Primary Intracranial Ewing Sarcoma With EWSR1-FLI1 Gene Translocation Mimicking a Meningioma and a Multidisciplinary Therapeutic Approach: A Case Report and Systematic Review of Literatures

Abstract

Ewing sarcoma and peripheral primitive neuroectodermal tumor (ES/pPNET) is an undifferentiated malignant tumor that is most prevalent in children and young adults and often radiologically mimics a meningioma. A 38-year-old female patient visited our hospital with complaints of right-sided tinnitus, right hemiparesis, and imbalance. She underwent preoperative imaging and was subsequently diagnosed as having a meningioma on the petrous ridge. After partial resection, EWSR1-FLI1 gene fusion was confirmed, and she was diagnosed with ES/pPNET. The tumor was successfully treated using a multidisciplinary approach of adjuvant chemo- and radiotherapy. This case is noteworthy because it is an extremely rare case of an intracranial ES/pPNET, and it is worth sharing our clinical experience that the tumor was successfully treated through a multidisciplinary therapeutic approach even though complete resection was not achieved.

INTRODUCTION

Ewing sarcoma and peripheral primitive neuroectodermal tumor (ES/pPNET) is an undifferentiated malignant tumor with small and round cells radiologically mimicking meningioma [1,2,3,4]. ES/pPNET arises from soft tissues and long bones in children and young adults, whereas it is rarely reported in adults due to its extremely low incidence [1,5,6]. A meningioma is not always treated immediately but is rather subjected to a wait-and-see strategy. Unlike a meningioma, ES/pPNET is a malignant tumor that requires chemotherapy and radiotherapy, so it is crucial to distinguish ES/pPNET from meningioma [5,6,7,8,9]. However, differentiating between ES/pNET and meningioma is challenging for neurosurgeons and neurooncologists because of their radiological similarity to an extra-axial tumor with a well-demarcated margin and contrast enhancement.

In this study, we have introduced a case of an intracranial ES/pPNET in a 38-year-old female patient who was clinically diagnosed as having a meningioma before surgery and underwent a multidisciplinary treatment approach.

CASE REPORT

A 38-year-old female patient visited the outpatient clinic with right-sided tinnitus, right hemiparesis, and imbalance. Her hearing was preserved with a pure-tone average of 9 dB and 100% speech audiometry score. The muscle strength of all of her extremities was preserved, as indicated by a Medical Research Council scale of 5; however, she could only ambulate with assistance because of imbalance.

Axial T2-weighted MRI shows a large, 4.4×5.6×6.0 cm solid and cystic mass located on the right petrous ridge, extending to both the middle and posterior cranial fossae. The mass has displaced the pons to the left side. The central solid portion of the tumor shows heterogeneous contrast enhancement, a low apparent diffusion coefficient, and increased cerebral blood volume, suggesting high cellularity and hypervascularity (Fig. 1A-E). An ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission topography (PET) scan of the whole body and brain did not reveal any other abnormal hypermetabolic lesions that suggested malignancy, apart from the right tentorial mass (Fig. 1F). Comprehensively, the tumor was clinically diagnosed as a meningioma.

Fig. 1. Preoperative images of the patient: T1-weighted image (A), T2-weighted image (B), contrast-enhanced T1-weighted image (C), ADC map (D), and CBV map (E) of MRI; and ¹⁸F-FDG PET/CT (F). ADC, apparent diffusion coefficient; CBV, cerebral blood volume; FDG, fluorodeoxyglucose; PET/CT, positron emission tomography/computed tomography.

Operative findings

In the supine position under general anesthesia, the head was rotated 90 degrees to the left and fixed using a Mayfield fixator. After an inverted U-shaped skin incision centered on the ear, the temporal base was exposed, and a combined approach with supra- and infratentorial approaches was performed. A dark reddish-colored tumor was exposed when the temporal base was retracted upward. The tumor was soft enough to be sucked out by an ultrasonic surgical aspirator in an outside-to-inside manner. On intraoperative frozen section biopsy, a highly cellular neoplasm was reported, and the possibility of meningioma, hemangiopericytoma, or glial tumors was not observed. The tumor was partially resected. The bone flap was not closed after duroplasty using artificial dura mater due to swelling of the temporal lobe, and extraventricular drainage (EVD) was performed through right Kocher’s point after the patient’s position was changed.

Pathologic findings

In the hematoxylin and eosin stain, monotonous cells with large nuclei were observed, and pseudorosettes with necrosis were also observed (Fig. 2A). It showed high cellularity and up to four mitoses per ten high power fields (Ki-67 index, 8%). Immunohistochemical staining was positive for CD99 and vimentin and negative for specific markers for glioma, meningioma, hemangiopericytoma, and melanoma, such as GFAP, vimentin, EMA, CD34, and HMB45 (Fig. 2B-E). On fluorescence in situ hybridization using dual-color break-apart rearrangement probes that flank the EWSR1 breakpoint, the nucleus of the tumor showed split red and green signals, indicating a rearrangement of the EWSR1 gene at 22q12 (Fig. 2F). EWSR1-FLI1 (11:22) translocation was confirmed in whole exome sequencing with a mean depth of 875.2 and 100X coverage of 98.2% using the GRCh37/hg19 genome as a reference, and there was no copy number variation. The tumor was diagnosed as ES/pPNET.

Fig. 2. Pathologic results of the patient. Tissue stained by hematoxylin and eosin (A), immunohistochemically stained by GFAP (B), VMA (C), CD99 (D), and vimentin (E), and tissue with fluorescence in situ hybridization using dual-color break-apart rearrangement probes which flank the EWSR1 breakpoint (F). Pseudorosette formation and rearranged chromosome 22 are annotated by white triangles (A) and arrows (B), respectively. GFAP, glial fibrillary acidic protein; VMA, vimentin antibodies; CD, cluster of differentiation.

Postoperative treatment and prognosis

Because weaning of the EVD failed, endoscopic third ventriculostomy was performed on postoperative day (POD) 13, and a VAC regimen, consisting of vincristine, adriamycin, and cyclophosphamide, was started at POD 23 (Fig. 3A and B). An IE regimen, consisting of ifosfamide and etoposide, was started at POD 44 and then the VAC and IE regimens were alternated every 2 weeks. At the end of the third cycle of the VAC/IE regimen (3 months after surgery), most of the volumes of the residual tumors were reduced, thereby corresponding to a partial response according to the Response Assessment in Neuro-Oncology (RANO) criteria (Fig. 3C). At 4 months after surgery, radiotherapy was performed with 55 Gy in 25 fractions. After completing the 11th cycle of VAC/IE chemotherapy regimen (10 months after surgery), no residual tumor was seen on MRI, indicating a complete response according to the RANO criteria (Fig. 3D). She was followed up for 12 months after resection, and the 8th cycle of VAC/IE was completed. Her Eastern Cooperative Oncology Group performance score was 1 and her Karnofsky performance scale score was 90. There were no complications related to chemotherapy other than mild neutropenia.

Fig. 3. Postoperative images of the patient: T2-weighted image at POD 15 (A), CT at POD 31 (B), contrast-enhanced T1-weighted image 3 months after surgery (C), and contrast-enhanced T1-weighted image 10 months after surgery (D). POD, postoperative day.

Systematic review of the literature

A literature search was conducted on the electronic PubMed database up to September 1, 2023, and limited to adult cases. Only articles written in English were subjected. The terms intracranial primary Ewing’s sarcoma or intracranial pPNET and various combinations of the words, central nervous system, dural, osseous, Ewing sarcoma, primitive neuroectodermal tumor, and intracranial, were used.

Previously reported adult cases with primary intracranial ES/pPNET were summarized in Table 1[2,3,4,5,9,10,11,12,13,14,15,16,17,18,19,20,21,22]. We identified 19 adult primary intracranial ES/pPNET patients from 18 papers, with a mean age of 40 years (standard deviation, 15 years) and a male-to-female ratio of 8:11. There were 3 cases with tumors located at the cerebellopontine angle, 1 with the tumor located in the posterior fossa, and the rest had supratentorial lesions. In 14 cases, the tumors were sufficiently removed with subtotal resection or more. Among these 14 cases, one was initially misdiagnosed as meningioma but experienced a recurrence 7 years later, necessitating a reoperation followed by adjuvant chemotherapy and radiotherapy. Among the remaining 13 patients, 5 (38.5%) underwent adjuvant chemotherapy and radiotherapy, and 8 (61.5%) underwent only adjuvant radiotherapy. Among 6 patients who underwent only a biopsy or partial resection, 5 received both adjuvant chemotherapy and radiotherapy. The other patient died due to the rapid progression of the disease while waiting for chemotherapy after radiation therapy.

Table 1. Summary of cases of adult primary intracranial Ewing sarcoma (peripheral primitive neuroectodermal tumor) reported in the literature.

Author/year	Age (yr)/sex	Initial symptom	Site	Tumor maximal diameter (cm)	Contrast enhancement	Cystic feature	Dural base	Bone involvement	Initial metastasis	Extent of resection	EWSR1-FLI1 fusion	Chemotherapy	Radiotherapy	Follow-up period (months)	Outcome
Present	38/F	Tinnitus, hemiparesis	Petrous ridge, right	6.0	Y	Y	Y	N	N	PR	NGS (WES)	VAC/IE until 48 weeks	55 Gy in 25 Fx	12	Alive/controlled
Geng et al./2023 [3]	21/F	IICP signs*	Bilateral PL	4.0	Y	Y	Y	N	N	STR	NGS	N	60 Gy in 30 Fx	6	Alive/controlled
Deshpande et al./2021 [2]	33/M	IICP signs*	Left TL	NA	NA	NA	NA	NA	NA	Excision	RT-PCR	VAC/IE until 48 weeks	55.8 Gy in 31 Fx	18	Alive/controlled
Deshpande et al./2021 [2]	33/F	Left eye movement impairment, left frontal swelling	Left FL	NA	NA	NA	NA	NA	NA	Excision	FISH	VC until 2 weeks (discontinued due to intolerance)	54 Gy in 30 Fx	17	Alive/recurred after 17 months
Jiang et al./2020 [4]	55/F	Memory impairment	Left FL	6.5	Y	Y	Y	N	N	GTR	FISH	N	Y	18	Alive
Cherif El Asri et al./2018 [5]	28/M	IICP signs,* left V, VI, VII, VIII, and lower cranial nerves palsies	Left CPA	5.0	Y	N	Y	N	N	PR	FISH	VCD/IE x1	56 Gy	3	Died due to nosocomial pneumopathy
Ke et al./2017 [10]	43/M	Epilepsy	Right PL	NA	Y	NA	Y	N	N	GTR	FISH	VACA/VAIA	50 Gy	48	Alive
Kumar et al./2017 [11]	22/M	Seizure, right hemiparesis	Left FL	8.8	Y	N	Y	Y	N	GTR	NA	Y	Y	7	Alive/controlled
VandenHeuvel et al./2015 [12]	61/M	Motor dysphasia and left-sided weakness	Right TL	6.2	Y	Y	Y	NA	N	GTR	FISH	N	N	NA	NA
Salunke et al./2014 [13]	52/M	IICP sign,* fever, diminution of vision, and ataxia	Posterior fossa	6.0	Y	NA	Y	Y	N	NTR	NA	VAC/IE until 16 weeks	50 Gy	10	Died/locally recurred after 10 months
Cole et al./2014 [14]	51/F	Visual disturbance	Left TL + PL	3.5	Y	N	Y	N	N	GTR	FISH	VCD/IE x4 VAC/IE x10	N	24	Alive
Tanboon et al./2012 [9]	22/F	Enlarging skull mass in right frontal resion	Right FL	8.0	Y	N	Y	Y	N	STR	FISH	N	N	6	Died
Antonelli et al./2011 [15]	37/M	Comatose state following IICP sign*	Right FL + TL	NA	Y	Y	Y	N	N	GTR	RT-PCR	N	Y	5	Alive/controlled
Mellai et al./2010 [16]	56/F	IICP sign,* left hemiparesis	Right TL	NA	Y	Y	Y	Y	NA	GTR	RT-PCR	N	N	18	Alive/controlled
Attabib et al./2006 [17]	48/F	Headache and left maxillary and oculomotor nerve palsies	Lt cavernous sinus	4.0	Y	N	N	N	N	STR	RT-PCR	VCD/IE	54 Gy	14	Alive/controlled
Mobley et al./2006 [18]	21/M	IICP sign,* diplopia, left partial homonymous hemianopia	Right OL	3.5	Y	N	Y	N	N	PR	Karyotyping	VACA	54 Gy	21	Alive/recurred after 18 months
D’Antonio et al./2004 [19]	50/F	IICP sign*	Right TL	NA	Y	N	Y	NA	N	GTR	FISH	N	N	12	Alive
Simmons et al./2001 [20]	67/F	Right facial pain, facial palsy, hearing disturbance, headache	Right CPA	NA	Y	NA	N	N	N	Biopsy	NA	N	Y	13	Died/rapid decline following no symptoms progression for 13 months
Kalamarides et al./2001 [21]	34/F	Vertigo, tinnitus, gait disturbance	Left CPA	1.8	Y	N	Y	Y	N	STR	NA	N	55 Gy	12	Alive/controlled
Papotti et al./1998 [22]	30/F	Headache, vertigo	Right FL (2 lesions)	7 and 4	NA	NA	Y	NA	NA	GTR (misdiagnosed as a meningioma)	RT-PCR	VAC (at 9 years after initial surgery)	50 Gy (misdiagnosed as a meningioma)	120	Died/recurred twice at 7 and 9 years after initial surgery

^*IICP signs included headache, nausea, vomiting, or loss of consciousness. M, male; F, female; IICP, increased intracranial pressure; PL, parietal lobe; FL, frontal lobe; TL, temporal lobe; OL, occipital lobe; CPA, cerebellopontine angle; NA, not applicable (or no information); Y, yes; N, no; GTR, gross total resection; NTR, near total resection; STR, subtotal resection; PR, partial resection; NGS, next generation sequencing; WES, whole exome sequencing; RT-PCR, reverse transcriptase-polymerase chain reaction; FISH, fluorescence in situ hybridization; VAC, vincristine, adriamycin, and cyclophosphamide; IE, ifosfamide and etoposide; VC, vincristine and cyclophosphamide; VCD, vincristine, cyclophosphamide, and doxorubicin; VACA, vincristine, adriamycin, cyclophosphamide, and dactinomycin; VAIA, vincristine, adriamycin, ifosfamide, and dactinomycin; Fx, fractions

DISCUSSION

In this case, the tumor was preoperatively misdiagnosed as a meningioma but was successfully controlled through a multidisciplinary therapeutic approach using both chemotherapy and radiotherapy following partial resection.

Because of the rarity of intracranial ES/pPNETs, there are only a few previous reports, and its true incidence has not revealed, so findings on preoperative images should be used for the differential diagnosis [2,3,5,23]. However, some previous reports have suggested that heterogeneous contrast enhancement is the key point for distinguishing ES/pPNET [4,24]. In the present case, heterogeneous enhancement was also observed, but heterogeneous contrast enhancement on preoperative images is not a highly specific radiological finding, which can also be seen in some other tumors, such as meningioma or hemangiopericytoma. In addition, the patient was 38 years old, which was different from most previous reports for ES/pPNETs where the patients were children or young adults. Therefore, differentiating ES/pPNETs from other mimicking tumors preoperatively is very challenging for neurosurgeons and neurooncologists. Ultimately, surgical tissue confirmation and laboratory testing for gene translocation are essential for the diagnosis of ES/pPNET with EWSR1-FLI1 gene fusion.

What differentiates this case from previous reports is that the response to chemotherapy only was prominent [1,3,4,5,23]. Adjuvant radiotherapy or chemotherapy or both for the treatment of ES/pPNET is known to be helpful in controlling ES/pPNET, especially when complete resection is not achieved. However, the regimen has not yet been standardized. One of the most frequently reported chemotherapy regimens thus far is the VAC/IE regimen, and in this case, after the administration of only three cycles of the VAC/IE regimen, most of the tumor was already reduced even before radiotherapy, despite an infratentorial location known to show a poor prognosis. This multidisciplinary approach is crucial for the treatment of ES/pPNETs.

ES/Ppnet is a malignant tumor with an unfavorable prognosis that is difficult to differentiate from other mimicking tumors before surgery. However, in this case, despite incomplete tumor resection, the tumor was well controlled by both chemotherapy and radiotherapy.

Availability of Data and Material

The institutional data used in this study is not publicly available due to protection of private patient health information. The data is available from the corresponding author on reasonable request after anonymization.