Aggressive osteoblastomas are extremely rare tumors that are considered as borderline lesions between benign osteoblastomas and osteosarcomas (Dorfman and Weiss, 1984). They have a higher growth potential than conventional osteoblastomas, and typically exceed 4 cm in diameter. Clinically, aggressive osteoblastomas are characterized by destructive growth and high risk for recurrence, but they have virtually no metastatic potential.

Microscopically, the presence of so-called epithelioid osteoblasts is the main histological difference between conventional and aggressive osteoblastomas (Miyayama et al, 1993). Epithelioid osteoblasts are round cells with abundant eosinophilic cytoplasm and an eccentrically located, large, oval nucleus with a prominent nucleolus. The nucleus is often displaced by a clear cytoplasmic area, which ultrastructurally represents an enlarged Golgi apparatus.

Osteoid osteomas are practically never diagnosed by cytology. Aspirations of benign osteoblastic lesions are typically performed on larger lesions involving deep anatomic sites that require major surgery for an open biopsy (Fig. 36-3A). Aspirations from osteoblastoma are highly cellular and contain oval osteoblastic cells with eccentric nuclei and dense eosinophilic cytoplasm (epithelioid osteoblasts) (Fig. 36-3D). Some of these cells contain a well demarcated cytoplasmic halo representing a prominent Golgi center, a feature frequently seen in activated osteoblastic cells (Fig. 36-3, upper inset). Scattered multinucleated giant cells are usually present. Mitotic figures are rare. No atypical mitoses or nuclear pleomorphism can be seen. Aggressive osteoblastoma should be considered if an aspirate from an osteoblastic lesion, exceeding 4 cm in diameter, contains a large population of enlarged epithelioid osteoblasts with some nuclear pleomorphism and more than occasional mitotic figures.

Osteosarcoma is a malignant tumor of bone in which malignant mesenchymal cells have the ability to produce osteoid matrix or immature bone (Unni, 1998).

It accounts for approximately 20% of all primary sarcomas of bone, excluding multiple myeloma and hematopoietic neoplasms. The most frequent sites of skeletal involvement and the peak age incidences are shown in Figure 36-4. The age distribution is bimodal, with the first peak occurring during the second decade of life, and the second, smaller peak occurring in patients older than 50 years. The incidence within the specific bone corresponds to the site of greatest growth rate. Accordingly, the distal femoral and proximal tibial metaphyses are the most common sites for osteosarcoma. The humerus is the third most frequently involved bone, with the majority of cases involving the proximal humeral metaphyses. Other, less frequent locations include the axial skeleton, craniofacial bones, and pelvis (Clark et al, 1983). This description is limited to the most frequent conventional high-grade intramedullary form of osteosarcoma frequently diagnosed by aspiration cytology.
A more comprehensive description of all variants of osteosarcoma is beyond the scope of this review.

Although the vast majority of osteosarcomas are de novo lesions, approximately 10% to 15% of them arise in patients with rare clinical syndromes, such as familial osteosarcoma, retinoblastoma-associated osteosarcoma, Rothmund-Thomson syndrome, and multifocal osteosarcoma. Some tumors may develop in association with several neoplastic and nonneoplastic precursor lesions (Dick et al, 1982; Haibach et al, 1985; Hansen et al, 1985). Familial osteosarcoma occurs in several generations of families that are most frequently affected by retinoblastoma (Draper et al, 1986). Li-Fraumeni syndrome is another familial cancerpredisposing syndrome in which a germ line mutation of
the tumor-suppressor gene p53 is associated with a high incidence of osteosarcoma (Garber et al, 1991). Rothmund-Thomson syndrome is a very rare condition characterized by lesions of the skin, eye, genitals, central nervous system, and bone. This disorder predisposes an individual to squamous cell carcinoma of the skin and osteosarcoma, which may be multicentric.

Paget’s disease is the most frequent nonneoplastic precursor lesion of osteosarcoma in older patients (Haibach et al, 1985). Osteosarcomas complicating Paget’s disease are usually of high grade and most frequently involve the pelvis, humerus, and femur. In general, secondary osteosarcomas that complicate predisposing conditions are associated with a significantly worse prognosis then conventional de novo high-grade osteosarcomas. Radiation-induced osteosarcomas develop with a latency period of 3 years or more after radiation treatment; most such tumors are of high grade and follow an aggressive course with short survival (Sim et al, 1972). Bone infarcts rarely give rise to osteosarcomas. A small number of high-grade osteosarcomas have been reported in patients who have received metallic prosthetic implants (Martin et al, 1988). Other nonneoplastic conditions, such as fibrous dysplasia and chronic osteomyelitis, are associated with a very low incidence of secondary malignancy (Johnston and Miles, 1973).

Current multidrug chemotherapeutic regimens substantially reduce tumor mass in at least 50% of patients; in some of these patients, complete or near complete necrosis can be accomplished. The latter is associated with a substantially better prognosis compared to a tumor that responds less favorably to chemotherapy (Raymond et al, 1987). Thus, pathologic assessment of chemotherapy effect is now universally accepted as an integral element of the multimodal approach (Ayala et al, 1984). Moreover, the degree of necrosis in the postchemotherapy specimen is used as a factor in modifying the postoperative treatment protocol (Raymond et al, 1995).

The radiographic presentation of osteosarcoma varies greatly, from completely lytic to sclerotic lesions, but typically the combination of these features enables a radiographic diagnosis to be established (Sweet et al, 1981; deSantos and Edeiken, 1982; Sundaram et al, 1987). The production and mineralization of the bone matrix by the tumor results in cloudy opacities that vary in size, shape, and density (Fig. 36-5A). These opacities may be uniformly distributed throughout the lesion or they may cluster in one or several areas of the tumor. Occasionally, osteosarcoma can present as a large, solid, ivory-like sclerotic mass with heavy mineralization. The growth pattern is destructive, with ill-defined boundaries between the tumor and normal bone (Madewell et al, 1981). Usually the cortex is at least partially, or more often completely, disrupted. In such instances, the tumor extends to subperiosteal tissue and elevates the periosteum, forming the so-called Codman’s triangle. An obvious extension of tumor into the periosteal soft tissue is seen in the majority of such cases (deSantos et al, 1979a; Ragsdale et al, 1981).

The gross appearance of osteosarcoma is best described in its typical location, i.e., in the metaphyseal portion of a long bone. A combination of bony and soft-tissue areas is responsible for the heterogeneous appearance of the tumor, which has areas that vary in color, consistency, and degree of ossification (Fig. 36-5B). Heavily ossified areas are ivorycolored and can be as hard as normal cortical bone. Less ossified lesions are soft, fleshy, and lighter yellow (deSantos and Edeiken, 1982). The tumor exhibits an invasive, bone-destructive growth pattern. Small lesions are usually eccentrically located and attached to the inner surface of the cortex. More advanced lesions fill the medullary cavity and show evidence of cortical destruction with elevation of periosteum and extension into the soft tissue.

The microscopic findings may vary considerably from lesion to lesion and from area to area. Evidence of direct production of an osteoid matrix by sarcomatous cells is required before a lesion can be classified as an osteosarcoma. The relations between two tumor components—the tumor cells and an extracellular matrix—are very important for diagnosis. According to the predominant type of matrix involved, the osteosarcoma is subdivided into three main categories: osteoblastic, chondroblastic, and fibroblastic (Dahlin and Unni, 1977; Unni and Dahlin, 1989). Osteosarcoma frequently presents as an undifferentiated sarcoma with predominant pleomorphic, round, or spindle cells showing only scattered foci of osteoid production. The tumor cells may have densely eosinophilic cytoplasm with eccentrically placed nuclei, and resemble osteoblasts, but are usually larger than normal or even activated osteoblasts. These cells may infiltrate the medullary cavity or extraosseous tissue in a dispersed manner or they may grow in large cohesive sheets with epithelioid features (Yoshida et al, 1989).

The osteoblastic nature of the tumor cells is best recognized by close appositions of sarcomatous cells to tumor bone trabeculae, or by their entrapment in lace-like osteoid depositions (Fig. 36-6A-D). It is important to remember that osteosarcoma can show the whole spectrum of sarcomatous
features, from small and undifferentiated, to oval and spindle-shaped, to highly pleomorphic neoplasms (Edeiken et al, 1987; Ayala et al, 1989; Nakajima et al, 1997). As in other high-grade sarcomas, a prominent vascular hemangiopericytoma-like pattern can be found. Numerous atypical mitoses are usually present. At the opposite end of the spectrum are highly ossified sclerosing lesions in which a full range of tumor bone production can be observed. Osteosarcoma can also exhibit cartilaginous differentiation. In some instances, the cartilaginous component may be extensive and dominant throughout the lesion, but even in predominantly chondroid tumors, at least focal direct osteoid production by sarcomatous tumor cells can be found. Tumors with predominantly chondroblastic features are frequently found in the craniofacial bones. The fibroblastic type of osteosarcoma is characterized by the presence of a predominant spindle-cell component similar to that seen in fibrosarcoma. The production of osteoid by fibroblast-like cells discloses the bone-forming nature of these lesions and helps to differentiate them from other spindle-cell neoplasms of the bone (see Table 36-1).

Aspirates from osteosarcomas are usually, but not always, highly cellular and contain frankly malignant mesenchymal cells arranged in large clusters and smaller groups, or individually dispersed (see Fig. 36-5E-G). Osteosarcoma cells are spindled, oval, rounded, epithelioid, or pleomorphic, and show a high degree of cellular atypia. The malignant cells often have abundant dense cytoplasm and large nuclei containing prominent nucleoli that do not show any specific feature of osseous differentiation. The overall cytologic picture, in most instances, is indistinguishable from that of a pleomorphic malignant tumor, such as a malignant fibrous histiocytoma (Hakky et al, 1990). Cytologic preparations from osteosarcoma may contain variable amounts of collagen that mimics an osteoid. Fragments of cartilage matrix, as well as multinucleated giant cells, may also be present (Ellison et al, 1996). In general, a correlation of cytologic findings with clinical and radiographic presentations permits a preoperative cytologic diagnosis of osteosarcoma to be established in most cases (White et al, 1988).

Chondromyxoid fibroma is composed of myxoid mesenchymal tissue, corresponding to early primitive phases of
cartilaginous differentiation. It accounts for less than 1% of all primary bone tumors (Feldman et al, 1970). Chondromyxoid fibroma has a predilection for metaphyseal parts of the long tubular bones, predominantly of the lower extremity.

Approximately 30% of cases are diagnosed in the knee region, where the proximal tibial metaphysis is the most frequently involved site, followed by the distal femoral metaphysis. A unique subset of chondromyxoid fibromas involves the small bones of the acral skeleton, predominantly the feet. The pelvis, especially the ilium, is a frequently affected flat bone. Most patients are in their second or third decade of life, but there are scattered cases involving patients in the later decades of life (Batsakis and Raymond, 1989).

Radiographically, chondromyxoid fibromas are well demarcated eccentric lytic lesions whose long axis parallels the affected bone (Fig. 36-8A,B). The intramedullary margin has characteristic sharply demarcated, scalloped borders with sclerosis.

Grossly, chondromyxoid fibroma presents as a sharply demarcated, firm, gray-white lobulated mass that is eccentrically located and is always surrounded by intact periosteum.

Microscopically, chondromyxoid fibroma shows a pseudolobulated architecture with myxomatous and chondroid areas separated by hypercellular tissue (Fig. 36-9A,B). The hypercellular component is composed of mononuclear cells with scattered multinucleated giant cells, and shows an overall resemblance to chondroblastoma. Immature myxoid mesenchymal tissue, which creates a pseudolobulated pattern, contains stellate or oval cells that may present some degree of hyperchromasia. Foci of early primitive chondroid differentiation may be present (Bleiweiss and Klein, 1990).

Approximately 30% of chondromyxoid fibromas, especially these located in the small bones of the acral skeleton, show focal features of nuclear atypia. If the microscopic features are analyzed without correlation with clinical and radiologic presentations, they may be misinterpreted as myxoid chondrosarcoma (Wu et al, 1998).

Fine-needle aspirates of chondromyxoid fibroma typically show ill-defined lakes of myxoid material with scattered, isolated, primitive mesenchymal cells and occasional multinucleated giant cells (Fig. 36-9C). Less frequently, three-dimensional hypercellular clusters of loosely arranged cells, corresponding to more cellular chondroblastoma-like areas, are present (Fig. 36-9D). In general, a cytologic diagnosis of chondromyxoid fibroma can be established when the microscopic features are correlated with a characteristic radiologic presentation in its typical location. If the chondromyxoid fibroma involves less typical anatomic sites and the radiographic presentation is equivocal, it is usually cytologically diagnosed as an unclassified benign myxoid lesion.

Chondroblastoma is a distinct benign cartilage tumor composed of mononuclear chondroblastic cells that focally produce
immature cartilaginous matrix (Dahlin and Ivins, 1972). Chondroblastomas are rare lesions, accounting for only about 1% of all primary bone tumors. They have a predilection for the epiphyses of the major long tubular bones. The distal femoral and proximal tibial epiphyses, followed by the proximal humerus and proximal femur, are the most frequently involved sites. Epiphyseal-equivalent sites of flat bones, such as the periacetabular region in the pelvis, may also be involved. Most chondroblastomas are diagnosed in skeletally immature patients in their second decade of life. Approximately 10% of these lesions are diagnosed in patients older than 50 years (Turcotte et al, 1993a).

Chondroblastoma may recur after simple curettage, and may produce benign lung implants that can be successfully treated by surgery. In extremely rare instances, long-lasting chondroblastomas may progress to a high-grade sarcomatoid malignancy.

Radiographically, chondroblastomas are benign-appearing oval or round lytic lesions located in the epiphysis, with a sharply demarcated sclerotic margin (Fig. 36-10A-D). Larger tumors may expand the bone contour but they do not erode the overlying cortex (Bloem and Mulder, 1985

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