Residency · Residency · Orthopedic Surgery

Primary Bone Tumors: Osteosarcoma and Ewing Sarcoma

Introduction

Osteosarcoma and Ewing sarcoma are the two most common primary malignant bone tumors in children and young adults. Advances in neoadjuvant chemotherapy, surgical technique, and endoprosthetic design have transformed these once uniformly fatal diagnoses into conditions with long-term survival rates exceeding 60-70% for localized disease. The orthopedic surgeon must understand the presentation, staging, and surgical principles that underpin modern multimodal treatment.

Osteosarcoma

Epidemiology

Osteosarcoma is the most common primary malignant bone tumor overall. It has a bimodal age distribution with a peak at 10-20 years (corresponding to the adolescent growth spurt) and a secondary peak over 60 years (associated with Paget disease and prior radiation). The male-to-female ratio is 1.5:1, with an annual incidence of approximately 400 new cases per year in the United States.

Location

Osteosarcoma has a predilection for the metaphysis of long bones around the knee. The distal femur (40%) is the most common site, followed by the proximal tibia (20%) and proximal humerus (10%). Axial skeleton involvement is more common in older adults.

Clinical Presentation

Patients present with progressive pain and swelling around the affected bone, often for weeks to months before diagnosis. Pain is initially activity-related then progresses to night pain and rest pain. A palpable mass may be present with large tumors. Pathologic fracture occurs in approximately 5-10% at presentation, and constitutional symptoms are uncommon in the absence of metastatic disease.

Imaging Characteristics

On plain radiograph, osteosarcoma appears as a destructive metaphyseal lesion with aggressive features including osteoid matrix (cloud-like, amorphous mineralization), Codman triangle (periosteal elevation at the tumor margin), sunburst pattern (radiating spicules of periosteal new bone), moth-eaten or permeative cortical destruction, and soft tissue mass extending beyond the cortex. MRI is essential for local staging, defining intraosseous extent, skip metastases, and soft tissue mass. CT chest is mandatory for staging as pulmonary metastases are present in 15-20% at diagnosis. Bone scan evaluates for skeletal metastases and skip lesions.

Histologic Subtypes

Conventional (intramedullary) osteosarcoma is high grade and accounts for 75% of cases, with subtypes including osteoblastic, chondroblastic, and fibroblastic. Telangiectatic osteosarcoma has lytic, blood-filled spaces mimicking aneurysmal bone cyst and is high grade. Small cell osteosarcoma resembles Ewing sarcoma histologically and is high grade. Parosteal (surface) osteosarcoma is low grade, arises from the periosteal surface, and has the best prognosis. Periosteal osteosarcoma is intermediate grade with chondroblastic matrix.

Treatment

Neoadjuvant chemotherapy (typically MAP: methotrexate, doxorubicin/Adriamycin, cisplatin) is given for 10-12 weeks before surgery. Surgical resection requires wide margins (at least 2 cm of normal tissue or a fascial barrier around the tumor). Limb salvage surgery is achievable in 85-90% of cases; options include endoprosthetic reconstruction, osteoarticular allograft, and allograft-prosthesis composite. Amputation is reserved for cases where limb salvage cannot achieve adequate margins or functional outcomes. Adjuvant chemotherapy continues after surgery for a total treatment duration of approximately 6-12 months. Histologic response to neoadjuvant chemotherapy (percentage tumor necrosis) is the most important prognostic factor: greater than 90% necrosis indicates a good response and favorable prognosis, while less than 90% necrosis indicates a poor response and modification of the chemotherapy regimen may be considered.

Prognosis

Localized disease has a 60-75% 5-year survival with modern treatment. Metastatic disease at presentation has a 20-30% 5-year survival. Pulmonary metastasectomy can improve survival in patients with limited pulmonary disease.

Ewing Sarcoma

Epidemiology

Ewing sarcoma is the second most common primary malignant bone tumor in children and adolescents, with peak incidence at 10-15 years. The male-to-female ratio is 1.5:1. It is extremely rare in African American and Asian populations. Annual incidence is approximately 200-250 cases per year in the United States.

Molecular Biology

Ewing sarcoma is characterized by a chromosomal translocation producing an oncogenic fusion protein. The translocation t(11;22)(q24;q12) producing the EWSR1-FLI1 fusion is present in approximately 85% of cases, with the remainder having variant translocations (EWSR1-ERG, EWSR1-ETV1, etc.). Detection of the fusion transcript by FISH or RT-PCR is diagnostic.

Location

Ewing sarcoma preferentially involves the diaphysis of long bones (in contrast to the metaphyseal predilection of osteosarcoma). The femur is the most common site, followed by the pelvis, tibia, and fibula. Flat bones (pelvis, scapula, ribs) are affected more commonly than in osteosarcoma, and pelvic tumors have a worse prognosis than extremity tumors.

Clinical Presentation

Patients present with pain and swelling with a soft tissue mass. Systemic symptoms are more common than in osteosarcoma, including fever, malaise, weight loss, elevated ESR and WBC, which may mimic osteomyelitis. Large tumors may present with pathologic fracture or neurologic compromise.

Imaging Characteristics

On plain radiograph, Ewing sarcoma appears as a permeative, moth-eaten diaphyseal lesion with onion-skin periosteal reaction (lamellated, the classic finding), moth-eaten cortical destruction without matrix production, and a large soft tissue mass often disproportionately large relative to the bony change. There is no matrix mineralization because there is no osteoid or chondroid production. MRI demonstrates the soft tissue component, which is often much larger than the bony lesion suggests. Complete staging includes CT chest, bone scan, and PET-CT.

Differential Diagnosis

Osteomyelitis is the most important differential because Ewing sarcoma and osteomyelitis can present identically with fever, pain, leukocytosis, and elevated ESR. Biopsy is mandatory when diagnostic uncertainty exists. Other considerations include lymphoma, Langerhans cell histiocytosis, and osteosarcoma (small cell variant).

Treatment

Neoadjuvant chemotherapy uses the VDC/IE protocol (vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide) for 12-16 weeks. Local control is achieved through surgery, radiation, or both. Surgical resection with wide margins is preferred when achievable without excessive morbidity. Radiation therapy is effective for local control and is used as the primary modality for unresectable tumors (pelvis, spine) or as adjuvant therapy for close or positive margins. Adjuvant chemotherapy continues for a total treatment course of approximately 12-14 months. A major distinguishing feature from osteosarcoma is that Ewing sarcoma is radiosensitive, while osteosarcoma is radioresistant.

Prognosis

Localized disease has a 65-75% 5-year survival. Metastatic disease at presentation has a 20-30% 5-year survival. Pelvic tumors and large tumor volume are associated with worse outcomes. Histologic response to chemotherapy (similar to osteosarcoma) is prognostic.

Surgical Principles Common to Both Tumors

Margin Classification (Enneking)

Intralesional margins pass through the tumor and are inadequate, associated with local recurrence. Marginal margins pass through the reactive zone surrounding the tumor. Wide margins pass through normal tissue with a cuff of normal tissue around the tumor and are the goal for malignant tumors. Radical margins remove the entire compartment and are rarely performed in modern practice.

Limb Salvage Reconstruction

Endoprosthetic replacement uses modular metallic implants replacing the resected bone and adjacent joint and is the most commonly used option. Osteoarticular allograft uses cadaveric bone for biologic reconstruction but carries risks of nonunion, fracture, and infection. Allograft-prosthesis composite (APC) combines biologic reconstruction with prosthetic joint replacement. Rotationplasty (Van Nes) rotates the distal limb 180 degrees so the ankle functions as the knee joint, providing excellent function, particularly in growing children. Expandable endoprostheses are used for skeletally immature patients, allowing limb lengthening as the child grows.

Key Clinical Pearls

Osteosarcoma is metaphyseal with osteoid matrix production (sunburst, Codman triangle) while Ewing sarcoma is diaphyseal with no matrix production and onion-skin periosteal reaction; these patterns are classic but not absolute. Ewing sarcoma may present with systemic symptoms mimicking osteomyelitis, and biopsy is mandatory when the diagnosis is uncertain. Histologic response to neoadjuvant chemotherapy (greater than 90% necrosis) is the strongest prognostic factor after staging for both tumors. Limb salvage surgery is achievable in 85-90% of extremity sarcomas; referral to a musculoskeletal oncology center before biopsy is essential to preserve limb salvage options.

References

1. Meyers PA, Schwartz CL, Krailo MD, et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival. J Clin Oncol. 2008;26(4):633-638.
2. Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003;348(8):694-701.
3. Ritter J, Bielack SS. Osteosarcoma. Ann Oncol. 2010;21(Suppl 7):vii320-vii325.
4. Gaspar N, Hawkins DS, Dirksen U, et al. Ewing sarcoma: current management and future approaches through collaboration. J Clin Oncol. 2015;33(27):3036-3046.

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