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Osteosarcoma
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Osteosarcoma
Definition
Osteosarcoma is a malignant tumor defined by the production of osteoid matrix or mineralized bone by malignant cells. It is the most common non-hematologic primary malignancy of bone, with an estimated annual incidence of approximately 3-4 per million population.
- Robbins & Kumar Basic Pathology, p. 782
- Campbell's Operative Orthopaedics 15th Ed 2026, p. 1212
Epidemiology
| Feature | Details |
|---|---|
| Age | Bimodal: Peak in 2nd decade (adolescent growth spurt); 2nd smaller peak in older adults |
| Sex | Slight male predominance (1.35-1.6 : 1); exception - parosteal type is more common in females |
| Location | Most common in metaphysis of long bones; ~50-75% near the knee (distal femur, proximal tibia), also proximal humerus |
| Race | No significant racial differences |
About 75% occur before age 20. The tumor peaks near the growth plate of rapidly growing bones, where increased proliferation predisposes to oncogenic mutations.
Classification (WHO 2013)
Seven distinct categories:
- Conventional osteosarcoma (~75% of all cases) - high-grade intramedullary
- Telangiectatic osteosarcoma - purely lytic, can mimic aneurysmal bone cyst
- Low-grade central (intramedullary) osteosarcoma - indolent, can mimic fibrous dysplasia
- Small cell osteosarcoma
- Parosteal osteosarcoma - low-grade, arises on bone surface; peak in 3rd-4th decades; posterior distal femur
- Periosteal osteosarcoma - intermediate grade surface lesion
- High-grade surface osteosarcoma - rarest, most aggressive surface type
Secondary osteosarcoma arises in the setting of Paget disease, previous radiation, bone infarcts, or dedifferentiated chondrosarcoma.
- Grainger & Allison's Diagnostic Radiology, p. 1048
Pathogenesis & Molecular Genetics
Osteosarcomas have complex karyotypes with numerous chromosomal aberrations:
- RB mutations: present in up to 70% of sporadic cases; germline RB mutation increases risk 1000-fold
- TP53 mutations: germline mutations underlie Li-Fraumeni syndrome; common in sporadic tumors
- MDM2 and CDK4 overexpression (inhibit p53 and RB): found in many low-grade osteosarcomas
- CDKN2A (INK4a) inactivation: encodes p16 and p14 tumor suppressors
- MYC amplification: seen in up to half of cases; associated with particularly poor prognosis
Predisposing syndromes: Li-Fraumeni syndrome, hereditary retinoblastoma, Rothmund-Thomson syndrome.
- Robbins & Kumar Basic Pathology, p. 782-783
Clinical Presentation
-
Pain is the primary symptom - initially may mimic benign musculoskeletal conditions
-
Progressive, painful, enlarging mass
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Night pain occurs in only ~25% of patients
-
Pathologic fracture may be the first presentation
-
Diagnosis delay averages ~15 weeks (6 weeks patient delay + 9 weeks physician delay) - key reasons: failure to obtain or repeat radiographs when symptoms persist
-
Campbell's Operative Orthopaedics 15th Ed 2026, p. 1212
Imaging
Plain Radiographs (most valuable for diagnosis)
Typically an aggressive metaphyseal lesion with mixed lytic and sclerotic appearance:
- Codman triangle: lifting of the periosteum forms a triangular shell of reactive bone - indicates aggressive tumor but is NOT pathognomonic
Distal femur osteosarcoma. Prominent bone formation extending into soft tissue. Arrow = Codman triangle (Robbins & Kumar Basic Pathology, Fig. 19.15)
- Periosteal new bone can also appear sunburst/spiculated or onion-skin (lamellated) pattern
- Spectrum: entirely lytic (13%) → mixed → entirely sclerotic
MRI
- Not essential for diagnosis but mandatory for local surgical staging
- Defines tumor extent within bone, soft tissue involvement, joint involvement, neurovascular proximity
- Full-bone sequence required to exclude skip metastases
CT Chest
- Must be done to screen for pulmonary metastases (most common site)
FDG-PET/CT
- Superior to bone scan for detecting bone metastases when resources allow
Gross and Histologic Morphology
Gross: Bulky, gritty, tan-white tumor; areas of hemorrhage; destroys cortex and invades soft tissue; extensive intramedullary spread
Osteosarcoma of distal femur: extensive cortical disruption and subperiosteal expansion. Tumor confined to metaphyseal side of growth plate (Robbins & Kumar, Fig. 19.16)
Histology:
- Diagnosis requires malignant tumor cells producing unmineralized osteoid or mineralized bone - typically fine, lace-like; may form broad sheets or primitive trabeculae
- Tumor cells show pleomorphism, large hyperchromatic nuclei, bizarre giant cells, abundant mitoses (including abnormal bipolar forms)
- Extensive necrosis and intravascular invasion common
- Histological subtypes: osteoblastic, fibroblastic, chondroblastic (all classified as conventional if they produce osteoid)
Lace-like osteoid produced by pleomorphic malignant tumor cells bridging lamellar bone. Arrow = abnormal mitotic figure (Robbins & Kumar, Fig. 19.17)
Management
Treatment of high-grade osteosarcoma requires a multimodal approach:
| Phase | Approach |
|---|---|
| Neoadjuvant chemotherapy | MAP protocol (Methotrexate, Adriamycin/doxorubicin, Cisplatin) before surgery |
| Surgery | Wide excision (limb-salvage surgery in most cases); amputation if limb salvage not achievable |
| Adjuvant chemotherapy | Continued postoperatively |
Key points:
- All osteosarcomas are assumed to have occult micrometastases at diagnosis
- Chemotherapy has dramatically improved outcomes
- Histological response to neoadjuvant chemo is a major prognostic factor (>90% necrosis = "good responder")
- Limb-salvage surgery does not compromise survival compared to amputation when adequate margins are achieved
Prognosis
| Group | 5-Year Survival |
|---|---|
| Localized disease (no overt metastases) | ~70% with chemotherapy |
| Metastatic at presentation, recurrent, or secondary | <20% |
Metastasis occurs hematogenously - most commonly to lungs, then bones, brain, and other sites.
Prognostic factors for relapsed disease include: site of relapse, time to relapse, number of metastases, and surgical resectability of metastases (per 2025 systematic review, PMID: 40731087).
- Robbins & Kumar Basic Pathology, p. 783
Summary Table
| Feature | Detail |
|---|---|
| Most common site | Distal femur > proximal tibia > proximal humerus |
| Classic age | 10-20 years |
| Key radiologic sign | Codman triangle, sunburst pattern |
| Diagnostic requirement | Malignant cells producing osteoid |
| Key mutations | RB (70%), TP53, MDM2, CDKN2A, MYC |
| First-line treatment | Neoadjuvant chemo + surgery + adjuvant chemo |
| 5-year survival (localized) | ~70% |
| Primary metastatic site | Lungs |
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