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 bimodal distribution first peak in second decade of life (10-14 years of age is most common) 75% diagnosed before age 20 ossification centers more active during puberty/adolescence which may predispose this age group second peak in patients over 65 usually secondary to underlying conditions such as Paget's disease, extensive bone infarcts, prior osteochondromas/osteoblastomas, and prior radiation gender male:female = 1.5:1 (overall) males have a longer period of growth 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 distal femur proximal tibia proximal humerus these are the most rapidly growing sites of the body and are at highest risk for malignant transformation less common sites proximal femur pelvis jaw and skull 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 main genetic characteristic is chromosomal instability 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) lung is most common site of metastasis (~80%) bone is second most common site (16%) bone metastases rare without pulmonary metastases (5% of bone metastases occur without detectable lung metastases) patients can also present with synchronous bone lesions without pulmonary metastases (multicentric osteosarcoma) skip metastases intraosseous skip metastases: within the same bone, usually proximal to the main tumor trans-articular skip metastases: cross the joint 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 large soft-tissue mass evidenced by soft-tissue shadow periosteal reaction (Codman's triangle) characteristic blastic lesion "sunburst" or "hair-on-end" pattern of matrix mineralization usually mixed blastic and lytic but may be purely blastic or purely lytic ossification (mineralized osteoid) usually detectable in tumor/bone or soft tissue mass 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 soft tissue and neurovascular involvement extent of the tumor for safe resection level presence of skip metastases if skip metastases are found, this is equivalent to metastatic (stage III) disease 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) elevated ALP and LDH can suggest more aggressive disease elevated secondary to bone metabolism/osteoblastic activity from aggressive malignancy Invasive studies biopsy indications required for diagnosis improper biopsy techniques are associated with increased rates of complications, especially the need for an amputation biopsy should be performed by the surgeon responsible for definitive treatment of the sarcoma, or after discussion with the definitive surgeon histology characteristics of conventional intramedullary osteosarcoma tumor cells show significant atypia and produce "lacey" osteoid (woven bone) stromal cells show malignant characteristics with atypia, high nuclear-to-cytoplasmic ratio, and abnormal mitotic figures may have mixed histology with different combinations of chondroblastic, osteoblastic, or fibroblastic-looking cells depends on the subtype of conventional intramedullary osteosarcoma numerous subtypes of intramedullary osteosarcoma main types include conventional (numerous subtypes depending on presence of other tissues such as cartilage, fibrous, giant cells, small round blue cells), telangiectatic osteosarcoma, and low grade intraosseous giant cells may be present in giant cell-rich conventional osteosarcoma often confused with giant cell tumor (GCT) of bone GCT of bone does not display the degree of cellular atypia or osteoid production 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) 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 cellslack nuclear atypia and atypical mitoses 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 high-grade conventional intramedullary osteosarcoma also indicated for other high-grade osteosarcoma (e.g., telangiectatic intramedullary osteosarcoma) pathologic fracture can undergo limb salvage if the fracture is stabilized throughout neoadjuvant chemotherapy (ex-fix or cast) safe if patient has good response to preoperative chemotherapy (overall survival same as amputation or limb salvage without pathological fracture) indications of good response to preoperative chemotherapy fracture healing decrease in pain and swelling decreasing increasing radiographic ossification of the tumor angiogram shows absence of a tumor vascular blush (indicates tumor death) chemotherapy agents standard chemotherapy is methotrexate, doxorubicin (adriamycin), cisplatin, +/- ifosfamide multi-agent chemotherapy with MAP therapy is superior to single-agent chemotherapy surgical techniques endoprosthesis reconstruction indications salvageable limb after reconstruction reconstruction options metallic endoprosthesis, autograft, allograft or composite allograft and prosthesis dependent on patient, tumor location and surgeon plan choice of reconstruction should ideally be reliable and minimize complications restore function and mobility. enable patient to resume adjuvant chemotherapy postoperatively as soon as possible (preferably within 2 weeks of surgery) rotationplasty indications sarcomas of the hip, femur, knee, proximal tibia failed limb salvage with intact distal leg proximal femoral focal deficiency (PFFD) recommended in cases that limb sparing surgery would result in a dramatic leg length discrepancy it is not utilized when an amputation would be indicated because of extensive disease and neurovascular involvement advantages optimizes the patient's function and is most commonly done in a pediatric population disadvantages cosmetic concerns as foot is turned backwards so the ankle can function as a knee outcomes >90% necrosis after neo-adjuvant chemotherapy is good prognostic sign 85% 5 year survival with good response to preopchemotherapy expression 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 overall survival in osteosarcoma is equal after limb salvage vs. amputation amputation and chemotherapy historically the standard of care with improved chemotherapy and surgical techniques, this is now typically reserved for failure of limb salvage indications the only absolute indication for amputation is when a functional AND disease-free extremity cannot be achieved with limb salvage encasing neurovascular bundle enlarging during preop chemo AND adjacent to neurovascular bundle inappropriately performed biopsy contaminating important tissues or neurovascular structures. infected tumor Technique Chemotherapy 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 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 positive margins good response to preoperative chemo (<10% viable tumor on postop pathology; >90% tumor necrosis) continue same neoadjuvant chemo regimen, consider additional resection +/- radiation inadequate response to preoperative chemo (>10% viable tumor on postop pathology; <90% tumor necrosis) consider alternative neoadjuvant chemo regimen, additional resection +/- radiation negative margins good response to preoperative chemo (<10% viable tumor on postop pathology; >90% tumor necrosis ) continue same neoadjuvant chemo regimen, no further resection required inadequate response to preoperative chemo (>10% viable tumor on postop pathology; <90% tumor necrosis) continue same neoadjuvant chemo regimen or consider alternative regimen, no further resection required endoprosthetic reconstruction approach dependent on location with goals including safe resection margins with adequate proximal or distal bone for stable fixation of the implant technique most megaprostheses are cemented implants, however, press-fit options are available once wide resection is complete, preparation of the canal is completed through sequential reaming until appropriate fit is realized for cemented implants, it is common practice to ream 1-2mm over selected implant size to accommodate cement mantle implant length should equal resection length, may have to resect more bone if necessary so the limb is not over-lengthened utilize good pressurized cement technique and notify anesthesia of pressurization due to the risk of embolization complications deep infection aseptic loosening soft tissue failures example: extensor mechanism in proximal tibia megaprosthesis rotationplasty approach multiple approaches utilized based on the location of the tumor and the planned resection goal is to have the rotated ankle at the same level of the contralateral knee at skeletal maturity techniques must first have functioning sciatic nerve AND planned resection does not involve resection of any part of the sciatic nerve the lower leg's posterior and anterior compartments now function at the quadriceps and hamstring equivalents, respectively multiple described incisions, most commonly used is two "fish mouth" style incisions on the thigh and leg that can accommodate one another after 180deg rotation is made posterior thigh/knee approached first with dissection of the neurovascular structures and release of the gastrocnemius insertion off the distal femur must keep sural artery branches intact off popliteal artery to maintain perfusion to the gastrocnemius muscle bellies transect soft tissues/musculature of anterior and medial compartments to the level of the femoral osteotomy, keeping neurovascular structures in continuity femoral osteotomy and tibial osteotomies are made and the intercalary segment is removed and sent to pathology as it contains the resected specimen the distal segment is rotated externally 180 degrees and secured proximally using IMN, plate and screws or external fixation the quadriceps remnant is sutured to gastrocsoleus complex and hamstrings to tibialis anterior and peroneal muscles neurovascular structures are coiled and tucked into anteromedial thigh pouch 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 JNK-mediated cellular apoptosis is a known cellular mechanism in response to ionizing radiation osteosarcoma routinely expresses NFkB, which is an INHIBITOR of the JNK radiation-induced apoptosis pathway and is thus a radioresistant tumor palliative control usually reserved for palliative control in inoperable primary tumors, metastatic sites or after resection of selected tumors with close margins especially pelvic and spine tumors extraskeletal osteosarcoma is an exception, which is radiosensitive with reduced local recurrence rates COMPLICATIONS Endoprosthetic reconstruction Prosthetic joint infection incidence occurs in 2-10% of patients after reconstruction no benefit to extended (5-days) antibiotic prophylaxis compared to one-day risk factors increased operative time (≥8 hours) prolonged drain use (≥14 days) Aseptic loosening incidence occurs in approximately 6% of patients depending on anatomic site most common reason for reconstruction failure tibia most common site of mechanical failure Allograft or autograft fracture osteoarticular allografts have notoriously been associated with early infection, fracture, joint degeneration and nonunion risk factors usually occurs at the native bone-graft junction as this is the weakest point 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 85% with good response to preoperative chemotherapy 65% with localized osteosarcoma in an extremity 55% with localized pelvic osteosarcoma pelvic disease inherently more aggressive higher rates of metastatic disease on presentation larger size higher rates of local recurrence (up to 44%) despite negative margins with detectable metastases at initial presentation approximately 15-20% with detectable pulmonary metastases at initial diagnosis 15-25% who present with pulmonary metastases that can be removed 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 prognosis is similar to that of patients with lung metastases 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