Bone & joints

Other osteogenic tumors

Ewing sarcoma


Resident / Fellow Advisory Board: Farres Obeidin, M.D.
Editorial Board Member: Jose G. Mantilla, M.D.
Laura Warmke, M.D.

Topic Completed: 27 July 2021

Minor changes: 27 August 2021

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PubMed search: Ewing sarcoma[TI] bone pathology review[PT]

Laura Warmke, M.D.
Page views in 2020: 43,294
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Cite this page: Warmke L. Ewing sarcoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/boneewing.html. Accessed September 21st, 2021.
Definition / general
  • Small round cell sarcoma showing gene fusions involving one member of the FET family of genes (usually EWSR1) and a member of the E26 transformation specific (ETS) family of transcription factors
  • American pathologist James Ewing (1866 - 1943) first described the tumor as diffuse endothelioma of bone (CA Cancer J Clin 1972;22:95)
Essential features
  • Small round cell sarcoma
  • CD99 diffuse membranous expression
  • Gene fusion involving FET family of genes (usually EWSR1) and member of ETS family of transcription factors, most commonly EWSR1-FLI1 (~85 - 90%)
Terminology
  • Ewing sarcoma of bone
  • Extraskeletal Ewing sarcoma
  • Adamantinoma-like Ewing sarcoma
  • Primitive neuroectodermal tumor (PNET), term no longer recommended
  • Askin tumor (Ewing sarcoma arising in chest wall), term no longer recommended
ICD coding
  • ICD-O: 9260/3 - Ewing sarcoma
  • ICD-11: 2B52.3 - Ewing sarcoma of soft tissue
  • ICD-11: 2B52.Y - Ewing sarcoma of bone and articular cartilage of other specified sites
Epidemiology
Sites
  • Diaphyseal or metaphyseal - diaphyseal region of long bones (lower > upper extremity)
  • Pelvic bones and ribs common
  • Bone > soft tissue, approximately 12% extraskeletal (Nat Rev Dis Primers 2018;4:5)
Pathophysiology
Etiology
  • Chromosomal translocation commonly involving EWSR1 and ETS partner
  • Cell of origin possibly mesenchymal stem cell (Cancer Cell 2007;11:421)
Diagrams / tables

Images hosted on other servers:
Clinical features
  • Localized pain and swelling (J Bone Joint Surg Am 2000;82:667)
  • Painful enlarging mass
  • Associated pathologic fracture sometimes present
  • Systemic findings (fever, weight loss, anemia, leukocytosis and increased sedimentation rate) can occur
Diagnosis
  • Integration of clinical, radiographic, immunohistochemical and molecular information
  • Small round cell morphology
  • CD99 diffuse membranous expression
  • Genetic confirmation often required (all cases harbor FET-ETS fusion)
Laboratory
  • Anemia, leukocytosis and elevated sedimentation rate can occur
Radiology description
  • Plain radiograph
    • Osteolytic permeative lesion
    • Poorly defined margins
    • Moth eaten bone destruction
    • Aggressive periosteal reaction (onion skin appearance)
    • Sunburst periosteal reaction less common than osteosarcoma
    • Saucerization, extraosseous tumor erodes cortex
    • No evidence of tumor osteoid / matrix production
    • Often underestimates extent of tumor
  • CT / MRI / PET (Semin Musculoskelet Radiol 2019;23:36)
    • Fully define primary lesion
    • Evaluate soft tissue extension
    • Assess for metastatic disease (~25%)
    • T1 weighted MRI: low to intermediate signal intensity
    • T2 weighted MRI: heterogeneous but predominantly high signal
Radiology images

AFIP images
Saucerization

Saucerization



Images hosted on other servers:

Radiograph of humeral lesion

Radiograph of humeral lesion (close up)

CT of humeral lesion

Radiograph of humeral head lesion

MRI of humeral head lesion

Prognostic factors
  • Presence of metastases main prognostic factor
  • Localized, resectable disease with 5 year survival rate of 70%
  • Metastatic disease with 5 year survival rate of < 30%
  • Surgical removal of resectable lung metastases improves survival
  • Favorable: complete pathologic response to neoadjuvant chemotherapy, small tumor size, superficial location, easily resectable (Bone Joint J 2016;98-B:1138)
  • Unfavorable: early relapse, presence of metastases, anatomic location in trunk / pelvis
Case reports
Treatment
  • Neoadjuvant chemotherapy and surgery
  • Ewing specific protocol of alternating vincristine / doxorubicin / cyclophosphamide and ifosfamide / etoposide (VDC / IE)
  • Chemotherapy improved prognosis to 75% for 5 year survival
  • Radiotherapy for surgically inaccessible tumors, inadequate margins and palliation
  • Limited efficacy of immunotherapeutic approaches (J Immunother Cancer 2020;8:e000653)
Clinical images

Images hosted on other servers:

Extraosseus Ewing sarcoma of the forearm

Gross description
  • Gray-tan mass with infiltrative borders (Semin Diagn Pathol 2014;31:39)
  • Intramedullary mass with soft tissue involvement
  • Areas of hemorrhage and necrosis frequent
  • Assess chemotherapy induced necrosis (≥ 90% good) with mapping
Gross images

Contributed by Mark R. Wick, M.D.
Ewing sarcoma

Ewing sarcoma



Images hosted on other servers:

Ewing sarcoma of foot

Amputation for Ewing sarcoma

Frozen section description
  • Small round blue cell tumor
Frozen section images

Contributed by Laura Warmke, M.D.
Small round cells

Small round cells

Necrosis

Necrosis

Microscopic (histologic) description
  • Classical Ewing sarcoma (Virchows Arch 2009;455:397)
    • Uniform small round cells
    • Tumor cells 1 - 2x size of lymphocytes
    • Round nuclei
    • Finely stippled chromatin
    • Inconspicuous nucleoli
    • Scant clear to eosinophilic cytoplasm
    • Indistinct cytoplasmic membranes
    • Sheet-like growth pattern
    • Islands separated by dense fibrous tissue
    • Subset with neuroectodermal differentiation (Homer-Wright pseudorosettes)
  • Atypical Ewing sarcoma (Virchows Arch 2011;458:281)
    • Nuclear enlargement
    • Irregular nuclear contours
    • Vesicular or coarse chromatin
    • Prominent nucleoli
  • Adamantinoma-like Ewing sarcoma (Head Neck Pathol 2020;14:59, Am J Surg Pathol 1999;23:159, Am J Surg Pathol 2015;39:1267)
    • Nests of basaloid cells
    • Peripheral palisading and cording
    • Prominent myxoid, fibromyxoid or hyalinized stroma
    • Focal keratin pearl formation
    • High grade features with minimal pleomorphism
Microscopic (histologic) images

Contributed by Laura Warmke, M.D., Mark R. Wick, M.D. and Erdener Özer, M.D., Ph.D.
Small round cells

Small round cells

Clear cell change

Clear cell change

Apoptotic cells

Apoptotic cells

"Light" cell and "dark" cell appearance


Rosettes

Rosettes

CD99

CD99

FLI1

FLI1

Virtual slides

Images hosted on other servers:

Ewing sarcoma (H&E)

Cytology description
Cytology images

Contributed by Laura Warmke, M.D. and Erdener Özer, M.D., Ph.D.
Round cells

Round cells

Fine chromatin

Fine chromatin

Small nucleoli

Small nucleoli

Cytological appearance

Cytological appearance

Positive stains
Negative stains
Electron microscopy images

Images hosted on other servers:

Ultrastructure analysis of tumor

Molecular / cytogenetics description
Molecular / cytogenetics images

Images hosted on other servers:

Dual color break apart probe FISH test

Videos

Ewing family of tumors

Sample pathology report
  • Bone, right proximal humerus mass, core biopsy:
    • Ewing sarcoma (see comment)
    • Comment: This biopsy shows an undifferentiated small round cell sarcoma involving bone with focal areas of necrosis and scattered mitotic figures. Immunohistochemical studies show that the tumor cells are positive for CD99 (diffuse, membranous) and NKX2.2, while they are negative for cytokeratin cocktail, S100 protein, SMA, desmin and CD45. RT-PCR demonstrates the presence of an EWSR1-FLI1 fusion, confirming the above diagnosis.
Differential diagnosis
Board review style question #1

Ewing sarcoma characteristically shows strong, diffuse membranous staining with which of the following immunohistochemical stains?

  1. CD99
  2. Desmin
  3. FLI1
  4. S100 protein
Board review style answer #1
A. CD99

Comment Here

Reference: Ewing sarcoma
Board review style question #2

A 12 year old boy injured his left arm while playing football. Radiograph demonstrated an aggressive lesion in the mid diaphyseal region of his left humerus with permeative appearance and lamellated periosteal reaction (onion skin). Biopsy shows a small round blue cell tumor. What is the most likely diagnosis?

  1. Chondrosarcoma
  2. Ewing sarcoma
  3. Lymphoma
  4. Osteosarcoma
Board review style answer #2
B. Ewing sarcoma

Comment Here

Reference: Ewing sarcoma
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