Papillary tumor of the pineal region: analysis of DNA methylation profiles and clinical outcomes in 76 cases.

Papillary tumor of the pineal region (PTPR) is an uncommon tumor of the pineal region with distinctive histopathologic and molecular characteristics. Experience is limited with respect to its molecular heterogeneity and clinical characteristics. Here, we describe 39 new cases and combine these with 37 previously published cases for a cohort of 76 PTPR's, all confirmed by methylation profiling. As previously reported, two main methylation groups were identified (PTPR-A and PTPR-B). In our analysis we extended the subtyping into three subtypes: PTPR-A, PTPR-B1 and PTPR-B2 supported by DNA methylation profile and genomic copy number variations. Frequent loss of chromosome 3 or 14 was found in PTPR-B1 tumors but not in PTPR-B2. Examination of clinical outcome showed that nearly half (14/30, 47%) of examined patients experienced tumor progression with significant difference among the subtypes (p value = 0.046). Our analysis extends the understanding of this uncommon but distinct neuroepithelial tumor by describing its molecular heterogeneity and clinical outcomes, including its tendency towards tumor recurrence.

Surgical Management of a Massive Frontal Bone Hemangioma: Case Report.

Intraosseous hemangiomas are rare, benign tumors that can arise from the calvarium. These lesions often invade the outer table of the skull, but typically spare the inner table and intracranial structures. En bloc surgical resection is the standard treatment for intraosseous hemangiomas. However, a piecemeal resection may be required to safely remove the tumor in cases involving the inner table to protect the underlying brain parenchyma and vascular structures. Proper reconstruction is critical to optimize the cosmetic outcome, and a staged procedure allowing implantation of a custom-made implant can be considered for large lesions involving the forehead. We present a case of a patient with a large frontal intraosseous hemangioma with intradural involvement to highlight the surgical nuances of resection and review the existing literature regarding optimal management of these patients.

Epigenetic and genomic profiling of chordoid meningioma: implications for clinical management.

Chordoid meningioma is a morphological variant of meningioma designated as WHO grade 2. However, the recurrence rates varied widely in different case series, and to date, a unifying molecular genetic signature has not been identified. Among 1897 meningiomas resected at our institution, we identified 12 primary chordoid meningiomas from 12 patients. Histologically, all 12 cases had predominant (> 50%) chordoid morphology. Ten were otherwise grade 1, and two were also atypical. We performed DNA global methylation profile, copy number variation analysis, and targeted next-generation sequencing on 11 chordoid meningiomas, and compared to those of 51 non-chordoid, mostly high grade meningiomas. The chordoid meningiomas demonstrated a unique methylation profile in tSNE, UMAP, and hierarchical heatmap clustering analyses of the most differentially methylated CpGs. The most common copy number variation in chordoid meningioma was loss of 1p (7/11, 64%). Three chordoid meningiomas had 2p loss, which was significantly higher than the non-chordoid control cohort (27% vs 7.2%, p = 0.035). 22q loss was only seen in the two cases with additional atypical histological features. Chordoid meningiomas were enriched in mutations in chromatin remodeling genes EP400 (8/11,73%) KMT2C (4/11, 36%) and KMT2D (4/11, 36%), and showed low or absent NF2, TERT, SMO, and AKT1 mutations. Prognosis wise, only one case recurred. This case had atypical histology and high-grade molecular features including truncating NF2 mutation, 1p, 8p, 10, 14, 22q loss, and homozygous deletion of CDKN2A/B. Progression free survival of chordoid, otherwise grade 1 meningioma was comparable to non-chordoid WHO grade 1 meningioma (p = 0.75), and significantly better than chordoid WHO grade 2 meningioma (p = 0.019). Conclusion: the chordoid histology alone may not justify a universal WHO grade 2 designation. Screening for additional atypical histological or molecular genetic features is recommended.

Distant Pituitary Adenoma Spread: A Systematic Review and Report of 2 Cases.

BACKGROUND: Distant spread of pituitary adenoma outside the sellar/suprasellar region is classified as pituitary carcinoma. Cerebrospinal fluid (CSF)-born spread of pituitary adenoma can occur after tumor cell spillage into the CSF space after surgery, irradiation, or apoplexy and is not necessarily related to intrinsic tumor biology. OBJECTIVE: To systematically review the literature and describe the clinical characteristics and treatment strategies of patients with pituitary carcinomas. We further present 2 cases from our institution. METHODS: A single-center retrospective review of patients with pituitary adenoma spread to distant intracranial locations between 2000 and 2020 was performed. Electronic databases were searched from their inception to May 25, 2021, and studies describing patients with pituitary spread to distant locations were included. RESULTS: Of 1210 pituitary adenoma cases reviewed, 2 (0.16%) showed tumor spread to distant locations. We found 134 additional cases (from 108 published articles) resulting in a total of 136 cases (61.9% were male). The time to tumor spread ranged between 0 and 516 months (median: 96 months). The follow-up duration ranged between 0 and 240 months (median: 11.5 months). All but 2 patients (98.5%) underwent surgical resection before adenoma spread. The 2 exceptions included a patient with evidence of an apoplectic event on autopsy and another patient with leptomeningeal pituitary spread but an unclear history of apoplexy. Elevated tumor markers were not linked to poor outcomes. CONCLUSION: Distant spread of pituitary adenoma may occur after surgery, irradiation, or apoplexy. It is not necessarily associated with a malignant clinical course.

The efficacy of immunohistochemistry in the diagnosis of molecular genetic alterations in central nervous system gliomas: Next-generation sequencing of 212 mutations in 112 patients.

Identification of molecular genetic alterations has become an important part of diagnosis and care of patients with brain tumors. Comparisons of immunohistochemistry (IHC) with DNA sequencing techniques have suggested that IHC is useful for identifying surrogates of mutations in gliomas; however, studies of the efficacy are relatively few. Our aim was to compare IHC in our neuropathology laboratory with a commercially available next-generation sequencing (NGS) platform, Tempus xT. We studied 212 immunohistochemically stained sections of gliomas to identify mutations of isocitrate dehydrogenase (IDH), p53, BRAF, the α-thalassemia/mental retardation syndrome X-linked protein (ATRX), and histone H3. Tempus xT NGS confirmed the IHC diagnosis of IDH1/R132H in 102 of 102 patients (100%), BRAF/V600E in 14 of 14 (100%) patients and H3/K27M in 10 of 10 (100%) patients. For p53, NGS confirmed the IHC diagnosis of mutation in 47 of 53 (87%) patients. For 6 patients, IHC was interpreted as wild-type while NGS indicated a mutation. NGS confirmed the IHC diagnosis of ATRX mutation in 29 of 31 (94%) patients. In 1 patient, IHC predicted a mutation that was not confirmed by NGS, and in another, IHC predicted wild-type, but NGS showed mutant. In 2 other patients, IHC diagnosis of ATRX mutation was equivocal; 1 was mutant and 1 was wild-type by NGS. Our single-center study suggests that IHC for IDH1/R132H, BRAF/V600E, and H3/K27M is highly reliable and may be used confidently in clinical practice. IHC for p53 and ATRX mutations is often reliable but possibly problematic, and genetic studies may be necessary to determine astrocytic or oligodendroglial differentiation.

Alterations in the RB Pathway With Inactivation of RB1 Characterize Glioblastomas With a Primitive Neuronal Component.

A primitive neuronal component is a feature of some glioblastomas but defining molecular alterations of this histologic variant remains uncertain. We performed next-generation sequencing of 1500 tumor related genes on tissue from 9 patients with glioblastoma with a primitive component (G/PN) and analyzed 27 similar cases from the Cancer Genome Atlas (TCGA) dataset. Alterations in the RB pathway were identified in all of our patients' tumors and 81% of TCGA tumors with the retinoblastoma tumor suppressor gene (RB1) commonly affected. Although RB1 mutations were observed in some conventional glioblastomas, the allelic fractions of these mutations were significantly higher in tumors with a primitive neuronal component in both our and TCGA cohorts (median, 72% vs 25%, p < 0.001 and 80% vs 40%, p < 0.02, respectively). Further, in 78% of patients in our cohort, RB expression was lost by immunohistochemistry. Our findings indicate that alterations in the RB pathway are common in G/PNs and suggest that inactivation of RB1 may be a driving mechanism for the phenotype.

Lymphomatoid granulomatosis of the central nervous system (CNS-LYG) posing a management challenge.

Isolated central nervous system lymphomatoid granulomatosis (CNS-LYG) can mimic aggressive glioblastomas. We describe a complex presentation of CNS-LYG coexisting with immune thrombocytopenia successfully managed with rituximab and ultra-low-dose radiation therapy.

Extraneural metastatic anaplastic ependymoma: a systematic review and a report of metastases to bilateral parotid glands.

BACKGROUND: Anaplastic ependymoma with extraneural metastases is associated with a poor clinical outcome. Metastatic spread to the parotid gland is a rare clinical entity that requires multidisciplinary intervention. Herein, we present a systematic review of anaplastic ependymoma with extraneural metastases and report on a case with metastases to both parotid glands. METHODS: Electronic databases were searched from their inception to February 2019. Inclusion criteria included reports of anaplastic ependymoma with extraneural metastasis. Studies were excluded if the tumor grade was not reported. A case illustration is provided. RESULTS: The search yielded 15 cases of anaplastic ependymoma with extraneural metastases, including the present case. Mean age at diagnosis was 15 years. The initial tumor location was predominantly supratentorial (93.3%). All cases demonstrated leptomeningeal seeding before extraneural metastasis. Mean survival from initial diagnosis was 4.5 years. Metastasis to the parotid gland occurred in 2 cases, including the present case. We present a 17-year-old female patient who underwent gross total resection of a supratentorial, paraventricular anaplastic ependymoma followed by adjuvant external beam radiation therapy. The patient developed recurrent leptomeningeal seeding, treated with Gamma Knife radiosurgery over a 5-year period. She returned with a parotid mass and cervical lymphadenopathy and underwent parotidectomy and modified radical neck dissection. She continued to experience recurrences, including the left parotid gland, and was ultimately placed in hospice care. CONCLUSIONS: Anaplastic ependymoma with extraneural metastasis is rare. A combination of repeated surgical resection, radiation therapy, and chemotherapy can be used to manage recurrent and metastatic disease, but outcomes remain poor.

Glycine by MR spectroscopy is an imaging biomarker of glioma aggressiveness.

BACKGROUND: High-grade gliomas likely remodel the metabolic machinery to meet the increased demands for amino acids and nucleotides during rapid cell proliferation. Glycine, a non-essential amino acid and intermediate of nucleotide biosynthesis, may increase with proliferation. Non-invasive measurement of glycine by magnetic resonance spectroscopy (MRS) was evaluated as an imaging biomarker for assessment of tumor aggressiveness. METHODS: We measured glycine, 2-hydroxyglutarate (2HG), and other tumor-related metabolites in 35 glioma patients using an MRS sequence tailored for co-detection of glycine and 2HG in gadolinium-enhancing and non-enhancing tumor regions on 3T MRI. Glycine and 2HG concentrations as measured by MRS were correlated with tumor cell proliferation (MIB-1 labeling index), expression of mitochondrial serine hydroxymethyltransferase (SHMT2), and glycine decarboxylase (GLDC) enzymes, and patient overall survival. RESULTS: Elevated glycine was strongly associated with presence of gadolinium enhancement, indicating more rapidly proliferative disease. Glycine concentration was positively correlated with MIB-1, and levels higher than 2.5 mM showed significant association with shorter patient survival, irrespective of isocitrate dehydrogenase status. Concentration of 2HG did not correlate with MIB-1 index. A high glycine/2HG concentration ratio, >2.5, was strongly associated with shorter survival (P < 0.0001). GLDC and SHMT2 expression were detectable in all tumors with glycine concentration, demonstrating an inverse correlation with GLDC. CONCLUSIONS: The data suggest that aggressive gliomas reprogram glycine-mediated one-carbon metabolism to meet the biosynthetic demands for rapid cell proliferation. MRS evaluation of glycine provides a non-invasive metabolic imaging biomarker that is predictive of tumor progression and clinical outcome. KEY POINTS: 1. Glycine and 2-hydroxyglutarate in glioma patients are precisely co-detected using MRS at 3T.2. Tumors with elevated glycine proliferate and progress rapidly.3. A high glycine/2HG ratio is predictive of shortened patient survival.

Mutation Status and Epithelial Differentiation Stratify Recurrence Risk in Chordoid Meningioma-A Multicenter Study with High Prognostic Relevance.

Chordoid meningioma is a rare WHO grade II histologic variant. Its molecular alterations or their impact on patient risk stratification have not been fully explored. We performed a multicenter, clinical, histological, and genomic analysis of chordoid meningiomas from 30 patients (34 tumors), representing the largest integrated study to date. By NHERF1 microlumen immunohistochemical detection, three epithelial differentiation (ED) groups emerged: #1/fibroblastic-like, #2/epithelial-poorly-differentiated and #3/epithelial-well-differentiated. These ED groups correlated with tumor location and genetic profiling, with NF2 and chromatin remodeling gene mutations clustering in ED group #2, and TRAF7 mutations segregating in ED group #3. Mutations in LRP1B were found in the largest number of cases (36%) across ED groups #2 and #3. Pathogenic ATM and VHL germline mutations occurred in ED group #3 patients, conferring an aggressive or benign course, respectively. The recurrence rate significantly correlated with mutations in NF2, as single gene, and with mutations in chromatin remodeling and DNA damage response genes, as groups. The recurrence rate was very high in ED group #2, moderate in ED group #3, and absent in ED group #1. This study proposes guidelines for tumor recurrence risk stratification and practical considerations for patient management.

Distinct Expression Patterns of Carbonic Anhydrase IX in Clear Cell, Microcystic, and Angiomatous Meningiomas.

Clear cell, microcytic, and angiomatous meningiomas are 3 vasculature-rich variants with overlapping morphological features but different prognostic and treatment implications. Distinction between them is not always straightforward. We compared the expression patterns of the hypoxia marker carbonic anhydrase IX (CA-IX) in meningiomas with predominant clear cell (n = 15), microcystic (n = 9), or angiomatous (n = 11) morphologies, as well as 117 cases of other World Health Organization recognized histological meningioma variants. Immunostaining for SMARCE1 protein, whose loss-of-function has been associated with clear cell meningiomas, was performed on all clear cell meningiomas, and selected variants of meningiomas as controls. All clear cell meningiomas showed absence of CA-IX expression and loss of nuclear SMARCE1 expression. All microcystic and angiomatous meningiomas showed diffuse CA-IX immunoreactivity and retained nuclear SMARCE1 expression. In other meningioma variants, CA-IX was expressed in a hypoxia-restricted pattern and was highly associated with atypical features such as necrosis, small cell change, and focal clear cell change. In conclusion, CA-IX may serve as a useful diagnostic marker in differentiating clear cell, microcystic, and angiomatous meningiomas.

Intracranial anaplastic hemangiopericytoma presenting with simultaneous extra-cranial metastases: A case report and review of the literature.

BACKGROUND: Intracranial solitary fibrous tumor/hemangiopericytoma (SFT/HPC) is a rare mesenchymal tumor with a propensity to recur and metastasize extracranially years after treatment. Accordingly, there are no reported cases of a patient presenting with a simultaneous intracranial primary and extracranial metastases. We present the case of a patient presenting with an intracranial SFT/HPC and simultaneous liver metastases and propose a treatment paradigm. CASE DESCRIPTION: A 74-year-old male smoker presented with confusion. An MRI of the brain revealed a heterogeneously enhancing left frontal extra-axial mass. Systemic workup revealed multiple small liver lesions concerning for metastases. The patient underwent gross total resection (GTR) of the intracranial lesion with adjuvant CyberKnife stereotactic radiotherapy to the resection cavity. Pathology was consistent with a WHO Grade III SFT/HPC (previously known as anaplastic HPC). The liver lesions were biopsied and confirmed to be metastases. They were subsequently treated with stereotactic body radiation therapy, temozolomide, and bevacizumab. Eighteen months postoperatively, the patient is alive with no evidence of intracranial malignancy and regression of the hepatic lesions. CONCLUSION: Several studies support GTR and adjuvant radiotherapy to treat intracranial SFT/HPC. The role of adjuvant chemotherapy is less clear. Metastatic disease is typically detected several years after the initial diagnosis, and there is no consensus regarding the optimal treatment strategy. We propose that the rare presentation of intracranial SFT/HPC with simultaneous extracranial metastases should be treated in a multidisciplinary fashion with surgical resection, adjuvant radiotherapy, and chemotherapy.

Stem cell injections for axial back pain: a systematic review of associated risks and complications with a case illustration of diffuse hyperplastic gliosis resulting in cauda equina syndrome.

OBJECTIVE: Axial low-back pain is a disease of epidemic proportions that exerts a heavy global toll on the active workforce and results in more than half a trillion dollars in annual costs. Stem cell injections are being increasingly advertised as a restorative solution for various degenerative diseases and are becoming more affordable and attainable by the public. There have been multiple reports in the media of these injections being easily available abroad outside of clinical trials, but scientific evidence supporting them remains scarce. The authors present a case of a serious complication after a stem cell injection for back pain and provide a systematic review of the literature of the efficacy of this treatment as well as the associated risks and complications. METHODS: A systematic review of the literature was performed using the PubMed, Google Scholar, and Scopus online electronic databases to identify articles reporting stem cell injections for axial back pain in accordance with the PRISMA guidelines. The primary focus was on outcomes and complications. A case of glial hyperplasia of the roots of the cauda equina directly related to stem cell injections performed abroad is also reported. RESULTS: The authors identified 14 publications (including a total of 147 patients) that met the search criteria. Three of the articles presented data for the same patient population with different durations of follow-up and were thus analyzed as a single study, reducing the total number of studies to 12. In these 12 studies, follow-up periods ranged from 6 months to 6 years, with 50% having a follow-up period of 1 year or less. Most studies reported favorable outcomes, although 36% used subjective measures. There was a tendency for pain relief to wane after 6 months to 2 years, with patients seeking a surgical solution. Only 1 study was a randomized controlled trial (RCT). CONCLUSIONS: There are still insufficient data to support stem cell injections for back pain. Additional RCTs with long-term follow-up are necessary before statements can be made regarding the efficacy and safety.

Genome-Wide Analysis of Glioblastoma Patients with Unexpectedly Long Survival.

Glioblastoma (GBM), representing WHO grade IV astrocytoma, is a relatively common primary brain tumor in adults with an exceptionally dismal prognosis. With an incidence rate of over 10 000 cases in the United States annually, the median survival rate ranges from 10-15 months in IDH1/2-wildtype tumors and 24-31 months in IDH1/2-mutant tumors, with further variation depending on factors such as age, MGMT methylation status, and treatment regimen. We present a cohort of 4 patients, aged 37-60 at initial diagnosis, with IDH1-mutant GBMs that were associated with unusually long survival intervals after the initial diagnosis, currently ranging from 90 to 154 months (all still alive). We applied genome-wide profiling with a methylation array (Illumina EPIC Array 850k) and a next-generation sequencing panel to screen for genetic and epigenetic alterations in these tumors. All 4 tumors demonstrated methylation patterns and genomic alterations consistent with GBM. Three out of four cases showed focal amplification of the CCND2 gene or gain of the region on 12p that included CCND2, suggesting that this may be a favorable prognostic factor in GBM. As this study has a limited sample size, further evaluation of patients with similar favorable outcome is warranted to validate these findings.

Genomic analysis demonstrates that histologically-defined astroblastomas are molecularly heterogeneous and that tumors with MN1 rearrangement exhibit the most favorable prognosis.

Astroblastoma (AB) is a rare CNS tumor demonstrating abundant astroblastomatous pseudorosettes. Its molecular features have not been comprehensively studied and its status as a tumor entity is controversial. We analyzed a cohort of 27 histologically-defined ABs using DNA methylation profiling, copy number analysis, FISH and site-directed sequencing. Most cases demonstrated mutually exclusive MN1 rearrangements (n = 10) or BRAFV600E mutations (n = 7). Two additional cases harbored RELA rearrangements. Other cases lacked these specific genetic alterations (n = 8). By DNA methylation profiling, tumors with MN1 or RELA rearrangement clustered with high-grade neuroepithelial tumor with MN1 alteration (HGNET-MN1) and RELA-fusion ependymoma, respectively. In contrast, BRAFV600E-mutant tumors grouped with pleomorphic xanthoastrocytoma (PXA). Six additional tumors clustered with either supratentorial pilocytic astrocytoma and ganglioglioma (LGG-PA/GG-ST), normal or reactive cerebrum, or with no defined DNA methylation class. While certain histologic features favored one genetic group over another, no group could be reliably distinguished by histopathology alone. Survival analysis between genetic AB subtypes was limited by sample size, but showed that MN1-rearranged AB tumors were characterized by better overall survival compared to other genetic subtypes, in fact, significantly better than BRAFV600E-mutant tumors (P = 0.013). Our data confirm that histologically-defined ABs are molecularly heterogeneous and do not represent a single entity. They rather encompass several low- to higher-grade glial tumors including neuroepithelial tumors with MN1 rearrangement, PXA-like tumors, RELA ependymomas, and possibly yet uncharacterized lesions. Genetic subtyping of tumors exhibiting AB histology, particularly determination of MN1 and BRAFV600E status, is necessary for important prognostic and possible treatment implications.

H3 K27M Mutations in Thalamic Pilocytic Astrocytomas with Anaplasia.

BACKGROUND: The revised World Health Organization classification of central nervous system tumors, published in 2016, has recognized the H3 K27M mutation as a critical genetic signature defining a new group of infiltrative astrocytomas designated as diffuse midline glioma, H3 K27M mutant. Although most H3 K27M mutations arise in the setting of diffusely infiltrative tumors, there are rare reports of compact tumors with low-grade histologic features harboring this mutation. The prevalence and clinical significance of this mutation in pilocytic astrocytomas remain unclear. CASE DESCRIPTION: We report 2 young adult patients with H3 K27M-mutated thalamic pilocytic astrocytomas who presented to medical attention with symptomatic hydrocephalus requiring urgent intervention. We present our experience with this unusual tumor and recommend a treatment paradigm of maximal safe surgical resection followed by chemotherapy and radiation. CONCLUSIONS: Stereotactic biopsies may undergrade some adult thalamic pilocytic astrocytomas. Therefore, we recommend that all these tumors be evaluated for the H3 K27M mutation. Further, we think H3 K27M-mutant thalamic pilocytic astrocytomas require aggressive multimodality treatment and these treatments should be guided by the molecular findings, as opposed to the histologic ones.

Successful Novel Treatment of a Paraspinal Primitive Neuroectodermal Tumor with Predominantly Glial Differentiation: A 3-Year Follow-Up After Surgery, Intensity-Modulated Radiation Therapy and Oral Temozolomide.

BACKGROUND: Paraspinal masses are a relatively uncommon but diverse group of lesions that can be neoplastic or non-neoplastic. Peripheral primitive neuroectodermal tumors of the lumbar paraspinal region with diffuse and strong glial differentiation have never been reported before. CASE DESCRIPTION: We report a primary paraspinal primitive neuroectodermal tumor with overwhelming glial differentiation in a 23-year-old female patient who presented with intractable right lower extremity pain. The patient underwent a 2-staged operation with gross total resection of the mass followed by intensity-modulated radiation therapy and oral temozolomide, a regimen employed for high-grade intracranial gliomas. Serial imaging revealed no evidence of recurrence after 3 years. CONCLUSIONS: Although these lesions appear to be exceptionally rare, an approach similar to that of intracranial high-grade glial tumors was effective in our experience. Our patient had no evidence of recurrence at 3-year follow-up.

Epithelial differentiation with microlumen formation in meningioma: diagnostic utility of NHERF1/EBP50 immunohistochemistry.

Meningioma is a primary brain tumor arising from the neoplastic transformation of meningothelial cells. Several histological variants of meningioma have been described. Here we show that NHERF1/EBP50, an adaptor protein required for structuring specialized polarized epithelia, can distinguish meningioma variants with epithelial differentiation. NHERF1 decorates the membrane of intracytoplasmic lumens and microlumens in the secretory variant, consistent with a previously described epithelial differentiation of this subtype. NHERF1 also labels microlumens in chordoid meningioma, an epithelial variant not previously known to harbor these structures, and ultrastructural analysis confirmed the presence of microlumens in this variant. NHERF1 associates with the ezrin-radixin-moesin (ERM)-NF2 cytoskeletal proteins, and moesin but not NF2 was detectable in the microlumens. In a meningioma series from 83 patients, NHERF1 revealed microlumens in 87.5% of the chordoid meningioma (n = 25) and meningioma with chordoid component (n = 7) cases, and in 100% of the secretory meningioma cases (n = 12). The most common WHO grade I meningioma variants lacked microlumens. Interestingly, 20% and 66.6% of WHO grades II (n = 20) and III (n = 3) meningiomas, respectively, showed microlumen-like NHERF1 staining of ultrastructural tight microvillar interdigitations, mainly in rhabdoid, papillary-like or sheeting areas, revealing a new subset of high grade meningiomas with epithelial differentiation. NHERF1 failed to detect microlumens in 12 additional cases of chordoid glioma of the 3rd ventricle, chordoma and chondrosarcoma, neoplasms that may mimic the histological appearance of chordoid meningioma. This study uncovers features of epithelial differentiation in meningioma and proposes NHERF1 immunohistochemistry as a method of discriminating chordoid meningioma from neoplasms with similar appearance.