Unusual Cancers of Childhood

Introduction

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.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.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.

Frequency

In the United States, the incidence of osteosarcoma is 400 cases per year (4.8 per million population < 20 y).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:-

  • 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

  • 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.

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, 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

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).Incisional biopsies or core needle biopsies (Craig needle biopsy) are the most common types of biopsies performed by orthopedic surgeonsOpen 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, 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

See Surgical therapy.

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 and/or hospice care outweigh the potential benefits of surgical intervention.

Treatment 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.

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

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