Myxoid mesenchymal intraventricular brain tumour with EWSR1-CREB1 gene fusion in an adult woman.

Myxoid mesenchymal tumours harbouring fusions between EWSR1 and the CREB family transcription factors have recently been described. Whether they represent a novel entity or a myxoid variant of angiomatoid fibrous histiocytoma (AFH) remains a matter of debate. We describe the case of a 58-year-old woman with a previous history of breast cancer that developed progressive neurological decline due to a large mass located in the left lateral ventricle of the brain. Histology revealed a mesenchymal tumour with multinodular growth, variable cellularity, prominent myxoid stroma and numerous amianthoid fibres. No evidence of pseudo-capsule or lymphoid cuffing was identified. RNA sequencing disclosed EWSR1-CREB1 gene fusion. Only 20 cases of intracranial mesenchymal tumours harbouring these translocations have been described, mostly in adolescents and young adults and with dural attachment. Occurrence in this age group and with intraventricular location has been even more rarely reported. A better understanding of tumour behaviour is needed to establish treatment guidelines and improve patient outcome.

Adult Intracranial Myxoid Mesenchymal Tumor with EWSR1-ATF1 Gene Fusion.

BACKGROUND: Intracranial myxoid mesenchymal tumors (IMMTs) carrying an EWSR1-CREB gene family fusion are extremely rare and have only been identified in 10 previous reports. All but one has been found in children or young adults. Although there appear to be similarities to a myxoid variant of angiomatoid fibrous histiocytoma (AFH), clear histologic differences exist that appear to distinguish IMMTs as a distinct and novel entity. Previous reports have lacked detailed long-term follow-up and recommendations regarding treatment approach. CASE DESCRIPTION: This case describes a 48-year-old woman who presented with a left intraventricular mass that was identified on histology as an IMMT with an EWSR1-ATF1 gene fusion. After initial resection, the tumor demonstrated local recurrence. Repeat resection was performed followed by immediate demonstration of local and distant tumor recurrence. Histologic analysis of the tumor demonstrated a myxoid mesenchymal tumor distinct from AFH. Fractionated stereotactic radiation therapy was administered after the second resection, and tumor control was achieved at 1 year. CONCLUSIONS: Intracranial myxoid mesenchymal tumor is a novel and rare entity that has been previously identified in only 10 cases. This case is particularly remarkable because it is only the second IMMT case to occur in a middle-aged adult and shares striking similarities in clinical presentation to the previously reported case. Given the aggressive recurrence seen with the presented case, we recommend the treatment plan to be surgical resection followed by adjuvant radiation therapy.

Myxoid glioneuronal tumor, PDGFRA p.K385-mutant: clinical, radiologic, and histopathologic features.

"Myxoid glioneuronal tumor, PDGFRA p.K385-mutant" is a recently described tumor entity of the central nervous system with a predilection for origin in the septum pellucidum and a defining dinucleotide mutation at codon 385 of the PDGFRA oncogene replacing lysine with either leucine or isoleucine (p.K385L/I). Clinical outcomes and optimal treatment for this new tumor entity have yet to be defined. Here, we report a comprehensive clinical, radiologic, and histopathologic assessment of eight cases. In addition to its stereotypic location in the septum pellucidum, we identify that this tumor can also occur in the corpus callosum and periventricular white matter of the lateral ventricle. Tumors centered in the septum pellucidum uniformly were associated with obstructive hydrocephalus, whereas tumors centered in the corpus callosum and periventricular white matter did not demonstrate hydrocephalus. While multiple patients were found to have ventricular dissemination or local recurrence/progression, all patients in this series remain alive at last clinical follow-up despite only biopsy or subtotal resection without adjuvant therapy in most cases. Our study further supports "myxoid glioneuronal tumor, PDGFRA p.K385-mutant" as a distinct CNS tumor entity and expands the spectrum of clinicopathologic and radiologic features of this neoplasm.

Intraventricular meningiomas frequently harbor NF2 mutations but lack common genetic alterations in TRAF7, AKT1, SMO, KLF4, PIK3CA, and TERT.

Intraventricular meningiomas (IVMs) account for less than 5% of all intracranial meningiomas; hence their molecular phenotype remains unknown. In this study, we were interested whether genetic alterations in IVMs differ from meningiomas in other locations and analyzed our institutional series with respect to clinical and molecular characteristics. A total of 25 patients with surgical removal of an IVM at our department between 1986 and 2018 were identified from our institutional database. Median progression-free survival (PFS) was 79 months (range of 2-319 months) and PFS at 5 years was 86%. Corresponding tumor tissue was available for 18 patients including one matching recurrence and was subjected to targeted panel sequencing of 130 selected genes frequently mutated in brain cancers by applying a custom hybrid capture approach on a NextSeq500 instrument. Loss of chromosome 22q and 1p occurred frequently in 89 and 44% of cases. Deleterious NF2 mutations were found in 44% of IVMs (n = 8/18). In non-NF2-mutated IVMs, previously reported genetic alterations including TRAF7, AKT1, SMO, KLF4, PIK3CA, and TERT were lacking, suggesting alternative genes in the pathogenesis of non-NF2 IVMs. In silico analysis revealed possible damaging mutations of APC, GABRA6, GSE1, KDR, and two SMO missense mutations differing from previously reported ones. Interestingly, all WHO°II IVMs (n = 3) harbored SMARCB1 and SMARCA4 mutations, indicating a role of the SWI/SNF chromatin remodeling complex in aggressive IVMs.

Intraventricular Pilocytic Astrocytoma With KIAA1549/BRAF Fusion Arising in a 44-Year Old.

Rare pilocytic astrocytomas (PA) have been described to arise in the ventricles of children. They are even less common in this location for the adult population. We present the case of a 44-year old man presenting with vision and mental status changes. Brain imaging revealed an intraventricular mass within the right ventricular atrium, most consistent with a meningioma. Microscopic examination revealed a neoplasm composed of elongated to plump bipolar astrocytes arranged in a fascicular architecture, accompanied by foci containing numerous Rosenthal fibers. By immunohistochemistry, the tumor cells were positive for vimentin and glial fibrillary acid protein, whereas negative for epithelial membrane antigen. Isocitrate dehydrogenase 1 (R132H) was also negative. By fluorescence in situ hybridization, we detected a KIAA1549/BRAF fusion gene. These findings supported the diagnosis of intraventricular PA arising in an adult.

A recurrent point mutation in PRKCA is a hallmark of chordoid gliomas.

Chordoid glioma (ChG) is a characteristic, slow growing, and well-circumscribed diencephalic tumor, whose mutational landscape is unknown. Here we report the analysis of 16 ChG by whole-exome and RNA-sequencing. We found that 15 ChG harbor the same PRKCA D463H mutation. PRKCA encodes the Protein kinase C (PKC) isozyme alpha (PKCα) and is mutated in a wide range of human cancers. However the hot spot PRKCA D463H mutation was not described in other tumors. PRKCA D463H is strongly associated with the activation of protein translation initiation (EIF2) pathway. PKCαD463H mRNA levels are more abundant than wild-type PKCα transcripts, while PKCαD463H is less stable than the PCKαWT protein. Compared to PCKαWT, the PKCαD463H protein is depleted from the cell membrane. The PKCαD463H mutant enhances proliferation of astrocytes and tanycytes, the cells of origin of ChG. In conclusion, our study identifies the hallmark mutation for chordoid gliomas and provides mechanistic insights on ChG oncogenesis.

A recurrent kinase domain mutation in PRKCA defines chordoid glioma of the third ventricle.

Chordoid glioma is a rare brain tumor thought to arise from specialized glial cells of the lamina terminalis along the anterior wall of the third ventricle. Despite being histologically low-grade, chordoid gliomas are often associated with poor outcome, as their stereotypic location in the third ventricle makes resection challenging and efficacious adjuvant therapies have not been developed. Here we performed genomic profiling on 13 chordoid gliomas and identified a recurrent D463H missense mutation in PRKCA in all tumors, which localizes in the kinase domain of the encoded protein kinase C alpha (PKCα). Expression of mutant PRKCA in immortalized human astrocytes led to increased phospho-ERK and anchorage-independent growth that could be blocked by MEK inhibition. These studies define PRKCA as a recurrently mutated oncogene in human cancer and identify a potential therapeutic vulnerability in this uncommon brain tumor.

Intraventricular Epithelioid Glioblastoma: A Case Report.

BACKGROUND: Epithelioid glioblastoma, a high-grade, diffuse astrocytic tumor variant, comprises closely packed epithelioid cells and rhabdoid cells. This rare tumor usually develops in the cerebral cortex and diencephalon; however, in the case reported here, it was located intraventricularly. CASE DESCRIPTION: A 47-year-old woman was referred to our hospital with a right intraventricular mass that had rapidly increased in size. On discovery of the tumor 3 years earlier at the referring hospital, the mass was small, calcified, and attached to the periventricular parenchyma. Over the next 2 years, the mass grew slowly, as observed on periodic magnetic resonance imaging scans. Forty days before the referral, the patient experienced headache and nausea, and marked growth and intratumoral hemorrhage were visible on a computed tomography scan of the head. The tumor was partially removed via a superior parietal lobule corticotomy. Histopathological examination confirmed an isocitrate dehydrogenase-wild-type epithelioid glioblastoma with a BRAF V600E mutation, but the original slow-growing lesion was no longer detected. Consequently, we assume that in this case, a low-grade glioma transformed into an aggressively malignant epithelioid glioblastoma. CONCLUSIONS: We present the first case of an intraventricular epithelioid glioblastoma that might have arisen from a low-grade glioma with calcification. We recommend including this tumor variant in the differential diagnosis of lateral ventricle tumors.

Intraventricular melanocytoma diagnosis confirmed by gene mutation profile.

Primary leptomeningeal melanocytic tumors (PLMTs) are rare. They usually arise along the spinal cord and at the skull base. Here we report on a patient with a very rare intraventricular melanocytoma. Histologically, a melanocytic tumor was clearly diagnosed. However, to make the uncommon diagnosis of an intraventricular melanocytoma, metastatic melanoma needed to be excluded. Next generation sequencing covering gene mutations that may occur in PLMTs and cutaneous melanoma was performed. The unique gene mutation profile detected, consisting of an activating CYSLTR2 L129Q mutation and EIF1AX G9R mutation and a lack of mutations in genes known to occur in metastatic melanoma (i.e. BRAF or NRAS) confirmed the diagnosis of an intraventricular melanocytoma. This case report is the second intraventricular melanocytoma published to date and demonstrates the value of applying novel genetic assays to make this diagnosis.

Giant Cell Ependymoma of Lateral Ventricle: Case Report, Literature Review, and Analysis of Prognostic Factors and Genetic Profile.

BACKGROUND: Giant cell ependymoma (GCE) is a rare primary central nervous system neoplasm. We report a case of GCE arising in the lateral ventricle. CASE DESCRIPTION: A 22-year-old female presented with generalized seizures. Magnetic resonance imaging demonstrated a diffuse, nonenhancing, multicystic mass centered in the atrium of the right lateral ventricle with extension throughout the frontal and temporal horns. An initial subtotal resection yielded the signature biphasic pattern of GCE. The dominant component contained pleomorphic, bizarre-appearing giant cells with low mitotic index, and a minor component comprised monomorphic, highly cellular, mitotically active cells that formed perivascular pseudorosettes. Array-comparative genomic hybridization showed copy number abnormalities consistent with chromosomal instability without evidence of RELA- or YAP1-fusion-features most often seen in posterior fossa ependymoma group B. Given expectedly poor radiation sensitivity, a second-look surgery was undertaken to minimize residual before proton beam radiotherapy. LITERATURE REVIEW: Review of the literature identified 28 reported cases, with a median age of 34 and bimodal peaks at approximately 20 and 50 years of age, including 9 supratentorial, 5 infratentorial, and 15 spinal ependymomas. Two infratentorial cases involved the fourth ventricle; no cases arose from the third or lateral ventricles. Supratentorial tumors predominated in younger patients, whereas other locations were observed among older patients (21.6 vs. 46.3 years of age; P = 0.01). Cases with Ki-67 index ≥10% showed worse progression-free survival than those of <10% (P = 0.049). CONCLUSION: Although rare, GCE should be considered in the differential of young patients with atypical intraventricular lesions, particularly given that extent of resection is associated with increased survival and GCE is thought to be radiation resistant.

Chordoid glioma of the third ventricle: report of a rapidly progressive case.

Chordoid gliomas are slowly growing third ventricular tumors that can be challenging to manage clinically. Rapid progression causing death has not been previously reported for this tumor type. We present and discuss a case of chordoid glioma that arose in a 46-year-old female who presented with progressive fatigue, headache, and altered mental status, attributable to severe hydrocephalus caused by a third ventricular mass. She underwent urgent subtotal resection and ventriculo-peritoneal shunt placements. Post-operative MRI noted residual tumor in the anterior resection cavity. An MRI performed 9 weeks later showed substantial progression, with marked tumor enlargement and compression of adjacent hypothalamic structures and the optic chiasm. Despite a course of radiation therapy, the tumor continued to enlarge, and the patient died from tumor progression 7 months after initial presentation. Post-mortem exam demonstrated a mass that expanded the third ventricle and compressed adjacent hypothalamic, thalamic and suprasellar structures. Histologic and immunohistochemical studies confirmed a chordoid glioma and revealed multifocal coagulative necrosis and intravascular thrombosis, which are unusual in this tumor type. Cytogenomic microarray testing revealed numerous DNA copy number abnormalities, many of which had not previously been reported in this tumor. The pathologic and cytogenetic changes may correlate with the aggressive behavior of this chordoid glioma and can be pursued by future investigation of additional cases.

[Ectopic craniopharyngioma and Gardner's syndrome: Case report and literature review]. / Craneofaringioma ectópico y síndrome de Gardner: a propósito de un caso y revisión de la literatura.

INTRODUCTION: Craniopharyngioma accounts for around 3% of all primary tumours of the central nervous system. It is usually located in the suprasellar region, although it may also have an ectopic location. CASE REPORT: The case is presented on 29 year-old male who underwent surgery for a jaw osteoma when he was 19 years old and was subsequently diagnosed with Gardner's syndrome. He was admitted in our Hospital with right facial paresis and diplopia of one day onset. The examination showed mild right VII and VI cranial nerves paresis. Magnetic resonance imaging of the brain demonstrated a rounded solid and cystic lesion with well-defined contours of about 2cm in diameter filling the fourth ventricle. The patient underwent a posterior fossa craniotomy using a telovelar approach with complete removal of the tumour implanted at roof level of the fourth ventricle. The final histology of the tumour was reported as adamantinomatous craniopharyngioma. CONCLUSION: Craniopharyngioma may appear in another location other than the suprasellar region. Its atypical location may be related to Gardner syndrome by still unknown pathogenic mechanisms.

Subependymal giant cell astrocytoma in a genetically negative tuberous sclerosis complex adult: Case report.

INTRODUCTION: The well-described entity of Subependymal Giant Cell Astrocytoma (SEGA) in the setting of Tuberous Sclerosis Complex (TSC) is profound in current literature. It has been described in children as well as adults with or without identifiable clinical presentations of tuberous sclerosis. To our knowledge there has not been any report of a negative genetic workup of Tuberous Sclerosis Complex in an adult patient presenting with an isolated SEGA. CASE REPORT: We present a case of a 25-year-old female with no medical history who presented to the emergency room for headaches. Further workup included gadolinium enhanced MRI of the brain which revealed a homogenously enhancing mass in the left lateral ventricle with eccentric calcification and resultant obstructive hydrocephalus. A left frontal craniotomy with an interhemispheric transcallosal approach was taken for complete removal of the mass. DISCUSSION: Final pathological diagnosis was SEGA with suggestive cell population, positive GFAP and positive synaptophysin. Genetic testing included TSC1 (MLPA, DNA Sequencing) and TSC2 (MLPA, DNA Sequencing), which were all negative. The panel did not identify mutations associated with Tuberous Sclerosis. CONCLUSION: Rare cases of isolated SEGA have been reported in patients who do not have typical features of tuberous sclerosis, and may represent minimal penetrance of the disease with an attenuated phenotype. Negative genetic testing, as demonstrated, can be seen in adults with isolated SEGA. With a negative genetic workup of TSC, regular follow up may still be necessary; however this may prove to be low yield for identifying any TSC features in the future.

Histology and molecular aspects of central neurocytoma.

Central neurocytoma (CN) is a well-differentiated tumor of neural cells occurring within the ventricles. It is composed of monomorphic cells with round, regular nuclei within clear cytoplasm and must be distinguished from other clear cell tumors. Immunohistochemical markers of CN that aid in diagnosis include synaptophysin and neuronal nuclear antigen. The molecular biology of these tumors is becoming increasingly elucidated, particularly with the use of microarray analyses. Several oncogenic pathways have been suggested by these studies. Although progress continues to be made, knowledge of CN has yet to dictate targeted therapies in treating patients with these tumors.

FGFR1 mutations in Rosette-forming glioneuronal tumors of the fourth ventricle.

Rosette-forming glioneuronal tumors (RGNTs) are rare glioneuronal tumors of the fourth ventricle region that preferentially affect young adults. Despite their histologic similarity with pilocytic astrocytomas (PAs), RGNTs do not harbor KIAA1549-BRAF fusions or BRAF mutations, which represent the most common genetic alteration in PAs. Recently, mutations affecting the hotspot codons Asn546 and Lys656 of fibroblast growth factor receptor 1 (FGFR1) have been described in PAs. They are considered to be the most frequent mechanism of mitogen-activated protein kinase activation, alternative to KIAA1549-BRAF fusion and BRAF mutations. To uncover possible molecular similarities between RGNTs and PAs, we performed a mutational study of FGFR1 in 8 RGNTs. An FGFR1 N546K mutation and an FGFR1 K656E mutation were found in the tumors of 2 patients. Notably, the patient with an FGFR1 K656E mutated RGNT had undergone a resection of a diencephalic pilocytic astrocytoma with pilomyxoid features 5 years before the discovery of the fourth ventricle tumor; the mutational analysis uncovered the presence of the same FGFR1 K656E mutation in the diencephalic tumor. These results indicate that, in addition to histologic similarities, at least a subgroup of RGNTs may show close molecular relationships with PAs. Whether FGFR1 mutated RGNTs represent a specific subset of this rare tumor entity remains to be determined.

Simultaneous subependymomas in monozygotic female twins: further evidence for a common genetic or developmental disorder background.

In this paper, a rare case of subependymoma of the fourth ventricle in identical female twins is reported. Magnetic resonance imaging and CT showed nearly identical locations of the tumors in the fourth ventricle and similar growth patterns of the tumors in both sisters. Likewise, postoperative histopathological analysis of both tumors revealed the typical histological appearance of subependymomas. Subependymoma is a rare, low-grade glioma of the CNS, slowly growing and usually asymptomatic. If symptomatic, a subependymoma can in some cases lead to sudden death caused by pressure on the brainstem or decompensated secondary hydrocephalus. This case demonstrates the importance of detecting tumors early and thereby preventing symptoms arising from increasing intracranial pressure, and optimizing therapy options.

Coexpression of glial and neuronal markers in the neurocytic rosettes of rosette-forming glioneuronal tumors.

Rosette-forming glioneuronal tumor of the fourth ventricle (RGNT) is a new entity in the WHO 2007 Classification of Tumors of the Central Nervous System. RGNT has two components: neurocytic rosettes and low-grade gliomas. Neurocytic rosettes are conventionally described as consisting of uniform neurocytes. However, some studies have reported rosette-forming tumor cells that expressed glial markers such as Olig2. We indicated the expression of glial markers including Olig2, cyclinD1, glial fibrillary acidic protein (GFAP), and platelet-derived growth factor receptor alpha (PDGFRα) in the neurocytic rosettes in our previous study, and we suggested that these tumor cells had a heterogeneous nature. In this study, we used double and triple immunostaining to demonstrate that these tumor cells have both glial and neuronal characteristics. We found that rosette-forming tumor cells coexpressed Olig2/cyclinD1 and synaptophysin. Furthermore, the cores of the rosettes coexpressed GFAP/PDGFRα in the peripheral zone and synaptophysin in the central zone. These findings imply that rosette-forming tumor cells have a similar nature to neuronal-glial progenitor cells, and we believe that the nomination "neurocytic rosette" may be unsuitable given their heterogeneous nature. Our study appears to clarify some of the properties of RGNT tumor cells and may help elucidate the histogenesis of RGNT.

Cribriform neuroepithelial tumor arising in the lateral ventricle.

Cribriform neuroepithelial tumor (CRINET) is a recently recognized central nervous system neoplasm that arises in the ventricles of young children and is characterized by primitive, non-rhabdoid SMARCB1-deficient cells with prominent cribriform architecture. We report a 14-month-old male who presented with signs of increased intracranial pressure. Neuroimaging revealed a large solid and cystic mass in the lateral ventricle. Tumor cells were small, primitive appearing, and arranged in cribriform and trabecular patterns with interspersed solid cellular areas. Rhabdoid cells were absent. Immunohistochemical staining showed no SMARCB1 (INI11, BAF47, hSNF5) expression and strong epithelial membrane antigen (EMA) immunoreactivity along luminal surfaces. Electron microscopy showed epithelial characteristics, including abundant basal lamina. Genetic analysis of the tumor revealed deletion of 1 SMARCB1 allele, while the other contained an intronic point mutation predicted to disrupt splicing. This case further illustrates the distinct histopathologic and molecular genetic features of CRINET and identifies distinctive ultrastructural features.

Subependymal nodules and giant cell tumours in tuberous sclerosis complex patients: prevalence on MRI in relation to gene mutation.

PURPOSE: The purpose of this study was to estimate the association among the presence of subependymal nodules (SENs), subependymal giant cell tumours (SGCTs) and gene mutation in tuberous sclerosis complex (TSC) patients. METHODS: Clinical records and images of 81 TSC patients were retrospectively reviewed by two neuroradiologists in consensus. All patients were assessed for gene mutations and were categorized as TSC1 or TSC2 mutation carriers, or no-mutations-identified (NMI) patients. They underwent a brain magnetic resonance imaging (MRI) using 0.1 mmol/kg of gadobutrol. Any enhancing SEN ≥ 1 cm and placed near the foramen of Monro was considered SGCT. Two MRI follow-up exams for each patient with SGCT were evaluated to assess tumour growth using Wilcoxon and chi-squared tests. RESULTS: Of 81 patients, 44 (54%) were TSC2 mutation carriers, 20 (25%) TSC1 and 17 (21%) NMI. Nine (11%) had a unilateral and three (4%) a bilateral SGCT. Fifty of 81 patients (62%) showed at least one SEN. None of the 31 patients without SEN showed SGCTs, whilst 12 (24%) of the 50 patients with at least one SEN showed SGCTs (p = 0.003). The association between the presence of SGCT or SEN and gene mutation was not significant (p = 0.251 and p = 0.187, respectively). At follow-up, the median SGCT diameter increased from 14 to 15 mm (p = 0.017), whilst the median SGCT volume increased from 589 to 791 mm(3) (p = 0.006). CONCLUSIONS: TSC patients with SENs are more likely to present with SGCT than those without SENs, in particular for TSC2 mutation carriers. The SGCT growth rate may be missed if based on the diameter instead of on the volume.

Absence of KIAA1549-BRAF fusion in rosette-forming glioneuronal tumors of the fourth ventricle (RGNT).

Rosette-forming glioneuronal tumors (RGNT) of the fourth ventricle are rare mixed glioneuronal tumors included in the revised WHO classification of central nervous system tumors, showing partial histological similarities to pilocytic astrocytomas. To evaluate potential similarities at the molecular level between these tumors, we analysed a series of 10 RGNT for the presence of KIAA1549-BRAF fusions using interphase fluorescence in situ hybridisation. However, we found no cases showing KIAA1549-BRAF gene fusion or BRAF (V600E) mutation. Our data support the hypothesis that RGNT may represent a distinct entity among the glioneuronal tumors of the central nervous system, with molecular features different from pilocytic astrocytomas.