The annual incidence of osteosarcoma in the USA is 5.6 cases per million children <15 yr of age. The highest risk period for development of osteosarcoma is during the adolescent growth spurt, suggesting an association between rapid bone growth and malignant transformation. Patients with osteosarcoma are taller than their peers of similar age.
Pathogenesis.
Although the cause of osteosarcoma is unknown, certain genetic or acquired conditions predispose patients to development of osteosarcoma.
Patients with hereditary retinoblastoma have a significantly increased risk of developing osteosarcoma. The sites of osteosarcoma in these patients initially were thought to be located only in previously irradiated areas, but more recently they have been shown to arise in sites far from the radiation field. Predisposition to development of osteosarcoma in these patients may be related to loss of heterozygosity of the RB gene.
Osteosarcoma also occurs in the Li-Fraumeni syndrome, which is a familial cancer syndrome associated with germline mutations of the p53 gene.
The pathologic diagnosis of osteosarcoma is made by demonstration of a highly malignant, pleomorphic, spindle cell neoplasm associated with the formation of malignant osteoid and bone.
Clinical Manifestations.
Pain, limp, and swelling are the most common presenting manifestations of osteosarcoma. Because these tumors occur most often in active adolescents, initial complaints may be attributed to a sports injury or sprain; any bone or joint pain not responding to conservative therapy within a reasonable amount of time should be investigated thoroughly. Additional clinical findings may include limitation of motion, joint effusion, tenderness, and warmth. Results of routine laboratory tests, such as a complete blood cell count and chemistry panel, usually are normal, although alkaline phosphatase or lactic dehydrogenase levels may be elevated.
Diagnosis.
Bone tumor should be suspected in a patient who presents with deep bone pain, often causing nighttime awakening, a palpable mass, and a radiograph demonstrating a lesion. The lesion may be mixed lytic and blastic in appearance, but new bone formation usually is visible. The classic radiographic appearance of osteosarcoma is the sunburst pattern . When osteosarcoma is suspected, the patient should be referred to a center with experience in managing bone tumors. The biopsy and the surgery should be performed by the same surgeon so that the incisional biopsy site can be placed in a manner that will not compromise the ultimate limb salvage procedure. Tissue usually is obtained for molecular and biologic studies at the time of the initial biopsy. Before biopsy, MRI of the primary lesion and the entire bone should be performed to evaluate the tumor for its proximity to nerves and blood vessels, soft tissue and joint extension, and skip lesions. The metastatic work-up should be performed before biopsy and includes CT of the chest and radionuclide bone scan to evaluate for lung and bone metastases, respectively.
The differential diagnosis of a lytic bone lesion includes histiocytosis, Ewing sarcoma, lymphoma, and bone cyst.
Treatment.
With chemotherapy and surgery, the 5-yr disease-free survival rate of patients with nonmetastatic extremity osteosarcoma is 65–75%. Complete surgical resection of the tumor is important for cure. The current approach is to treat patients with preoperative chemotherapy in an attempt to facilitate limb salvage operations and to treat micrometastatic disease immediately. Up to 80% of patients are able to undergo limb salvage operations after initial chemotherapy. Some institutions use intra-arterial chemotherapy to infuse chemotherapy directly into an artery feeding the tumor, although this has not been shown to be better than conventional intravenous chemotherapy. It is important to resume chemotherapy as soon as possible after surgery. Lung metastases present at diagnosis should be resected by thoracotomies at some time during the course of treatment. Active agents currently in use in multidrug chemotherapy regimens for conventional osteosarcoma include doxorubicin, cisplatin, methotrexate, and ifosfamide.
One of the most important prognostic factors in osteosarcoma is the histologic response to chemotherapy. An international cooperative group is evaluating a randomized trial of the postoperative addition of high-dose ifosfamide with etoposide to standard three-drug therapy with cisplatin, doxorubicin, and methotrexate to improve the outcome of patients with a poor histologic response. Good histologic responders will be randomized to the addition of PEGylated interferon ?2b. After limb salvage surgery, intensive rehabilitation and physical therapy is necessary to ensure maximal functional outcome.
For patients who require amputation, early prosthetic fitting and gait training is essential to enable them to resume activities as normally as possible. Before definitive surgery, patients with tumors on weight-bearing bones should be instructed to use crutches to avoid stressing the weakened bone and causing a pathologic fracture. The role of chemotherapy in parosteal and periosteal osteosarcoma is not well defined.
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