Epidemiology

The annual incidence of osteosarcoma in the USA is 5.6 cases/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 for development of osteosarcoma. The sites of osteosarcoma in these patients were initially thought to be located only in previously irradiated areas, but later studies have shown them 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. Kindreds with Li-Fraumeni syndrome have a spectrum of malignancies in 1st-degree relatives, including carcinoma of the breast, soft tissue sarcomas, brain tumors, leukemia, adrenal cortical carcinoma, and other malignancies. Rothmund-Thomson syndrome is a rare syndrome associated with short stature, skin telangiectasia, small hands and feet, hypoplasticity or absence of the thumbs, and a high risk of osteosarcoma. Osteosarcoma also can be induced by irradiation for Ewing sarcoma, craniospinal irradiation for brain tumors, or high-dose irradiation for other malignancies. Other benign conditions that can be associated with malignant transformation to osteosarcoma include Paget disease, enchondromatosis, multiple hereditary exostoses, and fibrous dysplasia.

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. There are four pathologic subtypes of conventional high-grade osteosarcoma: osteoblastic, fibroblastic, chondroblastic, and telangiectatic. No significant differences in outcome are associated with the various subtypes, although the chondroblastic component of that subtype may not respond as well to chemotherapy. The role in prognosis of various genes such as drug resistance-related genes, tumor suppressor genes, and genes related to apoptosis is being evaluated.

Telangiectatic osteosarcoma may be confused with aneurysmal bone cyst because of its lytic appearance on radiography. High-grade osteosarcoma typically arises in the diaphyseal region of long bones and invades the medullary cavity. It also may be associated with a soft tissue mass. Two variants of osteosarcoma, parosteal and periosteal osteosarcoma, should be distinguished from conventional osteosarcoma because of their characteristic clinical features. Parosteal osteosarcoma is a low-grade, well-differentiated tumor that does not invade the medullary cavity and most commonly is found in the posterior aspect of the distal femur. Surgical resection alone often is curative in this lesion, which has a low propensity for metastatic spread. Periosteal osteosarcoma is a rare variant that arises on the surface of the bone but has a higher rate of metastatic spread than the parosteal type and an intermediate prognosis.

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 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, are usually normal, although alkaline phosphatase or lactic dehydrogenase values may be elevated.

Diagnosis

Bone tumor should be suspected in a patient who presents with deep bone pain often causing nighttime awakening in whom there is a palpable mass, and radiographs demonstrate a lesion. The lesion may be mixed lytic and blastic in appearance, but new bone formation is usually visible. The classic radiographic appearance of osteosarcoma is the sunburst pattern (Fig. 495-2). 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, which should be performed before biopsy, includes CT of the chest and radionuclide bone scanning to evaluate for lung and bone metastases, respectively. The differential diagnosis of a lytic bone lesion includes histiocytosis, Ewing sarcoma, lymphoma, and bone cyst.

Figure 495-2 Radiograph of an osteosarcoma of the femur with typical “sunburst” appearance of bone formation.

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 approach 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 performing 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. Patients with good histologic response will be randomized to the addition of PEGylated interferon-α2b. For patients with metastatic disease, a new approach currently being investigated is the addition of zoledronic acid, a bisphosphonate, to intensive chemotherapy. After limb salvage surgery, intensive rehabilitation and physical therapy are necessary to ensure maximal functional outcome.

For patients who require amputation, early prosthetic fitting and gait training are essential to enable them to resume normal activities as soon as possible. Before definitive surgery, patients with tumors on weight-bearing bones should be instructed to use crutches to avoid stressing the weakened bones and causing pathologic fracture. The role of chemotherapy in parosteal and periosteal osteosarcomas is not well defined.

Prognosis