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Ewing’s Sarcoma: A Case Report

 

Article By

N.K. Gaude

R.G.W. Pinto

 

Abstract

Ewing’s sarcoma is a rare primary neoplasm of bone representing approximately 6% to 8% of all malignant bone tumors.[1] Ewing’s sarcoma initially regarded as an undifferentiated type of bone sarcoma of children, is now linked with the neoplasm originally described in the soft tissue as primitive neuroectodermal tumor.[2] Recently, Ewing’s sarcoma and primitive neuroectodermal tumor (PNET) have been unified into a single category; Ewing’s Sarcoma Family Tumors (ESFT) based on shared clinical, morphological, biochemical, and molecular features.

 

Introduction:

Of all bone sarcomas, ESFT have the youngest average age at presentation, since approximately 80% of patients are younger than 20 years. Boys are affected slightly more frequently than girls. Most ESFT contain a t(11;22)(q24;q12) translocation generating an in-frame fusion of Ewing Sarcoma (EWS) gene on chromosome 22to the FLI1 gene.

Most commonly it involves the long bones, usually the diaphysis or metadiaphysis. The flat bones like ilium and ribs may be involved. The tumor typically involves the shaft of the bone. Most tumors are associated with a soft tissue mass, a feature best appreciated by magnetic resonance imaging (MRI) and computed tomography (CT).[1]

 

History:

In 1918, Stout reported a case with an ulnar nerve tumor composed of undifferentiated round cells that forms rosettes, subsequently defined as PNET of soft tissue.

In 1921, James Ewing reported a case of round cell tumor in the radius of a 14  year-old girl as a diffuse endothelioma of bone, proposing an endothelial derivation (Ewing’s Sarcoma).

It was in 1975 that Angervall and Enzinger reported the first case of Ewing’s sarcoma arising in the soft tissue.

In 1979, Askin reported a malignant small cell tumor of the thoraco-pulmonary region with similar features of PNET.

In 1984, Jaffe, described a small round cell tumor of bone calling it a neuroectodermal tumor of bone.

Recent clinicopathological studies have revealed that these lesions have overlapping features, supporting a common histogenesis. Identification of a common translocation t(11;22)(q24;q12) that results in the formation of EWS-ETS fusion gene in cases of Ewing’s sarcoma PNET and Askin’s tumor strongly supported the hypothesis that these lesions are related. Therefore, all these lesions are now included in the same classification, the Ewing’s sarcoma family.[3]

 

Case Report:

An 11-year-old presented to the orthopedic clinician with a history of pain in the knee for the past one month. The x-ray finding showed a cystic, bony lesion at lower end of the femur with periosteal reaction; radio diagnosis of osteomyelitis was made. Further open curettage was done and curetting was sent for histopathological examination.

 

Histopathology:

Gross: Gross examination showed brownish-white bits aggregating to 3.5 x 2.5 centimetres (cm).

Microscopy: The biopsy showed bony, trabecular, soft tissue and muscle. In bony trabeculae there is proliferation of hyperchromatic round cells in sheets separated by fibrous tissue (Figure 1). A few pseudorosettes were also seen. In superficial areas, secondary chronic inflammatory infiltrate was also observed.

A final histopathological diagnosis of Ewing’s sarcoma of the lower end of femur with secondary infection was made.

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Discussion:

Ewing’s sarcoma is a small round cell tumor. It is the second most prevalent primary malignant bone cancer in children, following osteosarcoma.[4] It belongs to Ewing sarcoma family of tumors which includes primitive neuroectodermal tumor (PNET) and Askin tumor.[5] Usually seen in patients between the ages of 5-20 years. Ewing’s sarcoma demonstrates a predilection for the trunk and long bones. In the truncal skeleton, the pelvis predominates, followed by the scapula, vertebral column, ribs, and clavicle. Of the long bones, the most common site is the femur, followed by the humerus, tibia, and bones of forearm. Ewing’s sarcoma of the long bones arises from the diaphysis rather than the metaphysis.[1]

Ewing’s sarcoma primarily occurs in bones, with rare occurrence in soft tissue. Most extra-skeletal Ewing’s sarcoma affects patients between 10-30 years of age. The most common sites are the chest wall paravertebral muscles, extremities, buttocks and retroperitoneal space.

The earliest symptom is pain. At first, the pain is intermittent and mild, but rapidly progresses to an intense pain warranting analgesic drugs.

Other symptoms include fever, weight loss, anemia, and non-specific signs of inflammation such as increase in sedimentation rate, leukocytosis, and increase in serum LDH.

Tumor growth eventually leads to visible or palpable swelling of the affected site, this swelling is tense, elastic, hard, tender, rapidly increasing swelling, accompanied by local heat.

The typical radiographic changes in bone associated with ES/PNET are cortical thickening and widening of the medullary canal. With progression of the lesions, reactive periosteal bone may be deposited in layers parallel to the cortex giving rise to an onion skin appearance or at right angles to the cortex giving rise to the sunray appearance.[1]   

 

Differential Diagnosis:

Histologic classification of Ewing’s sarcoma includes three major subtypes: classic or conventional type, primitive neuroectodermal tumor, and a typical Ewing’s sarcoma. These tumors share the same immunohistochemical and molecular features, differing only in the extent of neural differentiation.[2]

Classic Ewing’s sarcoma is composed of small round uniform cells. The nuclei are round, and the nucleoli are inconspicuous. The cytoplasmic boundaries are indistinct, such that, the cytoplasm of several cells seems to form a syncytium with nuclei are embedded in it. Mitotic activity is usually not prominent.[2]

PNET: the diagnosis requires the presence of Homer Wright rosettes with central core of neuropil, the background contains monotonous fields of conventional Ewing’s Sarcoma.[6,7]

A typical Ewing’s sarcoma difficult to recognize because these tumors have a greater degree of cytologic variability or growths patterns bringing a broad variety of primary or metastatic small round cell tumors in differential diagnosis.[7]

Immunological stains are essential in the diagnosis of Ewing’s sarcoma. The most useful and sensitive marker is CD99.[8,9] Up to 99% of Ewing tumors express CD99 in a strong diffuse membranous pattern. It is sensitive but not specific marker as various small round cells tumors may be immunoreactive with CD99, including lymphoblastic lymphoma, small cell osteosarcoma, and metastatic neuroendocrine tumors.[8]

Therefore, a panel of immunostains should include FLI-1, Cytokeratin and CD99. Ewing’s sarcoma was the first sarcoma to be associated with recurrent chromosomal translocation. The most common is t(11;22)(q24;q12) which result in the formation of the fusion gene EWSRI-FLI1.[2]

 

Treatment:

Treatment of ES/PNET include the combination of high dose irradiation and multidrug chemotherapy and sometimes combined with limited surgery. Local control is achieved in over 85% of the cases, and the actuarial 5-year disease-free survival is 75%.[1]

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References:

  1. Rosai and Ackerman’s surgical pathology. 10th edition.
  2. Fletcher CDM. Diagnostic histopathology of tumors: 2 volume set. 4th edition. Churchill Livingstone. 2013.
  3. Iwamoto Y. Diagnosis and treatment of Ewing’s sarcoma. Japanese Journal of Clinical Oncology. 2007; 37(2), 79-89.
  4. Heare T, Hensley MA,Dell’Orfano S. Bone tumors: osteosarcoma and Ewing sarcoma. Curr Opin Pediatr. 2009; 21(3):365-72.
  5. Maheshwari AV Cheng EY. Ewing sarcoma family of tumors. J Am Acad Orthop Surg. 2010; 18:94-107.
  6. Flope AL, Goldblum JR, Rubin BP, et al. Morphologic and immunophenotypic diversity in Ewing family tumors, a study of 66 genetically confirmed cases. Am J Surg Pathol. 2005; 29:1025-1033.
  7. Llombart-Bosch A, Machado I, Navarro S,Bertoni F, Bacchini P, et al.Histological heterogeneity of Ewing’s sarcoma/PNET: an immunohistochemical analysis of 415 genetically confirmed cases with clinical support. Virchows Arch. 2009; 455(5):397-411.