Primary Orbital Extraskeletal Ewing Sarcoma FREE

Extraskeletal Ewing sarcoma is a rare soft tissue sarcoma histologically indistinguishable from osseous Ewing sarcoma. Tefft et al¹ first described the tumor in children with paravertebral soft tissue masses. Subsequent larger case series have shown that the tumor has a predilection for the paravertebral area and lower extremities.² The tumor most often occurs in the extremities and paraspinal areas and has been reported to occur in the head and neck region in 5% to 11% of patients.^3- 5 While osseous Ewing sarcoma, both primary and metastatic, has been reported in the orbit, ⁶ to our knowledge, ours is the first case of extraskeletal Ewing sarcoma to occur in the orbit. Furthermore, extraskeletal Ewing sarcoma manifesting as late as the sixth decade of life has not been reported, to our knowledge. We report a case of primary orbital extraskeletal Ewing sarcoma in a 56-year-old man, which was diagnosed using monoclonal antibody 013 to the p30/32 MIC2 gene product, CD99.

A previously healthy 56-year-old white man had a 5-month history of progressive right upper eyelid swelling, diplopia, dizziness, and a right-sided headache. His medical history was significant for mild chronic obstructive pulmonary disease treated with albuterol inhalers as needed. On ophthalmic examination, the left eye was normal. His visual acuity was 20/100 OD and 20/30 OS, with a 1+ right afferent pupillary defect. He had right upper eyelid swelling. Hertel measurements showed 8 mm of right exophthalmos. The right orbit exhibited resistance to retropulsion. Examination of ocular motility revealed limited movement of the right eye in all gaze positions. Funduscopic examination of the right eye revealed choroidal folds and mild optic nerve edema.

Axial and coronal magnetic resonance images of the orbits with and without gadolinium revealed a well-circumscribed enhancing nonhomogeneous intraconal mass in the right orbit, measuring 3 × 2.2 × 2.5 cm (Figure 1). No bony invasion was apparent. The nonhomogeneous areas within the tumor were interpreted as vascular flow voids. Based on the appearance of the tumor on magnetic resonance imaging, a diagnosis of cavernous hemangioma was suspected. The patient underwent a lateral orbitotomy via a swinging eyelid approach. The periorbita was found to be intact as it was dissected off the lateral orbital wall. The bone of the lateral orbital wall was removed to improve visualization and was found to be clinically normal.

On opening the periorbita, the large tumor was found to be a solid mass and a biopsy of the mass was performed. A frozen section pathologic examination showed sheets of cells with round to ovoid nuclei and scant cytoplasm separated by fibrous septae and numerous blood vessels. Further histopathologic studies on permanent sections showed no rosette formation (Figure 2).

Reactions were negative on immunohistochemical analyses using pancytokeratin, chromogranin, synaptophysin, CD34, S100 protein, and leukocyte common antigen. The tumor showed positive reaction with monoclonal antibody 013 to CD99 (Figure 3) and to neuron-specific enolase. Our evaluation, based on histopathologic appearance combined with immunohistochemical findings, established the diagnosis of extraskeletal Ewing sarcoma.

The patient underwent systemic evaluation, including a full-body bone scan and computed tomography of the chest. All test results were normal except for mild apical scarring in the lungs, consistent with his history of pulmonary disease. Computed tomography performed after the biopsy demonstrated an intact greater sphenoid wing of the lateral orbital wall, with an anterior surgical defect.

He underwent chemotherapy, consisting of intravenous ifosfamide (1800 mg/m²), intravenous mesna (360 mg/m²), and intravenous etoposide (100 mg/m²) for 5 days, followed 3 weeks later by a combination of vincristine (1.4 mg/m²), doxorubicin (50 mg/m²), and cytoxan (750 mg/m²). After 5 cycles of chemotherapy during 6 months, the results of clinical and radiologic examinations of the right orbit remained unchanged.

Subsequently, he received radiation therapy, with a total of 4500 rad(45 Gy) to the right orbit during 41 days. After radiation treatment, the patient's right exophthalmos quickly improved. Positron emission tomography after radiation therapy showed at least 80% necrosis of the orbital mass, and magnetic resonance imaging showed a decrease in tumor size (Figure 4).

Thirty-three months after the initial examination, he remains clinically stable without evidence of metastatic disease. His visual acuity has improved to 20/25 OD, and the afferent pupillary defect has resolved. Hertel measurements reveal 1 mm of right exophthalmos. Ocular motility is now normal in both eyes.

The histologic appearance of extraskeletal Ewing sarcoma consists of uniform round cells with scant cytoplasm, making it indistinguishable from osseous Ewing sarcoma, and difficult to distinguish from other small cell tumors, such as neuroblastoma and rhabdomyosarcoma. Recent immunohistochemical studies have been devised to aid in distinguishing small round cell tumors. The crucial marker in distinguishing Ewing sarcoma, both osseous and extraskeletal, is antibody 013 to glycoprotein p30/32, or CD99.⁷ The tumor in our patient was strongly positive for this epitope. Although CD99 may be positive in other tumor types, such as lymphoblastic lymphoma or rhabdomyosarcoma, other immunohistochemical stains exclude these from the diagnosis.

Most cases of extraskeletal Ewing sarcoma occur during the second or third decade of life. Reports have indicated that the extremities are most often the initial site of involvement. The paravertebral area is also commonly involved. When extraskeletal Ewing sarcoma was first described, the prognosis for the disease was poor. Angervall and Enzinger² reported a 63% mortality rate in 35 cases, with 12 of 20 deaths within 1 year of diagnosis. The mainstay of treatment in this study was surgical excision alone. Some patients were reported to receive postoperative radiation or chemotherapy, but in no standard doses. In contrast, the Intergroup Rhabdomyosarcoma Study reported a 64% disease-free survival rate, with a median follow-up of 2 years in 26 patients treated with radiation and chemotherapy.⁴ Subsequently, combined-modality treatment was established by Kinsella et al, ⁸ who reported 64% disease-free survival in 11 patients after radiation treatments(5000 rads [50 Gy] at 180-200 fractions during 5-6 weeks) and concomitant combination chemotherapy (vincristine, actinomycin, and cyclophosphamide) for 4 cycles.

Ahmad et al⁹ studied 24 patients and found that tumor size did not have a significant effect on disease-free survival. Positive prognostic indicators included younger age at diagnosis and surgical resection with wide margins when combined with chemotherapy and irradiation. Chao et al¹⁰ also advocates wide surgical excision, particularly when the spinal cord may be compromised.

In contrast, Kinsella et al's study did not show radical surgical excision to be crucial in survival. The findings in our patient support those of Kinsella et al. Our patient underwent subtotal tumor excision. Nevertheless, he experienced improvement following chemotherapy and radiation therapy. Multiagent chemotherapy appeared to halt the growth of his tumor, but the tumor did not regress until radiation therapy was administered.

The authors have no relevant financial interest in this article.

Corresponding author and reprints: John McCann, MD, PhD, Division of Orbit and Oculoplastic Surgery, Jules Stein Eye Institute/University of California–Los Angeles, 100 Stein Plaza, Los Angeles, CA 90095-7000(e-mail: mccann@jsei.ucla.edu).