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Meningeal solitary fibrous tumors (SFT) are rare and have a high frequency of local recurrence and distant metastasis. In a cohort of 126 patients (57 female, 69 male; mean age at surgery 53.0 years) with pathologically confirmed meningeal SFTs with extended clinical follow-up (median 9.9 years; range 15 days-43 years), we performed extensive molecular characterization including genome-wide DNA methylation profiling (n = 80) and targeted TERT promoter mutation testing (n = 98). Associations were examined with NAB2::STAT6 fusion status (n = 101 cases; 51 = ex5-7::ex16-17, 26 = ex4::ex2-3; 12 = ex2-3::exANY/other and 12 = no fusion) and placed in the context of 2021 Central Nervous System (CNS) WHO grade. NAB2::STAT6 fusion breakpoints (fusion type) were significantly associated with metastasis-free survival (MFS) (p = 0.03) and, on multivariate analysis, disease-specific survival (DSS) when adjusting for CNS WHO grade (p = 0.03). DNA methylation profiling revealed three distinct clusters: Cluster 1 (n = 38), Cluster 2 (n = 22), and Cluster 3 (n = 20). Methylation clusters were significantly associated with fusion type (p < 0.001), with Cluster 2 harboring ex4::ex2-3 fusion in 16 (of 20; 80.0%), nearly all TERT promoter mutations (7 of 8; 87.5%), and predominantly an "SFT" histologic phenotype (15 of 22; 68.2%). Clusters 1 and 3 were less distinct, both dominated by tumors having ex5-7::ex16-17 fusion (respectively, 25 of 33; 75.8%, and 12 of 18; 66.7%) and with variable histological phenotypes. Methylation clusters were significantly associated with MFS (p = 0.027), but not overall survival (OS). In summary, NAB2::STAT6 fusion type was significantly associated with MFS and DSS, suggesting that tumors with an ex5::ex16-17 fusion may have inferior patient outcomes. Methylation clusters were significantly associated with fusion type, TERT promoter mutation status, histologic phenotype, and MFS., (© 2024 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to evaluate and make practical recommendations on recent advances in the field of CNS tumor classification, particularly in light of the rapid progress in molecular insights into these neoplasms. For Round 2 of its deliberations, cIMPACT-NOW Working Committee 3 was reconstituted and convened in Utrecht, The Netherlands, for a meeting designed to review putative new CNS tumor types in advance of any future World Health Organization meeting on CNS tumor classification. In preparatory activities for the meeting and at the actual meeting, a list of possible entities was assembled and each type and subtype debated. Working Committee 3 recommended that a substantial number of newly recognized types and subtypes should be considered for inclusion in future CNS tumor classifications. In addition, the group endorsed a number of principles-relating to classification categories, approaches to classification, nomenclature, and grading-that the group hopes will also inform the future classification of CNS neoplasms., (© 2020 International Society of Neuropathology.)

High-grade astrocytomas (HGAs), corresponding to World Health Organization grades III (anaplastic astrocytoma) and IV (glioblastoma; GBM), are biologically aggressive, and their molecular classification is increasingly relevant to clinical management. PDGFRA amplification is common in HGAs, although its prognostic significance remains unclear. Using fluorescence in situ hybridization (FISH), the most sensitive technique for detecting PDGFRA copy number gains, we determined PDGFRA amplification status in 123 pediatric and 263 adult HGAs. A range of PDGFRA FISH patterns were identified and cases were scored as non-amplified (normal and polysomy) or amplified (low-level and high-level). PDGFRA amplification was frequent in pediatric (29.3%) and adult (20.9%) tumors. Amplification was not prognostic in pediatric HGAs. In adult tumors diagnosed initially as GBM, the presence of combined PDGFRA amplification and isocitrate dehydrogenase 1 (IDH1)(R132H) mutation was a significant independent prognostic factor (P = 0.01). In HGAs, PDGFRA amplification is common and can manifest as high-level and focal or low-level amplifications. Our data indicate that the latter is more prevalent than previously reported with copy number averaging techniques. To our knowledge, this is the largest survey of PDGFRA status in adult and pediatric HGAs and suggests PDGFRA amplification increases with grade and is associated with a less favorable prognosis in IDH1 mutant de novo GBMs., (© 2013 International Society of Neuropathology.)

Glioblastoma (GBM) is an aggressive primary brain tumor with an average survival of approximately 1 year. A recently recognized subtype, glioblastoma with oligodendroglioma component (GBM-O), was designated by the World Health Organization (WHO) in 2007. We investigated GBM-Os for their clinical and molecular characteristics as compared to other forms of GBM. Tissue samples were used to determine EGFR, PTEN, and 1p and 19q status by fluorescence in situ hybridization (FISH); p53 and mutant IDH1 protein expression by immunohistochemistry (IHC); and MGMT promoter status by methylation-specific polymerase chain reaction (PCR). GBM-Os accounted for 11.9% of all GBMs. GBM-Os arose in younger patients compared to other forms of GBMs (50.7 years vs. 58.7 years, respectively), were more frequently secondary neoplasms, had a higher frequency of IDH1 mutations and had a lower frequency of PTEN deletions. Survival was longer in patients with GBM-Os compared to those with other GBMs, with median survivals of 16.2 and 8.1 months, respectively. Most of the survival advantage for GBM-O appeared to be associated with a younger age at presentation. Among patients with GBM-O, younger age at presentation and 1p deletion were most significant in conferring prolonged survival. Thus, GBM-O represents a subset of GBMs with distinctive morphologic, clinical and molecular characteristics., (© 2013 The Authors; Brain Pathology © 2013 International Society of Neuropathology.)

Chordoid gliomas are rare, slow-growing neoplasms of the anterior third ventricle. We reported a case of chordoid glioma in a 41-year-old man with obstructive hydrocephalus. Histologically, the tumor consisted of polygonal epithelioid cells admixed with elongated cells in a myxoid stroma. A prominent lymphoplasmacytic infiltrate was present. The tumor cells expressed glial fibrillary acidic protein (GFAP), epithelial membrane antigen (EMA), vimentin, CD31, CD34, epidermal growth factor receptor (EGFR) and S100 but were negative for pankeratin and E-cadherin. The percentage of Ki67 positive cells was approximately 3%. Weak p53 immunoreactivity was seen in less than 10% of the cells. Array comparative genomic hybridization performed on this case, as well as on four other archived cases, showed losses at several loci. Fluorescence in situ hybridization (FISH) confirmed consistent genetic alterations at 9p21 and 11q13. These are the fifth through ninth reported cases of chordoid gliomas with molecular characterization suggesting a distinct genetic origin from other gliomas.

The presence of necrosis within a diffuse glioma is a powerful predictor of poor prognosis, yet little is known of its origins. Intravascular thrombosis is a frequent finding in glioblastoma [GBM; World Health Organization (WHO) grade IV] specimens and could potentially be involved in astrocytoma progression to GBM or represent a surrogate marker of GBM histology. We investigated whether intravascular thrombosis was more frequent or prominent in GBM than other central nervous system (CNS) malignancies and considered its prognostic significance in anaplastic astrocytoma (AA; WHO grade III), which lacks necrosis. Histologic sections were examined for thrombosis, necrosis and microvascular hyperplasia from each of 297 CNS tumors, including 103 GBMs, 46 AAs, 20 diffuse astrocytoma (DAs; WHO grade II), eight anaplastic oligodendrogliomas (AOs; WHO grade III), 20 oligodendrogliomas (ODs; WHO grade II), 49 metastatic carcinomas (METs), 31 primary central nervous system lymphomas (PCNSLs) and 20 medulloblastomas (MBs). Among newly diagnosed tumors, thrombosis was present in 92% of GBM resections, significantly greater than other types of CNS malignancies. Of tumors with thrombosis, GBMs had a higher frequency of affected vessels than AAs, DAs, AOs, ODs and MBs, but had a frequency similar to METs and PCNSLs. The sensitivity of thrombosis for the diagnosis of GBM in this set of tumors was 92% and the specificity was 91%. Intravascular thrombosis was uncommon in AAs and was only noted in stereotactic biopsies. This subset of patients had shorter survivals than those AAs without thrombosis. Thus, intravascular thrombosis is more frequent in GBM than other CNS malignancies. When present in AAs, it appears to indicate aggressive clinical behavior.

The 4(th) edition of the WHO Classification of Tumours of the Nervous System (WHO 2007) introduces changes that reflect both the recognition of new brain tumour types and a better understanding of neoplastic behavior. Three new tumours, angiocentric glioma (AG), pilomyxoid astrocytoma (PMA), and pituicytoma are added to the section on gliomas. AG is a slowly growing cerebral tumour that typically presents with seizures in children and young adults. It is characterized by monomorphous, bipolar tumour cells with a striking perivascular growth pattern. Although the 'cell of origin' of AG is not clear, ultrastructural evidence points to an ependymal derivation. Typically, AG can be cured by total resection, and is designated WHO grade I. PMA is a solid, circumscribed tumour occurring mainly in the hypothalamic region of young children. It is composed of a monomorphous population of bipolar tumour cells within a rich myxoid background, with a conspicuous anglocentric arrangement. While PMA is considered a more aggressive variant of pilocytic astrocytoma, this relationship awaits further clarification. The PMA has been designated WHO grade II. The pituicytoma, involves the posterior pituitary and/or its stalk and affects adults. It is solid in architecture, composed of spindle cells and presumably derived from pituicytes. Pituicytomas are indolent tumours, and are designated WHO grade I.

Congenital central nervous system (CNS) tumors are uncommon, accounting for 1% of all childhood brain tumors. They present clinically either at birth or within the first 3 months. Glioblastoma (GBM) only rarely occurs congenitally and has not been fully characterized. We examined clinicopathologic features and genetic alterations of six congenital GBMs. Tumors were seen by neuroimaging as large, complex cerebral hemispheric masses. All showed classic GBM histopathology, including diffuse infiltration, dense cellularity, GFAP-positivity, high mitotic activity, endothelial proliferation and pseudopalisading necrosis. Neurosurgical procedures and adjuvant therapies varied. Survivals ranged from 4 days to 7.5 years; two of the three long-term survivors received chemotherapy, whereas the three short-term survivors did not. Paraffin-embedded tissue sections were used for FISH analysis of EGFR, chromosomes 9p21 (p16/CDKN2A) and 10q ( PTEN/DMBT1); sequencing of PTEN and TP53; and immunohistochemistry for EGFR and p53. We uncovered 10q deletions in two cases. No EGFR amplifications, 9p21 deletions, or mutations of TP53 or PTEN were noted; however, nuclear p53 immunoreactivity was strong in 5/6 cases. Tumors were either minimally immunoreactive (n = 3) or negative (n = 3) for EGFR. We conclude that congenital GBMs show highly variable survivals. They are genetically distinct from their adult counterparts and show a low frequency of known genetic alterations. Nonetheless, the strong nuclear expression of p53 in these and other pediatric GBMs could indicate that p53 dysregulation is important to tumorigenesis.

The May 2003 COM. A 57-year-old woman presented with slurring of her speech and right arm weakness. Her past medical history included idiopathic hypertrophic subendocardial stenosis (IHSS), arthritis, asthma, congestive heart failure, hypertension and NIDDM. Neurological examination showed persistent word finding difficulty but her motor and sensory function had essentially returned to normal. Extensive laboratory studies were unrevealing. Imaging studies showed a meningeal lesion over the left posterior parietal lobe and the findings suggested an infectious or inflammatory process. A biopsy of the involved dura and meninges was performed and revealed leptomeningeal Rosai-Dorfman disease. Emperipolesis was noted. The finding of emperipolesis is characteristic of Rosai-Dorfman disease of the leptomeninges, but in 30% of cases, this feature will not be identified. Large pale histiocytes of Rosai-Dorfman disease are immunoreactive for S-100 protein and KP1, but negative for CD1a. The differential diagnosis of a chronic inflammatory infiltrate containing numerous, large histiocytes includes granulomatous diseases such as Wegener graulomatosis and sarcoid, Hodgkin disease, and Langerhans histiocytosis. CNS Rosai-Dorfman most commonly involves patients between 20- and 40-years-old, with a slight male predominance. Approximately 75% of cases are intracranial, whereas 20% involve the spine. Over 90% of CNS Rosai-Dorfman cases involve the leptomeninges and are seen by neuroimaging as a dural-based, contrast-enhancing masses that often elicit vasogenic edema in the underlying brain. Thus, clinically and radiologically, the disease is thought to represent meningioma. Leptomeningeal Rosai-Dorfman disease is considered a benign condition and in most cases surgical resection is the treatment of choice. Although the number of cases in the literature is small, disease progression following surgical resection is uncommon. Little is known regarding the pathogenesis of Rosai-Dorfman disease. Most have suggested that it represents either an autoimmune disease or a reaction to an infectious agent that has yet to be discovered. Currently it is best considered a benign, idiopathic histiocytosis.

Granular cell astrocytomas (GCA) are an uncommon morphologic variant of infiltrative glioma that contains a prominent population of atypical granular cells. As a rule, they are biologically aggressive compared to similar tumors without granular features. We sought to determine whether GCAs possess distinct genotypic alterations that might reflect their unique morphology or clinical behavior. Eleven GCAs occurring in 7 men and 4 women ranging in age from 46 to 75 years were investigated for genetic alterations of known significance in glial tumorigenesis, including LOH at 1p, 9p, 10q, 17p, and 19q, point mutations of TP53, deletions of p16(CDKN2A) and p14ARF, as well as EGFR amplifications. Tumors included had an infiltrative growth pattern and consisted of large, round cells packed with eosinophilic, PAS-positive granules that varied in quantity, ranging from 30 to 100% of tumor cells. Three tumors were of WHO grade II, one was grade III, and 7 were grade IV lesions. Overall, the tumors showed higher frequencies of LOH at 1p, 9p, 10q, 17p, and 19q than typical infiltrating astrocytomas of similar grades. Losses on 9p and 10q occurred in nearly all cases, including low grade lesions. TP53 mutations were identified in 2 grade IV GCAs, while combined p14ARF and p16(CDKN2A) homozygous deletions were noted in only one grade IV lesion. None showed EGFR amplification. We found no genetic alterations specific for GCA. Instead, it appears that granular cell change occurs across genetic subsets. The high frequency of allelic loss, especially on 9p and 10q, may confer aggressive growth potential and be related to their rapid clinical progression.

Astroblastomas are uncommon brain tumors whose classification and histogenesis have been debated. Precise criteria for diagnosis have been described only recently, but have not found wide acceptance. We report the clinical, radiographic, and histopathologic features of 20 astroblastomas, and the chromosomal alterations in seven cases as detected by comparative genomic hybridization (CGH). The tumors occurred both in children and young adults (average age, 14 years), most often as well circumscribed, peripheral, cerebral hemispheric masses. Radiographically, the lesions were contrast-enhancing and solid, often with a cystic component. All were characterized histologically by astroblastic pseudorosettes, and most displayed prominent perivascular hyalinization, regional hyaline changes, and pushing borders in regard to adjacent brain. Tumor cells were strongly immunoreactive for S-100 protein, GFAP, and vimentin. Staining for EMA was focal. Ten of 20 astroblastomas were classified as "well differentiated" and 10 were classified as "malignant," largely on the basis of hypercellular zones with increased mitotic indices, vascular proliferation, and necrosis with pseudopalisading. All 10 well differentiated lesions and 8 of 10 malignant lesions were completely resected. None of the well differentiated astroblastomas recurred within the limited follow-up period. Three malignant astroblastomas recurred, including two incompletely resected tumors, and one that had been totally resected. One patient died of disease following recurrence. The most frequent chromosomal alterations detected by CGH were gains of chromosome arm 20q (4/7 tumors) and chromosome 19 (3/7). The combination of these gains occurred in three, including two well differentiated and one malignant astroblastoma. Other alterations noted in two tumors each were losses on 9q, 10, and X. These chromosomal alterations are not typical of ependymoma or infiltrating astrocytic neoplasms, and suggest that astroblastomas may have a characteristic cytogenetic profile in addition to their distinctive clinical, radiographic, and histopathologic features.