Primary Malignant Bone Tumor – Causes, Symptoms, Diagnosis, Treatment and Ongoing care

Basics

Description

  • 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

Epidemiology

Incidence

  • 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).
  • Race:
    • 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.

Risk Factors

  • Previous irradiation is a risk factor for osteosarcoma and MFH.
  • Rapid bone growth, teenage growth spurt
  • Fibrous dysplasia

Genetics

  • 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)
  • 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-mycmdm-2SAS, and cyclin-dependent kinase.

General Prevention

Irradiation is the only known environmental risk factor.

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 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.

Ewing Sarcoma, Ewing, Osteosarcoma, Bone tumor, malignant bone tumors, giant cell tumor, malignant fibrous histiocytoma, childhood malignancies, spindle cells, growth spurt,

Diagnosis

History

  • Pain with weight bearing, at rest, and at night; often dull or aching
  • Swelling
  • Tenderness
  • Fracture with minor trauma (pathologic fracture present in 10–15% of cases)
  • Minor injury may bring attention to lesion.

Physical Exam

  • 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

Lab

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

Imaging

Initial approach

  • 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

Diagnostic Procedures/Surgery

  • 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.

Pathological Findings

  • 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

Differential Diagnosis

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  • 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

Treatment

Medication

  • 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].
  • Osteosarcoma:
    • 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
  • Precautions:
    • 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:
    • Myelosuppression
    • Renal tubular dysfunction with ifosfamide
    • Renal and hepatic dysfunction and GI mucositis with MTX
    • Nephrotoxicity and ototoxicity with cisplatin

Surgery/Other Procedures

  • 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.

Ongoing Care

Follow-Up Recommendations

Patient Monitoring

  • 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.

Patient Education

Refer to local branch of American Cancer Society for information and support groups.

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% (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.

Complications

  • 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.

References

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.

Codes

ICD9

  • 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

Snomed

  • 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)

Clinical Pearls

  • 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.

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