Updated: 3/21/2022

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/6e_moved.jpg
https://upload.orthobullets.com/topic/8047/images/SA histo_moved.jpg
https://upload.orthobullets.com/topic/8047/images/Case C - femur - xray  - Parsons_moved.png
  • summary
    • Ewing's Sarcoma is a malignant, distinctive small round cell sarcoma associated with a t(11:22) translocation which most commonly occurs in the diaphysis of long bones in patients <25 with 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 and immunostaining positive for CD99.
    • Treatment is usually neo-adjuvant chemotherapy and limb salvage surgical resection, followed by adjuvant chemotherapy +/- radiation. 
  • Epidemiology
    • Incidence
      • 3/1,000,000 (rare)
      • second most common primary malignant bone tumor in children
        • accounts for 3% of all pediatric malignancies and 10% of all primary malignant bone tumors
    • Demographics
      • male:female ratio = 1.5:1
      • 5-25 years of age most common 
        • 80-90% of patients are <20 years of age with peak incidence between 10-15 years old
      • uncommon in African Americans and Asian populations
    • Location
      • bone
        • split evenly between axial skeleton and long bones of appendicular skeleton
          • metadiaphysis of long bones (~50%)
            • femur
            • tibia
            • humerus
          • pelvis (~25%)
          • scapula
      • soft tissue
        • rare
  • Etiology
    • Pathophysiology 
      • cell biology
        • cell of origin in Ewing's Sarcoma unknown, however, thought to be of neuroectodermal origin
    • Genetics
      • mutations
        • t(11:22) translocation
          • found in 85-95% of cases
          • leads to the formation of a fusion protein (EWS-FLI1)
            • can be identified with PCR/FISH and useful to differentiate Ewing sarcoma from other round cell lesions
        • less common translocations including t(21:22) with fusion protein EWS-ERG comprise remaining 10-15%
    • Associated conditions
      • metastatic disease
        • lungs (50%), bone (25%), bone marrow (20%) are common sites
        • 26-28% present with distant macrometastases
      • secondary malignant neoplasm
        • secondary to treatment with chemotherapy +/- radiation
        • hematologic secondary malignancy
          • acute myeloid leukemia
          • myelodysplastic syndrome
        • solid secondary tumors
          • sarcoma
          • carcinoma
  • Classification
    • Staging
      • almost all tumors are MSTS stage IIB or III (see table below)
      • presence of macrometastases has prognostic significance
      • MSTS staging
      • MSTS Staging for Malignant tumors
      • Stage
      • Grade
      • Site
      • Metastasis
      • IA
      • Low Grade
      • T1 - intracompartmental
      • M0 (none)
      • IB
      • Low Grade
      • T2 - extracompartmental
      • M0 (none)
      • IIA
      • High Grade
      • T1 - intracompartmental
      • M0 (none)
      • IIB
      • High Grade
      • T2 - extracompartmental
      • M0 (none)
      • III
      • Metastatic
      • T1 or T2 - intra or extra-compartmental
      • M1 (regional or distant)
  • Presentation
    • History
      • >50% have symptoms for over 6 months before diagnosis
        • delayed diagnosis more common in pelvis, axial skeleton
    • Symptoms
      • pain
        • most common presenting symptom
        • often worsens at night
      • swelling, erythema
        • often mimics an infection
      • mass
        • may not be palpable until it is quite large
      • fever (25%)
      • weight loss
    • Physical exam
      • inspection
        • swelling
        • local tenderness
      • motion
        • limp and decreased range of motion possible depending on location of tumor
  • Imaging
    • Radiographs
      • recommended views
        • AP and lateral of affected and surrounding areas
      • findings
        • large destructive lesion in the diaphysis or metaphysis with an ill-defined, 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
        • large, associated soft tissue mass appreciated in >80% of cases
    • Bone scan
      • indications
        • used as part of staging workup to detect skip or distant metastases
          • occur in 10% of cases
      • findings
        • will show very "hot" lesion
    • MRI 
      • indications
        • used to identify:
          • soft-tissue extension
          • marrow involvement
          • relationship of lesion to adjacent neurovascular structures
        • can be used to assess response to neoadjuvant chemotherapy and radiation
      • findings
        • defines local extent of tumor
        • demonstrates large soft tissue component
        • T1: low to intermediate signal
        • T1 w/ contrast: prominent enhancement with heterogeneity 
        • T2: high signal w/ heterogeneity
    • CT chest
      • indications
        • required as initial staging workup to look for pulmonary metastasis
          • useful for staging and detecting macrometastases
  • Studies
    • Labs
      • ESR is elevated
      • WBC is elevated
      • anemia is common
      • lactic dehydrogenase (LDH) is elevated
    • Tissue biopsy/histology
      • gross appearance
        • gray/white with variable amount of necrosis, hemorrhage or cyst formation
        • may have liquid consistency mimicking pus
      • findings
        • sheets of monotonous small round blue cells
        • high nuclei: cytoplasm ratio 
        • may have pseudo-rosettes (circle of cells with necrosis in center)
      • immunostaining
        • positive
          • CD99 (in 95%)
          • MIC2
          • CD45
          • vimentin
          • PAS positive (intracellular glycogen)
          • neuron specific enolase (NSE)
          • S100
          • Leu7 (CD57)
        • negative
          • cytokeratin
          • reticulin (positive in lymphoma)
          • neurofilament (positive in neuroblastoma)
          • myoglobin (positive in embryonal rhabdomyosarcoma)
          • see complete immunostaining chart
    • Bone marrow biopsy
      • required as part of workup for Ewing's to rule out metastasis to the marrow
  • 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
      • o
      • o
      • o
      • Osteosarcoma
      • o
      • o
      • Lymphoma
      • o
      • o
      • Leukemia
      • o
      • o
      • Eosinophilic Granuloma
      • o
      • o
      • Osteomyelitis
      • o
      • Desmoplastic fibroma
      • o
      • Metastatic disease
      • Neuroblastoma (soft tissue)
      • o
      • Rhabdomyosarcoma (soft tissue)
      • Secondary Sarcoma
      • Dediff. Chondrosarcoma
      • o
      • MFH/Fibrosarcoma
      • Multiple Myeloma
      • o
  • Treatment 
    • Nonoperative
      • chemotherapy + radiation therapy
        • indications
          • non-resectable tumors (e.g. large spinal/pelvic tumors)
          • sites where functional deficit is unacceptable
        • outcomes
          • higher rates of local recurrence (35%) without surgical resection (5-10%)
          • high rates of radiation related complications (>60%)
            • limb-length discrepancies, joint contracture, muscle atrophy, pathologic fracture, secondary malignancy
              • trend is towards surgical resection and away from radiation therapy because of associated morbidity
      • Operative
        • chemotherapy + surgical resection ± adjuvant radiation
          • indications
            • standard of care in most patients
            • where primary tumor can be completely removed (expendable and surgically reconstructible sites)
          • techniques
            • chemotherapy
              • neoadjuvant (8-12 weeks) + adjuvant (6-12 months) 
            • surgical resection
              • goal is to obtain local control and prevent late recurrence of chemoresistant cells
              • when wide margins are obtained, 5-year survival rates are improved
            • 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
                  • all patients with pulmonary metastases should undergo radiation
                • where chemotherapeutic response has been poor
          • outcomes
            • 5-year survival rate of 39% and 82% in those with and without metastases at diagnosis, respectively
            • 10-year survival rate of 32% and 63% in those with and without metastases at diagnosis, respectively
  • Techniques
    • Chemotherapy
      • technique
        • standard regimen includes vincristine, doxorubicin, cyclophosphamide
          • some studies have suggested addition of ifosfamide and etoposide improve survival and decrease failure rates
        • neoadjuvant chemotherapy for 8-12 weeks followed by surgical resection
          • neoadjuvant therapy helps to eradicate micrometastases and reduce size of primary tumor
        • adjuvant chemotherapy for 6-12 months after resection
        • modes of administration and dose intensity vary between protocols
    • Radiation therapy
      • technique
        • radiation field should include pretreatment tumor volume plus a 2-3 cm margin
        • dose is 56-60 Gy
        • no difference in standard fractionation (5 days a week) vs. hyperfractionation (twice daily at lower dose)
    • Surgical resection
      • limb salvage
        • must obtain negative surgical margins
          • 5-year survival improves by over 10% with negative margins
          • if positive margins identified, re-resection should be performed +/- radiation therapy
        • technique
          • vascularized and nonvascularized autograft reconstruction
            • fibular, scapula, iliac crest, rib, clavicle
          • allograft reconstruction
          • allograft-prosthetic composites
          • endoprosthetic reconstruction
          • rotationplasty
        • complications
          • failure to maintain functional limb
          • recurrence of disease
      • amputation
        • more likely in following cases:
          • extremely large tumors involving vital structures (nerves/vessels)
          • unmanageable/displaced pathologic fractures
          • lesion of foot/ankle
            • difficult to obtain negative margins and maintain functional limb
  • Complications
    • Secondary neoplasms
      • bone sarcoma 
        • incidence
          • previously described as 20% at 20 years
        • risk factors 
          • prior radiation therapy
            • sarcoma arises in prior radiation treatment field
            • thought to be dose dependent
              • <60 Gy confers <5% risk
        • treatment
          • wide resection +/- chemotherapy/radiation
      • hematologic malignancy (acute myeloid leukemia/myelodysplasia)
        • incidence
          • 1-2% of survivors affected
          • arises 2-5 years following diagnosis most commonly
        • risk factors
          • prior chemotherapy
            • dose-intensive regimens may increase risk
        • treatment
          • chemotherapy, stem-cell transplantation, targeted drug therapy
    • Recurrence/progression
      • incidence
        • ~20% rate in those without metastases at initial presentation and >60% rate in those with metastases at initial presentation
      • risk factors (see prognosis)
      • treatment
        • extremely poor prognosis after recurrence
          • <10% 5-year survival rate
        • options are limited but may attempt radiation, further radical resection or additional chemotherapy agents
    • Metastases
      • incidence
        • 26-28% have macrometastases on presentation (lungs, bone, bone marrow)
      • treatment
        • 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
      • incidence
        • >60% of patients undergoing radiation have some complication
      • complications
        • limb length discrepancy (especially in skeletally immature)
        • joint contracture
        • muscle atrophy
        • secondary sarcoma
        • pathologic fracture
    • 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
        • 65-82% for localized disease
        • 25-40% for metastatic disease
      • 10 yr survival
        • 60-65% for localized disease
        • 30-35% for metastatic disease
    • Poor prognostic factors
      • metastases (most important prognostic indicator)
        • lung metastases better prognosis than bone/bone marrow mets
        • skip metastases (same bone) better prognosis than metastases to another site
      • amount of bone marrow involvement
      • tumor size/location
        • tumors greater than >8cm in size
        • spine and pelvic tumors (worst) > proximal extremities > distal extremities (best prognosis)
      • age and gender
        • older age (>14) worse prognosis
        • male worse prognosis
      • chemotherapy response
        • < 90% tumor necrosis with chemotherapy
      • laboratory parameters
        • elevated lactic dehydrogenase levels (>200 IU/L) 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

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Questions (28)

(OBQ18.158) A 15-year old male without previous medical history has been complaining of right shoulder pain for 1 month. He also reports that he has lost 5 pounds within that same timeframe. He states that he has difficulty sleeping at night due to feeling warm and sweaty. Current imaging is shown in Figures A and B. A bone marrow biopsy is performed and is found to be positive for a EWS-FL1 fusion protein. Which of the following combines the correct diagnosis with the correct translocation?

QID: 213054
FIGURES:

Synovial sarcoma; t(x;18)

1%

(20/1890)

Ewing's sarcoma; t(12;22)

5%

(99/1890)

Osteosarcoma; t(9;22)

3%

(49/1890)

Osteosarcoma; t(x;18)

1%

(20/1890)

Ewing's sarcoma: t(11;22)

90%

(1692/1890)

N/A A

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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:

t (x:18), EWS-FL1

3%

(128/4205)

t (2:13), PAK3-FKHR

2%

(79/4205)

t (11: 22), EWS-FL1

82%

(3468/4205)

t (11: 22), EWS-CHN

10%

(409/4205)

t (9: 22), EWS-CHN

2%

(89/4205)

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:

t(10;20)

1%

(35/4243)

t(11;22)

87%

(3710/4243)

t(X;18)

4%

(172/4243)

t(9;22)

6%

(265/4243)

t(2;13)

1%

(41/4243)

L 1 B

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

QID: 3264

Embryonal rhabdomyosarcoma

10%

(271/2722)

Primitive neuroectodermal tumors (PNET)

7%

(189/2722)

Ewings sarcoma

3%

(70/2722)

Neuroblastoma

5%

(141/2722)

Leiomyosarcoma

75%

(2041/2722)

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

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

12%

(263/2284)

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

4%

(96/2284)

3-year-old boy with pituitary intracranial mass

8%

(172/2284)

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

66%

(1502/2284)

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%

(234/2284)

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:

Ewing's sarcoma

82%

(1730/2106)

Osteosarcoma

9%

(182/2106)

Osteomyelitis

7%

(153/2106)

Giant cell tumor

0%

(10/2106)

Chondrosarcoma

1%

(11/2106)

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:

t (9; 22)

5%

(91/1980)

t (11;22)

87%

(1729/1980)

t (12;16)

3%

(58/1980)

t (X;18)

3%

(57/1980)

t (12;22)

2%

(34/1980)

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

Neoadjuvant radiotherapy, marginal surgical resection, adjuvant chemotherapy

3%

(67/2076)

Neoadjuvant chemotherapy, marginal surgical resection, adjuvant radiotherapy

6%

(126/2076)

Neoadjuvant chemotherapy, wide surgical resection, adjuvant chemotherapy

83%

(1729/2076)

Wide surgical excision and reconstruction

5%

(105/2076)

Radiotherapy and chemotherapy without surgery

2%

(36/2076)

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

MRI

3%

(86/2611)

CT scan

3%

(77/2611)

Bone scan

6%

(169/2611)

Protein electrophoresis

12%

(310/2611)

Bone marrow biopsy

75%

(1947/2611)

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

Neoadjuvant chemotherapy and surgical excision

7%

(58/805)

Neoadjuvant chemotherapy, surgical excision, and radiation therapy

17%

(135/805)

Neoadjuvant chemotherapy, surgical excision, and adjuvant chemotherapy

71%

(568/805)

Neoadjuvant radiation therapy and surgical excision

4%

(30/805)

Surgical excision and hormonal therapy

0%

(1/805)

L 2 A

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