Osteosarcoma

Tumor biology and incidence

• Also referred to as osteogenic sarcoma
• Malignant bone tumor in which cancer cells produce immature bone (osteoid matrix)
• Second most common primary bone tumor after myeloma; accounts for approximately 20% of all primary malignant bone tumors
  • Eighth most common form of childhood cancer, accounting for 2.4% of all malignancies in children
• Population-based incidence of 1 to 2 cases per million population per annum
  • Approximately 900 new cases every year in the United States

Age

• Most common in ages of rapid bone growth, such as adolescence
• Tumor incidence rises again in the fifth and sixth decades of life
  • Among older patients, osteosarcoma may be related to other primary causes, such as Paget's disease or prior radiation

Gender

M:F = 3:2

Classification

Nearly all – 90% – of osteosarcomas are high-grade intramedullary lesions, so called conventional osteosarcoma. Other variants include:

• Parosteal osteosarcoma
• Periosteal osteosarcoma
• Low-grade intramedullary osteosarcoma
• Telangiectatic osteosarcoma
• Small-cell osteosarcoma
• Multifocal osteosarcoma
• High-grade surface osteosarcoma
• Intracortical osteosarcoma
• Secondary osteosarcomas, such as those seen after radiation or in conjunction with Paget's disease

Presentation

• Progressively enlarging mass with focal pain, usually of several months' duration
• Pain may initially be present only with activity, but progress to pain at rest as well
• Restriction of function (joint movement or deformity) evident in advanced disease
• Systemic symptoms, such as fever, chills or weight loss, generally absent

Physical findings

• Soft tissue mass, often large and tender to palpation
• Patient may have numbness and weakness in extremity distal to site of involvement if mass compresses a nerve
• First presenting sign or symptoms may be sudden fracture of bone though the tumor (rare)
• Approximately 20% of patients have metastatic disease at diagnosis; initial symptoms from distal sites rare, though
  • Most common site of metastasis is lungs; wheezing may suggest spread of disease

Bloodwork

• Serum alkaline phosphatase elevated in many patients
• LDH may be elevated as well

Plain films

Site

• In young patients, tumors most commonly originate in metaphysis and may extend across physis
  • Less commonly, lesions may originate in the diaphysis
• Most commonly affected bones: distal femur, proximal tibia, proximal humerus, and flat bones (in descending order of frequency)

Size

Generally large (> 5 cm) lesions

Tumor effect on bone

• Lesions most frequently have patchy areas of radiolucency and increased radiodensity
• Osteoblastic lesions may be entirely sclerotic
• Tumors usually permeative

Bone response to tumor

• Usually no marginating reaction by endosteal host bone because lesions grow rapidly
• Periosteum usually affected, resulting in sunburst pattern or Codman's triangle

   
Plain AP (left) and lateral radiographs pre-chemotherapy for osteosarcoma

Matrix

Malignant osteoid generally sclerotic on x-ray (degree of osteosclerosis may vary)

Cortex

• Tumors may demonstrate cortical destruction
• Soft tissue mass may be evident without cortical destruction secondary to tumor spreading through Haversian canals

Soft tissue mass

• Tumors generally have soft tissue mass that may demonstrate osteoid formation
• Ossification within soft tissue mass differentiates osteosarcoma from other aggressive bony lesions that may produce bony sclerosis as a reactive host bone response

MRI

• Has higher sensitivity than x-rays for defining soft tissue
• Best method for staging local extent of intraosseous and extraosseous tumor
• Tumor will have high signal in T2-weighted images

Bone scan and chest CT

• Necessary for systemic staging, detection of distant metastases and so-called skip lesions within same bone
• CT scans not required for evaluation of the primary tumor, but needed to exclude possible pulmonary metastasis

Differential Diagnosis

• Other malignant bone tumors, such as Ewing sarcoma, lymphoma, and metastases
• Benign bone tumors, such as osteoid osteoma, chondroblastoma, and osteoblastoma
• Non-neoplastic conditions, such as osteomyelitis, eosinophilic granuloma, giant cell tumor, and aneurysmal bone cysts

Natural History

Osteosarcoma is an aggressive, malignant tumor, and left untreated, will kill the patient. The tumor often spreads to the lung or other bones (such as the spine) or both. Prior to the advent of chemotherapy for osteosarcoma in the early 1970s, amputation alone was the primary treatment and only 20% of patients survived beyond 5 years. Today, with the use of so-called neoadjuvant chemotherapy (that is, chemotherapy prior to surgery) and modern surgical techniques, approximately 65% of patients are cured of the disease.

Pathology

• Gross: Tan-white tissue with variable ossification
  • Often contains areas of hemorrhage and cystic degeneration
• Microscopic: Malignant cells producing osteoid which may have a lace-like, trabecular or sheet-like pattern
• Tumor cells can be spindle, epithelioid, or small and round
• Chondroblastic and/or fibroblastic features may be seen in same lesion

Tumors frequently destroy the overlying cortex and produce a soft tissue mass. They spread widely in the medullary canal, infiltrating and replacing the marrow. Infrequently, they may break through the end of the bone and enter the joint. Microscopically, the presence of eosinophilic osteoid within the malignant stroma containing malignant osteoblasts is characteristic of osteosarcoma. The malignant osteoblasts are frequently pleomorphic with cytologic atypia and atypical mitoses. These cells produce the irregular, amorphous, eosinophilic osteoid with or without central calcification. Multinucleated osteoclast-like giant cells may also be seen.

   
H&E stain showing malignant osteoblasts, at 10X (left) and 40X magnification

Mutations of several tumor suppressor genes are associated with the development of osteosarcoma. Individuals with hereditary retinoblastomas (who inherit a mutant allele of the RB tumor suppressor gene, rendering it inactive) have a several hundred fold greater risk of developing osteosarcoma than those without hereditary retinoblastomas. Many osteosarcomas develop at sites where and when bone growth and bone cell mitotic activity is at its peak.

Treatment

• Biopsy, undertaken in consultation with musculoskeletal surgical oncologist
• Chemotherapy and surgery required for usual high-grade osteosarcoma
  • Neo-adjuvant chemotherapy generally used prior to limb salvage surgery
  • Limb salvage surgery has slightly higher risk of local recurrence than amputation; local recurrence virtually always associated with metastases
• Selection of patients for limb salvage surgery or amputation based on the extent of local disease, presence of a pathologic fracture, and patient's age and growth potential
  • Pathologic fracture does not always preclude limb salvage surgery
• Type of reconstructive procedure based on anatomical site, growth potential, extent of bone and soft tissue resection necessary for tumor removal, and expertise of the treating center
  • Thoracotomy and removal of resectable pulmonary lesions prolongs overall survival and results in long disease-free survival in 20-40 % of patients with metastases
• Prognosis highly dependant on presence of metastases at presentation and extent of pathologic necrosis resulting from neo-adjuvant chemotherapy
  • Tumor size, axial location, and positive margins of resection also risk factors.
• Radiation of unresectable disease results in unpredictable palliative effect and rarely alters local disease progression
• Best chemotherapy protocol for this sarcoma is subject of ongoing clinical trials
  • Active agents include high-dose methotrexate, adriamycin, cisplatin, and ifosphamide

At the time of resection, the specimen is analyzed for amount of necrosis, which is a surrogate marker for response of the primary tumor to the chemotherapy. High necrosis indicates good response and, therefore, a better prognosis. CT and plain radiographs are also useful for monitoring response to chemotherapy: An intense calcification/peripheral zone of calcification is a sign of good response.

H&E stain of a resected specimen following chemotherapy, >95% tumor cell kill rate. A good response to chemotherapy (>90% tumor cell kill rate) is associated with a 90% cure rate.

   
Plain AP (left) and lateral radiographcs post-chemotherapy for osteosarcoma

Complications

• Immune suppression from chemotherapy
• Risk of periprosthetic fracture, device failure, deep or superficial wound infection, local recurrence, and skin necrosis from prosthetic replacements

Outcome

• One patient in three will die within 5 years of sarcoma, despite treatment
• Single most predictive factor of long-term outcome is presence or absence of detectable metastatic disease at presentation
• If no metastatic disease present, response to preoperative chemotherapy is most important prognostic factor
• Tailored PT and OT interventions may improve functional outcomes

Psychosocial impact

• Large en-bloc resection of tumor may require amputation if limb-salvage cannot be done; may cause psychological stress
• Report shows, however, that patients with amputation have a similar psychological and quality of life outcome as patients with limb salvage surgery