SUMMARY Intramedullary osteosarcomas are malignant, aggressive, osteogenic bone tumors most commonly found in the distal femur or proximal tibia. Patients are typically children or young adults that present with rapidly progressive pain and swelling. Diagnosis is made with a biopsy showing malignant mesenchymal cells with significant atypia and the presence of lacey osteoid. Treatment is usually neo-adjuvant chemotherapy, wide surgical resection, followed by adjuvant chemotherapy. Epidemiology Incidence incidence ~5 cases per 1 million people per year prevalence approximately 2.4% of all pediatric cancers Demographics age bracket usually occurs in children and young adults bimodal distribution of occurrence first peek is the second decade of life (10-14 years of age is most common) the second peak is in patients over 65 seen in those with Paget's disease and those who have received prior radiation male: female ratio males > females race more common in black/hispanic patients compared to white patients Location primarily affects the metaphyseal region of long bones of the appendicular skeleton the most common sites are the distal femur and proximal tibia these are the most rapidly growing sites of the body and are at highest risk for malignant transformation other common sites include the proximal humerus, proximal femur, pelvis, jaw and skull ETIOLOGY Genetics tumor suppressor genes (AD inheritance) 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 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 PRESENTATION Symptoms pain and swelling are the usual initial presenting symptoms 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 neurovascular can cause nerve or vascular compression with mass effect provocative tests pain with axial loading if lower extremity lesion CLASSIFICATION Grading and staging most commonly diagnosed as MSTS Stage IIB (high grade, extra-compartmental, no metastases) approximately 90% of diagnosed osteosarcomas are high-grade 20-25% of patients present with radiographically detectable metastases the lung is the most common site of metastasis (~80%) bone is the second most common site Subtypes Subtypes (Based on histological grade) High-grade intramedullary Conventional Can be sub-classified depending on histology fibroblastic chondroblastic osteoblastic-like giant-cell rich Telangiectatic Histology is similar in appearance to aneurysmal bone cyst with blood-filled sinusoids with osteoid production Small-cell Considered to be a histologic combination of Ewing sarcoma and osteosarcoma as there is small round blue cells with immature osteoid production High-grade surface Dedifferentiated surface osteosarcoma Low-grade intramedullary Fibrous dysplasia-like High-volume fibrous stroma with immature osteoid production Desmoplastic fibroma-like Low-volume fibrous stroma with immature osteoid production Low-grade surface Parosteal ostesarcoma surface osteosarcoma coming from outer layer of periosteum Intermediate-grade surface Periosteal osteosarcoma osteosarcoma coming from between surface of bone and inner layer of periosteum Imaging Radiographs recommended views image entire bone findings characteristic blastic and destructive lesion sun-burst or hair on end pattern of matrix mineralization periosteal reaction (Codman's triangle) large soft-tissue mass evidenced by soft-tissue shadow CT indications chest CT is required at presentation to evaluate for pulmonary metastases MRI with and without contrast recommended views must include the entire involved bone indications used to determine: soft tissue and neurovascular involvement evaluate the extent of the tumor for safe resection level presence skip metastases if skip metastases are found, this is equivalent to metastatic (stage III) disease Bone scan indications useful to evaluate the extent of local disease and the presence of bone metastases findings very hot in osteosarcoma 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 and seeing the most metabolic portion of the lesion for optimal biopsy location findings can differentiate between benign and malignant pulmonary nodules STUDIES Labs serum 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 histology characteristics tumor cells show significant atypia, and produce "lacey" osteoid stroma 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 osteosarcoma numerous subtypes, the main ones include conventional (intramedullary), telangiectatic, surface (parosteal or periosteal), and extraskeletal giant cells may be present in giant cell-rich osteosarcoma often confused with giant cell tumor (GCT) of bone GCT of bone does not display the degree of cellular atypia or osteoid production biopsy required for diagnosis improper biopsy techniques are associated with increased rates of complications biopsy should be performed by the surgeon responsible for definitive treatment of the sarcoma, or after discussion with the definitive surgeon DifferentiaL Osteosarcoma Differential* Destructive bone lesion in young patients Treatment is Wide Resection & Chemotherapy Osteosarcoma (intramed. & periosteal) o o Ewing's sarcoma o o Leukemia o Lymphoma o Eosinophilic granuloma o Osteomyelitis o Desmoplastic fibroma o MFH / fibrosarcoma o Dedifferentiated chondrosarcoma o Secondary sarcoma o Rhabdomyosarcoma (soft tissue) o Treatment Operative neoadjuvant chemotherapy, limb salvage resection, followed by adjuvant chemotherapy indications high-grade osteosarcoma technique chemotherapy preoperative chemotherapy given for 8-12 weeks followed by maintenance chemotherapy for 6-12 months after surgical resection surgical techniques rotationplasty optimizes the patient's function and is most commonly done in a pediatric population endoprosthesis reconstruction metallic, autograft, or allograft dependent on patient and surgeon plan outcomes >90% necrosis after neo-adjuvant chemotherapy is good prognostic sign 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 wide surgical resection alone indications low grade surface osteosarcoma such as parosteal osteosarcoma amputation indications the only absolute indication for amputation is when a functional AND disease-free extremity cannot be achieved with limb salvage pathologic fracture can undergo limb salvage if the fracture is stabilized throughout neoadjuvant chemotherapy (ex-fix or cast) encasing neurovascular bundle enlarging during preop chemo AND adjacent to neurovascular bundle Technique Chemotherapy technique standard chemotherapy is methotrexate, doxorubicin (adriamycin), and cisplatin (MAP therapy) multi-agent chemotherapy with MAP therapy is superior to single-agent chemotherapy Radiation Osteosarcoma is a radioRESISTANT tumor, therefore radiation is not indicated 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 Limb salvage resection rotationplasty indications sarcomas of the hip, femur, knee, proximal tibia failed limb salvage with intact distal leg proximal femoral focal deficiency (PFFD) 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 technique 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 complications 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 endoprosthetic reconstruction indications salvageable limb after 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 Amputation used to be the standard of care, however, with improved chemotherapy and surgical techniques, this is typically reserved for failure of limb salvage technique above-knee amputation below-knee amputation complications wound healing contractures neuroma formation phantom limb symptoms deep/superficial infection COMPLICATIONS Prosthetic joint infection incidence occurs in 2-10% of patients after reconstruction Aseptic loosening of endoprosthesis incidence occurs in approximately 6% of patients Allograft or autograft fracture risk factors usually occurs at the native bone-graft junction as this is the weakest point Amputation secondary to limb salvage failure Prognosis approximately 75% 5-year survival with standard treatment of pre/post-operative chemotherapy and wide resection in those without detectable metastases at initial presentation Approximately 26-65% 5-year survival in patients with detectable metastases at initial diagnosis Poor prognostic factors include advanced stage of disease (most predictive of survival) age > 40 at the time of diagnosis response to neoadjuvant chemotherapy (as judged by percent tumor necrosis of resected specimen) >90% necrosis is a good prognostic indicator males tumor site and size expression of P-glycoprotein high ALP/LDH significantly high LDH on initial labs may indicate the presence of metastases vascular involvement positive surgical margins