ABSTRACT
Despite their unique histologic features, gliosarcomas belong to the group of glioblastomas and are treated according to the same standards. Fibroblast activation protein (FAP) is a component of a tumor-specific subpopulation of fibroblasts that plays a critical role in tumor growth and invasion. Some case studies suggest an elevated expression of FAP in glioblastoma and a particularly strong expression in gliosarcoma attributed to traits of predominant mesenchymal differentiation. However, the prognostic impact of FAP and its diagnostic and therapeutic potential remain unclear. Here, we investigate the clinical relevance of FAP expression in gliosarcoma and glioblastoma and how it correlates with 68Ga-FAP inhibitor (FAPI)-46 PET uptake. Methods: Patients diagnosed with gliosarcoma or glioblastoma without sarcomatous differentiation with an overall survival of less than 2.5 y were enrolled. Histologic examination included immunohistochemistry and semiquantitative scoring of FAP (0-3, with higher values indicating stronger expression). Additionally, 68Ga-FAPI-46 PET scans were performed in a subset of glioblastomas without sarcomatous differentiation patients. The clinical SUVs were correlated with FAP expression levels in surgically derived tumor tissue and relevant prognostic factors. Results: Of the 61 patients who were enrolled, 13 of them had gliosarcoma. Immunohistochemistry revealed significantly more FAP in gliosarcomas than in glioblastomas without sarcomatous differentiation of tumor tissue (P < 0.0001). In the latter, FAP expression was confined to the perivascular space, whereas neoplastic cells additionally expressed FAP in gliosarcoma. A significant correlation of immunohistochemical FAP with SUVmean and SUVpeak of 68Ga-FAPI-46 PET indicates that clinical tracer uptake represents FAP expression of the tumor. Although gliosarcomas express higher levels of FAP than do glioblastomas without sarcomatous differentiation, overall survival does not significantly differ between the groups. Conclusion: The analysis reveals a significant correlation between SUVmean and SUVpeak in 68Ga-FAPI-46 PET and immunohistochemical FAP expression. This study indicates that FAP expression is much more abundant in the gliosarcoma subgroup of glioblastomas. This could open not only a diagnostic but also a therapeutic gap, since FAP could be explored as a theranostic target to enhance survival in a distinct subgroup of high-risk brain tumor patients with poor survival prognosis.
Subject(s)
Glioblastoma , Gliosarcoma , Adult , Aged , Female , Humans , Male , Middle Aged , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Endopeptidases , Gelatinases/metabolism , Glioblastoma/diagnostic imaging , Glioblastoma/metabolism , Glioblastoma/pathology , Gliosarcoma/diagnostic imaging , Gliosarcoma/metabolism , Gliosarcoma/pathology , Membrane Proteins/metabolism , Positron-Emission Tomography , Prognosis , Quinolines , Serine Endopeptidases/metabolism , Survival AnalysisABSTRACT
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.
Subject(s)
Brain Neoplasms , Glioblastoma , Gliosarcoma , Isocitrate Dehydrogenase , Osteosarcoma , Humans , Glioblastoma/genetics , Glioblastoma/pathology , Gliosarcoma/genetics , Gliosarcoma/pathology , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Osteosarcoma/genetics , Osteosarcoma/pathology , Middle Aged , Isocitrate Dehydrogenase/genetics , MaleABSTRACT
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.
Subject(s)
Brain Neoplasms , Glioblastoma , Glioma , Gliosarcoma , Humans , Glioblastoma/metabolism , Gliosarcoma/genetics , Gliosarcoma/metabolism , Gliosarcoma/pathology , Brain Neoplasms/metabolism , Neoplasm Recurrence, Local/pathology , Glioma/pathology , Neoplastic Stem Cells/metabolism , ErbB Receptors/metabolism , Cell Line, TumorABSTRACT
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.
Subject(s)
Brain Neoplasms , Glioblastoma , Gliosarcoma , Humans , Gliosarcoma/drug therapy , Gliosarcoma/genetics , Gliosarcoma/pathology , Bevacizumab/therapeutic use , Glioblastoma/drug therapy , Glioblastoma/genetics , Genetic Profile , Brain Neoplasms/pathologyABSTRACT
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.
Subject(s)
Brain Neoplasms , Glioblastoma , Gliosarcoma , Lung Neoplasms , Humans , Gliosarcoma/genetics , Gliosarcoma/diagnosis , Gliosarcoma/pathology , Brain Neoplasms/pathology , Glioblastoma/pathology , Lung Neoplasms/genetics , Lung Neoplasms/secondary , Lung/pathologyABSTRACT
Purpose: Gliosarcoma is a histopathological variant of glioblastoma, which is characterized by a biphasic growth pattern consisting of glial and sarcoma components. Owing to its scarcity, data regarding the impact of available treatments on the clinical outcomes of gliosarcoma are inadequate. The purpose of this retrospective cohort study was to analyze the prognostic factors of gliosarcoma. Methods: By screening the clinical database of neurosurgical cases at a single center, patients with gliosarcoma diagnosed histologically from 2013 to 2021 were identified. Clinical, pathological, and molecular data were gathered founded on medical records and follow-up interviews. Prognostic factors were derived using the Cox proportional hazards model with backward stepwise regression analysis. Results: Forty-five GSM patients were included. Median overall survival was 25.6 months (95% CI 8.0-43.1), and median relapse-free survival was 15.2 months (95% CI 9.7-20.8). In multivariable analysis, total resection (p = 0.023, HR = 0.192, 95% CI 0.046-0.797) indicated an improved prognosis. And low expression of Ki-67 (p = 0.059, HR = 2.803, 95% CI 0.963-8.162) would be likely to show statistical significance. However, there might be no statistically significant survival benefit from radiotherapy with concurrent temozolomide (n = 33, 73.3%, log-rank p = 0.99) or adjuvant temozolomide (n = 32, 71.1%, log-rank p = 0.74). Conclusion: This single-center retrospective study with a limited cohort size has demonstrated the treatment of gross total resection and low expression of Ki-67 which are beneficial for patients with GSM, while radiotherapy or temozolomide is not.
Subject(s)
Brain Neoplasms , Glioblastoma , Gliosarcoma , Humans , Temozolomide , Gliosarcoma/diagnosis , Gliosarcoma/therapy , Gliosarcoma/pathology , Retrospective Studies , Prognosis , Ki-67 Antigen , Brain Neoplasms/pathology , Neoplasm Recurrence, Local , Glioblastoma/pathologyABSTRACT
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.
Subject(s)
Brain Neoplasms , Glioblastoma , Gliosarcoma , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Brain Neoplasms/therapy , Glioblastoma/pathology , Gliosarcoma/genetics , Gliosarcoma/pathology , Gliosarcoma/therapy , Humans , Mutation , PrognosisABSTRACT
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.
Subject(s)
Astrocytoma , Brain Neoplasms , Glioblastoma , Gliosarcoma , Adult , Aged , Brain Neoplasms/pathology , Female , Gliosarcoma/genetics , Gliosarcoma/pathology , Humans , Magnetic Resonance Imaging , ParesisABSTRACT
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.
Subject(s)
Brain Neoplasms , Glioblastoma , Gliosarcoma , Brain Neoplasms/genetics , Brain Neoplasms/pathology , DNA Copy Number Variations/genetics , Genomics , Glioblastoma/genetics , Glioblastoma/pathology , Gliosarcoma/genetics , Gliosarcoma/pathology , Gliosarcoma/therapy , HumansABSTRACT
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.
Subject(s)
Brain Neoplasms , Glioma , Gliosarcoma , Telomerase , Brain Neoplasms/diagnosis , Glioma/pathology , Gliosarcoma/genetics , Gliosarcoma/pathology , Humans , Isocitrate Dehydrogenase , Prognosis , Proto-Oncogene Proteins B-raf/genetics , Telomerase/genetics , Telomerase/metabolismABSTRACT
Gliosarcoma is a biphasic central nervous system malignancy composed of glial and mesenchymal components. It is recognized as a rare variant of glioblastoma with unique histology, immunostaining properties, and natural history. Although usually described to primarily involve the brain, a search of the published literature revealed four reported cases of gliosarcoma arising in the spinal cord. This report describes the case of a 35-year-old woman with progressive back pain with loss of sensation and power of both lower limbs. Magnetic resonance imaging showed an intramedullary unifocal space-occupying lesion in her thoracolumbar spinal cord. Subtotal resection and subsequent histopathological and immunohistochemical studies confirmed the diagnosis of gliosarcoma of the spinal cord. This report further establishes the clinical entity of primary spinal gliosarcoma and proposes the need to consider this possibility among the differential diagnoses of a space-occupying spinal lesion.
Subject(s)
Brain Neoplasms , Glioblastoma , Gliosarcoma , Spinal Cord Neoplasms , Adult , Brain Neoplasms/pathology , Female , Gliosarcoma/diagnosis , Gliosarcoma/pathology , Gliosarcoma/surgery , Humans , Magnetic Resonance Imaging , Spinal Cord Neoplasms/diagnostic imaging , Spinal Cord Neoplasms/surgeryABSTRACT
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.
Subject(s)
Bone Neoplasms , Brain Neoplasms , Gliosarcoma , Osteosarcoma , Brain Neoplasms/genetics , Brain Neoplasms/pathology , DNA Copy Number Variations , Female , Gliosarcoma/genetics , Gliosarcoma/pathology , Gliosarcoma/therapy , Humans , Osteosarcoma/genetics , Osteosarcoma/pathologyABSTRACT
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.
Subject(s)
Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/genetics , Brain Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Glioblastoma/genetics , Gliosarcoma/genetics , Antineoplastic Combined Chemotherapy Protocols , Biomarkers, Tumor/metabolism , Brain Neoplasms/diagnosis , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Databases, Factual , ErbB Receptors/genetics , ErbB Receptors/metabolism , Female , Gene Expression Profiling , Glioblastoma/diagnosis , Glioblastoma/drug therapy , Glioblastoma/pathology , Gliosarcoma/diagnosis , Gliosarcoma/drug therapy , Gliosarcoma/pathology , Humans , Male , Middle Aged , Mutation , Neurofibromin 1/genetics , Neurofibromin 1/metabolism , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/metabolism , Prognosis , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Telomerase/genetics , Telomerase/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolismABSTRACT
BACKGROUND: Captopril is a well-characterized, FDA-approved drug that has demonstrated promise as a repurposed oncology therapeutic. Captopril's known anti-cancer effects include inhibition of Matrix Metalloproteinase-2 (MMP-2), an endopeptidase which selectively breaks down the extracellular matrix to promote cell migration. MMP-2 is a known therapeutic target in gliomas, tumors with significant clinical need. Using an aggressive gliosarcoma model, we assessed captopril's effects on MMP-2 expression in vitro and in vivo as well as its efficacy as an adjuvant in combination therapy regimens in vivo. METHODS: Following captopril treatment, MMP-2 protein expression and migratory capabilities of 9 L gliosarcoma cells were assessed in vitro via western blots and scratch wound assays, respectively. Rats were intracranially implanted with 9 L gliosarcoma tumors, and survival was assessed in the following groups: control; captopril (30 mg/kg/day); temozolomide (TMZ) (50 mg/kg/day), and captopril+TMZ. In vivo experiments were accompanied by immunohistochemistry for MMP-2 from brain tissue. RESULTS: In vitro, captopril decreased MMP-2 protein expression and reduced migratory capacity in 9 L gliosarcoma cells. In a gliosarcoma animal model, captopril decreased MMP-2 protein expression and extended survival as a TMZ adjuvant relative to untreated controls, captopril monotherapy, and TMZ monotherapy groups (27.5 versus 14 (p < 0.001), 16 (p < 0.001), and 23 (p = 0.018) days, respectively). CONCLUSIONS: Captopril decreases gliosarcoma cell migration, which may be mediated by reduction in MMP-2 protein expression. Captopril provided a survival advantage as a TMZ adjuvant in a rat intracranial gliosarcoma model. Captopril may represent a promising potential adjuvant to TMZ therapy in gliosarcoma as a modulator of the MMP-2 pathway.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Brain Neoplasms/drug therapy , Captopril/therapeutic use , Gliosarcoma/drug therapy , Animals , Antineoplastic Agents, Alkylating/therapeutic use , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Cell Culture Techniques , Disease Models, Animal , Female , Gliosarcoma/metabolism , Gliosarcoma/pathology , Matrix Metalloproteinase 2/metabolism , Rats , Rats, Inbred F344 , Temozolomide/therapeutic use , Tumor Cells, CulturedABSTRACT
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.
Subject(s)
Glioblastoma/pathology , Gliosarcoma/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Child , Child, Preschool , DNA Copy Number Variations , Epithelial-Mesenchymal Transition , Female , Glioblastoma/genetics , Glioblastoma/metabolism , Gliosarcoma/genetics , Gliosarcoma/metabolism , Humans , Male , Middle Aged , Neoplasm Grading , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism , Retrospective Studies , Young AdultABSTRACT
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.
Subject(s)
Brain Neoplasms/pathology , Gliosarcoma/pathology , Aged , Biomarkers/analysis , Brain Neoplasms/diagnosis , Brain Neoplasms/genetics , Carcinoma, Neuroendocrine/diagnosis , Diagnosis, Differential , Gliosarcoma/diagnosis , Gliosarcoma/genetics , Humans , Male , Mutation , PTEN Phosphohydrolase/genetics , Telomerase/genetics , Tumor Suppressor Protein p53/geneticsABSTRACT
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.
Subject(s)
Brain Neoplasms/therapy , Chemoradiotherapy/adverse effects , Glioblastoma/therapy , Gliosarcoma/diagnosis , Neoplasms, Second Primary/diagnosis , Animals , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Brain/diagnostic imaging , Brain/pathology , Brain/surgery , Brain Neoplasms/diagnosis , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Cell Cycle Proteins/analysis , Cell Cycle Proteins/genetics , Chemoradiotherapy/methods , Craniotomy , Female , Glioblastoma/diagnosis , Glioblastoma/genetics , Glioblastoma/pathology , Gliosarcoma/etiology , Gliosarcoma/genetics , Gliosarcoma/pathology , Humans , Magnetic Resonance Imaging , Mice , Middle Aged , Mutation , Neoplasms, Second Primary/etiology , Neoplasms, Second Primary/genetics , Neoplasms, Second Primary/pathology , Primary Cell Culture , Temozolomide/therapeutic use , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Primary intracranial gliosarcoma is a rare malignant brain tumour, and the most effective treatment for gliosarcoma remains unclear. This study aimed to identify risk factors for progression-free survival (PFS) and overall survival (OS) in these cases. This retrospective single-centre study evaluated 103 patients (median age, 51 years; 67 men [65%]) with primary intracranial gliosarcoma between 2006 and 2017. Treatments included surgery (GTR, 63 patients; STR, 39 patients; biopsy, 1 patient), radiotherapy (adjuvant, 76 patients; exclusive treatment, 1 patient), and chemotherapy (adjuvant temozolomide, 52 patients; adjuvant nimustine/teniposide, 19 patients; adjuvant bevacizumab, 1 patient; exclusive nimustine/teniposide treatment, 1 patient). The median OS was 13.3 months, and the median PFS was 9.1 months. In the multivariate analyses, the poor prognostic factors were ependymal lining enhancement of the lateral ventricle (PFS, HR 2.406, p = 0.005; OS, HR 2.946, p = 0.009) and enhancement in the motor functional cortex (PFS, HR 2.892, p = 0.002; OS, HR 2.639, p = 0.009). Good OS was predicted by adjuvant radiotherapy alone (HR 0.071, p < 0.001), adjuvant temozolomide-based chemotherapy alone (HR 0.063, p = 0.005), adjuvant temozolomide-based chemotherapy with concurrent radiotherapy (HR 0.056, p < 0.001), and salvage surgery at recurrence (HR 0.449, p = 0.031). The present study revealed that, in patients with primary intracranial gliosarcoma, enhancement in the functional motor cortex and ependymal lining enhancement of the lateral ventricle were both poor prognostic factors. Survival was optimized in cases treated using maximal safe resection followed by adjuvant temozolomide-based chemotherapy with concurrent radiotherapy. Furthermore, salvage surgery provided meaningful therapeutic benefits for recurrent gliosarcoma.
Subject(s)
Brain Neoplasms/diagnostic imaging , Brain Neoplasms/therapy , Gliosarcoma/diagnostic imaging , Gliosarcoma/therapy , Adult , Aged , Antineoplastic Agents, Alkylating/administration & dosage , Brain Neoplasms/pathology , Dacarbazine/administration & dosage , Female , Gliosarcoma/pathology , Humans , Immunohistochemistry , Male , Middle Aged , Neoplasm Recurrence, Local/diagnostic imaging , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/therapy , Progression-Free Survival , Retrospective Studies , Risk Factors , Salvage Therapy/methods , Salvage Therapy/trends , Temozolomide/administration & dosage , Treatment OutcomeABSTRACT
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.
Subject(s)
DNA Modification Methylases/genetics , DNA Repair Enzymes/genetics , Exome Sequencing/methods , Exome , Gliosarcoma/pathology , Mutation , Neurofibromatosis 1/pathology , Tumor Suppressor Proteins/genetics , Child , Female , Gliosarcoma/complications , Gliosarcoma/genetics , Humans , Male , Neurofibromatosis 1/complications , Neurofibromatosis 1/genetics , Prognosis , Promoter Regions, GeneticABSTRACT
OBJECTIVE: Gliosarcoma (GSC) is a rare histological variant of glioblastoma (GBM). Due to limited evidence regarding clinical, genetic and radiographic characteristics of GSC, this study aimed to analyze independent outcome predictors of GSC, and to address the differences between GSC and GBM concerning the baseline characteristics and patients' survival. METHODS: Patients treated between 2001 and 2018 for the diagnosis of GBM and GSC were included in this study. Patients' records were reviewed for demographic, clinical, genetic and radiographic characteristics. Univariate, multivariate and propensity score matched analyses were performed. RESULTS: In the GSC sub-cohort (N = 56), patients' age, preoperative clinical status, midline tumor location and tumor size were found to be independently associated with overall survival. As compared to GBM individuals (N = 1249), a temporal location (p = 0.002), presence of eccentric tumor cysts (p < 0.001), a higher ratio of TP53 staining (p = 0.002) and a lower ratio of GFAP staining (p = 0.005) were characteristic for GSC. The diagnosis of GSC was associated with a poorer survival (p = 0.002) independently of the patients' age, sex, clinical status and extent of resection, However, this association was no more significant, when enhancing the multivariate analysis with molecular-genetic characteristics (IDH1 mutation and MGMT promotor methylation status). DISCUSSION: Certain radiographic and molecular-genetic patterns present the distinct characteristics of GSC. There is an association between the diagnosis of GSC and a poorer outcome. This difference might be linked to different genetic alterations in GBM and GSC. Prospective studies are needed to further elucidate the characteristics of GSC and develop targeted treatment approaches for this rare variant.