BONE TUMOR, PRIMARY MALIGNANT

BONE TUMOR, PRIMARY MALIGNANT - Mark R. Dambro, MD
BASICS
DESCRIPTION
• Primary malignant bone tumors are rare. 4 types make up the majority
- Malignant fibrous histiocytoma (malignant fibrous histiocytoma): 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 sarcoma: Small, blue-round cell neoplasm
• System(s) Affected: Musculoskeletal
ALERT
Pregnancy Considerations
• Increased growth of musculoskeletal malignancies during pregnancy
• Soft-tissue desmoid tumors have estrogen and progesterone receptors.
GENERAL PREVENTION
None identified
EPIDEMIOLOGY
• Predominant age
- Malignant fibrous histiocytoma: Teens and elderly
- Osteogenic sarcoma: Teens and early 20s
- Chondrosarcoma: Very young and very old
- Ewing sarcoma: Children, teens, and early 20s
• Predominant sex: Male = Female
Incidence
• Rare
• 5,000 bone and soft-tissue sarcomas diagnosed per year in the US
• A practicing orthopedic surgeon may see 1 primary malignant tumor of bone in every 5 years of practice.
• Ewing sarcoma is less common in African Americans.
RISK FACTORS
• Multiple enchondromatosis (Ollier disease): Chondrosarcoma
• Multiple hereditary exostosis: Chondrosarcoma
• Previous irradiation, risk factor for malignant fibrous histiocytoma
• Previous history of bilateral retinoblastoma: Osteosarcoma
Genetics
• Ewing sarcoma has 11/22 chromosomal translocation and EW5-FLI-1 fusion protein.
• Osteosarcoma shows loss of retinoblastoma and p53 suppressor genes and amplification of the genes C-myc, mdm-2, SAS, and cyclin-dependent kinase.
ETIOLOGY
• 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 pre-existing enchondroma or exostosis.
ASSOCIATED CONDITIONS
• A higher incidence of chondrosarcoma is seen in patients with multiple hereditary exostosis, multiple enchondromatosis (Ollier disease), and patients with enchondromatosis and hemangiomatosis (Maffucci syndrome).
• Patients with enchondromatosis more often die of gastrointestinal (GI) malignancies than of metastatic chondrosarcoma.


DIAGNOSIS
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
TESTS
• A rectal exam should be done to exclude prostate nodules
• 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 be excised in continuity with the tumor at the time of resection.
Lab
• 50% of osteosarcomas have an elevated alkaline phosphatase.
• Ewing sarcoma may be associated with an elevated ESR and lactate dehydrogenase.
• Prostatic-specific antigen to exclude prostatic carcinoma
• Calcium, phosphate, alkaline phosphatase
• Thyroid function tests to exclude thyroid carcinoma
• Elevated ESR and WBCs in osteomyelitis
• Serum protein electrophoresis and urine electrophoresis to exclude myeloma
Imaging
• Plain films provide the most important information regarding the nature of the lesion and guide further testing.
• Bone scan is done prior to biopsy, to look 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 radiograph and chest CT for metastatic disease
• Mammogram to exclude breast carcinoma
Diagnostic Procedures/Surgery
Bone biopsy
Pathological Findings
• Histology and special studies in combination with radiographic findings confirm the diagnosis.
• Ewing sarcoma expresses MIC-2 protein (CD99).
• Electron microscopy
- Glycogen granules in Ewing 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 that may respond more favorably to trastuzumab (Herceptin).
DIFFERENTIAL DIAGNOSIS
• Solitary metastatic lesion or myeloma, especially in patients >40 years
• 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, hyperparathyroidism)
• Synovial diseases (pigmented villonodular synovitis, synovial chondromatosis, degenerative or inflammatory synovitis)
• Myositis ossificans and repair reaction to trauma
• Avascular necrosis
TREATMENT
Inpatient surgery
GENERAL MEASURES
Diet
No special diet
Activity
Varies with stage of disease and treatment
MEDICATION (DRUGS)
First Line
• These drugs are administered according to specific protocols. Other protocols may be appropriate.
• Malignant fibrous histiocytoma 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 immune-modulating agent for osteosarcoma (under trial in Cancer Center Support Group and Pediatric Oncology Group studies)
• Ewing 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 nuclear multiple-gated acquisition ventriculogram 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
Second Line
Ondansetron (Zofran), dronabinol (Marinol), metoclopramide (Reglan), and others for nausea control.
SURGERY
• Resection with adequate margin is required to minimize risk of local persistence.
• For malignant fibrous histiocytoma and osteosarcoma, preresection neoadjuvant 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 dedifferentiated high-grade variety.
• Ewing 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 sarcoma lesions were irradiated. However, despite irradiation, local recurrence is common in up to 25% with pelvic lesions. Therefore, surgery with limb salvage is increasingly accepted. A dramatic decrease in size in Ewing 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.
FOLLOW-UP
PROGNOSIS
• 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%.
• Favorable prognostic factors for malignant fibrous histiocytoma and osteosarcoma include responsiveness to chemotherapy, distal portions of the extremities, small size, 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.
• Malignant fibrous histiocytoma, osteosarcoma, and Ewing sarcoma have an overall 50% survival with combined treatment modalities.
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 follow-up.
• Local recurrence risk for osteosarcoma with limb salvage is 10%.
• Leg-length discrepancy, infection, wound dehiscence, skin coverage problems, arterial and nerve injury, nonunion of bone grafts, and mechanical loosening of prosthetic implants can occur.
• Thoracotomy and continued chemotherapy are often recommended for metastatic disease to the lung.
• Ewing sarcoma, metastatic to the lung, is quite diffuse and is less amenable to thoracotomy.
PATIENT MONITORING
• Patients who require adjuvant chemotherapy are treated with maintenance chemotherapy after resection of the tumor.
• Blood counts for myelosuppression
• Serial echocardiograms when Adriamycin is being used; G-CSF often used to minimize neutropenia
• Chest radiographs obtained every 2 months for the 1st year, every 3 months for the 2nd year, and every 4 months in the 3rd year
• CT scans of the lungs are initially repeated every 6 months during 1st 2 years.
• Ewing sarcoma may recur >5 years after diagnosis.
REFERENCES
1. Enneking WF. Musculoskeletal Tumor Surgery, Vols. 1 and 2. New York: Churchill Livingstone, 1983.
2. Mendelsohn J. Jeremiah Metzger Lecture. Targeted cancer therapy. Trans Amer Clin Climatol Assoc. 2000;111:95-110.
3. Schajowicz F, McGuire MH. Diagnostic difficulties in skeletal pathology. Clin Orthop Rel Res. 1991;240:281-310.
4. 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(6):582-588.
5. Velez-Yanguas MC, Warrier RP. The evolution of chemotherapeutic agents for the treatment of pediatric musculoskeletal malignancies. Orthop Clin North Amer. 1996;27:545-549.
6. Womer RB. The cellular biology of bone tumors. Clin Orthop Rel Res. 1991;262:1221.
MISCELLANEOUS
• 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, postirradiation, and post-Paget osteosarcoma metastasize early.
• Chordoma: Rare malignant bone tumor that develops from the remnants of the primitive notochord. May be located in the sacrum or near the base of the skull. Usual course: Slowly progressive; recurrent; cure possible.