AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

This article focuses on high-grade intramedullary osteosarcoma (also referred to as simply osteosarcoma), including its classic osteoblastic form and its fibroblastic and chondroblastic forms. Osteosarcoma is the most common malignant bone tumor.^{1, 2} This disease is thought to arise from primitive mesenchymal bone-forming cells, and its histologic hallmark is the production of malignant osteoid. Other cell populations may also be present, as these types of cells may also arise from pluripotential mesenchymal cells, but any area of malignant bone in the lesion establishes the diagnosis as osteosarcoma.

The mainstay of therapy is surgical removal of the malignant lesion. Most often, limb-sparing (limb-preserving) procedures can be used to treat patients with this disease and, thus, preserve function. Chemotherapy is also required to treat micrometastatic disease, which is present but often not detectable in most patients (about 80%) at the time of diagnosis.

For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education articles Cancer: What You Need to Know and Understanding Lung Cancer Medications.

Related eMedicine topic:
Osteosarcoma, Variants

Related Medscape topics:
Resource Center Cancer: Biologic Therapies
Specialty Site Oncology
Specialty Site Orthopaedics
CME/CMLE Highlights of ASCP 2007 Annual Meeting
Chemotherapy Plus Muramyl Tripeptide Improves Osteosarcoma Survival
Orthopedic Surgery Options for the Treatment of Primary Osteosarcoma
Spectrum's Levoleucovorin Approved by US FDA for Treatment of Osteosarcoma

History of the Procedure

Osteosarcoma is an ancient disease that is still incompletely understood. The term "sarcoma" was introduced by the English surgeon John Abernathy in 1804 and was derived from Greek roots meaning "fleshy excrescence."³ In 1805, the French surgeon Alexis Boyer (personal surgeon to Napoleon) first used the term "osteosarcoma."^{3, 4} Boyer realized that osteosarcoma is a distinct entity from other bone lesions, such as osteochondromas (exostoses).

Evidence of further organized thought and purposeful investigation regarding this disease was found by the mid 1800s. Peltier recorded that in 1847, the Baron Guillaume Dupuytren demonstrated his intimate knowledge of the gross pathologic appearance of osteosarcoma when he wrote the following³:

"Osteosarcoma, which is a true cancerous degeneration of bone, manifests itself in the form of a white or reddish mass, lardaceous and firm at an early stage of the disease; but presenting at a later period, points of softening, cerebriform matter, extravasating blood, and white or straw colored fluid of a viscid consistence in its interior."³

Under the auspices of the American College of Surgeons, Ernest Amory Codman (along with James Ewing and Joseph Bloodgood) created the Registry of Bone Sarcoma in 1921.⁵ This was a significant step forward in studying these rare and ominous tumors, as individual surgeons had only limited experience to guide them.

Another major institution that began to take shape in the early 1900s was the Rizzoli Institute in Bologna, Italy. This institute, whose bone tumor roots were nurtured by Vittorio Putti (1880-1940), prospered under the later guidance of persons such as Scaglietti and Campanacci.⁶ Major contributions from this institution have included innovative treatment for unicameral bone cysts (Scaglietti) and intense study of osteofibrous dysplasia (Campanacci tumor).

By the mid 1900s, great strides were being made in the United States in the field of bone pathology by Henry L. Jaffe (1896-1979) and his colleague Louis Lichtenstein (1906-1977). Each of these men published textbooks devoted to bone pathology. Jaffe is also often credited with bringing order to the chaos that was orthopedic pathology. Together, Jaffe and Lichtenstein established virtually all of the key histologic criteria that are used to diagnose most of the commonly encountered bone tumors.

A different Dr Jaffe (Norman Jaffe), along with other researchers, helped expand the use of a variety of effective chemotherapeutic agents in the 1970s and early 1980s.⁷ Not the least of these agents were Adriamycin and methotrexate. These medications (and others that followed) dramatically improved the treatment of patients with osteosarcoma through their ability to treat the micrometastatic disease that was thought to be present in approximately 80% of patients.⁸ These drugs were found to be useful both preoperatively and postoperatively in patients with osteosarcoma, a discovery made at the Sloan-Kettering Memorial Cancer Center somewhat serendipitously while custom-made prostheses were being fabricated for patients awaiting surgery.⁹ Such preoperative use of chemotherapy came to be referred to as neoadjuvant chemotherapy.

An orthopedic surgeon from Gainesville, Florida, William F. Enneking, MD, introduced his surgical staging system for musculoskeletal sarcomas.^{10, 11} This staging system helped organize the orthopedic surgical approach to both biopsy and definitive tumor resection for osteosarcoma, as well as for other musculoskeletal sarcomas. Dr. Enneking's influence extended far beyond his staging system because of his intense commitment to educating others regarding musculoskeletal tumors. He has educated numerous orthopedic oncology fellows, published numerous research articles, and continued to conduct a yearly continuing medical education course focusing on benign and malignant tumors.

Problem

Osteosarcoma is a deadly form of musculoskeletal cancer that most commonly causes patients to die from pulmonary metastatic disease.^{3, 6, 12, 13, 14} Image 1 illustrates the chest radiograph of a patient who died from pulmonary metastatic disease. Most osteosarcomas arise as solitary lesions within the fastest growing areas of the long bones of children. The top 3 affected areas are the distal femur, the proximal tibia, and the proximal humerus, but virtually any bone can be affected. Images 2-6 illustrate the clinical and radiologic findings of a patient who presented with osteosarcoma of the proximal humerus.

Not all osteosarcomas arise in a solitary fashion, as multiple sites may become apparent within a period of about 6 months (synchronous osteosarcoma), or multiple sites may be noted over a period longer than 6 months (metachronous osteosarcoma).¹² Such multifocal osteosarcoma is decidedly rare, but when it occurs, it tends to be in patients younger than 10 years.¹²

Frequency

In the United States, the incidence of osteosarcoma is 400 cases per year (4.8 per million population <20 y).¹⁵ The overall 5-year survival rate for patients diagnosed between 1974 and 1994 was 63% (59% for males, 70% for females).

The incidence is slightly higher in blacks than in whites. Data from the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Pediatric Monograph 1975-1995 are as follows¹⁵:

• Blacks – 5.2 cases per million per year (persons <20 y)
• Whites – 4.6 cases per million per year

The incidence of osteosarcoma is slightly higher in males than in females. In males, it is 5.2 per million per year. In females, the incidence is 4.5 per million per year.

Osteosarcoma is very rare in young children (0.5 cases per million per year in children <5 y). However, the incidence increases steadily with age, increasing more dramatically in adolescence, corresponding with the adolescent growth spurt.

• Age 5-9 years – 2.6 (black) or 2.1 (white) cases per million per year
• Age 10-14 years – 8.3 (black) or 7 (white) cases per million per year
• Age 15-19 years – 8.9 (black) or 8.2 (white) cases per million per year

Etiology

The exact cause of osteosarcoma is unknown. However, a number of risk factors are apparent, as follows^{3, 6, 12, 13, 14, 16, 17, 18, 19, 20, 21}:

• Rapid bone growth: Rapid bone growth appears to predispose persons to osteosarcoma, as suggested by the increased incidence during the adolescent growth spurt, the high incidence among large-breed dogs (eg, Great Dane, St. Bernard, German shepherd), and osteosarcoma's typical location in the metaphyseal area adjacent to the growth plate (physis) of long bones.
• Environmental factors: The only known environmental risk factor is exposure to radiation. Radiation-induced osteosarcoma is a form of secondary osteosarcoma and is not discussed further in this article.
• Genetic predisposition: Bone dysplasias, including Paget disease, fibrous dysplasia, enchondromatosis, and hereditary multiple exostoses and retinoblastoma (germ-line form) are risk factors. The combination of constitutional mutation of the RB gene (germline retinoblastoma) and radiation therapy is associated with a particularly high risk of developing osteosarcoma, Li-Fraumeni syndrome (germline p53 mutation), and Rothmund-Thomson syndrome (autosomal recessive association of congenital bone defects, hair and skin dysplasias, hypogonadism, and cataracts).

Related eMedicine topics:
Enchondroma and Enchondromatosis
Fibrous Dysplasia
Li-Fraumeni Syndrome
Paget Disease
Retinoblastoma
Rothmund-Thomson Syndrome

Pathophysiology

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

A number of variants of osteosarcoma exist, including conventional types (osteoblastic, chondroblastic, and fibroblastic), telangiectatic, multifocal, parosteal, and periosteal. This article only addresses conventional osteosarcoma.

Clinical

Symptoms may be present for weeks or months (occasionally longer) before patients are diagnosed. The most common presenting symptom of osteosarcoma is pain, particularly pain with activity. Patients may be concerned that their child has a sprain, arthritis, or growing pains. Often, there is a history of trauma, but the precise role of trauma in the development of osteosarcoma is unclear.

Pathologic fractures are not particularly common. The exception is the telangiectatic type of osteosarcoma, which is more commonly associated with pathologic fractures. The pain in an extremity may result in a limp. There may or may not be 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 usually indicates extensive lung involvement. Metastases to other sites are extremely rare, and, therefore, other symptoms are unusual.

Physical examination findings are usually limited to the site of the primary tumor, as follows:

• Mass: A palpable mass may or may not be present. The mass may be tender and warm, although these signs are indistinguishable from osteomyelitis. Increased skin vascularity over the mass may be discernible. Pulsations or a bruit may be detectable.
• Decreased range of motion: Involvement of a joint should be obvious on physical examination.
• Lymphadenopathy: Involvement of local or regional lymph nodes is unusual.
• Respiratory findings: Auscultation is usually uninformative unless the disease is extensive.

Related eMedicine topics:
Osteomyelitis, Acute Pyogenic
Osteomyelitis, Chronic

INDICATIONS

Section 3 of 12  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

The 2 main procedures performed by orthopedic surgeons in patients with osteosarcoma are biopsy and wide resection. Neither of these procedures should be undertaken unless complete tumor staging has been completed preoperatively. Such staging would typically include (but not be limited to) the following:

• Plain radiography of the involved bone, including the joint above and the joint below the affected region
• Total body bone scanning
• Magnetic resonance imaging (MRI) of the primary tumor area to include the entire bone of origin
• Computed tomography (CT) scanning of the lungs

The biopsy of malignant bone lesions is not an insignificant procedure. An improperly performed biopsy can result in the amputation of an otherwise salvageable extremity. It has also been shown repeatedly that oncologic outcomes are optimized when the biopsy is performed by the same surgeon who will be responsible for the definitive tumor resection (if one is needed).^{22, 23} Incisional biopsies or core needle biopsies (Craig needle biopsy) are the most common types of biopsies performed by orthopedic surgeons.²⁴ Open lines of communication between the orthopedic surgeon and the pathologist are vital to help ensure that adequate tissue is obtained for diagnostic purposes (see Images 10-11).

Wide resection is the goal for patients in whom primary tumor resection is contemplated. Simply defined, a wide resection means that the entire malignant tumor has been surgically excised, and no microscopic evidence of tumor cells at the resection margins remains (ie, negative margins). Over the years, many authors have suggested variable and arbitrary amounts of the normal tissue cuff to remove along with the primary tumor to increase the likelihood of negative margins.

No universally accepted definition exists of the appropriate thickness of the normal cuff. In a technical sense, a wide margin still exists even if the distance between the normal tissue and tumor is 1 cell thick. From an oncologic standpoint, the width achieved is less important (limb-sparing surgery vs amputation) than the achievement of a negative margin. In other words, a limb-sparing surgery without wide margins could do the patient less of a service than an amputation with wide margins. This would apply in most cases in which maximal preservation of life is considered the primary goal.

RELEVANT ANATOMY

Section 4 of 12  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

See Surgical therapy.

CONTRAINDICATIONS

Section 5 of 12  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

Because osteosarcoma is a deadly form of cancer, no absolute contraindications to treatment exist. Relative contraindications would include situations in which the patient is so frail that the risks of general anesthesia outweigh any potential benefits of surgery. Another relative contraindication would be a situation in which the patient has extensive, overwhelming metastatic disease, and the benefits of comfort and/or hospice care outweigh the potential benefits of surgical intervention.

WORKUP

Section 6 of 12  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

Lab Studies

• Most of the laboratory studies that are obtained relate to the use of chemotherapy. It is important to assess organ function before administering chemotherapy and to monitor function after chemotherapy. The only blood tests with prognostic significance are lactic dehydrogenase (LDH) and alkaline phosphatase (ALP). Patients with an elevated ALP at diagnosis are more likely to have pulmonary metastases. In patients without metastases, those with an elevated LDH are less likely to do well than are those with a normal LDH.
• Important laboratory studies include the following:
• • LDH
  • ALP (prognostic significance)
  • Complete blood cell (CBC) count, including differential
  • Platelet count
  • Liver function tests: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, and albumin
  • Electrolyte levels: Sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphorus
  • Renal function tests: blood urea nitrogen (BUN), creatinine
  • Urinalysis

Imaging Studies

• Plain films – Primary, posteroanterior (PA), and lateral chest views
• • Obtain plain films of the suspected lesions in 2 views. No single feature on a radiograph is diagnostic.
  • Osteosarcoma lesions can be purely osteolytic (approximately 30% of cases), purely osteoblastic (approximately 45% of cases), or a mixture of both.
  • Elevation of the periosteum may appear as the characteristic Codman triangle. Codman described this entity in 1909, stating, "In many cases near the junction of the healthy bone with the tumor, there is a reactive new bone formation beneath the periosteum. At the edge of the tumor, this layer of new bone ends abruptly and gives a characteristic appearance in the skiagraph [radiograph]."³
  • Extension of the tumor through the periosteum may result in a so-called sunburst appearance (approximately 60% of cases). Obtain an image of the entire bone and adjacent joint to assess for skip lesions or joint involvement. Telangiectatic osteosarcomas are often very cystic and can be mistaken for an aneurysmal bone cyst.
• CT scanning
• • Obtain a CT scan of the primary lesion and a CT scan of the chest (high resolution).
  • CT scanning of the primary lesion helps delineate the location and extent of the tumor and is critical for surgical planning.
  • CT scanning of the chest is more sensitive than is plain film radiography for assessing pulmonary metastases. Ideally, obtain the CT scan of the chest before performing a biopsy to avoid ambiguity that can arise from postanesthesia atelectasis.
• MRI
• • MRI of the primary lesion is the best method to assess the extent of intramedullary disease as well as associated soft-tissue masses and skip lesions.
  • This imaging modality is perhaps the single most important study for accurate surgical staging of the lesion with use of the Enneking staging system.
• Radionuclide bone scanning with technetium-99 (^99mTc)-methylene diphosphonate (MDP/MDI)
• • It is important to evaluate for the presence of metastatic or multifocal disease with a bone scan.
  • Subsequently, obtain an image of abnormal areas with CT scanning or MRI.
• Echocardiography or multiple gated acquisition scanning: Assess cardiac function before, and at various intervals following, treatment with Adriamycin.

Related eMedicine topic:
Aneurysmal Bone Cyst

Related Medscape topics:
Resource Center Adverse Drug Events Reporting
Resource Center Cancer: Biologic Therapies

Other Tests

• Audiography: Hearing loss is an adverse effect of cisplatin. Hearing loss typically occurs during treatment. Once treatment is completed, obtaining audiograms is not typically a part of long-term follow-up care.

Related Medscape topics:
Resource Center Adverse Drug Events Reporting
Resource Center Cancer: Biologic Therapies

Diagnostic Procedures

• Biopsies should be performed by an orthopedic surgeon (see Surgical therapy).
• Definitive resection
• • Resections of the primary lesion and of any pulmonary metastases are essential for cure.
  • These resections should be performed by orthopedic (primary lesion) and thoracic surgeons (pulmonary metastases) (see Surgical therapy).
  • Presurgical (neoadjuvant) chemotherapy often aids the surgeon in performing the resection by shrinking tumors as well as enables the assessment of histopathologic tumor responsiveness, a major predictor of outcome.

Histologic Findings

Two elements are important to the histologic examination of the tumor. The first can be assessed on the biopsy, the tumor type. The second can be assessed on the definitive resection following chemotherapy, the response to treatment.

In general, the characteristic feature of osteosarcoma is the presence of osteoid in the lesion, even at sites distant from bone (eg, lung). Although osteoid formation is usually obvious, electron microscopy occasionally may be required to reveal this process. Stromal cells may be spindle-shaped and atypical, with irregularly shaped nuclei.

A number of different histologic types of osteosarcoma exist. The conventional type is the most common in childhood and adolescence and has been subdivided based on the predominant features of the cells (osteoblastic, chondroblastic, fibroblastic), although the subtypes are clinically indistinguishable.

The telangiectatic type contains large, blood-filled spaces and is seen commonly in adolescence and early adulthood. The parosteal type usually arises from the bone cortex, has an intermediate prognosis, and can be seen in childhood or adulthood. It most commonly arises on the distal posterior aspect of the femur. Periosteal osteosarcoma is a low- to intermediate-grade tumor that typically arises immediately below the periosteum in children. It most frequently involves the tibia.

Staging

The purpose of staging tumors is to stratify risk groups. The conventional staging used for other solid tumors is not appropriate for skeletal tumors because these tumors rarely involve lymph nodes or regional spread. Rather, the staging devised and introduced by Enneking in 1980 is based on grade, extracompartmental spread, and whether or not metastases are present. This system applies to all musculoskeletal tumors (both bone and soft tissue). The Enneking staging system (also referred to as the staging system of the Musculoskeletal Tumor Society) has been credited with bringing order to the surgical treatment of a group of tumors for which treatment was previously approached rather haphazardly.

The key components to the staging system are the histologic grade of the tumor (low grade vs high grade), the anatomic location of the tumor (intracompartmental vs extracompartmental), and the absence or presence of metastatic disease. The staging system is typically depicted as follows:

• Low-grade tumor, intracompartmental – I-A
• Low-grade tumor, extracompartmental – I-B
• High-grade tumor, intracompartmental – II-A
• High-grade tumor, extracompartmental – II-B
• Any tumor with evidence of metastasis – III

The definition of "a compartment" is a central and crucial concept related to the Enneking staging system. In general, a compartment may be defined as any individual bone (ie, each bone is a compartment unto itself), intra-articular space (ie, a purely intra-articular lesion is intracompartmental), and clearly identified fascially enclosed space (eg, the anterior compartment of the lower leg). Many of these compartments are the same ones that a surgeon would release in the setting of compartment syndrome; these relate much more to soft-tissue tumors than to bone tumors such as an osteosarcoma.

Some areas of the body are considered to be extracompartmental by definition according the Enneking staging scheme. These areas include the antecubital fossa, the inguinal region, the popliteal space, and intrapelvic and paraspinal lesions. Because of the unique challenges of spinal tumors, an entirely separate staging system has been proposed for these areas by Weinstein, Boriani, and Biagin. It is referred to as the WBB staging system and was introduced in 1996. This system focuses on the general anatomic location about the spine (conceptualizing a spinal segment as if it were the face of a clock), as well as the specific anatomic location about the spine (eg, extraosseous soft-tissue extension into muscular areas vs intradural extraosseous extension). Just as spinal anatomy is complex, the WBB staging system is complex, but its use is slowly increasing.

For osteosarcoma, the foremost initial question regarding staging is whether the tumor has metastasized. Other features of the tumor, although not technically used in the staging, may impact the prognosis. These include the LDH and ALP measurements (see Lab studies), site of primary tumor (mostly related to ease of complete resection), histologic response to chemotherapy, and cause of the disease (patients with osteosarcomas arising from Paget disease have a particularly poor prognosis). Patients with isolated jaw lesions tend to do better and have a lower incidence of metastases.

• Stage I – Low-grade lesions
• Stage II – High-grade lesions
• Stage III – Metastases
• • Substage A – Intracompartmental lesion (intramedullary lesion for bone tumors)
  • Substage B – Extracompartmental lesion (extramedullary spread for bone tumors)
• Site of primary tumor
• • Distal extremity – Best
  • Distal femur – Intermediate
  • Axial skeleton – Worst
• Size of the initial tumor: In a retrospective study by Kim et al, the records of 331 patients with stage II osteosarcoma who underwent surgery and chemotherapy were reviewed.²⁶ The authors found that the initial tumor size appears to be associated with histologic response and is an important prognostic factor in osteosarcoma.
• Histologic response: Patients with tumors that have a good histologic response (the definition of which is still under debate) to preoperative chemotherapy appear to have a better prognosis, although this still is under investigation.

Related eMedicine topics:
Compartment Syndrome, Lower Extremity
Compartment Syndrome, Upper Extremity

TREATMENT

Section 7 of 12  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

Medical therapy

Before the use of chemotherapy (which began in the 1970s), osteosarcoma was treated primarily with surgical resection (usually amputation). Despite such good local control, 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 the time of diagnosis. Therefore, the use of adjuvant (postoperative) systemic chemotherapy is critical for the treatment of patients with osteosarcoma.

So-called neoadjuvant (preoperative) chemotherapy has been found not only to facilitate subsequent surgical removal by causing tumor shrinkage but also to provide oncologists with an important risk parameter. Patients in whom there has been 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 adjuvant tumor cell kill to provide risk-adapted treatment regimens.

Patients receiving methotrexate should not be given folate supplementation or Bactrim, both of which interfere with the effects of methotrexate. Otherwise, the patient's diet is not restricted.

Consultations

As usual for any child with cancer, consultations should be made with an oncologist, as well as with any provider with a subspecialty related to the specific clinical circumstances. Social services, psychology, dentistry, and child life specialists are usually involved with these patients and their families throughout their treatment course.

Activity

Restrictions on activity vary with the location of the tumor and the type of surgical procedure required for treatment.

Related Medscape topics:
Resource Center Adverse Drug Events Reporting
Resource Center Cancer: Biologic Therapies

Surgical therapy

The orthopedic surgeon is of paramount importance in the care of patients with osteosarcoma. Often, patients thought to have osteosarcoma are referred to the orthopedic surgeon first to make the diagnosis. In addition, because osteosarcomas are not particularly responsive to radiotherapy, surgery is the only option for definitive tumor removal (local control). In addition, an oncologic type of total joint prosthesis or complex bone reconstruction may be required following surgical resection. Therefore, close involvement of the orthopedic surgeon with the medical oncologist at the time of diagnosis, as well as during and after chemotherapy, is critical.

Biopsy

Biopsy procedures include open biopsy (preferred to avoid sampling error and to provide adequate tissue for biologic studies), trephine biopsy or core needle biopsy (preferred for vertebral bodies and many pelvic lesions), or fine needle aspiration (not recommended). Images 7-8 illustrate the Craig needle (core needle) biopsy set. Carefully plan the incision for an open biopsy to avoid tumor contamination of the neurovascular structures and to facilitate removal of the biopsy tract en bloc during definitive surgery. Image 9 illustrates excision of the biopsy tract during definitive tumor resection.

Regardless of the technique, a frozen section should be examined to be certain that the tumor has been sampled accurately. Images 10-11 illustrate intraoperative consultation with the pathologist for purposes of evaluation of the frozen-section specimen. If possible, extraosseous components should be sampled rather than bone to lessen the risk of fracture. Seal bone holes with Gelfoam or a similar material to decrease the risk of hematoma and tumor spread. Drains should be of the closed-suction variety, and they should be placed directly in line with the skin incision (a short distance away).

Definitive resection

The primary aim of definitive resection is patient survival. As such, margins on all sides of the tumor must contain normal tissue (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 an abnormality depicted on MRI or bone scan. Radical margins, defined as removal of the entire involved compartment (bone, joint to joint; muscle, origin to insertion), are usually not required for cure. A less-than-wide margin (marginal or intralesional margin) may be functionally helpful as a debulking therapy, but intrinsically, it will not be locally curative. Amputation may be the treatment of choice in some circumstances. If possible, a number of options exist for limb-salvage reconstruction, which must be chosen based on individual considerations, as follows:

• Autologous bone graft: These may be vascularized or nonvascularized. Rejection does not occur with these grafts, and the rate of infection is low. The growth plates of patients who are skeletally immature may limit options for stable bone fixation (osteosynthesis).
• Allograft: Graft healing and infection can be problematic, particularly during chemotherapy. Immunologic rejection can also occur. Allograft-prosthesis composites are also an option.
• Prosthesis: Prosthetic joint reconstruction can be solitary or expandable, although it is usually expensive. The longevity of such implants is a major concern in young children.
• Rotationplasty: This technique is particularly suited for patients with distal femur and proximal tibia tumors, particularly large tumors in which a high amputation is the only alternative. Lesions located in other areas of the femur or tibia may also be amenable to this treatment approach. Images 12-13 are clinical photographs that illustrate several aspects of a Van Ness rotationplasty procedure. Patients who are very young or athletic may benefit greatly from this procedure from a functional standpoint and this procedure may also serve to minimize the number of future surgeries needed.
• • Following tumor resection, vessels are repaired in an end-to-end fashion in most instances to optimize vessel patency. The distal portion of the leg is then rotated 180º and reattached to the thigh at the proximal edge of the resection. Other osteosynthesis variations are also possible.^{1, 26} 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.
  • It is best if before the decision to pursue a Van Ness rotationplasty procedure, patients and families either meet or review 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 may occasionally be required for clear margins. This procedure should be performed at the time of the primary tumor resection. Although 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 (each side separated by a few weeks). For an osteosarcoma that recurs as one or more lung lesions only more than 1 year after the patient is off therapy, surgical resection alone can be curative, as the likelihood of metastases to other sites is low. Chemotherapy is warranted if recurrence occurs earlier, as the risk of other micrometastatic disease is high.

Follow-up

Inpatient care

• Further cycles of chemotherapy: These generally require inpatient admission for administration and monitoring. Active drugs include methotrexate, cisplatin, doxorubicin, and ifosfamide. Patients treated with high-dose alkylating agents are at higher risk for myelodysplasia and leukemia. Therefore, a CBC count should be performed periodically.
• Fever and neutropenia: Admission is required for intravenous (IV) antibiotics and monitoring.
• Local control: Admission is required perioperatively for local control (surgical resection, amputation), usually around week 10 of therapy. Resection of metastatic disease (eg, lung nodules) is also performed at this time.
• Other: Patients may require admission for a multitude of other medical problems during their chemotherapy treatment phase, including, but not limited to, varicella infection (for IV acyclovir and monitoring), mucositis (for narcotics), dehydration, meningitis, constipation, fungal pneumonia, and cystitis.

Outpatient care

• CBC count: Perform a CBC measurement twice each week for patients on granulocyte colony-stimulating factor (G-CSF), so that G-CSF can be discontinued when the absolute neutrophil count has reached a predetermined level (usually 1000 or 5000/μL).
• Blood chemistries: It is important to monitor the blood chemistries and liver function test results for patients on parenteral nutrition or who have a history of toxicity (especially if nephrotoxic or hepatotoxic antibiotics or other drugs are continued).
• Monitoring for recurrence: Patients should continue to have 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 and, perhaps, third year; and yearly thereafter.
• Long-term follow-up: When patients have been without therapy for 5 or more years, they are considered long-term survivors. These individuals should be seen annually in a late-effects clinic and monitored with appropriate studies depending on their therapy and side effects. Visits may include hormonal, psychosocial, cardiology, and neurologic evaluations.

COMPLICATIONS

Section 8 of 12  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

Hearing loss is an adverse effect of cisplatin. Fever and neutropenia may occur, and if they do, patient admission is required for IV antibiotics and monitoring. Patients may require admission for a multitude of other medical problems during their chemotherapy treatment phase, including, but not limited to, varicella infection (for IV acyclovir and monitoring), mucositis (for narcotics), dehydration, meningitis, constipation, fungal pneumonia, and cystitis.

OUTCOME AND PROGNOSIS

Section 9 of 12  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

The present understanding of outcome and prognosis for osteosarcoma is driven by certain serum markers, clinical staging, and histologic response to chemotherapeutic agents.

The overall 5-year survival rate for patients diagnosed between 1974 and 1994 was 63% (59% for males, 70% for females). Patients with an elevated ALP at diagnosis are more likely to have pulmonary metastases. In patients without metastases, those with an elevated LDH are less likely to do well than are those with a normal LDH.

See Staging for a discussion of prognosis as it relates to clinical staging.

In a retrospective study by Kim et al, the records of 331 patients with stage II osteosarcoma who had underwent surgery and chemotherapy were reviewed.²⁵ The authors found that the initial tumor size appears to be associated with histologic response and is an important prognostic factor in osteosarcoma. Other studies have shown that patients in whom a good histopathologic response to neoadjuvant chemotherapy has been achieved (>95% tumor cell kill or necrosis) have a better prognosis than those whose tumors do not respond as favorably. 

FUTURE AND CONTROVERSIES

Section 10 of 12  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

The genetic roots of cancer are irrefutable, and gene-focused basic science research holds tremendous promise for risk stratification as well as effective and innovative treatments. Multidrug-resistant varieties of osteosarcoma are a case in point. These cell lines have been shown to be genetically encoded with a certain membrane-bound glycoprotein that helps render these cancer cells "immune" to many chemotherapeutic agents. Early identification of such patients (perhaps at the time of the initial biopsy) would allow for a tailored approach to neoadjuvant chemotherapy.

Metastatic or locally recurrent osteosarcoma presents an especially tough treatment challenge that remains incompletely answered. Patients in such cases find themselves in a particularly poor survival bracket. Future efforts need to be aimed at improving chemotherapeutic and surgical treatments that can be offered to these patients. One potential example of this is the bone-seeking radioisotope samarium (153-samarium ethylene diamine tetramethylene phosphonate), which has the potential to selectively deliver high doses of radiation to osteosarcoma cells. The safety and efficacy of this agent are being studied in patients with metastatic and locally recurrent osteosarcoma.

MULTIMEDIA

Section 11 of 12  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

Media file 1:  Chest radiograph of patient with osteosarcoma who died from pulmonary metastatic disease. Note the presence of a pneumothorax as well as radiodense (bone-forming) metastatic lesions.
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Media file 2:  Clinical appearance of a teenager who presented with osteosarcoma of the proximal humerus (same patient in Images 2-6). Note the impressive swelling throughout the deltoid region, as well as the disuse atrophy of the pectoral musculature.
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Media file 3:  Radiographic appearance (plain radiograph) of a proximal humeral osteosarcoma (same patient in Images 2-6). Note the radiodense matrix of the intramedullary portion of the lesion, as well as the soft-tissue extension and aggressive periosteal reaction.
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Media type:  X-RAY

Media file 4:  Intense radionuclide uptake of the proximal humerus is noted on a bone scan (same patient in Images 2-6).
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Media type:  Nuclear Image

Media file 5:  A comparison bone scan of the involved shoulder (right image) with the uninvolved shoulder (left image) (same patient in Images 2-6).
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Media type:  Nuclear Image

Media file 6:  Magnetic resonance image appearance (T1-weighted image) of osteosarcoma of the proximal humerus (same patient in Images 2-6). Note the dramatic tumor extension into the adjacent soft-tissue regions.
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Media type:  MRI

Media file 7:  Core needle biopsy instruments commonly used for bony specimens. Craig needle set.
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Media file 8:  Close-up view of Craig needle biopsy instruments. Cutting cannula with T-handle attached (top) and sheath through which the cutting cannula passes (bottom).
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Media file 9:  Resected specimen of a proximal tibia osteosarcoma. The primary lesion was such that the knee joint was resected with the primary lesion. Note that the previous longitudinal biopsy tract was completely excised with the specimen.
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Media file 10:  Intraoperative consultation with the pathologist, in which the surgeon and pathologist view the microscopic appearance of the biopsy specimen.
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Media file 11:  Intraoperative consultation with the pathologist. A frozen section of the biopsy specimen is being performed.
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Media file 12:  Intraoperative photograph of a Van Ness rotationplasty procedure. Osteosynthesis of the tibia to the residual femur is being performed. Courtesy of Alvin H. Crawford MD, FACS.
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Media file 13:  Clinical photograph taken at the conclusion of a Van Ness rotationplasty procedure (same patient as in Image 12). Note that the new "knee" of the operative side (left side) is purposely reconstructed distal to the normal right knee. This is in anticipation of the future growth potential of the unoperated limb. Courtesy of Alvin H. Crawford MD, FACS.
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Media type:  Photo

REFERENCES

Section 12 of 12

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

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