2. Identified in 1921 by James Ewing
2nd most common bone tumor in children
Ewing’s Sarcoma Family of tumors:
◦ Ewing’s sarcoma (Bone –87%)
◦ Extraosseous Ewing’s sarcoma (8%)
◦ Peripheral PNET(5%)
◦ Askin’s tumor
2
3. 2% of cancer childhood malignancy
Occurs most commonly in 2nd decade
◦ 80% occur between ages 5 and 25
M:F 1.3:1 < 10 yrs
1.6:1 > 10 yrs
Rare in African-Americans and Asians
Epidemiology
4. One of many ‘small round
blue cell’ tumors seen in
pediatrics
Poorly differentiated
tumor
Unknown origin, Thought
to be of neural crest
progenitor cells origin
5. Consistent cytogenetic abnormality, t(11;22)(q24;q12) present in
90-95%
◦ resultant fusion gene is EWS/FLI-1
Also seen:
◦ t(21;22)(q22;q12) 5-10%
EWS/ERG
◦ t(7;22) and t(17;22) the remainder
EWS/ETV1 and EWS/E1AF respectively
◦ t(1;16)(q21;q13)
present along with t(11;22)
The c-myc protooncogene is frequently expressed in Ewing’s.
CD 99 ( MIC2)
PAS +ve
7. Pain & swelling of affected area
May also have systemic
symptoms:
◦ Fever
◦ Anemia
◦ Weight loss
◦ Elevated WBC & ESR,LDH
Longest lag time in diagnosis for
any pediatric solid tumor (mean of
146 days)
Pathological fracture
8. more common in diaphysis or
metadiaphysis
central axis (47%):
◦ pelvis, chest wall, spine, head &
neck
extremities (53%)
Scapula (3.8%)
Skull(3.8%)
9. direct extension into adjacent bone or soft tissue.
Metastases generally spread through bloodstream
25% present with metastatic disease
◦ Lungs (38%)
◦ Bone (31%)
◦ Bone Marrow (11%)
Nearly all pts. have micromets at diagnosis, so all Need
chemo.
No mets
75%
Lu+Bone/BM 4 %
Lung 13%
Bone/BM 7 %
Other 1 %
10. No uniform staging system.
The AJCC staging systems for bone or soft-tissue
sarcomas may be used.
11. Primary tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Tumor 8 cm or less in greatest dimension
T2 Tumor more than 8 cm in greatest dimension
T3 Discontinuous tumors in the primary bone site
Regional lymph nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
Note: Because of the rarity of lymph node involvement in bone sarcomas, the
designation NX may not be appropriate and cases should be considered N0 unless
clinical node involvement is clearly evident.
Distant metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
M1a Lung
M1b Other distant sites
12. IA T1 N0 M0 G1,2 low grade, GX
IB T2 N0 M0 G1,2 low grade, GX
T3N0 M0 G1,2 low grade, GX
IIA T1 N0 M0 G3, 4 high grade
IIB T2 N0 M0 G3, 4 high grade
III T3 N0 M0 G3, 4
IVA Any T N0 M1a any G
IVB Any T N1 any M any G
Any T any N M1b any G
13. Disease factors Favorable prognosis Unfavorable prognosis
Site Distal extremity (tibia,
fibula, radius, ulna,
hands, feet)
Central lesions (especially pelvic
bones) less favorable: proximal
extremity (humerus, femur), ribs
Size <8 cm in greatest
diameter or <200 mL
estimated volume
Larger tumors
Soft tissue
extension
Absence of
radiographically
identifiable soft tissue
extension
Presence of soft tissue extension by
radiograph or significant extension
by computed tomography
Extent of
disease
Localized Metastatic
Site of
Metastasis
Lung Bone / bone marrow
Both Lung and Bone
Response to CT Responsive Unresponsive
16. Confirmation of diagnosis:
◦ biopsy and histopathologic examination
core needle / open Inx biopsy
◦ Cytogenetics and IHC
17. X-RAY
◦ Moth eaten lesion
◦ Lytic or mixed lytic-sclerotic areas
present
◦ Multi-Layered sub periosteal reaction
(onion skinning)
◦ Lifting of periosteum (Codman's
triangle)
CT SCAN: bone destruction best
seen
Intramedullary space
extra osseous involvement
19. Involvement detected by MRI extends
beyond the anticipated area seen on plain
X-ray
Intra-medullary extent
Soft tissue extension
Skip lesions
Relation Adjacent structures, vessels ,
nerves
Multi-planar
20. Bone scan:
◦ To detect polyostotic involvement
◦ to detect bone metastasis
Bone marrow biopsy
CXR/CT of chest: lung mets
21. Fig: bone scan shows increased
activity in the distal femur.
Bone Scan: Ewing Sarcoma of
Left Humerus demonstrates
Intense Uptake
Gross Pathology: Ewing Sarcoma of
Metadiaphysis of Proximal Humerus. (Top
arrow) Permeative Marrow Lesion.
(Bottom arrow) Surrounding Soft Tissue
Mass
22. newer technique
Under evaluation to detect
◦ local and distal extent,
◦ Predictor of outcome and recurrence
23. Laboratory tests:
◦ CBC, Alkaline phosphatase, liver/kidney function tests,
◦ LDH:
useful as gauge of tumor burden
Falls with effective therapy and rises with disease recurrence
24. Multidisciplinary approach
◦ Chemotherapy: control of micrometasis
◦ Surgery: local control where possible
◦ Radiotherapy: local control where surgery not
possible or incomplete
24
25. Effective local and systemic chemotherapy
necessary for cure.
Induction chemotherapy preferred over starting
the systemic and local therapy
Advantage of this approach:
◦ Evaluation of effectiveness of the regimen
◦ Decreases the vol. of local therapy for surgery or RT
◦ Some bone healing occurs during CT, diminish the risk of
pathological fracture
26. All patients require chemotherapy
◦ Induction chemotherapy
◦ Maintenance chemotherapy
Effective chemotherapy has improved local
control rates achieved with radiation to 85-90%
26
27. First Line therapy:
◦ VAC/IE
Vincristine 2.0 mg/m2 on D1
Adriamycin 75 mg/m2 on D1
Cyclophosphamide 1.2 gm/m2 on D1
Ifosphamide 1.8 gm/m2 on D1-5
Etoposide 100 mg/m2 on D1-5
◦ **Substitute adriamycin with dactinomycin (1.2 mg/m2 on D1) after
375 mg/m2
◦ VAI (Vincristine, Adriamycin, Ifosphamide)
◦ VIDE ( Vincristine, ifosphamide, Doxorubicin, Etoposide)
27
28. Cyclophosphamide (250 mg/m2)and
topotecan(0.75 mg/m2) D1-D5
Temozolomide and irinotecan
Ifosfamide and etoposide
Ifosfamide ,etoposide and carboplatin
Docetaxel and gemcitabine
29. IESS-1and IESS-2 showed 4 drug regimen VACD is superior to 3
drug VAC in terms of RFS and OS.
INT-OO91:Adding IE improved 5-year OS (61→72%) for localized
disease, but not for metastatic disease (25%).
30.
31. Induction Multiagent chemotherapy for at least 12-
24 weeks prior to local therapy.
Maintenance (adjuvant chemotherapy) with or
without Radiotherapy is recommended following
local control treatment and the duration of
chemotherapy should be between 28-49 weeks.
**NCCN guidelines version 2.2012
33. Development of Innovative Surgical Techniques:
Limb preservation & Structural bone function
preservation
Chemo - cytoreduction makes resection
possible
Local failure rates with RT in historical series :
9 - 25% *
Concern over second malignancies
* Horonitz et al, Pediatr Clin Nor Am, 1991
33
34. Surgical Indications
◦ Expendable bone (fibula, rib, clavicle)
◦ Bone defect able to be reconstructed with modest loss of function
◦ May consider amputation if considerable growth remaining
◦ After pre-op RT
Limb-salvage surgery is preffered.
Curative surgery requires wide local excision and negative
margin
◦ Bony margins of at least 1 cm, with a 2 to 5 cm margin recommend.
◦ Soft tissue at least 5mm in fat or muscle , with 2mm through fascial
planes.
34
36. radiation responsive tumor.
There are no randomized trials that have directly compared
Radiotherapy to surgery for local control of Ewing’s
sarcoma.
Radiotherapy can, in combination with chemotherapy,
achieve local control, but complete surgery when feasible
has to be regarded as the first choice of local therapy.**
**ESMO clinical practice Guidelines for diagnosis, treatment and follow-up for Bone sarcomas. Ref.
Annals of Oncology 21 (Supplement 5) 13,2010
37.
38. FIG. Changes in treatment volume. (A) Field
encompassing the entire length of the medullary cavity
for a tumor involving the proximal left humerus. (B)
Tailored field encompassing only the proximal aspect of
the leg for a limited tumor of the left tibia.
39. Definitive Radiation Therapy:
◦ Tumors where Resection is Impossible
◦ For skull, face, vertebra, or pelvic primary
◦ where only an intra-lesional resection is achievable
◦ Patient with poor Surgical risk
◦ Patient refusing surgery
Note: Surgery is the preferred arm where wide or marginal
resection is possible
39
40. Pre-operative Radiation Therapy
◦ Indicated when narrow resection margins are expected
◦ Principle :
To sterilize the tumor compartment before surgery & to
potentially reduce the risk of dissemination during surgery
◦ Local recurrence with pre-op RT
<5%
EI-CESS-92 : Schuck et al – IJROBP-1998 & 2003
40
41. Post-operative Radiation Therapy
◦ For gross or microscopic positive margin
◦ For marginal Resection
◦ For wide-resection with Poor Histological response to Neo-
adjuvant Chemotherapy
(>10% viable tumor cells in the specimen)
Based on CESS-81, CESS-86, EICESS-92 Studies : Schuck et al,IJROBP-1998 & 2003
41
42. For rib primary ,with pleural effusion, RT to hemithorax
For lung mets ,whole lung RT(15-18 Gy) or consider
resection if< 4 mets.
Pain palliation– advanced disease.
Isolated bone secondaries.
42
43. • Every 2- 3 months
• Increase interval after 24 months
• Annually after 5 years indefinitely
Physical Exam, Local and Chest
Imaging:
CBC and other lab studies as
indicated
Consider Bone Scan or Pet scan
43
44. 30-40% of patients develop relapse with <20%
survival
Early relapse – less than 2 years:
Consider Changing Chemotherapy
Late relapse – more than 2 years:
Continue the previously used chemotherapy
44
45. Functional results : Of all the patient’s treated
with RT
◦ 60 % have good functional activity
◦ 20 % have mild morbidities
◦ 20 % have significant morbidities
Risk for Post treatment Fractures
Lymphedema
Dermatitis; recall reaction may occur with doxo,
dactinomycin.
Adriamycin cardiomyopathy.
Ifosphamide renal toxicity.
45
46. Second malignancy after RT
◦ Cumulative risk at 15yrs = 6 – 6.7%
( CESS-81 & CESS-86; IJROBP:1997; 39)
◦ No secondary sarcomas seen at doses <48 Gy
( Kutterch et al; JCO:1996, 14 )
◦ Risk increased by anthracycline and alkylating agent
chemotherapy
◦ Osteosarcoma most common.
◦ Leukemia can also occur.
46
47. Use of 3D-CRT / IMRT as a standard protocol
Incorporation of functional imaging modalities e.g. PET-
CT / PET-MRI for Target Volume delineation, Boost
treatment and IMRT
TARGATED therapy :Molecular agents like Apoptosis
directed targeted therapies e.g. TRAIL therapy (TNF
Related Apoptosis Inducing Ligand),anti IGF-1R
antibodies…etc
47
48.
49. Second most common childhood bone tumor.
Small round cell tumor with CD99 (MIC2), PAS
positive
Lytic lesion with onion peel appearance on X-Ray
Overall survival with localized disease (55%) and
metastatic disease 22%
Multimodal treatment approach
Induction Chemotherapy for 3-6 cycles and another 6-
10 cycles for maintenance.
Surgery when feasible first choice of local therapy
Radiation responsive tumor
There are no randomized trials that have directely
compared Radiotherapy to surgery for local control of
Ewing’s sarcoma.
