Updated: 6/22/2021

Ewing's Sarcoma

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https://upload.orthobullets.com/topic/8047/images/Case B - tibia - xray A - Parsons_moved.png
https://upload.orthobullets.com/topic/8047/images/Case B - tibia - xray B - Parsons_moved.png
https://upload.orthobullets.com/topic/8047/images/Case B - tibia - T1 - Parsons_moved.png
https://upload.orthobullets.com/topic/8047/images/Case C - femur - xray  - Parsons_moved.png
https://upload.orthobullets.com/topic/8047/images/6e_moved.jpg
https://upload.orthobullets.com/topic/8047/images/SA histo_moved.jpg
  • summary
    • Ewing's Sarcoma is a malignant, distinctive small round cell sarcoma associated with a t(11:22) translocation and most commonly occurs in the diaphysis of long bones.
    • Patients typically present at age < 25 with insidious onset of regional pain, swelling, and fevers. 
    • Diagnosis is made with a biopsy showing sheets of monotonous small round blue cells with prominent nuclei and minimal cytoplasm. Immunostaining will show positive CD99.
    • Treatment is usually neo-adjuvant chemotherapy, limb salvage surgical resection, followed by adjuvant chemotherapy with or without radiation. 
  • Epidemiology
    • Demographics
      • typically found in patients from 5-25 years of age
      • second most common malignant bone tumor in children
      • uncommon in African Americans and Chinese
    • Anatomic location
      • ~50% are found in the diaphysis of long bones
        • most common locations pelvis, distal femur, proximal tibia, femoral diaphysis, and proximal humerus
      • 5% metaphysis
  • Etiology
    • Genetics
      • t(11:22) translocation
        • found in 95% of cases
        • leads to the formation of a fusion protein (EWS-FLI1)
          • can be identified with PCR and useful to differentiate Ewing sarcoma from other round cell lesions
    • Staging
      • almost all tumors are MSTS stage IIB or III
  • Presentation
    • Symptoms
      • pain
        • often accompanied by fever
        • often mimics an infection
    • Physical exam
      • swelling and local tenderness
  • Imaging
    • Radiographs
      • required images
        • AP and lateral of affected area
      • findings
        • large destructive lesion in the diaphysis or metaphysis with a permeative moth-eaten appearance
        • lesion may be purely lytic or have variable amounts of reactive new bone formation
        • periosteal reaction may give an "onion skin" or "sunburst" appearance
    • Bone scan
      • indications
        • required as initial staging workup
      • findings
        • will show very "hot" lesion
    • MRI
      • indications
        • required as initial staging workup to identify soft-tissue extension and marrow involvement
      • findings
        • often shows a large soft tissue component
    • CT chest
      • indications
        • required as initial staging workup to look for pulmonary metastasis
  • Studies
    • Labs
      • ESR is elevated
      • WBC is elevated
      • anemia is common
      • lactic dehydrogenase
    • Bone marrow biopsy
      • required as part of workup for Ewing's to rule out metastasis to the marrow
  • Histology
    • Gross appearance
      • may have liquid consistency mimicking pus
    • Characteristic findings
      • sheets of monotonous small round blue cells
      • prominent nuclei and minimal cytoplasm 
      • may have pseudo-rosettes (circle of cells with necrosis in center)
    • Immunostaining
      • positive
        • CD99 (in 95%)
        • MIC2
        • vimentin
        • PAS positive (intracellular glycogen)
        • neuron specific enolase (NSE)
        • S100
        • Leu7
      • negative
        • cytokeratin
        • reticulin (positive in lymphoma)
        • neurofilament (positive in neuroblastoma)
        • see complete immonostaining chart
  • Differential
    • Small-round-cell tumor differential (by age)
      • < 5 yrs: neuroblastoma or leukemia
      • 5-10 yrs: eosinophilic granuloma
      • 5-30 yrs: Ewing's sarcoma
      • >30 yrs: lymphoma
      • > 50 yrs: myeloma
    • Osteosarcoma
    • Osteomyelitis
    • Differential of Ewing's Sarcoma
      Destructive lesion in young patients
      Small round cell tumors
      Treatment is Wide Resection & Chemotherapy
      Ewing's Sarcoma
      Osteosarcoma
      Lymphoma
      Leukemia
      Eosinophilic Granuloma
      Osteomyelitis
      Desmoplastic fibroma
      Metastatic disease
      Neuroblastoma (soft tissue)
      Rhabdomyosarcoma (soft tissue)
      Secondary Sarcoma
      Dediff. Chondrosarcoma
      MFH/Fibrosarcoma
      Multiple Myeloma
  • Treatment
    • Nonoperative
      • chemotherapy + radiation therapy
        • indications
          • non-resectable tumors (eg. large spinal tumors)
          • sites where functional deficit is unacceptable
          • trend is towards surgical resection/away from RT because of morbidity associated with radiation and risk of secondary malignancies
      • Operative
        • chemotherapy + limb salvage resection ± adjuvant radiation
          • indications
            • standard of care in most patients
            • where primary tumor can be completely removed (expendable and surgically reconstructible sites)
          • chemotherapy
            • vincristine, doxorubicin, cyclophosphamide, and dactinomycin
            • preoperative chemotherapy (neoadjuvant) given for 8-12 weeks followed by surgical resection and maintenance (adjuvant) chemotherapy for 6-12 months
          • adjuvant radiation
            • not necessary if margins are adequate and there is good response to chemotherapy
            • indications
              • positive post-resection surgical margins
              • patients who present with widely metastatic disease
              • where chemotherapeutic response has been poor
  • Complications
    • Secondary neoplasms
      • bone sarcoma (from radiation therapy)
        • risk is 10-20% at 20y
        • arises in prior RT treatment field
        • dose dependant
          • ≥ 60Gy of RT confers 20% risk
          • 50-60Gy confers 5% risk
          • <48Gy has no risk
      • treatment related acute myeloid leukemia / myelodysplasia (tMDS/AML)(from chemotherapy)
        • in 2% of survivors of ES
        • arises at ~5y after diagnosis
    • Recurrence/progression
      • extremely poor prognosis (<10% 5YS)
    • Metastases
      • 25-30% have macrometastases on presentation (lungs, bone, bone marrow)
      • 10% have bone mets on presentation
      • cure rates with chemotherapy
        • 30% cure rate for lung mets alone
        • 20% cure rate for bone mets alone
        • 15% cure rate for combined bone and lung mets
    • Radiation therapy complications
      • limb length discrepancy (especially in skeletally immature)
      • joint contracture
      • muscle atrophy
      • pathologic fracture
      • secondary sarcoma
    • Venous thromboembolism
      • high rate of venous thromboembolic events in patients with sarcoma
      • tumor activation of factor X to factor Xa
  • Prognosis
    • Survival
      • 5 yr survival
        • 65-80% for localized disease
        • 25-40% for metastatic disease
      • 10 yr survival
        • 60% for localized disease
        • 30% for metastatic disease
    • Poor prognostic factors
      • tumor size/location
        • tumors greater than 100cm3 or >8cm in size
        • spine and pelvic tumors (worst) > proximal extremities > distal extremities (best prognosis)
      • age and sex
        • older age (>14) worse prognosis
        • male worse prognosis
      • laboratory parameters
        • elevated lactic dehydrogenase levels (>200IUml) indicates large tumors/metastatic disease
        • anemia and elevated WBC indicates extensive disease
      • molecular pathology
        • p53 mutation in addition to t(11:22) translocation
        • overexpression of cell proliferation antigen Ki-67
        • overexpression of HER-2/neu
      • metastases (most important prognostic indicator)
        • presence of mets has poor prognosis
        • lung metastases better prognosis than bone/bone marrow mets
        • skip metastases (same bone) better pronosis than metastases to another site
      • chemotherapy response
        • < 90% necrosis with chemotherapy

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Questions (28)
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(OBQ12.222) A 10-year-old male presents with ongoing complaints of left thigh pain after falling during a soccer game. A clinical photo is seen in Figure A. He has tenderness and general warmth over the lateral aspect of his left thigh. His ESR is 82 and his WBC is 15. A radiograph and histology slide are shown in Figures B and C. What is the most likely translocation and fusion protein associated with this condition?

QID: 4582
FIGURES:
1

t (x:18), EWS-FL1

3%

(126/4018)

2

t (2:13), PAK3-FKHR

2%

(74/4018)

3

t (11: 22), EWS-FL1

82%

(3308/4018)

4

t (11: 22), EWS-CHN

10%

(395/4018)

5

t (9: 22), EWS-CHN

2%

(87/4018)

L 2 B

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(OBQ10.194) A 15-year-old cross country runner complains of vague shin pain. A radiograph of the tibia is seen in Figure A. A biopsy is performed and is shown in Figure B. Which of the following chromosomal translocations is most likely associated with this condition?

QID: 3286
FIGURES:
1

t(10;20)

1%

(33/4078)

2

t(11;22)

87%

(3558/4078)

3

t(X;18)

4%

(166/4078)

4

t(9;22)

6%

(261/4078)

5

t(2;13)

1%

(40/4078)

L 1 B

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(OBQ10.171) Each of the following neoplasms demonstrate round cells when examined histologically EXCEPT

QID: 3264
1

Embryonal rhabdomyosarcoma

10%

(264/2617)

2

Primitive neuroectodermal tumors (PNET)

7%

(183/2617)

3

Ewings sarcoma

2%

(63/2617)

4

Neuroblastoma

5%

(138/2617)

5

Leiomyosarcoma

75%

(1961/2617)

L 2 A

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(OBQ08.53) For which of the following patients would a bone marrow biopsy be indicated during tumor staging?

QID: 439
1

15-year-old girl with bone forming distal femoral lesion on radiographs

11%

(230/2063)

2

7-year-old boy with lipomatous lesion in his proximal thigh

4%

(92/2063)

3

3-year-old boy with pituitary intracranial mass

8%

(164/2063)

4

5-year-old girl with lytic diaphyseal femur lesion positive for the EWS-FLI1 transgene

65%

(1351/2063)

5

12-year-old boy with shepard's crook deformity of his proximal femur and deactivating mutation in the G-beta subunit of the G-protein coupled receptor.

10%

(210/2063)

L 3 A

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(OBQ06.65) An 8-year-old girl comes to the office with increasing thigh pain mostly at night. Radiograph and biopsy specimen are shown in Figures A and B. The patients WBC and ESR are both elevated. What is the most likely diagnosis?

QID: 176
FIGURES:
1

Ewing's sarcoma

82%

(1573/1924)

2

Osteosarcoma

9%

(165/1924)

3

Osteomyelitis

8%

(147/1924)

4

Giant cell tumor

0%

(8/1924)

5

Chondrosarcoma

1%

(11/1924)

L 2 A

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(OBQ06.161) A 13-year old female complains of constant, dull right knee pain for the past several months. The pain is worse at night and with walking. She denies weight loss or fatigue. An AP and lateral radiograph are shown in Figures A and B, respectively. She was found to have a bony lesion in the distal femur which was biopsied at an outside institution which is shown in Figure C. What is the genetic translocation with this type of condition?

QID: 347
FIGURES:
1

t (9; 22)

5%

(86/1846)

2

t (11;22)

87%

(1609/1846)

3

t (12;16)

3%

(56/1846)

4

t (X;18)

3%

(55/1846)

5

t (12;22)

2%

(29/1846)

L 1 B

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(OBQ06.214) After tumor staging, what is the most appropriate treatment for a 17-year-old male with stage IIb Ewing's sarcoma in his proximal tibia?

QID: 225
1

Neoadjuvant radiotherapy, marginal surgical resection, adjuvant chemotherapy

3%

(59/1890)

2

Neoadjuvant chemotherapy, marginal surgical resection, adjuvant radiotherapy

6%

(113/1890)

3

Neoadjuvant chemotherapy, wide surgical resection, adjuvant chemotherapy

83%

(1567/1890)

4

Wide surgical excision and reconstruction

5%

(103/1890)

5

Radiotherapy and chemotherapy without surgery

2%

(35/1890)

L 1 A

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(OBQ06.239) Which of the following tests is required for a standard work-up of Ewing's sarcoma that is not routinely obtained for staging of osteosarcoma?

QID: 250
1

MRI

3%

(79/2434)

2

CT scan

3%

(69/2434)

3

Bone scan

7%

(161/2434)

4

Protein electrophoresis

12%

(290/2434)

5

Bone marrow biopsy

75%

(1814/2434)

L 2 A

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(OBQ04.116) What is the appropriate treatment for a 10-year-old boy with Ewing's sarcoma isolated to the proximal femur?

QID: 1221
1

Neoadjuvant chemotherapy and surgical excision

7%

(45/636)

2

Neoadjuvant chemotherapy, surgical excision, and radiation therapy

19%

(119/636)

3

Neoadjuvant chemotherapy, surgical excision, and adjuvant chemotherapy

68%

(434/636)

4

Neoadjuvant radiation therapy and surgical excision

4%

(24/636)

5

Surgical excision and hormonal therapy

0%

(1/636)

L 2 A

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