Gliosarcoma (GS) was first described by Strӧebe in 1895, but its acceptance and complete understanding developed later thanks to the detailed description provided by Feigen and Gross in 1955. They were the first to recognize three malignant brain tumors composed of two different tissues: one of glial origin, similar to Glioblastoma, and the other of mesenchymal origin, with characteristics reminiscent of spindle cell sarcomas ^[1][2][3][1,2,3]. In the 2000 World Health Organization (WHO) Classification, GS was first recognized as a variant of GBM [4]. In 2016 and 2021, WHO successfully classified GS as a variant of GBM with IDH-wild type phenotype ^[5][6][5,6]. Effectively, the radiological, biomolecular, and clinical features reported in the literature about GS are similar to those of GBM. GS is described as a rare form of neoplasm with an inferior prognosis [7]. Its incidence varies between 1% and 8% of all malignant gliomas, representing only 0.48% of all brain tumors and from 1.8% to 2.8% of cases of GBM ^[2][7][8][9][2,7,8,9]. GS are most common in adults, with a median age of diagnosis of 60 years, with a male predilection (M:F 1.8:1). In pediatric individuals, it is scarce. With regard to ethnicity, it is more frequent in the white and non-Hispanic races ^{[1][2][8][10][11]}[1,2,8,10,11]. This type of cancer can occur in both primary and secondary forms, with the latter thought of arising from previously treated GBM. From a therapeutic point of view, the commonly used strategy is the same adopted for GBM, or the Stupp protocol, which involves the administration of TMZ concomitantly with RT ^[2][12][13][2,12,13]. Nevertheless, without any treatment, the prognosis of GS is inferior, with a median survival of approximately four months [9]. While with standard treatments, survival for GS remains still poor, with a median survival of 9 months, compared to other forms of GBM associated with an average of 15 months survival ^[9][14][15][9,14,15]. Moreover, the most recent literature suggests that GS may have neuroradiological, histological, and biomolecular characteristics that differ from GBM ^[8][11][16][8,11,16].

2. Radiological Features: GS vs. GBM

GS may have some radiological characteristics that can help to distinguish it from GBM. These features include well-demarcated margins, solid-cystic components, the salt and pepper (S–P) sign (a crescent-shaped area of enhancement at the junction of the solid and cystic components), an uneven rim- and a ring-like or paliform enhancement (P-E) patterns enhancement, intra-tumoral strip enhancement, involvement of deep structures such as the thalamus, brainstem, and spinal cord. In addition, GS may also present with other radiological findings, such as midline shift, mass effect, and calcifications ^[3][11][3,11]. However, although they are typical radiological features of GS, similar radiological features can also be observed in several brain tumors, including GBM and high-grade gliomas (HGG) ^{[3][11][17][18]}[3,11,55,56]. Yi et al. ^[17][55], in their radiological analysis, found that the degree of tumor wall thickening tends to be more significant in GS compared to GBM. Moreover, GS, unlike GBM, seems to have a higher rate of bleeding, S–P signs, an eccentric cystic portion (ECP), and a P-E pattern. In their 48 patients, they found that GS tumors are typically larger than GBM tumors, with more areas of enhancement. Unlike GBM, GS tumors are more likely to involve the brain’s cortex and are less likely to have necrosis, invade the ependyma, and cause edema that crosses the brain’s midline ^[17][55]. Moreover, a higher percentage of eccentric tumor cysts in GS was found (19/48, 39.6%) [12]. Zhang et al. [11], in their retrospective single-center study focused on 103 GS, found that 67 tumors were single lesions, and 31 were cystic, solid lesions. All GS showed marked enhancement, and most tumors showed it in functional areas. Notably, 35, 4, 15, 13, and 22 patients showed a pattern of enhancement in the thalamus, brainstem, motor available cortex, sensory functional cortex, and the ependyma of the lateral ventricle, respectively. On T2WI MRI sequences, the average edema diameter was calculated at 7.90 cm (range, 3.55–12.88 cm), and the median tumor diameter evaluated by contrast-enhanced T1WI was 4.84 cm (range, 1.58–8.73 cm) [11]. Tumors involved the frontal, parietal, temporal, or multiple lobes in 18, 6, 29, and 40 patients. While only in 5 patients, the tumors were located in different areas (thalamus, ventricle, brainstem, and spinal cord). Similar results have been reported by Xi et al. ^[17][55]. In their series of 48 patients, GS was mainly located in the temporal lobe (27%), frontal lobe (17%), and ventricles (10%), while more rarely in the parieto-occipital lobes (2%), brainstem, and cerebellum (2%). Regarding the laterality, the right hemisphere is mainly affected ^[17][55]. Aya Fukuda et al. ^[19][57], in their report of three patients, described that at the CT scan, GS typically appears as an expansive lesion with well-delimited and irregular contours, associated with perilesional edema with a frequent hyperattenuating sign of the solid part. Regarding MRI on the T1- and T2-weighted sequences of MRI, GS were characterized as uneven, heterogeneous tumors correlated with bleeding at distinct stages with a hypo-isointense on T1 and as hypo/iso/hyperintense on T2 of the solid part. Similarly, the necrotic part was described as hypointense on T1 and hyperintense on T2. Inhomogeneous enhancement of the solid components occurred after the injection of gadolinium. The SWI or T2* sequence supplied other information; the variable magnetic susceptibility (high heterogeneity) areas showed hypointensity within the tumor due to bleeding or newly formed vessels/flow voids. On DWI/ADC mapping sequences, GSM has previously been associated with hyperintensity on DWI and hypointensity in the solid component on the ADC map (compatible with restricted diffusion) ^[19][57]. Han et al. ^[20][58]. classified two different subgroups of patients: one with tumors that resembled the characteristics of meningioma (meningioma-like) and the other that mimicked the appearance of GBM (GBM-like). The meningioma-like tumors displayed significant rim enhancement on MRI, and more of them demonstrated homogeneous enhancement compared to the GBM-like sub-group ^[20][58]. However, these findings were not found to be statistically significant ^[20][58]. Results are summarized in Table 1.

3. Genetics and Biomolecular Patters: GS vs. GBM

It has been observed that the monoclonal origin of GS would be associated with the p53 mutation, found in 23% of GS compared to 11% of primary GBM, and the deletion of p16. Epidermal Growth Factor Receptor (EGFR) amplification was only seen in 4% of GS compared to 35% of GBM ^{[2][3][21][22]}[2,3,59,60]. There were slight differences between GBM and GS in Phosphatase and Tensin homolog (PTEN) mutations and Cyclin-dependent kinase (CDK) amplification found in both glial and sarcomatous components ^[23][61]. In addition, less than 12% of GS have methylation of the O6-methylguanine-DNA methyltransferase gene promoter (pMGMT), which is associated with a good prognosis [11]. From a biomolecular point of view, GS has mutations in common with soft tissue sarcoma due to involvement in the promoter of the Telomerase reverse transcriptase gene (pTERT), Tumor Protein 53 (TP53), Neurofibromin 1 (NF1), Cyclin-dependent kinase inhibitor 2A (CDKN2A), Cyclin-dependent kinase inhibitor 2B (CDKN2B) and Retinoblastoma associated Protein Type 1 (RB1) ^[22][24][60,62]. Similarly, to GBM, GS shows mutations in PTEN, EGFR, Stromal Antigen 2 (STAG2), and Protein Tyrosine Phosphatase Non-Receptor Type 11 (PTPN11) ^[7][9][11][7,9,11]. Sarcomatous-predominant GS has several features similar to meningioma. It is characterized by positivity to reticulin and the absence of GFAP expression, while predominant gliomatous GS has characteristics reminiscent of GBM, such as necrosis, lack of reticulin production, and GFAP positivity [8]. Zaki et al., in their study, compared common gene alteration, greater than 5%, in GS, GBM, and soft tissue sarcoma. Among these, GS shared only four genes with GBM, none with sarcomas, while nine common genes were found unique for GS amongst the 5% threshold for each respective tumor type [2]. They concluded that most of these mutations overlap with GBM and other cancers; nevertheless, GS has its own genetic mutations, such as MutS Homolog 6 (MSH6), B-Raf proto-oncogene serine/threonine kinase (BRAF), Suppressor of Zeste 12 (SUZ12), Sex Determining Region Y Box Transcription Factor 2 (SOX2), and Box and WD Repeat Domain Containing 7 (FBXW7) ^{[2][7][11][16][22]}[2,7,11,16,60]. Nevertheless, it has been previously reported that, BRAF V600E mutation, SOX2 amplifications, and MSH6 mutation are present approximately in 3%, 10% and 20% of GBMs, respectively ^[16][25][16,63]. Results are summarized in Table 2.

Biomolecular Markers	GS	GBM	Study
p53 mutation	23%	11%	Saadeh et al. (2019) [9]
			Wojtas et al. (2019) [22][60]
p16 deletion	37%	No	Saadeh et al. (2019) [9]
			Zaki et al. (2021) [2]
EGFR amplification EGFR mutation	4% No	35% Yes	Romero et al. (2013) [3]
			Zaki et al. (2021) [2]
PTEN mutation	(37%)	Yes	Saadeh et al. (2019) [9]
CDK amplification	Yes	Yes	Dardis et al. (2021) [16]
pMGMT methylation	<12%	Yes	Smith et al. (2018) [10]
pTERT mutation	Yes	Yes	Zaki et al. (2021) [2]
NF1 mutation	Yes	Yes	Zaki et al. (2021) [2]
CDKN2A/B mutation	Yes	Yes	Wojtas et al. (2019) [22][60]
RB1 mutation	Yes	Less common (~20%)	Wojtas et al. (2019) [22][60]
STAG2 mutation	Yes	Yes	Wojtas et al. (2019) [22][60]
PTPN11 mutation	Yes	Yes	Saadeh et al. (2019) [9]
Reticulin positivity	Sarcomatous-predominant GS	No	Han et al. (2010) [20][58]
GFAP expression	Gliomatosus-predominant GS	Yes	Han et al. (2010) [20][58]
MSH6 mutation L1244dup, T1133A	Yes	No	Zaki et al. (2021) [2]
BRAF mutation BRAF mutations (all alteration types)	10%	3%	Zaki et al. (2021) [2]
	10%	0%	Zaki et al. (2021) [2]
SUZ12 mutation	Yes	No	Zaki et al. (2021) [2]
SOX2 mutation	Yes	No	Zaki et al. (2021) [2]
FBXW7 mutation	Yes	No	Zaki et al. (2021) [2]