Primary Intracranial Ewing Sarcoma With an Unusual Presentation: A Case Report

Abstract

Primary extraosseous intracranial Ewing sarcoma (ES) is an extremely rare disease, limited to the pediatric population, that primarily originates in the skull. Here, we present an unusual case of adult Ewing’s sarcoma originating from the brain parenchyma. The 50-year-old male patient visited our hospital with severe headache lasting 3 weeks. MRI presented 6.1×6.2×5.2 cm sized heterogeneously enhanced mass containing peritumoral edema in the right frontal lobe. The patient underwent right frontal craniotomy, at which time the gray and red masses adhered to the surrounding brain parenchyma. The mass was completely resected using neuronavigation and electrophysiological monitoring. Histopathological examination revealed ES-compatible findings of small round cell tumor and CD-99 positive membranous immunostaining. Next generation sequencing revealed translocation and fusion of EWSR1 and FLI1, consistent with a confirmed diagnosis of ES. Consequently, the patient underwent postoperative radiotherapy. The present case revealed adult primary intracranial ES arising from the frontal lobe. Although its etiology remains poorly understood, intraparenchymal ES should be included in the differential diagnosis of parenchymal brain tumors.

INTRODUCTION

Ewing sarcomas (ESs) are rare tumors comprising small round undifferentiated embryonal-type cells. These tumors are highly malignant and typically originate from bone and soft tissue [1]. Moreover, these tumors predominantly occur in children and young adults, with only 10 reported cases in patients over 30 years of age [2,3]. At middle age, primary intracranial ESs are sometimes observed as dura-based tumors which require differential diagnosis from other extra-axial tumors such as hemangiopericytoma, solitary fibrous tumors, or meningioma [3,4]. Translocation and fusion of the EWSR1 gene with the erythroblast transformation specific family gene FLI1 is a typical finding and the primary cause of ESs [1]. Herein, we present an unusual case of an intracranial ES located in the right frontal lobe, which presents brain parenchymal adhesion at intraoperative finding.

CASE REPORT

A 50-year-old previously healthy male patient, without the history of ES, visited our institution with presenting headache for 3 weeks, which were not controlled with medication. The patient was cooperative, and the neurological examination was normal.

MRI revealed a 6.1×6.2×5.2 cm round shaped extra-axial mass-like lesion in the right frontal lobe, displaying hypointense signals on T1-weighted imaging (T1WI), variable signals on T2-weighted imaging (T2WI), and heterogeneous enhancement in gadolinium enhanced T1-weighted imaging (Fig. 1A-C). The relative cerebral blood volume was increased on perfusion-weighted imaging (Fig. 1D). CT revealed a heterogeneous hypo- to iso-dense mass without calcification in the right frontal lobe and did not reveal any bony erosion or hypertrophy (Fig. 1E). Cerebral angiography revealed that blood supply to the tumor was derived from the ethmoidal branch of the ipsilateral ophthalmic artery (Fig. 1F).

Fig. 1. Representative radiologic images of the patients: T1-weighted MRI imaging (A) displaying hypointense signals, T2-weighted MRI imaging (B) showing variable signals, post-contrast T1-weighted imaging (C) presenting heterogeneous enhancement in right frontal lobe. Perfusion-weighted MRI (D) shows increased cerebral volume. CT (E) presenting a heterogeneous hyper dense-to-isodense mass without calcification. Cerebral angiography (F) revealed that the blood supply of the tumor was derived from ethmoidal branch of right ophthalmic artery. Postoperative CT (G) and MRI (H) revealed the total removal of the tumor.

The patient underwent right frontal craniotomy, assisted by neuronavigation and electrophysiological monitoring of somatosensory and muscle-evoked potentials. The mass was soft and consistent with a red and greyish color (Fig. 2). No clear margin between the dura and tumor surface was observed, instead, the tumor adhered to the brain parenchyma, which suggests an intra-axial origin of the tumor itself.

Fig. 2. Intraoperative images. D, dura, T, tumor, P, parenchyme.

Histopathological examination revealed uniform small round to oval undifferentiated cells with hyperchromatic nuclei and scanty basophilic cytoplasm (Fig. 3A). Immunostaining revealed positive reactivity and a membranous pattern for CD99, whereas the CK showed focal positivity (Fig. 3B and C). CD34, CD20, CD3, GFAP, Neu-N, Synaptophysin, STAT6 were negative on immunostaining. Next-generation sequencing revealed the translocation and fusion of the EWSR1 and FLI1 genes, confirming the diagnosis of ES (Fig. 3D).

Fig. 3. Histopathologic images and next-generation sequencing results from the resected tumor: histopathologic examination showing small round to oval cells with scanty cytoplasm in hematoxilin-eosin staining (A, ×200), membranous pattern positive on CD99 (B, ×200), and focal positivity on cytokeratin (C, ×200). Next-generation sequencing (D) confirmed the translocation and fusion of the EWSR1 and FLI1 gene.

Postoperatively, the patient was free of neurological deficits. A systemic workup was performed to identify metastatic ES. Additionally, CT scans of the chest and abdomen did not reveal evidence of any other lesions. Bone scans and positron emission tomography CT scans also showed no indication of metastatic lesions. Postoperative CT and MRI revealed no evidence of remnant enhancing lesion with implying complete tumor removal (Fig. 1G and H). The patient underwent conventional fractionated radiotherapy and is currently scheduled to undergo chemotherapy (vincristine, adriamycin, cyclophosphamide, and mensa).

DISCUSSION

Primary intracranial ES is an extremely rare malignant tumor, which accounts for only 0.03% of all intracranial tumors [5]. Most related studies have shown a slight male predominance, and the median age of onset is approximately 15 years of age [2]. Intracranial ES occurs in the bone or in soft tissues surrounding the bones. Additionally, ES is primarily discovered at the supratentorial location [6]. Primary intracranial ES has also been observed in middle-aged patients; however, its incidence is rare, with only ten cases having been reported. The mean age of these ten middle-aged patients with intracranial ES was 49 (range: 38–61), and they included five men and five women. Furthermore, seven cases of intracranial ES (70%) were located in the cerebral hemisphere and two cases (20%) were located in the posterior fossa. In all cases, the tumor was located in the dura. However, there have been no reported cases originating from the brain parenchyma as a tumor bed (Table 1).

Table 1. Summary of previously reported cases of primary intracranial ES in patients over 30 years of age (only genetically confirmed cases).

Study	Age/sex	Symptom duration (mo)	Location	Tumor bed	Diameter (cm)	MRI		Local invasion	Treatment	Recurrence	Follow-up (mo)
						T1WI	T2WI
Batur [17]	44/M	Headache	Left posterior fossa	Dura	-	High	Iso	N	Gross total removal	N	Alive
		4									36
Jiang et al. [2]	55/F	Memory decline	Left frontal lobe	Dura	6.5	Low-Iso	Low-High	Bone	Gross total removal	N	Alive
		1							RTx		18
Chen et al. [5]	43/M	Epilepsy	Right parietal lobe	Dura	-	Low-Iso	Low-High	N	Gross total removal	Y	Dead
		1							CTx (VAC+Actinomycin D)		48
									RTx
Ke et al. [18]	43/M	Epilepsy	Right parietal lobe	Dura	-	Low-Iso	Low-High	N	Gross total removal	Y	Dead
		-							CTx (VACA/VAIA)		48
									RTx
VandenHeuvel et al. [8]	61/M	Left hemiparesis	Right frontal lobe	Dura	6.2	Low	-	N	Biopsy	-	F/U loss
Salunke et al. [9]	52/M	Headache	Posterior fossa	Dura	6	-	-	Bone	Gross total removal	Y	Dead
		Ataxia							CTx (VACI)		6.5
		1							RTx
Mellai et al. [10]	56/F	Headache	Right temporal lobe	Dura	-	Low	High	N	Gross total removal	N	Alive
		Left hemiparesis									18
		-
Attabib et al. [11]	48/F	Headache	Left cavernous sinus	Dura	4	-	-	N	Partial removal	N	Alive
		Left ptosis							CTx (VCD)		12
		6							RTx
D’Antonio et al. [19]	50/F	Headache	Right parieto-temporal lobe	Dura	6	Iso	Low	N	Gross total removal	N	Alive
		Vomiting									12
		Drowsiness
		-
Hyun et al. [20]	38/F	Tinnitus	Right petrous ridge	Dura	6	-	-	N	Gross total removal	N	Alive
		Hemiparesis							CTx (VAC/IE)		12

ES, Ewing sarcoma; T1WI, T1-weighted image; T2WI, T2-weighted image; RTx, radiotherapy; CTx, chemotherapy; V, vincristine; A, adriamycin; C, cyclophosphamide; I, ifosfamide; D, doxorubicin; E, etoposide

Primary intracranial ES appear as hypointense to heterointense on T1WI and heterogeneously hyperintense on T2WI with diverse patterns of enhancement, which is consistent with our case. Primary intracranial ES is predominantly identified as a dura-based tumor [7]. This characteristic makes preoperative differential diagnosis from other extra-axial tumors, such as meningioma, hemangiopericytoma, solitary fibrous tumors, and smooth muscle tumors, challenging [2].

The origin of ES remains controversial [8]. It is thought to originate from primitive pluripotent cells, including neuroectodermal cells or mesenchymal stem cells [9,10]; however, a recent experimental study illustrated that ES is generated by engineering t(11;22)(q24;q12) translocation together with a combination of STAG2, TP53, or CDKN2A mutations in mesenchymal stem cells (MSCs) [11]. The similarities between stem cells and pericytes in the central nervous system have been well documented, and it is further known that the pericytes contribute to brain repair [12,13]. During this process, adult pericytes become activated MSCs when vessels become damaged or inflamed. These activated MSCs respond by secreting a cascade of bioactive molecules that regulate the activity of local immune cells [14]. As such, it is possible that genetic alterations in brain parenchymal pericytes give rise to the development of primary intraparenchymal ES, as in our case.

CD99, a transmembrane glycoprotein which is pivotal in the mesenchymal stem cell differentiation, is a highly sensitive biomarker of primary intracranial ES [3,15]. However, it is not considered as a specific marker, because high expression of CD99 is also observed in lymphoblastic lymphoma, malignant glioma, rhabdomyosarcoma, hemangiopericytoma, and sex-cord stromal tumors [16]. For this reason, confirmation of EWSR1 gene rearrangement is the gold standard of the diagnosis of ES [6]. The chromosomal translocation t(11;22)(q24;q12) is the most common genetic aberration which occupies 85%–90% of all ES, followed by t(21;22)(q22;q12) [2]. In our case, the chromosomal translocation t(11;22)(q24;q12) was identified to confirm the diagnosis of primary intracranial ES.

Due to the rare incidence of primary intracranial ES, standard treatment guidelines have not yet been fully established. However, based on current evidence, gross total resection with wide margins is recommended to prevent local recurrence [2]. The optimal adjuvant therapies are also not established; however, it has been suggested that combination therapy with vincristine, adriamycin, cyclophosphamide, ifosfamide, and doxorubicin can significantly improve the long-term survival rate and lower recurrence rates [2]. Radiotherapy can also be helpful in increasing the median survival time [5]. Therefore, in our case, combination of radiotherapy and chemotherapy has been planned for improving the patient survival.

Herein, we present an unusual case of primary intracranial ES that originated from the brain parenchyma in a middle-aged man. This case highlights the difficulties in the preoperative diagnosis of this rare tumor owing to its similarity to other tumors. Intraoperative findings and genetic testing are critical for confirming the diagnosis.

Availability of Data and Material

Data sharing not applicable to this article as no datasets were generated or analyzed during the study.