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Primitive neuroectodermal tumor/Ewing sarcoma of the retina.

The most common primary malignant intraocular tumor in childhood is retinoblastoma. Retinoblastoma may be unifocal or multifocal and unilateral or bilateral. This tumor arises in the retina and is a small, round blue cell tumor that exhibits apoptosis, with rosette and fleurette formation. (1) Medulloepithelioma is another primary intraocular tumor of childhood that arises in the ciliary epithelium and may contain small round blue cells similar in histologic appearance to retinoblastoma. (2) The differential diagnosis of primary small round blue cell tumors of childhood includes neuroblastoma primitive neuroectodermal tumor (PNET)/Ewing sarcoma, which may rarely occur as a primary tumor of the orbit. (3) We recently examined a child with a primary unilateral intraocular tumor. The eye was enucleated and the tumor, which appeared to arise in the peripheral retina, was determined by polymerase chain reaction (PCR) to be a PNET/Ewing sarcoma. This tumor should be distinguished from retinoblastoma and medulloepithelioma as a rare, primary intraocular small round blue cell tumor.


An 11-year-old boy was seen approximately 10 months ago and was found to have an intraocular mass in his left eye. He was lost to follow-up. However, he was referred to us 6 weeks ago for a vitreous hemorrhage. A vitrectomy was performed at an outside hospital and during the vitrectomy, a tumor was seen within the eye. The vitrectomy specimen was evaluated by 1 author (H.E.G.) and found to contain a small, round blue cell tumor. The best corrected vision in his left eye was count fingers at 1 foot. The intraocular pressure was 28 mm Hg. Examination showed a white, smooth tumor with associated hemorrhages in the area of the peripheral retina/ciliary body (Figure 1). B-scan ultrasonography showed that the tumor measured 11.1 X 15.9 X 13.7 mm (Figure 1, inset) and an A-scan showed low to medium internal reflectivity in the tumor. Laboratory tests including a complete blood count; toxocara titer; toxoplasmosis titer; chest, abdominal, and pelvic computed tomography; and magnetic resonance imaging of the brain all yielded normal results. Other than the left eye findings, the results of a complete physical examination, including examination of the extremities, were normal. The left eye was enucleated. Examination of the enucleated left eye showed an 11 X 10-mm white tumor (Figure 2) arising in the area of the peripheral retina/ciliary body from the area of the ora serrata temporally (Figure 2, upper right inset). The vitreous contained blood. The macula and optic nerve were not visualized. The choroid and sclera were normal. Microscopic examination showed that the tumor was composed of sheets of small, round, hyperchormatic nuclei and scanty cytoplasm (Figure 2, upper left inset). There were vascular channels throughout the tumor. The iris leaflets near the iridocorneal angle were adherent to the posterior aspect of the trabecular meshwork. Lens remnants were present. The number of mitotic figures was 1 per 40 high-power fields in the tumor. Toward the base of the tumor, tumor cells formed focal aggregates. There were peripheral tubuloacinar configurations of the retinal pigment epithelium. The tumor extended around the lens remants and onto the anterior surface of the iris leaflet. The retina otherwise displayed atrophy of its nerve fiber and ganglion cell layers. The vitreous contained erythrocytes and fibrocellular tissue in the vitreous base (proliferative vitreoretinopathy). The optic nerve displayed atrophic changes. Immunohistochemical staining was positive for neuron-specific enolase (1:200; Dako, Capintera, California), vimentin (1:320; Dako), and cluster of differentiation (CD) 99 (CD99) (1:40; Signet, Dedham, Massachusetts) throughout the tumor (Figure 2, lower right inset); synaptophysin in nodules (Figure 3 and Figure 3, upper left inset) of tumor cells; CD56 (1:80; Zymed, San Francisco, California) in intervening tumor cells (Figure 3, lower left inset); glial fibrillary acid protein (GFAP) (1:100; Dako) in the retina along the edge of the tumor; and partially for Friend leukemia integration 1 (FLI1) (1:60; Santa Cruz, Santa Cruz, California) in tumor cells (Figure 3, lower right inset). Immunohistochemical staining was negative for S100 (1:3200; Dako). Electron microscopic examination showed sheets of tumor cells with pleomorphic nuclei, indented chromatin, prominent nucleoli, intracytoplasmic vesicles, patches of basal lamina, and occasional dense core granules. The tumor was interpreted to represent a PNET, which was confirmed by PCR positivity for the Ewing sarcoma (EWS)/FLI-1 fusion gene in tumor cells; the fusion gene was sequenced (Figure 4). The patient was evaluated 1 year after enucleation and found to be healthy without any sign of tumor recurrence.





Ewing sarcoma, first described by Dr James Ewing in 1921, is the second most common malignancy of bone diagnosed in children and adolescents. Although EWS is most often a skeletal tumor, on rare occasions, extra-skeletal lesions have been identified in the chest wall (Askin tumor), retroperitoneum, pelvis, thyroid gland, and brain. (4-7) Ewing sarcoma/primitive neuroectodermal tumor (EWS/PNET) is a primitive round cell tumor with varying degrees of neuroectodermal differentiation. (8) It is now recognized that EWS/PNET represents a single entity with a shared molecular genetic profile, clinical course, and prognosis. This unifying concept places these entities under 1 rubric in the World Health Organization classification of tumors of soft tissue and bone. (8) EWS/PNET accounts for up to 15% of cases of bone and soft tissue sarcomas in children. (9)

The histology of EWS/PNET ranges from small, round cells with round nuclei, fine chromatin, scant cytoplasm, and indistinct cell borders to larger, more irregular cells with irregular nuclear contours, pseudorosettes, a nesting pattern, and in some instances, spindle cells. Necrosis, with preserved perivascular clusters of tumor cells, may be present. Ultrastructural findings include relatively undifferentiated mesenchymal cells to neural differentiation. Tumor cells usually contain intermediate filaments, have cell junctions, and may contain glycogen, dense core granules, and neurotubles. (10-12) Typical immunohistochemical findings include positivity for vimentin, CD99, FLI1, and variable reactivity for neuron-specific enolase, CD57, synaptophysin, and cytokeratin. Rare cases may stain positively for desmin and glial fibrillary acidic protein, but not typically for leukocyte common antigen or actin. (12,13) CD99 typically displays a membranous staining pattern and was initially thought to be highly specific for EWS/PNET, but it is now recognized that, although its sensitivity ranges from 84% to 100% in EWS/PNET, the specificity is limited.


A translocation involving the EWS gene on chromosome band 22q12 and other partners, most frequently the FLU gene on chromosome band 11q24, is typical for EWS/PNET and there are several different subtypes of the EWS/FLU fusion transcripts. (14) Overexpression of the FLI1 protein resulting from the translocation between EWS and FL/2 genes is observed in 71% to 100% of EWS/PNETs. (15) Prognostic and biologic immunohistochemical markers for EWS/PNET include p53 and p16 mutation. Overexpression of p53 by immunohistochemistry has been associated with a poor outcome.

Primary Ewing sarcoma of the orbit (3) and metastatic Ewing sarcoma to the choroid of the eye (16) have been previously reported. Additionally, rhabdomyosarcoma, a small round blue cell tumor, has been reported to arise in a ciliary body medulloepithelioma. Our case was a primary intraocular tumor that appeared to arise in the peripheral retina. It was histologically and immunophenotypically distinct from other small round blue cell tumors of childhood, including rhabdomyosarcoma, lymphoma, and leukemia. Our report represents the first documented case of primary intraocular PNET/Ewing sarcoma of the retina. The tumor was completely removed and did not exhibit high-risk features for retinoblastoma, such as choroid or optic nerve invasion. This tumor should be distinguished from retinoblastoma and medulloepithelioma, 2 other primary intraocular tumors of childhood that may contain small, round blue cells.


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(12.) Llombart-Bosch A, Lacombe MJ, Peydro-Olaya A, et al. Malignant peripheral neuorectodermal tumors of bone other than Askin's neoplasm: characterization of 14 new cases with immunohistochemistry and electron microscopy. Virchows Arch A Pathol Anat Histopathol. 1988; 412(5):421-430.

(13.) Ozdemirli M, Fanburg-Smith JC, Hartmann DP, et al. Differentiating lymphoblastic lymphoma from Ewing's sarcoma: lymphocyte markers and gene rearrangement. Mod Pathol. 2001; 14(11):1175-1182.

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(15.) Folpe AL, Hill CE, Parham DM, et al. Immunohistochemical detection of FLI-1 protein expression: a study of 132 round cell tumors with emphasis on CD99-positive mimics of Ewing's sarcoma/primitive neuorectodermal tumor. Am J Surg Pathol. 2000; 24(12):1657-1662.

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Hans E. Grossniklaus, MD; Bahig Shehata, MD; Poul Sorensen, MD, PhD; Chris Bergstrom, MD; G. Baker Hubbard, MD

Accepted for publication October 21, 2011.

From the Departments of Ophthalmology (Drs Grossniklaus, Bergstrom, and Hubbard) and Pathology (Drs Grossniklaus and Shehata), Emory University School of Medicine, Atlanta, Georgia; Childrens Healthcare of Atlanta, Atlanta, Georgia (Dr Shehata); and the Department of Molecular Pathology, British Columbia Cancer Research Centre, Vancouver, Canada (Dr Sorensen).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Hans E. Grossniklaus, MD, Emory University School of Medicine, BT 428, 1365 Clifton Rd, Atlanta, Georgia 30322 (e-mail:
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Title Annotation:Case Report
Author:Grossniklaus, Hans E.; Shehata, Bahig; Sorensen, Poul; Bergstrom, Chris; Hubbard, G. Baker
Publication:Archives of Pathology & Laboratory Medicine
Date:Jul 1, 2012
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