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Bone tumor, primary malignant
OVERVIEW: Primary malignant bone tumors are rare. Four types make up the majority.
• Malignant fibrous histiocytoma (MFH) - a pleomorphic sarcoma of storiform pattern without differentiation
• Osteosarcoma - similar to malignant fibrous histiocytoma with differentiation to osteoid production
• Chondrosarcoma - cellular cartilaginous lesion with abundant binucleate cells, myxoid areas, and pushing borders
• Ewing's sarcoma - small, blue-round cell neoplasm
System(s) affected: Musculoskeletal
Genetics:
• Ewing's sarcoma has 11/22 chromosomal translocation and EW5-FLI-1 fusion protein
• Osteosarcomas shows loss of retinoblastoma and p53 suppressor genes and amplification of the genes C-myc, mdm-2, SAS, and cyclin-dependent kinase
Incidence/Prevalence in USA:
Rare: 5000 bone and soft tissue sarcomas per year, a practicing orthopedic surgeon may see one primary malignant tumor of bone in every five years of practice. Ewing's sarcoma is less common in blacks.
Predominant age:
• MFH - teens and elderly
• Osteogenic sarcoma - teens and early twenties
• Chondrosarcoma - very young and very old
• Ewing's sarcoma - children, teens, and early twenties
Predominant sex: Male = Female
SIGNS AND SYMPTOMS: • Pain with weight bearing, at rest and at night
• Swelling
• Tenderness
• Fracture with minor trauma
• Minor injury may bring attention to lesion
CAUSES: • Generally unknown
• MFH often follows irradiation or arises in old bone infarct
• Osteosarcoma has association with loss of suppressor retinoblastoma and p53 genes
• Chondrosarcoma may arise in pre-existing enchondroma or exostosis
RISK FACTORS: • Multiple enchondromatosis (Ollier's disease) - chondrosarcoma
• Multiple hereditary exostosis - chondrosarcoma
• Previous irradiation, risk factor for MFH
• Previous history of bilateral retinoblastoma - osteosarcoma
DIAGNOSIS DIFFERENTIAL DIAGNOSIS: • Solitary metastatic lesion or myeloma especially in the patient over age 40
• Lymphoma at any age
• Benign bone tumors and benign bone tumors that look aggressive (aneurysmal bone cyst, giant cell tumor, eosinophilic granuloma)
• Infection (osteomyelitis)
• Metabolic bone disease (osteopenia, Paget's, hyperparathyroidism)
• Synovial diseases (pigmented villonodular synovitis, synovial chondromatosis, degenerative or inflammatory synovitis)
• Myositis ossificans and repair reaction to trauma
• Avascular necrosis
LABORATORY: • 50% of osteosarcomas have an elevated alkaline phosphatase
• Ewing's sarcoma may be associated with an elevated ESR and LDH
• Acid phosphatase, prostatic specific antigen to exclude prostatic carcinoma
• Calcium, phosphate, alkaline phosphatase
• Thyroid function tests to exclude thyroid carcinoma
• Elevated ESR and WBC in osteomyelitis
• Serum protein electrophoresis and urine electrophoresis to exclude myeloma
Drugs that may alter lab results: N/A
Disorders that may alter lab results: N/A
PATHOLOGICAL FINDINGS: • Histology and special studies in combination with radiographic findings confirms the diagnosis
• Ewing's sarcoma expresses MIC-2 protein (CD99)
• Electron microscopy: glycogen granules in Ewing's sarcoma; neurosecretory granules in neuroectodermal tumors; Birbeck bodies in histiocytosis-X
• Osteosarcoma may express Her-2/neu indicating, if present a more aggressive tumor, but one which may respond more favorably to trastuzumab (Herceptin)
SPECIAL TESTS: • Open biopsy or needle biopsy. Needle biopsies may not provide enough tissue for frozen section, touch prep, permanent section, snap freezing, electron microscopy, cytogenetic and molecular studies, DNA indices, immunoperoxidase staining and immunophenotyping (lymphoma).
• Biopsy of associated soft tissue mass may lessen the risk of pathologic fracture
• Biopsy tract should to be excised in continuity with the tumor at the time of resection.
IMAGING: • Plain films provide the most important information regarding the nature of the lesion and guide further testing
• Bone scan - prior to biopsy, looking for other lesions
• CT scan for cortical destruction and internal calcification or ossification. Abdominal CT, MRI or renal ultrasound to exclude hypernephroma.
• MRI scan determines the extent of marrow involvement and associated soft tissue mass
• Chest x-ray and chest CT for metastatic disease.
• Mammogram to exclude breast carcinoma
DIAGNOSTIC PROCEDURES: • Rectal exam for prostatic nodules
• Laboratory studies for metabolic bone disease
TREATMENT APPROPRIATE HEALTH CARE: Inpatient surgery
GENERAL MEASURES: N/A
SURGICAL MEASURES: • Resection with adequate margin is required to minimize risk of local persistence
• For MFH and osteosarcoma, pre-resection neo-adjuvant chemotherapy treats micrometastatic disease immediately, allows time for ordering replacement prosthesis and bone graft, allows for an in vivo assessment of the chemotherapy responsiveness of the tumor, and may facilitate limb salvage by allowing a safer close margin
• Chondrosarcoma in the extremities should be treated exclusively by surgery unless it is of the mesenchymal or de-differentiated high grade variety
• Ewing's sarcoma was traditionally treated with chemotherapy and surgery was limited to those lesions that were extremely large, associated with pathologic fracture, or involved an expendable bone. Most Ewing's sarcoma lesions were irradiated. However, despite irradiation, local recurrence is common up to 25% in pelvic lesions. Therefore, surgery with limb salvage is increasingly accepted. A dramatic decrease in size in Ewing's sarcoma occurs after initial chemotherapy and a decision can then be made after restaging as to whether to irradiate or to resect the primary lesion.
• The treatment goal is to minimize local recurrence while preserving function. Limb salvage is employed whenever a safe margin can be obtained.
ACTIVITY: Varies with stage of disease and treatment
DIET: No special diet
PATIENT EDUCATION: Refer to local branch of American Cancer Society for information and support groups
MEDICATIONS DRUG(S) OF CHOICE: These drugs are administered according to specific protocols. Other protocols may be appropriate.
• MFH and osteosarcoma:
• Doxorubicin (Adriamycin)
• Intra-arterial and intravenous cisplatin
• High dose methotrexate with leucovorin rescue
• Ifosfamide [with mesna to protect against hemorrhagic cystitis]
• Cyclophosphamide (Cytoxan)
• Dactinomycin (actinomycin-D)
• Bleomycin
• Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (liposomal MTP-PE) immune modulating agent for osteosarcoma (under trial in CCSG and POG)
• Ewing's sarcoma:
• Cyclophosphamide
• Vincristine
• Actinomycin D
• Doxorubicin (Adriamycin)
• Ifosfamide
• Etoposide
Contraindications: Refer to manufacturer's literature
Precautions:
• Left ventricular dysfunction with Adriamycin. Cumulative dose > 450 mg/m2 increases risk. Follow with serial echocardiograms and/or MUGA scans when cumulative dose > 250 mg/m2.
• With high dose methotrexate, hydration, alkalinization of the urine, and close monitoring of plasma levels are needed
Significant possible interactions:
• Myelosuppression
• Renal tubular dysfunction with ifosfamide
• Renal and hepatic dysfunction and GI mucositis with methotrexate
• Nephrotoxicity and ototoxicity with cisplatin
ALTERNATIVE DRUGS: • Ondansetron (Zofran), dronabinol (Marinol), metoclopramide (Reglan), and others for nausea control
FOLLOW UP PATIENT MONITORING: • Patients who require adjuvant chemotherapy are treated after resection of the tumor with maintenance chemotherapy
• Blood counts for myelosuppression
• Serial echocardiograms when Adriamycin is being used. G-CSF often used to minimize neutropenia.
• Chest x-rays obtained every two months for the first year, every three months for the second year, and every four months in the third year
• CT scans of the lungs are initially repeated every six months during first two years
• Ewing's sarcoma may recur > 5 years after diagnosis
PREVENTION/AVOIDANCE: None identified
POSSIBLE COMPLICATIONS: • Limb salvage with any primary malignant bone tumor is fraught with potential complications
• Micrometastatic disease may have occurred at the time of presentation and can appear at any time during the course of treatment or followup
• Local recurrence risk for osteosarcoma with limb salvage is about 10%
• There can be leg length discrepancy, infection, wound dehiscence, skin coverage problems, arterial and nerve injury, non-union of bone grafts, and mechanical loosening of prosthetic implants
• Thoracotomy and continued chemotherapy is often recommended for metastatic disease to the lung
• Ewing's sarcoma, metastatic to the lung, is quite diffuse and is less amenable to thoracotomy
EXPECTED COURSE AND PROGNOSIS: • With amputation alone, 80% of patients with osteosarcoma had pulmonary metastatic disease by two years. With chemotherapy, the five year disease-free survival rate is 50-85%.
• Favorable prognostic factors for MFH and osteosarcoma include responsiveness to chemotherapy, distal portions of the extremities, small size, age over ten
• 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's sarcoma have an overall 50% survival with combined treatment modalities
MISCELLANEOUS ASSOCIATED CONDITIONS: • A higher incidence of chondrosarcoma is seen in patients with multiple hereditary exostosis, multiple enchondromatosis (Ollier's disease) and patients with enchondromatosis and hemangiomatosis (Maffucci's syndrome)
• Patients with enchondromatosis more often die of GI malignancies than metastatic chondrosarcoma
AGE-RELATED FACTORS:
Pediatric: N/A
Geriatric: N/A
Others: N/A
PREGNANCY: • Increased growth of musculoskeletal malignancies during pregnancy
• Soft tissue desmoid tumors have estrogen and progesterone receptors
SYNONYMS: N/A
ICD-9-CM: 170.9 Malignant neoplasm of bone and articular cartilage, site unspecified
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