Intracranial Ewing sarcoma (IES) is a primitive neuroectodermal tumor of the peripheral
nervous system consisting of undifferentiated small and round cells.[1] Ewing sarcoma typically arises in the bones or soft tissues in children and adolescents,
and its intracranial occurrence in adults is exceptionally uncommon, comprising only
0.03% of all intracranial tumors.[2]
[3]
[4]
[5] Ewing sarcomas arise due to peculiar balanced chromosomal translocations, with 85
to 90% of patients having t(11,22) (q24;q12) translocation resulting in the EWSR1-FLI1
fusion gene. In approximately 10% of patients, the t(21,22) (q22;q12) translocation
is the second most common, resulting in the EWSR1-ERG fusion gene.[5]
[6]
[7] In approximately 3% of patients, EWSR1 gene fusion with other ETS family transcription
factors, such as FEV1, is seen.[5] Publications on IES are scarce, most of which are isolated case reports.[1] Neuroimaging techniques, histopathological examination with immunohistochemical
staining, and cytogenetic/molecular studies remain crucial for accurate diagnosis.
Treatment protocols typically involve multimodal approaches, including surgical resection,
chemotherapy, and radiotherapy. However, the optimal management strategy for adult
primary IES (PIES) is not well-defined due to the limited available evidence.[8] Given the extreme rarity of PIES, it is not often included in the usual differentials
in most clinical scenarios.[2] We aim to contribute to the scarce data on adult PIES by detailing the clinical
course of a 24-year-old male patient with Ewing sarcoma in the left frontal lobe.
The tumor was misinterpreted as glioblastoma on initial histopathology.
A 24-year-old man presented with a week-long history of headache (persistent, unrelieved
by medication) accompanied by several days of vomiting and blurred vision. An initial
noncontrast magnetic resonance imaging (MRI) of the brain revealed a large intra-axial
mass lesion with both solid and cystic components in the left frontal lobe. A subsequent
contrast-enhanced MRI provided further details, revealing a large tumor with the “cyst-with-mural-nodule”
morphology in the left frontal lobe. The tumor measured 7.5 × 4.8 × 6.3 cm, with the
solid component constituting almost half of the lesion and located toward the surface
cortex, while the cystic component was present toward the white matter, distorting
the frontal horns of the left and right lateral ventricles. The cystic portion showed
hyperintense signals of fluid content relative to cerebrospinal fluid on FLAIR (fluid-attenuated
inversion recovery), T1W, and T2W images ([Fig. 1A–D]).
Fig. 1 (A) Sagittal T2-weighted MRI showing a large intra-axial mass lesion in the left frontal
lobe with solid and cystic components. The solid component is seen toward the surface
cortex, and the cystic portion, which contains hyperintense fluid relative to CSF,
is located deeper toward the white matter. (B) Axial diffusion-weighted imaging (DWI) demonstrating restricted diffusion within
the solid component of the mass, suggesting high cellularity typical of Ewing sarcoma.
(C) Coronal T1-weighted post-contrast MRI highlighting the “cyst-with-mural-nodule”
morphology of the lesion, with the solid component showing significant contrast enhancement,
indicative of its aggressive nature. (D) Axial T2-weighted MRI showing the cystic component of the lesion with perilesional
edema and a mass effect, displacing the adjacent brain structures. CSF, cerebrospinal
fluid; MRI, magnetic resonance imaging.
The patient underwent a left frontal craniotomy with tumor decompression under general
anesthesia. The procedure was uneventful, and the patient was transferred to the intensive
care unit for further management. However, he developed an extradural hemorrhage necessitating
re-exploration and a left temporoparietal craniotomy on the same day.
An excisional biopsy was performed, and the specimen was sent for histopathological
analysis to determine the tumor's origin and type. Since the setting has limited resources,
immunohistochemistry could not be done and initial histopathological examination suggested
a glioblastoma. To differentiate Isocitrate Dehydrogenase (IDH)-wild versus IDH-mutant
types of glioblastoma, the tissue block was sent to a higher center for immunohistochemical
staining. Interestingly, histopathological examination at the higher center revealed
a highly cellular tumor with extensive necrosis. Immunohistochemistry showed the tumor
cells to be diffusely immunopositive for CD99, FLI-1, and NKX2.2 ([Fig. 2A–D]), and immunonegative for GFAP, Olig2, CD45, SALL4, NeuN, STAT6, and Chromogranin
A. The Ki67 proliferation index was approximately 95%, indicating high proliferative
activity.
Fig. 2 (A) Low-power view showing a monomorphic appearing blue cell tumor with adjacent normal
brain parenchyma (H&E x40X). (B) High-power view showing primitive-looking cells in sheets with occasional Homer–Wright
rosettes (red arrow) and active frequent mitosis (black arrow), (H&E x400X). (C) The tumor cells are immunopositive for CD99 (IHC x100X), (D) and for NKX2–2 (IHC x100X).
Four days postoperatively, the patient experienced severe chest pain and was diagnosed
with an anterior wall myocardial infarction, followed by three episodes of monomorphic
ventricular tachycardia. He was managed conservatively in the cardiology care unit,
where his stay was uneventful. Postoperatively, the patient exhibited no neurological
deficits. High-resolution computed tomography (CT) thorax and noncontrast CT abdomen
showed no evidence of additional lesions. A postoperative CT of the brain confirmed
near-complete tumor decompression. The patient was subsequently put on an adjuvant
chemotherapy regimen comprising etoposide and ifosfamide. Mesna was added for ifosfamide
toxicity.
IES is a rare entity, and its demarcation from other similar intracranial tumors is
crucial for accurate diagnosis and effective management. Authors in published studies
have referred to IES as “an entity of unacquaintance,” underscoring its importance
and rarity in the differential diagnosis of intracranial neoplasms.[2] The clinical features are varied, but headache is the most consistent symptom. Other
signs and symptoms at presentation reported in previous cases include vision problems,
seizures, hyposmia, papilledema, vomiting, fever and malaise, tinnitus, dizziness,
hemiparesis, imbalance, and memory and mental status impairment.[1]
[2]
[4]
[8]
[9]
[10] Most IES cases reported in the literature are in the pediatric age group.[1]
[2]
[9]
[11] In our case, it was found in a 24-year-old adult, which further adds to the rarity
of this case.
The radiological presentation of IES can be variable, often mimicking other intracranial
lesions. Advanced neuroimaging techniques may provide valuable insights into the tumor's
characteristics and aid in preoperative planning.[10] In our case, MRI had revealed a left frontal lobe mass with both solid and cystic
components similar to radiological findings in previously published cases.[2]
[4]
[10]
[11]
Immunohistochemical analysis plays a crucial role in the diagnosis, with markers such
as CD99, FLI1, and NKX2.2 typically demonstrating positivity in IES. Immunohistochemical
analysis also aids in differentiating IES from other intracranial neoplasms. Diffuse
membranous CD99 positivity is a highly reliable and sensitive marker for Ewing Sarcoma.
However, although sensitive, CD99 is not a specific marker for Ewing sarcoma as it
can be found in other malignancies.[1]
[5]
[12]
[13] Molecular studies (via reverse transcription polymerase chain reaction/fluorescence
in situ hybridization) and cytogenetic studies revealing balanced translocation of
EWSR1 gene conspicuous of Ewing sarcoma are currently gold standard tests for confirmatory
diagnosis of Ewing Sarcoma.[4]
[13]
Due to the extreme rarity of PIES, the current body of evidence for management strategies
for the tumor remains limited. The optimal management of IES remains unclear due to
its rarity, and no established standard treatment protocol exists.[1]
[8]
[9]
[10] IES is treated similarly to Ewing sarcoma anywhere else in the body. The current
consensus on treating Ewing sarcoma of bone involves multiagent therapy, which is
believed to be highly efficacious; however, its efficacy for IES is doubtful.[8] Surgical resection remains the mainstay treatment.[9] Surgical resection, along with chemotherapy and/or radiotherapy, provides favorable
results.[4]
[8]
[9] As per the EE99 protocol, the induction chemotherapy regimen involves using VIDE—vincristine,
ifosfamide, doxorubicin, and etoposide. The central nervous system penetration of
ifosfamide is believed to be good, while that of others is contentious.[1]
[14] Given the resource constraints, ifosfamide and etoposide were used in our case.
In terms of prognosis, the outcomes for patients with PIES vary. A study reported
a 3-year event-free survival of 64% and an overall survival of 70% for patients with
PIES.[1] In our case, early surgical resection coupled with adjuvant chemotherapy was done
to mitigate the risk of recurrence. While the patient in our case had a favorable
postoperative course, long-term follow-up is essential due to the potential for late
recurrence, as highlighted by similar cases.[2]
[9]
[10]
PIES in adults is an extremely uncommon occurrence and is often missed on differentials
in routine clinical scenarios. It is highly malignant and bears a poor prognosis.
Accurate diagnosis becomes difficult in scenarios where it mimics other intracranial
neoplasms. Given the scarcity of reported cases, there is a pressing need for multicentered
collaborations and long-term follow-up studies to better elucidate the natural history,
prognostic factors, and optimal management strategies for IES. Such efforts would
enhance our understanding of this rare entity and potentially lead to the development
of targeted therapies and improved patient outcomes.
