Dr.

Nazim Mughal
MS ORTHO, DNB ORTHO
FNB SPINE SURGERY
  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
 Epidemiol
ogy
 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
 • American Pathologist

• Suffered from OM at the age

of 14yrs.

• Confined to bed for 2 yrs.

• Served as Prof of Pathology for

33 yrs at Cornell Univ. New York.

• Died of bladder cancer at 76yrs.

• Described in 1921 as an
undifferentiated tumor involving
the diaphysis of long bones that is
radiation sensitive (in contrast to
osteosarcoma).

James Stephen Ewing (1866-1943)

At Presentation:

• Pain (>90%)
• Swelling or mass (65%)
• Limitation in movement (25%)
• Neurologic changes (15% overall, though 50%
in central tumors)
• Pathologic fracture (15%)
• Fever (10%)

• Approximately 25% have overt metastases

at presentation.
 Clinical
presentation
Symptoms
• Local pain- universal complaint-
intermittent, mild at first increase in
severity with time worse at night
• Pain may be accompanied by paresthesia
in pelvic or vertebral tumors
Conservative treatment of pain can delay
the diagnosis for weeks to months
• Swelling- rapidly growing and painful,
tense, elastic, hard with local raise of
temperature. Not palpable if it is deep
seated. Periods of remission can be
present
• Few cases present with pathological
fractures
• Weight loss, fatigue, intermittent pyrexia
 Sign
 Palpable tender mass with prominent veins
s
 Fever, erythema and swelling
 Joints and neurological manifestation, joint effusion
with limited mobility
 Paralysis and root pain if spine involved
 Investigat
ions
• Hb% reduced
• Increased ESR, CRP & TC
• Leucocytosis
• Aspirate may grossly resemble
pus
 Plain
Radiography
• Presents as extensive diaphyseal lesion
• At midshaft of the long bone, the cortex
displays increased density, extending
externally as periosteal new bone,
forming
multiple thin parallel layers giving ‘onion
peel appearence’
 PLAIN
RADIOGRAPHY
• A 24-year-old man
• pain and swelling - 8
wks; fever
• destructive lesion of the distal
fibula - permeative type of
bone destruction
• lamellated periosteal reaction
• soft-tissue mass
• mimics infection
• biopsy revealed Ewing
sarcoma.
14
 PLAIN
RADIOGRAPHY
 17-year-old boy

 significant degree of
sclerosis

 originally interpreted as
osteosarcoma

 biopsy revealed Ewing

sarcoma 15
 PLAIN
RADIOGRAPHY

16
SOFT TISSUE MASS -
SCALLOPING

17
 CT
SCAN

• 12-year-old boy
• poorly defined – permeative lesion
• aggressive periosteal reaction
• Axial CT - a large soft-tissue
mass,
not clear on conventional study.
• complete obliteration of the
marrow cavity by tumor.
18
 CT
SCAN

19
MRI

20
 MRI
7 yr old girl, permeative & destructive lesion
with soft tissue shadow in metadiaphyseal
region
MRI shows intra & extraosseous
extension

21
RADIOISOTOPE
BONE SCAN

• 13yr old girl

• ES of lt.iliac bone

• Due to morbidity
with surgical Rx,
Radio &
Chemotherapy was
given

• Free of lesion
3.5yrs after
treatment 22
• Periosteal reactions may also have codmans
triangle- lifting of periosteum from the
bone.
• Ewing sarcoma appears as ill defined,
permeative, focally moth eaten, destructive
intramedullary lesion accompanied by a
periosteal reaction(onion skin)
• Lesion may have both lytic and sclerotic regions
• Extraosseous component is radiolucent with
the same density of soft tissue.
 Isotope
scans
• Technetium-99 whole-body
radionucleotide bone scan to identify
skeletal metastasis
• Fluorine-18 fluorodeoxyglucose positron
emission tomography (FDG-PET) increases
the sensitivity of detection of metastasis.
• Will show other clinically unsuspected sites
 RADIOISOTOPE
BONE SCAN
• Technetium-99m methylene diphosphonate (99mTc-
MDP) - Increased uptake in areas of bone
destruction

• Gallium-67-citrate - Soft tissue extension

• Scintigraphy – nonspecific but reliable

in identifying metastatic lesions

• Metastases may be present in up to 30% of

cases at time of diagnosis (mostly to bones & 25
RADIOISOTOPE
BONE SCAN

26
 Angiogr
am
• Shows hypervascular reaction &
intrinsic neoplastic vasculature quite
well
• Early arterial phase shows the reactive and
a capsular vessel as well as extent of the
soft tissue mass
 CT
scanning
• Shows details of radiolucent portion of
the lesion and areas of cortical
destruction
• Does not outline the soft tissue extent
 MRI
• scanning
Most precise in defining the local extent of
the tumor
• Evaluate the extent of soft tissue masses
• For staging and surgical planning
• To assess the response to
neoadjuvant chemotherapy or
irradiation
 Differential
diagnosis
• Chronic osteomyelitis
• Metastatic neuroblastoma – first 3 years
of life, neural filamentous material,
elevated urinary catecholamines, Homer-
wright rosettes.
• Lymphosarcoma - larger nuclei and
less uniform, lack of intracellular
glycogen.
• Reticulum cell sarcoma - PAS negative
and reticulin positive(doesn't have
Ewings sarcoma Chronic osteomyelitis

Most common in diaphysis Most common in metaphysis

Very Aggressive Not aggressive

Onion peel Moth eaten and osteoporotic and areas

of sclerosis

More of small round cell Shows granulocytes

Soft tissue mass Ulceration and sinuses of the skin

commonly accompanies
the lesion
 Histopatho
• Gross appearence logy
Soft, gray white, occasionally shiny
Areas of haemorrhage and
necrosis
Cortex may be partially or completely
destroyed & periosteum may be reflected
• Usually show an area of bone destruction which is predominantly in the mid-diaphysis.
• New bone formation may extend along the shaft and sometimes appears as fusiform layers of bone around the
lesion
– ‘onion-peel’ effect.
•Often the tumour extends into the surrounding tissues, with radiating streaks of ossification (‘sunray’
appearance) and reactive periosteal bone at the proximal and distal margins (Codman’s triangle).
The definitive diagnosis is based
on
• Histomorphologic findings
• Immunohistochemistry
• Molecular pathology

HISTOMORPHOLOGICAL FINDINGS:
• Neuroectodermal tissue is the embryonic tissue of origin for EWS and it is
derived from primordial BM mesenchymal stem cells.

• Ewing's sarcoma is a small-blue-round-cell tumors

• Have a clear cytoplasm on H&E staining, due to glycogen.
• The presence of the glycogen can be demonstrated with
• Positive PAS staining and
• Negative PAS diastase staining.

• Differential for small round blue cell tumors (mnemonic LEMONS):

Lymphoma, Ewing’s, Medulloblastoma, Other (rhabdomyosarcoma,
pineoblastoma, ependymoblastoma, etc.), Neuroblastoma, Small cell
carcinoma.
• The characteristic immunostain is CD99, which diffusely
marks
the cell membrane.
(CD99 is not specific for Ewing's sarcoma)

• The most common translocation, present in about 90% of

Ewing sarcoma cases, is t(11;22)(q24;q12)
• Generates an aberrant transcription factor through fusion of the
EWSR1 gene with the FLI1 gene.[FLI1(11): EWS(22)]

• Other minor translocations include:

• t(21;22), c-Myc proto-oncogene(chromosome 21) and EWS
gene(chromosome 22) in 10% of cases.
• t(7;22)
• Ewing’s family of tumors includes
• Ewing’s sarcoma (bone 87%),
• Extraosseous Ewing’s sarcoma (8%),
• Peripheral PNET (5%), and
• Askin’s tumor (PNET of chest wall).

• Markers that differentiate EWS:

1. Vimentin
2. HBA-71
3. β2-microglobulin
4. ↑c-myc (vs. n-myc in NB)

• PNET and EWS have similar translocations and are both CD99 (MIC2)+ and
vimentin+.
• PNET is NSE+, S100+, more differentiated, and has more
neuroendocrine features.
• EWS is NSE−, S100 variable, and Homer Wright rosettes+.
 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
  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
• Talleur (IJROBP 2016):
– St. Judes phase II trial of 45 EWS
patients
– Randomised to 55.8 vs. 64.8 Gy based
on tumor size <8 vs. ≥8 cm,
respectively.
– All patients treated with 1 cm margins
on gross tumor.
– LF rate 4.4% at 10 year.
1
  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
 Skull(3.8%
)
Scapula (3.8%)

 more common in diaphysis or

metadiaphysis

 central axis (47%):

◦ pelvis, chest wall, spine, head &
neck

 extremities (53%)
  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.
Lung 13%

Bone/BM 7 %
Lu+Bone/BM 4
%
Other 1
No %
mets
75%
  No uniform staging
system.

 The AJCC staging systems for bone or soft-

tissue sarcomas may be used.
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
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
Disease factors Favorable prognosis Unfavorable prognosis
Site Distal extremity (tibia, Central lesions (especially pelvic
fibula, radius, ulna, bones) less favorable: proximal
hands, feet) extremity (humerus, femur), ribs
Size <8 cm in greatest Larger tumors
diameter or <200 mL
estimated volume
Soft tissue Absence of Presence of soft tissue extension by
extension radiographically radiograph or significant extension
identifiable soft tissue by computed tomography
extension
Extent of Localized Metastatic
disease
Site of Lung Bone / bone marrow
Metastasis Both Lung and Bone
Response to CT Responsive Unresponsive
14
 Primary Staging
History & Physical Examination
Histo-pathology -Biopsy -Bone Marrow
-Genetics
-IHC
Imaging -X-ray -CT Thorax
-CT scan -Bone scan
-MRI -PET scan
Lab Test - Renal – RFT
- Cardiac – 2D-ECHO
Confirmation


of diagnosis:

◦ biopsy and histopathologic examination

 core needle / open Inx biopsy
◦ Cytogenetics and IHC
  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
18
 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
 Bone
◦ To detect polyostotic involvement
scan: ◦ to detect bone metastasis

 Bone marrow biopsy

 CXR/CT of chest: lung mets

 Bone Scan: Ewing Sarcoma
of Left Humerus
demonstrates Intense Uptake

Fig: bone scan shows Gross Pathology: Ewing Sarcoma of

increased activity in the distal Metadiaphysis of Proximal Humerus. (Top
femur. arrow) Permeative Marrow Lesion.
(Bottom arrow) Surrounding Soft Tissue
Mass
◦ local and distal extent,
◦ Predictor of outcome and recurrence
  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
 Multidisciplinary
approach
◦ Chemotherapy: control of micrometasis

◦ Surgery: local control where

possible
◦ Radiotherapy: local control where surgery
possible or not
incomplete

24
  Effective local and systemic
chemotherapy necessary for
cure.
 Induction chemotherapy
preferred over starting the
systemic
 Advantage and
of this local therapy
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
  All patients require chemotherapy

◦ Induction chemotherapy
◦ Maintenance chemotherapy

 Effective chemotherapy has improved local

control rates achieved with radiation to 85-90%

26
  First Line
therapy:
◦ VAC/IE
 2.0 mg/m2 on D1
Vincristine
 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
 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
  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%).
 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

32
  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
 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
35
 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
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.
 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
 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
 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
  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
 Physical Exam, Local and
Chest
Imaging:
• Every 2- 3 months
• Increase interval after 24 months
• Annually after 5 years indefinitely

CBC and other lab studies as

indicated

Consider Bone Scan or Pet scan

43
 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
  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
  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
 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
 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