Ewing Sarcoma

Introduction

Highly malignant tumor composed of small round cells of bone.

History:

In 1918, Arthur Purdy Stout described a tumor composed of small round cells with rosettes, in the ulnar nerve, which came to be known as primitive neuroectodermal tumor (PNET). Later, James Ewing described a tumor of long bones composed of undifferentiated cells, which was radiosensitive (Ewing’s sarcoma). Over the years, these two tumors were described at various sites as two distinct entities. The distinction between these two tumors began to blur when Angervall and Enzinger (1975) described “an extraskeletal neoplasm resembling Ewing’s sarcoma” and Jaffe et al. published an article on “the neuroectodermal tumour of bone” in 1984. We now know that both Ewing’s sarcoma and PNET show similar translocations and are considered to be the ends of a histological spectrum of “Ewing’s family of tumors” (EFT). In the past two decades, our knowledge about the molecular events responsible for the development and progression of EFT has increased dramatically. Numerous technological developments have contributed to this greater understanding of cell biology and have shed light on the molecular mechanisms of malignant transformation. The analysis of these tumors by various molecular techniques may allow us not only to understand the biology of these lesions better but also to develop better techniques for their diagnosis and potential treatment.

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Epidemiology

• #2 M/C malignant bone tumour occurring in children and young adults (10–15% of all primary bone tumours)
• #2 M/C tumor in childhood
• Represents < 5% of all soft tissue sarcomas

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Pathophysiology

EWS-ETS gene translocations:

ES tumors often express a balanced translocation involving the EWS gene on chromosome 22 and a member of the ETS family of transcription factors

ES is characterized by non-random gene rearrangements between the EWS gene and ETS (E26 transformation-specific or E-twenty-six) gene family. A hybrid gene EWS–FLI1 is generated by the fusion of the EWS gene on 22q12 with the FLI1 gene on 11q24 occurs in greater than 80% of the cases. The resulting EWS-FLI1 fusion protein acts as an aberrant transcription factor, and thus it can be reasonably assumed that it may play a role in the pathogenesis of ES

Translocation	Fusion gene	% of tumors exhibiting EWS gene rearrangement
t(11;22)(q24;q12)	EWSR1–FLI1	85
t(21;22)(q22;q12)	EWSR1–ERG	10
t(7;22)(q22;q12)	EWSR1–ETV1	rare
t(17;22)(q21;q12)	EWSR1–ETV4	rare
t(2;22)(q35;q12)	EWSR1–FEV	rare

EW metastasis:

Commmon sites;

• Lower extremity (M/C, 45%): Femur is M/C affected bone, with the tumour usually arising in the midshaft.
• Pelvis (20%)
• Upper extremity (13%)
• Axial skeleton and ribs (13%)
• Face (2%)

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Clinical Features

• Persistent pain and swelling over the site of involvement.
  • Intermittent pain that worsens at night
• Location-specific features:
  • Pathological fractures: Metastatic lesions within long bones
  • Back pain: Pelvic location of ES
• Systemic symptoms (20% cases) (indicates metastatic disease): Fever, weight loss

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Diagnosis

Plain radiograph:

• Destructive confluent moth-eaten lesions
• Codman’s triangle of the elevated periosteum
• Multilayered onion-skin periosteal reaction

Computed tomography (CT):

Useful for depicting extraskeletal soft tissue masses, destruction of the bone cortex, and pulmonary metastasis

Magnetic resonance imaging (MRI):

ES exhibits low signal intensity on T1-weighted images and high signal intensity on T2-weighted images, and appears as large extraskeletal soft tissue masses derived from bone. Skip lesions affecting the bone are often clearly depicted on MRI.

Tissue biopsy:

• Small round cell tumor group: Family of small round blue cell tumors of childhood (e.g., retinoblastoma, neuroblastoma, rhabdomyosarcoma, and nephroblastoma) that feature small round cells with increased nuclear-cytoplasmic ratio
• Ewing cells: Scant eosinophilic cytoplasm containing abundant glycogen that is often detected by staining with periodic-acid-Schiff

Molecular analysis:

Detection of specific chromosomal translocations

• Reverse transcription polymerase chain reaction (RT-PCR)
• Fluorescent in situ hybridization (FISH)

Differential diagnosis:

• Other small round cell tumors: Neuroblastoma, rhabdomyosarcoma, lymphoma, neuroectodermal tumors, desmoplastic small round cell tumor and synovial sarcoma.
• Other bone tumours: Osteomyelitis, osteogenic sarcoma, and eosinophilic granuloma

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Management

The standard of care for patients with or without metastasis includes interprofessional treatment with chemotherapy and local therapy, including surgery and radiotherapy (RT).

Chemotherapy:

The purpose of preoperative chemotherapy is (1) to eradicate any micrometastases that exist at the time of diagnosis, (2) to reduce the volume of the tumor in order to facilitate its excision, and (3) to provide information that will aid the selection of anti-tumor drugs for postoperative chemotherapy.

The current chemotherapy protocols used to treat ES include various combinations of the following six drugs:

• Doxorubicin (DOX)
• Cyclophosphamide (CPM)
• Vincristine (VCR)
• Actinomycin-D (ACT-D)
• Ifosfamide (IFO)
• Etoposide (ETO)

Local treatment: radiotherapy and tumor excision

As ES is sensitive to radiotherapy, radiotherapy was performed as a local treatment before the introduction of chemotherapy.

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Summary: