What is the recommended diagnosis and treatment approach for suspected osteosarcoma?

Suspected Osteosarcoma: Diagnosis and Treatment Approach

All patients with radiographic findings suggestive of osteosarcoma must be immediately referred to a specialized bone sarcoma center BEFORE any biopsy is performed, as inappropriate biopsy techniques can irrevocably compromise limb salvage and cure. 1

Clinical Presentation and Initial Recognition

Key Symptoms to Identify

• Persistent non-mechanical bone pain, predominantly at night, is the hallmark symptom that should prompt immediate radiological assessment 1
• Pain often occurs at rest and during nighttime, followed by localized swelling and limitation of joint movement 1
• Swelling and functional impairment typically appear later when tumor has progressed through the cortex and distended the periosteum 1

Age-Based Differential Diagnosis

• Patients < 5 years old: Consider metastatic neuroblastoma or Langerhans cell histiocytosis first 1
• Patients > 5 years old: Primary bone sarcoma becomes more likely 1
• Patients > 40 years old: Bone metastases and myeloma are the most common diagnoses, not primary osteosarcoma 1

Diagnostic Imaging Algorithm

Step 1: Initial Radiographic Assessment

• Conventional radiograph in two planes is the mandatory first radiological investigation 1
• Look for mixed sclerotic and lytic lesions arising in the metaphyseal region, calcifications, periosteal bone formation, and cortical destruction 1

Step 2: Advanced Imaging (Before Biopsy)

• MRI of the whole compartment with adjacent joints is the gold standard for local staging of extremity and pelvic tumors 1
• MRI must include the entire involved bone and neighboring joints to detect skip lesions (intramedullary tumor foci without direct contact with primary lesion) 1
• CT may provide additional information for better visualization of calcifications, periosteal bone formation, and cortical destruction 1

Step 3: Systemic Staging

• Chest CT (high-resolution spiral CT with ≤5 mm collimation) to detect pulmonary metastases 1
• Radionuclide bone scan to detect skeletal metastases, complemented by X-rays and/or MRI of affected areas 1
• All imaging must be repeated before surgery of the primary tumor or known metastases 1

Laboratory Evaluation

Prognostic Markers (Mandatory)

• Alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) must be measured at baseline, as elevated levels correlate with adverse outcomes 1, 2
• These are non-specific markers but have established prognostic significance 1

Comprehensive Baseline Panel (Before Treatment)

• Complete blood count with differential 1, 2
• Blood group typing for potential transfusions 1, 2
• Coagulation profile 1, 2
• Serum electrolytes including magnesium and phosphate 1, 2
• Renal function tests (creatinine and glomerular filtration rate) 1, 2
• Liver function tests (transaminases) 1, 2
• Hepatitis and HIV testing 1

Pre-Chemotherapy Cardiac and Auditory Assessment

• Baseline echocardiogram or radionuclide ventriculography is mandatory, as chemotherapy causes cardiac dysfunction 1
• Audiogram is required, as chemotherapy causes auditory dysfunction 1
• Sperm banking should be offered to male patients of reproductive age 1

Biopsy Protocol (Critical for Cure)

Referral Before Biopsy

• The biopsy must be performed at the reference bone sarcoma center by the surgical team who will perform definitive tumor resection or by a dedicated interventional radiologist 1
• This is non-negotiable: inappropriate biopsy techniques can irrevocably compromise limb salvage and cure 1

Biopsy Technique

• Core-needle biopsy under imaging control is appropriate for most patients as an alternative to open biopsy 1
• If open biopsy is required, use a longitudinal incision 1
• Minimize contamination of surrounding tissue and provide adequate multiple sampling of representative areas 1
• The biopsy approach and tumor area to be sampled must be predetermined after multidisciplinary review of imaging 1

Critical Biopsy Considerations

• The biopsy tract and drain channels are considered potentially contaminated and must be removed with the resection specimen to minimize local recurrence risk 1
• Mark biopsy tracts with a small incision or ink tattoo to ensure recognition at definitive surgery 1
• If osteomyelitis is in the differential, send samples for microbiological culture 1
• Avoid laminectomy or decompression in spinal involvement unless necessary to relieve cord compression 1

Pathological Requirements

• Samples must be interpreted by an experienced bone sarcoma pathologist in collaboration with the radiologist and discussed in a multidisciplinary team 1
• Fresh frozen tissue collection is strongly encouraged for molecular diagnostics 1
• If decalcification is needed, use EDTA instead of methanoic acid to preserve tissue for molecular studies 1
• By definition, the malignant cell population must produce osteoid for classification as osteosarcoma 1

Treatment Approach

Multidisciplinary Team Requirement

• Treatment must occur in specialized centers with access to the full spectrum of care, including pediatric/medical oncologists, orthopedic oncologists, surgeons, pathologists, radiologists, and pain management 1, 3, 4, 5, 6
• Children and adolescents require centers with age-specific expertise 1
• Therapy should be administered within prospective multicenter trials when possible 1, 6

Standard Treatment Protocol

• Curative treatment consists of surgery and chemotherapy 1
• Multimodal treatment increases disease-free survival from 10-20% (surgery alone) to >60% 1
• Preoperative (neoadjuvant) plus postoperative (adjuvant) chemotherapy is preferred over postoperative chemotherapy alone 1, 6
• Neoadjuvant chemotherapy allows preparation for safe surgery and appropriate prosthesis preparation 6

Chemotherapy Regimen

• The regimen should include several or all of the following four drugs: doxorubicin, high-dose methotrexate with leucovorin rescue, cisplatin, and ifosfamide 1, 6
• Total treatment time is typically 6-12 months 1

Surgical Considerations

• Limb salvage procedures are performed in 80-90% of extremity tumors in specialist centers 1, 5
• Wide surgical margin is critical to avoid local recurrence, regardless of tumor response 1
• The choice of surgical procedure depends on anatomical site, relationship to vessels/nerves, patient age, growth potential, and tumor response to preoperative chemotherapy 6

Prognostic Factors

Adverse Prognostic Indicators

• Detectable metastases at presentation 1
• Proximal extremity or axial tumor site 1
• Large tumor volume 1
• Elevated serum ALP or LDH 1, 4
• Poor histological response to preoperative chemotherapy 1
• Age >40 years 1

Common Pitfalls to Avoid

• Never perform biopsy before referral to a bone sarcoma center – this is the single most critical error that compromises cure 1
• Do not perform laminectomy or decompression in spinal involvement unless absolutely necessary for cord compression 1
• Do not fail to mark the biopsy tract – it must be excised with the definitive resection 1
• Do not skip MRI of the entire bone and adjacent joints – skip lesions must be identified before surgery 1
• Do not delay cardiac and auditory baseline assessment – chemotherapy toxicity monitoring requires baseline values 1