EWING SARCOMA

PRESENTATION BY-

Dr NIKHIL S.U.

JSSH, MYSORE

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)

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

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

• 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.

Incidence

• Incidence: one per 1 million per year.

• 9% of primary malignancies of bone

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 30yrselimination of small-cell carcinoma and large-cell

lymphoma, to be done

Less than 5yrs- metastatic neuroblastoma or acute leukemia to be ruled out

Sex

• M: F - 1.3-1.5 : 1

• Caucasians > Asians

• Africans and African-Americans rarely suffer.

Race

Skeletal distribution

• Any bone can be the site

• Lower half > upper half

• Most common diaphysis > metaphysis of long bones.

• Rare in epiphysis

• Pelvis- 26%• Femur-20%• Tibia-10%• Fibula-8%• Humerus-6%• Spine -6%

• Chest wall-16%Ribs-10%Scapula -4%

Metastasis

• High potential of metastasis

• To lungs & bones

• > 10% patients presents with bone metastasis - initial diagnosis

• Metastasis to lymph nodes are rare

• 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

Association with Retinoblastoma

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

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

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

Investigations

• 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’

• Periosteal reactions may also have codmanstriangle- lifting of periosteum from the bone.

• Ewing sarcoma appears as ill defined, permeative, focally moth eaten, destructive intramedullarylesion accompanied by a periostealreaction(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 radionucleotidebone 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

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

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 neoadjuvantchemotherapy or irradiation

Differential diagnosis

• Chronic osteomyelitis

• Metastatic neuroblastoma – first 3 years of life, neural filamentous material, elevated urinary catecholamines, Homer- wrightrosettes.

• Lymphosarcoma - larger nuclei and less uniform, lack of intracellular glycogen.

• Reticulum cell sarcoma - PAS negative and reticulin positive(doesn't have glycogen)

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

Histopathology• Gross appearence

Soft, gray white, occasionally shiny

Areas of haemorrhage and necrosis

Cortex may be partially or completely destroyed & periosteum may be reflected

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.

• 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 uptothree nuclei per cell, variant called as large cell Ewing sarcoma)

• 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)

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

Staging for Ewings sarcoma

• Based on histological grade of the tumor, local extent, presence or absence of the metastasis

• 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.

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.

Treatment

• Goal - make patient free from disease

• Minimize pain and preserve function

• Includes neoadjuvant and adjuvant chemotherapy

• Radiation therapy

• Surgery

Chemotherapy

Types of chemotherapy

When given Intention Comments

Neoadjuvant Before definitive RTor Surgery

To decrease tumorbulk 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 andpalliation

Used to stop growth

• 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

Name of regimen Drugs Daily dose Administrtionday

Frequency

VAC VincristineAdriamycinCyclophosphamide

1.5mg/m250mg/m2750mg/m2

111

Recycle every 3 weeks

VACA VincristineAdriamycinCyclophosphamideActinomycin

1.5mg/m260mg/m2500mg/m20.015mg/m2

Weekly(3-7)Week 7Weekly(3-7)1-5(wk1)

Recycle every 3 months

AV alternating with CV

VincrystineAdriamycinalternating with CyclophasmideVincrystine

1.4mg/m260mg/m21000mg/m21.4mg/m2

1-8111-8

Alternate each course every 4 weeks

IA IfosfamideG-CSFAlternating with Adriamycin, G-CSF

20mg/m2480ug

100mg/m2480ug

1-910-16

1-23-9

Give 4 such courses

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

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)

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

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

Surgical management

• Indications

Expendable site

Lesion near major epiphysis

Failed radiation therapy

Large lesion with irreparable pathological fracture

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

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

Recent advances and Journals

• 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

References

1. Canale & Beaty: Campbell's Operative Orthopaedics, 12th edition2. Turek -Orthopaedics & their application 4th edition3. Orthopaedics & trauma- GS Kulkarni4. Dahalins- Bone Tumors- 6th edition5. Differential diagnosis in orthopaedic oncology- 2nd edition6. MRI of bone and soft tissue tumor & tumor like lesions- Steven P Meyer 7. Robbins basic pathology- 9th edition8. 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)

• http://en.wikipedia.org/wiki/James_Ewing_(pathologist)