to estimate the prognosis value of the age, location, size, WHO grade, and surgical extent on overall survival (OS), progression-free survival (PFS), and local recurrence-free survival (LRFS). RESULTS: Eighty-eight patients were included with a median age of 54.5 years. New iSFT cases were treated with gross tumour resection (GTR) (n = 75) or subtotal resection (STR) (n = 9) and postoperative radiotherapy (PORT) (n = 32, 57%). The median follow-up time was 7 years. The median OS, PFS, and LRFS were 13 years, 7 years, and 7 years, respectively. Forty-two patients experienced recurrence. Extracranial metastasis occurred in 16 patients. Median OS and PFS after the first recurrence were 6 years and 15.4 months, respectively. A higher histological grade was a prognosis factor for PFS (p = 0.04) and LRFS (p = 0.03). GTR influenced LRFS (p = 0.03). CONCLUSION: GTR provided benefits as a first treatment for iSFTs. However, approximately 40% of patients experienced relapse, which remains a challenging state.

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

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

GAB1 as a Marker of Recurrence in Anterior Skull Base Meningioma.

BACKGROUND: About one-third of anterior skull base meningiomas show Hedgehog pathway activation. We have recently identified GAB1 as a surrogate marker for Hedgehog pathway-activated meningiomas. OBJECTIVE: To determine the reproducibility and prognostic value of GAB1 marker in anterior skull base meningiomas. METHODS: A retrospective bicentric cohort of anterior skull base meningiomas, operated from 2005 to 2015, was constituted. GAB1 immunohistochemistry was performed in 2 centers, and the GAB1 score was assessed. Clinical and pathological data were reviewed to determine the prognostic value of the GAB1 score, along with classical factors of recurrence. RESULTS: One hundred forty-eight patients were included (median follow-up of 72 ± 46 months). 78% of patients had gross total resection. Eighty-four percentage of patients harbored grade 1 meningiomas. GAB1 immunohistochemistry was positive (ie, GAB1 staining score was >250) in 53 cases (35%). GAB1-positive cases were mainly at olfactory groove, of meningothelial grade 1 subtype, and showed greater recurrence (36% vs 14%, P = .002), greater requirement for multiple surgeries (17% vs 4.2%, P = .014), and more likely evolution toward diffuse skull base infiltration (15% vs 3%, P = .0017). By multivariable Cox regression analysis, incomplete surgical resection (hazard ratios [HR] = 8.3, 95% IC [3.7-18.2], P < .001), male sex (HR = 5.4, 95% IC [2.2-13.5], P < .001), GAB1 positivity (HR = 3.2, 95% CI [1.5-6.9], P = .004), and Ki67 index >4 (HR = 2.2, 95% IC [1.2-4.6], P = .035) were independent prognostic factors for recurrence. CONCLUSION: GAB1 marker is an independent prognostic factor for anterior skull base meningioma and could be useful for both prognostic evaluation and identification of Hedgehog-activated meningiomas.

LZTR1 Mutation Mediates Oncogenesis through Stabilization of EGFR and AXL.

LZTR1 is the substrate-specific adaptor of a CUL3-dependent ubiquitin ligase frequently mutated in sporadic and syndromic cancer. We combined biochemical and genetic studies to identify LZTR1 substrates and interrogated their tumor-driving function in the context of LZTR1 loss-of-function mutations. Unbiased screens converged on EGFR and AXL receptor tyrosine kinases as LZTR1 interactors targeted for ubiquitin-dependent degradation in the lysosome. Pathogenic cancer-associated mutations of LZTR1 failed to promote EGFR and AXL degradation, resulting in dysregulated growth factor signaling. Conditional inactivation of Lztr1 and Cdkn2a in the mouse nervous system caused tumors in the peripheral nervous system including schwannoma-like tumors, thus recapitulating aspects of schwannomatosis, the prototype tumor predisposition syndrome sustained by LZTR1 germline mutations. Lztr1- and Cdkn2a-deleted tumors aberrantly accumulated EGFR and AXL and exhibited specific vulnerability to EGFR and AXL coinhibition. These findings explain tumorigenesis by LZTR1 inactivation and offer therapeutic opportunities to patients with LZTR1-mutant cancer. SIGNIFICANCE: EGFR and AXL are substrates of LZTR1-CUL3 ubiquitin ligase. The frequent somatic and germline mutations of LZTR1 in human cancer cause EGFR and AXL accumulation and deregulated signaling. LZTR1-mutant tumors show vulnerability to concurrent inhibition of EGFR and AXL, thus providing precision targeting to patients affected by LZTR1-mutant cancer. This article is highlighted in the In This Issue feature, p. 517.

Pan-cancer landscape of AID-related mutations, composite mutations, and their potential role in the ICI response.

Activation-induced cytidine deaminase, AICDA or AID, is a driver of somatic hypermutation and class-switch recombination in immunoglobulins. In addition, this deaminase belonging to the APOBEC family may have off-target effects genome-wide, but its effects at pan-cancer level are not well elucidated. Here, we used different pan-cancer datasets, totaling more than 50,000 samples analyzed by whole-genome, whole-exome, or targeted sequencing. AID mutations are present at pan-cancer level with higher frequency in hematological cancers and higher presence at transcriptionally active TAD domains. AID synergizes initial hotspot mutations by a second composite mutation. AID mutational load was found to be independently associated with a favorable outcome in immune-checkpoint inhibitors (ICI) treated patients across cancers after analyzing 2000 samples. Finally, we found that AID-related neoepitopes, resulting from mutations at more frequent hotspots if compared to other mutational signatures, enhance CXCL13/CCR5 expression, immunogenicity, and T-cell exhaustion, which may increase ICI sensitivity.

Clinical results after surgical resection of benign solitary schwannomas: A review of 150 cases.

INTRODUCTION: Peripheral nerve schwannomas are the most common nerve tumors. While they are efficiently treated with surgery, the risk of neurological complications, especially sensory deficits, remains debated. HYPOTHESIS: We postulate that rates of post-operative sensory deficits in peripheral schwannoma surgery are low and are not increased in schwannomas of the hand, in which preservation of discriminative tact is of prime functional importance. MATERIALS AND METHODS: A retrospective multicenter study was carried out on 150 patients with an isolated peripheral schwannoma operated between 2002 and 2018, including 11 patients with schwannomas of the hand. All cases were reviewed preoperatively and postoperatively with a detailed exam of the neurological status. RESULTS: Most schwannomas were located in the lower limbs (58%). The two main affected trunks were the posterior tibial nerve in the lower limb and the median nerve in the upper limb. The average preoperative tumor volume measured on MRI was 2.93 cm3 [0.11 cm3-25 cm3]. The most common preoperative symptoms were paresthesia (77.1%) and pseudo-Tinel sign (55.7%). Less frequently, pain (50.3%) and hypoesthesia (18.1%) were observed. On the other hand, preoperative neurological motor manifestations remained exceptional (3.3%). The rates of new post-operative motor deficits, paresthesias, and sensory deficits were 4.6%, 10.9% and 8% respectively and were not increased in schwannomas of the collateral nerves of the hand. CONCLUSION: Surgical resection is a safe procedure for peripheral nerve schwannoma treatment with satisfying functional results and an acceptable risk of nerve injury, especially for sensory function. LEVEL OF PROOF: D; Multicenter retrospective study.

ERN GENTURIS clinical practice guidelines for the diagnosis, treatment, management and surveillance of people with schwannomatosis.

A Guideline Group (GG) was convened from multiple specialties and patients to develop the first comprehensive schwannomatosis guideline. The GG undertook thorough literature review and wrote recommendations for treatment and surveillance. A modified Delphi process was used to gain approval for recommendations which were further altered for maximal consensus. Schwannomatosis is a tumour predisposition syndrome leading to development of multiple benign nerve-sheath non-intra-cutaneous schwannomas that infrequently affect the vestibulocochlear nerves. Two definitive genes (SMARCB1/LZTR1) have been identified on chromosome 22q centromeric to NF2 that cause schwannoma development by a 3-event, 4-hit mechanism leading to complete inactivation of each gene plus NF2. These genes together account for 70-85% of familial schwannomatosis and 30-40% of isolated cases in which there is considerable overlap with mosaic NF2. Craniospinal MRI is generally recommended from symptomatic diagnosis or from age 12-14 if molecularly confirmed in asymptomatic individuals whose relative has schwannomas. Whole-body MRI may also be deployed and can alternate with craniospinal MRI. Ultrasound scans are useful in limbs where typical pain is not associated with palpable lumps. Malignant-Peripheral-Nerve-Sheath-Tumour-MPNST should be suspected in anyone with rapidly growing tumours and/or functional loss especially with SMARCB1-related schwannomatosis. Pain (often intractable to medication) is the most frequent symptom. Surgical removal, the most effective treatment, must be balanced against potential loss of function of adjacent nerves. Assessment of patients' psychosocial needs should be assessed annually as well as review of pain/pain medication. Genetic diagnosis and counselling should be guided ideally by both blood and tumour molecular testing.

A case of Epstein-Barr virus-associated smooth muscle tumor of the posterior interosseous nerve mimicking schwannoma.

Here we report a case of Epstein-Barr virus (EBV)-associated smooth muscle tumor (SMT) of the peripheral nerve in a young man seropositive for human immunodeficiency virus (HIV). Initially, the lesion was clinically and radiologically confused with a schwannoma of the forearm's posterior interosseous nerve. The diagnosis was corrected by histological examination, which revealed a well-defined tumor consisting of eosinophilic spindle cells, positive for α-smooth muscle actin on immunohistochemistry and positive for EBV-encoded early RNA (EBER) on in situ hybridization. EBV-associated SMTs are well described in the literature; they are frequently multiple and arise in many organs. They occur preferentially in young adults with poorly controlled and chronic HIV infection. The prognosis is influenced by the complications of immunodeficiency. To our knowledge, this is the first description of a peripheral nerve location. Because EBV-associated SMT should be considered in the differential diagnosis of a tumor in the peripheral or central nervous systems in immunocompromised patients, EBV should be tested in these locations. Thus, a cause of immunodeficiency should be identified when the diagnosis of EBV-associated SMT is made.

Implementation of TERT promoter mutations improve prognostication of the WHO classification in meningioma.

TERT promoter mutations have been associated with increased risk of recurrence in meningioma cohorts, thus a potential biomarker for aggressive phenotypes. A main purpose of refining tumour classification is better predictions on the patient level. We compiled data from previous published cohorts to investigate patient-level predictions of recurrence based on TERTp-mut status. Implementation of TERTp-mut into the WHO grading led to better patient prognostication by improved prediction of recurrence. Our results support implementation of TERTp-mut into diagnostics and classification of meningiomas.

Somatic PIK3CA Mutations in Sporadic Cerebral Cavernous Malformations.

BACKGROUND: Cerebral cavernous malformations (CCMs) are common sporadic and inherited vascular malformations of the central nervous system. Although familial CCMs are linked to loss-of-function mutations in KRIT1 (CCM1), CCM2, or PDCD10 (CCM3), the genetic cause of sporadic CCMs, representing 80% of cases, remains incompletely understood. METHODS: We developed two mouse models harboring mutations identified in human meningiomas with the use of the prostaglandin D2 synthase (PGDS) promoter. We performed targeted DNA sequencing of surgically resected CCMs from patients and confirmed our findings by droplet digital polymerase-chain-reaction analysis. RESULTS: We found that in mice expressing one of two common genetic drivers of meningioma - Pik3ca H1047R or AKT1 E17K - in PGDS-positive cells, a spectrum of typical CCMs develops (in 22% and 11% of the mice, respectively) instead of meningiomas, which prompted us to analyze tissue samples from sporadic CCMs from 88 patients. We detected somatic activating PIK3CA and AKT1 mutations in 39% and 1%, respectively, of lesion tissue from the patients. Only 10% of lesions harbored mutations in the CCM genes. We analyzed lesions induced by the activating mutations Pik3ca H1074R and AKT1 E17K in mice and identified the PGDS-expressing pericyte as the probable cell of origin. CONCLUSIONS: In tissue samples from sporadic CCMs, mutations in PIK3CA were represented to a greater extent than mutations in any other gene. The contribution of somatic mutations in the genes that cause familial CCMs was comparatively small. (Funded by the Fondation ARC pour la Recherche contre le Cancer and others.).

Mouse Models in Meningioma Research: A Systematic Review.

Meningiomas are the most frequent primitive central nervous system tumors found in adults. Mouse models of cancer have been instrumental in understanding disease mechanisms and establishing preclinical drug testing. Various mouse models of meningioma have been developed over time, evolving in light of new discoveries in our comprehension of meningioma biology and with improvements in genetic engineering techniques. We reviewed all mouse models of meningioma described in the literature, including xenograft models (orthotopic or heterotopic) with human cell lines or patient derived tumors, and genetically engineered mouse models (GEMMs). Xenograft models provided useful tools for preclinical testing of a huge range of innovative drugs and therapeutic options, which are summarized in this review. GEMMs offer the possibility of mimicking human meningiomas at the histological, anatomical, and genetic level and have been invaluable in enabling tumorigenesis mechanisms, including initiation and progression, to be dissected. Currently, researchers have a range of different mouse models that can be used depending on the scientific question to be answered.