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Osteosarcoma

  • Author: Charles T Mehlman, DO, MPH; Chief Editor: Harris Gellman, MD  more...
 
Updated: Nov 19, 2014
 

Background

This article focuses on high-grade intramedullary osteosarcoma (often referred to simply as 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.[3]

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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."[4] In 1805, the French surgeon Alexis Boyer (personal surgeon to Napoleon) first used the term osteosarcoma.[4, 5] 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 following[4] :

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.

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.[6] This was a significant step forward in studying these rare and ominous tumors, in that 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.[7] 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.[8] 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.[9]

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.[10] Such preoperative use of chemotherapy came to be referred to as neoadjuvant chemotherapy.

An orthopedic surgeon from Gainesville, Florida, William F Enneking, MD, introduced a surgical staging system for musculoskeletal sarcomas.[11, 12] 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.

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Problem

Osteosarcoma is a deadly form of musculoskeletal cancer that most commonly causes patients to die of pulmonary metastatic disease (see the image below).[4, 7, 13, 14, 15] Most osteosarcomas arise as solitary lesions within the fastest growing areas of the long bones of children. The top three affected areas are the distal femur, the proximal tibia, and the proximal humerus, but virtually any bone can be affected.

Chest radiograph of patient with osteosarcoma who 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.

Not all osteosarcomas arise in a solitary fashion. 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).[13] Such multifocal osteosarcoma is decidedly rare, but when it occurs, it tends to be in patients younger than 10 years.[13]

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Epidemiology

Frequency

In the United States, the incidence of osteosarcoma is 400 cases per year (4.8 per million population < 20 years).[16] 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 follows[16] :

  • Blacks – 5.2 cases per million per year (< 20 years)
  • 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, it is 4.5 per million per year.

Osteosarcoma is very rare in young children (0.5 cases per million per year in children < 5 years). However, the incidence increases steadily with age, rising more dramatically in adolescence in correspondence with the adolescent growth spurt, as follows[17] :

  • 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
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Etiology

The exact cause of osteosarcoma is unknown. However, a number of risk factors have been identified.[4, 7, 13, 14, 15, 18, 19, 20, 21, 22, 23, 24, 25]

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.

Genetic predisposition plays a role. Bone dysplasias, including Paget disease, fibrous dysplasia, enchondromatosis, and hereditary multiple exostoses and retinoblastoma (germline form) are risk factors. The combination of constitutional mutation of the RB gene (germline retinoblastoma) and radiation therapy is linked 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).

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.

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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 as follows:

  • Femur (42%, 75% of which are in the distal femur)
  • Tibia (19%, 80% of which are in the proximal tibia)
  • Humerus (10%, 90% of which are in the proximal humerus)
  • Skull and jaw (8%)
  • 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.

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Presentation

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 (see the image below), depending on the size of the lesion and its location. Systemic symptoms, such as fever and night sweats, are rare.

Clinical appearance of a teenager who presented wi Clinical appearance of a teenager who presented with osteosarcoma of the proximal humerus (same patient as in the following images). Note the impressive swelling throughout the deltoid region, as well as the disuse atrophy of the pectoral musculature.

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, though 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
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Indications

The two 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 would not be limited to) the following (see Imaging Studies):

  • 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) of the lungs

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).[26, 27]

Incisional biopsies or core needle biopsies (Craig needle biopsy) are the most common types of biopsies performed by orthopedic surgeons.[28] Open lines of communication between the orthopedic surgeon and the pathologist are vital to help ensure that adequate tissue is obtained for diagnostic purposes.

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

There is no universally accepted definition of the appropriate thickness of the normal cuff. Technically, a wide margin still exists even if the distance between normal tissue and tumor is 1 cell thick. Oncologically, 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 where maximal preservation of life is the primary goal.

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Contraindications

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 or hospice care outweigh the potential benefits of surgical intervention.

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Contributor Information and Disclosures
Author

Charles T Mehlman, DO, MPH Professor of Pediatrics and Pediatric Orthopedic Surgery, Division of Pediatric Orthopedic Surgery, Director, Musculoskeletal Outcomes Research, Cincinnati Children's Hospital Medical Center

Charles T Mehlman, DO, MPH is a member of the following medical societies: American Academy of Pediatrics, American Fracture Association, Scoliosis Research Society, Pediatric Orthopaedic Society of North America, American Medical Association, American Orthopaedic Foot and Ankle Society, American Osteopathic Association, Arthroscopy Association of North America, North American Spine Society, Ohio State Medical Association

Disclosure: Nothing to disclose.

Coauthor(s)

Timothy P Cripe, MD, PhD, FAAP Chief, Division of Hematology/Oncology/BMT, Gordon Teter Endowed Chair in Pediatric Cancer, Nationwide Children's Hospital; Professor of Pediatrics, Ohio State University College of Medicine

Timothy P Cripe, MD, PhD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American Association for Cancer Research, American Pediatric Society, American Society of Gene and Cell Therapy, American Society of Pediatric Hematology/Oncology, Connective Tissue Oncology Society, Society for Pediatric Research, Children's Oncology Group

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Sean P Scully, MD 

Sean P Scully, MD is a member of the following medical societies: American Academy of Orthopaedic Surgeons, International Society on Thrombosis and Haemostasis, Society of Surgical Oncology

Disclosure: Nothing to disclose.

Chief Editor

Harris Gellman, MD Consulting Surgeon, Broward Hand Center; Voluntary Clinical Professor of Orthopedic Surgery and Plastic Surgery, Departments of Orthopedic Surgery and Surgery, University of Miami, Leonard M Miller School of Medicine, Clinical Professor, Surgery, Nova Southeastern School of Medicine

Harris Gellman, MD is a member of the following medical societies: American Academy of Medical Acupuncture, American Academy of Orthopaedic Surgeons, American Orthopaedic Association, American Society for Surgery of the Hand, Arkansas Medical Society

Disclosure: Nothing to disclose.

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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.
Clinical appearance of a teenager who presented with osteosarcoma of the proximal humerus (same patient as in the following images). Note the impressive swelling throughout the deltoid region, as well as the disuse atrophy of the pectoral musculature.
Radiographic appearance (plain radiograph) of a proximal humeral osteosarcoma (same patient as previous image). Note the radiodense matrix of the intramedullary portion of the lesion, as well as the soft-tissue extension and aggressive periosteal reaction.
Intense radionuclide uptake of the proximal humerus is noted on a bone scan (same patient as previous 2 images).
A comparison bone scan of the involved shoulder (right image) with the uninvolved shoulder (left image) (same patient as previous 3 images).
Magnetic resonance image appearance (T1-weighted image) of osteosarcoma of the proximal humerus (same patient as previous 4 images). Note the dramatic tumor extension into the adjacent soft-tissue regions.
Core needle biopsy instruments commonly used for bony specimens. Craig needle set.
Close-up view of Craig needle biopsy instruments. Cutting cannula with T-handle attached (top) and sheath through which the cutting cannula passes (bottom).
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.
Intraoperative consultation with the pathologist, in which the surgeon and pathologist view the microscopic appearance of the biopsy specimen.
Intraoperative consultation with the pathologist. A frozen section of the biopsy specimen is being performed.
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.
Clinical photograph taken at the conclusion of a Van Ness rotationplasty procedure (same patient as previous image). 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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