Multifocal primary central nervous system Ewing sarcoma presenting with intracranial hemorrhage and leptomeningeal dissemination: illustrative case

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  • 1 Departments of Neurosurgery,
  • | 2 Pathology and Immunology, and
  • | 3 Radiation Oncology, Washington University in St. Louis, Missouri
Open access

BACKGROUND

Ewing sarcoma is a neoplasm within the family of small round blue cell tumors and most frequently arises from skeletal bone. Primary involvement of the central nervous system in these lesions is extremely rare, with an incidence of 1%.

OBSERVATIONS

A case is presented of a 34-year-old man who presented with left facial numbness, multiple intracranial lesions, a lumbar intradural lesion, and diffuse spinal leptomeningeal involvement. A lumbar laminectomy and biopsy were performed, which revealed the diagnosis of extraskeletal Ewing sarcoma/primitive neuroectodermal tumor. The patient had a rapidly progressive clinical decline despite total neuroaxis radiation and multiple lines of chemotherapeutic treatments, eventually dying from his disease and its sequelae 6 months after diagnosis.

LESSONS

The authors’ review of 40 cases in the literature revealed only 2 patients with isolated intraaxial cranial lesions, 4 patients with cranial and spine involvement, and an additional 34 patients with spine lesions. The unique characteristics of this patient’s case, including his presentation with diffuse disease and pathology that included a rare V600E BRAF mutation, are discussed in the context of the available literature.

ABBREVIATIONS

CNS = central nervous system; cPNET = central primitive neuroectodermal tumor; CSF = cerebrospinal fluid; CT = computed tomography; ES = Ewing sarcoma; GFAP = glial fibrillary acidic protein; MRI = magnetic resonance imaging.

BACKGROUND

Ewing sarcoma is a neoplasm within the family of small round blue cell tumors and most frequently arises from skeletal bone. Primary involvement of the central nervous system in these lesions is extremely rare, with an incidence of 1%.

OBSERVATIONS

A case is presented of a 34-year-old man who presented with left facial numbness, multiple intracranial lesions, a lumbar intradural lesion, and diffuse spinal leptomeningeal involvement. A lumbar laminectomy and biopsy were performed, which revealed the diagnosis of extraskeletal Ewing sarcoma/primitive neuroectodermal tumor. The patient had a rapidly progressive clinical decline despite total neuroaxis radiation and multiple lines of chemotherapeutic treatments, eventually dying from his disease and its sequelae 6 months after diagnosis.

LESSONS

The authors’ review of 40 cases in the literature revealed only 2 patients with isolated intraaxial cranial lesions, 4 patients with cranial and spine involvement, and an additional 34 patients with spine lesions. The unique characteristics of this patient’s case, including his presentation with diffuse disease and pathology that included a rare V600E BRAF mutation, are discussed in the context of the available literature.

ABBREVIATIONS

CNS = central nervous system; cPNET = central primitive neuroectodermal tumor; CSF = cerebrospinal fluid; CT = computed tomography; ES = Ewing sarcoma; GFAP = glial fibrillary acidic protein; MRI = magnetic resonance imaging.

Ewing sarcoma (ES) is a part of a family of small round blue cell neoplasms that primarily affects patients in the first and second decades of life.1 Approximately 75% of cases arise from bone, whereas the other 25% arise from soft tissue.2 Often, ES can cause neurological symptoms by developing in the bony structures such as the calvaria and spinal column, causing mass effect on adjacent structures. Primary central nervous system (CNS) involvement by ES is rare, with an estimated incidence of 1%.3 The most common origin is the dura, and primary intraparenchymal disease is extremely rare. There are only 2 cases of isolated intraaxial ES and 4 cases of cranial and spine involvement reported in literature (Table 1). In cases with intracranial lesions, patients often present with symptoms of increased intracranial pressure or neurological deficits associated with tumor location. Of note, it is important to distinguish primary CNS ES from CNS embryonal tumors, previously called “central primitive neuroectodermal tumors” (cPNETs), as they differ in underlying genetics, treatment, and prognosis.4 We report a case of multifocal primary CNS ES that presented with intraparenchymal hemorrhage in a 34-year-old man.

TABLE 1.

Reported cases in the literature for primary CNS extraskeletal ES

StudyAge (yrs)/GenderLocationOther SpreadPresentationHemorrhageCD99/t(11:22)TreatmentOutcome
VandenHeuvel et al., 2015322/FFrontal lobeNone, CSF negativePartial seizuresNo+/+Surgery: GTR; chemo: VCR, CYA, DXR; radiation: focal radiationAlive at 6 yrs
VandenHeuvel et al., 20153261/MFronto-temporal lobeNone, CSF negativeSlurred speech, lt facial droop, lt hemiparesisNo+/+Surgery: STR; no adjuvant chemo or radiationLost to follow-up
Weil et al., 20011421/MT10–11, L1–2, 2 parietal lesionsCSF negativeThoracic back pain, lower extremity weakness/spasticityNo+/+Surgery: STR cranial & spinal lesion; chemo: VCR, DXR, CPM, ETP, IFO; radiation: craniospinal radiation, boost to tumor bedAlive at 30 mos
Mateen et al., 20111260/ML2–3Delayed diffuse cranial & spine leptomeningeal spreadBack pain, bilat leg radiculopathyNo+/+Surgery: STR; chemo: IFO, ETP, DXR, TMZ; radiation: radiation to L1–4Dead at 48 mos
Tan et al., 20191334/FC4–T3Diffuse leptomeningeal disease of spine, rapid intracranial spreadUpper extremity paresthesias, urinary retentionNo+/+Surgery: STR; chemo: none; radiation: urgent radiotherapy to craniospinal axisDead at 11 mos
Izubuchi et al., 20201035/FT12–L1, L4–5Diffuse meningeal spread, multiple intracranial lesions at 10 mosRadiculopathy & bilat leg paresthesiasNo+/+Surgery: STR; chemo: VCR, DXR, CPM, IFO, ETP; radiation: total spinal radiation, later WBRT due to metsDead at 16 mos
Hisaoka et al., 19973314/MCauda equinaNoneBack pain & lt leg radiculopathyNo+/+Surgery: GTR; no adjuvant chemo or radiationAlive at 3 mos
Uesaka et al., 20033411/FC7–T1NoneProgressive paraparesisNo+/+Surgery: STR; no adjuvant chemo or radiation documentedUnknown
Harimaya et al., 20032130/FC2–4NoneExtremity paresthesias, urinary retentionNo+/+Surgery: GTR; chemo: VCR, DXR, IFO, ACD; radiation: focal radiotherapyDead at 14 mos
Harimaya et al., 20032114/MCauda equina (L1–2)NoneLow back pain & lower extremity radiculopathyNo+/+Surgery: GTR; chemo: VCR, DXR, IFO, ACD, CBP, ETP; radiation: noneAlive at 67 mos
Woestenborghs et al., 20053511/MC4–T2NoneProgressive quadriparesisNo+/+Surgery: STR; chemo: VCR, IFO, ACD, ETP; radiation: noneUnknown
Mobley et al., 20062232/MCauda equina (L2–4)NoneBack pain, distal lower extremity weaknessNo+/+Surgery: GTR; chemo: ACD, VCR, DXR, CPM, ETP, IFO; radiation: regional radiation T12–S3 w/ boost to resection siteDead at 12 mos
Haresh et al., 20081826/MCauda equina (T11–S2)Delayed spread to T6–7Back pain, lower extremity weaknessNo+/?Surgery: GTR; chemo: VCR, DXR, CPM, IFO, CDDP, ETP; radiation: focal radiationAlive at 6 mos
Kim & Shin, 20093632/FC3–5NoneProgressive upper extremity paresisNo+/+Surgery: STR; chemo: ETP, IFO; radiation: focal radiationAlive at 12 mos
Klimo et al., 20093710/ML4–5NoneRt leg pain & paresthesiasNo+/+Surgery: STR; chemo: VCR, DXR, CPM, ETP, IFO; radiation: radiation to L3–5Alive at 12 mos
Theeler et al., 20093828/FT5–8NoneLt arm pain, lower extremity paresthesiasNo+/+Surgery: none (CT-guided biopsy); chemo: VCR, CPM, DXR, IFO, ETP; radiation: palliative spinal radiationAlive at 2 mos
Vincentelli et al., 2010940/FCauda equina (T11–L4)NoneParaparesis & urinary retentionYes?/+Surgery: STR; chemo: DXR, IFO; radiation: conformational radiotherapyAlive at 6 mos
Muzzafar et al., 2010638/MCauda equina (L2–S2)NoneBack pain, bilat leg radiculopathyYes+/+Surgery: GTR; chemo: systemic therapy; radiation: noneUnknown
Karikari et al., 20113956/FL1None, CSF negativeBack pain, leg radiculopathyNo+/+Surgery: GTR; chemo: VCR, DXR, CPM, IFO, ETP; radiation: local radiationUnknown
Yan et al., 20112310/MC2–3None, CSF negativeNeck pain, rt hemiparesisNo+/?Surgery: GTR; dead prior to adjuvant therapyDead at 30 days
Duan et al., 2011408/ML2–L4NoneUnknownNo+/?Surgery: GTR; chemo: systemic therapy; radiation: local radiationUnknown
Duan et al., 20114025/ML2/3NoneUnknownNo+/?Surgery: GTR; chemo: systemic therapy; radiation: focal radiationUnknown
Mateen et al., 20111250/MT10–L1NoneProgressive lower extremity paresthesiasNo+/+Surgery: GTR; chemo: VCR, CPM, DXR, IFO, ETP; radiation: focal to thoracolumbar spineAlive at 26 mos
Pancucci et al., 2013755/ML4–S2None, bone marrow biopsy negativeLower extremity weakness, urinary retentionYes+/+Surgery: GTR; chemo: DXR, IFO, ETP; radiation: fractionated external radiotherapyAlive at 13 mos
Pancucci et al., 2013725/FL2–3None, bone marrow biopsy negativeLower extremity weakness, urinary urgencyNo+/+Surgery: GTR; no adjuvant therapy given patient’s poor performance statusLocal relapse at 14 mos
Khalatbari et al., 2013528/FL5–S1NoneBack & rt leg pain, acute cauda equinaYes+/+Surgery: GTR; chemo: VCR, DXR, CPM, IFO, ETP; radiation: focal radiationAlive at 72 mos
Bazzocchi et al., 20131544/FT6–7, L1–2NoneSudden-onset paraplegiaNo+/?Surgery: GTR of largest lesion; chemo: VCR, CPM, DXR, IFO, ETP; radiation: focal to lumbar spineUnknown
Lozupone et al., 20144144/FCauda equina (L1–S3)NoneLow back pain & radiculopathyNo+/+Surgery: GTR; chemo: VCR, EPIR, EDX; radiation: focal conformational radiotherapyAlive at 6 mos
Zhao et al., 20144214/ML4–5NoneRt leg pain & paresthesiasNo+/+Surgery: GTR; chemo: CPM, DXR, IFO; radiation: focal radiationAlive at 12 mos
Mardekian et al., 20144326/MT12–L1NoneBack painNo+/+Surgery: GTR; no adjuvant therapies describedUnknown
Mardekian et al., 20144370/MT12–L1NoneBack painNo+/+Surgery: STR; no adjuvant therapies describedUnknown
Gong et al., 20151939/FC4–6Delayed development of L4–S1 massProgressive lt arm paresthesias & painNo+/+Surgery: GTR; chemo: CPM, VCR; radiation: local radiotherapyAlive at 3 yrs
Bostelmann et al., 20162029/MC6–T1Delayed development of additional spinal metastatic lesionsRt C7 radiculopathy followed by hemiparesisNo+/+Surgery: GTR, re-resection 4 wks later for recurrence; chemo: VCR, IFO, DXR, ETP, TOPO, CPM; radiation: total spine & local boostAlive at 18 mos
Kartal & Akatlı, 2016445/MT4–7NoneLow back pain & gait disturbanceNo+/?Surgery: GTR; no adjuvant therapies describedUnknown
Chihak et al., 20161625/MC4–7NoneRt hand numbness/tinglingNo+/+Surgery: STR; chemo: IFO, ETP, VCR, DXR, CPM; radiation: urgent radiation to tumor bed, total craniospinal radiation, additional boost to tumor areaAlive at 20 mos
Chihak et al., 20161634/ML4–5, S1–2, S4–5NoneCauda equina symptomsNo+/+Surgery: STR; chemo: VCR, DXR, CPM, IFO, ETP; radiation: craniospinal radiation w/ local boostAlive at 3 mos
Paterakis et al., 20171731/ML2–3, sacral lesionDelayed bone metastasisProgressive paraparesisNo+/+Surgery: GTR of lumbar lesion; chemo: VCR, DXR, CPM, IFO, ETP; radiation: noneAlive at 24 mos
Scantland et al., 2018814/FConus medullarisNoneProgressive back painYes+/+Surgery: STR; chemo: VCR, DXR, CPM, IFO, ETP; radiation: proton beam radiotherapyAlive at 2 yrs
Takami et al., 20184561/ML1–3NoneLt leg paresthesias, urinary retentionNo+/+Surgery: GTR; chemo: VCR, DXR, CPM, IFO, ETP; radiation: focal to lumbar spineAlive at 3 mos
Khwaja et al., 20191144/FC7–T1Diffuse leptomeningeal disease of spinePain in lower extremities, paraplegiaNo+/+Surgery: STR; chemo: CDDP, CCNU, IFO, CBP, ETP; radiation: craniospinal irradiation, focal boost w/ CyberKnifeAlive at 8 yrs

+ = mutation present; ? = presence of mutation unknown; ACD = actinomycin D; CBP = carboplatin, CCNU = lomustine; CDDP = cisplatin; chemo = chemotherapy; CPM = cyclophosphamide; CYA = cyclosporine; DXR = doxorubicin (Adriamycin); EDX = epidoxorubicin; EPIR = epirubicin; ETP = etoposide; GTR = gross total resection; IFO = ifosfamide; STR = subtotal resection; t(11:22) = translocation (11:22); TMZ = temozolomide; TOPO = topotecan; VCR = vincristine; WBRT = whole brain radiotherapy.

Includes cranial intraparenchymal lesions, spine lesions, and patients with brain and spine involvement. Note, none of these cases describe a BRAF mutation.

Illustrative Case

History and Examination

A 34-year-old man without prior significant history presented with worsening right-sided headache and back pain. He had 3 months of worsening headaches, frequently nocturnal in nature, with interval development of associated nausea and vomiting 3 weeks prior to presentation. Additionally, he was having increasing low back pain that he had been managing with muscle relaxers, oral steroids, and over-the-counter pain medication. In the previous week, he also noted new, intermittent numbness and tingling affecting both his left leg and face.

On neurological examination, he had present but abnormal sensation in all three divisions of the left trigeminal nerve. His ocular and facial movements were all normal. Motor and sensory examinations of his upper and lower extremities were normal.

The computed tomography (CT) scan of the head obtained upon presentation (Fig. 1) was remarkable for a 1.5 × 3.7–cm ovoid, uniformly hyperdense intraaxial lesion in the right frontal medial orbital gyrus. There was surrounding hypodensity, consistent with vasogenic edema. There was local mass effect with an associated adjacent 3-mm right-to-left midline shift.

FIG. 1.
FIG. 1.

Non-contrast CT scans of the brain showing a hyperdense intraaxial lesion in the right frontal medial orbital gyrus (A, arrow), and adjacent cerebral edema (B).

Subsequent magnetic resonance imaging (MRI) of the brain with and without contrast (Fig. 2) redemonstrated this intraaxial, right-sided, medial orbital gyrus lesion. The lesion demonstrated rim enhancement as well as diffusion restriction. A 5-mm enhancing lesion was seen at the right brachium pontis, and a 1.4 × 2–cm uniformly enhancing lesion was seen expanding Meckel’s cave on the left. Finally, there was evidence of enhancement along cranial nerves V, VII, and VII on the left.

FIG. 2.
FIG. 2.

T1 postcontrast MRI of the brain. A: Rim-enhancing right frontal lesion with an associated hemorrhagic component with mild mass effect, shown in coronal, sagittal, and axial planes. B: Enhancing lesion within the left Meckel’s cave (arrows), shown in coronal, sagittal, and axial planes.

On the 2nd day of admission, the patient developed new weakness of dorsiflexion on his left side, prompting MRI of the total spine (Fig. 3). This MRI demonstrated diffuse, nodular, leptomeningeal enhancement, with a significant epidural enhancing soft tissue component in the lumbar spine with mass effect on the adjacent conus and cauda equina. Subsequent whole-body fluorodeoxyglucose–positron emission tomography CT scans of the chest, abdomen, and pelvis and scrotal ultrasound all revealed no evidence of tumor outside the CNS.

FIG. 3.
FIG. 3.

Sagittal slices from MRI of the lumbar spine, with sequences of T2 (A), T1 without contrast (B), and T1 with contrast (C). There is a contrast-enhancing soft tissue epidural mass filling the thecal sac and compressing the adjacent conus medullaris (arrows) and, below that, the nerve roots of the cauda equina.

Operative Details

In light of the relatively accessible nature of the intradural spinal lesions, a left partial L5 hemilaminectomy and biopsy of the intradural lumbar spinal lesion was performed. During the dissection, it was noted that the dura had an abnormal purple-blue hue. Once the dura was incised, there was an immediate return of dark orange fluid, believed to be related to the presence of tumor and blood within the cerebrospinal fluid (CSF). As the dissection continued, abnormal small purplish-tan clumps of tissue were identified adherent to the lumbar nerve roots. Several specimens were collected and sent for frozen and permanent pathology. There were no immediate postoperative complications.

Pathology

Histopathological examination revealed a high-grade malignant neoplasm, partially involving a nerve root, with an overall solid growth pattern. The tumor cells demonstrated minimal to scant pale eosinophilic cytoplasm with indistinct cell borders in a fibrillary appearing background. Nuclei ranged from round to oval to short-spindled, with substantial pleomorphism, hyperchromasia, irregular contours, and inconspicuous nucleoli (Fig. 4). Mitotic figures and karyorrhectic debris were abundant. Focally prominent neutrophilic infiltrates were present in the tumor (Fig. 4).

FIG. 4.
FIG. 4.

Histopathological characteristics of resected lumbar intradural tumor—extraskeletal ES/PNET. Original magnifications ×400. Hematoxylin and eosin–stained images (A and B) show a small blue cell tumor, with variably round to spindle-shaped nuclei, karyorrhexis, brisk mitotic activity, and a patchy neutrophilic infiltrate. Immunohistochemical stains were performed, and the tumor cells show membranous expression of CD99 (C) and nonreactivity for CAM5.2 (D), GFAP (E), and synaptophysin (SYN) (F). SYN highlights entrapped axons within the involved nerve root.

Immunohistochemical stains showed the tumor cells to be strongly and diffusely positive for vimentin and CD99, with nonreactivity for glial fibrillary acidic protein (GFAP), synaptophysin, CD3, CD20, epithelial membrane antigen, CAM5.2, CD56, WT1, and human melanoma black-45. Neurofilament highlighted few remaining axons of the involved nerve root (Fig. 4). INI-1 nuclear expression was retained throughout the tumor. Ki-67 (MIB-1 antibody) was high at around 40% focally.

Fluorescence in situ hybridization using an EWSR1 break-apart probe showed the presence of EWSR1 gene rearrangement. FLI1 immunohistochemistry showed multifocal variable nuclear positivity, suggesting an EWSR1-FLI1 gene fusion. Altogether, these findings supported a diagnosis of extraskeletal ES/PNET. Follow-up targeted next-generation sequencing showed the presence of mutations in BRAF (V600E), PTCH1 (p.G115 K), EZH2 (p.E249), HIST1H1D (p.K214*), TP53 (p.H179Y), and loss of exons 2–3 in CDKN2A/B.

Postoperative Course

Postoperatively, the patient had progressive worsening of his left leg weakness, followed by progressive weakness of his right leg and eventual bowel and bladder incontinence. He also developed a left corneal abrasion secondary to his V1 numbness. Later, his course was complicated by multiple deep venous thrombi and a pulmonary embolus.

Adjuvant therapy included radiation to a dose of 1260 cGy in 5 fractions to the T12–S1 levels, followed by craniospinal radiation to a dose of 3060 cGy in 180 cGy per fraction. He also received one cycle of chemotherapy with cisplatin, Cytoxan, and vincristine. He was then transitioned to high doses of ifosfamide and etoposide. Unfortunately, he continued to have clinical deterioration and progression of his multifocal disease refractory to medical therapy. The patient was transitioned to palliative measures and died 6 months after presentation.

Literature Review

A literature search was performed to better characterize the anatomical distribution, management strategies, and treatment outcomes of primary CNS ES. A search using keywords “primary central nervous system Ewing sarcoma” in PubMed and Ovid-MEDLINE yielded 78 articles. Several of these articles included their own literature reviews, and from these, an additional 44 unique articles were identified for our review. Of these 122 papers, articles referencing peripheral ES with metastatic CNS involvement and those describing cPNETs were excluded. In order to highlight the unique characteristics of our case, we further narrowed our search by excluding 42 papers that described isolated dural-based intracranial tumors.

The remaining 33 papers we included in our study described 40 cases of CNS ES, including patients with isolated intraparenchymal lesions, spinal lesions, and a combination of spine and cranial involvement (Table 1). The average age at diagnosis was 30.9 years, and 60% of the patients were male. All tumors underwent immunohistochemical staining for CD99, genetic analysis (translocation 11:22), or both. None of the cases reported a BRAF mutation from tumor genetic sequencing, as was seen in our case.

The symptoms at the time of presentation for these patients were mainly associated with the location of the lesion. Tumors in the frontal lobe resulted in contralateral hemiparesis or seizures, whereas spinal cord tumors resulted in weakness, radiculopathy, or paresthesias below that level.

In our selected cases, gross-total resection was obtained in 22 cases, with gross-total resection of only the largest lesion in 2 cases, subtotal resection in 15 cases, and CT-guided biopsy alone in 1 case. Hemorrhage at the time of presentation was uncommon and was featured in only 5 cases.5–9 However, many authors reported that the tumor was highly vascular in their intraoperative findings.

Of the cases we reviewed, 4 patients presented with or developed diffuse leptomeningeal disease,10–13 5 patients were found to have multiple lesions on initial presentation,10,14–17 and an additional 4 patients developed new discrete lesions later in the course of the disease.17–20

Duration of follow-up in our reviewed cases was variable, with no documented case outcome in 11 patients. Of those with documented outcomes, 5 patients died within 2 years of diagnosis. Of these patients, all initially presented with spine lesions. Two developed delayed diffuse leptomeningeal disease, including intracranial spread.10,13 Two patients underwent gross-total resection with adjuvant chemotherapy and focal radiation.21,22 One patient underwent gross-total resection but died from their disease before adjuvant therapy could be given.23

Discussion

Observations

In this report, we discuss the case of a 34-year-old man who was diagnosed with, and eventually died from, an extraskeletal, primary multifocal CNS ES. This is a rare clinical entity, with limited literature available to guide appropriate management or predict prognosis. Unique to our case, the patient’s largest lesion was a hemorrhagic intraparenchymal lesion. There was also extensive CNS dissemination at the time of presentation, with numerous intracranial and spine lesions and diffuse leptomeningeal disease.

Lessons

For both CNS ES and non–CNS ES, resection is a mainstay of treatment, although the recommendations for timing often differ. For ES involving the extremities or pelvis, treatment conventionally begins with induction chemotherapy prior to subsequent resection,24 which allows for cytoreduction and increased ability to perform a complete resection. However, in cases of ES involving the CNS, patients often present with progressive neurological deficits or increased intracranial pressure requiring urgent surgical intervention. This can present a challenge to the surgeon, as complete resection becomes more difficult to accomplish. In cases such as that of our patient, diffuse disease prevents more definitive surgical resection.

Radiation and chemotherapy are important adjuvant therapies in the treatment of CNS ES.25 The common chemotherapy regimens utilized include cyclophosphamide, doxorubicin, etoposide, ifosfamide, and vincristine. It is important to note that, although chemotherapy is effective for ES/PNET, it comes with significant side effects, including cardiac toxicity, particularly with doxorubicin.25

With regard to prognosis, predictors of a poor outcome for any patient with ES include the size of the lesion, the presence of metastatic disease, a pelvic location, a high serum lactate dehydrogenase, and an age greater than 17 years.26–28 The average time of survival for a patient with ES involving the CNS is believed to be between 6 months and 3 years.25,29 Ibrahim et al. proposed a set of prognostic indicators for CNS ES that include age greater than 17 years, surgically inaccessible location, incomplete resection, multifocal disease, and unfavorable tumor biology (e.g., poor histological response to initial chemotherapy, non–type 1 EWS-FLI1 fusions, P53 and P16 mutations, and lower levels of vascular endothelial growth factor expression).29 However, these prognostic characteristics have not been confirmed through large cohort studies.

Based on the available literature, our patient had several factors that portended a poor clinical course, including his age, his widely metastatic disease, and his inability to undergo complete resection given the locations and diffusivity of his lesions. His disease progressed rapidly over the course of 6 months despite neuroaxis radiation and multiple chemotherapeutic agents.

Another distinct finding in our patient was the presence of a V600E BRAF mutation, which was not identified in any of the other cases we reviewed. Ahmed et al. previously used their tumor bank of 68 ES tumors to perform immunohistochemistry and evaluate for mutations that may inform pathway-specific therapies in ES.30 Although high expression of Akt-1 and nuclear factor-kappa beta was common, high expression of BRAF was seen in only 3% of cases. Furthermore, they found no significant correlation between BRAF expression and prognosis in these patients.30

Work performed by Gouravan et al. targeted V600E BRAF mutations in sarcomas using vemurafenib.31 Vemurafenib has previously been used to target melanoma with V600E BRAF mutations with a good response rate and prolonged progression-free survival, though similar results were not seen in colorectal cancer patients with the same mutation owing to rapid resistance. In this preclinical trial using four sarcoma lines, one of which was an ES, there was evidence of poor response to vemurafenib, suggesting that it may be an ineffective candidate for clinical application in sarcomas.31 Future studies may reveal a more effective agent for targeting this specific mutation in sarcomas.

Given the rarity of this disease, it is important that clinicians continue to amass the clinical, pathological, and radiological characteristics of these patients to better guide clinical management and prognostic discussions with patients and their families.

Disclosures

Dr. Perkins is employed by Washington University and is a paid member of the medical advisory committee for Mevion Medical Systems, Inc. Dr. Chicoine received grants from IMRIS, Inc., The Head for the Cure Foundation, Mrs. Carol Rossfeld, The Alex & Alice Aboussie Family Charitable Foundation, and Subcortical Surgery Group Research Grant Program, all of which are outside of the submitted work.

Author Contributions

Conception and design: Huguenard, Li, Dahiya, Chicoine. Acquisition of data: Huguenard, Li, Dahiya, Chicoine. Analysis and interpretation of data: Huguenard, Li, Perkins, Dahiya, Chicoine. Drafting the article: all authors. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Huguenard. Study supervision: Chicoine.

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    • Export Citation
  • 18

    Haresh KP , Chinikkatti SK , Prabhakar R , et al. . A rare case of intradural extramedullary Ewing’s sarcoma with skip metastasis in the spine . Spinal Cord . 2008 ;46 (8 ):582 584 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Gong HS , Huang QS , Liu GJ , et al. . Cervical primary Ewing’s sarcoma in intradural and extramedullary location and skip metastasis to cauda equina . Turk Neurosurg . 2015 ;25 (6 ):943 947 .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Bostelmann R , Leimert M , Steiger H-J , et al. . The importance of surgery as part of multimodal therapy in rapid progressive primary extraosseous Ewing sarcoma of the cervical intra- and epidural space . Clin Pract . 2016 ;6 (4 ):897 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Harimaya K , Oda Y , Matsuda S , et al. . Primitive neuroectodermal tumor and extraskeletal Ewing sarcoma arising primarily around the spinal column: report of four cases and a review of the literature . Spine (Phila Pa 1976) . 2003 ;28 (19 ):E408 E412 .

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Mobley BC , Roulston D , Shah GV , et al. . Peripheral primitive neuroectodermal tumor/Ewing’s sarcoma of the craniospinal vault: case reports and review . Hum Pathol . 2006 ;37 (7 ):845 853 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Yan Y , Xu T , Chen J , et al. . Intraspinal Ewing’s sarcoma/primitive neuroectodermal tumors . J Clin Neurosci . 2011 ;18 (5 ):601 606 .

  • 24

    Craft A , Cotterill S , Malcolm A , et al. . Ifosfamide-containing chemotherapy in Ewing’s sarcoma: the Second United Kingdom Children’s Cancer Study Group and the Medical Research Council Ewing’s Tumor Study . J Clin Oncol . 1998 ;16 (11 ):3628 3633 .

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Rosen G . Progress in the treatment of Ewing sarcoma: are the rumors of the demise of cytotoxic chemotherapy premature? Klin Padiatr . 2015 ;227 (3 ):105 107 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Craft AW , Cotterill SJ , Bullimore JA , Pearson D . Long-term results from the first UKCCSG Ewing’s Tumour Study (ET-1) . Eur J Cancer . 1997 ;33 (7 ):1061 1069 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Denny CT . Ewing’s sarcoma—a clinical enigma coming into focus . J Pediatr Hematol Oncol . 1998 ;20 (5 ):421 425 .

  • 28

    Alvarez-Berdecia A , Schut L , Bruce DA . Localized primary intracranial Ewing’s sarcoma of the orbital roof. Case report . J Neurosurg . 1979 ;50 (6 ):811 813 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Ibrahim GM , Fallah A , Shahideh M , et al. . Primary Ewing’s sarcoma affecting the central nervous system: a review and proposed prognostic considerations . J Clin Neurosci . 2012 ;19 (2 ):203 209 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Ahmed AA , Sherman AK , Pawel BR . Expression of therapeutic targets in Ewing sarcoma family tumors . Hum Pathol . 2012 ;43 (7 ):1077 1083 .

  • 31

    Gouravan S , Meza-Zepeda LA , Myklebost O , et al. . Preclinical evaluation of vemurafenib as therapy for BRAFV600E mutated sarcomas . Int J Mol Sci . 2018 ;19 (4 ):969 .

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32

    VandenHeuvel KA , Al-Rohil RN , Stevenson ME , et al. . Primary intracranial Ewing’s sarcoma with unusual features . Int J Clin Exp Pathol . 2015 ;8 (1 ):260 274 .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Hisaoka M , Hashimoto H , Murao T . Peripheral primitive neuroectodermal tumour with ganglioneuroma-like areas arising in the cauda equina . Virchows Arch . 1997 ;431 (5 ):365 369 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Uesaka T , Amano T , Inamura T , et al. . Intradural, extramedullary spinal Ewing’s sarcoma in childhood . J Clin Neurosci . 2003 ;10 (1 ):122 125 .

  • 35

    Woestenborghs H , Debiec-Rychter M , Renard M , et al. . Cytokeratin-positive meningeal peripheral PNET/Ewing’s sarcoma of the cervical spinal cord: diagnostic value of genetic analysis . Int J Surg Pathol . 2005 ;13 (1 ):93 97 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Kim S-W , Shin H . Primary intradural extraosseous Ewing’s sarcoma . J Korean Neurosurg Soc . 2009 ;45 (3 ):179 181 .

  • 37

    Klimo P Jr , Codd PJ , Grier H , Goumnerova LC . Primary pediatric intraspinal sarcomas. Report of 3 cases . J Neurosurg Pediatr . 2009 ;4 (3 ):222 229 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Theeler BJ , Keylock J , Yoest S , Forouhar M . Ewing’s sarcoma family tumors mimicking primary central nervous system neoplasms . J Neurol Sci . 2009 ;284 (1-2 ):186 189 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Karikari IO , Mehta AI , Nimjee S , et al. . Primary intradural extraosseous Ewing sarcoma of the spine: case report and literature review . Neurosurgery . 2011 ;69 (4 ):E995 E999 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Duan X-H , Ban X-H , Liu B , et al. . Intraspinal primitive neuroectodermal tumor: imaging findings in six cases . Eur J Radiol . 2011 ;80 (2 ):426 431 .

  • 41

    Lozupone E , Martucci M , Rigante L , et al. . Magnetic resonance image findings of primary intradural Ewing sarcoma of the cauda equina: case report and review of the literature . Spine J . 2014 ;14 (4 ):e7 e11 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Zhao M , Zhang B , Liang F , Zhang J . Primary spinal intradural extraskeletal Ewing sarcoma mimicking a giant nerve sheath tumor: case report and review of the literature . Int J Clin Exp Pathol . 2014 ;7 (12 ):9081 9085 .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Mardekian SK , Gandhe A , Miettinen M , et al. . Two cases of spinal, extraosseous, intradural Ewing’s sarcoma/peripheral neuroectodermal tumor: radiologic, pathologic, and molecular analysis . J Clin Imaging Sci . 2014 ;4 :6 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Kartal A , Akatlı A . Primary intradural extraosseous Ewing’s sarcoma in a young child . Childs Nerv Syst . 2016 ;32 (3 ):409 410 .

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45

    Takami H , Kumar R , Brown DA , Krauss WE . Histologic features and prognosis of spinal intradural extramedullary Ewing sarcoma: case report, literature review, and analysis of prognosis . World Neurosurg . 2018 ;115 :448 452.e2 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • View in gallery

    Non-contrast CT scans of the brain showing a hyperdense intraaxial lesion in the right frontal medial orbital gyrus (A, arrow), and adjacent cerebral edema (B).

  • View in gallery

    T1 postcontrast MRI of the brain. A: Rim-enhancing right frontal lesion with an associated hemorrhagic component with mild mass effect, shown in coronal, sagittal, and axial planes. B: Enhancing lesion within the left Meckel’s cave (arrows), shown in coronal, sagittal, and axial planes.

  • View in gallery

    Sagittal slices from MRI of the lumbar spine, with sequences of T2 (A), T1 without contrast (B), and T1 with contrast (C). There is a contrast-enhancing soft tissue epidural mass filling the thecal sac and compressing the adjacent conus medullaris (arrows) and, below that, the nerve roots of the cauda equina.

  • View in gallery

    Histopathological characteristics of resected lumbar intradural tumor—extraskeletal ES/PNET. Original magnifications ×400. Hematoxylin and eosin–stained images (A and B) show a small blue cell tumor, with variably round to spindle-shaped nuclei, karyorrhexis, brisk mitotic activity, and a patchy neutrophilic infiltrate. Immunohistochemical stains were performed, and the tumor cells show membranous expression of CD99 (C) and nonreactivity for CAM5.2 (D), GFAP (E), and synaptophysin (SYN) (F). SYN highlights entrapped axons within the involved nerve root.

  • 1

    Esiashvili N , Goodman M , Marcus RB Jr . Changes in incidence and survival of Ewing sarcoma patients over the past 3 decades: Surveillance Epidemiology and End Results data . J Pediatr Hematol Oncol . 2008 ;30 (6 ):425 430 .

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  • 2

    Balamuth NJ , Womer RB . Ewing’s sarcoma . Lancet Oncol . 2010 ;11 (2 ):184 192 .

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    Agrawal A , Dulani R , Mahadevan A , et al. . Primary Ewing’s sarcoma of the frontal bone with intracranial extension . J Cancer Res Ther . 2009 ;5 (3 ):208 209 .

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    • PubMed
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  • 4

    Antonelli M , Caltabiano R , Chiappetta C , et al. . Primary peripheral PNET/Ewing’s sarcoma arising in the meninges, confirmed by the presence of the rare translocation t(21;22) (q22;q12) . Neuropathology . 2011 ;31 (5 ):549 555 .

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  • 5

    Khalatbari MR , Jalaeikhoo H , Moharamzad Y . Primary intradural extraosseous Ewing’s sarcoma of the lumbar spine presenting with acute bleeding . Br J Neurosurg . 2013 ;27 (6 ):840 841 .

    • Crossref
    • PubMed
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  • 6

    Muzzafar S , Rhines LD , Bruner J , Schellingerhout D . Intradural extramedullary Ewing tumor of the lumbar spine . Radiol Case Rep . 2015 ;5 (4 ):421 .

  • 7

    Pancucci G , Simal-Julian JA , Plaza-Ramirez E , et al. . Primary extraosseous intradural spinal Ewing’s sarcoma: report of two cases . Acta Neurochir (Wien) . 2013 ;155 (7 ):1229 1234 .

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    • Export Citation
  • 8

    Scantland JT , Gondim MJ , Koivuniemi AS , et al. . Primary spinal intradural extraosseous Ewing sarcoma in a pediatric patient: case report and review of the literature . Pediatr Neurosurg . 2018 ;53 (4 ):222 228 .

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9

    Vincentelli F , Caruso G , Figarella-Branger D . Primary intradural Ewing’s sarcoma of the cauda equina presenting with acute bleeding . Acta Neurochir (Wien) . 2010 ;152 (3 ):563 564 .

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  • 10

    Izubuchi Y , Nakajima H , Honjoh K , et al. . Primary intradural extramedullary Ewing sarcoma: a case report and literature review . Oncol Lett . 2020 ;20 (3 ):2347 2355 .

    • Crossref
    • PubMed
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    Khwaja R , Mantilla E , Fink K , Pan E . Adult primary peripheral PNET/Ewing’s sarcoma of the cervical and thoracic spine . Anticancer Res . 2019 ;39 (8 ):4463 4465 .

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    • PubMed
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  • 12

    Mateen FJ , Nassar A , Bardia A , et al. . Spinal intradural extraosseous Ewing’s sarcoma . Rare Tumors . 2011 ;3 (1 ):e7 e24 .

  • 13

    Tan CH , Tan D , Phung TB , Lai LT . Primary intradural extramedullary Ewing sarcoma of the cervical spine: a case report and review of the literature . J Clin Neurosci . 2019 ;66 :280 284 .

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    • PubMed
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    • Export Citation
  • 14

    Weil RJ , Zhuang Z , Pack S , et al. . Intramedullary Ewing sarcoma of the spinal cord: consequences of molecular diagnostics. Case report . J Neurosurg . 2001 ;95 (2 suppl ):270 275 .

    • PubMed
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    • Export Citation
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    Bazzocchi A , Bacci A , Serchi E , et al. . Intradural extramedullary Ewing’s sarcoma. Recurrence with acute clinical presentation and literature review . Neuroradiol J . 2013 ;26 (4 ):476 481 .

    • Crossref
    • PubMed
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  • 16

    Chihak MA , Ahmed SK , Lachance DH , et al. . Patterns of failure and optimal radiotherapy target volumes in primary intradural extramedullary Ewing sarcoma . Acta Oncol . 2016 ;55 (8 ):1057 1061 .

    • Crossref
    • PubMed
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    • Export Citation
  • 17

    Paterakis K , Brotis A , Tasiou A , et al. . Intradural extramedullary Ewing’s sarcoma: a case report and review of the literature . Neurol Neurochir Pol . 2017 ;51 (1 ):106 110 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Haresh KP , Chinikkatti SK , Prabhakar R , et al. . A rare case of intradural extramedullary Ewing’s sarcoma with skip metastasis in the spine . Spinal Cord . 2008 ;46 (8 ):582 584 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Gong HS , Huang QS , Liu GJ , et al. . Cervical primary Ewing’s sarcoma in intradural and extramedullary location and skip metastasis to cauda equina . Turk Neurosurg . 2015 ;25 (6 ):943 947 .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Bostelmann R , Leimert M , Steiger H-J , et al. . The importance of surgery as part of multimodal therapy in rapid progressive primary extraosseous Ewing sarcoma of the cervical intra- and epidural space . Clin Pract . 2016 ;6 (4 ):897 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Harimaya K , Oda Y , Matsuda S , et al. . Primitive neuroectodermal tumor and extraskeletal Ewing sarcoma arising primarily around the spinal column: report of four cases and a review of the literature . Spine (Phila Pa 1976) . 2003 ;28 (19 ):E408 E412 .

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Mobley BC , Roulston D , Shah GV , et al. . Peripheral primitive neuroectodermal tumor/Ewing’s sarcoma of the craniospinal vault: case reports and review . Hum Pathol . 2006 ;37 (7 ):845 853 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Yan Y , Xu T , Chen J , et al. . Intraspinal Ewing’s sarcoma/primitive neuroectodermal tumors . J Clin Neurosci . 2011 ;18 (5 ):601 606 .

  • 24

    Craft A , Cotterill S , Malcolm A , et al. . Ifosfamide-containing chemotherapy in Ewing’s sarcoma: the Second United Kingdom Children’s Cancer Study Group and the Medical Research Council Ewing’s Tumor Study . J Clin Oncol . 1998 ;16 (11 ):3628 3633 .

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Rosen G . Progress in the treatment of Ewing sarcoma: are the rumors of the demise of cytotoxic chemotherapy premature? Klin Padiatr . 2015 ;227 (3 ):105 107 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Craft AW , Cotterill SJ , Bullimore JA , Pearson D . Long-term results from the first UKCCSG Ewing’s Tumour Study (ET-1) . Eur J Cancer . 1997 ;33 (7 ):1061 1069 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Denny CT . Ewing’s sarcoma—a clinical enigma coming into focus . J Pediatr Hematol Oncol . 1998 ;20 (5 ):421 425 .

  • 28

    Alvarez-Berdecia A , Schut L , Bruce DA . Localized primary intracranial Ewing’s sarcoma of the orbital roof. Case report . J Neurosurg . 1979 ;50 (6 ):811 813 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Ibrahim GM , Fallah A , Shahideh M , et al. . Primary Ewing’s sarcoma affecting the central nervous system: a review and proposed prognostic considerations . J Clin Neurosci . 2012 ;19 (2 ):203 209 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Ahmed AA , Sherman AK , Pawel BR . Expression of therapeutic targets in Ewing sarcoma family tumors . Hum Pathol . 2012 ;43 (7 ):1077 1083 .

  • 31

    Gouravan S , Meza-Zepeda LA , Myklebost O , et al. . Preclinical evaluation of vemurafenib as therapy for BRAFV600E mutated sarcomas . Int J Mol Sci . 2018 ;19 (4 ):969 .

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32

    VandenHeuvel KA , Al-Rohil RN , Stevenson ME , et al. . Primary intracranial Ewing’s sarcoma with unusual features . Int J Clin Exp Pathol . 2015 ;8 (1 ):260 274 .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Hisaoka M , Hashimoto H , Murao T . Peripheral primitive neuroectodermal tumour with ganglioneuroma-like areas arising in the cauda equina . Virchows Arch . 1997 ;431 (5 ):365 369 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Uesaka T , Amano T , Inamura T , et al. . Intradural, extramedullary spinal Ewing’s sarcoma in childhood . J Clin Neurosci . 2003 ;10 (1 ):122 125 .

  • 35

    Woestenborghs H , Debiec-Rychter M , Renard M , et al. . Cytokeratin-positive meningeal peripheral PNET/Ewing’s sarcoma of the cervical spinal cord: diagnostic value of genetic analysis . Int J Surg Pathol . 2005 ;13 (1 ):93 97 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Kim S-W , Shin H . Primary intradural extraosseous Ewing’s sarcoma . J Korean Neurosurg Soc . 2009 ;45 (3 ):179 181 .

  • 37

    Klimo P Jr , Codd PJ , Grier H , Goumnerova LC . Primary pediatric intraspinal sarcomas. Report of 3 cases . J Neurosurg Pediatr . 2009 ;4 (3 ):222 229 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Theeler BJ , Keylock J , Yoest S , Forouhar M . Ewing’s sarcoma family tumors mimicking primary central nervous system neoplasms . J Neurol Sci . 2009 ;284 (1-2 ):186 189 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Karikari IO , Mehta AI , Nimjee S , et al. . Primary intradural extraosseous Ewing sarcoma of the spine: case report and literature review . Neurosurgery . 2011 ;69 (4 ):E995 E999 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Duan X-H , Ban X-H , Liu B , et al. . Intraspinal primitive neuroectodermal tumor: imaging findings in six cases . Eur J Radiol . 2011 ;80 (2 ):426 431 .

  • 41

    Lozupone E , Martucci M , Rigante L , et al. . Magnetic resonance image findings of primary intradural Ewing sarcoma of the cauda equina: case report and review of the literature . Spine J . 2014 ;14 (4 ):e7 e11 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Zhao M , Zhang B , Liang F , Zhang J . Primary spinal intradural extraskeletal Ewing sarcoma mimicking a giant nerve sheath tumor: case report and review of the literature . Int J Clin Exp Pathol . 2014 ;7 (12 ):9081 9085 .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Mardekian SK , Gandhe A , Miettinen M , et al. . Two cases of spinal, extraosseous, intradural Ewing’s sarcoma/peripheral neuroectodermal tumor: radiologic, pathologic, and molecular analysis . J Clin Imaging Sci . 2014 ;4 :6 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Kartal A , Akatlı A . Primary intradural extraosseous Ewing’s sarcoma in a young child . Childs Nerv Syst . 2016 ;32 (3 ):409 410 .

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45

    Takami H , Kumar R , Brown DA , Krauss WE . Histologic features and prognosis of spinal intradural extramedullary Ewing sarcoma: case report, literature review, and analysis of prognosis . World Neurosurg . 2018 ;115 :448 452.e2 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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