Introduction

Ewing sarcoma is a highly aggressive round cell mesenchymal neoplasm affecting children and adolescents, commonly metastasizing to the bones, bone marrow, and lungs [1, 2]. Ewing sarcoma can also involve or metastasize into the structures protecting the central nervous system (spinal vertebrae and meninges), wherefrom it can compress or invade the central nervous system. However, Ewing sarcoma occurring within the spinal cord is extremely rare. To the best of our knowledge, there have been 35 previous reports of spinal intramedullary Ewing sarcoma including both primary (n = 31) and recurrent (n = 4) cases (Tables 1, 2) [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32]. Herein we report a recurrent case of cervical intramedullary Ewing sarcoma with 10-year disease-free survival after the primary surgery for a thoracic lesion, followed by an extremely poor postoperative prognosis.

Table. 1 Summary of reported cases of primary spinal intramedullary Ewing sarcoma.
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Table. 2 Summary of reported cases of recurrent spinal intramedullary Ewing sarcoma.
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Case presentation

A 39-year-old man with a three-month history of neck pain was referred to our department. The patient also exhibited a right-hand clumsiness gradually deteriorating, whose onset was concomitant with the neck pain. He was recently diagnosed with an intramedullary tumor at the cervical C3 level based on magnetic resonance imaging (MRI) in a previous hospital. He had a history of surgery and chemoradiotherapy for a thoracic paravertebral primary Ewing sarcoma located at Th4-5 level. During the primary surgery performed 10 years ago in another hospital, he underwent a gross total resection of the thoracic tumor and had been subsequently asymptomatic.

Physical examination revealed a numbness in the upper extremity and hypoesthesia below C5 level. The muscle strength of his right finger extensor and flexor measured by manual muscle testing was scored 3, and no muscle weakness of lower extremities was noted, showing a normal ambulatory ability. His deep tendon reflexes of lower extremities were upregulated with positive Babinski reflexes bilaterally. He exhibited no bladder or rectal disorders. His right hand showed myelopathy signs with 14 times of grip and release during the so-called 10-s test, while his left hand scored 22 times. The hand grip strength was 6.7 kg on the right and 35 kg on the left, respectively. While serial radiographs of the cervical spine showed no structural abnormality, cervical MRI revealed a well-demarcated intramedullary lesion at the C3 level, which appeared isointense on both T1- and T2-weighted images with marked heterogeneous gadolinium-enhancement, accompanied by extensive edematous changes on T2 sagittal MRI image within the cord extending from the medulla oblongata to Th1 (Fig. 1). The appearance of the tumor on T1-weighted gadolinium (Gd)-enhanced sagittal MRI image was spherical on its rostral edge while adopting a tear-drop shape at the caudal edge (Fig. 1c). On positron emission tomography (PET)/computed tomography (CT) using fluorodeoxyglucose (18F) (FDG), a hot spot with FDG-uptake was detected only at C3 level of the spinal cord (Fig. 2). No other lesion was detectable on PET/CT in his whole body (Fig. 2b). The differential diagnosis of this intramedullary lesion was presumed to be ependymoma, astrocytoma, or metastasis of Ewing sarcoma based on MRI findings. Given his rapidly progressive cervical myelopathy manifested by right-hand motor weakness, he underwent surgery for this intramedullary lesion in our hospital.

Fig. 1: Preoperative cervical MR images.
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Sagittal images of T1-weighted (a), T2-weighted (b), and T1-weighted post-Gd (c) contrast administration and axial images of T2-weighted (d), and T1-weighted post-Gd (e) administration are presented. The tear-drop shaped intramedullary tumor at the C3 level was iso-intense on T1- and T2-weighted images and demonstrated strong and diffuse enhancement with Gd. On T2-weighted sagittal image, the tumor was accompanied with diffuse intramedullary high intensity edematous change.

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Fig. 2: Preoperative PET-CT scanning.
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PET-CT showed a FDG-hot spot only at the C3 spinal cord, consistent with an intramedullary lesion. There were no other lesions detected on PET-CT.

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After a C2 double-door laminoplasty and C3–C4 wide laminectomy with the muscle-preserving technique of attaching to C2–C4 spinous processes [33], we confirmed the rostro-caudal limits of the tumor using ultrasonography. Then we incised the dura and arachnoid matter under surgical microscope. Macroscopically, the tumor appeared orangish with dorsally exophytic growth over the pia mater (Fig. 3a), containing cloudy serous fluids. We performed a myelotomy via the posterior median sulcus of the cord and tried to dissect out the tumor. However, the boundary between the tumor and the normal cord was unclear, and the tumor tissues were easily hemorrhagic. Furthermore, his heart rate became bradycardic while dissecting the tumor’s ventral boundary, resulting in subtotal resection of the tumor (Fig. 3b). A piece of tumor specimen was examined by a pathologist intraoperatively, resulting in the diagnosis of malignant small round cell tumor.

Fig. 3: Intraoperative findings on microscope.
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The macroscopic appearance of the tumor was orangish with dorsally exophytic growth over the pia mater (a), which resulted in partial resection of the tumor (b).

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Histopathological analysis using paraffin sections of the resected specimen showed a solid tumor composed by monotonous small round cells with high N/C ratio, hyperchromatic nuclei, and high mitotic rate (Fig. 4a, b). Immunohistochemistry revealed that the resected tumor cells were positive for CD99 (Fig. 4c), Nkx2.2 (Fig. 4d), INI1 (retained, not shown), S-100 (not shown), and synaptophysin (not shown), but negative for cytokeratin AE1/AE3 (Fig. 4e), CD79a, TdT (terminal deoxynucleotidyl transferase), desmin, and myogenin. Taken together with the history of thoracic paravertebral Ewing sarcoma, although we did not confirm the presence of chimeric genes such as EWS-FLI1, the pathological findings led to the final diagnosis of intramedullary metastasis of Ewing sarcoma.

Fig. 4: Histopathologic findings.
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Low (a) and high (b) magnification views of hematoxylin and eosin (H-E) stain revealed the solid tumor composed by small round cells with high N/C ratio and hyperchromatic nuclei. Immunohistochemistry showed that the resected tumor cells were positive for CD99 (c) and Nkx2.2 (d), but negative for cytokeratin AE1/AE3 (e). (Scale bars: 4 mm in a, and 100 µm in b–e).

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Postoperatively, the right-hand clumsiness was improved, and the patient could ambulate independently. He was transferred to another hospital for an adjuvant chemotherapy on the 15th day after surgery. However, two and a half months after the surgery for intramedullary lesion, he died of cranial dissemination of the tumor.

Discussion

Ewing sarcoma comprises 10–15% malignant bone tumors and 40–45% pediatric malignant bone tumors. The overall 5-year survival rate is of 70% in localized cases and 30% in metastatic cases [34]. To the best of our knowledge, only 35 cases of intramedullary spinal Ewing sarcoma were identified in the literature, including 31 primary (Table 1) and four recurrent/metastatic intramedullary cases (Table 2) [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32]. Intramedullary Ewing sarcomas are commonly located at thoracic or lumbar spinal cord [25]. Initial intramedullary Ewing sarcoma symptoms are similar to other intramedullary spinal cord tumors such as ependymoma or astrocytoma, which include sensory disturbance first followed by motor paralysis and bladder and bowel dysfunctions [31]. Unlike usual spinal intramedullary tumors, intramedullary Ewing sarcomas are presumed to show an acute onset with rapid progressive aggravation of myelopathy, consequently followed by severe myeloplegia [31].

As shown in the Table 2, there were only four cases of recurrent intramedullary metastasis of Ewing sarcoma in the literature. The mechanism of metastasis from the brain lesion was presumed to be drop metastasis via cerebrospinal fluid. Although there was no consistent trend of these recurrent cases due to the small number of cases, notably, the current case was the first case of intramedullary metastasis of Ewing sarcoma with 10-year disease-free survival after treatment for a primary lesion of Ewing sarcoma (Table 2). Despite very late (16 and 19 years) local recurrence of Ewing sarcoma in extremities and pelvis has been reported [35], the current case was the first case of intramedullary metastatic case after a long latent phase. The recent advances in the treatment strategy for Ewing sarcoma, including neoadjuvant and adjuvant chemotherapies with surgery and/or radiotherapy, could succeed in improving the prognosis of primary localized Ewing sarcoma lesion, and could increase the number of cancer survivors in the adolescent and young adult (AYA) generation like this case [34, 36]. Survivors of AYAs sarcoma face significantly higher risks for cardiovascular disease, infertility, and secondary malignancies due to the adjuvant therapy [36]. Therefore, careful long-term follow-up is essential for AYAs sarcoma. On the other hand, the prognosis of metastatic forms of Ewing sarcoma is poorer than that of localized ones [37]. The current case of intramedullary metastatic Ewing sarcoma showed indeed an extremely poor prognosis with less than 6 months of survival from the onset. It is possible that the surgical manipulation of the metastatic lesion might have facilitated the dissemination into the cerebrospinal fluid.

A well-known fusion protein, EWS-FLI1, plays a crucial role in Ewing sarcoma’s development, maintenance, and progression [38, 39]. In addition to EWS-FLI1, the expression of CD99, or MIC-2 gene product, on the cell surface is a sensitive diagnostic maker, although its specificity is relatively lower than EWS-FLI1 [40]. The resected specimen of the present case was indeed immunoreactive for both CD99 and Nkx2.2 (Fig. 4c, d). The combined use of these two markers is advocated as a powerful diagnostic tool that can differentiate Ewing sarcoma from other small round cell tumors with high sensitivity and specificity [41]. Although we have not confirmed the expression of EWS-FLI1 fusion protein in this case, together with the histologic features, the immunoreactivity for both CD99 and Nkx2.2 led to the final diagnosis of intramedullary Ewing sarcoma.

In conclusion, a rare case of cervical intramedullary recurrence of Ewing sarcoma with 10-year disease-free survival is reported. We performed tumor resection that resulted in partial resection of the tumor, followed by an extremely poor evolution with the patient’s death two and a half months after the surgery, most likely due to the cranial dissemination of tumor cells. Although the rapid aggravation of the myelopathy due to cervical intramedullary metastatic lesion growth compelled us to perform surgical treatment, there is no established treatment guideline due to the rarity of spinal intramedullary metastasis of Ewing sarcoma. Further collection of similar cases would be required.