There is considerable histologic and cytologic variability within conventional osteosarcomas. The predominant matrix pattern has been used to divide osteosarcoma into its variants, with osteoblastic osteosarcoma being more common than the chondroblastic and fibroblastic histologic subtypes. Mixtures of the patterns can and do occur. Tumor growth patterns are usually intramedullary but may be located on the bone surface.
The usual presentation is that of a poorly differentiated sarcoma with osteoblastic differentiation. The oval and round tumor cells contain significant pleomorphism with a brisk mitotic rate as well as atypical mitoses. The cytoplasm can be densely eosinophilic with an eccentric hyper-chromatic nucleus. The tumor cells are usually larger than the osteoblasts that they sometimes resemble (Fig. 5). The osteoid production may consist of broad islands to wispy trabecules and can be densely mineralized or undergo little mineralization. When thin and delicate interlacing osteoid trabeculae become mineralized, a "filigree" histologic pattern can emerge (33).
Some osteosarcomas consist of prominent chondroblastic foci that are cytologically medium-to-high grade. These tumors may need to be extensively sampled with a meticulous hunt performed for osteoid production by the neoplastic cells. Examination at the periphery of or in between cartilaginous lobules will often reveal the diagnostic regions.
The spindle cell stroma of this histologic variant can contain a deceptively bland cytology with a "herringbone" pattern, reminiscent of a fibrosarcoma. Another presentation is that of a highgrade spindle cell sarcoma mimicking a malignant fibrous histiocytoma (MFH) (34). In either case, there may be only focal osteoid production, which will require careful microscopic examination.
In this variant, large numbers of benign appearing stromal giant cells are present, which can mask the sarcomatous component. Once again, a thorough search needs to be performed to identify osteoid production and definitive stromal pleomorphism in order to arrive at the correct diagnosis.
Sheets of undifferentiated small round cells with minimal cytoplasm characterize this histologic entity. Three subtypes are recognized based on cell size. The first is the Ewing's sarcoma-like pattern. The tumor cells are round to oval with coarse clumped chromatin and mild cellular pleomorphism (Fig. 6). The second type is the lymphoma-like pattern, where cells are slightly larger. The chromatin is vesicular and prominent nucleoli are present. The third pattern contains crowded spindle-shaped cells with scant cytoplasm. Mixtures of these patterns may occur. Glycogen may be present within the cytoplasm similar to Ewing's sarcoma (35,36).
This lytic variant is made up of cystically dilated vascular spaces. The septa between the spaces contain conventional osteosarcoma cells. Two histologic variants are described. The first is the hemorrhagic and necrotic type. The malignant cells are often scattered and sometimes widely separated by the blood and necrosis. Osteoid tends to be minimal but can be absent in up to 20% of the biopsy cases. The second type is morphologically similar to aneurysmal bone cyst if examined on low magnification. The malignant cells contain hyperchromatic nuclei and are usually present in the cyst walls. Atypical mitotic figures are also noted. Osteoid, when present, is wispy and lace-like (37).
The hallmark of this type is the cytologically bland fibrous and osseous components that make up this entity. The fibroblasts have an "activated" appearance and mild atypia may be present; however, obvious pleomorphism is not present. Mitoses are present and number approximately 1 to 2 per 10 high-powered microscopic field. The osteoid production can be conspicuous, mature appearing, and hard to separate from surrounding normal bone. A minority of cases will contain only scant osteoid production, while a subset can resemble the histologic appearance of fibrous dysplasia (38,39).
Morphologically similar to its well-differentiated intraosseous counterpart, this variant is located in the juxtacortical region of long bones and tends to grow out from the cortex like a bony protrusion. Most occur in the posterior aspect of the distal femur. The woven bone trabeculae are often long, narrow, and separated by fibroblastic tissue with only minimal cytologic atypia (Fig. 7). Islands of osteoid production may be ill defined. Only scattered mitotic figures are identified and usually no atypical forms are present. Foci of high-grade osteosarcoma are sometimes found in these lesions, and, when present, are termed "dedifferentiated parosteal osteosarcoma" (40,41).
This surface osteosarcoma grows around the bone and encases it. It is more prevalent in the diaphyseal portion of the long bone as opposed to the metaphyseal region as in the other osteo-sarcoma variants. Its histologic appearance is that of cellular cartilage lobules with cytologic atypia, separated by fibrous stromal bands of tissue (Fig. 8). The neoplastic osteoid necessary for diagnosis can usually be found within the fibrous stroma (42,43).
Histologic examination of this rare variant will demonstrate a morphology very similar to conventional osteosarcoma. However, it arises from the surface of bone and will contain cortical
invasion in most cases. The tumor cells are pleomorphic with hyperchromatic nuclei. Mitotic figures as well as osteoid production are present (44).
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