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.

Gliosarcoma in a Young Filipino Woman: A Case Report and Review of the Literature.

BACKGROUND Gliosarcoma (GS) is a rare variant of glioblastoma (GBM), which is typically seen in patients age 40-60 years and located in the supratentorial region. We present an unusual case of GS in a young patient with an unusual presentation, which eventually led to the finding of this neoplasm. CASE REPORT Our patient was a 38-year-old woman originally from the Philippines who was transferred to our institution with an isolated left foot drop that developed over the course of several months. Subsequent neuroimaging revealed an extensive mixed cystic and solid mass in the posterior mesial right frontal lobe. Subtotal surgical resection revealed a multi-lobed tumor with a malignant glioma-like surface component overlying a smooth, well-encapsulated, avascular, sarcoma-like component. Neuropathologic examination of the resected tumor revealed a biphasic histologic pattern of predominantly sarcomatous components with fewer adjacent-area glial components. Post-operatively, the patient was left with a mild worsening of left leg segmental strength. She was referred to our neurooncologist colleagues for adjuvant treatment options. CONCLUSIONS Our case is unique in that it represents a rare neoplasm in a patient whose demographics are atypical for this type of tumor, as well as the unusual presentation of isolated foot drop.

Gliosarcoma in the Cerebellopontine Angle with Rapid Tumor Growth and Intratumoral Hemorrhage.

BACKGROUND: Gliosarcoma is a relatively rare and bimorphous brain tumor, predominantly located in the brain lobe. Here, we report a rare case of gliosarcoma presenting radiologically in the cerebellopontine angle (CPA) region. CASE DESCRIPTION: The patient was a 71-year-old woman with progressive tinnitus. A series of image examinations showed a rapidly growing CPA tumor, which enlarged from nonexistent to 4 cm in diameter with extension to the internal auditory canal in a short period of 6 months. The patient was operated on in emergency because of intratumoral hemorrhage and rapidly deteriorating neurologic symptoms. Under the diagnosis of gliosarcoma confirmed by pathologic examination, chemotherapy and radiotherapy were conducted after partial resection. The patient recovered uneventfully and the residual tumor disappeared nearly completely on the image taken 6 months later. CONCLUSIONS: Although rare, gliosarcoma should be considered in the differential diagnosis of CPA tumors, especially if it is associated with rapid tumor growth or intratumoral hemorrhage.

Gliosarcoma with leiomyomatous differentiation: A case report with an emphasis on histogenesis.

Gliosarcoma is an uncommon high-grade tumor which constitutes about 2% of all glioblastomas. These tumors have the histological hallmark of a biphasic pattern of high-grade glial and sarcomatous components. The histogenesis of these tumors is controversial. We report a case of primary gliosarcoma in an adult male with leiomyomatous differentiation and discuss the histogenesis as it appears in our case. Primary gliosarcomas of the brain are clinically challenging with a poor clinical outcome.

Transcriptional factors for epithelial-mesenchymal transition are associated with mesenchymal differentiation in gliosarcoma.

Gliosarcoma is a rare variant of glioblastoma characterized by a biphasic pattern of glial and mesenchymal differentiation. It is unclear whether mesenchymal differentiation in gliosarcomas is because of extensive genomic instability and/or to a mechanism similar to epithelial-mesenchymal transition (EMT). In the present study, we assessed 40 gliosarcomas for immunoreactivity of Slug, Twist, matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), which are involved in EMT in epithelial tumors. Nuclear Slug expression was observed in >50% of neoplastic cells in mesenchymal tumor areas of 33 (83%) gliosarcomas, but not in glial areas (P < 0.0001). Nuclear Twist expression was observed in >50% of neoplastic cells in mesenchymal tumor areas of 35 (88%) gliosarcomas, but glial tumor areas were largely negative except in four cases (P < 0.0001). Expression of MMP-2 and MMP-9 was also significantly more extensive in mesenchymal than in glial tumor areas. None of 20 ordinary glioblastomas showed Slug or Twist expression in >10% neoplastic cells. Thus, expression of Slug, Twist, MMP-2 and MMP-9 was characteristic of mesenchymal tumor areas of gliosarcomas, suggesting that mechanisms involved in the EMT in epithelial neoplasms may play roles in mesenchymal differentiation in gliosarcomas.

Delayed onset of paresis in rats with experimental intramedullary spinal cord gliosarcoma following intratumoral administration of the paclitaxel delivery system OncoGel.

OBJECT: Treatment options for anaplastic or malignant intramedullary spinal cord tumors (IMSCTs) remain limited. Paclitaxel has potent cytotoxicity against experimental intracranial gliomas and could be beneficial in the treatment of IMSCTs, but poor CNS penetration and significant toxicity limit its use. Such limitations could be overcome with local intratumoral delivery. Paclitaxel has been previously incorporated into a biodegradable gel depot delivery system (OncoGel) and in this study the authors evaluated the safety of intramedullary injections of OncoGel in rats and its efficacy against an intramedullary rat gliosarcoma. METHODS: Safety of intramedullary OncoGel was tested in 12 Fischer-344 rats using OncoGel concentrations of 1.5 and 6.0 mg/ml (5 µl); median survival and functional motor scores (Basso-Beattie-Bresnahan [BBB] scale) were compared with those obtained with placebo (ReGel) and medium-only injections. Efficacy of OncoGel was tested in 61 Fischer-344 rats implanted with an intramedullary injection of 9L gliosarcoma containing 100,000 cells in 5 µl of medium, and randomized to receive OncoGel administered on the same day (in 32 rats) or 5 days after tumor implantation (in 29 rats) using either 1.5 mg/ml or 3.0 mg/ml doses of paclitaxel. Median survival and BBB scores were compared with those of ReGel-treated and tumor-only rats. Animals were killed after the onset of deficits for histopathological analysis. RESULTS: OncoGel was safe for intramedullary injection in rats in doses up to 5 µl of 3.0 mg/ml of paclitaxel; a dose of 5 µl of 6.0 mg/ml caused rapid deterioration in BBB scores. OncoGel at concentrations of 1.5 mg/ml and 3.0 mg/ml paclitaxel given on both Day 0 and Day 5 prolonged median survival and preserved BBB scores compared with controls. OncoGel 1.5 mg/ml produced 62.5% long-term survivors when delivered on Day 0. A comparison between the 1.5 mg/ml and the 3.0 mg/ml doses showed higher median survival with the 1.5 mg/ml dose on Day 0, and no differences in median survival or BBB scores after treatment on Day 5. CONCLUSIONS: OncoGel is safe for intramedullary injection in rats in doses up to 5 µl of 3.0 mg/ml, prolongs median survival, and increases functional motor scores in rats challenged with an intramedullary gliosarcoma at the doses tested. This study suggests that locally delivered chemotherapeutic agents could be of temporary benefit in the treatment of malignant IMSCTs under experimental settings.

A 28-year-old man with headache, visual and aphasic speech disturbances.

A 28-year-old man presented with a short history of headache, visual and aphasic speech disturbances. MR scans revealed a large, partly cystic, contrast-enhancing lesion of the left temporal lobe that upon microscopic examination was diagnosed as pleomorphic xanthoastrocytoma (PXA) with anaplastic features (WHO grade III). Remarkably, this tumor featured an unusual gliovascular, rosette-like histoarchitecture, which had previously been hypothesized to possibly indicate a greater likelihood of PXA recurrence. Indeed, only 14 months later, the patient presented with a recurrent lesion, which contained the previous histology, but now also featured a distinct fibrosarcoma-like component replete with numerous osteoclast-type giant cells. In addition, whereas eosinophilic granular bodies were plentiful at the lesion's periphery, numerous CD34 - positive satellite cells were found in the adjacent non-infiltrated cortex. Regarding the origin of this recurrent tumor and in reflection of its composition of distinct PXA as well as sarcomatous components, the diagnosis of a pleomorphic xanthoastrosarcoma, to be conceptually considered as a gliosarcoma subtype, was made.To our knowledge, this is an unprecedented case of sarcomatous transformation of a PXA. Particular attention should be given to gliovascular pseudopapillary structures in PXAs, the presence of which may potentially herald a more aggressive clinical behavior.

Microsurgical removal of intramedullary spinal cord gliomas in a rat spinal cord decreases onset to paresis, an animal model for intramedullary tumor treatment.

OBJECTIVE: Intramedullary spinal cord tumors (IMSCT) pose significant challenges given their recurrence rate and limited treatment options. Using our previously described rat model of IMSCT, we describe a technique for microsurgical tumor resection and present the functional and histopathological analysis of tumor progression. METHODS: Twenty-four Fischer 344 rats were randomized into two groups. All animals received a 5-microl intramedullary injection of 9L gliosarcoma cells. Animals were evaluated daily for signs of paralysis using the Basso, Beattie, and Bresnahan (BBB) scale. Group 1 continued with daily assessments using the BBB scale following tumor implantation, but received no further treatment. Group 2 underwent surgical removal of intramedullary tumor on postoperative day five. At a BBB score less than 5 (e.g., functional paraplegia), all animals of both groups were killed and sent for histopathological analysis. RESULTS: Group 1 had a median onset of functional hind limb paraplegia at 15 +/- 1.0 days. Group 2 had a median onset of hind limb paresis at 53 +/- 0.46 days. Hematoxylin-eosin cross-sections confirmed the presence of intramedullary 9L tumor invading the spinal cord in both groups. CONCLUSION: Animals with 9L IMSCTs consistently developed hind limb paraplegia in a reliable and reproducible manner. Animals undergoing microsurgical resection of IMSCT had a significant delay in the onset of functional paraplegia compared to the untreated controls. These findings suggest that this model may mimic the behavior of IMSCTs following operative resection in humans and thus may be used to examine efficacy of new treatment options for high-grade intramedullary tumors.

Detrimental effects of tumor progression on cognitive function of patients with high-grade glioma.

PURPOSE: There is growing recognition that the primary cause of cognitive deficits in adult patients with primary brain tumors is the tumor itself and more significantly, tumor progression. To assess the cognitive performance of high-grade glioma patients, prospectively collected cognitive performance data were analyzed. PATIENTS AND METHODS: We studied 1,244 high-grade brain tumor patients entered onto eight consecutive North Central Cancer Treatment Group treatment trials that used radiation and nitrosourea-based chemotherapy. Imaging studies and Folstein Mini-Mental State Examination (MMSE) scores recorded at baseline, 6, 12, 18, and 24 months were analyzed to assess tumor status and cognitive function over time. RESULTS: The proportion of patients without tumor progression who experienced clinically significant cognitive deterioration compared with baseline was stable at 6, 12, 18, and 24 months (18%, 16%, 14%, and 13%, respectively). In patients without radiographic evidence of progression, clinically significant deterioration in MMSE scores was a strong predictor of a more rapid time to tumor progression and death. At evaluations preceding interval radiographic evidence of progression, there was significant deterioration in MMSE scores for patients who were to experience progression, whereas the scores remained stable for the patients who did not have tumor progression. CONCLUSION: The proportion of high-grade glioma patients with cognitive deterioration over time is stable, most consistent with the constant pressure of tumor progression over time. Although other factors may contribute to cognitive decline, the predominant cause of cognitive decline seems to be subclinical tumor progression that precedes radiographic changes.

The effect of dexamethasone on the uptake of p-boronophenylalanine in the rat brain and intracranial 9L gliosarcoma.

The steroid dexamethasone sodium phosphate (DEX) is routinely used to treat edema in brain tumor patients. The objective of the present study was to evaluate the effects of DEX on the uptake of boronophenylalanine (BPA) using the rat 9L gliosarcoma tumor model and surrounding brain tissue. Two steroid dosage protocols were used. The high-dose DEX protocol involved five 3mg/kg intraperitoneal injections at 47, 35, 23, 11 and 1 h prior to the administration of the BPA for a total dose of 15 mg DEX/kg rat. The low-dose DEX administration protocol involved two doses of 1.5mg/kg at 17 h and 1h prior to BPA injection for a total dose of 3mg DEX/kg rat. The control animals received no pretreatment, prior to the administration of BPA. Seventeen days after tumor implantation, rats were injected i.p. with 0.014 ml/g body weight BPA solution (1200 mg BPA/kg; approximately 59 mg (10)B/kg). In all groups, rats were euthanized at 3h after BPA injection. Administration of the steroid had an effect on tumor weight, which decreased to approximately 78% (p > 0.05) of the control weight in the low-dose DEX group, and approximately 48% (p < 0.001) of the control weight in the high-dose DEX group. At 3 h after the administration of BPA, the concentration of boron in tumor was comparable (p > 0.1) in the control and high-dose DEX groups. The lowest mean value (73.8+/-1.6 microg/g) was obtained in the low-dose DEX group. This was significantly lower (p > 0.02) than the tumor boron contents in the high-dose DEX and control groups, which were 81.1+/-1.9 and 79.9+/-1.7 microg/g, respectively. Tumor:blood boron partition ratios for the control, low- and high-dose DEX groups were 2.3, 2.3 and 2.5, respectively. Boron concentrations were also measured in the normal brain and in the zone of brain adjacent to the tumor exhibiting edema. Although treatment with DEX had no appreciable effect on boron uptake in the normal brain of the rat, after the administration of BPA, it did impact on the boron levels in the zone of peritumoral edema. After the high-dose DEX administration protocol, boron levels in the zone of edema were reduced by approximately 14% (p < 0.02). This finding suggests that BPA targeting of tumor cells in the peritumoral zone could be compromised by DEX. These cells appear to play a critical role in tumor recurrence after BNCT or conventional radiotherapy.

Thymoma and multiple malignancies: a case of five synchronous neoplasms and literature review.

The presence of five discrete synchronous or metachronous primary neoplasms in a single patient is an extremely rare event. This is a report of a patient with a malignant (invasive) thymoma and four other independent primary neoplasms including: gliosarcoma, papillary thyroid cancer, meningioma and metastatic adenocarcinoma of the colon, found synchronously at autopsy. Thymoma patients appear to have an inherent predisposition towards developing additional neoplasms. Other than the thymoma, the presented patient had no obvious risk factors for neoplasia. This case provides evidence for an unusual syndrome of thymoma and multiple primary neoplasms. Further research is required to elucidate the mechanism of this association. Meanwhile, heightened awareness of this association may allow earlier detection and treatment of additional cancers in patients with a history of thymoma.

Gliosarcoma associated with a huge cyst--case report.

A 55-year-old female presented with a unique case of gliosarcoma with a huge cystic component manifesting as loss of consciousness, left-sided hemiparesis, and anisocoria. Computed tomography demonstrated a large cyst in the right frontal lobe, and enhancement of the mural nodule after administration of contrast medium. Emergent operation was performed. Xanthochromic fluid was aspirated, and the tumor was resected. The histological diagnosis was gliosarcoma based on the presence of gliomatous and sarcomatous components. She underwent a second operation because of tumor regrowth 3 weeks after the first operation. The postoperative course was satisfactory during radiation therapy with 60 Gy and chemotherapy. The diagnosis of gliosarcoma was difficult to make preoperatively because of the neuroradiological findings similar to low-grade gliomas. Gliosarcoma should be included in the differential diagnosis of huge cystic tumors.

Gliosarcoma metastatic to the cervical spinal cord: case report and review of the literature.

BACKGROUND: We describe a case of an intramedullary metastasis to the cervical spinal cord from a temporal gliosarcoma. CASE DESCRIPTION: A 48-year-old man with known temporal lobe gliosarcoma presented with a new onset of ipsilateral hemiparesis. A MRI scan revealed the presence of an intramedullary lesion in the spinal cord behind the body of C2. Despite repeated craniotomy, radiation, and chemotherapy, the patient succumbed to a rapidly progressive disease. CONCLUSION: The case illustrates the ability of gliosarcoma to metastasize to other locations in the neuroaxis. We believe this to be the first case report of an intramedullary spinal cord metastasis from a gliosarcoma. The pathological features and available literature are reviewed.

Intrathecal 5-[125I]iodo-2'-deoxyuridine in a rat model of leptomeningeal metastases.

UNLABELLED: The antitumor effect of 5-[125I]iodo-2'-deoxyuridine (125IUdR) was examined in a rat model of leptomeningeal metastases. In this model, 50% of rats develop paralysis of hind limbs. In 9.20 +/- 0.02 days and die in 12.1 +/- 2.1 days after intrathecal (i.t.) implantation of 5 x 10(5) 9L rat gliosarcoma cells. METHODS: Three days after implantation of 9L gliosarcoma cells, 125IUdR was administered intrathecally to rats as: (a) a single injection (500 microCi/rat), (b) five daily injections (100 microCi/day) or (c) a continuous 5-day infusion (0.5 microliter/hr, total of 500 microCi), and the animals were monitored for the onset of paralysis. Control groups received physiologic saline. For biodistribution studies, rats received a bolus injection of 125IUdR (10 microCi) 5 days after tumor-cell implantation and were killed 1, 8, 24, and 48 hr later. Tissues and organs, including the spinal cord, were isolated and their radioactive content determined. The results were expressed as percent injected dose per gram of wet tissue. Histological sections of the spinal cord were also prepared and used for autoradiographic detection of DNA-incorporated 125IUdR. RESULTS: Treatment with i.t. administered 125IUdR (500 microCi/rat) significantly (p < or = 0.005) prolonged the median time of paralysis to 11.2 +/- 0.1, 12.3 +/- 0.1 and 15.2 +/- 0.4 days for the single-dose, five daily injections and continuous infusion groups, respectively. Radioactivity cleared rapidly from all tissues except the thyroid and tumor cells growing within the spinal cord. Autoradiography demonstrated that normal cells in the tumor-bearing spinal cord were void of radioactivity. CONCLUSION: The results suggest that a selective antitumor effect could be achieved in treating leptomeningeal metastases with i.t. administered 125IUdR.

Gliosarcoma developing from an irradiated ependymoma.

A 17-year-old girl was operated for a cystic mass located deep within the left parieto-occipital white matter. Histologically the tumor was an ependymoma with a vascular stroma. In spite of irradiation the tumor recurred locally twice, 1 and 2 years respectively after the original operation. The ependymoma portion of the tumor remained unchanged, but the stroma showed increased vascular hyperplasia at the time of the second operation and transformation into a fibrosarcoma in the third operative specimen. Proliferating cell markers (MIB-1) were positive only in the ependymoma cell nuclei in the first two specimens, but were also extensively present in the nuclei of the fibrosarcoma in the third specimen. In the latter, the fibrosarcoma portion greatly overwhelmed the residual ependymoma islands, but remained sharply delineated from them. This is the first observed case of a gliosarcoma originating from an ependymoma. The histological pattern of this mixed tumor clearly indicates that the source of the sarcomatous portions was the neoplastically transformed fibrovascular stroma of the original tumor, rather than "desmoplastic" alterations of the neoplastic ependymal cells themselves.

Relationship of perfusion to edema in the 9L gliosarcoma.

The relationship between tumor perfusion and edema was analyzed, with edema characterized as tumor wet/dry weight ratio. Perfusion of subcutaneous 9L gliosarcoma was measured by injection of 133Xe in saline into the tumor core, followed by gamma camera imaging of 133Xe washout kinetics. A significant inverse correlation was found between edema and tumor perfusion (p < 0.0002), suggesting that edema can limit tumor perfusion, perhaps through a mechanism of increased interstitial fluid pressure. The perfusion rate of highly edematous tumors was reduced to less than 10% of the perfusion rate of less edematous tumors (p < 0.001). It was also found that tumor edema increased significantly with increasing tumor volume (p < 0.001), which could account for the finding that perfusion declined significantly with increasing tumor volume (p < 0.02). These findings are potentially important because it is possible to quantify tumor edema in vivo, with millimeter resolution, using 1H magnetic resonance imaging (MRI). Thus MRI may provide a non-invasive technique for characterizing tumor perfusion or tumor drug delivery.