Ewing Sarcoma

Ewing sarcoma (ES) is a primary bone malignancy derived from primitive round cells affecting primarily children and teenagers. Ewing sarcoma commonly presents with a painful mass, swelling, and pathologic bone fractures. Diagnosis is established with imaging and biopsy. Treatment involves systemic chemotherapy and local control of the tumor with surgical resection or radiation. With proper treatment, the overall 5-year survival is over 70%.

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Overview

Definition

Ewing sarcoma (ES) is a primary bone malignancy derived from undifferentiated primitive round cells.

Epidemiology

  • Primary malignant bone tumors:
    • 6th most common neoplasm in children
    • 3rd most common neoplasm in adolescents and young adults
    • Approximately 3,000 primary malignant bone tumors are diagnosed annually.
    • Approximately 1,500 deaths result from primary malignant bone tumors annually. 
  • Ewing sarcoma:
    • 10%–15% of primary bone malignancies
    • Peak incidence is in the 2nd decade of life.
    • Men > women
    • Whites are most commonly affected.
    • Manifests in the diaphysis of long bones and flat bones (pelvis, scapula)

Etiology

  • Mutations result in the proliferation of primitive undifferentiated cells
  • Translocation of ESW and ETS regions (t(11;22)) implicated in > 80% of Ewing sarcomas
  • In addition to ES, the Ewing sarcoma family of tumors also include primitive neuroectodermal tumors and atypical ES.
  • Environmental triggers or congenital associations not identified

Pathophysiology and Clinical Presentation

Pathophysiology

  • Characterized by primitive round cells without differentiation
  • Histologically appears as sheets of round cells with hyperchromatic nuclei and scant cytoplasm
  • May be derived from neural crest cells, but exact origins are unknown
  • Closely related to primitive neuroectodermal tumors
  • Originates in medullary cavity but invades cortex, periosteum, and soft tissue
  • Tumor usually contains areas of hemorrhage and extensive necrosis
Ewing sarcoma on H&E stain

A hematoxylin and eosin (H&E) stained section from an Ewing sarcoma tumor magnified at 400x:
Sheets of small round cells with a high nuclear:cytoplasmic ratio

Image: “Ewing sarcoma” by Center for Children’s Cancer Research, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA. License: CC BY 3.0, cropped by Lecturio.

Clinical presentation

  • Localized pain and swelling:
    • Aggravated by exercise 
    • Worse at night
    • Can present in many locations
  • Palpable soft tissue mass:
    • Markedly tender on examination
    • Fixed to bone
    • Accompanied by erythema and swelling
  • Sometimes present with pathologic fracture
  • 10%–20% have constitutional symptoms (often correlate with metastatic disease).
  • Extremely aggressive with early metastasis (worst prognostic factor)
  • May metastasize to lungs, other bones, bone marrow

Diagnosis

Laboratory studies

  • Anemia (anemia of chronic disease)
  • Increased WBC count
  • Elevated erythrocyte sedimentation rate (ESR) and lactate dehydrogenase (LDH) (often misdiagnosed as osteomyelitis)
  • Classic cytogenetic abnormality translocation t(11;22) identified in biopsy specimens

Imaging

  • X-ray:
    • Typically 1st imaging test if diagnosis suspected
    • Destructive bone lesion associated with soft tissue mass
    • Onion skinning due to the lamellated appearance of the periosteal reaction
    • Periosteal displacement can create a Codman triangle.
    • Moth-eaten appearance due to lytic lesion and endosteal scalloping 
  • Other tests for evaluation of primary and metastatic disease:
    • CT scan: extent of cortical destruction and soft-tissue involvement
    • MRI: best to define the relationship of tumor to vessels and nerves 
    • Bone scan
    • PET scan

Biopsy

  • Definitive diagnosis
  • Open biopsy preferable to core needle
  • Histology: anaplastic small blue round cell sarcoma
  • Bone marrow biopsy should also be performed to rule out bone marrow metastasis.

Management

Systemic

  • Systemic chemotherapy is the mainstay of treatment.
  • Administered as induction (neoadjuvant) chemotherapy, and additional chemotherapy after local control
  • Regimens include vincristine, doxorubicin, cyclophosphamide, and dactinomycin.

Local treatment

  • Surgical excision:
    • Preferred management method of primary tumor site
    • Goal: limb salvage and minimal disfigurement
  • Radiation therapy: Use if surgery is not feasible.
Ewing sarcoma surgery

Ewing sarcoma:
a: Axial section of noncontrast CT scan showing Ewing sarcoma of the right clavicle
b: Photograph showing the resected right clavicle with tumor in situ

Image: “Ewing’s sarcoma of the right clavicle” by Department of Orthopaedics, All India Institute of Medical Sciences, Dr. B. R. A. Institute Rotary Cancer Hospital, Delhi, India. License: CC BY 2.0

Prognosis

  • Overall 5-year survival is > 70%.
  • Complete initial response to chemotherapy imparts a better prognosis.

Differential Diagnosis

  • Osteosarcoma: a malignant bone tumor characterized by the production of immature bone. Osteosarcoma is most common in children and young adults. Presentation includes pain, swelling, palpable mass, and pathologic fracture. Diagnosis is suspected on imaging and confirmed with tissue biopsy. Management includes surgical resection and systemic chemotherapy.
  • Chondrosarcoma: malignant bone tumor of cartilage producing cells. Chondrosarcoma is most common in older adults and usually presents as a slowly growing mass associated with dull, achy pain. Diagnosis is based on imaging and biopsy, and treatment is wide surgical excision.
  • Bone metastasis: metastatic bone lesions from primary cancers arising at other sites (commonly prostate, breast, and lung). Presentation includes bone pain, pathologic fracture, and constitutional symptoms. Diagnosis is made based on clinical history and imaging. Treatment includes systemic chemotherapy as well as supportive measures aimed at minimizing pain and pathologic fractures.
  • Benign bone tumors: more common than malignant bone tumors; may present the risk of malignant transformation. Benign bone tumors include enchondroma, osteochondroma, nonossifying fibroma, chondroblastoma, osteoid osteoma, osteoblastoma, periosteal chondroma, giant cell tumor, and chondromyxoid fibroma, among others.
  • Osteomyelitis: bone infection most commonly due to pyogenic bacteria in the setting of orthopedic injury, or chronic nonhealing wound eroding into bone. Presentation includes localized pain, signs of inflammation/infection, and fever. Osteomyelitis can progress to sepsis and limb loss. Treatment is aggressive antibiotic therapy with or without surgical debridement.
  • Orthopedic injury: strain, sprain, growing pain, fracture, etc. are precipitating events that bring bony tumors to clinical attention. However, a more innocent injury or process may be to blame when considering the possibility of bony neoplasm. Orthopedic injury is characterized by localized pain, inflammation, and/or swelling. Diagnosis is usually made clinically and management is supportive.

References

  1. DeLaney T.F., Hornicek F.J., Bahrami A. (2020). Ewing sarcoma family of tumors. Retrieved March 17, 2021, from https://www.uptodate.com/contents/clinical-presentation-staging-and-prognostic-factors-of-the-ewing-sarcoma-family-of-tumors
  2. Gerbhardt M.C., Dubois S.G. (2020). Treatment of the Ewing sarcoma family of tumors. Retrieved March 17, 2021, from https://www.uptodate.com/contents/treatment-of-the-ewing-sarcoma-family-of-tumors
  3. Kasper, D., Fauci, A., Hauser, S., Longo, D., Jameson, J., Loscalzo, J. (2012). Harrison’s principles of internal medicine (18th edition.). New York: McGraw Hill Education.
  4. Robbins and Cotran Pathologic Basis of Disease. (2015). 9th Edition. p.1197-1203.
  5. Shaikh H. (2020). Ewing Sarcoma. Retrieved February 26, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/21419/

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