Osteosarcoma & Ewings

Osteosarcoma & Ewings Sarcoma clinical features, diagnosis and management.

1. Osteosarcoma & Ewing's Sarcoma Dr. Mirant Dave

2. Topics Covered Introduction Patient Presentation Genetic Basis Classification Radiological Findings Biopsy Management Prognosis Case Report

3. Osteosarcoma Characterized by the production of Osteoid by Malignant Cells.

4. Most common Second Most Common Primary Malignant Tumor of Bone, accounting for approximately 20% of primary bone cancers. Most Common Bone Tumor Multiple Myeloma (40%) M>F Onset Primary high-grade - Second decade of life Par- osteal - Third and Fourth decades Secondary (Paget disease or previous radiation therapy) - Older individuals Campbell 13 th Ed.

5. Patient Presentation High Grade – Progressive Pain, Short Duration Night Pain – Important Clue (25% Patients) Swelling Low Grade – Painless Mass Pathologic fractures are not particularly common Tumor spread to the lungs only rarely results in respiratory symptoms and usually indicates extensive lung involvement

6. Clinical Examination Mass - A palpable mass may or may not be present; the mass may be tender and warm, though these signs are indistinguishable from osteomyelitis; increased skin vascularity over the mass may be discernible; pulsations or a bruit may be detectable Decreased range of motion - Involvement of a joint Lymphadenopathy - Involvement of local or regional lymph nodes is unusual Respiratory findings - Auscultation is usually uninformative unless the disease is extensive

7. Study on average delay in diagnosis The average delay from the onset of symptoms to the correct diagnosis was approximately 15 weeks in one study. The average patient delay of 6 weeks (the time between the onset of symptoms and initial physician encounter) The average physician delay of 9 weeks (the time from the first visit to the correct diagnosis) Failure to obtain radiographs at the initial visit Failure to repeat the radiographs when a patient’s symptoms persisted or worsened. Campbell 13 th Ed.

8. Genetic Basis Very Rare More Common in Retinoblastoma (i nvolves specific somatic loss of constitutional heterozygosity for the region of human chromosome 13 that includes the RB1 locus) Rothmund -Thomson syndrome ( Patients with RTS due to genetic mutations of  RECQL4  genes carry a high risk of developing osteosarcoma during childhood) Li-Fraumeni syndrome ( a hereditary cancer predisposition syndrome that is commonly associated with a germline mutation in the tumor suppressor gene  p53)

9. Skeletal Locations All skeletal locations can be affected Most occur at the sites of Rapid Bone Growth Distal Femur Proximal Tibia Proximal Humerus Most common - aggressive lesion in the Metaphysis of a long bone. 10% are primarily Diaphyseal & <1% are primarily Epiphyseal.

10. Types Primary Osteosarcomas Conventional (M/C) Telangiectatic Small Cell Osteosarcoma Low-grade Intramedullary High-grade Surface Par- osteal Periosteal Secondary osteosarcoma (10 to 15 Years) Paget Disease Previous Radiation Therapy Fibrous Dysplasia

11. Types Synchronous Osteosarcoma Multiple sites may become apparent within a period of about 6 months Metachronous Osteosarcoma Multiple sites may be noted over a period longer than 6 months

12. Conventional osteosarcoma High-grade tumors Intramedullary location - may break through the cortex - soft-tissue mass. Histologically Osteoblastic Fibroblastic Chondroblastic However, to establish the diagnosis, Osteoid production must be shown. The spindle cell component - hypercellularity, abundant mitotic figures, and marked nuclear pleomorphism

13. Telangiectatic osteosarcoma Purely lytic lesion Radiograph - invasive appearance or ballooned appearance Grossly, resembles a blood-filled cyst – very small solid portion Microscopically, Low power, resembles an aneurysmal bone cyst with blood- filled spaces separated by thin septa Higher-power magnification, the cells in the septa - frankly malignant.

14. Small cell osteosarcoma Rare variant, high- grade lesion Small blue cells (resemble Ewing sarcoma or lymphoma) Small quantity, osteoid difficult to differentiate from the fibrin-like material in Ewing sarcoma Cytogenetic and immunohistochemistry studies needed (The strong IHC expression of SATB2 associated with CD99 immunonegativity and the absence of EWSR1 and FUS gene rearrangements in small cell osteosarcoma argues against the existence of a morphologic/genetic continuum with Ewing sarcoma.)

15. Low-grade intramedullary osteosarcoma Rare type Intramedullary Indolent course - benign features on radiograph (In some patients it can be mistaken radiographically and histologically for an osteoblastoma or fibrous dysplasia) If left untreated - erode through the cortex very late Microscopically, slightly atypical spindle cells producing slightly irregular osseous trabeculae.

16. High-grade surface osteosarcoma Least common type Aggressive tumor , Outer aspect of the Cortex, Medullary involvement early Radiographs - invasive lesion with ill-defined borders Microscopy - hypercellularity, mitotic figures, and marked nuclear pleomorphism

17. Periosteal osteosarcoma Intermediate- grade malignancy Surface of the bone Diaphyses of the femur and tibia Histologically strands of Osteoid-producing Spindle cells radiating between Lobules of Cartilage

18. Parosteal osteosarcoma Rare, Low- grade Surface of the bone, invades the medullary cavity - late stage Peculiar lobulated ossified - Posterior aspect Distal Femur CT Differential Diagnosis Myositis ossificans – Ossification more mature at the periphery of the lesion, Parosteal osteosarcoma - Center is more heavily ossified Osteochondroma - Medullary cavity containing marrow in continuity with the medullary canal of the involved bone. Microscopically, slightly atypical spindle cells producing slightly irregular osseous trabeculae.

19. Secondary osteosarcomas Rare in young patients, but almost half of the osteosarcomas in patients >50 years. Paget disease Incidence approximately 1% and may be higher (5% to 10%) for patients with advanced polyostotic disease. Sixth to Eighth decades of life Pelvis M/C

20. Secondary osteosarcomas Radiation-associated Approximately 1% of patients, >2500 cGy Unusual locations, skull, spine, clavicle, ribs, scapula, and pelvis. Osteosarcoma M/C (fibrosarcoma and malignant fibrous histiocytoma can also occur) 10 to 15 years after radiation exposure but may occur 3 years to several decades after treatment. Other conditions associated fibrous dysplasia, bone infarcts, osteochondromas, chronic osteomyelitis, melorheostosis , and osteogenesis imperfecta

21. X-ray Identification Lesion – Blastic /Sclerotic OR Lytic OR Mixed More commonly - Areas of bone production and bone destruction Permeative , borders are ill defined Broken through the cortex => a Soft-Tissue mass Periosteal reaction - Codman triangle/Sunburst/Hair-on-end appearance

22. Types of Bone destruction Geographic Bone Destruction Moth-eaten Appearance Permeative Bone Destruction

23. MRI The best imaging modality to measure the Extent within the bone & soft tissue Determine relationship to nearby anatomic structures Superior to CT for evaluation of invasion of muscle, neurovascular structures, adjacent fat planes and the degree of marrow involvement Superior in assessing intra-articular extension and the presence of intra-tumoral necrosis and hemorrhage Osteosarcoma lesion is usually dark on both T1W and T2W images because of the osseous matrix

24. Bone Scan/PET Scan Skeletal Metastases Its ability to detect multicentric disease, soft tissue involvement and viability of tumor are invaluable aids in the management of such tumors as osteosarcoma, Ewing’s family of tumors

25. CT Scan In tumor imaging, CT is useful for both detection and characterization. Detection of tumors in flat bones and bones with complex anatomy is best done with CT, especially in bones such as the scapula, ribs, pelvis. The matrix is also well seen with CT, especially when it is necessary to differentiate osseous from chondroid matrices. CT is superior to MRI in the detection and characterization of matrix mineralization, cortical involvement and periosteal reaction CT is useful to check for Pulmonary Metastases Soft tissue Window - Compartment Affected (MRI being too sensitive) Bony Window – Bone Cortex

26. Biopsy Biopsy diagnosis is mandatory Biopsy to be done only after all local imaging is completed In most cases a core needle biopsy is adequate ( it may need to be image guided depending on anatomical location of lesion) Ideally performed at centre which will do definitive management of disease

27. Biopsy Two types of biopsy, percutaneous and open, may be used to confirm the diagnosis. Large soft-tissue mass, a true-cut needle biopsy of the soft tissue may be an adequate biopsy. When there is not a large soft-tissue mass, a Craig needle or small trephine can be used to obtain an adequate specimen. Open biopsy will yield more tissue for biologic studies and will facilitate biopsy of both the soft tissue and the bone. The biopsy incision must be placed in line with the eventual definitive resection because it will need to be excised when the definitive treatment is performed.

28. Laboratory Studies Though there are no specific laboratory tests for diagnosis some maybe of prognostic value; e.g. alkaline phosphatase (ALP) and lactate dehydrogenase (LDH)

29. Osteosarcoma Proximal Humerus A 6-year-old female presents with a 2-month history of pain in her right shoulder. This pain has become increasingly severe, and she is now no longer using her arm normally. X- ray at presentation included a plain film of the humerus . Orthopedic Oncology by Ernest Conrad Thieme

30. Osteosarcoma distal femur A 10-year-old boy presents with a 3-month history of a painful left knee. Before the onset of his pain, he was a fully functional youth, riding horses and working on his parents’ ranch. He now presents in a wheelchair with a painful, swollen left knee; examination is difficult secondary to his extreme pain. Radiographic presentation includes plain X-rays and a magnetic resonance image (MRI) of the knee.

31. Surgical MAnagement Surgery of the primary tumor should be performed only after adequate preoperative staging and planning The goal is to achieve adequate oncologic clearance. Conventionally, quantitative parameters are used to define resection margins. A marrow margin of 3 cms as evaluated on the T1 weighted MRI image is usually considered adequate clearance in bone lesions whereas a 2 cm margin away from the tumor is what most surgeons should aim to achieve in soft tissue lesions

32. Surgical Management Due to anatomical constraints it is not always possible to achieve these absolute distances. The margin can be quantitatively less in the case of resistant anatomic barriers, such as muscular fasciae, periosteum, joint capsule, tendon, tendon sheath, epineurium, vascular sheath and cartilage. Decisions about the optimal surgical procedure (i.e. limb salvage or amputation) should be made on an individual case to case basis depending on various factors (patient’s age, tumor site, size, extent and response to neoadjuvant therapy).

33. NCCN and ESMO- PaedCan -EURACAN Clinical Practice Guidelines for Treatment of Osteosarcoma Guidelines for the treatment of osteosarcoma have been published by the following organizations: National Comprehensive Cancer Network (NCCN)  [30]  European Society for Medical Oncology (ESMO), European Reference Network for Paediatric Cancers ( PaedCan ), and European Network for Rare Adult Solid Cancer (EURACAN)  [31]  Guideline recommendations on treatment of osteosarcoma vary by disease stage.

34. stages IA-IB (low grade) osteosarcomas Localized, low-grade osteosarcomas – The NCCN recommends wide excision alone; chemotherapy prior to excision is not typically recommended but could be considered for periosteal lesions  Low-grade intramedullary and surface osteosarcoma and periosteal sarcomas with pathological findings of high-grade disease – The NCCN recommends postoperative chemotherapy  [30]  ; ESMO- PaedCan -EURACAN recommends surgery alone for low-grade parosteal osteosarcomas, and finds no benefit for chemotherapy for periosteal lesions   Unresectable or incompletely resected osteosarcoma – The NCCN and ESMO- PaedCan -EURACAN guidelines concur that combined photon/proton or proton beam radiotherapy for local control is an option

35. Stages IIA-IVB (high grade) and metastatic disease Preoperative chemotherapy is recommended for all stages of high-grade disease (category 1) If good margins can be achieved, limb-sparing surgery is preferred for patients with good histologic response to chemotherapy; amputation for tumors in unfavorable anatomical locations Postoperative chemotherapy should continue with preoperative regimen if there has been a good histologic response; for patients with a poor response, consider postoperative chemotherapy with a different regimen Surgical re-resection with or without radiation therapy for positive margins should be considered For unresectable osteosarcomas following preoperative chemotherapy, consider radiation therapy or chemotherapy

36. metastatic disease at presentation For resectable metastatic disease (pulmonary, visceral or skeletal), preoperative chemotherapy followed by wide excision of primary tumor ; chemotherapy and metastasectomy is also a treatment option For unresectable metastatic disease, chemotherapy with or without radiation therapy; reassess primary site for local control ESMO- PaedCan -EURACAN recommends that primary metastatic osteosarcoma be treated with a curative intent, following the principles of non-metastatic osteosarcomas 

37. relapsed or refractory osteosarcoma Re-resection, if possible Clinical trial Palliative radiation therapy or best supportive treatment

38. Chemotherapy regimens For first-line osteosarcoma therapy (primary/neoadjuvant/adjuvant therapy or for metastatic disease), NCCN recommendations are as follows  [30]  : Cisplatin and doxorubicin (category 1) MAP (high-dose methotrexate, cisplatin, and doxorubicin) (category 1) Doxorubicin, cisplatin, ifosfamide , and high-dose methotrexate Ifosfamide , cisplatin, and epirubicin

39. Chemotherapy regimens For second-line therapy (relapsed/refractory or metastatic disease), NCCN recommendations are as follows  [30]  : Docetaxel and gemcitabine Cyclophosphamide and etoposide Cyclophosphamide and topotecan Gemcitabine Ifosfamide (high dose) ± etoposide Ifosfamide , carboplatin, and etoposide High-dose methotrexate, etoposide, and ifosfamide Samarium-153 ethylene diamine tetramethylene phosphonate (SM-EDTMP) for relapsed or refractory disease beyond second-line therapy Radium-223 Sorafenib

40. https:// tmc.gov.in / tmh /PDF/ clinicalguidelines /DOC/BST- Guidelines.pdf

41. https:// tmc.gov.in / tmh /PDF/ clinicalguidelines /DOC/BST- Guidelines.pdf

42. Types of Limb Salvage Autografts Allografts Bone lengthening Endoprosthetic replacement Rotationplasty Arthrodesis

43. Limb salvage Simon described four issues that must be considered whenever contemplating limb salvage instead of an amputation, 1. Would survival be affected by the treatment choice? 2. How do the short-term and long-term morbidity compare? 3. How would the function of a salvaged limb compare with that of a prosthesis? 4. Are there any psychosocial consequences?

44. Long Term Survival Stats Today’s multiple-agent chemotherapy regimens and appropriate surgical treatment, Long-term survival of; 60% to 75% - high-grade osteosarcoma without metastases at initial presentation; 90% - low-grade lesions. Approximately 15% pts - detectable Pulmonary metastases at the time of diagnosis - 20% long term survival (One or a few resectable pulmonary metastases >50% long-term survival; many, large, or unresectable pulmonary metastases, extremely poor prognosis) Non-Pulmonary metastases (e.g., bone metastases) - Worse Prognosis, 5% long- term survival “Skip” metastases (within the same bone as the primary tumor or across the joint from the primary tumor ) - Poor Prognosis Campbell 13 th Ed.

45. Prognosis Grade of the lesion - Low-grade lesions rarely metastasize Size of the primary tumor - Large tumors have a worse prognosis Skeletal location - Proximal tumors do worse ALP High – Poor Prognosis Paget osteosarcomas <15% long-term survival Radiation-associated osteosarcomas - Poor prognosis (unusual locations - resection difficult) Histologic response to neoadjuvant chemotherapy - >90% tumor necrosis - Good Prognosis

46. Surgical Margin

47. Poor prognosis Rapid relapse after completion of the initial treatment Many (more than eight) pulmonary nodules Large (>3 cm) pulmonary nodules Unresectable pulmonary nodules

48. Ewing’s Sarcoma Round Cell Tumor

49. Most common Third most common nonhematologic primary malignancy of bone (after osteosarcoma & chondrosarcoma) (9%) Second most common (after osteosarcoma) in patients <30 years Most common in patients <10 years of age Most common mutation that causes Ewing sarcoma involves two genes, the  EWSR1  gene on chromosome 22 and the  FLI1  gene on chromosome 11 5 – 25 Years Old (M/C) M>F Metaphyses of long bones, Flat bones of the Shoulder, Pelvic Girdles, rarely Spine, small bones of Hand & Feet Campbell 13 th Ed.

50. Patient Presentation Pain – Universal Complaint Onset – Insidious Mild & Intermittent, initially Fever, Erythema, and Swelling, suggesting Osteomyelitis

51. Laboratory tests Increased white blood cell count Elevated erythrocyte sedimentation rate Elevated C-reactive protein level Needle aspirate of Ewing sarcoma – Resemble pus, and the tissue may be sent in its entirety to microbiology and none to pathology. (As a general rule, most biopsy specimens should be sent for culture and pathologic analysis.) Bone Marrow Aspirate – Rule out diffuse systemic disease Immunohistochemistry

52. Study on average delay in diagnosis The average delay from the onset of symptoms to the correct diagnosis was approximately 34 weeks in one study. The average patient delay of 15 weeks (the time between the onset of symptoms and initial physician encounter) The average physician delay of 19 weeks (the time from the first visit to the correct diagnosis) Failure to obtain radiographs at the initial visit Failure to repeat the radiographs when a patient’s symptoms persisted or worsened. Campbell 13 th Ed.

53. X-Ray identification Destructive lesion in the diaphysis of a long bone “Onion skin” periosteal reaction (In reality, Ewing sarcoma more often originates in the metaphysis of a long bone but frequently extends for a considerable distance into the diaphysis) Typical “triad’’ of findings on imaging:, (1) a “diaphyseal’’ location, (2) a “round-cell’’ or “ permeative ’’ appearance (3) an obvious or large soft-tissue mass associated with the tumor Periosteal Reaction – Codman’s Triangle, Sunburst Appearance can be seen

54. MRI Evaluate the full extent of the lesion, which typically extends beyond the abnormality apparent on plain films Extent of the soft-tissue mass MRI is especially useful in demonstrating the large soft- tissue mass surrounding the bone One should be careful to distinguish a true soft-tissue mass from periosteal edema commonly seen on MRI with osteomyelitis.

55. MRI The MRI demonstrates the intramedullary extent of the tumor , which is not easily distinguished on plain radiographs. “Skip’’ metastases are best demonstrated on MRI After chemotherapy, MRI is very useful in demonstrating the reduction in size of the soft tissue component of the tumor , which is an indication of the effective response to preoperative chemotherapy.

56. CT Scan Pulmonary Metastasis (M/C) Bone scan Bone Metastasis (2 nd M/C)

57. PeT scan Fluorodeoxyglucose (FDG) positron emission tomography (PET) is also useful to evaluate the extent of disease. The level of tumor metabolic activity is markedly elevated in Ewing’s sarcoma. The pre treatment FDG PET serves as a baseline for therapy response assessment. A significant decrease in FDG uptake after neoadjuvant chemotherapy may indicate improved response and outcome. The whole body FDG PET can also evaluate the remainder of the body for tumor and metastases.

58. PET SCAN Maximum Standardized Uptake Values ( SUVmax ) Cutoffs for Malignant Pathologic Fracture, SUVmax 12.0 (Range 4 to 45) Benign SUVmax 2.9 (Range 0.6 to 5.5) Malignant Tumors SUVmax 6.8 +- 4.7 Benign Tumors SUVmax 4.5 +- 3.3

59. Biopsy Biopsy diagnosis is mandatory Biopsy to be done only after all local imaging is completed In most cases a core needle biopsy is adequate ( it may need to be image guided depending on anatomical location of lesion) Ideally performed by the same surgeon who will do definitive management of disease Immunohistochemistry confirmation desirable , may need additional cytogenetic and molecular studies

60. Histology Small blue cells with very little intercellular matrix Cytogenetic or immuno- histochemical studies - t(11;22) (q24;q12) is the most common translocation >90% of cases. Other diagnostic translocations, t(21;22)(q22;q12) and t(7;22)(p22;q12) Immunohistochemical staining - MIC-2 gene product specific for Ewing sarcoma Periodic acid–Schiff positive (owing to intracellular glycogen) Reticulin negative

61. Histological D/D Lymphomas Periodic acid–Schiff negative Reticulin positive Stain positive for leukocyte common antigen and other T- and B-cell antigens. Embryonal Rhabdomyosarcoma stains positive for Desmin , Myoglobin, and Muscle-specific actins. Hemangiopericytomas stain positive for Factor VIII Small cell Metastatic Carcinomas & Melanomas stain positive for Cytokeratin. Osteomyelitis (Most Imp) – Fever, Increased ESR, CRP, WBC, Biopsy is diagnostic

62. Ewing’s Sarcoma Midshaft Humerus A 26-year-old male presents for evaluation of a left proximal humerus bone lesion. He states he has had left shoulder pain for more than a year. Recently, the pain became more significant and bothered him at night. He has been taking ibuprofen every 4 h, keeping the pain fairly well controlled. The patient sought the opinion of his primary care physician, who put him on nonsteroidal anti-inflammatory drug (NSAID) for 3 weeks. The patient was referred to physical therapy for treatment of presumed impingement syndrome when NSAIDS did not alleviate pain. He was then referred to a local orthopaedic surgeon, who obtained X-rays at his first appointment and gave him a subacromial steroid injection. The injection did not alleviate the pain and a magnetic resonance image (MRI) of his left shoulder was obtained to evaluate an abnormality on the X-ray. This image showed a bone lesion in his left proximal humerus with soft tissue extension. He was then referred to an orthopaedic oncologist for further evaluation. Orthopedic Oncology by Ernest Conrad Thieme

63. Ewing’s sarcoma femur An otherwise healthy 20-year-old male developed a sudden increasing pain in his right femur. The pain is so severe that he is unable to walk, needs crutches, and requires high doses of narcotics. The pain awakes him from sleep. There is no history of associated trauma. He has not noticed any pal- pable mass nor antecedent pain in his right femur. Of note, he had a prior anterior cruciate ligament reconstruction on his right side, but this procedure was done in the distant past and is unrelated to any of his pain. He has actually had excellent rehabilitation from that procedure and tolerated the procedure well. He has had no associated fever or chills. White count and infectious laboratory work reveal normal sedimentation rate and C-reactive protein (CRP). Anteropos - terior and lateral femur ( Fig. 19–1 and Fig. 19–2 ) films show a lytic lesion of the middiaphyseal region with a sun burst periosteal reaction. Magnetic resonance imaging (MRI) ( Fig. 19–3 and Fig. 19–4 ) revealed a soft tissue mass with a right peritumoral inflammatory zone associated with it. The mass measures approximately 5 × 4 × 3 cm. Computed tomogra - phy (CT) scan shows cortical erosions as well. A chest CT also was performed, showing no obvious pulmonary metastases. A bone scan was ordered as well ( Fig. 19–5 ). Orthopedic Oncology by Ernest Conrad Thieme

64. Chemotherapy Multiple-agent chemotherapy - long-term survival rates of 60% to 75% Agents considered most active in Ewing’s sarcoma include doxorubicin, cyclophosphamide, ifosfamide , vincristine, dactinomycin, and etoposide. Most current protocols are based on four to six drug combinations.

65. Chemotherapy Chemotherapeutic drugs may result in renal, cardiac, and auditory dysfunction in addition to common side effects like myelosuppression, infection and neuropathy. Patients must therefore have baseline renal function testing and assessment of cardiac function as well as an audiogram (in case of treatment with cisplatin). Sperm banking is recommended for male patients of reproductive age while female patients would benefit with counselling by a fertility physician.

66. Radiotherapy Ewing’s sarcoma being a radiation-sensitive tumor , radiotherapy is utilised as part of management. It may be used as definitive local therapy if surgery is not an option, with curative intent or may be used in combination with surgery, for patients who have had a poor histological response to chemotherapy, or when there are concerns regarding surgical resection margins. The dose administered depends on the resection margins and response to chemotherapy. 14-16 Portals are individually tailored for every patient and target volumes are MRI based to include both, the bone and soft tissue component.

67. Radiotherapy Radiotherapy has a definite role in the management of soft tissue sarcomas especially high grade tumors > 5 cms . Radiotherapy may be in the form of intraoperative brachytherapy, external beam radiotherapy or a combination of the two. The dose of external beam radiotherapy can range from 45 Gy when combined with brachytherapy to 70 Gy when external beam radiotherapy alone is used in excisions with macroscopic residual disease.

68. Treatment Radiation Large, Central, Unresectable tumors Wide margins would be Difficult to obtain or Functional Deficit resulting from surgery unacceptable Short term/Long term Risks Surgery Smaller, more Accessible lesions Decrease Soft-tissue mass after Chemo. Amputation/Limb Salvage

69. https:// tmc.gov.in / tmh /PDF/ clinicalguidelines /DOC/BST- Guidelines.pdf

70. https:// tmc.gov.in / tmh /PDF/ clinicalguidelines /DOC/BST- Guidelines.pdf

71. Prognosis Size of the primary tumor - Large tumors have a worse prognosis Skeletal location - Proximal tumors do worse Histologic response to neoadjuvant chemotherapy - >90% tumor necrosis - Good Prognosis Histologic grade is of no prognostic significance (all considered High Grade) Patients who relapse - first year after primary treatment – worse prognosis

72. Surgical Management KAWAGUCHI – Covering layer is important Periosteum equivalent 5 cm Muscle 2 cm Quantity is not imp, Qualitive Matters

73. Lytic Lesions Mixed Lesions Blastic Lesions

74. lytic vs blastic lesions Prostate =  Blastic /Sclerotic (induces bone growth) Breast = Mixed Kidney, Thyroid, Lung = Lytic (induces bone destruction)

75. Thank You