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

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

Molecular and clonal evolution in recurrent metastatic gliosarcoma.

We discuss the molecular evolution of gliosarcoma, a mesenchymal type of glioblastoma (GBM), using the case of a 37-yr-old woman who developed two recurrences and an extracranial metastasis. She was initially diagnosed with isocitrate dehydrogenase (IDH) wild-type gliosarcoma in the frontal lobe and treated with surgery followed by concurrent radiotherapy with temozolomide. Five months later the tumor recurred in the left frontal lobe, outside the initially resected area, and was treated with further surgery and radiotherapy. Six months later the patient developed a second left frontal recurrence and was again treated with surgery and radiotherapy. Six weeks later, further recurrence was observed in the brain and bone, and biopsy confirmed metastases in the pelvic bones. To understand the clonal relationships between the four tumor instances and the origin of metastasis, we performed whole-genome sequencing of the intracranial tumors and the tumor located in the right iliac bone. We compared their mutational and copy-number profiles and inferred the clonal phylogeny. The tumors harbored shared alterations in GBM driver genes, including mutations in TP53, NF1, and RB1, and CDKN2A deletion. Whole-genome doubling was identified in the first recurrence and the extracranial metastasis. Comparisons of the metastatic to intracranial tumors highlighted a high similarity in molecular profile but contrasting evidence regarding the origin of the metastasis. Subclonal reconstruction suggested a parallel evolution of the recurrent tumors, and that the metastatic tumor was largely derived from the first recurrence. We conclude that metastasis in glioma can be a late event in tumorigenesis.

Temporal Lobe Gliosarcoma After Gamma Knife Radiosurgery for Vestibular Schwannoma.

OBJECTIVE: Secondary tumorigenesis after exposure to ionizing radiation is a well-described phenomenon. The probability of developing a malignancy after stereotactic radiosurgery (SRS) is theoretically less than conventional external beam radiation therapy; however, the exact risk remains unknown. Such information is important for patient counseling when considering treatment of benign conditions such as vestibular schwannoma (VS). The objective of the current report is to describe a case of a temporal lobe gliosarcoma developing 3 years after radiosurgical treatment of a sporadic VS. SETTING: Tertiary academic referral center. PATIENT: A 54-year-old man was diagnosed with a left-sided 1.6 cm cerebellopontine angle mass, consistent with VS. After reviewing treatment options, the patient proceeded with radiosurgery, and a tumor volume of 2.4 cm was treated with a marginal dose of 12.5 Gy prescribed to the 50% isodose line. RESULTS: Serial magnetic resonance imaging (MRI) revealed good treatment response, demonstrated by central necrosis and tumor shrinkage. However, 3 years after treatment, the patient presented to the emergency department for a month long history of progressive word finding difficulties. Imaging revealed a 5 cm temporal lobe mass consistent with a high-grade glial neoplasm. He subsequently underwent stereotactic resection and final pathology confirmed World Health Organization Grade IV gliosarcoma. CONCLUSION: De novo malignancy after radiosurgery for VS is rare. We present only the second case of a gliosarcoma arising within the low-dose radiation field of the radiosurgery treatment plan. Some of the challenges of establishing causality between radiation treatment and secondary tumor development are discussed. The reporting of malignancy after radiation therapy, and even microsurgery, warrants continued vigilance.

Gliosarcoma arising from a fibrillary astrocytoma.

We report a 67-year-old woman who was diagnosed with a gliosarcoma at a second operation after diagnosis of a fibrillary astrocytoma 5 months previously. Initially, she underwent a CT-guided stereotactic biopsy. Histological examination showed fibrillary astrocytoma (World Health Organization [WHO] grade II). Loss of heterozygosity (LOH) on 1p, 10q, and 19q was not detected. She received chemotherapy, but no radiotherapy. Five months after the biopsy, MRI revealed rapid tumor growth. Tissue obtained from partial removal of the tumor revealed gliosarcoma (WHO grade IV), and LOH on 10q and 19q was detected. The history, histopathology, and genetic alterations of this patient are discussed.

Sarcoma arising as a distinct nodule within glioblastoma: a morphological and molecular perspective on gliosarcoma.

Gliosarcoma is a variant of glioblastoma and is characterized by distinct glial and sarcomatous components. Typically, there is no macroscopic boundary between the components and special stains are often required to distinguish the glial and sarcomatous elements. Some studies suggest similar genetic alterations in both components pointing to a common origin. We present an extreme case of gliosarcoma arising as a discrete fibrous nodule adjacent to a typical glioblastoma. A 65 year-old woman presented with progressive weakness, seizures and right-sided hemiparesis. CT scan demonstrated an irregular enhancing left frontal lobe mass and an adjacent discrete nodule with different imaging characteristics. The unique nature of this macroscopically biphasic neoplasm allowed us to compare the molecular characteristics of glial and sarcomatous elements which were strikingly similar except for small losses and gains in Chr 3. Studies are under way to determine the significance of chromosome 3 alterations in gliosarcomas.

Secondary gliosarcoma after diagnosis of glioblastoma: clinical experience with 30 consecutive patients.

OBJECT: Gliosarcoma can arise secondarily, after conventional adjuvant treatment of high-grade glioma. The current literature on the occurrence of secondary gliosarcoma (SGS) after glioblastoma multiforme (GBM) is limited, with only 12 reported cases. The authors present a large series of histologically confirmed SGSs, with follow-up to describe the clinical and radiological presentation, pathological diagnosis, and treatment outcomes. METHODS: Gliosarcoma cases were identified using the University of California, San Francisco's Departments of Neurological Surgery and Neuropathology databases. Through a retrospective chart review, cases of gliosarcoma were considered SGS if the following inclusion criteria were met: 1) the patient had a previously diagnosed intracranial malignant glioma that did not have gliosarcoma components; and 2) the histopathological tissue diagnosis of the recurrence confirmed gliosarcoma according to the most current WHO criteria. Extensive review of clinical, surgical, and pathology notes was performed to gather clinical and pathological data on these cases. RESULTS: Thirty consecutive patients in whom SGS had been diagnosed between 1996 and 2008 were included in the analysis. All patients had previously received a diagnosis of malignant glioma. For the initial malignant glioma, all patients underwent resection, and 25 patients received both external-beam radiation and chemotherapy. Three patients received radiotherapy alone, 1 patient was treated with chemotherapy alone, and 1 patient's tumor rapidly recurred as gliosarcoma, requiring surgical intervention prior to initiation of adjuvant therapy. The median time from diagnosis of the initial tumor to diagnosis of gliosarcoma was 8.5 months (range 0.5-25 months). All but 1 patient (who only had a biopsy) underwent a second operation for gliosarcoma; 8 patients went on to receive radiotherapy (4 had brachytherapy, 3 had external-beam radiation, and 1 had Gamma Knife surgery); and 14 patients received additional chemotherapy. The median length of survival from the time of gliosarcoma diagnosis was 4.4 months (range 0.7-46 months). The median survival from the time of the original GBM diagnosis was 12.6 months (range 5.7-47.4 months). Patients who had received concurrent and adjuvant temozolomide for GBM had worse outcomes than those who had not (4.3 and 10.5 months, respectively; p = 0.045). There was no difference in time to diagnosis of gliosarcoma in these 2 groups (8 and 8.5 months; p = 0.387). Two patients who had not received radiation therapy for GBM had an anecdotally very prolonged survival (20.9 and 46.4 months). CONCLUSIONS: The data underscore the difficulty associated with management of this disease. The strikingly poor survival of patients with SGS who had previously received combined radiation and temozolomide chemotherapy for GBM may reflect a unique molecular profile of GBM that eventually recurs as SGS. Further work will be required, controlling for multiple prognostic factors with larger numbers of patients.

Induction of gliosarcoma and atypical meningioma 13 years after radiotherapy of residual pilocytic astrocytoma in childhood.

BACKGROUND: Malignant transformation of pilocytic astrocytomas in children is rare and often linked to previous radiotherapy. METHODS AND RESULTS: We report a patient who underwent subtotal resection of a right temporal and insular pilocytic astrocytoma at age 8 in 1988 followed by high-dose radiation therapy. A local recurrence, grade WHO III, with signs of focal sarcomatous transformation, was subtotally resected 13 years later in 2001. A new and fast growing right frontal meningioma, grade WHO II, was removed in 2003. In 2004 a second glioma recurrence was partially resected, this time graded gliosarcoma WHO IV. The patient was treated thereafter with repeated courses of temozolomide. Another tumor mass reduction in 2005 was followed by stereotactic radiotherapy. Nevertheless, he deceased 3 months later. CONCLUSION: Most of the reported cases of malignant transformation of pilocytic astrocytomas received radiation therapy beforehand. Irradiation-induced meningiomas in children are known to occur, however not following radiotherapy of low-grade hemispheric gliomas. The presented case illustrates why adjuvant radiotherapy of residual pilocytic astrocytoma in children is not recommended anymore. For children who underwent radiotherapy in the past, we recommend MRI surveillance on a yearly basis far beyond 10 years, even in those who seem to have achieved total remission.

Gliosarcoma arising from an anaplastic ependymoma: a case report of a rare entity.

We report the first case of a gliosarcoma arising from an anaplastic ependymoma and the second case of gliosarcoma arising from any type of ependymal neoplasm. The patient was a 48-year-old woman with a solid and cystic, peripherally enhancing, 7-cm right frontal mass lesion. Histologically, the lesion displayed characteristics of anaplastic ependymoma (grade III, World Health Organization scale). The tumor recurred despite multiple cycles of postoperative radiation and chemotherapy. After the fourth recurrence, the tumor displayed a biphasic pattern of differentiation. The first pattern was similar to the original anaplastic ependymoma, whereas there was a second new sarcomatous pattern resembling fibrosarcoma that was admixed with and overrunning the ependymal component. The spectrum of gliosarcoma is therefore expanded to include not only astrocytic and oligodendroglial components but ependymal components as well.

Gliosarcoma occurring 8 years after treatment for a medulloblastoma.

CASE REPORT: We present a rare case of a gliosarcoma occurring 8 years following treatment for a medulloblastoma. The patient was diagnosed with a medulloblastoma at the age of 13 years. We considered the possibility of a radiation-induced tumour and present evidence supporting this view. The second cerebral tumour was excised and confirmed to be a gliosarcoma. The tumour bed was re-irradiated with three-dimensional conformal radiotherapy (3DCRT). She remained well for 6 months, after which there was clinicoradiological progression. CONCLUSIONS: During long-term follow-up of patients with medulloblastomas, the possibility of radiation-induced neoplasms must be borne in mind.

Radiation-associated gliosarcoma.

The authors report a case of radiation-associated intracerebral gliosarcoma with fibrosarcomatous predominance, arising at the site of a low-grade glioma treated 10 years previously. The features of this case conform to the accepted criteria for radiation-induced tumour, in that the tumour developed within the radiation field, differed dramatically in histologic features from the original tumour and did not develop until 10 years after treatment. Although such tumours are most uncommon, this case suggests that radiation-induced gliosarcoma should be considered in the differential diagnosis of recurrent mass at the site of a treated intracranial neoplasm.

Radiation-induced gliosarcoma. Case report and review of the literature.

A 13-year-old boy presented with a cerebral gliosarcoma 12 years after having acute lymphoblastic leukemia treated by chemotherapy and central nervous system prophylaxis treated by radiation therapy (24 Gy) and intrathecal methotrexate. A review of the literature disclosed 129 possible radiation-induced gliomatous and/or sarcomatous brain tumors: namely, 89 gliomas, 36 sarcomas, and four gliosarcomas, including the present case. An analysis of these cases revealed several characteristics that differentiate them from similar spontaneous brain tumors, thus providing arguments for the carcinogenic effect of radiation therapy on intracranial tumors.