Ewing sarcoma

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Tumor biology and incidence

  • Small, malignant, round-cell tumor
  • Second most common primary malignant bone tumor in children
  • Accounts for approximately 10% of all primary malignant bone tumors
  • Recent genetic, biochemical, and electron microscopic studies suggest Ewing sarcoma is a spectrum of tumors
  • Closely related to peripheral/primitive neuro-ectodermal tumor (PNET)
    • Aame chromosomal translocation between chromosomes 11 and 22
    • Both thought to arise from the neural crest
    • Similar presentations
    • Identical treatments
    • Almost identical histologic characteristics

Age

5-25 years; rare in children younger than age 5 or adults older than age 30

Gender

M:F = 3:2

Presentation

  • Pain and localized swelling, representing an associated soft tissue mass
  • Constitutional symptoms, such as fever, malaise, and weight loss common, especially with metastatic disease
  • 25% of patients present with overt metastases
    • Poor prognostic finding
    • Metastases typically found in lungs, bone marrow, bone

Physical findings

  • Mass often warm, firm, and tender, almost presenting like an infective/inflammatory lesion
  • If located in rib, may have pleural effusion
  • If located in spine or pelvis, may have neurologic signs

Bloodwork

  • Increased ESR and LDH common.
  • Possibly anemia and leukocytosis

Plain films

Site
  • Femur, tibia, fibula, pelvis most common sites
  • May be found in humerus, clavicle, scapula, ribs
  • In long tubular bones, lesion often found in diaphysis, but could be metaphyseal/epiphyseal
Size

Usually greater than 5 cm

Tumor effect on bone
  • Diffuse, permeative bone destruction
  • Destruction of bone may be minimal compared with soft tissue mass
Bone response to tumor
  • Poorly defined margins
  • Permeative or moth-eaten bone destruction
  • Onion skinning periosteal response
  • Dense host bone sclerosis rare
Matrix

None produced

Cortex
  • Often moth-eaten but structurally intact underlying the typical soft tissue mass
    • Caused by rapid growth of tumor through the Haversian canals of intact cortex
    • Onion skinning periosteal reaction frequent, as are "sunburst" or "spiculated" patterns of periosteal reaction
Soft tissue mass
  • Often present (large, non-calcified)
  • May be more visible on radiographs than bone lesion

Bone scan and chest CT

  • Necessary for systemic staging
  • Remote site of bone marrow aspiration also needed to complete staging

MRI

  • The extraosseous soft tissue mass and medullary canal involvement can be best seen on MRI; usually more extensive than what was expected from plain radiographs
  • Usually repeated after several cycles of chemotherapy
    • Assess the response of the tumor to neoadjuvant chemoherapy
    • Help plan definitive treatment of primary lesion

Differential diagnosis

  • Osteomyelitis
    • Presents with pain, fever, elevated WBC count, elevated ESR
    • Can involve diaphysis or metaphysis as well
  • Lymphoma
  • Osteosarcoma
  • Eosinophilic granuloma
  • MFH
  • Fibrosarcoma
  • Metastatic neuroblastoma (in very young patients)

Natural History

  • Advances in chemotherapy have improved long-term survival rate from 10% to over 70%
  • Good prognosis: small, distal extremity lesion
  • Poor prognosis: metastases on presentation (other bones or lungs), proximal extremity or axial, large lesion

Pathology  

  • Gross: Gray-white tumor with a variable amount of necrosis, hemorrhage, or cyst formation
    • At times, the tumor tissue may be almost liquid, mimicking a purulent mass
  • Microscopic: Numerous small, round cells with a diffuse homogeneous growth pattern and sparse intercellular stroma
    • Cells have ill-defined borders and finely dispersed chromatin pattern
    • Cells uniform
    • Mitotic activity seldom high
    • Glycogen granules in cytoplasm, which produce positive periodic acid-Schiff (PAS) stain on routine histology
  • Recent advances in cytogenetics and immunohistochemistry allow for more precise diagnostic evaluations
    • Ewing sarcoma/PNET cells strongly express p30/32 MIC2 antigen, a cell-surface glycoprotein encoded by the MIC2 gene
    • MIC2 analysis has sensitivity of 95% in diagnosing Ewing sarcoma/PNET
    • Cytogenetic studies have revealed that 85% of Ewing sarcoma/PNET contain a translocation either of chromosomes 11 and 22 [t(11;22)] or of chromosomes 21 and 22 [t(21;22)]
    • Resultant fusion gene is composed of part of the EWS gene from chromosome 22 and the FLY1 gene from chromosome 11 or the ERG gene from chromosome 21

Treatment

Chemotherapy
  • Non-metastatic cases treated with administration of multiagent chemotherapy to achieve local control
  • Chemotherapeutic agents most widely used include:
    • Vincristine
    • Cyclophosphamide
    • Doxorubicin
    • Ifosfamide
    • Etoposide
  • Chemotherapy dramatically reduces soft tissue component of lesion in most cases
  • 2-year disease-free survival rates vary from 50% to 80% in patients treated with chemotherapy
Surgery
  • Resection of primary lesion with wide surgical margins recommended for local control of Ewing sarcoma/PNET, provided functional consequences of resection are acceptable
  • Limb-salvage surgery possible in most patients
  • Amputation may be necessary if limb-salvage is contraindicated
Radiation
  • Postoperative irradiation usually recommended when surgical margins are close and significant viable tumor is present in resected specimen
  • Irradiation alone can be used when there is extreme morbidity of resecting primary tumor
  • Total dosage should be kept as low as possible, usually around 50 Gray, because dosages of more than 60 Gray can be associated with increased incidence of secondary irradiation-induced sarcomas
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