DESCRIPTION

Osteosarcoma is an aggressive bone cancer that arises from primitive cells of likely mesenchymal origin. The malignant cells are usually pleomorphic spindle cells that lay down abnormal appearing bone (osteoid).

EPIDEMIOLOGY

• Osteosarcoma is the most common pediatric bone cancer.
• There is a bimodal age distribution in incidence, with the first peak in adolescence (median age of 16 years) and the second peak in adults aged >65 years, often as a second malignancy or in association with Paget disease.
• In the United States, there are approximately 450 cases of osteosarcoma in children ages 0 to 19 years each year.
• Incidence of osteosarcoma coincides with skeletal growth spurt and is often seen in tall individuals.
• Males are more frequently affected than females (5.4 and 4 per million persons per year, respectively)—particularly males aged 15 to 19 years.
• Osteosarcoma is more common in African American (6.8 per million per year) and Hispanic children (6.5 per million per year) compared to European American children (4.6 per million per year).

RISK FACTORS

• Ionizing radiation exposure to bones from prior radiation therapy for another cancer and less commonly from diagnostic imaging
• Hereditary cancer predisposition syndromes (germline mutations):
  • Hereditary retinoblastoma (Rb gene mutation): autosomal dominant; commonly presents with leukocoria or strabismus
  • Li-Fraumeni syndrome (TP53 mutation): autosomal dominant; also increases risk for other sarcomas, brain tumors, adrenocortical carcinomas, and premenopausal breast cancer
  • Werner syndrome (RECQL2/WRN mutation): autosomal recessive; presents with skin changes associated with premature aging, short stature, bilateral cataracts
  • Bloom syndrome (RECQL3/BLM mutation): autosomal recessive; sensitivity to sunlight, short stature, mild microcephaly, café au lait spots, predisposition to variety of cancers
  • Rothmund-Thomson syndrome (RECQL4 mutation): autosomal recessive; poikilodermatous skin, juvenile cataracts, skeletal dysplasia, predisposition to skin cancer
  • RAPADILINO syndrome (RECQL4 mutation); autosomal recessive; the name is an acronym for the characteristic features: radial malformations, patella and palate anomalies, dislocated joints and diarrhea, limb abnormalities and normal intelligence.
  • Baller-Gerold syndrome (RECQL4 mutation); autosomal recessive; craniosynostosis and abnormalities of bones and hands
  • Diamond-Blackfan anemia (ribosomal gene and GATA1 mutations); autosomal dominant; congenital erythroid aplasia presenting with severe anemia in infancy
• Bone diseases
  • Enchondromatosis
  • Hereditary multiple exostoses
  • Fibrous dysplasia, which can be seen in McCune-Albright syndrome
  • Paget disease of the bone—more relevant in patients >65 years of age

PATHOPHYSIOLOGY

• No single genetic change, although karyotypes are typically highly abnormal
• Histologic hallmark of osteosarcoma is osteoid formation.
• Most cases of pediatric osteosarcoma are high-grade cancers, although lower grade variants are seen.
• At diagnosis, 80% of patients will have radiographically localized disease, and 20% will have radiographically metastatic disease.
• In >80% of cases, the tumor originates in the metaphysis of long bones (most commonly distal femur, tibia, and humerus). Less common primary sites include the pelvis, facial bones, and scapula.
• The most common sites of metastases are lungs and other bones. Regional lymph node or extraosseous involvement are rare.