Gliosarcomas (GS) are an uncommon histopathological subtype of glioblastoma accounting for 2% of cases. They have a similar age distribution and a male:female ratio of 1.6:1, and, unfortunately, they present the same poor prognosis as their glioblastoma counterparts. The clonal evolution of the tumour is thought to underlie the phenotypic changes observed in the glioblastoma cells.1,2 Patterns resembling osseous or chondroid differentiation are extremely rare. In some cases, the extensive sarcomatous area may obscure the real nature of the tumour, complicating the clinical management of the patient.

A 48-year-old woman was admitted to our institution with a sudden-onset headache that woke her up during the night, accompanied by nausea and a hypertensive crisis. Computed tomography (CT) revealed a lesion measuring 49mm×37mm×49mm with small calcifications. Magnetic resonance imaging (MRI) subsequently showed a right temporoparietal lesion with intense enhancement, a necrotic centre, a dural base with a dural tail sign, and hyperostosis of the inner table. The lesion was associated with significant adjacent oedema and a mass effect, causing a 7mm midline shift, which suggested a tumour with malignant characteristics (Fig. 1A and B). The patient underwent a right fronto-parieto-temporal craniotomy, which revealed a soft, well-demarcated nodular lesion, focally adhered to the dura but easily resectable. Total resection was achieved and confirmed on the post-operative MRI scan. No post-operative neurological deficits were detected.

Figure 1.

Magnetic resonance imaging (MRI). (A) Pre-operative axial T1-weighted MR image without gadolinium enhancement. (B) Pre-operative axial T1-weighted MR image with gadolinium enhancement. (C) Axial T1-weighted MR image without gadolinium enhancement, prior to the second surgery. (D) Axial T1-weighted MR image with gadolinium enhancement, prior to the second surgery.

Multiple whitish and fleshy fragments, with a total volume of approximately 10cm3, were received, and the entire sample was thoroughly examined. The pathologic findings suggested a diagnosis of primary cerebral osteosarcoma. Under the microscope, the lesion appeared as a highly cellular intraparenchymal tumour, composed of bundles of spindle cells arranged in a storiform pattern (Fig. 2). Extensive osteoid islands with a central chondroid appearance were clearly defined with the fusocellular population. All areas of spindle cells, chondroid tissue, and osteocytes exhibited nuclear atypia and high mitotic activity (20 mitotic figures per 2mm2). Necrotic areas comprised 50% of the tumour. This lesion, clearly resembling osteosarcoma, was surrounded by densely packed glial tissue, with some atypical forms, and focal microvascular proliferation, initially interpreted as reactive gliosis. Immunohistochemical analysis confirmed osteosarcoma differentiation, with MDM2 nuclear expression in the osteoid islands, but negative for CDK4 or nuclear STAT6. IDH1 immunohistochemistry was negative and GFAP was expressed in the peripheral area but minimally in the inner regions. Thus, the lesion was diagnosed as a primary cerebral chondroblastic osteosarcoma. A total body CT did not reveal any additional lesions. The patient was placed on a chemotherapy regimen consisting of cisplatin and doxorubicin.

Figure 2.

Gliosarcoma with osteosarcomatous component. (A) Glial component (#) with marked atypia and focal vascular proliferation (black arrow). (B) Osteoid islands interspersed between fusocelular population. Spindle cell, chondroid, and osteocyte areas exhibited nuclear atypia and high mitotic activity. (C) Osteoid islands with central chondroid appearance were clearly defined. (D) Endovascular proliferation and atypical glial cells. (E) GFAP immunohistochemical expression in the glial component. (F) MDM2 immunohistochemical nuclear expression. (G) Ki67 immunohistochemical expression at nuclear level (proliferative index: 50%).

The eighth-month follow-up MRI showed a local relapse, with a new mass measuring 27mm×14mm×19.5mm in the former resection cavity, along with a second nodular lesion measuring 4.5mm in a frontal location (Fig. 1C and D). As the patient experienced a recurrence despite osteosarcoma-directed chemotherapy, the initial diagnosis was reassessed by a second pathologist and reinterpreted as a gliosarcoma, based on the presence of atypical glial foci. A mild left hemiparesis was observed following the second surgery. A total body MRI revealed no other lesions. The recurrent tumour exhibited a histological appearance similar to the previous one, with extensive chondroblastic osteosarcoma-like areas surrounded by glial tissue with vascular proliferation and atypical glial cells, expressing GFAP and ATRX, and negative for IDH1 or p53. The Ki-67 proliferative index was 60% in the osteosarcoma-like areas and 20% in the glial areas. A comprehensive molecular next generation sequencing (NGS) study, using two panels comprising 250 genes, was performed on the first tumour (Oncomine Precision Assay and Oncomine Childhood Cancer Research Assay; Genexus, Thermofisher Scientific, Waltham, MA, USA). Three somatic mutations were identified: p.C136R in PTEN (in 75% of the cells), a homozygous deletion of CDKN2A, and a p.R175H mutation in TP53 (in 12% of the cells). No typical molecular changes of osteosarcoma were observed, including mutations in CDK4, RUNX, MYC, or MDM2 amplification. Molecular changes associated with primary cerebral sarcomas were also excluded, as there were no mutations in DICER, CIC, SMARCA, or SMARCB. A second craniotomy was performed, and the tumour was resected. Given the histological findings and the NGS data from the primary tumour, the recurrent tumour was microdissected in order to separately analyse the peripheral glioblastoma-like component and the central osteosarcoma-like component by NGS. Identical genetic changes were found in both components, including the p.C136R PTEN mutation and the homozygous deletion of CDKN2A. The second samples did not harbour the TP53 mutation. The final diagnosis was gliosarcoma with osteosarcomatous component.

When the histological appearance suggests a specific tumour type but its location raises questions, the expertise of the pathologist is essential. A glial area with minimal atypia, accompanied by endovascular proliferation or glomeruloid formations, should raise suspicion for gliosarcoma when a distinct sarcomatous component is present. Both primary and secondary intracranial sarcomas are well recognized1–3 and determining their intra- or extra-axial location can sometimes be challenging. In this case, the minimal glial component was misinterpreted as reactive gliosis, leading to a diagnosis that primarily focused on the abundant osteosarcomatous component. Genetic analysis can support diagnosis, particularly in rare entities like this case, where experience is limited, highlighting its value as a clinical tool. The genetics of GS remain poorly understood, with a profile similar to glioblastoma but with infrequent EGFR amplification. The most characteristic genetic features of gliosarcoma are PTEN mutations, CDKN2A deletions, and TP53 mutations, along with the absence of EGFR amplification.3–5

Although morphological and immunohistochemical studies are essential and often sufficient for diagnosing gliosarcoma, exploring the underlying genetics can be valuable for decision-making when clinical findings, disease evolution, radiological features, and histology are not aligned. NGS is not always feasible due to its cost and lack of immediate therapeutic applications for CNS tumours. However, its growing use presents challenges for diagnosis and prognosis in these tumours. Genetic profiling of central nervous system tumours has contributed to the refinement of WHO classifications over time. Further characterization of gliosarcoma could help identify potential molecular targets for future therapies, such as PTEN or CDKN2A alterations.3,4,6 Although TP53 is commonly altered in both osteosarcoma and glioblastoma, the specific TP53 p.R175H mutation is much more prevalent and characteristic of glioblastoma, where it is the second most frequent TP53 mutation.7,8 The absence of this change in GS recurrence may reflect a response to chemotherapy in the 10% of TP53 mutant-positive cells, as previously reported in breast and ovarian cancers.9PTEN mutations are found in 50% of glioblastomas.10 Additionally, gliomas are among the top five tumours harbouring the p.C136R mutation reported here, while osteosarcoma typically display PTEN epigenetic silencing or loss of heterozygosity. Notably, there is no entry for PTEN p.C136R in the COSMIC database for bone tumours (https://cancer.sanger.ac.uk/cosmic). Homozygous deletions of CDKN2A, are present in 60% of gliomas, supporting the diagnosis of gliosarcoma in our patient. CDKN2A deletions are observed in only 10% of osteosarcomas, with the majority being germline losses, which have been ruled out in our case.5,11 To our knowledge, co-deletions of these two genes have been occasionally reported.3,4,7 However, there are no reports of osteosarcomas with simultaneous CDKN2A deletion and PTEN mutation. Although the concurrent occurrence of TP53, PTEN, and CDKN2A alterations is not unequivocally diagnostic, the specific mutations detected in this case support a diagnosis of gliosarcoma, as these genetic changes are frequently observed in glioblastomas. Despite histopathological differences, it has been hypothesized that both the glial and mesenchymal components of GS derive from a unique neural stem cell and share specific genetic alterations. Interestingly, our findings of identical initiating mutations in PTEN and CDKN2A in both components support this hypothesis.3,5,7

Osteosarcomatous differentiation in gliosarcoma (GS) is rare, and despite recent advances, large series describing its molecular pathological characteristics remain scarce.7,8,11 In conclusion, this study offers a comprehensive histopathological analysis, supplemented by genetic investigations of a GS, which highlights the complexity of distinguishing between a GS with an osteosarcomatous component and a primary intracerebral osteosarcoma. Gliosarcoma should be the preferred diagnosis given its higher incidence and the fact that the malignant glial component may not be apparent, either due to early transformation into osteosarcoma or because the sarcomatous component can obscure the basal glioblastoma, losing not only its classic morphology but also its glial immunophenotype. This differentiation can be challenging when the typical biphasic pattern of alternating areas is not clearly present. The differential diagnosis between these tumour types should primarily rely on morphological evaluation, with next generation sequencing (NGS) serving as an adjunct, where possible, to support the diagnosis and enhance our understanding of the genetic landscape of central nervous system tumours.

The procedures were carried out in accordance with relevant laws and institutional guidelines. The case presented here is part of a broader collection that has been approved by the Institutional Research Ethics Committee of CHGUV (code 97/2023).

No patient data are included in the article, and if any are present, they do not violate patient privacy and confidentiality, nor do they allow for identification. The samples stored in the Pathology Departments were collected for diagnostic purposes to promote and safeguard patient health, not for experimental procedures.

This study was conducted without specific funding to declare.

The authors declare no conflict of interest.

The data supporting the findings of this study are available from the corresponding author upon reasonable request.