EWINGS SARCOMA

EWING’S SARCOMA
HISTORY

James Ewing, 1866-1943, first described the tumor as a ‘bone tumor characterized by
small, blue, round cells and minimal mitotic activity’

Named after him in the 1921.

He was also a pioneer in the use of radiotherapy in the treatment of cancer.

James Ewing died from bladder cancer at the age of 76.

 History

• Turc-Carel (1983) identified a recurring reciprocal

t(11;22) chromosomal translocation in these tumors
 Etiological and Biological Characteristics
• The t(11;22)(q24;q12) translocation found in 90% of Ewing cases results in
fusion of portions of the EWSR1 gene on chromosome 22 with portions of the
FLI1 gene on chromosome 11

• Leads to the formation of a fusion protein (EWS-FLI1)  

that functions as an aberrant transcription factor

• EWS-FLI expression is required to maintain the oncologic phenotype of Ewing

cell lines
 EWING SARCOMA FAMILY TUMORS
• (ESFTs) defines a group of small, round cell neoplasms of neuroectodermal
origin that manifest as a continuum of neurogenic differentiation
• Most primitive form
• Includes:
~ Ewing’s Sarcoma of bones
~ Extraosseous ES (ES of soft tissue)
~ Peripheral PNET
~ Askin Tumor
 EWING’s SARCOMA

• 3rd most common primary malignancy of bone

• 2nd most common (after osteosarcoma) in patients younger than 30

years of age

• the most common in patients younger than

10 years of age.
 Incidence
• < 1 per 1 million per year

• about 9% of primary malignancies of bone.

• Male : Female 3:2

• Most occur in patients 5 to 25 years old.

• Race: rare in African children

 Pathology

• Site:
 50% in Long bones: Femur, tibia, fibula, metatarsals, humerus, radius, ulna, metacarpals

 Flat bones: Scapula, pelvis, ribs, clavicle, & skull

 Irregular bones: Tarsus esp. the calcaneus & vertebrae

• Localization: ~50% are found in the diaphysis of long bones

 C/F
• PAIN:
The average delay from the onset of symptoms to the diagnosis: 34 weeks.
The average patient delay from the onset of symptoms until the first medical appointment :
15 weeks
The average physician delay from the initial visit to correct diagnosis : 19 weeks

• TENDERNESS of the lesion area

• LUMP

• FEVER: may lead to mistaken diagnosis of osteomyelitis

 Spread
• via BLOOD and LYMPHATICS

• METASTATIC deposits at presentation : 30%

• Lung is the most common site of metastases

• Bone is the second most common site of metastases.

 Lab.
 Anaemia, Increased WBC, ESR and CRP

 Increased serum LDH

 Vanyl Mandilic Acid (VMA) in urine to exclude neuroblastoma

 Glycogen stains (PAS) to exclude Reticulum Cell Sarcoma

 Electron Microscopy usually differentiate RCS

 Biopsy is necessary
 Lab.

 Cyto-genetics to determine the cell origin & translocation

t(11:22)(q24:q12)

 IHC: CD45 and CD99 ( more specific)

 Specific surface glycoprotein HBA71 & MIC2 are specific

 X ray
• ILL DEFINED, PERMEATIVE or MOTH EATEN lesions

•large destructive lesion in the diaphysis or metaphysis with a moth-eaten appearance

• Usually LYTIC or mixed; but 40% may be sclerotic (patchy or streaky)

• Continuous lamellated ONION PEEL or SUN BURST periosteal reaction

Ewing’s sarcoma Lt ilium:
Nonspdecific destructive pattern in flat bone Periosteal reactions
 MRI
to evaluate the soft tissue involvement
• T1 - decreased intensity compared to the high intensity of BM
• T2 - tumour is hyper intense compared to muscle
 For Metastasis

• baseline radiograph and CT of the chest

• Bone scan: required as part of staging workup - will show very

"hot" lesion
 HPE
Macroscopically:
• Grey like BRAIN MATTER
• D/D inspissated pus of OM
• Occupy the medulla of the bone
HPE
MICROSCOPICALLY:

• HIGHLY CELLULAR tumor made

of packed solid sheets of small blue
cells

• Minimal intercellular substance

• NUCLEI: large / oval /HYPERCHROMATIC / fine regular

chromatin / mitotic figures

• A ring of 7-8 cells around a central area

of necrosis= "PSEUDOROSETTE"
 Special tests
• Cytogenetic: The t(11;22) (q24;q12) is the most common
translocation diagnostic of Ewing sarcoma and is present in
greater than 90% of cases.
• Immunohistochemical staining for the CD99 gene has high
specificity
• Periodic acid–Schiff positive (owing to intracellular glycogen)
and reticulin negative.
 D/D
1. Osteomyelitis is often the first diagnosis made : Metaphyseal

2. Neuroblastoma: True rosettes

3. Lymphoma: PAS –ve, reticulum +ve

4. Osteosarcoma: Metaphyseal

5. Chondrosarcoma : calcifications

6. Metastatic Ca

7. Metastatic embryonal rhabdomyosarcoma: +ve actin, desmin, myoglobin /electron microscopy shows cytoplasmic
filaments and Z-band
 Treatment Modalities
• Multiagent chemotherapy
preoperative chemotherapy given for 8-12 weeks followed by
surgical resection and maintenance chemotherapy for 6-12
months
• Radiotherapy VAC (vincristine, actinomycin cyclophosphamide)
Other chemotherapeutics: Doxorubicin,

• Surgery

• With surgery or radiotherapy alone, 5-year survival was <10%

• Multimodality trials including chemotherapy, survival is ∼60%–70% in
localised and ∼20%–40% in metastatic disease ,
 Treatment
• Operative
chemotherapy and limb salvage resection
– indications
• standard of care in most patients
• Neoadjuvant or adjuvant chemotherapy, or both, to treat distant metastases
that may or may not be readily apparent at the initial staging.
 Treatment
CHEMOTHERAPY

• Essential drugs :
vincristine, cyclophosphamide, dactinomycin
(VAC) , doxorubicin , etoposide and ifosfamide

• All current trials employ 3–6 cycles of initial combination

chemotherapy after biopsy, followed by local therapy, and another 6–
10 cycles of chemotherapy usually applied at 2- to 3-week intervals

• Treatment duration is thus 10–12 month

Ref; Bone Sarcomas: ESMO Clinical Practice Guidelines2014
 Chemotherapy
• RATIONALE :
~ EWS is chemo sensitive tumor
~ Mainstay of treatment for any microscopic or
gross metastatic disease at presentation
~ To reduce local treatment volume, making it more suitable for radiation
planning
• Facilitating surgical resection
• To improve the prognosis
• To assess prognosis in terms of tumor necrosis achieved with chemotherapy
 Treatment
RADIOTHERAPY
• current trend is towards surgical resection and away from
irradiation due to long term morbidity associated with
radiation(secondary malignancies/pathological #)
• adjuvant radiation may be helpful in these situations:  
– non-resectable tumors (eg. large spinal tumors)
– positive post-resection surgical margins
– patients who present with widely metastatic disease
 Treatment
Radiotherapy or Surgery??
• Radiosensitive; but RT has its own disadvantages (pathological #, secondary malignancies)

• Wide resection: decreased rate of local recurrence (<10%) and an increased rate of overall survival

• Wide resection increases morbidity (infection, bleeding)

• Large, central, unresectable tumors often are treated with radiation

• Smaller, more accessible lesions (which inherently have a better prognosis) are more likely to be
treated with surgery.
 Treatment
Radiotherapy or Surgery??
• the choice between surgery and radiation for treatment of the primary
lesion must be made on an individual basis.
• Repeat radiographs/MRI studies should be obtained after neoadjuvant
chemotherapy.
• if the lesion can be resected with wide margins with an acceptable
functional deficit, CHOOSE SURGERY
• If wide margins would be difficult to obtain or if the functional deficit
resulting from surgery would be unacceptable, CHOOSE RADIOTHERAPY
 Treatment
Radiotherapy plus Surgery??
 Treatment
Radiotherapy plus Surgery??
 Treatment
Radiotherapy plus Surgery??
• Treatment
Radiotherapy or Surgery??
 PROGNOSIS

– survival
• 60-70% long term survival with isolated extremity disease at presentation and appropriate
treatment/tumor response to chemotherapy
• 40% long term survival with pelvis lesions
• 15% long term survival if patient presents with metastatic disease
– poor prognostic factors
• spine and pelvic tumors
• tumors greater than 100cm3
• < 90% necrosis with chemotherapy
• elevated lactic dehydrogenase levels
• p53 mutation in addition to t(11:22) translocation
THANK YOU