Osteogenic Sarcoma (Osteosarcoma)

Definition

• Incidence: ~3-4 per million population per year
• Male predominance: M:F = 1.6:1 (exception: parosteal osteosarcoma is more common in females)

Epidemiology & Age Distribution

1. First peak (75% of cases): Adolescents - coincides with the pubertal growth spurt (most 10-20 years)
2. Second peak: Older adults (>40 years), almost always secondary osteosarcoma

Classification (WHO 2013)

Pathogenesis

• RB mutations - present in up to 70% of sporadic cases; germline RB mutations (hereditary retinoblastoma) increase risk 1000-fold
• TP53 mutations - germline mutations underlie Li-Fraumeni syndrome; somatic mutations common in sporadic tumors
• MDM2 and CDK4 overexpression - inhibit p53 and RB function respectively; common in low-grade osteosarcomas
• CDKN2A inactivation - encodes p16 and p14 tumor suppressors
• MYC amplification - in up to 50% of cases; associated with poor prognosis

Clinical Presentation

• Pain - progressive, initially mild, may be misattributed to sports injury; later becomes severe; ~25% have night pain
• Palpable mass - progressively enlarging
• Pathologic fracture - may be the initial presentation
• Average diagnostic delay: ~15 weeks (patient delay 6 weeks + physician delay 9 weeks)
• Low-grade surface lesions may present with a painless mass

Imaging

Plain Radiograph (most valuable first-line tool)

• Mixed lytic and sclerotic pattern (spectrum from entirely lytic 13% to entirely sclerotic)
• Permeative, ill-defined borders
• Cortical destruction and eccentric extra-osseous soft-tissue mass
• Codman triangle - triangular shell of reactive periosteal bone at tumor margin (indicates aggressive tumor, not pathognomonic)
• Sunburst / hair-on-end periosteal reaction
• Onion-skin (lamellated) periosteal reaction

MRI (mandatory for local staging)

• Best modality to define intramedullary extent and soft tissue involvement
• Must image the whole affected bone to identify skip metastases (intraosseous foci separate from main tumor; ~5% of cases)
• Dynamic contrast-enhanced MRI assesses chemotherapy response

Other imaging

• CT chest - for pulmonary metastases (most common metastatic site)
• Bone scan - for skeletal metastases
• FDG-PET-CT - superior to bone scan for bone metastases; established role in evaluating chemotherapy response and detecting recurrence
• Pulmonary metastases may be mineralized and visible on bone scintigraphy; rarely cause pneumothorax

Morphology (Gross & Histology)

• Mandatory diagnostic criterion: Malignant tumor cells producing unmineralized osteoid or mineralized bone (fine lacelike osteoid, or broad sheets/primitive trabeculae)
• Pleomorphic cells with large hyperchromatic nuclei
• Bizarre tumor giant cells
• Abundant mitoses including abnormal forms (e.g., bipolar mitoses)
• Extensive necrosis and intravascular invasion

Variant Subtypes - Key Points

Staging & Spread

• All high-grade osteosarcomas are assumed to have occult micrometastases at presentation
• Spread is hematogenous - lungs are the primary site (peripheral, may mineralize)
• Skip metastases occur in ~5% within the same bone
• Lymph node spread is uncommon
• Before chemotherapy era: 80% of patients with apparently localized disease died of distant metastases within 2 years

Treatment

Standard Protocol (High-Grade Osteosarcoma)

1. Neoadjuvant chemotherapy (pre-operative) - MAP regimen: Methotrexate (high-dose), Doxorubicin (Adriamycin), Cisplatin (Platinum)
2. Wide surgical resection (limb-salvage surgery in most patients) OR amputation
3. Adjuvant chemotherapy (post-operative)
4. Pulmonary metastases resected if feasible (thoracotomy preferred over thoracoscopy as CT underestimates lesion count)

Histological Response to Neoadjuvant Chemotherapy

• >90% tumor necrosis = excellent response = very good prognosis
• Histologic response is the strongest predictor of long-term survival
• Dynamic MRI can assess response pre-operatively

Low-Grade Osteosarcoma

• Wide resection or amputation alone, no chemotherapy required

Limb Salvage vs. Amputation

• Limb salvage has become standard in the majority (~90%) of extremity tumors
• Pathologic fracture does not necessarily mandate amputation - limb salvage remains viable in select cases, though fracture worsens overall survival and metastasis risk
• Local recurrence after wide resection (~10%) carries very poor prognosis; usually requires radical amputation

Prognosis

• 90% tumor necrosis after neoadjuvant chemotherapy

• Non-metastatic at presentation
• Small, peripheral, ipsilateral pulmonary metastases
• Disease-free interval >1 year before relapse
• Complete surgical resection achievable

• Metastases at presentation
• Axial skeleton or pelvic primary
• Large tumor size
• Poor neoadjuvant chemo response (<90% necrosis)
• MYC amplification
• Rapid relapse; >8 nodules; nodules >3 cm; unresectable disease

Summary Mnemonic: "OSTEOSARCOMA"

• O - Osteoid production by malignant cells (defining feature)
• S - Second decade of life (peak)
• T - Tumor in metaphysis of long bones (distal femur #1)
• E - Extensive intramedullary spread
• O - Occult micrometastases assumed at presentation
• S - Sunburst / Codman triangle on X-ray
• A - Adolescent growth spurt (pathogenesis)
• R - RB and TP53 mutations (genetics)
• C - Chemotherapy (MAP) + surgery standard
• O - >90% necrosis = good prognostic response
• M - Metastases to lung (hematogenous)
• A - Amputation if wide excision not feasible

• Robbins & Kumar Basic Pathology, pp. 782-783
• Campbell's Operative Orthopaedics 15th Ed 2026, pp. 1211-1215
• Grainger & Allison's Diagnostic Radiology, pp. 1048-1049
• Recent systematic review: Prognostic factors in relapsed high-grade osteosarcoma (Br J Cancer, 2025 - PMID 40731087)