Incidence and Location

Osteosarcoma accounts for approximately 20% of all primary sarcomas of bone, excluding multiple myeloma and other hematopoietic neoplasms. The most frequent sites of skeletal involvement and the peaks of age incidences are shown in Figure 5-1. The age distribution is bimodal, with the first major peak occurring during the second decade of life, and the second, much smaller, peak being observed in patients older than age 50 years. The presence of the second peak was originally documented in the Memorial Sloan-Kettering Cancer Center series⁹⁶ and has been confirmed by data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program⁵⁶ (Fig. 5-2). The SEER Program, containing population-based data on approximately 5000 cases of osteosarcoma, provides a detailed view on epidemiologic trends and survival rates for osteosarcoma.^56,157 The overall incidence rates are clearly age specific and indicate that individuals, during the first two decades of life and over age 60, have similar risk for the development of osteosarcoma with incidence rates of 4.4 and 4.2 per million respectively. The population between the third and sixth decades of life have a lower incidence rate of osteosarcoma, in a range of 1.7 per million. Osteosarcoma is rare in the first decade of life (<5% of cases). Most patients (~60%) are between 10 and 20 years old. The sex ratio varies among the series but a male predominance is clear (1.3 : 1 to 1.6 : 1). The higher rate in males is attributed to their longer period of skeletal growth. It appears that osteosarcoma has a tendency to develop earlier in females than in males, with a median age of 17 years compared with 18 years for males,⁹⁶ but the distribution of the age-related incidence and frequency from the SEER Program data do not confirm this trend⁵⁶ (Fig. 5-3). There are no major differences among races (white versus black), but it appears that the peak incidence during the second decade of life is somewhat higher in black males than in white males or in black or white females (Fig. 5-3).

The peak incidence of osteosarcoma in adolescents corresponds to the peak period of skeletal growth.^{64,65,71,76,90,163,174,175} The portions of the skeleton with the highest growth rate are the most frequently affected. The frequency of tumor occurrence within a specific bone corresponds to the site of greatest growth rate. Accordingly, the distal femoral and proximal tibial metaphyses, where most growth occurs during adolescence, are the most common sites for osteosarcoma. Some studies have documented that, on average, patients with osteosarcoma are taller than their peers in the corresponding age group and have increased levels of somatomedin.^71,136 In adolescents, osteosarcoma predominantly involves the appendicular skeleton. Approximately 50% of cases are located in the knee region. The distal femoral metaphysis is affected 2.5 times more frequently than the proximal tibial metaphysis. The humerus is the third most frequently involved bone in young patients and is the site of 15% of all cases, with the majority of osteosarcomas developing in the proximal humeral metaphysis and diaphysis. The distal portion of the humerus is seldom involved. Osteosarcoma is unusual in the bones of the forearm and in the small bones of the hands and feet. In older patients, the predilection for the appendicular skeleton and the knee region is less clear^59,94 (Figs. 5-4 and 5-5). In patients older than age 50 years, only 15% of the tumors occur in the knee area. In this age group, the axial skeleton and flat bones are more frequently affected (~40% of cases). Approximately 10% of osteosarcomas occur in the pelvis, and the ilium is the most frequently involved flat bone. Less than 10% of osteosarcomas occur in the mandible and other craniofacial bones.

The radiographic presentation of osteosarcoma varies greatly. The tumor may be completely lytic or sclerotic, but usually a combination of these features enables a preoperative radiographic diagnosis of osteosarcoma in the majority of cases⁹⁹ (Fig. 5-6). The mineralization of tumor matrix produces cloudy opacities that vary in size, shape, and density. These opacities can be relatively uniformly distributed throughout the lesion or can cluster in one area to form large, irregular sclerotic masses (Figs. 5-7 to 5-10). Occasionally, the tumor may appear to have a uniform ivory-like density with minimal or no lytic component (Figs. 5-11 and 5-12). The tumor exhibits a destructive growth pattern with a gradual transition from lytic or sclerotic areas to normal bone, which makes the borders of the lesion ill-defined. The process can be limited to the medullary space, but in most instances the cortex is also involved and often is destroyed, at least focally. In the area of penetration, the outer limits of the cortex are indistinct, but its original outline can usually still be traced. Usually the tumor extends into the soft tissue, and its mineralized shadow can be seen overlying the area of cortical penetration (Figs. 5-13 and 5-14).

Tumors that extend beyond the cortex can vary in size and degree of mineralization. In general, the size of the extracortical soft tissue component corresponds with the size of intramedullary tumor and to the extent of cortical destruction. The greater the extent of tumor within the bone and the more extensive the cortical disruption, the larger the extracortical soft tissue component is likely to be. In exceptional cases, long plugs of tumor can extend within the medullary cavity well beyond the level of cortical discontinuity. The pattern of destructive growth and extension into soft tissue is usually asymmetric with one side of the bone being more involved (see Figs. 5-6 and 5-8). Initially there is a single area of cortical penetration and expansion into soft tissue, but eventually with tumor progression, it may form an extensive soft tissue mass that circumferentially involves the affected long bone (see Figs. 5-7, 5-9, 5-10, 5-12, 5-14, and 5-16).

The outer surface of the cortex overlying the tumor may demonstrate a prominent periosteal reaction that can be in the form of parallel periosteal new bone, hazy cortical irregularity and fuzziness, or both features (Fig. 5-15). Occasionally the tumor may form perpendicular or radiating striations (“sunburst”). This type of periosteal reaction can be seen on the bone surface without radiographic evidence of extension into soft tissue but is usually observed within the soft tissue component of the tumor that overlies an area of cortical disruption. The tumor growing on the surface of bone can elevate the periosteum and induce a periosteal reaction in the form of an open triangle overlying the diaphyseal side of the lesion. This type of reaction is known as Codman’s triangle (see Figs. 5-6 and 5-15). Sometimes the periosteal reaction can be in the form of multiple layers (“onion skin”), which are more typically seen in small-cell tumors involving bone and in osteosarcomas that are in a diaphyseal rather than metaphyseal location.

Rapidly growing tumors can produce predominantly lytic masses with a permeative pattern of bone destruction and minimal or no periosteal reaction⁵³ (see Figs. 5-8 and 5-14). This type of osteosarcoma is more difficult to diagnose from radiographs and requires special care to distinguish it from other destructive lesions of bone, such as osteomyelitis. Osteosarcoma is usually suspected because of the presence of a destructive lesion in the metaphyseal area of a long bone in an adolescent, even when the characteristic pattern of tumor matrix mineralization is lacking. Occasionally osteosarcoma of quite high histologic grade can produce deceptively innocent radiographic defects with sharp or even sclerotic margins. In very rare instances, osteosarcoma can originate within the epiphysis (epiphyseal osteosarcoma) and may be mistaken on radiographs for chondroblastoma or clear-cell chondrosarcoma²⁰⁵ (see Figs. 5-19 and 5-20).

Computed tomography and especially magnetic resonance imaging (MRI) are used to evaluate the extent of disease.^52,74,83,193 These types of imaging are especially useful in evaluating the extent of intramedullary involvement and extension into soft tissue. Of particular importance for the therapy plan (limb-sparing procedure) is the relationship between the soft tissue extension and the neurovascular bundle. MRI is particularly useful to evaluate the extent of the tumor and plan the resection planes for surgical excisions.¹⁰² MRI reveals the heterogeneous nature of the tumor by exhibiting variable levels of signal intensity in different areas of the tumor tissue. Heavily mineralized areas typically show no signal on the T2-weighted images. On the contrary, well-vascularized sarcomatous areas may exhibit various degrees of signal enhancement. In general, in MRI techniques, contrast enhancement, combined with fat saturation, discloses the heterogeneous nature of the tumor and is helpful to evaluate tumor extent and its relationship to anatomic structures in the surrounding normal tissue (Fig. 5-16; see also Figs. 5-6 to 5-15).

The gross appearance of osteosarcoma is best described in its typical location (i.e., in the metaphyseal portion of a long bone). Osteosarcoma can be composed of predominantly ossified or nonossified tissue, but usually a combination of bony and soft tissue areas is responsible for the characteristic gross appearance of this tumor. In most instances, the tumor’s cut surface is very heterogeneous, with areas that vary in color, consistency, and degree of ossification (Fig. 5-17). Highly ossified ivory-like areas are yellow-white and may be as hard as normal cortical bone (see Fig. 5-11). The less ossified areas are soft and less yellow in appearance. Areas with minimal or no ossification are tan, fleshy, or of chondroid consistency. They can also exhibit features of hemorrhage and necrosis (see Figs. 5-17 and 5-18).

The large, densely ossified areas are usually the result of interaction between tumor osteoid and preexisting nontumor bone. In the central intramedullary portions of the tumor, large areas of bony condensation are produced by superimposition of tumor osteoid on the preexisting cancellous bone of the medullary cavity. Outside the medullary cavity, within the soft tissue extension, solid bony areas are formed by the deposition of tumor bone between spicules of reactive nontumor bone of periosteal origin. Overall, the tumor exhibits an invasive and bone-destroying pattern of growth (Figs. 5-18 to 5-20). The borders between the tumor tissue and adjacent structures are indistinct and irregular. This is particularly evident in the areas where heavily ossified tumor tissue merges with the adjacent cortex.

The smaller lesions are usually eccentrically located within the medullary cavity. Even relatively small lesions that do not fill the medullary cavity have a high propensity to invade the cortex and to induce periosteal reaction. More advanced lesions fill the medullary cavity and progress toward the shaft and growth plate (Figs. 5-21 and 5-22). At this stage, lesions usually exhibit clear areas of cortical destruction, elevation of periosteum, expansion into the soft tissue, or a combination of the features. These features correspond to the deposition of periosteal new bone, which can be detected on radiographs. Further growth produces an eccentric soft tissue mass that overlies the large cortical defect. Signs of periosteal impingement with associated periosteal bony reaction often can be seen at the periphery of the lesion, particularly in the diaphysis. This corresponds to the Codman’s triangle seen in radiographs (see Fig. 5-18). As a rule, the intramedullary progression of the tumor is more extensive than can be appreciated on plain radiographs. The intramedullary border may be irregular or may form a sharply demarcated dome-shaped structure. The growth plate serves as a substantial barrier to tumor growth and is seldom penetrated except in more advanced lesions (see Figs. 5-13 and 5-15). Serial block sections of the epiphyseal area may document foci of perforation of the physis and microscopic extension into the epiphysis, even in less advanced cases.^62,187 Rarely, the articular cartilage can be destroyed with extension of tumor into the joint cavity. The synovium is more frequently involved in advanced cases by tumor growth along the bone surface rather than by transarticular penetration.

The two basic microscopic components of osteosarcoma are the sarcomatous tumor cells and the extracellular matrix (see Fig. 5-23). The relationship between the tumor cells and the matrix is very important for diagnosis. Evidence of direct production of osteoid matrix by sarcomatous tumor cells is required to classify the lesion as an osteosarcoma (Figs. 5-23 to 5-25). Osteosarcomas can be subdivided into three main categories on the basis of their predominant matrix product: osteoblastic, chondroblastic, and fibroblastic.^{47–50,94,96,100,121,209} Osteosarcoma often presents as an undifferentiated sarcoma with predominance of giant pleomorphic, round or spindle cells with little intervening matrix (Figs. 5-26 to 5-28). Usually a mixture of several cellular components leads to a variegated pattern of matrix production. The tumor cells may have densely eosinophilic cytoplasm with eccentrically placed nuclei and resemble osteoblasts, but they are usually much larger than normal or even activated osteoblasts. They vary considerably in size and often exhibit pronounced nuclear atypia. These cells grow in large, cohesive sheets and may form areas with epithelioid features.^85,86,108 Focal epithelioid features are quite common in conventional osteosarcoma. Tumors with predominant organoid growth of cells with epithelioid features are refered to as epithelioid osteosarcoma, described in more detail below. The osteoblastic nature of the tumor cells is best recognized by their close apposition to trabeculae of tumor bone or by their entrapment in lacelike osteoid deposits (Figs. 5-29 and 5-30). A full gamut of sarcomatous features ranging from undifferentiated round, oval, or polygonal cells through various patterns of pleomorphic sarcoma and spindle-cell sarcoma may be seen. This mixture of patterns is best observed in predominantly lytic lesions with minimal osteoid production. Those lesions typically exhibit pronounced nuclear atypia and brisk mitotic activity with numerous atypical mitoses (see Figs. 5-27 and 5-38) and are easily diagnosed as malignant, but their bone-forming features can be very focal and inconspicuous. Such cases may simulate pleomorphic malignant fibrous histiocytoma of bone. As in other high-grade sarcomas, prominent stromal vascular patterns that mimic hemangiopericytoma can be found in osteosarcoma (see Fig. 5-38). At the opposite end of the spectrum are highly ossified, sclerosing lesions in which a full range of tumor bone production can be observed.

The production of tumor bone matrix begins with the elaboration of extracellular fibrillar collaginous matrix (osteoid). In its early stages, it can be recognized by the presence of a dense, fibrillar eosinophilic substance deposited between small groups of cells. At this stage, seams of dense eosinophilic matrix material separate and enmesh individual tumor cells. Larger areas of osteoid produce a lacelike pattern, in which rows of tumor cells are surrounded by a fibrillar ground substance that may begin to show early mineralization (Figs. 5-29 to 5-31). Further advance of ossification produces wide sheets of osteoid that separate tumor cells and show deposits of calcification (Figs. 5-32 and 5-33). More advanced mineralization produces clearly recognizable trabeculae of woven tumor bone. The tumor bone trabeculae differ considerably in size, shape, and degree of mineralization. They are haphazardly arranged, have highly irregular borders, and merge gradually with areas of less mature osteoid (Figs. 5-34 to 5-37). The tumor bone frequently is in direct contact with preexisting nontumor bone that represents cancellous bone trabeculae of the medullary cavity, the cortex, or the reactive bone of periosteal origin. The tumor bone characteristically fuses and merges with the preexisting nontumor lamellar bone and often forms large, ossified, solid areas (see Fig. 5-24). In such instances, the nontumor bone serves as a scaffold for the tumor bone and both occasionally form large solid areas of ossified tissue as dense as the normal cortex. Usually, however, there is a clearcut separation of the immature, woven tumor bone where it attaches to the lamellar, nontumor bone. In contradistinction, a gradual conversion of woven bone into mature lamellar bone can be seen in reactive lesions, such as fracture callus. The advancing tumor can partially or completely destroy the original bone, replacing it with tumor bone or with nonossified tumor tissue. The tumor osteoid can form well-defined islands that mimic trabecular bone or can be deposited in irregular sheets that contain entrapped tumor cells (see Fig. 5-32). Interestingly, the tumor cells entrapped by the osteoid are usually smaller and less pleomorphic than the tumor cells lying outside the osteoid and they more closely resemble normal osteoblasts. Jaffe¹⁰⁰ described this phenomenon as normalization in referring to the less malignant appearance of tumor cells deeply embedded in osteoid. Normalization can also be used in a general sense to describe a more mature appearance of osteosarcoma in highly ossified solid areas (see Fig. 5-32). The trabecular pattern of tumor bone sometimes focally mimics the appearance of benign reactive woven bone or that of benign osteoblastic tumors (i.e., osteoid osteoma and osteoblastoma). The major difference is in the cells that fill the intertrabecular spaces, which in osteosarcoma exhibit atypical, sarcomatous features. The infiltrating pattern within such areas, with destruction or engulfment of preexisting nontumor bone, facilitates the diagnosis of a malignant process. These tumors may have a deceptively benign look and may be mistaken for osteoblastomas of the conventional or aggressive type (for a more detailed description see Chapter 4 and the section on osteosarcoma with unique microscopic features in this chapter).