Basics
Description
Osteosarcoma is a malignant tumor of the bone and arises from mesenchymal cells. The malignant cells are usually pleomorphic spindle cells that lay down abnormal bone (osteoid formation).
Epidemiology
- Osteosarcoma is the most common pediatric primary bone cancer and is the 8th most common malignancy of childhood.
- A bimodal distribution is noted with the first peak in adolescence (median, age 16 years) and second peak during the 7th and 8th decade of life.
- Incidence of osteosarcoma parallels skeletal growth and is more frequently noted in tall individuals.
- Males are more commonly affected than females.
- In the United States, there are about 4.4 cases per million children and adolescents.
- Approximately 400 new pediatric cases of osteosarcoma are diagnosed each year in the United States.
Risk Factors
- Radiation exposure
- Hereditary retinoblastoma, in which patients with germline Rb gene mutation have increased risk of osteosarcoma with or without radiation exposure.
- Li-Fraumeni syndrome, in which patients have germline TP53 gene mutation and increased risk of a range of sarcomas, among other malignancies
- Rothmund-Thomson syndrome
- Bloom syndrome
- Enchondromatosis
- Hereditary multiple exostoses
- Fibrous dysplasia
- Paget disease of the bone, although less relevant to pediatric populations
Pathophysiology
- The histologic hallmark of osteosarcoma is the presence of osteoid.
- Most cases of pediatric osteosarcoma are high-grade cancers, although lower grade variants are seen.
- No classic genetic change, although karyotypes are typically highly abnormal
- Major subtypes of osteosarcoma include osteoblastic, chondroblastic, fibroblastic, telangiectatic, and small cell.
- At diagnosis, 80% of patients will have localized disease and 20% will have metastatic disease.
- In 80% of tumors, the metaphysis of long bones will be involved, such as the femur, tibia, and humerus, with distal femur the most common primary site. In 20% of tumors, other sites of involvement will include the pelvis, facial bones, and shoulder blade.
- The most common sites of metastatic disease are lungs and bone. Involvement of regional lymph nodes is rare.
Etiology
- The etiology of most cases is unknown.
- Abnormal TP53 and/or Rb function implicated in laboratory studies of osteosarcoma
- Radiation exposure is a known cause of osteosarcoma and usually presents 10 " 20 years after exposure.
Diagnosis
Signs & Symptoms
History
- Pain and palpable mass are the most common clinical symptoms.
- Pain is often described as dull or aching at the tumor site.
- Pain is often initially attributed to an injury in active children or adolescents.
- Symptoms of pain can vary prior to presenting to medical attention but warrant further investigation if present for several weeks to months and if it disrupts sleep.
- Presence of bone metastasis may result in pain at sites distant from the primary tumor.
- Systemic symptoms, such as fever and weight loss, are unusual.
Physical Exam
- Presence of a firm, often tender mass
- Swelling at the tumor location
- Depending on location of the tumor, one can have a loss of function, limp, or decreased range of motion
Diagnostic Tests & Interpretation
Lab
- 30% of patients will have an elevated lactate dehydrogenase (LDH).
- An elevated erythrocyte sedimentation rate (ESR) can be seen.
- May see an elevated alkaline phosphatase (AP), particularly with metastatic disease
- Leukocytosis may suggest osteomyelitis.
Imaging
- Conventional x-ray may show
- Osteolytic and sclerotic lesion
- Periosteal reaction including Codman sign (shadow from a lifted periosteum), onion-skinning as new layers of periosteum are laid down, and sunburst appearance reflecting calcified bone beyond periosteum
- Pathologic fracture
- An MRI from joint to joint of involved bone will show full extension of the tumor and involvement of surrounding structures.
- A technetium bone scan will show areas of intense primary tumor uptake and screen for bone metastasis.
- A chest CT should be performed to evaluate for pulmonary metastasis.
- Use of positron emission tomography with [F-18]-fluorodeoxyglucose (FDG-PET) is increasing, as it can characterize size, location of tumor, and can allow for assessment of response.
Diagnostic Procedures/Other
The diagnosis of osteosarcoma is a tissue diagnosis.
Alert
Biopsy should be performed at the center that will provide definitive treatment for the patient with a suspected primary malignant bone tumor. The placement of biopsy is critical to the planning of surgical local control and inappropriate biopsy could lead to adverse outcomes.
Differential Diagnosis
- Benign tumors
- Unicameral bone cyst
- Aneurysmal bone cyst
- Osteoblastoma
- Eosinophilic granuloma
- Osteochondroma
- Fibrous dysplasia
- Malignant tumors
- Ewing sarcoma
- Chondrosarcoma
- Fibrosarcoma
- Metastatic lesions
- Infection
- Osteomyelitis
- Septic arthritis
- Trauma: fracture with or without hematoma
Treatment
Chemotherapy
- Prior to the 1970s, overall survival for high-grade osteosarcoma was poor, as treatment primarily consisted of surgical resection allowing for relapse with metastatic disease. With the addition of both neoadjuvant and adjuvant chemotherapy, survival has improved.
- Neoadjuvant chemotherapy (before definitive surgery) allows for treatment of micrometastases and shrinkage of the primary tumor mass prior to resection.
- Neoadjuvant chemotherapy also allows time for complex endoprostheses to be constructed prior to planned limb salvage procedures.
- Response to neoadjuvant chemotherapy (percent of tumor that is necrotic at the time of complete resection) has proven to be an important prognostic factor.
- Most children and adolescents with high-grade osteosarcoma are treated based on or according to cooperative group chemotherapy protocols.
- In North America, the standard backbone of treatment is high-dose methotrexate, doxorubicin, and cisplatin. Treatment duration is usually 12 months, depending on the individual protocol, response to therapy, and tumor extent at diagnosis.
- Clinical trials in patients with newly diagnosed disease have investigated the role of ifosfamide and etoposide. The addition of interferon with chemotherapy did not improve survival.
Surgery/Other Procedures
- Complete surgical resection with wide margins is necessary for cure.
- Surgical options for osteosarcomas of the extremities include the following:
- Amputation
- Limb salvage with local resection and reconstruction of the limb
- Rotationplasty for tumors at the knee
- Surgical resection alone is curative in low-grade osteosarcoma.
- Surgical resection of lung metastases at presentation or at relapse also plays an important role in management.
Radiotherapy
Osteosarcoma is not a radiation-sensitive tumor although radiation has been used for palliative purposes to treat unresectable primary or metastatic lesions.
Physical Therapy
Physical therapy is critical after either amputation or limb-sparing procedures.
Ongoing Care
Issues for Referral
- Children with a suspected malignant bone tumor should be immediately referred to a children 's hospital with expertise in these tumors.
- Multidisciplinary teams include pediatric oncologists, orthopedic oncologists, pediatric surgeons, nurses, pharmacists, and social workers.
Prognosis
- Patients with localized disease have an estimated 5-year overall survival of 60 " 70%, whereas patients with metastatic disease have an estimated 5-year overall survival of 20 " 30%.
- Key adverse prognostic factors are as follows:
- Axial primary tumor location
- Metastatic disease
- Histologic necrosis <90% after neoadjuvant chemotherapy
- Inability to achieve wide surgical margins during resection
Complications
Orthopedic
- Surgical site wound infections
- Limb length discrepancy after surgical treatment in growing children
- Phantom leg pain after amputation
Acute Chemotherapy Toxicity
- Myelosuppression
- Ototoxicity and tinnitus
- Mucositis
- Renal dysfunction
Late Effects
- Cardiomyopathy from doxorubicin
- Hearing loss and nephrotoxicity from cisplatin
- Reduced fertility from ifosfamide
- Secondary malignancy from radiation or chemotherapy
Patient Monitoring
- Patients should be followed by a pediatric oncologist with serial imaging of the primary site (MRI and x-rays) and lungs (chest CT or chest x-ray) to monitor for recurrence.
- Patients should be monitored for long-term side effects/complications of therapy, ideally within the context of a survivorship clinic.
Additional Reading
- Bielack SS, Carrle D, Hardes J, et al. Bone tumors in adolescents and young adults. Curr Treat Options Oncol. 2008;9(1):67 " 80. [View Abstract]
- Gill J, Ahluvalia MK, Geller D, et al. New targets and approaches in osteosarcoma. Pharmacol Ther. 2013;137(1):89 " 99. [View Abstract]
- Heare T, Hensley MA, Dell 'Orfano S. Bone tumors: osteosarcoma and Ewing 's sarcoma. Curr Opin in Pediatr. 2009;21(3):365 " 372. [View Abstract]
- Longhi A, Errani C, De Paolis M, et al. Primary bone osteosarcoma in the pediatric age: state of the art. Cancer Treat Rev. 2006;32(6):423 " 436. [View Abstract]
Codes
ICD09
- 170.9 Malignant neoplasm of bone and articular cartilage, site unspecified
- 170.7 Malignant neoplasm of long bones of lower limb
- 170.4 Malignant neoplasm of scapula and long bones of upper limb
- 170.6 Malignant neoplasm of pelvic bones, sacrum, and coccyx
- 170.0 Malignant neoplasm of bones of skull and face, except mandible
ICD10
- C41.9 Malignant neoplasm of bone and articular cartilage, unsp
- C40.20 Malignant neoplasm of long bones of unspecified lower limb
- C40.00 Malig neoplasm of scapula and long bones of unsp upper limb
- C41.4 Malignant neoplasm of pelvic bones, sacrum and coccyx
- C40.02 Malig neoplasm of scapula and long bones of left upper limb
- C40.22 Malignant neoplasm of long bones of left lower limb
- C41.0 Malignant neoplasm of bones of skull and face
- C40.01 Malig neoplasm of scapula and long bones of right upper limb
- C40.21 Malignant neoplasm of long bones of right lower limb
SNOMED
- 307576001 Osteosarcoma of bone (disorder)
- 440397000 primary osteosarcoma of pelvis (disorder)
FAQ
- Q: How can we differentiate between malignant osteosarcoma and benign tumors?
- A: An experienced radiologist can look for defining features on imaging of malignant osteosarcoma that are not found with benign tumors. However, only a biopsy can confirm a diagnosis of osteosarcoma.
- Q: What are long-term survival rates of patients who relapse after treatment?
- A: Unfortunately, patients who relapse after treatment do poorly and long-term survival is poor at 10 " 20%. Late relapses (>24 months after completion of treatment), surgical resection of relapsed disease, and unilateral lung involvement at relapse appear to be more favorable.
- Q: Do siblings of children with osteosarcoma need to be evaluated?
- A: If there is suspicion for a genetic risk factor (i.e., Li-Fraumeni syndrome), then siblings and families should be evaluated by a geneticist to determine if the risk factor is present. This will provide education for families and siblings. Otherwise, siblings of children with osteosarcoma that are asymptomatic do not need evaluation for osteosarcoma.
- Q: What are the differences between Ewing sarcoma and osteosarcoma?
- A: The two sarcomas are the most common malignant bone tumors in pediatrics and both require multimodal therapy, although the chemotherapy regimens are different. Ewing sarcoma can have both bone or soft tissue involvement and presence of different histologic features will allow differentiation from osteosarcoma.