Screening and Diagnosis
Currently, there is no screening test for primary bone sarcomas. The diagnosis must be made by clinical and radiographic evaluations and confirmed by histopathologic analysis of biopsy-obtained tissue.
Physical Examination
Physical examination should include an assessment of the local extent of the soft-tissue mass, if present, and its relationship to the adjacent joint.
Laboratory Studies
A complete blood cell (CBC) count may demonstrate anemia and/or leukocytosis associated with Ewing sarcoma, but in general, results of these studies fall within the normal range. Alkaline phosphatase and lactic dehydrogenase (LDH) levels may be elevated in patients with osteosarcoma or Ewing sarcoma. An abnormal glucose tolerance test may be observed in patients with chondrosarcomas.
Radiographs
Biplanar (anteroposterior and lateral) plain radiographs of the affected extremity provide critical information on the nature of the bone lesion. The specific site of involvement within the bone, the pattern and extent of bone destruction, the type of periosteal changes, and the presence of matrix mineralization within the tumor and of soft-tissue extension may be gleaned from plain films.
CT
Standard computed tomography (CT) scans provide further delineation of many of these changes.
MRI
Magnetic resonance imaging (MRI) is the imaging study of choice for evaluating the extent of an associated soft-tissue mass and the relationship of the tumor to the neurovascular structures, surrounding soft tissues, and the adjacent joint. The intramedullary extent of the tumor and presence of skip metastases within the bone are best demonstrated by MRI.
Bone Scan
At presentation, a bone scan is performed to screen for distant osseous metastases. This may be repeated during surveillance at the discretion of the provider or cooperative study.
Chest Radiographic Studies
A plain film of the chest is required in any patient in whom a bone sarcoma is suspected. Once the diagnosis of malignancy has been established, a CT scan of the chest is a critical part of initial staging.
Biopsy
With few exceptions, a biopsy must be obtained to confirm the diagnosis. Tissue may be obtained by percutaneous (closed) or surgical (open) techniques. The biopsy should be performed by personnel who are expert in percutaneous biopsy techniques and familiar with bone tumors and their treatment.
Biopsies performed at referring institutions have been reported to be associated with a higher incidence of misdiagnosis and complications, which may affect patient outcome. Optimally, the biopsy should be performed at the institution where definitive treatment will be given.
Pathology
Histologic Subtypes
Current histopathologic classification of bone neoplasms is based on the putative cell of origin. Malignant tumors may arise from any cellular constituent present in bone, including osteogenic (osteosarcoma), chondrogenic (chondrosarcoma), hematopoietic (multiple myeloma, lymphoma), vascular (angiosarcoma, hemangioendothelioma, leiomyosarcoma), lipogenic (liposarcoma), neurogenic (neurofibrosarcoma, chordoma), and histiocytic and fibrohistiocytic (MFH, Ewing sarcoma) elements. Histologic subtyping is based on the predominant cellular pattern present within the tumor, the degree of anaplasia, and the relationship of the tumor to the bone (intramedullary vs surface).
A monoclonal antibody that recognizes a cell-surface glycoprotein, CD99 (p30/32MIC2), in human Ewing sarcoma and primitive neuroectodermal tumor (PNET) is helpful for diagnosis. There is strong immunoreactivity of CD99 in Ewing sarcoma and PNET that aids in distinguishing these tumors from other small, round-cell tumors of childhood and adolescence. Additional experience with CD99, however, demonstrates that it is not exclusively specific for Ewing sarcoma and PNET. Verification of the t(11;22) EWS/FLI1 translocation via fluorescent in situ hybridization or polymerase chain reaction should be performed.
Dedifferentiation
Primary bone sarcomas can exhibit the phenomenon of "dedifferentiation." These neoplasms demonstrate a dimorphic histologic pattern, which is characterized by the presence of a borderline malignant or low-grade malignant tumor juxtaposed against a high-grade, histologically different sarcoma. Enchondromas, low-grade chondrosarcomas, low-grade variants of osteosarcoma (surface and intramedullary), and chordomas may all develop an area of high-grade spindle-cell tumor, usually MFH.
Metastatic Spread
Approximately 10% to 20% of patients with osteosarcoma and 15% to 35% of patients with Ewing sarcoma have evidence of metastatic disease at initial presentation. In approximately 90% of patients with bone sarcomas, the initial site of distant metastasis is the lungs. Distant osseous sites, bone marrow, and viscera may also be involved as a manifestation of advanced disease, but involvement of these sites is less common and usually occurs after the development of pulmonary metastases. Regional lymph node involvement is rare.
Staging and Prognosis
Surgical staging of bone sarcomasStaging System
The staging system of the Musculoskeletal Tumor Society is currently used (Table 1). The MTS system is based on tumor grade (I = low or II = high); tumor extent (A = intraosseous involvement only or B = extraosseous extension); and presence of distant metastases, regardless of the extent of local disease (III). Patients with a localized tumor may have stage IA, IB, IIA, or IIB disease.
Prognostic Factors
Many studies have demonstrated that tumor response to preoperative chemotherapy, as determined by histologic analysis of the resected specimen, is the most powerful predictor of survival for patients with osteosarcoma. Adverse prognostic indicators, such as an axial primary tumor or elevated LDH and alkaline phosphatase levels, signal an even worse outcome.
Tumor size (low volume) and anatomic site (peripheral), absence of metastases at initial presentation, and good histologic response to chemotherapy are prognostic variables associated with better outcome in patients with osteosarcomas and Ewing sarcoma. Recent work has suggested that certain microRNA signatures are associated with the pathogenesis of osteosarcoma and may serve as potential pretreatment biomarkers of metastasis and response to chemotherapy. The translocation t(11;22), which results in the type 1 EWS-FLI1 fusion, is also a significant positive predictor of overall survival in Ewing sarcoma.
For low-grade malignant tumors, adequacy of surgery is the most significant predictor of outcome.
