Pathophysiology: Osteosarcoma is a bone tumor that can occur in any bone. It most commonly occurs in the long bones of the extremities near metaphyseal growth plates. The most common sites are femur (42%, with 75% of tumors in the distal femur), tibia (19%, with 80% of tumors in the proximal tibia), and humerus (10%, with 90% of tumors in the proximal humerus). Other significant locations are the skull or jaw (8%) and pelvis (8%).

Technically, any sarcoma that arises from bone is called an osteogenic sarcoma. Therefore, this term includes fibrosarcoma, chondrosarcoma, and osteosarcoma, all named for their cell of origin. The focus of this article is osteosarcoma. A number of variants of osteosarcoma exist, including conventional types (ie, osteoblastic, chondroblastic, fibroblastic) and telangiectatic, multifocal, parosteal, and periosteal types.

Frequency:

• In the US: Incidence is 400 cases per year (4.8 cases per million persons <20 y).

Mortality/Morbidity: The overall 5-year survival rate for patients diagnosed between 1974 and 1994 was 63% (59% for males, 70% for females).

Race: Incidence is slightly higher in African Americans than whites (data from the National Cancer Institute [NCI] Surveillance, Epidemiology, and End Results [SEER] Study Pediatric Monograph, 1975-1995).

• In African Americans, incidence is 5.2 cases per million population younger than 20 years per year.

• In whites, incidence is 4.6 cases per million population younger than 20 years per year.

Sex: Incidence is slightly higher in males than in females.

• In males, incidence is 5.2 cases per million population per year.

• In females, incidence is 4.5 cases per million population per year.

Age: Osteosarcoma is very rare in young children (approximately 0.5 cases per million <5 y per y). Incidence increases steadily with age; a more dramatic increase in adolescence corresponds with the growth spurt.

• In children aged 5-9 years, incidence is 2.6 cases for African Americans and 2.1 cases for whites per million population per year.

• In children aged 10-14 years, incidence is 8.3 cases for African Americans and 7 cases for whites per million population per year.

• In adolescents aged 15-19 years, incidence is 8.9 cases for African Americans and 8.2 cases for whites per million population per year.

History: Symptoms may be present for weeks or months (or occasionally longer) before osteosarcoma is diagnosed. The most common presenting symptom of osteosarcoma is pain, particularly with activity. Patients may complain of a sprain, arthritis, or so-called growing pains. Often, the patient has a history of trauma, though pathologic fractures are not particularly common. (The exception is the telangiectatic type of osteosarcoma, which is commonly associated with pathologic fractures.) If in an extremity, the pain may result in a limp.

The patient may have a history of swelling, depending on the size of the lesion and its location. Systemic symptoms, such as fever and night sweats, are rare. Tumor spread to the lungs only rarely results in respiratory symptoms, and such symptoms usually indicate extensive lung involvement. Metastases to other sites are extremely rare; therefore, other symptoms are unusual.

Physical: Physical examination findings are usually limited to those of the primary tumor site.

• Mass: A palpable mass may be present. The mass may be tender and warm, though these signs are indistinguishable from those of osteomyelitis. Increased skin vascularity over the mass may be discernible. Pulsations or a bruit may be detectable.

• Decreased range of motion: Joint involvement should be obvious on physical examination.

• Lymphadenopathy: Involvement of local or regional lymph nodes is unusual.

• Respiratory findings: Auscultation is usually uninformative unless extensive pulmonary disease is present.

Causes: The exact cause of osteosarcoma is unknown. However, a number of risk factors exist.

• Rapid bone growth appears to predispose patients to osteosarcoma, as suggested by the increased incidence during the adolescent growth spurt, the high incidence among large dogs (eg, Great Dane, St Bernard, German shepherd), and osteosarcoma’s typical location near the metaphyseal growth plate of long bones.

• Exposure to radiation is the only known environmental risk factor.

• A genetic predisposition may exist.

• Retinoblastoma, especially the combination of a constitutional mutation of the RB gene (germline retinoblastoma) with radiation therapy, is associated with a particularly high risk of osteosarcoma development. Of note, the retinoblastoma gene locus, band 13q14, has also been implicated in the pathogenesis of sporadic osteosarcoma.

• Bone dysplasias, including Paget disease, fibrous dysplasia, enchondromatosis, and hereditary multiple exostoses, increase the risk of osteosarcoma.

• Li-Fraumeni syndrome (germline TP53 mutation) is a predisposing factor for osteosarcoma development.

• Rothmund-Thomson syndrome (ie, autosomal recessive association of congenital bone defects, hair and skin dysplasias, hypogonadism, cataracts) is associated with increased risk of osteosarcoma.

Lab Studies:

• Most recommended laboratory studies relate to the use of chemotherapy. Assessing organ function before, during, and after chemotherapy is important. The only blood tests with prognostic significance are lactate dehydrogenase (LDH) and alkaline phosphatase. Patients with elevated alkaline phosphatase at diagnosis are more likely to have pulmonary metastases. Patients without metastases with an elevated LDH level are less likely to do well than those with an LDH level within the reference range. Important laboratory studies include the following:

• LDH, alkaline phosphatase (prognostic significance)

• Complete blood count (CBC), including differential and platelet count

• Liver function tests - Aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, albumin

• Electrolytes - Sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphorus

• Renal function tests - BUN, creatinine

• Urinalysis

Imaging Studies:

• Plain films

• Plain films (2 views) of the suspected lesions should be obtained. No single feature on radiographs is diagnostic. Osteosarcoma lesions can be purely osteolytic (~30% of cases), purely osteoblastic (~45% of cases), or a mixture of both. Elevation of the periosteum may appear as the characteristic Codman triangle. Extension of tumor through the periosteum may result in a so-called sunburst appearance (~60% of cases). The entire bone and adjacent joint should be imaged to assess for skip lesions and joint involvement. Telangiectatic osteosarcomas are often very cystic and can be mistaken for an aneurysmal bone cyst.

• Chest radiographs (posteroanterior and lateral views) should be obtained to evaluate for pulmonary metastases. If metastases are present and visible on chest x-ray films, this modality then can be used for follow-up of specific lesions.

• CT scan

• Both a CT scan of the primary lesion and a high resolution CT scan of the chest (at 3.75-7.5 mm intervals) should be obtained.

• CT scan of the primary lesion helps delineate the location and extent of the tumor and is critical for surgical planning.

• CT scan of the chest is more sensitive than plain films for assessing pulmonary metastases. Ideally, the chest CT should be obtained before biopsy to avoid ambiguity that can arise from postanesthesia atelectasis.

• MRI

• MRI of the primary lesion is the best method for assessing the extent of intramedullary disease.

• MRI also correlates best with the extent of disease assessed at the time of definitive surgery.

• Radionuclide bone scan (technetium Tc 99m diphosphonate)

• Evaluation for the presence of metastatic or multifocal disease by bone scan is imperative.

• Abnormal areas should be imaged subsequently using CT scan or MRI.

Other Tests:
 

• Audiogram: Hearing loss is an adverse effect of cisplatin.

• Echocardiogram or multiple-gated acquisition (MUGA) scan: Cardiac function should be assessed before and at various intervals following treatment with doxorubicin (Adriamycin).

Procedures:
 

Medical Care: Before the use of chemotherapy (which began in the 1970s), osteosarcoma was treated primarily with surgical resection (usually amputation). Despite such good local control of their disease, more than 80% of patients subsequently developed recurrent disease that typically presented as pulmonary metastases. The high recurrence rate indicates that most patients have micrometastatic disease at diagnosis. Therefore, the use of adjuvant (postoperative) systemic chemotherapy is critical for the treatment of patients with osteosarcoma.

Neoadjuvant (preoperative) chemotherapy has been found not only to facilitate subsequent surgical removal by shrinking the tumor but also has provided oncologists with an important risk parameter. Patients who have a good histopathologic response to neoadjuvant chemotherapy (>95% tumor cell kill or necrosis) have a better prognosis than those whose tumors do not respond as favorably. Thus, future chemotherapy trials will incorporate an assessment of neoadjuvant tumor cell kill to provide risk-adapted treatment regimens.

• Biopsy

• Open biopsy is preferred because it avoids sampling error and provides adequate tissue for biologic studies. Other options include trephine biopsy, which is preferred for vertebral bodies and iliac crests. Fine-needle aspiration is not recommended.
• Incision for an open biopsy should be planned carefully to avoid tumor contamination of neurovascular structures and to allow en bloc removal during eventual definitive surgery.
• Regardless of technique, a frozen section should be examined to be certain that the tumor has been sampled accurately. If possible, extraosseous components should be sampled rather than bone to decrease the risk of fracture.
• Bone holes should be sealed with polymethacrylate and extraosseous holes should sealed with absorbable gelatin sponge (Gelfoam) to decrease the risk of hematoma and tumor spread.
• Drains should be closed suction (to prevent infection) in line with the skin incision (to prevent tumor contamination in adjacent tissue).

• Definitive resection

• The primary aim of definitive resection is patient survival. As such, margins on all sides of the tumor must contain normal tissue (ie, wide margin).
• The thickness of the margin is important only for the marrow, where an adequate margin is thought to be 5-7 cm from the edge of the abnormality on MRI or bone scan.
• Radical margins, defined as removal of the entire involved compartment (bone, joint to joint; muscle, origin to insertion), usually are not required for cure.
• A less than wide margin (marginal or intralesional margin) may be functionally helpful as a debulking therapy but will not be locally curative.

• Amputation may be the treatment of choice.

• If possible, limb-salvage reconstruction is preferred over amputation; reconstruction technique must be chosen from the following on the basis of individual considerations:
  • Autologous bone graft: Advantages include no rejection and low rate of infection. This technique should be used only in skeletally mature patients, as epiphyseal growth will be inhibited by periosteal infusion.
  • Allograft: Graft healing and infection can be problematic with this technique, particularly during chemotherapy. Rejection also can occur.
  • Prosthetic: Prosthetic joints can be solitary or expandable; they usually are expensive. Their longevity is unknown.
  • Rotationplasty: This technique is suitable for patients with distal femur tumors, particularly large tumors for which a high amputation is the only alternative. Very young or athletic patients may benefit functionally from this procedure. After tumor resection, vessels are repaired or looped and kept in continuity. The distal portion of the leg is then rotated 180 degrees and reattached to the thigh at the proximal edge of the resection. The rotation allows the ankle to become a functional knee joint, so the length of the leg should be adjusted to match the contralateral knee. Before making the decision to undergo this procedure, patients and families should either meet a patient or view a videotape of a patient who has had the procedure.

• Resection of pulmonary nodules

• Metastatic lung nodules can be cured by complete surgical resection, most often by wedge resection. Lobar resection or pneumonectomy occasionally may be required for clear margins. This procedure should be done at the time of primary tumor resection.

• While bilateral nodules can be resected via a median sternotomy, surgical exposure is superior with a lateral thoracotomy. Therefore, bilateral thoracotomies are recommended for bilateral disease (ie, 2 lateral thoracotomies separated by a few weeks).

• For osteosarcoma that recurs more than 1 year after completing therapy as lung lesion(s) only, surgical resection alone can be curative, as the likelihood of metastases to other sites is low. If disease recurs less than 1 year after completing therapy, chemotherapy is warranted, as the risk of other micrometastatic disease is high.

Consultations: As is usual for any child with cancer, consultations with an oncologist as well as with any subspecialist related to the specific clinical circumstances are strongly recommended. Social services, psychology, dentistry, dietary, and child life specialists usually are involved with these patients and their families throughout their treatment course.

Diet: Patients receiving methotrexate should not be given folate supplementation. Diet is not otherwise restricted.

The chemotherapy drugs most active in osteosarcoma are doxorubicin, cisplatin, and high-dose methotrexate (low dose is ineffective). A number of pilot studies are currently being conducted to test the efficacy and safety of alkylator dose escalation, In addition, other therapies are being tested, such as the following:

• Anthracycline escalation using a cardioprotectant

   

• Topoisomerase I inhibitors

   

• Cyclosporin A to block the P-glycoprotein pump, which causes multidrug resistance

   

• Muramyl tripeptide phosphatidyl ethanolamine (MTP-PE) and other immune enhancers

   

• Monoclonal antibody against the Her2/neu antigen (which is overexpressed on some osteosarcomas)

As usual, physicians caring for patients with osteosarcoma should consult a pediatric oncologist affiliated with a center that participates in national or international trials to determine both the current standard treatment protocol and whether an appropriate investigational study is open for patient accrual.
 

Drug Category: Antineoplastic agents -- These agents disrupt DNA replication or cell division, thereby inhibiting tumor growth and promoting tumor cell death.

Drug Category: Antiemetic agents -- Emesis is a significant adverse effect of chemotherapy drugs, particularly the drugs used to treat osteosarcoma. Patients often require multiple antiemetics, and antiemetic regimens should be tailored for each patient. Commonly used antiemetics include serotonin receptor antagonists (eg, dolasetron, granisetron, ondansetron, tropisetron), corticosteroids (eg, dexamethasone), and dopamine receptor antagonists (eg, metoclopramide, prochlorperazine). The American Society of Clinical Oncology has published evidence-based clinical practice guidelines for the use of antiemetics used for chemotherapy-induced nausea and vomiting.

Drug Category: Colony-stimulating factors -- Act as hematopoietic growth factors that stimulate development of granulocytes. Used to treat or prevent neutropenia when receiving myelosuppressive cancer chemotherapy and to reduce the period of neutropenia associated with bone marrow transplantation.

Drug Category: Antidotes -- Used in the management of poisoning and overdose, prevention of toxic effects, or metabolic disorders where toxic substances accrue. Mechanisms of action are variable (eg, antagonists, toxin transformation, altered metabolism, chelation, directed antibodies).

Further Inpatient Care:

• Chemotherapy generally requires inpatient admission for administration and monitoring. In protocol CCD-7921, definitive surgery was performed after 2 cycles of induction chemotherapy. Four maintenance cycles were given beginning 2-3 weeks after surgery. Assuming no significant treatment delays, the entire course of treatment lasted approximately 46 weeks.

• In the presence of fever and neutropenia, admission is required for intravenous antibiotics and monitoring.

• Admission is required perioperatively for local control procedures (ie, surgical resection, amputation), usually around week 10 of therapy. Resection of metastatic disease (eg, lung nodules) usually is performed at the same time.

• Patients may require admission for a multitude of other medical problems during their chemotherapy treatment, including, but not limited to, varicella infection (for intravenous acyclovir and monitoring), mucositis (for pain control, usually with narcotics), dehydration, meningitis, constipation, fungal pneumonia, and cystitis.

Further Outpatient Care:

• CBC: Perform a CBC twice each week for patients on G-CSF; discontinue G-CSF when the ANC has reached a predetermined level (usually 1000 or 5000/mL).

• Blood chemistries: Monitoring blood chemistries, including monitoring with renal and liver function tests, is important for patients on parenteral nutrition or who have a history of organ toxicity (especially if continued on nephrotoxic or hepatotoxic antibiotics or other drugs).

• Monitoring for recurrence: After completing chemotherapy, patients should continue to have regular blood work and radiographic scans on an outpatient basis, with the frequency decreasing over time. Generally, these visits occur every 3 months for the first year, every 6 months for the second year and, perhaps, third year, and yearly thereafter.

• Long-term follow-up: Five or more years after patients have finished therapy, they are considered long-term survivors. They should be seen annually in a late-effects clinic and monitored with appropriate studies depending on their therapy and toxic effects. Visits may include hormonal, psychosocial, cardiologic, and neurologic evaluations.

In/Out Patient Meds:

• Trimethoprim-sulfamethoxazole: Some treatment centers routinely prescribe prophylaxis against pneumocystic pneumonia; others do not.

• Fluconazole: Systemic fungal prophylaxis is not necessary in this patient population.

• Clotrimazole: Prophylactic therapy for thrush may be discontinued when chemotherapy has been completed.

• Chlorhexidine mouth rinse: Prophylaxis against gingivitis and other mouth infections may be discontinued when chemotherapy has been completed.

Transfer:

• Pediatrician/general practitioner: While the major therapy for cancer should take place at a center staffed by pediatric oncologists, referring physicians should continue to play an important role in children's care throughout treatment. The referring physician can be critical in performing the first evaluation of an illness, particularly if the child lives far from the oncology center.

• Orthopedic surgeon: Often, the orthopedic surgeon is the first subspecialist to evaluate the patient with a suspected bone tumor. The surgeon's involvement is not only critical to establishing the diagnosis with biopsy but also paramount for local control (amputation versus limb-salvage resection). In addition, the orthopedic surgeon should continue to see the patient in follow-up to assess limb or prosthesis function.

Deterrence/Prevention:

• Unfortunately, no preventive measures for childhood cancers are known.

Complications:

• Cardiomyopathy is primarily a result of anthracycline (doxorubicin) use. Patients should receive routine follow-up echocardiograms after the completion of therapy.

• Secondary malignant neoplasms may arise as a result of chemotherapy, particularly alkylating agents.

• Infertility is a nearly universal effect of the high-dose alkylating agents used to treat osteosarcoma.

Prognosis:

• The prognosis for patients diagnosed with osteosarcoma depends primarily on whether metastases are detectable at diagnosis. Patients who present with metastases or with multifocal disease have a very poor prognosis, with long-term survival rates of less than 25%.

• For patients with initially localized disease, the prognosis depends mainly on 2 variables: resectability and response to chemotherapy. Those who have completely resectable disease and those whose tumors have an excellent histologic response to neoadjuvant chemotherapy have the best chance for cure.

• Before the 1970s, the 5-year survival rate of patients with nonmetastatic osteosarcoma was less than 20%, even with the use of aggressive surgery (mostly amputations). The fact that most relapses occurred at metastatic sites (primarily the lung) attests to the fact that most patients have undetectable metastatic disease at diagnosis (ie, micrometastatic disease). With the introduction of postoperative (adjuvant) chemotherapy, survival rates began to improve. According to data from the NCI SEER program, the 5-year survival rate from 1975-1984 was 49% and from 1985-1994 was 63%. For the latter period, females fared slightly better than males (5-year survival rates 70% for females and 59% for males).

• It is too early to know the results of the most recent cooperative group trial conducted by the Children's Cancer Group and the Pediatric Oncology Group. A recent report from Italy, however, monitored patients after therapy for a median of 11.5 years and demonstrated a 61% disease-free survival rate. Historically, patients with an unfavorable histologic response to neoadjuvant chemotherapy fare worse than those with a favorable response (>90% necrosis). In the Italian study, patients with less than 90% necrosis were treated with more intensive longer-term therapy and had a similar outcome to those with a favorable histologic response, suggesting that risk-adapted dose-intensified therapy may be beneficial.

• Future directions: Improving the survival rate and functional outcome and minimizing the short- and long-term side effects will continue to be a goal of clinical trials for osteosarcoma. The major challenge, however, is curing patients with unresectable metastatic disease. Strategies currently under consideration include dose intensification (eg, anthracycline dose-escalation facilitated by dexrazoxane cardioprotection), immune modulators, monoclonal antibodies targeting tumor cell antigens (eg, Her2/neu), and antiangiogenic agents that target components of the tumor vascular supply. High-dose administration of the bone-seeking radioisotope, samarium, is also being tested (with autologous stem cell support) for safety and efficacy in metastatic or nonresectable osteosarcoma limited to bone. Finally, the role of the emerging field of oncolytic viruses for the treatment of osteosarcoma has yet to be explored.

Patient Education:

• Chemotherapy: Parents and patients (if appropriate) must undergo formal chemotherapy teaching to learn about the adverse effects of the medications. They must know what is expected to happen as a result of the therapy and are encouraged to call with any questions.

• Central venous catheters: When patients have central venous catheters that exit the skin (eg, Hickman, Broviac), the patient or the parents must learn to care for the line properly. This usually involves daily heparin flushes. They must also know their limitations (eg, restriction from swimming). Patients with subcutaneous catheters (eg, MediPort) do not need to perform daily care routines but should learn to apply a topical anesthetic (eg, lidocaine/prilocaine [EMLA] cream) at least 1 hour before an anticipated needle stick.