What is osteosarcoma, its risk factors, clinical presentation, diagnosis, and management in teenagers and young adults?

Osteosarcoma: Comprehensive Overview

Basic Science and Pathophysiology

Osteosarcoma is a primary malignant bone tumor defined by the direct production of osteoid or immature bone by malignant cells. 1

Epidemiology and Demographics

• Osteosarcoma is the second most frequent primary bone cancer, comprising 4% of solid cancers in children and 3% in teenagers and young adults 1
• Incidence is 0.2-0.3 per 100,000 per year overall, but rises to 0.8-1.1 per 100,000 per year in adolescents aged 15-19 years 1
• Bimodal age distribution: first peak in teenagers/young adults (10-25 years), second peak in seventh and eighth decades 1, 2
• Male predominance with ratio of 1.4:1 1
• Slightly more common in Black patients 1
• Survival rates are higher in younger patients 1

Histologic Classification

• Conventional (high-grade) osteosarcoma accounts for 80-90% of cases with subtypes including osteoblastic, chondroblastic, and fibroblastic variants 1
• Other high-grade variants include telangiectatic, small cell, and high-grade surface osteosarcoma 1
• Low-grade variants include low-grade central and parosteal osteosarcoma 1
• Periosteal osteosarcoma is an intermediate-grade variant 1

Risk Factors

• Previous radiation therapy 1
• Paget's disease of bone 1
• Germline genetic abnormalities: Li-Fraumeni syndrome, Werner syndrome, Rothmund-Thomson syndrome, Bloom syndrome, and familial retinoblastoma 1

Molecular Pathogenesis

• Complex genome rearrangements via chromoplexy and chromothripsis are characteristic 3
• TP53 loss-of-function mutations and MYC amplification are associated features 3

History and Clinical Presentation

Cardinal Symptoms

Pain is the cardinal symptom, and night pain is a critical "red flag" requiring immediate investigation. 4

• Pain often occurs at rest or during the night, distinguishing it from mechanical musculoskeletal injuries 1, 4
• Pain is often intermittent initially and may be confused with growing pains 1
• Localized swelling follows pain and indicates tumor progression through cortex 1
• Limitations of joint movement develop as disease progresses 1
• Average duration of symptoms before presentation is 3 months 4
• A history of recent injury does NOT exclude bone cancer and must not prevent appropriate diagnostic workup 4

Anatomic Distribution

• Osteosarcoma usually arises in the metaphysis of extremity long bones, most commonly around the knee (distal femur and proximal tibia) 1, 4
• In younger patients, most arise in extremities 1
• Axial skeleton, pelvis, or craniofacial bone involvement occurs predominantly in adults and increases with age 1

Metastatic Pattern

• Osteosarcoma spreads hematogenously 1
• Lung is the most common metastatic site 1

Physical Examination

Focused Assessment

Physical examination must focus on size, consistency, and mobility of any mass, location in relation to bone, and regional and local lymph node examination. 4

• Assess for localized swelling indicating periosteal distension 1
• Evaluate joint range of motion limitations 1
• Palpate for mass characteristics: size, consistency, mobility 4
• Examine regional and local lymph nodes 4

Age-Based Diagnostic Considerations

• Under 5 years: destructive bone lesions more likely represent metastatic neuroblastoma or Langerhans cell histiocytosis 4
• Ages 5-40 years: primary bone sarcoma is more likely 4
• Over 40 years: metastatic carcinoma or myeloma becomes the most common diagnosis and should be investigated first 4

Investigation

Initial Imaging

Urgent plain radiographs in two planes are the mandatory first investigation. 1, 4

• Plain radiographs show typical findings: bone destruction, new bone formation, periosteal changes 1, 4
• Radiographs are mainly helpful to describe osseous changes 1
• Conventional osteosarcoma appears as an intramedullary mass with immature cloudlike bone formation in metaphyses of long bones 5

Advanced Imaging for Local Staging

MRI is essential for local staging and must be completed before biopsy. 1

• MRI reveals extent of lesion in adjacent soft tissues, medullary canal, and joints 6
• MRI demonstrates relationship to neurovascular structures and presence of skip lesions 6
• CT is preferred for evaluating bone matrix detail 6
• Complete radiological assessment of the entire affected bone must be performed before any biopsy 3

Metastatic Workup

• CT chest for pulmonary metastases 1
• Bone scintigraphy or PET/CT for detecting distant metastases 1, 6

Biopsy

Patients with findings suggestive of osteosarcoma must be referred to a specialized bone sarcoma center before biopsy, as inappropriate biopsy techniques can irrevocably compromise chances for limb salvage or even cure. 1, 3

• Definitive diagnosis requires histological examination showing malignant cells producing osteoid 1, 2
• Biopsy can be obtained by Jamshidi trocart or open biopsy 1
• Confirmation by a pathologist with expertise in bone tumors is recommended 1

Urgent Referral Criteria

Urgent referral to a bone sarcoma center is required if X-ray shows bone destruction, new bone formation, periosteal swelling, or soft tissue swelling. 4

• Patients under 40 years with suspected primary bone malignancy should be referred urgently 4
• All patients with suspected primary malignant bone tumor should be referred before biopsy 1

Management

Localized Disease (80% of cases at presentation)

For localized osteosarcoma, treatment consists of neoadjuvant chemotherapy, followed by surgical resection, followed by adjuvant chemotherapy. 2

Chemotherapy

• Standard regimen utilizes doxorubicin, cisplatin, and high-dose methotrexate 7
• This standard has not changed in more than 40 years 7
• Pre- and postoperative chemotherapy is essential 2

Surgery

• Surgery is conservative (limb salvage) in more than 90% of patients when treated in specialized centers 2
• Wide surgical excision is the goal 1
• Amputation was historically standard but is now rarely necessary 2

Outcomes

• For localized osteosarcoma treated in specialized bone tumor centers with pre- and postoperative chemotherapy plus surgery, cure rate is 60-70% 2
• Years ago with amputation alone, cure rate was under 10% and almost all patients died within a year 2

Metastatic Disease

• Prognosis is more severe with cure rate about 30% for patients with metastasis at onset 2
• Prognosis is also worse for tumors located in axial skeleton 2

Prognostic Factors

• Tumor site and size are significant prognostic factors 1
• Patient age at diagnosis predicts survival 1
• Presence and location of metastases affect prognosis 1
• Histologic response to chemotherapy is a key prognostic indicator 1
• Type of surgery and surgical margins influence outcomes 1

Novel Therapeutic Approaches

• Immunotherapy (immune checkpoint inhibitors, adoptive cellular therapy, cancer vaccines) is under investigation 8
• Targeted therapies including tyrosine kinase inhibitors are being studied 8
• Additional studies are required to delineate their roles in clinical practice 8

Critical Pitfalls to Avoid

• Never delay referral to a specialized center based on history of recent trauma 4
• Never perform biopsy before referring to a bone sarcoma center 1, 3
• Never dismiss night pain as benign, especially around the knee in any age group 1, 4
• Never assume a destructive bone lesion in a patient over 40 is primary bone cancer without first ruling out metastatic disease or myeloma 4