- Primary malignant bone tumors are rare.
- Osteogenic sarcomas arise from mesenchymal cells capable of differentiating into bone, cartilage, or fibrous tissue. Three histologic types:
- Osteosarcoma: Characterized by the production of osteoid or immature bone by the malignant cells; has multiple subtypes
- Chondrosarcoma: Cellular cartilaginous tumor with abundant binucleate cells, myxoid areas, pushing borders; lacks osteoid
- Fibrosarcoma: Spindle cells and collagen; no osteoid
- Ewing sarcoma: Small, round blue-cell neoplasm
- Malignant fibrous histiocytoma (MFH): Pleomorphic sarcoma of storiform (starlike) pattern without differentiation; 10-year survival 20% for high grade, 90% for low grade
- Giant cell tumor of bone: Has both benign (90%) and malignant forms; often recurs
- Chordoma: Develops from remnants of primitive notochord at base of skull or sacrum; rare; slowly progressive; recurrent; cure possible
- Rare: 2,380 primary bone tumors diagnosed per year in US; 1,470 deaths (1)
- Osteosarcoma most common; chondrosarcoma, 2nd; Ewing sarcoma, 3rd
- Predominant age:
- Bone tumors account for 6% of childhood malignancies.
- Osteosarcoma: Bimodal: Ages 13–16 and >65 years
- Chondrosarcoma: 3rd–7th decades
- Fibrosarcoma: 2nd–6th decades
- Ewing sarcoma: Children and teenagers usually 10–15 years old (70% of Ewing patients <20 years of age)
- MFH: Adults and elderly
- Chordoma: >30 years of age
- Predominant gender:
- For most, Male = Female.
- Osteosarcoma, Male > Female (1.5:1), and chondrosarcoma, Male > Female (2:1).
- Ewing sarcoma is significantly more common in Caucasian than in African-American children (2).
- Osteosarcoma is slightly more common in African-American than in Caucasian children.
- Previous irradiation is a risk factor for osteosarcoma and MFH.
- Rapid bone growth, teenage growth spurt
- Fibrous dysplasia
- Genetic risk factors include
- Bone dysplasias:
- Paget disease risk factor for osteosarcoma
- Multiple hereditary exostosis: Chondrosarcoma
- Multiple enchondromatosis (Ollier disease): Chondrosarcoma
- Enchondromatosis and hemangiomatosis (Maffucci syndrome)
- Germ-line retinoblastoma, especially after radiation: Osteosarcoma
- Li-Fraumeni syndrome (germ-line p53 mutation)
- Rothmund-Thomson syndrome (autosomal recessive association of congenital bone defects, hair and skin dysplasias, hypogonadism, and cataracts)
- Bone dysplasias:
- Tumor genetics:
- Ewing sarcoma has chromosomal translocation t(11;22)(q24;q12) in 90% of tumors and resulting EW5-FLI1 fusion protein.
- Ewing sarcoma breakpoint region EWSR1 gene encodes a putative ribonucleic acid (RNA)–binding protein.
- Ewing sarcoma caveolin-1 overexpression is necessary for malignant tumor growth (3).
- Osteosarcoma shows loss of retinoblastoma and p53 suppressor genes and amplification of the genes C-myc, mdm-2, SAS, and cyclin-dependent kinase.
Irradiation is the only known environmental risk factor.
- Generally unknown
- Malignant fibrous histiocytoma often follows irradiation or arises in old bone infarct.
- Osteosarcoma has association with loss of suppressor retinoblastoma and p53 genes.
- Chondrosarcoma may arise in preexisting enchondroma or exostosis.
Commonly Associated Conditions
- Genetic conditions listed previously
- Patients with enchondromatosis more often die of gastrointestinal (GI) malignancies than of metastatic chondrosarcoma.
- Pain with weight bearing, at rest, and at night; often dull or aching
- Fracture with minor trauma (pathologic fracture present in 10–15% of cases)
- Minor injury may bring attention to lesion.
- Bone tenderness
- Palpable bony or soft tissue mass
- Rectal exam, if risk for prostate cancer, should be done to exclude prostate nodules.
Diagnostic Tests & Interpretation
Initial lab tests
- Calcium, phosphate, alkaline phosphatase, lactate dehydrogenase (LDH)
- 50% of osteosarcomas have an elevated alkaline phosphatase.
- Ewing sarcoma may be associated with an elevated erythrocyte sedimentation rate (ESR) and LDH.
- Prostate-specific antigen to exclude prostatic carcinoma
- Thyroid function tests to exclude thyroid carcinoma
- Elevated ESR and white blood cells (WBCs) in osteomyelitis
- Serum protein electrophoresis and urine electrophoresis to exclude myeloma
- Plain films provide important information regarding the nature of the lesion and guide further testing.
- Classic plain-film findings include “onion skin” for Ewing sarcoma and Codman triangle formation and soft tissue “sunburst” for osteosarcoma.
- Bone scan is done prior to biopsy to look for other lesions.
- CT scan for cortical destruction and internal calcification or ossification
- MRI determines the extent of marrow involvement and associated soft tissue mass.
- Osteosarcoma: Location of lesion important: Surface osteosarcomas often may be cured by surgery alone.
- Chest radiograph and CT scan for metastatic disease
- Abdominal CT scan, MRI, or renal ultrasound
- Mammogram to exclude breast carcinoma
- Open biopsy or needle biopsy: Needle biopsies may not provide enough tissue.
- Frozen section problematic if calcified
- Touch prep
- Permanent section
- Snap freezing
- Electron microscopy
- Cytogenetic and molecular studies
- DNA indices
- Immunoperoxidase staining
- Immunophenotyping to rule out lymphoma
- Biopsy tract should be excised in continuity with the tumor at the time of resection (4).
- Biopsy of associated soft tissue mass may lessen the risk of pathologic fracture.
- Histology and special studies in combination with radiographic findings confirm the diagnosis.
- 90% of osteosarcomas are high-grade intramedullary tumors.
- Conventional osteosarcomas have histologic subtypes: Osteoblastic, chondroblastic, or fibroblastic depending on the predominant cellular component, but all are managed similarly.
- Osteosarcoma may express Her-2/neu, indicating, if present, a more aggressive tumor, but one that may respond more favorably to trastuzumab (Herceptin).
- Ewing sarcoma expresses MIC-2 protein (CD99).
- Electron microscopy: Glycogen granules in Ewing sarcoma
- Metastatic cancer: Breast, prostate, thyroid, lung, kidney
- Hematologic malignancy:
- Myeloma, especially in patients >40 years of age
- Lymphoma at any age
- Benign bone tumors: Endochondroma, osteochondroma, nonossifying fibroma, chondroblastoma, osteoid osteoma, osteoblastoma, periosteal chondroma, (benign) giant cell tumor, chondromyxoid fibroma
- Other space-occupying lesions: Aneurysmal bone cyst, unicameral bone cyst, fibrous dysplasia, eosinophilic granuloma
- Infection (osteomyelitis)
- Metabolic bone disease (osteopenia, Paget, hyperparathyroidism)
- Synovial diseases (pigmented villonodular synovitis, synovial chondromatosis, degenerative or inflammatory synovitis)
- Myositis ossificans and repair reaction to trauma
- Avascular necrosis
- Neoadjuvant chemotherapy treats micrometastatic disease, allows time for ordering replacement prosthesis and bone graft, and allows in vivo assessment of response to chemotherapy (5,6)[C].
- Standard agents: Doxorubicin, cisplatin, ifosfamide, and methotrexate (MTX)
- Recurrent disease: High-dose (HD) MTX, doxorubicin, and cisplatin
- Chondrosarcoma is not likely to respond to chemotherapy.
- MFH: Less histologic response to chemotherapy than conventional osteosarcoma; survival similar
- Ewing sarcoma response to induction chemotherapy important prognostic factor:
- A dramatic decrease in size of Ewing sarcoma usually occurs after initial chemotherapy.
- Adjuvant chemotherapy improves cure rate dramatically; cure rate is 10–20% with surgery or radiation alone.
- Standard agents: Vincristine, doxorubicin, and cyclophosphamide, alternating with ifosfamide, etoposide
- Left ventricular dysfunction with doxorubicin; cumulative dose >450 mg/m2 increases risk.
- With HD MTX, hydration, alkalinization of the urine, and close monitoring of plasma levels are needed.
- Significant adverse effects:
- Renal tubular dysfunction with ifosfamide
- Renal and hepatic dysfunction and GI mucositis with MTX
- Nephrotoxicity and ototoxicity with cisplatin
- Complete surgical resection with adequate margins is crucial (7)[C].
- Chondrosarcoma in the extremities should be treated exclusively by surgery, unless it is of the mesenchymal or dedifferentiated high-grade variety.
- Ewing sarcoma is radiosensitive; however, surgery with limb salvage is increasingly accepted.
- Surgery is preferred if lesion is resectable.
- Despite irradiation, local recurrence is common in up to 25% with pelvic lesions.
- After neoadjuvant chemotherapy, reassess resectability of lesion; either surgery or irradiation.
- Nonresectable tumors may be irradiated.
- Adjuvant radiotherapy is used for Ewing sarcoma only in some circumstances.
- Limb salvage is employed whenever a safe margin can be obtained.
- Primary goal is eradication of disease.
- Secondary goal is preservation of function.
- In selected patients, limb salvage does not increase risk of death.
- Limb-sparing surgery may require endoprosthesis or bone graft (allograft or homograft).
- Rotation-plasty is a procedure used when tumor dictates resection of the distal femur.
- Lower leg is spared and rotated 180 degrees; tibia is fused to femur.
- Reattached, reversed ankle serves as knee joint. Prosthesis is fitted to (reversed) foot.
- Blood counts for myelosuppression
- Serial electrocardiograms (ECGs) when Adriamycin is being used; granulocyte colony-stimulating factor (G-CSF) is often used to minimize neutropenia.
- Chest radiographs should be obtained every 2 months for the 1st year, every 3 months for the 2nd year, and every 4 months for the 3rd year.
- CT scans of the lungs are repeated every 6 months during the 1st 2 years.
- Ewing sarcoma may recur >5 years after diagnosis.
Refer to local branch of American Cancer Society for information and support groups.
- With amputation alone, 80% of patients with osteosarcoma had pulmonary metastatic disease by 2 years. With chemotherapy, the 5-year disease-free survival rate is 50–85% (8)[C].
- Favorable prognostic factors for MFH and osteosarcoma include responsiveness to chemotherapy, distal portions of the extremities, small size, and age >10 years.
- Most chondrosarcomas are of lower grade and have a low risk of metastatic spread and low incidence of local recurrence after adequate surgery.
- MFH, osteosarcoma, and Ewing sarcoma have an overall 50% survival with combined treatment modalities.
- For limb salvage with any primary malignant bone tumor, potential complications include leg-length discrepancy, infection, wound dehiscence, skin-coverage problems, and artery and nerve injury.
- Nonunion of bone grafts and mechanical loosening of prosthetic implants
- Local recurrence risk for osteosarcoma with limb salvage is <10%.
- Micrometastatic disease may have occurred by the time of presentation and can appear at any time during the course of treatment or follow-up.
- Thoracotomy and continued chemotherapy are often recommended for metastatic disease to the lung.
- Ewing sarcoma metastatic to the lung is often diffuse and not amenable to resection.
1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71–96.
2. Heare T, Hensley MA, Dell’Orfano S. Bone tumors: osteosaroma and Ewing’s sarcoma. Current Opinion in Pediatrics. 2009;21:365–372.
3. Lewis VO. What’s new in musculoskeletal oncology. J Bone Joint Surg Am. 2007;89:1399–407.
4. Schajowicz F, McGuire MH. Diagnostic difficulties in skeletal pathology. Clin Orthop Rel Res. 1991;240:281–310.
5. Longhi A, Pasini E, Bertoni F, et al. Twenty-year follow-up of osteosarcoma of the extremity treated with adjuvant chemotherapy. J Chemother. 2004;16:582–8.
6. Mendelsohn J. Jeremiah Metzger Lecture. Targeted cancer therapy. Trans Amer Clin Climatol Assoc. 2000;111:95–110.
7. Siegel HJ, Pressey JG. Current concepts on the surgical and medical management of osteosarcoma. Expert Rev Anticancer Ther. 2008;8:1257–69.
8. Bruland OS, Høifødt H, Saeter G, et al. Hematogenous micrometastases in osteosarcoma patients. Clin Cancer Res. 2005;11:4666–73.
- 170.0 Malignant neoplasm of bones of skull and face, except mandible
- 170.1 Malignant neoplasm of mandible
- 170.9 Malignant neoplasm of bone and articular cartilage, site unspecified
- 170.2 Malignant neoplasm of vertebral column, excluding sacrum and coccyx
- 170.3 Malignant neoplasm of ribs, sternum, and clavicle
- 170.4 Malignant neoplasm of scapula and long bones of upper limb
- 170.5 Malignant neoplasm of short bones of upper limb
- 170.6 Malignant neoplasm of pelvic bones, sacrum, and coccyx
- 170.7 Malignant neoplasm of long bones of lower limb
- 170.8 Malignant neoplasm of short bones of lower limb
- 93725000 Primary malignant neoplasm of bone (disorder)
- 93723007 primary malignant neoplasm of bone of skull (disorder)
- 93721009 primary malignant neoplasm of bone of face (disorder)
- 93886007 primary malignant neoplasm of mandible (disorder)
- 372028007 primary malignant neoplasm of vertebral column (disorder)
- 372107001 primary malignant neoplasm of ribs and/or sternum and/or clavicle (disorder)
- 93724001 primary malignant neoplasm of bone of upper limb (disorder)
- 94004004 primary malignant neoplasm of short bone of upper limb (disorder)
- 93951006 primary malignant neoplasm of pelvic bone (disorder)
- 93871001 primary malignant neoplasm of long bone of lower limb (disorder)
- 94003005 primary malignant neoplasm of short bone of lower limb (disorder)
- Osteosarcoma variants, such as parosteal, periosteal, and intraosseous osteosarcoma, are lower-grade lesions with a more favorable prognosis; they often do not require chemotherapy.
- Other variants and postirradiation and post-Paget osteosarcoma metastasize early.