Bone and Soft Tissue Sarcomas

1. Bone and Soft Tissue Sarcomas Resident Education Lecture Series

2. Benign Osteochondroma Osteoid Osteoma Enchondroma Chondroblastoma Non-ossifying fibroma akabenign cortical defect Hemangioma Eosinophilic granuloma Osteomyelitis Malignant Osteosarcoma Ewing sarcoma Malignant fibrous histiocytoma Non-Hodgkin Lymphoma Eosinophilic granuloma Pediatric Bone “Tumors”

3. Malignant bone tumors • Rare • 6% of all childhood malignancies • Annual US Incidence in children < 20 yrs • 8.7 per million ~ 650 to 700 children/year • For perspective, Annual US Incidence • Overall 4697 per million • Lung 610 per million • Breast 633 per million • Most often occur in young patients < 25 yrs • Most common bone tumors ← will focus on these • Osteosarcoma 56% • Ewing sarcoma 34%

4. Osteosarcoma (OS) • Primary malignant tumor of bone • Derived from primitive bone forming mesenchyme • Malignant spindle cells produce immature neoplastic bone matrix – osteoid • Can look heterogeneous under the microscope • Cell of origin?

5. Cell of origin may be mesenchymal stem cell Telangiectatic Small Cell Chondroblastic Fibroblastic Osteoblastic

6. Central (medullary) tumors Conventional OS (87%) Osteoblastic – 50% Chondroblastic – 25% Fibroblastic – 25% Telangiectatic (3%) Small cell Intraosseous well-differentiated (1%) Multifocal Surface tumors Parosteal (<5%) Periosteal High-grade surface OS High grade vs. Low grade Histologic subtype (WHO) OS

7. Epidemiology OS • Most common during 2nd decade • 75% between 10 and 20 yrs • Peak during adolescent growth spurt • Taller than average • Occurs earlier in girls • M:F 1.5:1 • African-American:Caucasian 1.4:1

9. Associations or Risk Factors OS • Ionizing radiation • Hereditary retinoblastoma (Rb mutations) • Li-Fraumeni syndrome (p53 mutations) • Rothmund-Thomson syndrome • No environmental risk factors • No consistent cytogenetic abnormality

10. Clinical presentation OS • Pain: dull, aching, constant, worse at night, often attributed to trauma • Average duration of symptoms prior to diagnosis is three months • May or may not have a mass • Diagnosis of pelvic lesions often delayed • 20% have detectable metastases at diagnosis – most often (>90%) pulmonary

11. Location OS • Most common in long bones • May have altered gait or function • 90% are metaphyseal • May cross growth plate • Location: • #1 distal femur • #2 proximal tibia • #3 proximal humerus

12. History and physical examination Laboratory tests: Blood tests: include LDH, Alkaline phosphataseAlso CBC, liver/kidney function tests Pathology Biopsy (open preferred) Radiologic tests Plain films of involved bone MRI of entire involved bone Whole body Bone Scan CXR and CT of Chest PET scan (in future) Pre-therapy evaluation also includes Audiogram, echocardiogram, GFR/creatinine clearance Diagnostic Workup OS

13. Radiographs OS • Usually blastic • May be lytic or mixed bone destruction and production • Poorly marginated • Cortical destruction • Soft tissue ossification

17. Prognostic Factors OS • Tumor Grade & Histology • Parosteal favorable; telangiectatic unfavorable • Disease Extent • metastatic disease unfavorable • Tumor Size / Site • axial skeletal primaries unfavorable • Age • < 10 yrs unfavorable • Response of the primary tumor to pre-operative chemotherapy: very powerful predictor • > 80-90% necrosis favorable

18. Treatment: Multimodal OS • Surgery • control of bulk disease • Chemotherapy • control of micrometastases • Radiation • Tumors not very radiosensitive, so this usually reserved for palliation

19. Treatment: Surgery OS • Removal of all gross tumorwith wide (>5cm) margins en bloc and biopsy site through normal tissue planesis required • Type of surgical procedure depends on tumor location, size, extramedullary extent, presence of distant metastatic disease, age, skeletal development, and life-style preference • limb-sparing • amputation • Metastatic sites must also be resected • If/when relapse occurs, retrieval therapy must include resection

20. Surgery alone 15-25% 5 year survival • Recurrence with local and (50%) metastatic disease within 6 months of resection • With multiagent chemotherapy  55-68% • No difference between adjuvant or neoadjuvant chemotherapy • Those with >90% tumor necrosis and complete resection  80-85%

21. Treatment: Chemotherapy OS • Bulky disease is considered somewhat chemotherapy resistant • Subclinical metastases are sensitive to chemotherapy • Most active agents include • adriamycin, cisplatinum, high-dose methotrexate, ifosfamide, etoposide • Best # and schedule of chemotherapy unclear • Role of intensification after local control unclear • Immune modulators under study • Role of adjuvant chemotherapy after thoracotomy for recurrent disease unclear

22. Outcomes OS • 60-68% of patients with nonmetastatic osteosarcoma of the extremity will survive without recurrence and be cured • 20% of patients with metastatic disease will be cured • Therapy with curative intent is possible following relapse: 10-20% of these patients may achieve long term survival

23. Ewing Sarcoma (EWS) • Represents a family of tumors including • Ewing sarcoma of bone • extraosseous Ewing sarcoma and • peripheral neuroectodermal tumor (PNET) of bone or soft tissue • 2nd most common bone tumor in children

24. Pathology EWS • One of many ‘small round blue cell’ tumors seen in pediatrics • Thought to be of neural origin, derived from post-ganglionic parasympathetic primordial cells • tumor cells synthesize acetylcholine transferase

25. Differential Diagnosis Lymphoma/Leukemia Rhabdomyosarcoma Metastatic Carcinoma Neuroblastoma PNET/Ewing Sarcoma Small Cell Osteosarcoma Ewing Tumor without differentiation PNET Tumor with neural differentiation Small, Round, Blue Cell Tumor

26. Incidence EWS • Occurs most commonly in 2nd decade • 80% occur between ages 5 and 25 • Most common bone tumor in children < 10 yrs • ~110 new cases/year < 15 yrs~200 new cases/year < 20 yrs • M:F 1.3:1 < 10 yrs 1.6:1 > 10 yrs • Rare in African-Americans and Asians

27. Associations or Risk Factors EWS • ??? • 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 remainderEWS/ETV1 and EWS/E1AF respectively • t(1;16)(q21;q13)present along with t(11;22)

28. Clinical Presentation EWS • Pain & swelling of affected area • May also have systemic symptoms: • Fever • Anemia • Weight loss • Elevated WBC & ESR • Mean duration of symptoms 9 months • 20-25% present with metastatic disease • Lungs (38%) • Bone (31%) • Bone Marrow (11%)

29. Location EWS • central axis (47%): • pelvis, chest wall, spine, head & neck • extremities (53%) #1 Femur #2 Ilium #3 Tibia/Fibula

30. Location EWS • Classical presentation is diaphyseal • Actually more common in metadiaphysis or metaphysis

31. History and physical examination Laboratory tests: CBC, liver/kidney function tests, LDH, ESR Urinalysis Pathology Bone marrow aspirate and biopsy Biopsy (open preferred) Radiologic tests Plain films of primary site CT/MRI of primary site CXR/CT of chest Whole body bone scan PET scan (in future) Pre-therapy evaluation also includes echocardiogram/EKG Diagnostic Work-Up EWS

32. Radiographs EWS • Destructive • Poorly Marginated • Permeative • Endosteal Cortical Erosion • Layered periosteal new bone • “Onion skinning”

33. Radiographs EWS

34. Radiology EWS • Large soft tissue mass • MRI necessary to determine • Soft tissue extent • Intraosseous extent

35. Prognostic factors EWS • Extent of disease • Metastatic disease unfavorable • Size of disease ??? • Primary site • Pelvis least favorable • Distal bones and ribs most favorable • Age • Younger (<10) more favorable • Histologic ??? • Response to chemotherapy • Neural differentiation

36. Treatment EWS • Multidisciplinary approach must provide both local control and systemic therapy • Local control measures should not compromise systemic therapy • When treatment fails, it is usually due to the development of distant metastatic disease

37. Treatment: Multimodal EWS • Surgery • local control where possible • Radiation • local control where surgery not possible or incomplete • Chemotherapy • control of micrometastases

38. Treatment: Local Control EWS • Surgery and/or Radiation therapy • No randomized studies comparing surgery to radiation therapy • slightly more local recurrence when radiation used for local control • current suggestion for surgery where possible without loss of function and without mutilation • Combination therapy if incomplete resection • Radiation doses usually 4500 – 5500 cGy

39. Surgical Indications EWS • Expendable bone (fibula, rib, clavicle) • Bone defect able to be reconstructed with modest loss of function • May consider amputation if considerable growth remaining • Trend toward improved outcomes with chemo + surgery vs. XRT

40. Radiation therapy Indications EWS • Unresectable without significant morbidity • Pelvic lesions • Spine lesions • Lung metastases • May consider chemo + XRT to allow for surgical resection or add XRT if surgical margins positive

41. Treatment: Chemotherapy EWS • All patients require chemotherapy • Active agents include • Vincristine, cyclophosphamide, adriamycin, dactinomycin, ifosfamide, etoposide, topotecan, melphalan • Effective chemotherapy has improved local control rates achieved with radiation to 85-90% • Role of SCT for high risk Ewing sarcoma still under investigation

42. Outcomes EWS • Local Rx only  >80% distant failure • Combination chemotherapy + local control • 55-75% EFS – localized tumors • 20-30% EFS – metastases present at diagnosis • Patients with spine or paravertebral disease have a slightly worse prognosis overall, as well as a higher rate of local failure and tumor recurrence

43. Bone tumors: “Compare & Contrast”

44. Soft Tissue Sarcomas RhabdomyosarcomaMOST COMMON

45. CT/MRI (primary) Helpful to delineate soft tissue planes; pre-surgical evaluation CT (chest) Look for metastatic disease in the lungs (common site of metastases) CT (body) Look for lymph node involvement Bone Scan Look for metastases to bone CT/PET May give helpful information about tumor ‘activity’ and response to therapy Bone Marrow Evaluation Look for metastatic disease Staging Work-Up – What are we looking for?

46. Rhabdomyosarcoma • Malignant tumor of mesenchymal origin, generally in cells of skeletal muscle lineage • Small, round, blue cell tumor • Two main histological types: embryonal and alveolar • About 20% are undifferentiated or have other histological subtypes

47. Incidence and Etiology • 250 US cases/yr; • most <9 • M:F ratio of 1.3:1.0 • higher in industrialized “West” • Histology varies according to age at dx • Associated with familial syndromes such as Li-Fraumeni and neurofibromatosis • Genetic factors may be involved

49. Clinical Presentation • Detected by mass appearance or functional disturbance • ‘systemic’ symptoms are Rare

50. Diagnostic Workup/Staging • H & P • Imaging studies of affected area and to determine mets; used as baseline data • Tumor biopsy is necessary for diagnosis • Formal ‘staging’ to determine ‘risk group’ a combination of • TNM system, classified per tumor histology • IRS Clinical Group Stage System