EWINGS SARCOMA, BONE TUMOR,

1. EWING SARCOMA
PRESENTATION BY-
Dr NIKHIL S.U.
JSSH, MYSORE

2. Introduction
• Its a small round cell tumour arising in the
bones, rarely in soft tissues of children and
adolescents.
• Third most common non hematologic primary
malignancy of bone.
• 2nd most common in patients younger than 30
years( after osteosarcoma)

3. History
• First reported by James Ewing in 1921 –
proposed endothelial origin
• Angervall & Enzinger reported 1st case of soft
tissue Ewings sarcoma in 1975
• Jaffe et al described small round cell tumor of
bone and called PNET( primitive
neuroectodermal tumor) of bone
James Ewing

4. Etiology
• Neuroectodermal in origin
• 90% have t(11;22) (q24;q12) translocation and
rest t(21;22) (q22;q12)and t(7;22) (p22;q12)
• EWS-ETS gene encodes multifunctional protein
involved in various cellular processes, including
gene expression, cell signalling, and RNA
processing and transport.
 ets- e transformation specific
 ewsr1- ewings sarcoma break point 1

6. • The protein includes an N-terminal
transcriptional activation domain and a C-
terminal RNA-binding domain.
• Chromosomal translocations result in the
production of chimeric proteins that are involved
in tumorigenesis.
• Mutations in EWS-ETS gene, specifically at
t(11;22)(q24;q12) cause Ewing sarcoma as well as
neuroectodermal and various other tumors.

7. Incidence
• Incidence: one per 1 million per year.
• 9% of primary malignancies of bone

8. Age
• Wide range but most common is 5-25 years
• Peak incidence 2nd decade
• The age of the patient is important diagnostically
When confronted with patients older than 30yrs
elimination of small-cell carcinoma and large-cell
lymphoma, to be done
Less than 5yrs- metastatic neuroblastoma or acute
leukemia to be ruled out

9. Sex
• M: F - 1.3-1.5 : 1
• Caucasians > Asians
• Africans and African-Americans rarely suffer.
Race

10. Skeletal distribution
• Any bone can be the site
• Lower half > upper half
• Most common diaphysis > metaphysis of long
bones.
• Rare in epiphysis

11. • Pelvis- 26%
• Femur-20%
• Tibia-10%
• Fibula-8%
• Humerus-6%
• Spine -6%
• Chest wall-16%
Ribs-10%
Scapula -4%

12. Metastasis
• High potential of metastasis
• To lungs & bones
• > 10% patients presents with bone metastasis
- initial diagnosis
• Metastasis to lymph nodes are rare

13. • Extra skeletal Ewings sarcoma occurs in
patients between 10-30yrs
• Most common sites - chest wall, para-
vertebral muscles, extremities, buttocks and
retro-peritoneal space
• Rapid growth and distant metastasis is present

14. Association with Retinoblastoma
• Few Patients with Retinoblastoma also
developed Ewings Sarcoma, it can be due to
chromosomal error.

15. 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

16. • 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

17. Signs
• Palpable tender mass with prominent veins
• Fever, erythema and swelling
• Joints and neurological manifestation, joint
effusion with limited mobility
• Paralysis and root pain if spine involved

18. Investigations
• Hb% reduced
• Increased ESR, CRP & TC
• Leucocytosis
• Aspirate may grossly resemble pus

19. 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’

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.

23. 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

24. Angiogram
• 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

25. CT scanning
• Shows details of radiolucent portion of the
lesion and areas of cortical destruction
• Does not outline the soft tissue extent

26. 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

27. 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 glycogen)

28. 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 commonly
accompanies the lesion
Ulceration and sinuses of the skin

29. Histopathology
• Gross appearence
Soft, gray white, occasionally shiny
Areas of haemorrhage and necrosis
Cortex may be partially or completely destroyed
& periosteum may be reflected

30. Histological features
• Composed of homogeneous population of small
round cells, with high nuclear to cytoplasmic ratios,
scanty cytoplasm, which is pale, vacuolated and
charecterised by faded boundaries.
• Low power examination often shows the tumor to be
modified by large area of necrosis, hemorrhage,
calcification.

31. • High power shows, cytoplasm- lightly stained and
lacy, nuclei are usually single, equal in size, round or
oval, 1 1/4th the size of lymphocyte, chromatin is
finely dispersed or powdery.
• Nucleoli are small and single,( may contain upto
three nuclei per cell, variant called as large cell Ewing
sarcoma)

32. • The cytoplasm of the tumor cells contain
glycogen demonstrated by PAS stain and this
differentiates from Reticulum cell sarcoma
and lymphomas which are PAS negative and
reticulin positive(doesn't have glycogen)

33. Biopsy
• FNAC
• Trocar puncture biopsy
• CT guided biopsy
• Open biopsy
The definitive diagnostic method is biopsy.
Although sampling can be done by FNAC or core needle.
It is most adequately achieved by incisional biopsy.
Open biopsy is best performed by an experienced
orthopaedic oncologist to avoid violation of tissue flap,
planes and neurovascular structures

34. Staging for Ewings sarcoma
• Based on histological grade of the tumor, local
extent, presence or absence of the metastasis

35. • Ewings sarcoma is a high grade lesion
designated as stage II and can be subdivided
according to local extent
• Almost all Ewings sarcoma tumors fall into IIB
or III
• Many oncologists stage malignant bone
tumors according to the American Joint
Committee on Cancer (AJCC) system, which is
similar to Enneking’s system.

36. Prognostic factors
• Unfavourable –distant metastasis
• Even with aggressive treatment, long term survival is 20%
in distant metastasis
• Bone or bone marrow metastasis at the time of initial
diagnosis have worse prognosis than with isolated
pulmonary metastasis
• Age older than 10 years
• Size larger than 200 ml
• More central lesions (as in the pelvis or spine)
• Poor response to chemotherapy
• Histological grade - no prognostic significance- high grade
• Fever, anemia, and elevation of the number and values of
WBC, ESR, and LDH have been reported to indicate more
extensive disease and a poorer prognosis.

37. Treatment
• Goal - make patient free from disease
• Minimize pain and preserve function
• Includes neoadjuvant and adjuvant
chemotherapy
• Radiation therapy
• Surgery

38. Chemotherapy
Types of
chemotherapy
When given Intention Comments
Neoadjuvant Before definitive RT
or Surgery
To decrease tumor
bulk for definitive
treatment
Most commonly
used
Concomitant Drug radiotherapy To increase
response to
radiation
Rarely used
Adjuvant After definitive
radiotherapy
To kill
micrometastasis
Mandatory in all
cases
Therapeutic In metastasic or
recurrent disease
when other
modalities have
failed
Growth restrain and
palliation
Used to stop growth

39. • Prior to multi agent chemotherapy, long term
survival was less than 10% now increased to 60%-
70%
• Drugs effective are Doxorubicin(DXR),
Cyclophosphamide(CPA), Vincristine(VCR),
Actinomycin-D(ACT), Ifosfamide(IFM) and
Etopside(VP16), G-CSF
• Not advisible in 1st trimester of pregnancy-
congenital anomalies in fetus
• Less hazardous in 2nd trimester and least in 3rd
trimester

40. Name of regimen Drugs Daily dose Administrtion
day
Frequency
VAC Vincristine
Adriamycin
Cyclophosphamide
1.5mg/m2
50mg/m2
750mg/m2
1
1
1
Recycle every 3
weeks
VACA Vincristine
Adriamycin
Cyclophosphamide
Actinomycin
1.5mg/m2
60mg/m2
500mg/m2
0.015mg/m2
Weekly(3-7)
Week 7
Weekly(3-7)
1-5(wk1)
Recycle every 3
months
AV alternating
with CV
Vincrystine
Adriamycin
alternating with
Cyclophasmide
Vincrystine
1.4mg/m2
60mg/m2
1000mg/m2
1.4mg/m2
1-8
1
1
1-8
Alternate each
course every 4
weeks
IA Ifosfamide
G-CSF
Alternating with
Adriamycin,
G-CSF
20mg/m2
480ug
100mg/m2
480ug
1-9
10-16
1-2
3-9
Give 4 such
courses

41. Adverse effects
• Cyclophosphamide -Myelosuppression (leukopenia), hemorrhagic cystitis,
alopecia, nausea and vomiting
Rx- Mesna
• Ifosfamide- Hemorrhagic cystitis, myelosuppression, nausea and vomiting,
nephrotoxicity, neurotoxicity
Rx- Albumin/Thiamine/Dialysis
• Etoposide (VP-16) Mucositis, nausea and vomiting
• Vincristine- Peripheral neuropathy (irreversible), tissue necrosis (with
extravasation), seizures, alopecia
• Doxorubicin- Myelosuppression (neutrophils), nausea and vomiting,
mucositis, alopecia, severe tissue necrosis (with extravasation), acute and
chronic cardiotoxicity
Rx-Dexrazoxane

42. Radiotherapy
• Goal- deliver maximum dose of radiation to tumor cells,
and minimize toxicity- linear accelerators used
• Highly radio sensitive & radiocurable
• Local failure - common when soft tissue involvement
present
• Tumors controlled by 5000-6000 rads(1 rad = 0.01 Gy = 0.01
J/kg)
• Megavoltage radiation of cobalt 60, - the entire bone shaft
and surrounding tissue is irradiated to a dose of 4000-6000
rads in 4-6 weeks
• 25 fractions over 5 weeks( 5 fractions per week)

43. Schedule
• Non metastatic; 1.8gy/day for 30days. Max
dose of 55-60gy for primary tumors
• Metastatic disease; 1.8/day for 30 days after 3
cycles of CT
• Total body irradiation; 4gy/day – 2 doses for
18 weeks

44. Complications
• Skin irritation, initial erythema- progressing to
desquamation
• Gastrointestinal upset, urinary frequency, anorexia and
extremity edema
• Rarely osteonecrosis
• Radiation induced pathological fractures
• Radiation sarcoma
• In children – sclerosis, kyphosis, chest wall deformities,
hypoplasia of ilium and limb length discrepancy
• Teratogen- increases exponentially with dose above
10cGy radiation- RT to be avoided in 1st trimester

45. Surgical management
• Indications
Expendable site
Lesion near major epiphysis
Failed radiation therapy
Large lesion with irreparable pathological
fracture

47. Reconstruction
• Large bone defects to be reconstructed to restore
function
• Autogenous bone graft, allogenic bone graft and
endoprosthesis
Vascularised bone graft- blood flow can be
preserved
Freeze dried bone allografts-limb salvage
procedures
Endoprosthetic replacement provide excellent
results

48. Surgery/Radiation
• Individual basis
• If possible to resect with wide margin
resection without irradiation is the treatment
of choice
• If surgical margins are uncertain pre operative
radiotherapy to be added
• If surgical margins are found inadequate after
surgery, postoperative radiotherapy may be
added

49. Recent advances and Journals

50. • Identified hypoalbuminaemia (<3.5 g/dl) as
the only poor prognostic factor to affect EFS
on multivariate analysis.
• None of the previously mentioned studies
identified this factor to predict outcome.
• Patients with hypoalbuminaemia had a higher
incidence of systemic symptoms

51. References
1. Canale & Beaty: Campbell's Operative Orthopaedics, 12th edition
2. Turek -Orthopaedics & their application 4th edition
3. Orthopaedics & trauma- GS Kulkarni
4. Dahalins- Bone Tumors- 6th edition
5. Differential diagnosis in orthopaedic oncology- 2nd edition
6. MRI of bone and soft tissue tumor & tumor like lesions- Steven P Meyer
7. Robbins basic pathology- 9th edition
8. Diagnosis and Treatment of Ewing’s Sarcoma (Jpn J Clin Oncol 2007;37(2)79–89
doi:10.1093/jjco/hyl142)
9. Outcome of multimodality treatment of Ewing’s sarcoma of the
extremities(www.ijoonline.com DOI: 10.4103/0019-5413.69307)
10. Ewing’s Sarcoma Family of Tumors: Current ManagementThe ( Oncologist 2006, 11:503-
519.)
11. http://en.wikipedia.org/wiki/James_Ewing_(pathologist)

57. • http://en.wikipedia.org/wiki/James_Ewing_(p
athologist)