Osteosarcoma

a lil bit of osteosarcoma

1. Osteosarcoma

2. Osteosarcoma (OS) is a primary skeletal malignancy characterized by spindle cells of mesenchymal origin depositing immature osteoid matrix Osteosarcoma is the most common primary malignancy of bone in children and young adults.

3. Incidence Affects ~1/200,000 population Accounts for 21% of malignant primary bone tumours M:F 2:1 3rd most common malignancy in adolescents, after leukaemia & lymphoma

4. Peak incidence 10-20 yrs (age of rapid growth), with 2nd peak at after 50 yrs (80% <30 & those >40 usually secondary to Paget's)  Epidemiology of conventional osteosarcoma. National Cancer Institute Surveillance, Epidemiology, and End Result Program 1973-2009. Age-adjusted incidence rate and age-specific frequency, all races, both sexes, 4962 cases.

5. 75% occur in distal femur or around knee 90% metaphyseal in long bones 10% present with macroscopic metastatic disease

6. Staging

7. Pathology most commonly diagnosed as  Stage IIB (high grade, extra-compartmental, no metastases) Over 75% of patients present with pulmonary metastases lung is most common site of metastasis bone is second most common site Metastasis via hematogenous

8. Syndrome associated with OS Li– Fraumeni syndrome – Mutation of p53 gene, 30% will have OS. Bloom’s syndrome, Werner’s syndrome, and Rothmund Thomson syndrome - Loss of RecQ helicases that unwind DNA Retinoblastoma - loss of RB1 in13q14 microdeletion cause Loss of pRb which induces unregulated cell cycle progression

9. Poor prognostic factors Advanced stage of disease (most predictive of survival) Response to chemotherapy (as judged by percent tumor necrosis of resected specimen) Tumor site and size Expression of P-glycoprotein High serum alkaline phosphatase   High lactic dehydrogenase Neurovascular involvement Surgical margins E xpression of multi-drug resistance (MDR) gene tends to have a poor prognosis - tumor cells can pump chemotherapy out of cell with MDR expression present in 25% of primary lesions and 50% of metastatic lesions

10. Types Intramedullary (classical) osteosarcoma (75%) Surface/ juxtacortical osteosarcomas (1-6%) Parosteal osteosarcoma Periosteal osteosarcoma Telangiectatic/giant cell/small cell osteosarcoma Secondary osteosarcomas Paget’s (not well understood) Post-radiation (DNA damage)

11. Clinical Pain which is constant & worse at night May have a tender lump which may lack a definite edge & may be attached to muscle Restricted ROM, pain with weight bearing If vascular may pulsatile & feel warm Be aware of # following minimal trauma as if secondary to osteosarcoma often -> late diagnosis of tumour (5 to 10%) Constitutional sx – advance disease and not sensitive in children

12. Radiology X-ray Variable with combination of bone destruction & bone formation 25% lytic 35% sclerotic 40% mixed Wide zone of transition, cortical breach common Sun ray spicules (radial ossification) & Codman's triangle (lifting of periosteum) Adjacent soft tissue mass Joint space rarely involved

13. CT scan CT is inferior to MRI To detect radiographically occult pulmonary metastasis

14. MRI will clearly demonstrate the extent of the bone marrow invasion, the presence and size of any soft-tissue mass, and the relationship to surrounding vital structures. Hypointense on T1, hyperintense on T2 and STIR imaging. But most of time, exhibit mixed heterogeneity surrounding peri- tumor edema , and show abundant enhancement with contrast administration. It is important to image the entire bone involved to detect potential skip lesion and accurately plan resection and reconstruction efforts

15. Bone scan or PET scan Both recommended to detect metastatic bone and soft-tissue disease Bone scan is more cost-effective and superior to PET for bony disease PET allows for better detection in soft tissue, and includes the chest and abdomen. Both are effective scanning techniques; the choice made usually varies by institution. An additional advantage of PET is that it may be able to identify tumors with higher metabolic activity and, therefore, higher-grade malignancies

16. Lab Ix Nondiagnostic but high levels of alkaline phosphatase (ALK-P) and lactate dehydrogenase (LDH) have been shown to predict a poorer prognosis

17. Biopsy Biopsy needed for tissue confirmation Can be obtained from Core needle biopsy Open biopsy

18. Histopathology malignant spindle mesenchymal cells with pleomorphic nuclei, scattered mitotic figures, and varying levels of anaplasia (Fig. 3). Immature and disorganized osteoid production is a characteristic hallmark and must be present for diagnosis. Classical osteosarcomas matrix dominated by osseous, cartilaginous or fibrous elements. (50% -> osteoblastic, 25% -> chondroid, 25% -> fibroblastic)

19. Treatment Untreated -> 95% death in 2 years 10% have macro-metastasis and 90% micro-metastasis at presentation Consider osteosarcoma as systemic disease, therefore Remove primary site by en bloc excision Treat microscopic disease by chemotherapy Even with metastatic (Stage 3) disease 5 years survival now 30-40% (10-20% with surgery alone) Multiagent chemo -> survival rate up to 60%

20. Chemotherapy Multi-agent chemotherapy has significant impact on limb salvage & disease-free survival for osteosarcoma Commonly used agents include doxorubicin, cisplatin, high-dose methotrexate, ifosfamide , cyclophosphamide Methotrexate -> 80% response T10 regimen (methotrexate, vincristine, adriamycin ) -> 60-75% survival 45% of patients with T10 regimen -> 100% kill rate -> 100% survival Survival >10 yrs = cure Neo-adjuvant chemotherapy x 8-12/52 (3 cycles) Good response to chemotherapy is indicated by 90% tumor necrosis on biopsy Regimen continued postop or changed to cisplatin depending on histology Chemotherapy continues for 1 yr

21. Radiotherapy Indication Palliation of local pain, to treat surgically inaccessible lesions and painful metastatic deposits Relatively radio-resistant tumour but radiotherapy may also be used preop to decrease size & vascularity of tumour Prophylactic irradiation of chest has not been shown to be effective

22. Surgery Limb Salvage vs amputation No difference in local recurrence rate Better quality of life with limb salvage Better 5 years survival rate Limb salvage require: Preserve nerves Preserve or reconstruct vessels Preserve sufficient muscle for functional motor power & soft tissue coverage Achieve safe, tumour -free margins (wide) Reconstruction options Autografts/Allografts Endoprosthesis Combination

23. A 13-year-old girl presents with right thigh pain and constitutional symptoms for 8 weeks. The patient's serum LDH and alkaline phosphatase are elevated. A radiograph of the right femur is shown in Figure A. Computed tomography (CT) of the chest reveals no pulmonary metastases. Magnetic resonance imaging (MRI) of the right femur shows erosion of the tumor through the cortex into the adjacent soft tissue, but no skip lesions are seen. A biopsy specimen is shown in Figures B and C. What stage does this patient's case most appropriately represent using the Enneking Staging System for Musculoskeletal Tumors ? Ia Ib IIa IIb III

24. A 13-year-old girl presents with knee pain for 2 months especially at night. She denies fevers and weight loss. Her physical exam reveals a painful thigh mass. A radiograph is shown in Figure A. What is the next most appropriate step in management? A. Repeat radiographs in 3 months with observation B. External beam radiation and chemotherapy C. Surgical biopsy and culture directed intravenous antibiotics D. Neoadjuvant chemotherapy followed by wide excision and adjuvant chemotherapy E. MRI of the entire bone, whole body bone scan and CT chest

25. A 24-year-old male presents with increasing knee pain over the last 6 months. He reports that he sustained a non-contact twisting injury to the knee 7 months ago while playing softball. His knee range of motion is full and his knee is stable to varus and valgus at 0 and 30 degrees of knee flexion. There is a grade 1 Lachman examination. A radiograph is shown in Figure A. A biopsy is performed and is shown in Figure B. What is the most appropriate definitive management? A. Reassurance and observation in 6 months with repeat knee radiographs B. Neoadjuvant external beam radiation, wide surgical resection, and adjuvant chemotherapy C. Wide surgical resection D. Neoadjuvant chemotherapy, wide surgical resection, adjuvant chemotherapy E. Neoadjuvant chemotherapy, marginal surgical resection, adjuvant chemotherapy