20. Ewing Sarcoma powerpoint presentation

20. Ewing Sarcoma powerpoint presentation

1. EWING SARCOMA PRESENTER- Dr. ABHISHEK MEWARA MODERATOR- Dr. MANISH CHATURVEDI DATED- 6.3.2025 1

2. OVERVIEW INTRODUCTION PATHOGENESIS TYPES CLINICAL PRESENTATION DIAGNOSTIC WORKUP STAGING TREATMENT PROGNOSIS FOLLOW UP 2

3. INTRODUCTION 3

4. Named after James R. Ewing, an American pathologist who described the first cases in 1921. Ewing sarcoma family of tumor (ESFT) is the second most common primary tumor of the bone in childhood. Uncommon before 8 and after 25 years. 5-year OS in localized ESFT has increased from about 45% to 60%–68%, & 30% to 40% in metastatic disease. 4

5. Primary bone sarcomas are rare tumours, approximately 0.2% of all cancers. Osteosarcoma, Chondrosarcoma, and Ewing sarcoma/ primitive neuroectodermal tumour (PNET) are common bone sarcomas. Ewing is a tumor of bone and soft tissues in 10-15 years age. Cell of origin are neural crest stem cells and mesenchymal stem cells. Male predominance (1.6:1). Flat bones of axial skeleton are commonly affected, and in long bones, it arises in the diaphysis. Most common sites are pelvic bones, long bones of extremities, and bones of chest wall. In 25%, primary metastasis is seen in lungs, bones, bone marrow. Metastasis to lymph nodes, liver, or CNS is rare. 5

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7. PATHOGENESIS 7

8. Light microscopy shows small, round, blue cells. ESFTs have a translocation between the EWS gene on chromosome 22 and the FLI1 gene on chromosome 11 (t[11;22][q24;q12]); or the ERG gene on chromosome 21 (t[21;22][q22;q12]). Encodes a chimeric EWS/FLI1 protein that binds to chromatin and dysregulates transcription, leading to uncontrolled growth and abnormal differentiation. Homer-Wright Rosettes which are rounded cell clusters with central fibrillary core indicates neuroectodermal differentiation in PNET. ESWR1 with ETS family members (ERG,ETV1,ETV4 or FEV fusions)-less common. ESWR1 gene rearrangement can be seen by FISH technique and PCR. 8

9. CD99/MIC2 – strong diffuse membrane staining (95-100% cases). Synaptophysin, S-100, NSE helps to characterise tumours as Ewing sarcoma or PNET. Vimentin +, Cytokeratin +/-, Desmin -. 9

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11. TYPES 11

12. Ewing sarcoma family of tumour(ESFT) includes- Ewing sarcoma of bone Extra-osseous ewing sarcoma, referred as extra skeletal ewing sarcoma (tumour growing outside the bone) PNET (Peripheral Neuro-Ectodermal Tumour) Peripheral neuroepithelioma Askin’s tumour (chest wall) Atypical ewing sarcoma 12

13. CLINICAL PRESENTATION 13

14. Locoregional pain - MC presenting symptom, and can be intermittent and variable in intensity. Localized pain, swelling, and palpable mass. Constitutional symptoms- fever, weight loss and fatigue in advanced or metastatic stages, and are characteristic. Can arise in virtually any bone and in soft tissue. Patients with chest wall or pelvic primaries may experience significant complaints only at a very late stage. Neurologic symptoms or signs occur in 15% of children, either as spinal cord compression or as peripheral nerve compression. 14

15. DIAGNOSTIC WORKUP 15

16. Routine blood investigations- CBC, LFT, RFT, RBS. BM aspirate and HPE. Simple radiograph. ESFTs are defined as a destructive lesion of the bone. Tumor related osteolysis Detachments of the periosteum from the bone ( Codman triangle ) are commonly seen. Diaphyseal location suggests an ESFT, as compared to the metaphyseal location, which is more common in osteosarcoma. CT Scan- bone and soft tissue extent, accurate in lung metastasis. MRI- local and intramedullary extension, relation with blood vessels and nerves. T1- low to intermediate signal. T1c- heterogenous but prominent enhancement. T2- heterogeneously high signal, may see hair on end low signal striations. Increased ESR, anemia, and moderate leucocytosis are seen commonly. LDH has prognostic value. FDG PET scan in selective cases. 16

17. Diaphysis. Poorly marginated destructive lesion. Erosion of cortex. Both lytic and sclerotic lesions may be present. Soft tissue extension. Multi-laminated Periosteal Reaction ( Onion Peel ). 17

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20. STAGING 20

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22. TREATMENT 22

23. 23 BM Biopsy Staging by- MRI for 1º Chest CT, FDG-PET for 2º INDUCTION CT LOCAL CONTROL THERAPY (Surgery and or Radiotherapy) MAINTAINENCE CT

24. Purpose of preoperative chemotherapy is- To reduce the volume of the tumor in order to facilitate its excision. To eradicate any micro metastases that exist at the time of diagnosis. Achieving better surgical margins. Evaluating the effectiveness of the regimen to adapt P/O CT and RT. Bone heals during CT which decreases the risk of pathological fracture. 24

25. 25 TRIALS FOR CT IN EWING SARCOMA

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27. INDUCTION/ MAINTAINENCE CHEMOTHERAPY 27 The VAC/ IE regimen is as follows- THE VAC Vincristine: 2 mg IV on day 1 Doxorubicin: 75 mg/m 2 IV on days 1, up to 375 mg/m 2 Cyclophosphamide: 1200 mg/m 2 IV on day 1

28. 28 THE IE Ifosfamide : 1,800 mg/m 2 IV from D1 to D5 (with Mesna ) Etoposide: 100 mg/m 2 IV from D1 to D5 3 cycles of VDC and 3 cycles of IE are given, alternatively, prior to local treatment. A total of 17 cycles are given including both pre op and post op CT. The dose dense regimen which is given every 2 weeks was recently demonstrated to provide a longer relapse-free survival and overall survival than the classic 3 weekly regimen. INDUCTION/ MAINTAINENCE CHEMOTHERAPY

29. LOCAL TREATMENT SURGERY &/OR RADIOTHERAPY 29

30. SURGERY Current recommendation regarding local treatment of ES is surgical resection with a wide margin. Resection is preferred unless poor functional results are anticipated. Resection also provides pathologic information post ICT. Resection without reconstruction can be done in small bones (dispensable bones like rib, proximal fibula, metatarsals/metacarpals). Large lesions may require allograft or endo prosthetic reconstructions. Adequate surgical margins as per COG-AEWS0031: >1 cm for bone >0.5 cm for soft tissue >0.20 cm for fascia 30

31. 31 ENNEKING CLASSIFICATION OF SURGICAL INTERVENTION INTRALESIONAL RESECTION Tumor opened during surgery, or surgical field contaminated, or microscopic or macroscopic residual disease MARGINAL RESECTION Tumor removed en bloc; however, resection through pseudo capsule of tumor; microscopic residual disease likely WIDE RESECTION Tumor and its pseudo capsule removed en bloc, surrounded by healthy tissue, within the tumor bearing compartment RADICAL RESECTION The whole tumor bearing compartment is removed en bloc Acc/to EI-CESS trials, local control with surgery alone was excellent in all patients who had wide resection (according to ENNEKING CLASSIFICATION ) and with good histological response following initial chemotherapy (< 10% viable tumor cells in resected specimen).

32. RADIOTHERAPY Indications for- DEFINITIVE RT: Resection impossible. Skull, face, vertebra or pelvic primary. Only intra-lesional resection is achievable. Poor surgical risk/ comorbidities. Refusal for surgery. NEO ADJUVANT RT : Narrow resection margins expected. <50% shrinkage of soft tissue mass after ICT. 32

33. ADJUVANT RT: Gross or microscopic positive margin. Close margins. Poor histological response to NACT (>10% viable tumour cells in the specimen/ <90% tumour necrosis). PALLIATIVE RT: Whole Lung irradiation. Bone metastasis. SC compression. 33

34. RADIATION DOSE & FRACTIONATION DEFINITIVE RT: 55-60 Gy I/C/O higher risk of local failure (large/ pelvic tumors/ >8 cm) -> 55.8 Gy to CTV (GTV +1 cm) & boost to GTV up to 64.8 Gy. ADJUVANT RT: 45-54 Gy, depending on individual risk factors (margins, response). NEOADJUVANT RT: 45-50.4 Gy 34

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36. RADIATION FIELD Historically, ES was treated with large RT portals, encompassing entire involved bone & marrow cavity With adjuvant CT, RT portals become smaller with equivalent or improved local control. POG-8346 showed that the traditional approach of irradiating the entire marrow cavity was not necessary. 36

37. 2-D Target Volume Circumferential irradiation of extremities is avoided (spare 1-2 cm strip of tissue). General rule is to take a 2 cm margin in case of both neoadjuvant RT or definitive RT. 2 parallel opposed fields are used. Growth plates are taken into consideration for patients below 7 years age, shouldn’t receive >30 Gy. Gonadal avoidance, or additional shielding (for testis) important to retain fertility. Immobilization by sand bags, vacuum pillows, Perspex cast. 37

38. 2-D DOSE 40-45 Gy in 20-25 # in 4-5 weeks to the entire bone, F/B localized boost to shrink volumes. First with 5 cm margin around gross disease to a dose of 10 Gy in 5 #, F/B a 2 cm margin to a dose of 5- 10 Gy in 2- 5 #. 38

39. PHASE 1: Gross tumor in bone & soft issue (Pre CT)+ 2 cm longitudinal margins+ 2 cm radial margins Dose: 45 Gy @ 1.8- 2.2 Gy/#. BOOST PHASE: Reduced 1-2 cm margins (bone & residual tissue). Up to total dose of 55.8 Gy (10.8 Gy/ 6#). 39 3-D Target Volume and Dose

40. GTV: Visible tumor on imaging at its maximal extent (using CT, PET-CT, MRI prior to any chemotherapy or surgery). CTV 1: Should encompass any sites of potential microscopic extension or contamination by GTV, including metallic prosthesis, drain sites and surgical scars and should be at least GTV+ 1 cm. PTV 1: Vary according to tumor location. Typically, PTV 1 = CTV 1+ 0.5- 1 cm. 40

41. BOOST VOLUMES: CTV 2: GTV at time of RT + 1 cm margin. Any initial bone or marrow abnormalities in primary bone should be included in GTV. CTV 2 does not need to include scars and drain sites. PTV 2: CTV 2+ 0.5- 1.0 cm. Extremity lesions require sparing at least 1-2 cm strip of tissue to prevent lymphedema. >20 Gy to epiphyseal growth plate can prematurely close epiphysis. 41

42. RT FOR PELVIC TUMORS: Radiation cystitis can be a significant risk even at doses as low as 20 Gy. Pelvic lesions rarely infiltrate tissue around bladder, but push it aside. NACT allows bladder to be spared by tumour shrinkage. RT TO CHEST WALL LESION: Rib lesions: conformally with minimum of lung & heart in high dose field. Hemithorax irradiation if pleural involvement (15 Gy @ 1.5 Gy/#, F/B boost to 1° till 55.8 Gy). In P/O cases, if pleural effusion/ infiltration and if intra OP contamination. EICESS 92 trial: 7 yr EFS – 63% (vs 46%) with hemithorax irradiation. 42

43. RT FOR VERTEBRAL LESIONS: Standard dose is usually 45 Gy, if spinal cord is in Rx volume. Large sacral lesions should be treated to full dose. RT FOR OTHER SITES: Definitive RT also used for skull, face, other primaries, and for unresectable disease. Gonadal avoidance or shielding may be required in pelvic or other primaries. Irradiation of Achilles tendon is usually avoided. 43

44. SEQUELAE OF TREATMENT The most common skeletal complication of RT is abnormal growth and development of the irradiated tissues. RT can cause premature closure of active epiphyses, producing growth deficits and limb-length discrepancies. Long bone lesions develop pathologic fractures. Extremity weakness, decreased range of motion secondary to fibrosis, pain in the extremity (particularly in the early morning), discoloration of the skin, and lymphedema are other complications. The risk of secondary neoplasia at the site of the primary lesion is related to RT dose, with an increased risk at doses >60 Gy. 44

45. CONCURRENT CTRT Vincristine- 1.5 mg/m 2 D1. Actinomycin D- 1 mg/m 2 D1. Cyclophosphamide- 600 mg/m 2 D1. Actinomycin withheld if RT to head and neck, thorax or pelvis. 45

46. METASTATIC EWING’S TO LUNGS WHOLE LUNG IRRADIATION- Following completion of CT/ metastatectomy . 15 Gy (1.5 Gy/#) for < 15 yr age 18 Gy for > 14 yr age 12 Gy for children < 6 years Consider resection if < 4 mets If residual mets after whole lung RT, focal boost to 45 Gy was used (not recommended I/V/O severe decline in pulmonary function). 46

47. PROGNOSIS 47

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49. FOLLOW UP 49

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51. R EFERENCES PEREZ AND BRADY 7 TH EDITION G.K. RATH DEVITA, HELLMAN AND ROSENBERG 12 TH EDITION AJCC 8 TH EDITION NCCN V. 2023 GOOGLE SEARCH ENGINE 51

52. THANK YOU, AND HAVE A NICE DAY! 52