Description

• Primary malignant bone tumors are rare (<1% of all tumors). Patients >40 years; rule out more common metastatic disease (breast, lung, prostate, thyroid, kidney).
• Osteogenic sarcomas arise from mesenchymal cells capable of differentiating into bone, cartilage, or fibrous tissue. The three histologic types are:
  • Osteosarcoma: characterized by the production of osteoid or immature bone by malignant cells
  • 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 of unknown histologic origin
• Malignant fibrous histiocytoma (MFH): pleomorphic sarcoma; 10-year survival 20% for high grade, 90% for low grade
• Giant cell tumor of bone (GCTB) has both benign (90%) and malignant forms; prefers epiphyseal long bone, often recurs; 5–10% of primary bone tumors; very destructive
• Chordoma develops from remnants of primitive notochord at base of skull or sacrum; rare; slowly progressive; recurrent; cure possible

Epidemiology

Incidence

• Rare: Estimated 2,970 primary bone tumors is diagnosed in the United States in 2015; 1,490 deaths
• In adults: most common osteosarcoma (35%), chondrosarcoma (30%), Ewing sarcoma (16%)
• In resource-rich populations: Malignant bone tumors represent 3–5% of cancers diagnosed in children 0 to 14 years of age and 7–8% of cancers in adolescents 15 to 19 years of age (1)[A]; third most common childhood cancer (after leukemia and brain tumor)
• In children: Most common is osteosarcoma (52%), Ewing sarcoma (34%) second, and chondrosarcoma third.
• Predominant age
  • Osteosarcoma: bimodal: ages 13 to 16 years and >65 years
  • Chondrosarcoma: 3rd to 7th decades
  • Fibrosarcoma: 2nd to 6th decades
  • Ewing sarcoma: children and teen aged 10 to 15 years (70% of Ewing patients <20 years of age)
  • MFH: adults and elderly
  • GCTB: skeletally mature young adult in 2nd to 4th decades
  • Chordoma: >40 years
• Predominant gender
  • For most, male = female
  • Osteosarcoma, male > female (1.5:1); Ewing sarcoma, male > female; chondrosarcoma, male > female (2:1); chordoma, males > females
• Race
  • Ewing sarcoma is more common in Caucasian than in African American children.
  • Osteosarcoma is slightly more common in African American than in Caucasian children.

Etiology and Pathophysiology

• Generally unknown but likely multifactorial
• Chondrosarcoma may arise in preexisting enchondroma or exostosis.
• MFH often follows irradiation or arises in old bone infarct.
• GCTB RANKL-RANK-OPG signal pathway involved

Genetics

• Genetic risk factors include:
  • Paget disease: osteosarcoma
  • Multiple hereditary exostosis: chondrosarcoma
  • Multiple enchondromatosis (Ollier disease): chondrosarcoma
  • Enchondromatosis and hemangiomatosis (Maffucci syndrome): chondrosarcoma
    • Germline retinoblastoma, especially after radiation: osteosarcoma
    • Li-Fraumeni syndrome (germline p53 or CHEK2 mutation): osteosarcoma
    • Rothmund-Thomson syndrome (autosomal recessive): osteosarcoma
    • RAPADILINO syndrome: osteosarcoma
    • Diamond-Blackfan anemia (disorder of bone marrow): osteosarcoma
• Tumor genetics
  • Ewing sarcoma has chromosomal translocation t(11;22) (q24;q12) in 90% of tumors and resulting EW5-FLI1 fusion protein. Mutation in the EWSR1 causes Ewing sarcoma (somatic mutation).
  • Osteosarcoma shows loss of retinoblastoma 1 gene (RB1) and p53 suppressor genes and amplification of the genes c-myc, mdm-2, SAS, and cyclin-dependent kinase.

Risk Factors

• High fluoride exposure, residing on farmland (1)[A]
• Previous irradiation is a risk factor for osteosarcoma and MFH.
• Rapid bone growth, teenage growth spurt
• Fibrous dysplasia, uncommon genetic disorder

Commonly Associated Conditions

• Genetic conditions listed previously
• Patients with enchondromatosis more often die of GI malignancies than of metastatic chondrosarcoma.