Epidemiology and Pathogenesis

OS is the most common malignancy of bone in childhood, representing 15% of all primary bone tumors. The disease is somewhat more common in boys than girls (1.5 : 1), and the incidence is slightly higher in African Americans than in whites. The incidence is highest in patients between 10 and 20 years of age. OS is extremely rare in children younger than 5 years of age. Three percent of patients with OS have a germ line mutation in p53; many of these patients’ families are affected by Li-Fraumeni syndrome. This is a familial cancer syndrome in which affected individuals have a risk of developing sarcomas, brain tumors, leukemia, breast cancer, and adrenal cortical carcinoma at a young age; this risk persists throughout patients’ lifetimes. Patients who have had hereditary retinoblastoma are also at higher risk for the development of OS. OS is also associated with Rothmund-Thomson syndrome (skin rash, short stature, and skeletal abnormalities) and Paget’s disease in patients older than 40 years of age.

The etiology of OS is unknown. Exposure to ionizing radiation, such as that used for treatment of previous malignancies, has been linked to secondary OS. There are no convincing data to support a link between other environmental or infectious exposures and OS.

Clinical Presentation

The most common clinical symptom at presentation is pain, often described as dull and aching, and typically of several months’ duration. Other complaints include a palpable mass with or without swelling. Systemic complaints such as fevers, weight loss, and decreased appetite are rare. Eighty percent of OS occur in the extremities, and on examination, a mass (tender or nontender) may be noted (Figure 60-1). The examination may also reveal decreased range of motion or muscle atrophy. Regional lymphadenopathy is rare. The most common sites of disease include the distal femur, proximal tibia, and proximal humerus, although OS may occur in any bone. Involvement of the axial skeleton can occur but is less common. Eighty percent of patients with OS have localized disease at the time of diagnosis. The lung is the most common site of detectable metastatic disease at diagnosis, although patients may present with multifocal bone disease without pulmonary involvement.

Figure 60-1 Osteosarcoma.

The differential diagnosis includes benign bone tumors, infections, and other malignant disorders. Benign tumors to be considered in the differential diagnosis include unicameral bone cysts, osteoblastomas, eosinophilic granulomas, giant cell tumors, aneurysmal bone cysts, osteochondromas, and fibrous dysplasia. Infections that may present in similar manner to OS include osteomyelitis and septic arthritis. Other malignancies must also be considered, including ESFT, chondrosarcoma, fibrosarcoma, leukemia, and metastatic lesions of other solid tumors.

Evaluation

Imaging studies are more helpful in making the diagnosis of OS than are laboratory tests. A plain radiograph will often reveal a lytic or blastic lesion of the bone with poorly defined borders (see Figure 60-1). Other findings include periosteal elevation adjacent to the primary lesion, a sunburst appearance, or a pathologic fracture. If OS is suspected, chest computed tomography (CT) and bone scan can be used to assess for pulmonary and bone metastases. Magnetic resonance imaging (MRI) should be performed to better evaluate the extent of the tumor and should include the joint above and below the involved area so that skip lesions are not missed (see Figure 60-1). In addition to delineating the intra- and extraosseous extent of the tumor, the MRI may provide information regarding tumor effects on critical neurovascular structures.

The diagnosis of OS can only be made by biopsy. Biopsies should be performed by an experienced orthopedic oncologist. The surgical approach at the time of biopsy may have an impact on the feasibility of future limb-sparing surgeries, which are necessary for local control of the tumor. In some situations, interventional radiologists are able to obtain the necessary biopsies with active participation by orthopedic oncologists. Involvement of the surgeon who will eventually perform the definitive surgical resection is preferable.

Under the microscope, OS classically appears to be composed of spindle cells associated with malignant osteoid (see Figure 60-1). The extent of osteoid production may vary among the osteoblastic, chondroblastic, fibroblastic, telangiectatic, and small cell subtypes; however, the presence of tumor osteoid is the key pathologic feature of this disease.

Management

Advances in chemotherapy over the past 30 years have resulted in higher overall survival rates and improved rates of limb salvage for patients with OS. Chemotherapy is used initially both to treat pulmonary micrometastases and to decrease the size of the primary tumor mass to facilitate surgical resection. Current treatment protocols for OS typically include preoperative (induction) and postoperative (adjuvant) chemotherapy. The total duration of treatment is approximately 8 to 12 months. Drugs that have been shown to be effective against OS include cisplatin, doxorubicin, and high-dose methotrexate. North American and European investigators are currently evaluating the role of ifosfamide and etoposide in OS therapy through an international clinical trial.

Complete surgical resection with wide margins is necessary for cure. Modern approaches to limb salvage surgery have resulted in local recurrence rates that are similar to those achieved with amputation. Limb salvage has therefore become the standard of care except when limb preservation would compromise disease control. Decision making with regard to approach to limb reconstruction is complex, particularly in patients who have not reached skeletal maturity. OS is not considered a radiosensitive tumor, although high-dose radiation may be considered for local control in rare cases in which tumor location precludes surgical resection. Surgery also remains the key therapeutic modality for macroscopic pulmonary metastases.

Prognosis

Most patients with localized OS involving an extremity can be cured. The 5-year survival rate for nonmetastatic OS is approximately 60% to 70%. Patients with clinically detectable metastatic disease have a far worse prognosis; the overall survival rate for this patient group is approximately 25% to 30%. Among patients with localized disease at diagnosis, an inability to achieve a complete surgical resection of the tumor with negative margins is also associated with a poorer prognosis. Response to preoperative chemotherapy (i.e., degree of necrosis at the time of surgical resection) has also been shown to be an important prognostic factor for patients with localized disease because relapse-free survival rates are higher in patients with near-complete eradication of viable tumor compared with patients with a less extensive histologic response to therapy.

Epidemiology

ESFT is the second most common cancer of bone in children and adolescents, with an incidence of 2.1 per million children in the United States. Most patients are diagnosed during the second decade of life, although young adults may also be affected. Ewing’s sarcoma (ES) of bone, Askin tumor (ES of the chest wall), extraosseous ES (arising from soft tissue), and peripheral neuroectodermal tumor make up the ESFT. ESFT is six times more common in white patients than in African Americans. It is slightly more common in males than in females. ESFT does not appear to be associated with familial cancer syndromes, and the etiology of ESFT remains largely obscure.

Clinical Presentation

As in patients with OS, the most common presenting symptom of patients with ESFT of bone is pain. Before the diagnosis of the malignancy, bone pain may have been attributed to trauma or to athletic activities. As a result, the duration of symptoms before diagnosis may range from weeks to years. In addition to pain, patients may also complain of swelling or a palpable mass (Figure 60-2). Tender soft tissue masses may be palpable on examination. Fever and weight loss may be seen in patients with large tumors, but these symptoms are more common in the 25% of patients found to have metastatic disease at the time of diagnosis. Patients with tumors of the axial skeleton may present with neurologic symptoms, including paraplegia or bowel or bladder dysfunction, secondary to the paraspinal locations of these tumors.

Figure 60-2 Ewing’s sarcoma.

The differential diagnosis in patients with ESFT and bony disease is similar to that of OS. It also includes benign bone tumors, infections, and other malignant disorders as discussed above. ESFT can only be definitively distinguished from OS and other bony lesions after a tumor biopsy; however, several characteristics might favor the diagnosis of ESFT. In contrast to OS, ESFT involves the axial skeleton more commonly than the long bones. Within the long bones, the diaphysis is the most common location for ESFT, but OS is more likely to arise in the metaphysis.

Evaluation

Radiography is typically the first imaging modality used to evaluate the primary site of disease (see Figure 60-2). Bony destruction with “onion skinning” of the periosteum may be seen. Tumor growth may lead to elevation of the periosteum and the formation of a triangular interface between the tumor and normal bone known as Codman’s triangle. MRI of the primary site is critical in determining the extent and size of an ESFT involving bone, and the relevant bone or compartment should be imaged in its entirety.

Biopsies of suspected ESFT should be performed with the same care used for biopsies of other suspected bony malignancies. Because there may be extensive necrosis within a ESFT at the time of presentation, frozen sections are often necessary to confirm the presence of adequate diagnostic material within a biopsy sample. Importantly, biopsy samples should provide sufficient material for microscopy, immunohistochemical studies, and molecular diagnostic studies and should ideally be performed at a center that has a pathologist experienced in interpreting these diagnostic tests.

Under the microscope, ESFT appear to be composed of sheets of small, round, blue cells with scant cytoplasms (see Figure 60-2). The peripheral primitive neuroectodermal variant of ESFT may appear to contain aggregates of cells known as Homer-Wright rosettes. ESFT cells will frequently demonstrate membranous CD99 (cluster of differentiation molecule) positivity with immunohistochemical staining. CD99 staining is helpful in making the diagnosis of ESFT, but CD99 positivity can be seen in cells other than ESFT cells, including lymphoblasts. For this reason, molecular diagnostic studies are of critical importance in the ES tumor setting. In 95% of cases, a rearrangement involving the EWS (ES) gene is detected. Most occur via a t(11,22) translocation, which results in production of the EWS-FLI1 fusion protein. In approximately 10% of cases, other members of the ETS transcription factor family, including ERG, ETV1, or E1AF, are involved in gene rearrangements in ESFT. EWS rearrangements can be detected by reverse transcriptase polymerase chain reaction or by fluorescent in situ hybridization.

After confirmation of the diagnosis of ESFT, a staging evaluation must be performed. The most common sites of metastatic disease at diagnosis are lung, bone, and bone marrow. CT of the chest and bone scintography are used for detection of metastatic pulmonary and skeletal disease (see Figure 60-2). Bilateral bone marrow aspirates and biopsies are performed to detect marrow involvement. Functional imaging such as FDG (fluorodeoxy-D-glucose) positron emission tomography is being increasingly used in the staging and follow-up of patients with ESFT.

Management

The therapy of patients with ESFT involves multiple treatment modalities, including chemotherapy, surgery, and radiation therapy. Typically, treatment for ESFT begins with neoadjuvant (before surgery) chemotherapy to decrease tumor burden and to permit planning for definitive local control. Chemotherapeutic agents known to be active against ESFT include vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide. Treatment typically consists of alternating cycles of these agents on an every-2-week (compressed) schedule.

Local control can be achieved in ESFT with surgery, radiation therapy, or a combination of both. Surgical techniques similar to those used in OS may be used in ESFT, and complete surgical resection with resection margins clear of tumor is a critical goal in therapy. In contrast with OS, ESFT are responsive to radiation. Therefore, in cases that are not amenable to surgical resection, radiation can be used as the primary therapeutic modality for local control. Radiotherapy is also used after surgery if tumor is detected at the margins of resection. Adjuvant systemic chemotherapy is administered after local control. The total duration of ESFT therapy using modern intensive regimens is approximately 8 to 9 months.

Prognosis

The most important prognostic factor in ESFT is the extent of disease at diagnosis. Despite aggressive treatment regimens, fewer than one-third of patients with metastatic disease at diagnosis survive. However, for patients with localized disease, 5-year event-free survival rates near 80% have been reported. Age, site of disease, serum lactate dehydrogenase level, and histologic response to chemotherapy have also been identified as potential prognostic factors in newly diagnosed patients. Identification of prognostic factors in the relapse setting may also be useful because patients with localized, late recurrences appear to fare better than other patients.