TGF-ß and BMP signaling are associated with the transformation of glioblastoma to gliosarcoma and then osteosarcoma.

Background: Gliosarcoma, an isocitrate dehydrogenase wildtype (IDH-WT) variant of glioblastoma, is defined by clonal biphasic differentiation into gliomatous and sarcomatous components. While the transformation from a glioblastoma to gliosarcoma is uncommon, the subsequent transformation to osteosarcoma is rare but may provide additional insights into the biology of these typically distinct cancers. We observed a patient initially diagnosed with glioblastoma, that differentiated into gliosarcoma at recurrence, and further evolved to osteosarcoma at the second relapse. Our objective was to characterize the molecular mechanisms of tumor progression associated with this phenotypic transformation. Methods: Tumor samples were collected at all 3 stages of disease and RNA sequencing was performed to capture their transcriptomic profiles. Sequential clonal evolution was confirmed by the maintenance of an identical PTEN mutation throughout the tumor differentiation using the TSO500 gene panel. Publicly available datasets and the Nanostring nCounter technology were used to validate the results. Results: The glioblastoma tumor from this patient possessed mixed features of all 3 TCGA-defined transcriptomic subtypes of an IDH-WT glioblastoma and a proportion of osteosarcoma signatures were upregulated in the original tumor. Analysis showed that enhanced transforming growth factor-ß (TGF-ß) and bone morphogenic protein signaling was associated with tumor transformation. Regulatory network analysis revealed that TGF-ß family signaling committed the lineage tumor to osteogenesis by stimulating the expression of runt-related transcription factor 2 (RUNX2), a master regulator of bone formation. Conclusions: This unusual clinical case provided an opportunity to explore the modulators of longitudinal sarcomatous transformation, potentially uncovering markers indicating predisposition to this change and identification of novel therapeutic targets.

PATZ1-Rearranged Tumors of the Central Nervous System: Characterization of a Pediatric Series of Seven Cases.

PATZ1-rearranged sarcomas are well-recognized tumors as part of the family of round cell sarcoma with EWSR1-non-ETS fusions. Whether PATZ1-rearranged central nervous system (CNS) tumors are a distinct tumor type is debatable. We thoroughly characterized a pediatric series of PATZ1-rearranged CNS tumors by chromosome microarray analysis (CMA), DNA methylation analysis, gene expression profiling and, when frozen tissue is available, optical genome mapping (OGM). The series consisted of 7 cases (M:F=1.3:1, 1-17 years, median 12). On MRI, the tumors were supratentorial in close relation to the lateral ventricles (intraventricular or iuxtaventricular), preferentially located in the occipital lobe. Two major histologic groups were identified: one (4 cases) with an overall glial appearance, indicated as "neuroepithelial" (NET) by analogy with the corresponding methylation class (MC); the other (3 cases) with a predominant spindle cell sarcoma morphology, indicated as "sarcomatous" (SM). A single distinct methylation cluster encompassing both groups was identified by multidimensional scaling analysis. Despite the epigenetic homogeneity, unsupervised clustering analysis of gene expression profiles revealed 2 distinct transcriptional subgroups correlating with the histologic phenotypes. Interestingly, genes implicated in epithelial-mesenchymal transition and extracellular matrix composition were enriched in the subgroup associated to the SM phenotype. The combined use of CMA and OGM enabled the identification of chromosome 22 chromothripsis in all cases suitable for the analyses, explaining the physical association of PATZ1 to EWSR1 or MN1. Six patients are currently disease-free (median follow-up 30 months, range 12-92). One patient of the SM group developed spinal metastases at 26 months from diagnosis and is currently receiving multimodal therapy (42 months). Our data suggest that PATZ1-CNS tumors are defined by chromosome 22 chromothripsis as causative of PATZ1 fusion, show peculiar MRI features (eg, relation to lateral ventricles, supratentorial frequently posterior site), and, although epigenetically homogenous, encompass 2 distinct histologic and transcriptional subgroups.

Competing Risk Model to Determine the Prognostic Factors for Patients with Gliosarcoma.

BACKGROUND: Gliosarcoma (GSM) is a highly aggressive variant of brain cancer with an extremely unfavorable prognosis. Prognosis is not feasible by traditional methods because of a lack of staging criteria, and the present study aims to screen more detailed demographic factors to predict the prognostic factors of the tumors. METHODS: For this study, we extracted data of patients diagnosed with GSM from the SEER (Surveillance Epidemiology and End Results) database between 2000 and 2019. To account for the influence of competing risks, we used a Cumulative Incidence Function. Subsequently, univariate analysis was conducted to evaluate the individual variables under investigation. Specifically for patients with GSM, we generated cumulative risk curves for specific mortality outcomes and events related to competing risks. In addition, we used both univariate and multivariate Cox analysis to account for non-GSM-related deaths that may confound our research. RESULTS: The competing risk model showed that age, marital status, tumor size, and adjuvant therapy were prognostic factors in GSM-related death. The analysis results showed that older age (60-70 years, ≥71 years) and larger tumor size (≥5.3 cm) significantly increased the risk of GSM-related death. Conversely, surgical intervention, chemotherapy, and being single were identified as protective factors against GSM-related death. CONCLUSIONS: Our study using a competing risk model provided valuable insights into the prognostic factors associated with GSM-related death. Further research and clinical interventions targeted at minimizing these risk factors and promoting the use of protective measures may contribute to improved outcomes and reduced mortality for patients with GSM.

Introducing Albumin and Interleukin 6 as Common Critical Dysregulated Proteins Between Migraine and Gliosarcoma.

Introduction: It is reported that migraine may be a risk factor for brain cancers. Since one of the best ways to assess this possible relationship is to study the molecular mechanism, here the common central dysregulated proteins between these diseases are investigated via network analysis. Methods: The dysregulated proteins of migraine and gliosarcoma are extracted from the STRING database and interacted via Cytoscape software, version 3.7.2. to form two separate networks. Central nodes of the networks are compared to find the common central district proteins. First neighbors of the common central proteins are studied. Results: The number of 11 hub bottlenecks was identified for each of the migraine and gliosarcoma cancer networks. Albumin (ALB) and interleukin 6 (IL6) were introduced as common differentially expressed central proteins. Kininogen 1 (KNG1), vascular endothelial growth factor A (VEGFA), and neurofibromatosis type I (NF1) the first neighbors of ALB-IL6 were connected to the central nodes of networks of the two studied diseases. Conclusion: ALB and IL6 can be considered molecular links between migraine and brain cancers. Highlights: Differentially expression of albumin (ALB) and interleukin 6 (IL6) is highlighted as the common key events in migraine and gliosarcoma.Kininogen 1 (KNG1), vascular endothelial growth factor A (VEGFA), and neurofibromatosis type I (NF1) are introduced as possible critical players in migraine and gliosarcoma.Based on four centrality parameters, ALB is characterized with stronger centrality properties relative to IL6. Plain Language Summary: Migraine is considered as a possible risk factor for brain cancers. Therefor exploring of relationship between brain cancers and migraine is attracted attention of researchers. Understanding of diseases molecular mechanism is an important tool to better diagnosis and therapy of the studied disorders. In the present study, the common features of molecular events in migraine and gliosarcoma are studied based on protein expression changes. Analysis indicates that a few numbers of proteins play critical roles in migraine and gliosarcoma. ALB, IL6, KNG1, VEGFA, and NF1 are highlighted as the key proteins which are dysregulated in the two studied diseases. Prominent role of ALB in development of cancers is pointed out by several researchers. Important role of IL6 in promotion of migraine is disused in the previous documents. Since some diseases are risk factors for the other disorders, understanding the common features of two diseases can provide suitable therapeutic protocol to prevent development of diseases. Our finding can be used to provide suitable procedure to prevent conversion of migraine to brain cancer.

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.

Pediatric gliosarcoma, a rare central nervous system tumor in children: Case report and literature review.

Gliosarcoma is a rare and highly malignant central nervous system tumor that accounts for 1%-8% of glioblastomas; it usually occurs in middle-aged and older adults between 40 and 60 years of age and is rare in children. We report an 11-year-old boy with right frontal lobe gliosarcoma who underwent aggressive gross total resection and postoperative radiotherapy, experienced recurrence and subsequently underwent a second operation. To better understand the disease and explore treatment options, we briefly report this case and review the relevant literature.

A Novel Setup Technique for Radiation Treatment of a Severely Obese Patient With a Primary Brain Tumor.

Modern external beam radiation therapy (EBRT) techniques rely on the accurate positioning of the patient using the treatment couch. These motorized couches have weight limits that have decreased over time and are not able to support severely obese patients requiring EBRT. We aimed to develop a technique to support obese patients who are above their weight tolerance while accurately delivering radiation treatment to a brain tumor. This technique was used on a patient receiving adjuvant radiation for gliosarcoma, a variant of glioblastoma. The patient was CT scanned, and the 3D conformal radiation therapy plan was created. A custom treatment couch was created using a transport stretcher, Styrofoam, a CT couch-top, and an IMRT board, which allowed for a thermoplastic mask to be used for a reproducible setup. AP and lateral portal films were taken prior to each treatment to confirm the accuracy of the manual daily setup of the patient on the custom couch. The patient received 60 Gy in 30 daily fractions of 3DCRT in a reproducible fashion. The average deviation from the isocenter fell within the 10 mm and 8 mm planning margins applied to the clinical target volume (CTV) for the initial and boost fields, respectively. The average daily shifts in the anterior-posterior (AP) direction for the patient were 7.97 (-16.19 to 12.04) mm and 1.98 mm (-1.1 to 4.3) mm for the initial and boost treatments, respectively. The average daily shifts in the superior-inferior (SI) direction were 2.2 (-5.08 to 9.04) mm and 3.88 (-2.9 to 8.0) mm for the initial and boost treatments, respectively. This novel approach allowed treatment at 60 Gy for a gliosarcoma patient who had previously been denied treatment due to his weight. By utilizing readily available materials within the department, our team was able to create a reproducible setup technique to safely treat the patient.

Gliosarcoma Invading the Temporal Bone, Temporalis Muscle, and Skull Base.

Gliosarcoma (GS) is a primary central nervous system tumor. It is an unusual type of glioblastoma multiforme (GBM) and rarely invades the skull base. It has a biomorphic tissue pattern with rapid alternation zones of glial and mesenchymal differentiation. We report the case of a 62-year-old male who presented with a one-month history of unsteady gait associated with dizziness. Brain MRI showed a right temporal mass that invaded the skull base with perilesional edema and a significant mass effect on the right lateral ventricle. The patient underwent a right-sided frontotemporal craniotomy with gross total resection. The pathology confirmed the diagnosis of GS. Postoperatively, the patient had an uneventful recovery with no complications and was discharged two days post-surgery.

Intracranial Gliosarcoma: A National Cancer Database Survey of Clinical Predictors for Overall Survival.

OBJECTIVE: Gliosarcoma (GSM) is a variant of glioblastoma, 1 of the most common and aggressive primary brain tumors in adults. Our study seeks to analyze a large cohort of patients with GSM in the National Cancer Database (NCDB) to elucidate clinical predictors of overall survival (OS). METHODS: Data was collected on patients diagnosed with histologically-confirmed GSM using the NCDB (2004-2016). OS was determined via univariate Kaplan-Meier analysis. Bivariate and multivariate Cox proportional-hazards analyses were also utilized. RESULTS: Our cohort of 1015 patients had a median age at diagnosis of 61 years. Six hundred thirty-one (62.2%) were male, 896 (89.0%) were Caucasian, and 698 (68.8%) lacked any comorbidities. Median OS was 11.5 months. Regarding treatment, 264 (26.5%) patients underwent surgery (S) only (OS = 5.19 months), 61 (6.1%) underwent surgery and radiotherapy (S + RT) (OS = 6.87 months), 20 (2.0%) underwent surgery and chemotherapy (S + CT); (OS = 15.51 months), and 653 (65.4%) underwent S + CT + RT (triple) combination therapy (OS = 13.8 months). Notably, on bivariate analysis, S + CT (Hazard ratio [HR] = 0.59, P-value = 0.04) and triple therapy (HR = 0.57, P < 0.01) were associated with increased OS. S + RT was not significantly associated with OS. Similarly, on multivariate Cox proportional-hazards analyses, gross total resection (HR = 0.76, P = 0.02), S + CT (HR = 0.46, P < 0.01), and triple therapy (HR = 0.52, P < 0.01) predicted significantly increased OS. Furthermore, age >60 years old (HR = 1.03, P < 0.01) and the presence of comorbidities (HR = 1.43, P < 0.01) predicted significantly decreased OS. CONCLUSIONS: Despite maximal multimodal treatment, GSMs have poor median OS. NCDB data suggest age, comorbidities, extent of resection, and adjuvant treatment each minimally delays poor outcomes.

Clinicopathological and Neuroimaging Features of Primary Gliosarcoma: A Case Series and Review of Literature.

BACKGROUND: Gliosarcoma (GS) is a rare primary high-grade brain neoplasm with a poor prognosis and challenging surgical resection. Although it is now considered a morphologic variant of IDH-wildtype glioblastoma (World Health Organization Classification of Tumours 2021), GS may display peculiarities that hamper both surgical and oncological management. METHODS: In this retrospective study, we searched our registry for histologically confirmed GS patients between 2006 and 2020. Cases were reviewed for clinical information, pathologic characteristics, imaging findings, management, and outcome. RESULTS: 21 patients with histologically confirmed GS were identified with a median age of 62 years. Twelve were men and 9 women. The temporal lobe was the most common location (9 patients, 42.9%). Nineteen patients underwent surgical resection, and only 4 (19%) demonstrated gross total resection on postsurgical MRI, with an overall median survival of 7 months (range, 0.5-37). Diagnostic MRI demonstrated heterogenous lesions with necrotic-cystic areas and a ring-enhancement pattern. Only 1 case of extracranial extension was seen in our sample, and no patient showed distant metastases. CONCLUSIONS: The rarity of primary GS and the absence of specific therapeutic guidelines represent a significant clinical challenge. Our study provides a comprehensive analysis of clinical and neuroimaging characteristics in a real-world patient cohort and compares our findings with the available literature.

Unusual extraneural metastasis of glioblastoma.

Background: Glioblastoma (GB) is the most common and aggressive malignant brain tumor in adults. Extracranial metastases are very rare, been described in the lungs, soft tissue, or the intraspinal space. Case Description: Through a PubMed-based bibliographic search, the authors reviewed the cases reported in the literature to date, emphasizing the epidemiology and pathophysiology of this rare condition. A clinical case of a 46-year-old man with an initial diagnosis of gliosarcoma, who received complete surgical and adjuvant treatment and later recurred as GB with incidental finding of a lung tumor, whose pathology reported metastasis of the primary, is illustrated. Conclusion: Understanding the pathophysiology, it is likely that the incidence of extraneural metastases may continue to increase. Considering improvements in diagnostic techniques that allow early diagnosis, as well as advances in neurosurgical therapy and multimodal management with the aim of improving patient survival, the period in which malignant cells can spread and form extracranial metastases could increase. When screening should be performed to detect metastases in these patients is still not clear. The neuro-oncologists should pay attention to the systematic survey for extraneural metastasis of the GB. Timely detection and early treatment improve overall quality of patients' life.

Metastatic secondary gliosarcoma: patient series.

BACKGROUND: Gliosarcoma is a rare and highly malignant cancer of the central nervous system with the ability to metastasize. Secondary gliosarcoma, or the evolution of a spindle cell-predominant tumor after the diagnosis of a World Health Organization grade IV glioblastoma, has also been shown to metastasize. There is little information on metastatic secondary gliosarcoma. OBSERVATIONS: The authors present a series of 7 patients with previously diagnosed glioblastoma presenting with recurrent tumor and associated metastases with repeat tissue diagnosis consistent with gliosarcoma. The authors describe the clinical, imaging, and pathological characteristics in addition to carrying out a systematic review on metastases in secondary gliosarcoma. LESSONS: The present institutional series and the systematic review of the literature show that metastatic secondary gliosarcoma is a highly aggressive disease with a poor prognosis.

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.

Radiation-induced intracranial rhabdomyosarcoma- A rare complication: Report of a case with literature review.

Radiation-induced sarcoma (RIS) of the central nervous system is an uncommon late complication of radiation therapy. We report a case of a 47-year-old male patient who underwent surgery followed by irradiation and chemotherapy with temozolomide for a frontal lobe gliosarcoma and presented 43 months later with a recurrent tumor in the same location with interval growth in the size of the lesion. Histology from surgical resection of the recurrent tumor revealed embryonal rhabdomyosarcoma (RMS). Adjacent brain parenchyma showed radiation-induced changes. There was no evidence of gliosarcoma at recurrence. In addition to the rarity of sarcomas arising following irradiation for glial tumors, this case represents one of the first reports of an intracerebral RMS arising in this setting.

A Novel Case of Primary Conus Medullaris Epithelioid Glioblastoma with Gliosarcomatous Differentiation.

Intramedullary location is seldom seen in spinal cord neoplasms. Ependymomas and astrocytomas comprise the vast majority of these intramedullary lesions. Primary spinal origin is rarely seen in gliosarcomas. No epithelioid glioblastomas have been reported in the spine. We describe the case of an 18-year-old male who presented with symptoms suggestive of a spinal mass lesion. Magnetic resonance imaging revealed a homogeneous intradural-intramedullary lesion involving the conus medullaris. Biopsy of the lesion showed a unique morphology comprising gliosarcoma and epithelioid glioblastoma differentiation, supported by relevant immunohistochemistry. The prognosis of such an entity is expected to be poor. However, the presence of mutant BRAF V600E, as seen in the current case, and the availability of targeted therapy against it are expected to improve the prognosis.

A Rare Tumor in a Rare Location: Radiology and Pathology Findings With a Literature Review on Intraventricular Gliosarcoma.

Gliosarcoma (GS) is an extraordinarily rare variant of glioblastoma, which is differentiated by its distinct biphasic histopathological morphology consisting of both glial and mesenchymal elements. Although GS has a predilection for the cortical hemispheres, rare occurrences of intraventricular gliosarcoma (IVGS) have been documented in the literature. In this report, we present a 68-year-old female patient with a primary IVGS arising from the frontal horn of the left ventricle with corresponding left ventricular entrapment. The clinical course as well as associated tumor features as observed on computed tomography (CT), magnetic resonance imaging (MRI), and immunohistochemical studies are presented along with a relevant review of the current literature.

A rare, giant, lateral intraventricular gliosarcoma.

A peculiar subtype of glioblastoma multiforme is gliosarcoma. According to histological analysis, it possesses a biphasic shape that clearly distinguishes between glial and sarcomatous tissue. A gliosarcoma is often seen in the supratentorial region. Here, we describe a rare instance of giant left intraventricular gliosarcoma that manifested in a 1-year-old male. Advanced brain scan using magnetic resonance imaging identified a supratentorial tumor with radiological characteristics comparable to choroid plexus carcinoma. Histopathology determined that the tumor was a gliosarcoma. Despite its rarity, gliosarcoma should be taken into consideration when determining the differential diagnosis of intraventricular tumors in children who exhibit radiological signs of choroid plexus carcinoma.

Primary Intracranial Gliosarcoma: Is It Really a Variant of Glioblastoma? An Update of the Clinical, Radiological, and Biomolecular Characteristics.

Gliosarcomas (GS) are sporadic malignant tumors classified as a Glioblastoma (GBM) variant with IDH-wild type phenotype. It appears as a well-circumscribed lesion with a biphasic, glial, and metaplastic mesenchymal component. The current knowledge about GS comes from the limited literature. Furthermore, recent studies describe peculiar characteristics of GS, such as hypothesizing that it could be a clinical-pathological entity different from GBM. Here, we review radiological, biomolecular, and clinical data to describe the peculiar characteristics of PGS, treatment options, and outcomes in light of the most recent literature. A comprehensive literature review of PubMed and Web of Science databases was conducted for articles written in English focused on gliosarcoma until 2023. We include relevant data from a few case series and only a single meta-analysis. Recent evidence describes peculiar characteristics of PGS, suggesting that it might be a specific clinical-pathological entity different from GBM. This review facilitates our understanding of this rare malignant brain tumor. However, in the future we recommend multi-center studies and large-scale metanalyses to clarify the biomolecular pathways of PGS to develop new specific therapeutic protocols, different from conventional GBM therapy in light of the new therapeutic opportunities.

Computed Tomography, Magnetic Resonance Imaging, and Pathological Features of Gliosarcoma.

Objective: To investigate the clinical, imaging, and pathological features of gliosarcoma. Methods: The clinical data of 14 patients with gliosarcoma confirmed by surgery and pathology at our hospital between 2010 and 2021 were analyzed retrospectively, and the relevant literature was reviewed. Results: In all 14 cases, the gliosarcoma was located in the supratentorial brain parenchyma and involved a single lesion. There were more male patients (64.3%) than female patients (35.7%), and 57.1% of all the patients were 40-60 years of age. The prognosis of all 14 patients was poor, and the average survival time was approximately seven months. The computed tomography findings revealed mostly mixed density lesions, and some cases were complicated with bleeding. The magnetic resonance imaging revealed irregularly shaped mass lesions of different sizes, with uneven or circular enhancement. Cystic degeneration and necrosis could be seen in all the masses, some of which showed signs of bleeding and were surrounded by different degrees of edema and space-occupying effects. The pathological examination revealed that the tumors had bidirectional differentiation of the glial and sarcoma components, while the immunohistochemistry examination revealed glial fibrillary acidic protein-positive and reticular fiber-positive staining in the sarcoma. Conclusion: The clinical manifestations of gliosarcoma are nonspecific, but imaging reveals that the condition has certain characteristics, typically consisting of a huge supratentorial mass, with an irregular heterogeneous periphery or obvious mass-like augmentation after enhancement. The final diagnosis depends on the results of a pathological examination.