SUMMARY Conventional intramedullary osteosarcomas are malignant, aggressive, osteogenic bone tumors most commonly found in the knee and shoulder regions. Patients are typically children, teenagers or young adults who present with rapidly progressive pain and swelling. Diagnosis is made with a biopsy showing malignant-appearing mesenchymal spindle cells with significant atypia, pleomorphism and mitotic figures producing lace-like woven bone (osteoid). Treatment is usually neo-adjuvant chemotherapy, limb sparing surgery (wide surgical resection and reconstruction), followed by adjuvant chemotherapy. Amputation may occasionally be required. Epidemiology Incidence most common type of osteosarcoma incidence first peak (adolescents): 7-8 cases per million second peak (elderly): 4.2 cases per million prevalence approximately 2.4% of all pediatric cancers Demographics age usually occurs in children and young adults login to view 6 more bullets gender male:female = 1.5:1 (overall) login to view 1 more bullet race more common in Black/Hispanic patients compared to White patients Location primarily arises from metaphyseal region of long bones of the appendicular skeleton 10% occur in the diaphysis most common sites are login to view 4 more bullets less common sites login to view 3 more bullets ETIOLOGY Genetics most cases are sporadic and not associated with an underlying genetic predisposition or familial inheritance some cases are associated with tumor suppressor genes (AD inheritance) including Retinoblastoma tumor suppressor gene (Rb) predisposes to osteosarcoma P53 tumor suppressor gene mutations (ie patients with Li-Fraumeni syndrome) predisposes to a high incidence of breast cancer and osteosarcoma login to view 1 more bullet Associated conditions Retinoblastoma Li-Fraumeni syndrome Rothmund-Thomson syndrome AR inheritance, mutations in RECQL4 gene sun-sensitive facial poikiloderma rash (pigmentation, thinned skin, prominent blood vessels), alopecia, juvenile cataracts, dental abnormalities increased risk osteosarcoma, fibrosarcoma, gastric adenocarcinoma, cutaneous BCC and SCC Bloom syndrome AR inheritance, mutations in BLM gene associated with UV-induced facial rash, short stature, insulin resistance, and sparse subcutaneous fat increased risk of osteosarcoma, leukemia, lymphoma, GI tumors Werner syndrome AR inheritance, mutations in WRN gene referred to as "adult progeria" characterized by premature aging, osteoporosis, cataracts increased risk of osteosarcoma Fibrous dysplasia more common in the polyostotic form PRESENTATION Symptoms pain and swelling are the usual initial presenting symptoms night pain and pain at rest are common often dismissed as a sports injury the median time of onset of symptoms to diagnosis is 4 months Physical exam inspection swelling palpable mass tenderness to palpation over area of concern motion may have decreased range of motion if large soft-tissue mass is present neurovascular can cause nerve or vascular compression with mass effect provocative tests pain with axial loading if lower extremity lesion CLASSIFICATION Grading and Staging Classification most commonly diagnosed as MSTS Stage IIB (high grade, extra-compartmental, no metastases) approximately 90-95% of conventional osteosarcomas are high-grade and penetrate cortex early to form soft tissue masses metastasis 20-25% of patients present with radiographically detectable metastases (Enneking Stage III) login to view 7 more bullets Osteosarcoma Subtypes Osteosarcoma Subtype Classification INTRAMEDULLARY High-grade Conventional Osteosarcoma (this topic) May consist of many different tissue types such as cartilaginous tissue, fibrous tissue, giant cells and small round blue cells; can be sub-typed accordingly Telangiectatic Osteosarcoma Histology is similar in appearance to aneurysmal bone cyst, with blood-filled cavities and sinusoids with scant osteoid production in the walls of the cystic cavities Small-cell Considered a histologic combination of Ewing sarcoma and osteosarcoma; small round blue cells with immature osteoid production Low-grade Fibrous dysplasia-like High-volume fibrous stroma with immature osteoid production Desmoplastic fibroma-like Low-volume fibrous stroma with immature osteoid production SURFACE High-grade Dedifferentiated surface Intermediate-grade Periosteal Osteosarcoma Osteosarcoma coming from between surface of bone and inner layer of periosteum Low-grade Parosteal Osteosarcoma Surface osteosarcoma coming from outer layer of periosteum INTRACORTICAL Intracortical osteosarcoma is the rarest type of bony osteosarcoma EXTRASKELETAL Extraskeletal is the rarest subtype (<5% of all osteosarcomas), and is generally considered a soft tissue sarcoma treated with wide resection and radiation. Imaging Radiographs recommended views AP and lateral X-rays of the entire bone findings medullary and cortical bony destruction usually with a soft tissue mass login to view 1 more bullet periosteal reaction (Codman's triangle) characteristic blastic lesion login to view 3 more bullets in skeletally immature patients, most tumors do not extend past the epiphyseal plate 10% present with pathologic fracture CT indications chest CT required at presentation to evaluate for pulmonary metastases CT of extremity may help detect subtle mineralization not visualized on an Xray MRI indications used to determine login to view 4 more bullets recommended views obtain with and without contrast must include the entire involved bone Bone scan indications useful to evaluate the extent of local disease and the presence of bone metastases technetium Tc-99m bone scan or FDG-PET scan can identify skip lesions findings very hot PET-CT indications no clear role for PET-CT imaging in osteosarcoma potential uses include correlating percent necrosis to standard uptake values (SUVs) in pre- and post-chemotherapy settings to see the most metabolic portion of the lesion for optimal biopsy location findings can differentiate between benign and malignant pulmonary nodules depending on size STUDIES Labs serum labs lactate dehydrogenase (LDH) alkaline phosphatase (ALP) login to view 2 more bullets Invasive studies biopsy indications login to view 3 more bullets histology characteristics of conventional intramedullary osteosarcoma login to view 2 more bullets may have mixed histology with different combinations of chondroblastic, osteoblastic, or fibroblastic-looking cells login to view 6 more bullets Diagnosis Diagnosis depends on 2 histological criteria tumor cells produce osteoid stromal cells are frankly malignant Differential Osteosarcoma Differential NON-NEOPLASTIC Radiographic Presentation Characteristic Histology Treatment Osteomyelitis Imaging findings lag by 2 weeks; 50% bone loss before evident on plain X-ray Bone lucency, sclerotic rim, osteopenia, periosteal reaction May present with sequestrum, involucrum, or Brodie's abscess Live osteocytes with numerous neutrophils (acute) No nuclei in osteocytes with fibrosis of marrow and lymphocytic infiltrate (chronic) IV antibiotics, irrigation + debridement BENIGN Eosinophilic granuloma Most common in children ages <20 years, "great mimicker" Well-defined intramedullary lytic lesions with cortical destruction and periosteal reaction Metaphyseal lesions that do not cross the physis Vertebra plana, hyperkyphosis Multiple lytic cranial lesions Langerhans cells, giant cells Lack nuclear atypia and atypical mitoses Observation if asymptomatic Bracing (corrects deformity in 90% of patients) Steroid injections (symptomatic lesions) Chemotherapy (diffuse HSC) MALIGNANT Osteosarcoma Medullary/cortical bony destruction with soft tissue mass, periosteal reaction Usually mixed blastic/lytic Tumor cells produce "lacey" osteoid Stroma appear malignant with high nucleus-to-cytoplasm ratio, abnormal mitotic figures Wide resection + chemotherapy Ewing Sarcoma Most common at age <20 years, peak incidence 10-15 years Large destructive lesion with ill-defined, permeative, moth-eaten appearance, periosteal reaction, and associated soft tissue mass Sheets of monotonous small round blue cells with high nucleus-to-cytoplasm ratio Wide resection + chemotherapy Dedifferentiated chondrosarcoma Bimorphic appearance Aggressive appearing unmineralized mass (spindle component) adjacent to a mineralized chondroid tumor, often with soft tissue mass Chondrosarcoma component adjacent to high grade spindle cell component (usually osteosarcoma, fibrosarcoma, MFH) with abrupt transition between the two Wide resection + chemotherapy Fibrosarcoma Usually older patients age >55 years Ill-defined, purely lytic lesion; permeative bone destruction resembling osteosarcoma Atypical spindle cells in a herringbone pattern, resembling soft tissue sarcoma Wide resection + chemotherapy Rhabdomyosarcoma Nonspecific soft tissue density, isointense to adjacent muscle on T1, hyperintense on T2 >20% with adjacent bony destruction Small round blue cells (embryonal) Aggregates of poorly differentiated round cells with multinucleate giant cells surrounded by dense fibrous septae (alveolar) Wide resection + chemotherapy (pediatric) or radiation (adults) Desmoplastic fibroma Most common in ages 15-25 years Purely lytic, soap-bubble appearance with endosteal scalloping Possible soft tissue mass Dense swirling fibrous spindle cells, mature fibroblasts without cellular atypia, abundant bundles of collagen Wide resection Leukemia (acute lymphoblastic) Peak incidence at age 4 years Diffuse osteopenia, metaphyseal bands, periosteal reaction, lytic lesions, mixed sclerosis/lysis, permeative destruction Increased cellularity packed with blasts and variable number of granulocytic/monocytic cells and erythroid precursors Chemotherapy Lymphoma Most common in ages 35-55 years Ill-defined diffuse lytic lesions with mottled appearance, more common in diaphysis, "ivory" vertebrae Extensive marrow involvement with large soft tissue mass Mixed small round blue cell infiltrate (different sizes and shapes) Diffuse infiltration of trabeculae Multi-agent chemotherapy +/- local irradiation Secondary sarcoma Tumor-specific Tumor-specific Wide resection + chemotherapy Treatment Operative limb salvage resection and chemotherapy indications login to view 10 more bullets chemotherapy login to view 3 more bullets techniques login to view 19 more bullets outcomes login to view 6 more bullets amputation and chemotherapy historically the standard of care login to view 1 more bullet indications login to view 5 more bullets Technique Chemotherapy login to view 1 more bullet administration preoperative (neoadjuvant chemotherapy) given for 8-12 weeks followed by maintenance chemotherapy for 6-12 months after surgical resection restage the lesion following neoadjuvant chemo (X-Ray, MRI, CT chest, Bone scan) Chemotherapy Agents used to Treat Osteosarcoma Mechanism Side effects Methotrexate Inhibits DNA synthesis by inhibiting dihydrofolate reductase myelosuppression; mucositis Doxorubicin Blocks DNA/RNA synthesis by inhibiting topoisomerase II Cardiotoxicity Cisplatin DNA disruption by covalent binding renal failure, hearing loss, neurotoxicity Ifosfamide DNA-alkylating agent renal failure, hemorrhagic cystitis Limb salvage resection resection surgical algorithm if restaging suggests that lesion is resectable, then perform wide excision login to view 10 more bullets endoprosthetic reconstruction approach login to view 1 more bullet technique login to view 5 more bullets complications login to view 4 more bullets rotationplasty approach login to view 2 more bullets techniques login to view 10 more bullets Amputation technique above-knee amputation below-knee amputation forequarter amputations for rare sites of presentation Radiation indications conventional intramedullary osteosarcoma is a radioresistant tumor, therefore radiation is not indicated except in selected cases login to view 2 more bullets palliative control login to view 1 more bullet extraskeletal osteosarcoma is an exception, which is radiosensitive with reduced local recurrence rates COMPLICATIONS Endoprosthetic reconstruction Prosthetic joint infection incidence login to view 1 more bullet no benefit to extended (5-days) antibiotic prophylaxis compared to one-day risk factors login to view 2 more bullets Aseptic loosening incidence login to view 3 more bullets Allograft or autograft fracture osteoarticular allografts have notoriously been associated with early infection, fracture, joint degeneration and nonunion risk factors login to view 1 more bullet Allograft or autograft fracture/nonunion chemo, radiation, extracorporeal treatment of autograft bone are all risk factors Reoperation primary malignant bone tumor higher reoperation rate than benign aggressive use of NPWT associated with increased reoperation rate (but not infection rate) Rotationplasty arteriovenous occlusion requires immediate exploration nonunion of the osteotomies revision ORIF with augmentation malrotation revision ORIF with rotational correction osteotomy deep infection complications/ulcers with prosthetic wear Amputation secondary to limb salvage failure wound healing contractures neuroma formation phantom limb symptoms deep/superficial infection Prognosis 5-year survival without detectable metastases at the initial presentation approximately 65% with standard treatment of pre/post-operative chemotherapy and wide resection login to view 7 more bullets with detectable metastases at initial presentation approximately 15-20% with detectable pulmonary metastases at initial diagnosis login to view 1 more bullet patients who present with or develop pulmonary mets can often be treated with pulmonary metastatectomy bone metastases are considered incurable Poor prognostic factors include advanced stage of disease most important predictor of survival ~30% 5-year survival with aggressive treatment of late (>1 year) pulmonary metastasis with thoracotomy skip lesions occur in 10% of patients login to view 1 more bullet response to neoadjuvant chemotherapy judged by percent tumor necrosis of resected specimen >90% necrosis is a good prognostic indicator age > 40 at time of diagnosis males tumor site and size expression of P-glycoprotein VEGF overexpression high ALP/LDH significantly high LDH on initial labs may indicate the presence of metastases vascular involvement positive surgical margins