The osteosarcoma is best defined as a malignant tumor of mesenchymal cells, characterized by the direct formation of osteoid or bone by the tumor cells. Some are composed largely of fibroblastic cells, others have abundant bone formation, some show chondroid differentiation, and still others are highly vascular (telangiectatic), but all have tumor-produced osteoid marked by trapping of anaplastic tumor cells within the lacunae of the osteoid matrix. Excluding plasma cell myelomas, osteosarcomas are the most common form of primary cancer in bones.
On the basis of clinical setting, these neoplasms can be divided into two large categories, primary and secondary. Primary osteosarcomas arise de novo in the apparent absence of underlying bone disease or recognized carcinogenic influences. Most of these cancers appear in young persons under 20 years of age in the long bones before the epiphyses have closed, with a definite male preponderance. Those of the jaws usually arise in older individuals. Secondary osteosarcomas develop against a background of preexisting bone pathology or previous exposure to some potentially carcinogenic influence. Most important is underlying disease (e.g., Paget's disease of bone, multiple enchondromas, multiple osteochondromas, chronic osteomyelitis, fibrous dysplasia, infarcts, and fractures of bone). Bone irradiation also is a well-recognized predisposing influence. Secondary osteosarcomas usually occur in considerably older individuals; they account for about 6 to 10% of all osteosarcomas.
On the basis of site of origin within the bone, osteosarcomas have been divided into many subsets (e.g., medullary, intracortical) that need not concern us save to point out the parosteal (juxtacortical) variant. It is applied to the periosteum and usually is well differentiated, with a much better prognosis than the other variants (80% five-year survival). Most of the following remarks relate to the most common pattern of osteosarcoma, sometimes referred to as conventional.
The origins of osteosarcomas are as mysterious as those of all other
forms of cancer. However, a number of interesting observations have been made
that can be considered under the categories of:
(1) genetic, (2) constitutional, and (3) environmental.
The evidence implicating genetic factors in the origin of some (possibly many) osteosarcomas mounts with each passing year. It is well established that about 40% of patients with retinoblastomas have a hereditary mutation in chromosome 13 within the q14 band. Patients who survive their genetic retinoblastoma have about a 500-fold greater risk of developing an osteosarcoma. Subsequently, it was discovered that some osteosarcomas are associated with homozygous mutations at the retinoblastoma locus on chromosome 13 even in the absence of retinoblastomas. It is hypothesized that the 13q14 locus constitutes a suppressor gene. Individuals who inherit a single mutation on one of the alleles are at risk of acquiring a somatic mutation in the other allele and, with homozygosity, of developing a retinoblastoma or osteosarcoma, or both.
The constitutional influences in the genesis of osteosarcomas point mostly to a possible contributory role for unusually active bone growth. The well-known association between these neoplasms and Paget's disease could relate to active bone growth. The male preponderance and the peak frequency in youth are additional straws in the wind. Of interest, large dogs, such as the Saint Bernard and Great Dane, have 13 times the frequency of bone sarcoma of smaller breeds (data are not available on the frequency in professional basketball players).
The best documented environmental influence is the effect of radiation, a well-recognized mutagen. In addition, therehas been some tenuous evidence pointing to a virus; a cell-free agent derived from human osteosarcomas, when injected into hamsters, has been reported to produce an increased incidence of a variety of mesenchymal sarcomas, the most common being osteosarcoma. Such an exogenous agent might fit with the fragmentary evidence of immunologic reactions to apparent tumor antigens, not only among patients harboring these neoplasms, but also among family members. Although the pathogenetic puzzle has not been solved,progress has been made.
Most conventional osteosarcomas arise in the medullary cavity of the metaphyseal end of the long bones of the extremities: in decreasing order of frequency, in the lower end of the femur, upper end of the tibia, upper end of the humerus, and upper end ofthe femur. About 60 to 70% of all tumors arise close to the knee. However, any bone may be involved, and in persons over the age of 25 the incidence in flat bones (e.g., jaws, pelvis) and long bonesis almost equal (Figure 28-18). By the time of diagnosis, most osteosarcomas have broken through the cortex and periosteum and are bulky masses that often cause obvious swelling of the extremity. The neoplasms appear as gray-white, aggressive masses thatoften contain areas of hemorrhage and cystic softening (Figure 28-19). They vary in consistency; some are largely fibroblastic and soft, whereas others have components of osteoid or chondroid and are firmer. As the neoplasm penetrates the cortex, it lifts the periosteum and a characteristic Codman s triangle is produced-the angle between the plane of the outer surface of the cortex and the elevated periosteum. This anatomic feature can often be visualized in radiographs, and although it is characteristic of osteogenic sarcoma, it is not pathognomonic. The tumor may spread widely in the marrow cavity, but it rarely penetrates the epiphyseal plate to involve the joint space; this may, however, occur after epiphyseal closure.
Histologically, these tumors vary in the richness of the osteoid or cartilaginous or vascular components, but common to all is a basically anaplastic mesenchymal parenchyma that in places is punctuated by the formation of osteoid matrix by tumor cells. Thus, frankly anaplastic cells are found lying within the lacelike patterns of osteoid matrix (Figure 28-20). Islands of cartilage may also be formed by tumor cells. The mesenchymal cells between the osteoid or cartilaginous matrix are often wildly anaplastic, with numerous tumor giant cells, atypical mitoses, and striking hyperchromasia. The vascularization may be subtle or take the form of large, cavernous telangiectatic channels, distributed throughout the tumor-telangiectatic osteosarcomas.
Extraskeletal osteogenic sarcomas are rare. The most common sites of origin are the retroperitoneum, mediastinum, and breast, but sometimes they arise in internal organs such as the uterus or lungs.
Whatever the morphologic variant and site of origin, all osteosarcomas are aggressive lesions that metastasize widely through the bloodstream, usually first to the lungs, but also to other parenchymal organs and other osseous sites. In contrast, lymph node involvement, even in the local region, is unusual. Approximately 30 to 40% of patients have demonstrable pulmonary metastases when first seen, and more than 90% of those who die of the neoplasm have metastases to the lungs, bones, brain, and elsewhere.
As with most malignant tumors of bone, the presenting clinical complaints are those of pain, tenderness, and swelling of the affected parts. Rapid growth is characteristic of many, sometimes producing expansion and enlargement of the limb or sudden fracture of the bone as the first symptom. The serum alkaline phosphatase level may be elevated but is usually of no diagnostic significance. Radiographs, CT scans, or MRI scans are distinctive in many instances. The radiodensity or radiolucency of the tumor varies according to the extent of bone formation. Lifting of the periosteum at Codman's triangle can sometimes be visualized but may be absent. Subperiosteal and soft tissue penetration of the tumor with its bony osteoid content may produce extraosseous radiodensities. However, in almost all cases, biopsy of these neoplasms is necessary to confirm the diagnosis before radical surgical procedures are performed.
Advances in treatment have substantially improved the prognosis. In the past, the five-year survival with surgery alone was about 20%. Currently, combined surgery, radiation, and chemotherapy yield about a 60% five-year disease-free survival with a remarkably small incremental loss over the next five years. In general, osteoblastic lesions respond the least favorably to therapy and fibroblastic lesions respond best.
From Cotran, Kumar and Robbins. Pathologic Basis of Disease. 4th edition.