Ewing's Sarcoma - Pathology

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

Action	Numeric Key	Letter Key	Function Key
Show Bullets		S	Enter (frontside only)
20%	1	N
40%	2	H
60%	3	F	Enter (backside only)
80%	4	E
100%	5	M
Toss	0	T

(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:

Type & Select Correct Answer

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Synovial sarcoma; t(x;18)

(21/1971)

Ewing's sarcoma; t(12;22)

(108/1971)

Osteosarcoma; t(9;22)

(54/1971)

Osteosarcoma; t(x;18)

(20/1971)

Ewing's sarcoma: t(11;22)

89%

(1758/1971)

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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)

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