Clinical Characteristics of Gliosarcoma and Outcomes From Standardized Treatment Relative to Conventional Glioblastoma

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Abstract

Background: Gliosarcoma (GS) is a rare histopathologic variant of glioblastoma (GBM) characterized by a biphasic growth pattern consisting of both glial and sarcomatous components. Reports regarding its relative prognosis compared to conventional GBM are conflicting and although GS is treated as conventional GBM, supporting evidence is lacking. The aim of this study was to characterize demographic trends, clinical outcomes and prognostic variables of GS patients receiving standardized therapy and compare these to conventional GBM.

Methods: Six hundred and eighty GBM patients, treated with maximal safe resection followed by radiotherapy with concomitant and adjuvant temozolomide at a single institution, were retrospectively reevaluated by reviewing histopathological records and tumor tissue for identification of GS patients. Clinico-pathological- and tumor growth characteristics were obtained via assessment of medical records and imaging analysis. Kaplan-Meier survival estimates were compared with log-rank testing, while Cox-regression modeling was tested for prognostic factors in GS patients.

Results: The cohort included 26 primary gliosarcoma (PGS) patients (3.8%) and 7 secondary gliosarcoma (SGS) patients (1.0%). Compared to conventional GBM tumors, PGS tumors were significantly more often MGMT-unmethylated (73.9%) and located in the temporal lobe (57.7%). GS tumors often presented dural contact, while extracranial metastasis was only found in 1 patient. No significant differences were found between PGS and conventional GBM in progression-free-survival (6.8 and 7.6 months, respectively, p = 0.105) and in overall survival (13.4 and 15.7 months, respectively, p = 0.201). Survival following recurrence was not significantly different between PGS, SGS, and GBM. Temporal tumor location and MGMT status were found associated with PGS survival ( p = 0.036 and p = 0.022, respectively).

Conclusion: Despite histopathological and location difference between GS and GBM tumors, the patients present similar survival outcome from standardized treatment. These findings support continued practice of radiation and temozolomide for GS patients.

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Most cited references 53

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Genetic profile of gliosarcomas.

Rui Reis, Dilek Könü-Lebleblicioglu, José Manuel Lopes … (2000)

There are distinct genetic pathways leading to the glioblastoma, the most malignant astrocytic brain tumor. Primary (de novo) glioblastomas develop in older patients and are characterized by epidermal growth factor (EGF) receptor amplification/overexpression, p16 deletion, and PTEN mutations, whereas secondary glioblastomas that progressed from low-grade or anaplastic astrocytoma develop in younger patients and frequently contain p53 mutations. In this study, we assessed the genetic profile of gliosarcoma, a rare glioblastoma variant characterized by a biphasic tissue pattern with alternating areas displaying glial and mesenchymal differentiation. Single-strand conformation polymorphism followed by direct DNA sequencing revealed p53 mutations in five of 19 gliosarcomas (26%) and PTEN mutations in seven cases (37%). Homozygous p16 deletion was detected by differential polymerase chain reaction in seven (37%) gliosarcomas. The overall incidence of alterations in the Rb pathway (p16 deletion, CDK4 amplification, or loss of pRb immunoreactivity) was 53%, and these changes were mutually exclusive. Coamplification of CDK4 and MDM2 was detected in one gliosarcoma. None of the gliosarcomas showed amplification or overexpression of the EGF receptor. Thus gliosarcomas exhibit a genetic profile similar to that of primary (de novo) glioblastomas, except for the absence of EGFR amplification/overexpression. Identical PTEN mutations in the gliomatous and sarcomatous tumor components were found in two cases. Other biopsies contained p16 deletions, an identical p53 mutation, or coamplification of MDM2 and CDK4 in both tumor areas. This strongly supports the concept of a monoclonal origin of gliosarcomas and an evolution of the sarcomatous component due to aberrant mesenchymal differentiation in a highly malignant astrocytic neoplasm.

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Primary gliosarcoma: key clinical and pathologic distinctions from glioblastoma with implications as a unique oncologic entity

Seunggu J Han, Isaac Yang, Tarik Tihan … (2009)

This report presents the historical experience, clinical presentation, treatment, prognosis, and pathogenesis of gliosarcoma described to date in the English literature. PubMed query of term “gliosarcoma” was performed, followed by a rigorous review of cited literature. Articles selected for analysis included: (1) case reports of gliosarcoma, (2) review articles of gliosarcoma, and (3) studies of the pathogenesis or genetics of gliosarcoma in humans. Our review identified 219 cases of gliosarcoma in 34 reports and eight articles addressing the pathogenesis. Survival in larger series ranged 4–11.5 months. Features unique to gliosarcoma compared to glioblastoma (GBM) include their temporal lobe predilection, potential to appear similar to a meningioma at surgery, repeated reports of extracranial metastases, and infrequency of EGFR mutations. Published experience is limited to small case series, and the pathogenesis remains unclear. Clinical and pathologic characteristics distinct from GBM suggest that they may warrant specific treatment, separate from conventional GBM therapy.

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Extra central nervous system metastases from cerebral glioblastoma multiforme in elderly patients. Clinico-pathological remarks on our series of seven cases and critical review of the literature.

Manolo Piccirilli, Giacoma Brunetto, Giovanni Rocchi … (2016)

The aim of the study was to evaluate the treatment of the extracranial metastases from glioblastoma multiforme in the elderly, discussing their uncommon occurrence and their pathogenesis. The authors report seven cases of elderly patients (mean age, 69 years), with an initial diagnosis of cerebral glioblastoma multiforme, treated by a grossly total surgical removal and followed by adjuvant radiotherapy (64 Gy in 6 weeks, using Linac) and adjuvant chemotherapy (temozolomide both concomitant and sequential to radiotherapy). All patients presented a postoperative course characterized by good functional and clinical conditions (Karnofsky performance scale > or =70), which remained unchanged for a mean period of about 21 months (range, 16-23), with no neuroradiological signs of lesion regrowth. After this interval, new clinical signs occurred, and their clinical and radiological investigation showed metastatic repetitions in different sites: lung, liver, humerus and lymph nodes. All the metastases were surgically treated, but regrowth of the brain tumor and progression to deep important neural structures caused the patients' exitus after a mean interval of about 10 months (range, 8-12) from the diagnosis of metastasis. We found 128 cases of extra CNS metastases in the English literature. The main features of the patients of the previous reports and of those of the present series were analyzed. The main modalities of glioblastoma multiforme spread, the few theories about the rarity of metastasis, and the probable biological, histological and immunogenetic mechanisms involved in the pathogenesis are described. Although several studies have reported a poor outcome in elderly patients, they affirm that the treatment of those with a Karnofsky performance status >60 should be just as aggressive as in younger patients. This allows them to obtain a longer survival time and to also treat metastases, which are uncommon particularly in the elderly.

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Author and article information

Contributors

Simone Frandsen: URI : http://loop.frontiersin.org/people/823281/overview

Signe Regner Michaelsen: URI : http://loop.frontiersin.org/people/773881/overview

Journal

Journal ID (nlm-ta): Front Oncol

Journal ID (iso-abbrev): Front Oncol

Journal ID (publisher-id): Front. Oncol.

Title: Frontiers in Oncology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 2234-943X

Publication date (Electronic): 17 December 2019

Publication date Collection: 2019

Volume: 9

Electronic Location Identifier: 1425

Affiliations

[1] ¹Department of Radiation Biology, Rigshospitalet , Copenhagen, Denmark

[2] ²Department of Pathology, Rigshospitalet , Copenhagen, Denmark

[3] ³Department of Radiology, Rigshospitalet , Copenhagen, Denmark

[4] ⁴Department of Oncology, Rigshospitalet , Copenhagen, Denmark

[5] ⁵Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen, Denmark

Author notes

Edited by: Marcos V. C. Maldaun, Hospital Sírio-Libanês, Brazil

Reviewed by: Brad E. Zacharia, Penn State Milton S. Hershey Medical Center, United States; Enrico Franceschi, IRCCS Institute of Neurological Sciences of Bologna (ISNB), Italy

*Correspondence: Signe Regner Michaelsen signe.regner.michaelsen@ 123456regionh.dk ; signe.michaelsen@ 123456bric.ku.dk

This article was submitted to Neuro-Oncology and Neurosurgical Oncology, a section of the journal Frontiers in Oncology

Article

DOI: 10.3389/fonc.2019.01425

PMC ID: 6928109

PubMed ID: 31921679

SO-VID: f6786b36-d38a-4a1e-8c26-d8ad21cc63a2

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 25 July 2019

Date accepted : 29 November 2019

Page count

Figures: 2, Tables: 3, Equations: 0, References: 57, Pages: 11, Words: 7381

Funding

Funded by: Rigshospitalet 10.13039/501100005111

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Clinical Characteristics of Gliosarcoma and Outcomes From Standardized Treatment Relative to Conventional Glioblastoma

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Karger: Oncology

Most cited references 53

Genetic profile of gliosarcomas.

Primary gliosarcoma: key clinical and pathologic distinctions from glioblastoma with implications as a unique oncologic entity

Extra central nervous system metastases from cerebral glioblastoma multiforme in elderly patients. Clinico-pathological remarks on our series of seven cases and critical review of the literature.

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