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.

Neuroinflammation After Stereotactic Radiosurgery-Induced Brain Tumor Disintegration Is Linked to Persistent Cognitive Decline in a Mouse Model of Metastatic Disease.

PURPOSE: Improved efficacy of anticancer therapy and a growing pool of survivors give rise to a question about their quality of life and return to premorbid status. Radiation is effective in brain metastasis eradication, although the optimal approach and long-term effects on brain function are largely unknown. We studied the effects of radiosurgery on brain function. METHODS AND MATERIALS: Adult C57BL/6J mice with or without brain metastases (rat 9L gliosarcoma) were treated with cone beam single-arc stereotactic radiosurgery (SRS; 40 Gy). Tumor growth was monitored using bioluminescence, whereas longitudinal magnetic resonance imaging, behavioral studies, and histologic analysis were performed to evaluate brain response to the treatment for up to 18 months. RESULTS: Stereotactic radiosurgery (SRS) resulted in 9L metastases eradication within 4 weeks with subsequent long-term survival of all treated animals, whereas all nontreated animals succumbed to the brain tumor. Behavioral impairment, as measured with a recognition memory test, was observed earlier in mice subjected to radiosurgery of tumors (6 weeks) in comparison to SRS of healthy brain tissue (10 weeks). Notably, the deficit resolved by 18 weeks only in mice not bearing a tumor, whereas tumor eradication was complicated by the persistent cognitive deficits. In addition, the results of magnetic resonance imaging were unremarkable in both groups, and histopathology revealed changes. SRS-induced tumor eradication triggered long-lasting and exacerbated neuroinflammatory response. No demyelination, neuronal loss, or hemorrhage was detected in any of the groups. CONCLUSIONS: Tumor disintegration by SRS leads to exacerbated neuroinflammation and persistent cognitive deficits; therefore, methods aiming at reducing inflammation after tumor eradication or other therapeutic methods should be sought.

Primary Cerebellar Gliosarcoma with Extracranial Metastases: An Orphan Differential Diagnosis.

BACKGROUND: Gliosarcomas are rare, malignant primary brain tumors, most commonly located in the temporal lobe, that contain both glial and mesenchymal elements. Gliosarcomas located within the cerebellum are exceedingly rare. The previously unreported finding of a cerebellar gliosarcoma concurrently with an extracranial metastasis to the lungs is discussed here. CASE DESCRIPTION: A 57-year-old man presented with a 3-month history of chest pain, weight loss, headaches, and vomiting. Physical examination revealed a left cerebellar dysfunction, and the radiological work-up revealed a 6 × 6-cm right apical pulmonary tumor and a 4 × 3.5 × 3.8-cm peripherally enhancing left cerebellar mass. On the basis of a smoking history in the setting of a lung lesion and cerebellar mass, the presumptive diagnosis was primary lung cancer with metastasis to the cerebellum. Gross total resection of a firm pseudo-encapsulated cerebellar mass was performed. The microscopic features and the immunohistochemical profile confirmed the diagnosis of Gliosarcoma. The thoracic lesion was removed subsequently, and pathology confirmed it as an extracranial metastasis from the cerebellar gliosarcoma. Adjuvant radiation and chemotherapy were then administered. No clinical or radiographic evidence of recurrence was observed during one year of follow-up monitoring. CONCLUSIONS: To the best of our knowledge, a primary infratentorial gliosarcoma with extracranial metastases has not been previously described.

Spinal metastasis of gliosarcoma: array-based comparative genomic hybridization for confirmation of metastatic spread.

We report a 64-year-old woman who underwent craniotomy and gross total resection of a left frontal lobe tumor initially diagnosed as glioblastoma. Multiple wound revisions were necessary due to repeated wound healing disorders under concomitant radio-chemotherapy. After 9 months there was local cranial tumor recurrence, requiring re-operation. Thereafter, temozolomide monotherapy was implemented. Histologically, a shift from glial to mesenchymal differentiation was observed in the recurrent tumor, resulting in the diagnosis of gliosarcoma. A further 9 months later a thoracic spinal tumor occurred requiring emergency tumor resection. Analysis showed a mesenchymal tumor without definite glial component. Being resistant to local radiation therapy, symptomatic local spinal tumor progression was observed within 1 month requiring re-resection. There was no response to chemotherapy with bevacizumab and irinotecan. Considering the pronounced sarcoma-like differentiation, a sarcoma chemotherapy regime with doxorubicin was initiated. This was also to no avail; the disease progressed and recurred at both the spinal and cerebral locations, respectively. This ambiguous tumor characteristic and therapy resistance encouraged us to retrospectively perform molecular and array-based comparative genomic hybridization (aCGH) analysis on the extirpated cerebral and spinal tumors. Tumors from both locations showed a consistent cytogenetic signature of gain of chromosome 7, and losses of chromosomes 10 and 13. This novel report of aCGH analysis of spinal gliosarcoma metastasis and the correlation to the clinical disease course shows that genotypic profiling may serve as a supplementary diagnostic tool in improving our knowledge of the biologic behavior of rare tumor variants.

A nonradiated grade II glioma that underwent delayed malignant transformation to a gliosarcoma with meningeal growth and dissemination.

BACKGROUND: Secondary gliosarcomas are rare tumors, especially those arising from a World Health Organization (WHO) grade II glioma not irradiated. We report a case with subtotal resection for a WHO grade II oligoastrocytoma, without adjuvant treatment, whose metaplastic transformation into gliosarcoma suddenly occurred 4 years later with meningeal dissemination. We show a favorable outcome after therapeutic management of this rare entity. PATIENT: A 46 year-old woman underwent surgery for a right premotor WHO grade II oligoastrocytoma discovered incidentally. Because of a subtotal resection with only 1 cc of residue, no complementary therapy was given, and the patient enjoyed a normal life for 4 years. In the meantime, the magnetic resonance images performed every 6 months showed a very low growth rate. Suddenly, the tumor switched toward a gliosarcoma profile with meningeal dissemination. RESULTS: Reoperation, radiotherapy, and chemotherapy were performed, enabling a control of the disease with 15 months of follow-up (i.e., with radiologic shrinkage of the multiple lesions and preservation of quality of life). CONCLUSION: A delayed sarcomatous transformation can acutely occur with a low proliferation index in a nonirradiated WHO grade II oligoastrocytoma. Furthermore, an aggressive therapeutic strategy can allow control of secondary gliosarcomas, even in cases of leptomeningeal spreading.

[Spinal cord metastasis from gliosarcoma. Case report and review of the literature]. / Metástasis medulares de gliosarcoma. Presentación de un caso y revisión de la literatura.

INTRODUCTION: Gliosarcoma is a rare neoplasm of the central nervous system, similar to glioblastoma multiforme. In contrast to glioblastoma, it is characterised by its propensity for extracranial metastasis (11% of the cases) due to its sarcomatous component. Intramedullary metastasis from primary gliosarcoma is extremely rare. CASE REPORT: A patient who had surgery for primary cerebral gliosarcoma developed paraparesis during the course of the disease. A magnetic resonance image showed an intramedullary spinal cord metastasis requiring surgical treatment. This article reviews the literature on intramedullary spinal cord metastasis from gliosarcoma, and highlights the characteristics, treatment and overall survival. CONCLUSIONS: Only 4 cases of intramedullary gliosarcoma metastasis are described in the literature. This extremely rare entity should be suspected with the onset of spinal cord symptoms during the course of primary cerebral gliosarcoma.

Secondary gliosarcoma with extra-cranial metastases: a report and review of the literature.

OBJECTIVE: To describe a unique case of secondary gliosarcoma (SGS) with widespread extra-cranial metastases that developed more than 5 years after the initial diagnosis of glioblastoma multiforme (GBM). This interval is the longest among the cases reported to date. METHODS: A PUBMED search using the key words "secondary gliosarcoma" and "extra-cranial metastases" was performed followed by a review of cited literature. RESULTS: Including our report, we found 44 cases of SGS, of which only 5 developed extra-cranial metastases. CONCLUSION: SGS with extra-cranial metastases is extremely rare. Of previously reported cases, the longest survival was 2 months after the diagnosis of SGS. The present case had a survival of 6.5 months. Our case highlights the importance of screening for extra-cranial metastases in SGS. The optimal treatment of SGS is not known and strategies based on GBM and sarcoma treatments have been employed with limited success. A combination of treatment modalities may extend survival as in the present report; however the prognosis remains poor.

Gliosarcoma metastatic to the leptomeninges and dura.

We describe a rare case of a patient with left frontotemporal gliosarcoma, which metastasized through the cerebrospinal fluid (CSF) to the leptomeninges and pachymeninges. Pathologically confirmed, magnetic resonance imaging-visible leptomeningeal spread of gliosarcoma via the CSF has not been previously reported.

Gliosarcoma of the pineal region with cerebellar metastasis: case illustration.

A very rare case of gliosarcoma of the pineal region with cerebellar metastasis is presented. A few cases of glioblastoma and fibrosarcoma have already been published however there was no reported case with gliosarcoma at the pineal region even with cerebellar metastases.

Case report: extracranial metastasis from gliosarcoma--the influence of immune system.

Extracranial metastasis of malignant glioma is an extremely rare event. We report on a 67-year-old patient with a primary gliosarcoma that was treated by open resection. The concomitant radio-chemotherapy which followed induced an unusually severe and early leucocytopenia. Ten months after diagnosis, the patient presented with multiple metastases in the lung and the skeletal system. The clinical, radiological and neuropathological findings are described. In addition, we discuss the possible role of a compromised immune system in the development of extracranial glioma metastasis.

Metastatic gliosarcoma mass extension to a donor fascia lata graft harvest site by tumor cell contamination.

BACKGROUND: Brain glioblastoma multiforme is a malignant and highly aggressive entity that rarely shows extracranial and extraneural invasion. In the past 70 years, only eight cases of subcutaneous metastases have been reported. CASE DESCRIPTION: A case of glioblastoma multiforme with extensive local cutaneous and subcutaneous involvement of previous surgical sites and a metastatic mass, which had developed in the graft donor area of the tensor fascia lata tendon used for the reconstruction of dura. According to the excisional biopsy results, the developed mass was defined as a gliosarcoma carrying the exact characteristics of the primary tumor. CONCLUSIONS: Contaminated surgical tools and instruments can facilitate the distant spread of tumor cells. Therefore, the renewal of the surgical tools and instruments and irrigation of the surgical area after primary tumor resection is emphasized.

Temporal gliosarcoma with extraneural metastasis: case report.

A 51-year-old woman presented with a rare case of temporal gliosarcoma manifesting as a 2-month history of headache that rapidly penetrated the middle fossa floor postoperatively and metastasized to the lung. The tumor included an anteroinferior component consisting of a sarcomatous lesion adjacent to the middle fossa floor, and a posterosuperior component consisting of a gliomatous lesion. The MIB-1 index of the sarcomatous component was 47.5%, and that of the gliomatous component was 36.5%. In addition to the highly proliferative nature of the sarcomatous component, the craniotomy with partial excision of the dura mater might have accelerated the tumor penetration through the temporal base and the hematogenous metastasis to the lung.

Metastatic gliosarcoma with a unique presentation and progression: case report and review of the literature.

A 51-year-old right-handed woman initially presented with generalized tonic-clonic seizures. MRI showed abnormal signal hyperintensity of the right temporal lobe that was thought to be consistent with ischemic stroke. Three years later, she developed an intensely enhancing centrally necrotic tumor in the right temporal-parietal lobes. A craniotomy was performed with gross total resection of the tumor followed by chemotherapy and radiation treatments. Histological examination demonstrated a gliosarcoma. A year later, she had a recurrence of the intra-axial gliosarcoma requiring a second craniotomy for tumor resection and placement of Gliadel wafers. Postoperatively, she developed plural effusions. A pulmonary workup revealed lung lesions that were biopsied and found to be gliosarcoma. After the second surgery, she underwent pleurodesis and one cycle of modified mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) chemotherapy, but died 5 months later from progression of the lung metastases. There are fewer than 20 reported cases of extracranial metastases of gliosarcoma. This is the first report of gliosarcoma with prolonged survival (over 2 years) and death from non-CNS metastatic gliosarcoma.

Secondary gliosarcoma: a review of clinical features and pathological diagnosis.

OBJECT: Although secondary gliosarcoma after treatment of primary glioblastoma multiforme has been described, little is known of these rare tumors. In this article the authors review the literature on secondary gliosarcoma, with attention to clinical course and pathological features. METHODS: A PubMed search of the key word intracranial "gliosarcoma" with and without "radiation" or "radiotherapy" in humans was performed. The 204 citations yielded were screened for relevancy to gliosarcomas that occur after treatment of previous intracranial neoplasms. RESULTS: A search of the literature yielded 24 relevant articles, combined for a total of only 12 cases of secondary gliosarcoma and 12 cases of radiation-induced gliosarcoma. Of the 12 cases of secondary gliosarcoma, all were previously treated with surgery and radiotherapy (mean dose 50.7 Gy), with a mean survival of 13 months since time of gliosarcoma diagnosis (range 6.9-19.4 months). In the cases of radiation-induced gliosarcoma, the mean dose of previous radiotherapy was 51.3 Gy (median 54 Gy, range 24-60 Gy), and the mean survival since gliosarcoma diagnosis was 6.7 months (median 6 months, range 2-10 months). CONCLUSIONS: Secondary gliosarcoma and radiation-induced gliosarcoma are exceedingly rare. The literature on secondary gliosarcoma illustrates a more favorable survival than for primary gliosarcoma but remains limited regarding clinical and radiographic presentation, response to treatment, and pathogenesis. The results of the present review also support the notion that secondary gliosarcomas and radiation-induced gliosarcomas are distinct entities, with longer survival and shorter latency of gliosarcoma induction seen in the former. Efforts to elucidate the role of radiotherapy in the induction of gliosarcomas may yield new insights into therapeutic risks of cranial radiation and CNS tumor pathogenesis.

Gliosarcoma with multiple extracranial metastases: case report and review of the literature.

Gliosarcoma is a rare malignant neoplasm of the central nervous system with a propensity for metastasis. There are fewer than 20 reported cases of extracranial metastases of gliosarcoma with the majority of cases reflecting a tendency for hematogenous dissemination. Here we describe the case of a 47-year-old man who developed pervasive extracranial metastases from a temporal gliosarcoma following radio- and chemotherapy for a primary glioblastoma. The patient initially presented with progressively worsening headaches, left-sided weakness and numbness associated with right temporo-parietal mass for which he underwent craniotomy with stereotactic gross-total excision. Two months postoperatively, interstitial brachytherapy and external beam radiotherapy were initiated. The patient initially declined chemotherapy. The tumor recurred twice and the patient underwent re-operation and multiple courses of chemotherapy; histopathological diagnosis remained glioblastoma multiforme. Nineteen months following initial resection the patient's clinical status deteriorated and CT scan demonstrated multiple intrathoracic, hepatic and splenic lesions. Postmortem examination revealed widespread, infiltrating gliosarcoma with intravascular gliomatosis and extensive visceral metastases. This is the first report of pervasive extracranial metastases to numerous sites, several of which have not been previously reported. The histogenesis and the potential role of therapeutic irradiation in the development of gliosarcoma are briefly reviewed.

Cavernous sinus tumor model in the canine: a simulation model for cavernous sinus tumor surgery.

OBJECTIVE: The recent limitations of working hours for neurosurgical trainees carry the risk of decreasing the amount of microsurgical experience. In the absence of enough surgical exposure to some pathological states, an alternative option of a more continuous source of tactile and visual experience that simulates the real-life state is needed. To help with this problem, we established a cavernous sinus tumor model in the canine. METHODS: A gliosarcoma cell line that was harvested from a tumor model in nude mice was implanted in six mongrel dogs. In the first group (two dogs), the cell line was implanted in the dural leaflets of the cavernous sinus. (Immunosuppression was used in one dog.) In the second group (four dogs), the cell line was implanted in the region of the gasserian ganglion. (Immunosuppression was used in all four dogs.) The condition of each dog was followed through neurological examinations and serial magnetic resonance imaging. The cavernous sinus region later was explored, after which the dogs were later killed and histopathological evaluations of the cavernous sinus region was carried out. RESULTS: The initial cell line implanted within the dural leaflets of the cavernous sinus showed no evidence of tumor growth. The tumor grew in all four dogs that had the gliosarcoma cell line implanted in the region of the gasserian ganglion. The clinical and radiological features as well as the experience of the surgical dissection of these tumors simulated cavernous sinus tumors in humans. CONCLUSION: We established the first cavernous sinus tumor model in the canine. This model simulates the real-life pathological state, and it can be used as an alternative source of surgical experience to advance surgical skills.