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Cutaneous angiosarcoma is a rare type of sarcoma with poor prognosis. Meningioma is the most frequent benign intracranial tumor. Despite the fact that meningiomas are mostly benign, bone and skin can be infiltrated. We report the rare case of an angiosarcoma on top of a meningioma with hyperostosis at exactly the same location mimicking a transosseous growth of a meningioma. An 84-year-old man presented with progressive swelling and ulcerous lesion of the forehead. The patient underwent surgery in an interdisciplinary setting together with a plastic surgeon, including resection of the intracranial tumor and infiltrated bone and skin. To the best of our knowledge, this is the only reported case of a meningioma and angiosarcoma in direct neighborhood. A preoperative biopsy of the skin tumor would have led initially to the correct diagnosis of an angiosarcoma and would have allowed a better planning of the operation and extent of resection., Competing Interests: None declared., (Thieme. All rights reserved.)

Background and Objectives: Spinal meningiomas, which are well characterized and are most frequently intradural extramedullary tumors, represent 25% of all intradural spinal tumors. The goal of this study was to compare the outcomes of surgically treated patients with spinal meningiomas in two time intervals with special emphasis on postoperative functional outcomes. Methods: Patients with spinal meningiomas admitted to our department between 1990 and 2020 were enrolled and divided into a historic cohort (HC; treated 1990−2007) and a current cohort (CC; treated 2008−2020). Patients’ clinical data and surgical and radiological reports were retrospectively analyzed up to 5 years. Preoperative and postoperative neurological function were assessed using the modified McCormick Scale (mMCS). The Charlson Comorbidity Index (CCI) was used to evaluate the effect of comorbidities on the preoperative status and postoperative outcome. Results: We included 300 patients. Participants in the CC (n = 144) were significantly younger compared to those in the HC (n = 156), with twice as many patients <50 years of age (p < 0.001). The most common tumor location was the thoracic spine (n = 204). The median follow-up was 38.1 months (±30.3 standard deviation). A symptom duration until surgery <12 months was significantly associated with an earlier improvement in the mMCS (p = 0.045). In the CC, this duration was shorter and patients’ neurological function at the first and last follow-ups was significantly better than for those in the HC (p < 0.001 for both). Conclusions: Our study results suggested that the impact of surgical management and postoperative rehabilitation on spinal meningioma patients’ long-term neurological outcome has reached important milestones over the last decades. An earlier diagnosis led to earlier surgical treatment and improved patients’ postoperative neurological recovery. Our results exposed that surgical therapy for spinal meningioma should be performed within 12 months after appearance of symptoms to achieve a better recovery.

Meningiomas are the most common primary intracranial tumors, of which atypical meningiomas account for ~ 20%. A loss of NF2 has been proven to be an initial step for meningioma development; however, the role of non- NF2 alterations is unknown. Here we report a case of an atypical meningioma with a NF2 splice donor mutation and four recurrences. Using a custom NGS panel, further complex heterogenic molecular alterations were discovered. At first, one subclone of the initial tumor showed an additional PIK3CA variant, most likely of no pathogenic relevance. Then, the first and second recurrences no longer harbored the PIK3CA variant and no tumor heterogeneity was found. The tumor-driving NF2 mutation persisted, however. The latest, third recurrence showed a remarkable genetic heterogeneity with multiple, additional non- NF2 variants and a pathogenic PIKC3A mutation. In detail, one subclone showed a SUFU and two SMARCE1 variants. Another, geographically separate tumor subclone, in contrast, showed several different non- NF2 variants in SMO , PIK3CA and SUFU . Most important, one of the newly acquired PIK3CA alterations in the kinase domain (L1006F) is likely to be an additional tumor-driving mutation, which activates the PI3K-AKT-mTOR pathway. The reported genetic heterogeneity in meningiomas has been addressed in only a few studies. Although some of the detected variants in our case are expected to have biochemical consequences, these consequences are usually not likely to promote tumor development, when taking into account the suggested role of the altered proteins in tumorigenic pathways. However, the occurrence of a single oncogenic missense mutation in a subclone of the third recurrence may indicate a clonal change towards enhanced aggressiveness. Taken together, our case supports the need to perform in-depth studies to clarify the role of non- NF2 mutations for meningioma growth and development.

Meningiomas are the most frequent primary intracranial tumors. The considerable variety of histological subtypes has been expanded by the definition of molecular alterations, which can improve both diagnostic accuracy and determination of individual patient's outcome. According to the upcoming WHO classification of brain tumors, the in-time analysis of frequent molecular events in meningiomas may become mandatory to define meningioma subtypes. We have compiled a custom-made amplicon-based next generation sequencing (NGS) meningioma panel covering the most frequent known recurrent mutations in 15 different genes. In an unselected consecutive meningioma cohort (109 patients) analyzed over a period of 12 months, we detected mutations in 11 different genes, with most frequent alterations in NF2 (43%), AKT1 E17K (15%), and TRAF7 (13%). In 39 tumors (36%), two different mutations were detected, with NF2 and SUFU (n = 5) and KLF4 and TRAF7 (n = 5) being the most frequent combinations. No alterations were found in POLR2A, CDKN2A, CDKN2B, and BAP1, and no homozygous CDKN2A/B deletion was detected. NF2 mutations were found in tumors of all WHO grades, whereas mutations in KLF4, TRAF7, and SMO were restricted to WHO grade I meningiomas. In contrast, SMARCE1 and TERT mutations were associated with WHO grade II meningiomas (according to the WHO classification 2016). The distribution of mutations across histological subtypes or tumor localization was in line with the existing literature, with typical combinations like KLF4K 409Q /TRAF7 for secretory meningiomas and preferential skull base localization of meningiomas harboring SMO and AKT1 E17K mutations. Thus, we present a custom-made NGS meningioma panel providing a time and cost-efficient reliable detection of relevant somatic molecular alterations in meningiomas suitable for daily routine., (© 2022 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Aims: Meningiomas are the most frequent primary brain tumours. Recently, knowledge about the molecular drivers underlying aggressive meningiomas has been expanded. A hotspot mutation in the AKT1 gene (AKT1 E17K ), which is found in meningiomas at the convexity and especially at the skull base, has been associated with earlier tumour recurrence., Methods: Here, we analysed the effects of the AKT1 E17K mutation and treatment response to the Akt inhibitor AZD5363 in transgenic meningioma cell clones and mouse xenografts modelling convexity or skull base meningiomas., Results: We show that the AKT E17K mutation significantly enhances meningioma cell proliferation and colony size in vitro, resulting in significantly shortened survival times of mice carrying convexity or skull base AKT1 E17K xenografts. Treatment of mutant cells or xenografts (150 mg/kg/d) with AZD5363 revealed a significant decrease in cell proliferation and colony size and a prolongation of mouse survival. Western blots revealed activation of AKT1 kinase (phosphorylation at Ser273 and Thr308) by the E17K mutation in human meningioma samples and in our in vitro and in vivo models., Conclusions: Our data suggest that AKT1 E17K mutated meningiomas are a promising selective target for AZD5363., (© 2021 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Meningioma represents the most common primary brain tumor in adults. Recently several non-NF2 mutations in meningioma have been identified and correlated with certain pathological subtypes, locations and clinical observations. Alterations of cellular pathways due to these mutations, however, have largely remained elusive. Here we report that the Krueppel like factor 4 (KLF4)-K409Q mutation in skull base meningiomas triggers a distinct tumor phenotype. Transcriptomic analysis of 17 meningioma samples revealed that KLF4 K409Q mutated tumors harbor an upregulation of hypoxia dependent pathways. Detailed in vitro investigation further showed that the KLF4 K409Q mutation induces HIF-1α through the reduction of prolyl hydroxylase activity and causes an upregulation of downstream HIF-1α targets. Finally, we demonstrate that KLF4 K409Q mutated tumors are susceptible to mTOR inhibition by Temsirolimus. Taken together, our data link the KLF4 K409Q mediated upregulation of HIF pathways to the clinical and biological characteristics of these skull base meningiomas possibly opening new therapeutic avenues for this distinct meningioma subtype.

This study was undertaken to analyze the functional outcome of surgically treated spinal meningiomas and to determine factors for surgical morbidity. Between January 1990 and December 2006 a total of 131 patients underwent surgical resection of a spinal menigioma. There were 114 (87%) female and 17 (13%) male patients. Age ranged from 17 to 88 years (mean 69 years). The mean follow-up period was 61 months (range 1-116 months) including a complete neurological examination and postoperative MRI studies. The pre- and postoperative neurological state was graded according to the Frankel Scale. Surgery was performed under standard microsurgical conditions with neurophysiological monitoring. In 73% the lesion was located in the thoracic region, in 16% in the cervical region, in 5% at the cervico-thoracic junction, in 4.5% at the thoraco-lumbar junction and in 1.5% in the lumbar region. Surgical resection was complete in 127 patients (97%) and incomplete in 4 patients (3%). At the last follow-up the neurological state was improved or unchanged in 126 patients (96.2%) and worse in 4 patients (3%). Permanent operative morbidity and mortality rates were 3 and 0.8%, respectively. Extensive tumour calcification proved to be a significant factor for surgical morbidity (P < 0.0001). Radical resection of spinal meningiomas can be performed with good functional results. Extensive tumor calcification, especially in elderly patients proved to harbor an increased risk for surgical morbidity.

Rationale: Meningiomas in the pediatric age group are very rare tumors, comprising about 1-4.2% of all primary pediatric intracranial tumors., Case Report: We present a 17-year-old patient who suffered from an intraventricular malignant meningioma. At the age of 2 years, acute lymphatic leukemia (common ALL [cALL]) was diagnosed and successfully treated with chemotherapy. There was no cranial radiation therapy. In December 2001, 13 years after diagnosis of cALL, he complained of headache, vomiting, and walking difficulties. Magnetic resonance imaging showed an enhancing mass with cystic components in the trigone of the right lateral ventricle. The tumor was removed completely. Histological diagnosis revealed a malignant papillary meningioma. After removal of a recurrent meningioma 16 months later, he received local radiotherapy., Conclusion: Pathogenetic mechanisms, treatment options, and prognosis of meningiomas and secondary malignancies of this age group are discussed.

Objective: To describe the interdisciplinary surgical approach in spheno-orbital meningiomas and to evaluate the operative results regarding resectability and functional outcome., Patients and Methods: A series of 16 patients underwent surgical resection of spheno-orbital meningiomas followed by bony reconstruction. Four patients presented with a recurrent meningioma and had undergone surgical resection previously. Radical tumour removal was attempted in all cases, although no aggressive effort was made to remove tumour tissue infiltrating the cavernous sinus or soft tissues deep in the orbit to avoid severe functional disturbances. All patients but one were female (mean age 53 years). Mean follow-up period was 68 months (range 4-155 months)., Results: The leading symptom was proptosis in 14 patients, accompanied in 7 cases by progressive visual impairment. Surgical resection was thought to have been complete in 11 patients (69%) and incomplete in 5 (31%). Residual tumour was deliberately left when there was infiltration of the cavernous sinus (n = 4), the pterygopalatine fossa (n = 2) and/or the deep intraorbital soft tissues (n = 1). Tumour recurrence was observed in 9 patients, among whom were 6 patients with an initially "completely" resected meningioma. Eight patients underwent re-operation. Complete resection was achieved in 3 of these latter patients with an isolated exclusively intraorbital tumour manifestation., Conclusion: By means of combined skull base approaches, spheno-orbital meningiomas are grossly resected totally with a long-term survival free of recurrence and an acceptable quality of life. In some cases, deliberate subtotal tumour resection is useful to avoid severe neurological damage with sufficient tumour control and a valuable progression-free survival.

Objective: This study evaluates the technique, indications, advantages and limitations of the minimal invasive supraorbital keyhole approach via an eyebrow skin incision for resection of tumors around the sella and the anterior skull base., Methods and Results: In 9 patients (5 males, 4 females) different tumors (6 meningiomas, 1 craniopharyngioma, 1 Rathke's cleft cyst and 1 hypophysitis) with a maximum diameter of 30 millimeters were resected via a small eyebrow incision and a supraorbital keyhole craniotomy. Details of the operative procedure include the use of a high-speed drill, a microsaw, bayonet-shaped instruments, careful microsurgical dissection, the use of a neuroendoscope and miniplates for closure. In all patients complete tumor removal was achieved. Mean duration of surgery was 01 h 51 min and mean hospital stay was 8.9 days. There were no significant postoperative complications. Clinical examination and MR imaging after a mean follow-up of 313 days revealed no tumor recurrence and a very satisfying overall functional and cosmetic result in all patients., Conclusion: The eyebrow incision supraorbital keyhole approach proved to be safe, effective and time-sparing. The authors recommend this approach for resection of small tumors around the sella and the anterior skull base in selected cases as a valuable alternative to standard skull base approaches.