Osteosarcoma — Diagnosis & Treatment

Osteosarcoma is the most common primary malignant bone tumour, accounting for approximately 35% of all primary bone sarcomas. It is a high-grade tumour characterised by the production of osteoid or immature bone by malignant stromal cells. Osteosarcoma predominantly affects adolescents and young adults (the classic bimodal peak is adolescent and elderly), arises in the metaphysis of long bones around the knee in the majority of cases, and is treated with a combination of neoadjuvant chemotherapy and wide surgical resection. Understanding the diagnosis, staging, management, and prognostic factors is essential for the orthopaedic trainee and consultant.

• Epidemiology: incidence approximately 3–5 per million per year; bimodal age distribution — primary peak in adolescence (10–20 years — during the rapid bone growth phase; male predominance 1.5:1); secondary peak in the elderly (6th–7th decade — associated with Paget`s disease, prior irradiation, or other predisposing conditions); the distal femur is the single most common site (approximately 30%), followed by the proximal tibia (approximately 15%) and proximal humerus (approximately 10%); approximately 80–85% arise in the appendicular skeleton
• Risk factors: Paget`s disease of bone (sarcomatous transformation occurs in approximately 1% — secondary osteosarcoma in elderly); prior irradiation (post-radiation sarcoma — develops 5–30 years after radiotherapy); hereditary retinoblastoma (RB1 gene mutation — both retinoblastoma and osteosarcoma are driven by RB1 loss of function); Li-Fraumeni syndrome (TP53 mutation); Rothmund-Thomson syndrome; bone infarcts; fibrous dysplasia (rarely)
• Molecular biology: loss of tumour suppressor genes — RB1 (retinoblastoma gene; located on chromosome 13q14) and TP53 (p53 gene) are the most important drivers; both are involved in cell cycle regulation; amplification of MDM2 (antagonises p53) is found in secondary osteosarcoma (Paget`s-related); the complex, highly rearranged karyotype of osteosarcoma makes targeted molecular therapy challenging

• History: persistent pain around the knee (or other affected site) — initially activity-related but becoming constant and nocturnal; swelling of the limb (palpable mass); the pain does not respond to NSAIDs (unlike osteoid osteoma); pathological fracture as the presenting feature in approximately 5–10% of cases; systemic symptoms (weight loss, fatigue, fever) are uncommon in localised osteosarcoma but may be present with metastatic disease
• Examination: a firm, tender mass over the affected bone; warmth and erythema of the overlying skin (due to increased vascularity of the tumour); restricted adjacent joint motion; the knee or hip is the most commonly affected joint; lymphadenopathy is rare (osteosarcoma spreads haematogenously to the lungs — lymph node metastases are uncommon); assess the neurovascular status of the limb
• Alkaline phosphatase (ALP) and LDH: elevated ALP and LDH are associated with osteosarcoma; elevated LDH is an independent adverse prognostic factor; these markers are not diagnostic but are used for monitoring response to chemotherapy and detecting recurrence

• Plain radiographs: the first investigation; the classic features of conventional osteosarcoma on X-ray — (1) mixed lytic and sclerotic lesion arising in the metaphysis; (2) Codman`s triangle — a triangular elevation of the periosteum at the margin of the tumour, representing reactive periosteum lifted by the expanding tumour; (3) sunburst pattern — spiculated periosteal new bone radiating perpendicular to the cortex along the fibrous septa; (4) cortical destruction and soft tissue mass; these features together are highly suggestive of osteosarcoma; however, plain X-ray alone is not diagnostic and must be followed by MRI and biopsy
• MRI: the gold standard for local staging; defines the intramedullary extent (including skip metastases — separate foci within the same bone or an adjacent bone), cortical breakthrough, soft tissue extension, and proximity to the neurovascular bundle; gadolinium enhancement maps the most viable tumour tissue (guides biopsy to the most representative site)
• Staging workup: (1) local MRI (with and without contrast); (2) CT chest (lung metastases are the primary site of distant spread — present in approximately 15–20% at diagnosis; multiple bilateral pulmonary nodules are the typical appearance); (3) bone scan or PET-CT (for skip metastases and distant bone metastases); (4) CT-guided core needle biopsy (performed at the specialist tumour centre — see biopsy principles); (5) blood: FBC, LFTs, ALP, LDH, CRP, renal function (for chemotherapy planning)
• Enneking staging: Stage IIA (high-grade, intracompartmental — within the bone and adjacent soft tissue compartment); Stage IIB (high-grade, extracompartmental — beyond the compartment boundary); Stage III (any grade with regional or distant metastases); conventional osteosarcoma is typically IIB at presentation

• Neoadjuvant (pre-operative) chemotherapy: the MAP protocol is the international standard — high-dose Methotrexate (with leucovorin rescue) + Adriamycin (doxorubicin) + cisPlatin; typically 3 cycles pre-operatively over 9–10 weeks; neoadjuvant chemotherapy allows: (1) treatment of micrometastatic disease; (2) tumour shrinkage (improving surgical margins); (3) assessment of tumour response (Huvos grade — histological necrosis of the resected specimen is the most important prognostic factor); (4) downstaging the soft tissue component; osteosarcoma chemosensitivity is high — approximately 60–70% of patients are `good responders` (Huvos Grade III/IV — >90% necrosis)
• Wide surgical resection (limb-salvage surgery): the goal is en bloc resection with wide margins; approximately 90% of osteosarcomas around the knee are now managed with limb salvage rather than amputation; reconstruction options — mega-prosthesis (most common for distal femur and proximal tibia), osteoarticular allograft, allograft-prosthesis composite, rotationplasty (for very young children — the distal part of the limb is rotated 180° and reattached so the ankle functions as a knee joint); the choice depends on the patient`s age, tumour size, and skeletal maturity
• Adjuvant (post-operative) chemotherapy: continuation of the MAP protocol after surgery (typically 3 further cycles — total of 6 cycles); the post-operative protocol may be adjusted based on the Huvos grade — in poor responders (Huvos I/II — <90% necrosis), additional agents (ifosfamide + etoposide) are added; this strategy (response-adapted chemotherapy) aims to improve outcomes in poor responders
• Pulmonary metastases: lung metastases are present in ~15–20% at diagnosis; patients with resectable pulmonary metastases who undergo complete surgical resection (thoracotomy and wedge resection of all metastases) have a 5-year survival of approximately 20–30%; bilateral thoracotomy is required if metastases are bilateral; all pulmonary nodules >4 mm identified on staging CT chest should be treated as metastatic disease; complete resection of all metastases is required — debulking (incomplete resection) is not beneficial

• Huvos grading and prognostic significance: the Huvos grading system classifies histological tumour response to neoadjuvant chemotherapy in the resected specimen; Grade I — <50% necrosis (poor response); Grade II — 50–90% necrosis; Grade III — >90% necrosis; Grade IV — 100% necrosis; Grades III–IV (`good responders`) have a 5-year survival of ~80–90%; Grades I–II (`poor responders`) have a 5-year survival of approximately 45–55%; the Huvos grade is the single most important prognostic factor in osteosarcoma (outweighing tumour size, site, and subtype)
• Skip metastases: satellite tumour deposits within the same bone or in the adjacent bone (e.g., a skip lesion in the proximal tibia from a primary in the distal femur); present in approximately 2–10% of cases; usually indicates a worse prognosis; must be identified on pre-operative MRI (the entire length of the bone must be imaged); if a skip metastasis is present, it must be included in the resection — the surgical field must extend to include both the primary tumour and the skip lesion; the presence of skip metastases does not automatically mandate amputation but significantly complicates limb salvage planning
• Second primary malignancies and RB1 mutation: patients with hereditary retinoblastoma (germline RB1 mutation) have a dramatically elevated lifetime risk of second primary malignancies — osteosarcoma, soft tissue sarcoma, and melanoma are the most common; osteosarcoma in RB1 mutation carriers is more commonly axial and less amenable to limb salvage; genetic counselling and long-term surveillance of RB1 mutation carriers is important; the orthopaedic surgeon who treats a child with osteosarcoma should be aware if the patient has a history of retinoblastoma

• Osteosarcoma: most common primary malignant bone tumour; adolescent peak (10–20 years); distal femur most common site; metaphysis of long bones; Codman`s triangle + sunburst pattern on X-ray
• X-ray features: Codman`s triangle (periosteal elevation at tumour margin); sunburst pattern (spiculated periosteal new bone); mixed lytic + sclerotic; cortical destruction; soft tissue mass
• RB1 + TP53: the two primary tumour suppressor genes; RB1 germline mutation = hereditary retinoblastoma + osteosarcoma risk; TP53 mutation = Li-Fraumeni syndrome; both drive cell cycle dysregulation
• MAP protocol: Methotrexate + Adriamycin + cisPlatin; neoadjuvant (3 cycles pre-op) + adjuvant (3 cycles post-op); total 6 cycles; response-adapted post-op protocol for poor responders (add ifosfamide + etoposide)
• Huvos grading: MOST IMPORTANT prognostic factor; Grade III/IV (>90% necrosis = good responder) → ~80–90% 5-year survival; Grade I/II (poor responder) → ~45–55%; determined on the resected specimen after neoadjuvant chemo
• Staging workup: MRI local + CT chest + bone scan/PET-CT + biopsy (at specialist centre); CT chest for pulmonary metastases (primary site of distant spread; present in 15–20% at diagnosis)
• Limb salvage: ~90% of cases; mega-prosthesis most common reconstruction; wide margins mandatory; biopsy must be planned in the resection field
• Parosteal osteosarcoma: low-grade; posterior distal femur; densely sclerotic; excellent prognosis (>90% survival); wide resection; chemotherapy not always required
• Secondary osteosarcoma: Paget`s disease (elderly; axial skeleton); prior irradiation; very poor prognosis (~15–30% 5-year survival)
• Pulmonary metastases: complete surgical resection (thoracotomy) required; 20–30% 5-year survival if completely resected; bilateral thoracotomy for bilateral disease; incomplete resection is not beneficial