Ewing sarcoma

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