Transformation of IDH-wildtype glioblastoma to gliosarcoma with features of osteosarcoma.

Gliosarcoma (GS) is a rare variant of IDH-wildtype glioblastoma. It is classified as grade 4 in the latest WHO CNS classification of both glial and mesenchymal components. Gliosarcoma may arise de novo or secondary from glioblastoma. It occurs in up to 2% of patients diagnosed with glioblastoma. We present a case report of a 51-year-old patient who was initially diagnosed with glioblastoma multiforme, which transformed into secondary gliosarcoma with an osteosarcoma component 16 months after the initial diagnosis. We believe that increasing reporting of secondary gliosarcoma (sGS) will be helpful in understanding, diagnosing and providing more effective treatment for this cancer.

Molecular signature of stem-like glioma cells (SLGCs) from human glioblastoma and gliosarcoma.

Glioblastoma multiforme (GBM) and the GBM variant gliosarcoma (GS) are among the tumors with the highest morbidity and mortality, providing only palliation. Stem-like glioma cells (SLGCs) are involved in tumor initiation, progression, therapy resistance, and relapse. The identification of general features of SLGCs could contribute to the development of more efficient therapies. Commercially available protein arrays were used to determine the cell surface signature of eight SLGC lines from GBMs, one SLGC line obtained from a xenotransplanted GBM-derived SLGC line, and three SLGC lines from GSs. By means of non-negative matrix factorization expression metaprofiles were calculated. Using the cophenetic correlation coefficient (CCC) five metaprofiles (MPs) were identified, which are characterized by specific combinations of 7-12 factors. Furthermore, the expression of several factors, that are associated with GBM prognosis, GBM subtypes, SLGC differentiation stages, or neural identity was evaluated. The investigation encompassed 24 distinct SLGC lines, four of which were derived from xenotransplanted SLGCs, and included the SLGC lines characterized by the metaprofiles. It turned out that all SLGC lines expressed the epidermal growth factor EGFR and EGFR ligands, often in the presence of additional receptor tyrosine kinases. Moreover, all SLGC lines displayed a neural signature and the IDH1 wildtype, but differed in their p53 and PTEN status. Pearson Correlation analysis identified a positive association between the pluripotency factor Sox2 and the expression of FABP7, Musashi, CD133, GFAP, but not with MGMT or Hif1α. Spherical growth, however, was positively correlated with high levels of Hif1α, CDK4, PTEN, and PDGFRß, whereas correlations with stemness factors or MGMT (MGMT expression and promoter methylation) were low or missing. Factors highly expressed by all SLGC lines, irrespective of their degree of stemness and growth behavior, are Cathepsin-D, CD99, EMMPRIN/CD147, Intß1, the Galectins 3 and 3b, and N-Cadherin.

An autopsy case of primary gliosarcoma with multiple extracranial metastases: pathology after administration of bevacizumab and genetic profile.

Gliosarcoma (GS), a morphological variant of glioblastoma, pathologically shows a biphasic pattern with gliomatous and sarcomatous components. It has been reported that GS has much higher metastatic capacity than glioblastoma. A few reports on the pathology of the extracranial metastasis of GS have shown that metastatic lesions had a sarcomatous component alone or a mixture of gliomatous and sarcomatous ones. Therefore, it is considered that GS tends to disseminate hematogenously due to its mesenchymal sarcomatous component. Herein, we report an autopsy case of GS with multiple extracranial metastases treated by craniotomy, radiotherapy, and bevacizumab. In this case, metastatic lesions at autopsy contained a gliomatous component alone, but no sarcomatous component. In addition, the sarcomatous component disappeared from the intracranial lesion at autopsy after the administration of bevacizumab. In this report, we discuss the clinical course and pathological findings at the initial state, recurrence, and autopsy, including the results of whole-genome analysis.

Gliosarcoma with extensive extracranial metastatic spread and familial coincidence: A case report.

Gliosarcoma is a rare histopathological subtype of glioblastoma. Metastatic spreading is unusual. In this report, we illustrate a case of gliosarcoma with extensive extracranial metastases with confirmation of histological and molecular concordance between the primary tumor and a metastatic lesion of the lung. Only the autopsy revealed the extent of metastatic spread and the hematogenous pattern of metastatic dissemination. Moreover, the case bared a familial coincidence of malignant glial tumors as the patient's son was diagnosed with a high-grade glioma shortly after the patient's death. By molecular analysis (Sanger and next generation panel sequencing), we could confirm that both patient's tumors carried mutations in the TP53 gene. Interestingly, the detected mutations were located in different exons. Altogether, this case draws attention to the fact that sudden clinical aggravation could be caused by the rare phenomenon of metastatic spread and should therefore be always taken into consideration, even at an early disease stage. Furthermore, the presented case highlights the contemporary value of autoptic pathological examination.

Gliosarcoma with unusual glial components: Two case reports.

Gliosarcoma is characterized by the presence of alternating lesions of glial and mesenchymal components. Although many mesenchymal components have been reported, there are few reports on glial components. We here report two cases of gliosarcoma. Case 1 was a 42-year-old woman with right hemiparesis and motor aphasia. Magnetic resonance imaging (MRI) identified a tumor in the left frontal lobe. Pathological analysis of the tumor removal specimen revealed gliosarcoma, with a glial component resembling pleomorphic xanthoastrocytoma. Postoperatively, radiotherapy and chemotherapy were conducted, and the patient was symptom-free over 12 months after surgery. Case 2 was a 67-year-old woman with a consciousness disorder and left hemiparesis. MRI revealed a tumor in the right frontal lobe. Pathological analysis of the first tumor removal specimen identified gliosarcoma, with a glial component characterized by large tumor cells. Additionally, the Ki-67 labeling index of the glial component was greater than that of the mesenchymal component, and molecular genetic analysis disclosed a mutation in the telomerase reverse transcriptase (TERT) gene (TERT). Chemotherapy and radiotherapy were performed. Four months later, MRI revealed recurrence, and the second surgery was performed. Pathological analysis revealed giant cell glioblastoma without TERT mutation. The patient died due to tumor progression 12 months after the first surgery. It is essential to continue histopathological evaluation of glial components, and further genetic evaluation on gliosarcoma is required.

Primary versus secondary gliosarcoma: a systematic review and meta-analysis.

INTRODUCTION: Gliosarcomas are extremely rare malignant brain tumors, which can be classified as primary gliosarcoma (PGS) if the tumors arise de novo or secondary gliosarcoma (SGS) in patients who had previously been treated for glioblastoma. Given their rarity, it is unclear if PGS is clinically and genetically different from SGS. This meta-analysis aimed to investigate the clinicopathological features, prognostic survivals, and molecular profiles of these rare tumors. METHODS: We searched PubMed and Web of Science for relevant studies. Odds ratio (OR), hazard ratio (HR), and their 95% confidence intervals (CI) were pooled using the random-effect model. RESULTS: We included eight studies with 239 PGS and 79 SGS for meta-analyses. Compared to PGS, SGS occurred at a younger age and had lower rates of gross total resection and radiation therapy. Bevacizumab was more commonly administered in SGS. SGS patients had a significantly worse PFS (HR 0.60; 95% CI 0.40-0.89) and OS (HR 0.46; 95% CI 0.31-0.68) in comparison to PGS. The incidences of EGFR mutation, IDH mutation, and MGMT methylation were not statistically different between PGS and SGS. CONCLUSION: Our results demonstrated that PGS and SGS had distinct clinicopathological profiles and prognoses but shared similar genetic profiles. This study facilitates our understanding of how these two malignant brain tumors behave clinically, but future studies will be required to elucidate the genetic pathways of PGS and SGS.

Gliosarcoma: The Distinct Genomic Alterations Identified by Comprehensive Analysis of Copy Number Variations.

Gliosarcoma (GSM), a histologic variant of glioblastoma (GBM), carries a poor prognosis with less than one year of median survival. Though GSM is similar with GBM in most clinical and pathological symptoms, GBM has unique molecular and histological features. However, as the rarity of GSM samples, the genetic information of this tumor is still lacking. Here, we take a comprehensive analysis of DNA copy number variations (CNV) in GBM and GSM. Whole genome sequencing was performed on 21 cases of GBM and 15 cases of GSM. CNVKIT is used for CNV calling. Our data showed that chromosomes 7, 8, 9, and 10 were the regions where CNV frequently happened in both GBM and GSM. There was a distinct CNV signal in chromosome 2 especially in GSM. The pathway enrichment of genes with CNV was suggested that the GBM and GSM shared the similar mechanism of tumor development. However, the CNV of some screened genes displayed a disparate form between GBM and GSM, such as AMP, BEND2, HDAC6, FOXP3, ZBTB33, TFE3, and VEGFD. It meant that GSM was a distinct subgroup possessing typical biomarkers. The pathways and copy number alterations detected in this study may represent key drivers in gliosarcoma oncogenesis and may provide a starting point toward targeted oncologic analysis with therapeutic potential.

Survival outcomes associated with MGMT promoter methylation and temozolomide in gliosarcoma patients.

PURPOSE: Gliosarcoma is an uncommon glioblastoma subtype, for which MGMT promoter methylation's relationship with response to temozolomide chemotherapy is unclear. We therefore examined this question using a national cohort. METHODS:  The National Cancer Database was queried for patients histopathologically diagnosed with gliosarcoma between 2010 and 2019. The associations between MGMT promoter methylation, first-line single-agent chemotherapy-presumed to be temozolomide herein-and overall survival (OS) were examined using log-rank tests and Cox regression, with correction for multiple testing (p < 0.01 was significant). RESULTS: 580 newly-diagnosed gliosarcoma patients with MGMT status were available, among whom 33.6% were MGMT promoter methylated. Median OS for gliosarcoma patients that received standard-of-care temozolomide and radiotherapy was 12.1 months (99% confidence interval [CI] 10.8-15.1) for MGMT promoter unmethylated and 21.4 months (99% CI 15.4-26.2) for MGMT promoter methylated gliosarcomas (p = 0.003). In multivariable analysis of gliosarcoma patients-which included the potential confounders of age, sex, maximal tumor size, extent of resection, and radiotherapy-receipt of temozolomide was associated with improved OS in both MGMT promoter methylated (hazard ratio [HR] 0.23 vs. no temozolomide, 99% CI 0.11-0.47, p < 0.001) and unmethylated (HR 0.50 vs. no temozolomide, 99% CI 0.29-0.89, p = 0.002) gliosarcomas. MGMT promoter methylation was associated with improved OS among temozolomide-treated gliosarcoma patients (p < 0.001), but not in patients who did not receive chemotherapy (p = 0.35). CONCLUSION: In a national analysis of gliosarcoma patients, temozolomide was associated with prolonged OS irrespective of MGMT status. These results provide support for the current practice of trimodal therapy for gliosarcoma.

Can a signature molecular-profile define disparate survival in BRAF-positive Gliosarcoma and identify novel targets for therapeutic intervention?

Purpose: Gliosarcoma (GS) has a low incidence but is aggressively invasive, with poor-survival. Even though GS is recognized as a different subgroup from glioblastoma (GB), there is no molecular panel available to define its clinical outcome. The objective was to identify the molecular imprint of GS in terms of expression of human telomerase reverse transcriptase (hTERT), high mobility group A1 (HMGA-1), kinesin superfamily protein-14 (KIF-14), epidermal growth factor receptor (EGFR) markers with reference to disparate prognosis and identify plausible targets for intervention. Materials and Methods: We retrieved 9-GS samples from a cohort of 57-GB patients during a 36 months study period and compared them with 10 molecularly typed GB-samples and 15 controls. Conventional-immunohistochemistry (IHC) was used for histopathology of GS and immunofluorescence-IHC was performed for quantification of identified marker-panel. Statistical tools for non-parametric data were used for inferring results. Results: GS was confirmed by reticulin-staining and positivity for glial fibrillary acidic protein, Vimentin, smooth muscle actin. Immune-reactivity for BRAF-V600Ewas present in both glial and sarcomatous cells and negative expression of isocitrate dehydrogenase, ATRX, TP53.Comparison between GS, GB, and control tissues showed that the expression of markers reached significance (P < 0.0001), without the influence of confounders. Significant correlation of EGFR was found with hTERT (r = 0.77), HMGA-1 (r = 0.72), KIF-14 (r = 0.82) suggesting that their combined analysis can define prognosis. To establish the diagnostic accuracy (threshold ≥80% specificity), AUC for EGFR was 0.78 (>3.95), KIF-14 0.97 (>7.45), hTERT 0.63 (>23.86), and HMGA-1 0.53 (>15.45). Conclusion: This is the first evidence-based investigation presenting differential expression of proliferation and stemness markers hTERT, HMGA-1, KIF-14 in-correlation with EGFR, indicating a plausible-association between survival and disease-progression in individual GS-cases. It can serve as a model for further studies in this glioma-subgroup and the designing of a target panel for personalized treatment.

Gliosarcoma with osteosarcomatous component: A case report and short review illustration.

BACKGROUND: Gliosarcoma (GS) represents a rare variant of glioblastoma in the central nervous system, characterized by biphasic histopathological features of gliomatous and sarcomatous components. Here, we present an unusual case of GS, which also demonstrated osteosarcomatous differentiation. CASE PRESENTATION: A 65-year-old female patient underwent gross total resection (GTR) of the right temporal lobe lesion. Subsequently received 60 Gy external beam radiation therapy and chemotherapy. Postoperative histopathological analysis indicated that the sarcomatous portion of the typical fibrosarcoma pattern mingled with areas of osteoid structure. The molecular pathological analysis demonstrated IDH1/2 wild-type and MGMT promoter island methylated phenotype. Target Enrichment Sequencing (TES) was performed on the gliomatous and sarcomatous components of the tumor tissues. TERT promoter, RB1, NF1, TP53 mutations and copy number variations (CNVs) on chromosome 7, 10q, 11q, 12, 13, 17 and 22 were observed in gliomatous and fibro-sarcomatous mixed tumor tissue; While we found TERT promoter, RB1, TP53 mutations and CNVs on chromosome 2q, 3q, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19 and 22 in osteosarcomatous component. Noteworthy, EGFR amplification was not observed in both gliomatous/fibro-sarcomatous and osteosarcomatous components. CONCLUSIONS: Integrated with histopathology, molecular pathology, and genomic alteration analysis, we report a case of GS with an extremely rare histopathologic phenotype of osteosarcomatous differentiation, who also suffered lung multi-metastases. Additionally, synthesizing the literature review, our study of this unusual differentiation of GS into osteosarcoma may provide novel insight into the natural history of GS.

Chasing a rarity: a retrospective single-center evaluation of prognostic factors in primary gliosarcoma.

BACKGROUND AND PURPOSE: Primary gliosarcoma (GS) is a rare variant of IDH-wildtype glioblastoma multiforme. We performed a single-center analysis to identify prognostic factors. PATIENTS AND METHODS: We analyzed the records of 26 patients newly diagnosed with primary WHO grade IV GS. Factors of interest were clinical and treatment data, as well as molecular markers, time to recurrence, and time to death. RESULTS: Median follow-up was 9 months (range 5-21 months). Gross total resection did not lead to improved survival, most likely due to the relatively small sample size. Low symptom burden at the time of diagnosis was associated with longer PFS (P = 0.023) and OS (P = 0.018). Median OS in the entire cohort was 12 months. Neither MGMT promoter hypermethylation nor adjuvant temozolomide therapy influenced survival, consistent with some previous reports. CONCLUSION: In this retrospective study, patients exhibiting low symptom burden at diagnosis showed improved survival. None of the other factors analyzed were associated with an altered outcome.

Genetic alteration and clonal evolution of primary glioblastoma into secondary gliosarcoma.

AIMS: Secondary gliosarcoma (SGS) rarely arises post treatment of primary glioblastoma multiforme (GBM), and contains gliomatous and sarcomatous components. The origin and clonal evolution of SGS sarcomatous components remain uncharacterized. Therapeutic radiation is mutagenic and can induce sarcomas in patients with other tumor phenotypes, but possible causal relationships between radiotherapy and induction of SGS sarcomatous components remain unexplored. Herein, we investigated the clonal origin of SGS in a patient with primary GBM progressing into SGS post-radiochemotherapy. METHODS: Somatic mutation profile in GBM and SGS was examined using whole-genome sequencing and deep-whole-exome sequencing. Mutation signatures were characterized to investigate relationships between radiochemotherapy and SGS pathogenesis. RESULTS: A mutation cluster containing two founding mutations in tumor-suppressor genes NF1 (variant allele frequency [VAF]: 50.0% in GBM and 51.1% in SGS) and TP53 (VAF: 26.7% in GBM and 50.8% in SGS) was shared in GBM and SGS. SGS exhibited an overpresented C>A (G>T) transversion (oxidative DNA damage signature) but no signature 11 mutations (alkylating-agents - exposure signature). Since radiation induces DNA lesions by generating reactive oxygen species, the mutations observed in this case of SGS were likely the result of radiotherapy rather than chemotherapy. CONCLUSIONS: Secondary gliosarcoma components likely have a monoclonal origin, and the clone possessing mutations in NF1 and TP53 was likely the founding clone in this case of SGS.

Genomic landscape of gliosarcoma: distinguishing features and targetable alterations.

Gliosarcoma is an aggressive brain tumor with histologic features of glioblastoma (GBM) and soft tissue sarcoma. Despite its poor prognosis, its rarity has precluded analysis of its underlying biology. We used a multi-center database to characterize the genomic landscape of gliosarcoma. Sequencing data was obtained from 35 gliosarcoma patients from Genomics Evidence Neoplasia Information Exchange (GENIE) 5.0, a database curated by the American Association of Cancer Research (AACR). We analyzed genomic alterations in gliosarcomas and compared them to GBM (n = 1,449) and soft tissue sarcoma (n = 1,042). 30 samples were included (37% female, median age 59 [IQR: 49-64]). Nineteen common genes were identified in gliosarcoma, defined as those altered in > 5% of samples, including TERT Promoter (92%), PTEN (66%), and TP53 (60%). Of the 19 common genes in gliosarcoma, 6 were also common in both GBM and soft tissue sarcoma, 4 in GBM alone, 0 in soft tissue sarcoma alone, and 9 were more distinct to gliosarcoma. Of these, BRAF harbored an OncoKB level 1 designation, indicating its status as a predictive biomarker of response to an FDA-approved drug in certain cancers. EGFR, CDKN2A, NF1, and PTEN harbored level 4 designations in solid tumors, indicating biological evidence of these biomarkers predicting a drug-response. Gliosarcoma contains molecular features that overlap GBM and soft tissue sarcoma, as well as its own distinct genomic signatures. This may play a role in disease classification and inclusion criteria for clinical trials. Gliosarcoma mutations with potential therapeutic indications include BRAF, EGFR, CDKN2A, NF1, and PTEN.

Gliosarcoma with PNET features mimicking a metastatic neuroendocrine carcinoma: A diagnostic dilemma.

OBJECTIVE: Gliosarcomas (GS) comprise ~ 2 - 8% of glioblastomas and are associated with a similar poor prognosis. GS have rarely been found with a primitive neuroectodermal component (PNET). We present a case of gliosarcoma with PNET features (GS-PNET) that mimicked a neuroendocrine carcinoma on initial biopsy. MATERIALS AND METHODS: A 68-year-old male presented with 2 weeks of increasing headaches and difficulties with reading, writing, and word-finding. He was found to have a left-sided parieto-occipital heterogeneously enhancing mass. RESULTS: Pathologic analysis after surgical resection initially diagnosed a poorly differentiated carcinoma with neuroendocrine features, and adjuvant therapy was guided by this diagnosis as well as systemic imaging, which was suggestive of gastrointestinal primary malignancy with central nervous system (CNS) metastasis. Subsequent progression and re-resection established a diagnosis of GS with PNET component. Genomic profiling showed shared PTEN, TERT promotor, and TP53 mutations in the original and recurrent tumors. CONCLUSION: There have only been 5 previously reported cases of GS-PNET, to our knowledge, with this case representing the first with comprehensive molecular profiling. The case also highlights the importance of further work-up of presumed metastatic carcinoma with indeterminate immunostaining and/or suspected non-epithelioid component.

Gliosarcoma vs. glioblastoma: a retrospective case series using molecular profiling.

BACKGROUND: Gliosarcoma (GS) refers to the presence of mesenchymal differentiation (as seen using light microscopy) in the setting of glioblastoma (GB, an astrocytoma, WHO Grade 4). Although the same approach to treatment is typically adopted for GS and GB, there remains some debate as to whether GS should be considered a discrete pathological entity. Differences between these tumors have not been clearly established at the molecular level. METHODS: Patients with GS (n=48) or GB (n=1229) underwent molecular profiling (MP) with a pan-cancer panel of tests as part of their clinical care. The methods employed included next-generation sequencing (NGS) of DNA and RNA, copy number variation (CNV) of DNA and immunohistochemistry (IHC). The MP comprised 1153 tests in total, although results for each test were not available for every tumor profiled. We analyzed this data retrospectively in order to determine if our results were in keeping with what is known about the pathogenesis of GS by contrast with GB. We also sought novel associations between the MP and GS vs. GB which might improve our understanding of pathogenesis of GS. RESULTS: Potentially meaningful associations (p<0.1, Fisher's exact test (FET)) were found for 14 of these tests in GS vs. GB. A novel finding was higher levels of proteins mediating immuno-evasion (PD-1, PD-L1) in GS. All of the differences we observed have been associated with epithelial-to-mesenchymal transition (EMT) in other tumor types. Many of the changes we saw in GS are novel in the setting of glial tumors, including copy number amplification in LYL1 and mutations in PTPN11. CONCLUSIONS: GS shows certain characteristics of EMT, by contrast with GB. Treatments targeting immuno-evasion may be of greater therapeutic value in GS relative to GB.

Secondary gliosarcoma: the clinicopathological features and the development of a patient-derived xenograft model of gliosarcoma.

BACKGROUND: Gliosarcoma (GSM) is a distinct and aggressive variant of glioblastoma multiforme (GBM) with worse prognosis and few treatment options. It is often managed with the same treatment modalities with temozolomide (TMZ) as in GBM. However, the therapeutic benefits on GSM from such treatment regimen is largely unknown. Patient-derived xenograft (PDX) models have been used widely to model tumor progression, and subsequently to validate biomarkers and inform potential therapeutic regimens. Here, we report for the first time the successful development of a PDX model of secondary GSM. METHODS: Tissue obtained from a tumor resection revealed a secondary GSM arising from GBM. The clinical, radiological, and histopathological records of the patient were retrospectively reviewed. Samples obtained from surgery were cultured ex vivo and/or implanted subcutaneously in immunocompromised mice. Histopathological features between the primary GBM, secondary GSM, and GSM PDX are compared. RESULTS: In explant culture, the cells displayed a spindle-shaped morphology under phase contrast microscopy, consistent with the sarcomatous component. GSM samples were subcutaneously engrafted into immunocompromised mice after single-cell suspension. Xenografts of serial passages showed enhanced growth rate with increased in vivo passage. We did not observe any histopathological differences between the secondary GSM and its serial in vivo passages of PDX tumors. CONCLUSIONS: Our PDX model for GSM retained the histopathological characteristics of the engrafted tumor from the patient. It may provide valuable information to facilitate molecular and histopathological modelling of GSM and be of significant implication in future research to establish precise cancer medicine for this highly malignant tumor.

Pediatric Gliosarcoma With and Without Neurofibromatosis Type 1: A Whole-exome Comparison of 2 Patients.

Gliosarcoma is rare among pediatric patients and among individuals with Neurofibromatosis Type 1 (NF1). Here we compare 2 pediatric gliosarcoma patients, one of whom has NF1. We performed whole-exome sequencing, methylation, and copy number analysis on tumor and blood for both patients. Whole-exome sequencing showed higher mutational burden in the tumor of the patient without NF1. Copy number analysis showed differences in chromosomal losses/gains between the tumors. Neither tumor showed O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. The NF1 patient survived without progression while the other expired. This is the first reported case of gliosarcoma in a child with NF1.

A rare case of BRAF V600E-mutated epithelioid glioblastoma with a sarcomatous component.

Epithelioid glioblastoma is a rare subtype of glioblastoma, but the coexistence of a sarcomatous component is even rarer. An 80-year-old woman was admitted to our hospital with somnolence. Magnetic resonance imaging revealed a cystic lesion with a solid component in the left temporal-parietal lobe. Histopathological examination of the resected tumor revealed three components; namely, typical glioblastoma, sarcomatous and epithelioid components at a ratio of about 5:3:2. All components were immunohistochemically positive for vimentin and mutated BRAF (V600E) and showed focal expression of glial fibrillary acidic protein and cytokeratin AE1/AE3, but they were negative for isocitrate dehydrogenase 1. Genetic analysis revealed that both the sarcomatous and epithelioid components harbored BRAF T1799A (V600E) mutation and homozygous deletion of cyclin-dependent kinase inhibitor 2A/B. We diagnosed this tumor as epithelial glioblastoma with a sarcomatous component. Our results indicate that even when the epithelial component is not dominant, immunohistochemical and genetic investigation of BRAF mutations is useful for the diagnosis of glioblastoma subtypes. In particular, although the prognosis of epithelial glioblastoma is poor, potentially effective targeted therapies for BRAF V600E-mutated tumors are available.

The Coexistence of Gliosarcoma and Arteriovenous Malformation with the BRAF V600E Mutation.

BACKGROUND: The authors report a case of a woman aged 33 years who suffered from the combination of primary gliosarcoma and arteriovenous malformation as the first clinical presentation of intracranial hemorrhage. CASE DESCRIPTION: Subsequently, gene examination rarely finds BRAF V600E mutation in the surgical specimen. The lesion was not completely identified with magnetic resonance imaging and digital subtraction angiography. CONCLUSIONS: This case illustrates the occult and unusual feature of gliosarcoma. The pathogenesis of such coexistence might be related to underlying genetic alterations.

Gliosarcoma: distinct molecular pathways and genomic alterations identified by DNA copy number/SNP microarray analysis.

PURPOSE: Gliosarcoma is a histologic variant of glioblastoma (GBM), and like GBM carries a poor prognosis. Median survival is less than one (1) year with less than 5% of patients alive after 5 years. Although there is no cure, standard treatment includes surgery, radiation and chemotherapy. While very similar to GBM, gliosarcoma exhibits several distinct differences, morphologically and molecularly. Therefore, we report a comprehensive analysis of DNA copy number changes in gliosarcoma using a cytogenomic DNA copy number (CN) microarray (OncoScan®). METHODS: Cytogenomic DNA copy number microarray (OncoScan®) was performed on 18 cases of gliosarcoma. MetaCore™ enrichment was applied to the array results to detect associated molecular pathways. RESULTS: The most frequent alteration was copy number loss, comprising 57% of total copy number changes. The number of losses far exceeded the number of amplifications (***, < 0.001) and loss of heterozygosity events (***, < 0.001). Amplifications were infrequent (4.6%), particularly for EGFR. Chromosomes 9 and 10 had the highest number of losses; a large portion of which correlated to CDKN2A/B loss. Copy number gains were the second most common alteration (26.2%), with the majority occurring on chromosome 7. MetaCore™ enrichment detected notable pathways for copy number gains including: HOXA, Rho family of GTPases, and EGFR; copy number loss including: WNT, NF-kß, and CDKN2A; and copy number loss of heterozygosity including: WNT and p53. CONCLUSIONS: The pathways and copy number alterations detected in this study may represent key drivers in gliosarcoma oncogenesis and may provide a starting point toward targeted oncologic analysis with therapeutic potential.