What is the clinical presentation, diagnosis, and treatment of osteosarcoma?

Osteosarcoma: High-Yield Board Review

Epidemiology & Demographics

Osteosarcoma is the most common primary malignant bone tumor with a bimodal age distribution peaking at 16 years (adolescence) and again at 60 years (elderly). 1

• Incidence: 0.2-0.3 cases per 100,000 per year in general population, but increases to 0.8-11 per 100,000 per year in adolescents aged 15-19 1
• Male:female ratio: 1.4:1 1
• Mortality: Approximately 0.15 per 100,000 per year 1
• Location: 65% arise in extremities (most commonly around the knee—distal femur and proximal tibia), with axial/craniofacial involvement more common in elderly patients 1

Clinical Presentation

The classic triad is pain, followed by localized swelling, and limitation of joint movement. 1

• Pain is typically the initial symptom, progressive in nature 1
• Pathologic fracture occurs occasionally 2
• Symptoms are often present for weeks to months before diagnosis 2

Diagnostic Workup

Initial Imaging & Biopsy Protocol

Any patient with radiographic findings suggesting bone sarcoma must be referred to a specialized bone sarcoma center BEFORE biopsy is performed. 1, 3

• Critical pitfall: Inappropriate biopsy technique can permanently compromise limb salvage options or even cure 1, 3
• Plain radiographs show mixed sclerotic and lytic lesion in the metaphyseal region 2
• Definitive diagnosis requires open surgical biopsy (not needle biopsy alone) performed by or under supervision of the surgical team 1
• Biopsy must be done AFTER complete imaging of the affected bone 1

Complete Staging Evaluation

Before any biopsy, obtain:

Local disease assessment:

• Plain radiographs in two planes of the entire affected bone 1
• MRI of entire involved bone plus neighboring joints to evaluate intramedullary extension, soft tissue involvement, neurovascular relationships, and skip lesions 1, 3

Metastatic disease assessment:

• Chest CT scan (spiral technique, ≤5mm collimation, single breath-hold) to detect pulmonary metastases 1, 3
• Bone scintigraphy (and/or whole-body MRI) to rule out bone metastases 1, 3
• Chest X-ray (though CT is superior) 1

Laboratory evaluation:

• Complete blood count with differential 1
• Renal function: creatinine and glomerular filtration rate 1
• Electrolytes including magnesium and phosphate 1
• Liver function: transaminases 1
• Alkaline phosphatase (AP) and lactate dehydrogenase (LDH) - non-specific but elevated levels correlate with adverse outcomes 1, 4
• Coagulation profile 1
• Cardiac echocardiogram (baseline before anthracycline therapy) 5

Special consideration: Sperm banking should be discussed before chemotherapy 1, 3

Histopathology

By definition, malignant cells must produce osteoid for diagnosis of osteosarcoma. 1

High-Grade Variants (80-90% of cases):

Conventional osteosarcoma subtypes:

• Osteoblastic (most common) 1
• Chondroblastic 1
• Fibroblastic 1
• Telangiectatic 1
• Mixed 1
• Small cell osteosarcoma 1
• High-grade surface osteosarcoma 1

Low-Grade Variants:

• Paraosteal osteosarcoma: Low-grade tumor arising on bone surface 1
• Low-grade central osteosarcoma 1

Intermediate-Grade:

• Periosteal osteosarcoma: Intermediate-grade chondroblastic variant 1

Secondary Osteosarcoma:

• High-grade malignancy in bone with pre-existing abnormalities (Paget disease, radiation-induced changes) 1

Confirmation by pathologist with bone tumor expertise is mandatory. 1

Staging Systems

Enneking (Musculoskeletal Tumor Society) System - Most Widely Used

Based on three factors:

1. Malignancy grade (low vs. high)
2. Extension (intracompartmental vs. extracompartmental)
3. Presence of metastases 1

Stage IIB: High-grade tumor extending into adjacent soft tissue without detectable metastases - represents approximately 70% of cases at presentation 1

UICC-TNM 6th Edition

• Advancement of Enneking system 1

Prognostic Factors

Adverse Prognostic Indicators (Board Favorite):

At presentation:

• Detectable metastases at diagnosis (most significant - reduces 2-year event-free survival from 75% to 21%) 1, 4
• Age >40 years 1, 4
• Non-extremity (axial) location 1, 4
• Large tumor volume 1
• Elevated serum alkaline phosphatase or LDH 1, 4

Post-treatment:

• Poor histological response to preoperative chemotherapy (<90% tumor necrosis) 1, 4

In metastatic disease:

• Multiple metastatic sites (especially bone ± lung) 4
• ≥3 metastatic lesions (2-year disease-free survival 28% vs. 78% for 1-2 lesions) 4
• Bilateral lung involvement 4

Favorable Prognostic Factors:

• Complete surgical resection of all disease sites (most important - 48% long-term survival vs. 5% without) 4, 5
• Good histologic response to chemotherapy (>90% necrosis) 4
• Longer time to first relapse 4
• Solitary metastases 4
• Unilateral lung metastases 4

Treatment Algorithm

Localized Disease (Standard of Care)

The standard treatment is neoadjuvant chemotherapy → surgical resection → adjuvant chemotherapy, which increases 5-year survival from <20% to 60-80%. 1, 3, 2

Phase 1: Neoadjuvant Chemotherapy (2-6 cycles)

MAP regimen is the most frequently used first-line treatment:

• M: High-dose Methotrexate (≥12 g/m² in children or ≥8 g/m² in adults with leucovorin rescue) 3, 5
• A: Doxorubicin (Adriamycin) 3, 5
• P: Cisplatin 3, 5

Alternative if methotrexate contraindicated: Doxorubicin + Cisplatin 5

Some centers add: Ifosfamide to the regimen 1, 3

Purpose of neoadjuvant therapy:

• Facilitate surgical resection 5
• Assess tumor response (prognostic information) 1
• Treat micrometastases 5

Critical point: High-dose methotrexate requires mandatory inpatient monitoring 3

Re-staging: Repeat all imaging modalities before surgery 1, 3

Phase 2: Surgical Resection

90-95% of patients should undergo limb-salvage surgery rather than amputation. 3, 2

Surgical principles:

• Wide surgical margins with histologically clear margins are essential to prevent local recurrence 1, 3, 5
• En bloc resection 5
• Margin adequacy is critical regardless of chemotherapy response 1
• Must be performed at specialized center with bone tumor surgical expertise 3
• Special consideration for skeletally immature patients requiring growth-preserving techniques 3

Timing: After completion of neoadjuvant chemotherapy 5

Phase 3: Adjuvant Chemotherapy

Use same agents as neoadjuvant therapy for total treatment duration of 6-12 months. 1, 3, 5

Important board concept: Although histological response provides prognostic information, altering adjuvant chemotherapy in poor responders has NOT been proven to improve outcomes 1, 5

Metastatic Disease at Presentation

Approximately 10-20% of patients present with metastatic disease, but 30% can become long-term survivors with aggressive multimodal therapy. 4, 5

Treatment approach:

• Same MAP chemotherapy regimen as localized disease 5
• Aggressive surgical resection of BOTH primary tumor AND all metastatic sites (when feasible, simultaneous resection preferred) 3, 5
• Complete surgical clearance of all lung metastases is essential for survival 5
• Repeated thoracotomies often indicated for recurrent pulmonary metastases 1, 5

Survival with limited pulmonary metastases: 40% 5-year survival achievable with complete surgical clearance 1, 4

Overall metastatic disease survival:

• 5-year overall survival: 20-30% (vs. 60% for localized) 4
• 2-year event-free survival: 21% (vs. 75% for localized) 4

Recurrent Disease

Treatment: Combination of second-line chemotherapy and metastasectomy 1, 5

Second-line chemotherapy options:

• Ifosfamide ± etoposide ± carboplatin 5
• High-dose methotrexate 1
• Gemcitabine + docetaxel 5
• Targeted agents: sorafenib or regorafenib 5

High-dose ifosfamide + etoposide: 59% overall response rate but considerable toxicity 4

Role of Radiotherapy

Radiotherapy is NOT standard treatment for resectable osteosarcoma. 3, 5

Limited indications:

• Unresectable primary tumors 3, 5
• Inadequate surgical margins 3
• Palliation of locally recurrent disease 3

Follow-Up Surveillance Protocol

Years 0-3: Every 3 months 1, 3 Years 3-5: Every 6 months 1, 3 Years 5-10: Every 8-12 months 1, 3 Beyond 10 years: Pediatric patients should be followed longer due to long-term toxicity 1, 3

Required examinations:

• Chest imaging (X-ray every 2-6 months, CT every 6 months) 1, 3
• Local imaging (plain radiographs and MRI) only for symptoms 3
• Monitor for chemotherapy, surgery, and radiotherapy toxicities 3

High-Yield Board Concepts

Most Common Sites of Metastasis:

1. Lung (most common) 4
2. Bone (second most common) 4

Relapse Statistics:

• 30-40% of initially localized disease will relapse 4
• 80% of metastatic disease at presentation will relapse 4

Skip Lesions:

• Intramedullary tumor foci without direct contact with primary lesion 1
• Detected by MRI of entire bone 1
• Must be identified before surgery 1

Chemotherapy-Induced Survival Improvement:

• Pre-chemotherapy era: 20% 5-year survival with surgery alone 1, 3
• Modern era with chemotherapy: 60-80% 5-year survival for localized disease 1, 2

Critical Pitfall to Avoid:

Never perform biopsy before referring to specialized center - inappropriate technique can eliminate limb salvage options 1, 3