Primary osteosarcoma: For the most part they originate in the long bone metaphysis (90 %), especially in the knee region and proximal humerus (locations with the most proliferative growth plates). The diaphysis is involved in 9 %; the epiphysis is implicated only rarely. Tumors involving the jaw, pelvis, and spine tend to occur in older patients. There is occasional involvement of the small bones of the extremities.
Secondary osteosarcomas in Paget’s disease are most common in the pelvis, femur, humerus, skull, sacrum, and spine, with 15–20 % of the cases being multifocal. Their distribution parallels the distribution of the skeletal sites involved.
In secondary postradiation CCOs, the pelvis and the shoulder regions are the most common regions involved.
In secondary CCOs in mature patients, only 39 % of the tumors arise in the long tubular bones, and, in comparison to primary CCO, the axial skeleton is the most common site.
Clinical Symptoms and Signs
In Primary CCO
Pain and swelling are the main symptoms.
Larger tumors may restrict the range of motion and interfere with musculoskeletal functions, and synovial effusion may be present.
Patients with CCO are only rarely asymptomatic. The duration of symptoms varies from a few weeks to several months before diagnosis. Symptoms in excess of a 1-year duration are very rarely reported.
Joint effusion may be present when the tumor extends to the periarticular structures and bone extremities.
In Secondary CCO
A progressive increase in swelling, progressive localized pain (indicating rapid progression of disease), and a palpable mass suggest a malignant evolution in Paget’s disease and in patients with a history of irradiation for benign conditions of the bone.
At best, a latency period of 2 years or longer between radiation treatment and the origin of the osteosarcoma is expected. Rapid progression of the disease is also an ominous sign in patients with a benign bone lesion, such as a cartilaginous tumor, fibrodysplasia, or bone infarct.
Evidence of pathologic fracture through the destructive mass is rare (5–10 % of cases).
Laboratory tests in primary and secondary CCOs show elevated serum alkaline phosphatase in 50 % of the patients (due to osteoblastic activity).
The radiographic appearance of primary CCO varies greatly, depending on the amount of ossification/calcification and the amount of the lytic component.
Tumors may be completely lytic or predominantly sclerotic, but they usually demonstrate a combination of these features.
In purely lytic lesions, there is an elevated probability that histology will show a telangiectatic (hemorrhagic) high-grade osteosarcoma.
The tumor is rarely confined to the epiphysis, and at times at imaging, it can be deceptive due to its completely benign appearance.
Ten percent of the lesions are diaphyseal.
The destructive process may be limited to the medulla, but the cortex is usually involved as well, and it is nearly always perforated by the growing tumor.
As the tumor growth progresses through the cortex into the soft tissue, a prominent mass can be identified which is contiguous to the bone (having a “cloud-like” radiodense appearance).
The proliferated bone produced by the neoplastic cells contains various degrees of density, causing this “cloud-like” appearance with ill-defined margins.
CT and MRI Features
Computed tomography (CT) and magnetic resonance imaging (MRI) are routinely used for preoperative staging studies in patients having osteosarcoma.
When the periosteum is elevated by the perforating tumor, nonneoplastic bone is deposited in parallel layers (onionskin-like) or has a radiating appearance (sunburst), and a Codman triangle is identified, namely, the angle created by the cortex and the elevated periosteum.
Periosteal reaction (reactive woven bone) occurs between the cortex and the periosteum elevated by the tumor.
Hot in primary and metastatic lesions
Secondary CCOs have the same features as those described for primary CCOs, but the affected bone displays the findings characteristic of an underlying disease process.
In Paget’s disease osteosarcoma, bone enlargement and alteration of shape and contour together with obscured corticomedullary demarcation (all of which are characteristic of Paget’s disease) are associated with an extensive osteolytic pattern or, less frequently, mixed and osteoblastic patterns. Computed tomography imaging shows bone destruction and a cortical breakthrough and extension into the soft tissue with cloudy opacity.
In bone infarct, secondary osteosarcoma appears to be irregular areas of destruction within, or sometimes at the edge of the infarct: they are ill-defined irregular, lytic lesions of the metaphysis with focal areas of calcification at the periphery, which corresponds to a bone infarct.
Image Differential Diagnosis
Primary myoepithelial carcinoma in the bone
Chondrosarcoma grade 3
Synovial sarcoma involving the bone
Hypertrophic callus (present in osteogenesis imperfecta or stress fractures)
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A CCO usually presents as a large metaphyseal, intramedullary mass.
The metaphyseal plate is frequently destroyed by the tumor which extends down practically to the articular cartilage.
Rupture of the cortex and a soft tissue mass can also be detected. They form eccentric or circumferential soft tissue components, peripherally displacing the periosteum.
The tumor forms a massive gritty partially hemorrhagic necrotic soft tissue mass.
The cartilaginous component, which is sometimes focally myxoid or mucinous, is underlined by non-mineralized glistening gray areas.
The tumor may focally spread extensively in the marrow cavity, and areas of medullary involvement are rarely detected intracompartmentally. They consist of firm, ovoid, tannish-white nodules both adjacent to and distant from the main mass.
Computed tomography and MRI are very useful in detecting this type of marrow involvement.
Secondary CCOs grossly show the same features as primary osteosarcomas, but the bone concerned occasionally displays findings characteristic of the underlying disease process.
In Paget’s sarcoma, the possibility of identifying the thickened cortex and medulla seen in Paget disease exists.
Radiation osteitis (trabecular coarsening and cortical lysis) is occasionally present (50 % of cases – WHO) in postradiation osteosarcoma.
Osteosarcomas found in other benign conditions do not grossly differ from primary CCOs, but occasionally old bone infarcts, fibrous dysplasia, osteochondroma, or osteopoikilosis may be detected in the host bone harboring the osteosarcoma.
The presence of a purely sarcomatous stroma and the direct formation of tumoral osteoid and bone by the malignant connective tissue cells are the characteristic histological features reported in the literature.
The histologic classification of CCO depends on:
The product of the malignant cells (osteoid, bone) and the dominant histologic differentiation pattern observed: osteoblastic, chondroblastic, and fibroblastic
The cytology of malignant cells (epithelioid, plasmacytoid, fusiform, ovoid, small round, mono- or multinucleated cells, spindle-stellate cells) and both their arrangement and relationship with the matrix (architecture)
The prominent differentiation (osteoblastic, chondroblastic, and fibroblastic of the malignant connective tissues) underscores the wide variation of aspects seen in the histopathology of osteosarcomas.
The amount of osteoid/bone produced by the malignant cells may be minimal or there may be extensive areas.
The associated necrosis and hemorrhage contribute extensively to the variability of the histologic presentation of a CCO.
The tumor growth is permeating, namely, infiltrating between the cancellous bone of the host bony trabeculae and the cortical bone.
This aggressive growing pattern results in the destructive permeation of preexisting trabeculae of the cancellous bone and the cortex and extension into the soft tissues.
Classification according to the abovementioned: The vast majority of CCOs are classified as osteoblastic (56 % at the Mayo Clinic, 76–80 % WHO).
Matrix: Osteoid/bone in a fine lace-like network between the individual tumor cells, with focal or extensive calcification.
Matrix bony trabeculae: Thin and anastomosing or thick and well formed.
When the mature bony trabeculae are very prominent and intermixed with the host bone trabeculae, rendering identification of the tumor cells difficult, the tumor is extremely sclerotic, and it is called a sclerotic osteosarcoma.
When a CCO shows chondroid differentiation together, with osteoid/bone production, in which the malignant cells are in lacunae and form lobules, with the crowded peripheral spindle cells forming hypercellular sheets, the pattern is called a chondroblastic-type CCO. In the Mayo Clinic series, 20 % of CCOs are chondroblastic, and in the WHO series, 10–13 % are chondroblastic.
Occasionally a CCO along with the osteoid/bone extracellular matrix shows prominent spindle- shaped cells in a herringbone arrangement. This pattern is termed fibroblastic osteosarcoma (24 % in the Mayo Clinic series, 10 % in the WHO series).
When a storiform pattern and extensive pleomorphism of the malignant cells are present, this pattern is called osteogenic fibroblastic osteosarcoma, a malignant fibrous histiocytoma-like variant. It is a variety of fibroblastic osteosarcoma having pleomorphic cells in a storiform arrangement.
Histologic variations exist in conventional central osteosarcoma (Table 11.1).
Histologic subtypes (variants) of primary CCO
Osteoblastic (sclerotic type)
Fibroblastic (malignant fibrous histiocytoma-like)
Giant Cell-Rich Osteosarcoma
In some CCOs the multinucleated giant cells are so numerous as to mimic the features of a giant-cell tumor.
Mononuclear cells, in between the giant cells, may show severe anaplasia; however, when the mononuclear cells show only subtle cytologic atypia, the differential diagnosis with a giant-cell tumor can be very difficult, and this morphologic appearance accounts for the histologic variety of CCO called giant cell-rich osteosarcoma.
When such a tumor is present in an unusual location (for a giant-cell tumor,) such as in the metaphysis or diaphysis, serious consideration should be given to calling it an osteosarcoma.
The major problem when the location is good for a giant-cell tumor and the cytologic atypia is not prominent.
Accurate radiographic evaluation, clinical history, and behavior may help in the differential diagnosis.
Some CCOs may produce regular trabeculae of the woven bone littered with osteoblasts, thus simulating the appearance of an osteoblastoma. This histologic configuration was called osteoblastoma-like osteosarcoma.
In this case the radiographic features may be indistinguishable from a typical osteoblastoma, and only the permeative growing pattern and the presence of sheets of monomorphic malignant cells without matrix will help in the differential diagnosis.
In biopsies with small amount of material, the diagnosis is sometimes not possible.
Some CCOs may have irregular bony trabeculae lined with malignant cells with an epithelioid appearance (epithelioid osteosarcoma).
Immunohistochemistry can occasionally confirm the focal epithelial differentiation.
In an adult patient, the epithelioid configuration of the osteoblasts suggests the differential diagnosis with metastatic carcinoma.
Gland-like formation is unusual in CCOs, but it is possible to see cells showing epithelioid cytologic features and clustering of the tumor cells in CCOs.
The epithelioid cells may have a rosette-like configuration with the production of matrix in the center.
It is sometimes possible to see sheets of epithelioid cells with pink cytoplasm, vesicular nuclei, and prominent central nucleoli, with varying amounts of osteoid.
When such a lesion is present in young patients, a CCO should be suspected. In older patients, primary or secondary CCO has to be differentiated from metastatic osteogenic carcinoma or from primary or metastatic myoepithelial carcinoma in the bone.
Some CCOs have tumor cells which simulate a chondroblastoma: chondroblastoma-like osteosarcoma.
Sheets of round-oval cells, without well-defined cellular borders having a syncytial-like arrangement are observed.
In spite of its similarity to chondroblastoma, the extraepiphyseal location is a useful hint in recognizing the osteosarcoma simulating a chondroblastoma.
Unfortunately, in the case of having subtle atypia, it is very difficult or impossible to reach a diagnosis especially if the lesion is in an appropriate location for a chondroblastoma and there is only a small amount of diagnostic tissue.
Occasionally, a CCO is completely lytic, grossly similar to a bag of blood and having histologically large hemorrhagic areas with septa, as in aneurysmal bone cyst.
The cells of the septa are highly malignant and pleomorphic, or there may only be highly malignant pleomorphic cells in a bloody background without any specific pattern.
Generally osteoid matrix is minimal.
These are the histological features indicative of a telangiectatic or hemorrhagic osteosarcoma.
A CCO is rarely characterized by a lace-like osteoid production associated with small cells which resemble lymphoma or Ewing’s sarcoma (1.5 % in WHO series).
The small cells may be round, oval, or spindle-shaped.
A small-cell osteosarcoma having a mineralized osteoid matrix is present when the translocation of an Ewing’s sarcoma is lacking and TdT markers for lymphoblastic B- and T-cell lymphoma and Fli-1 are negative. In addition, a mesenchymal chondrosarcoma may occasionally be suspected in the differential diagnosis with a small-cell osteosarcoma. Molecular biology can help in making the differential diagnosis.
Chondromyxoid Fibroma-Like Osteosarcoma
At times, a chondroblastic-type CCO may have extremely myxoid areas with a hypocellular center and a concentration of tumor cells toward the periphery.
The myxoid lobular appearance simulates chondromyxoid fibroma, and the highly malignant cytology along with osteoid production is indicative of a chondromyxoid fibroma-like osteosarcoma.
Osteosarcoma Mimicking a Plasma Cell Myeloma
Very rarely is it possible to see a high-grade osteosarcoma with unusual histological features mimicking a plasma cell myeloma, presenting with synchronous/metachronous multifocal osseous tumors.
The following immunostains all give negative reactions: CD3, CD20, CD43, CD79a, CD138, epithelial membrane antigen (EMA), lysozyme, myeloperoxidase, vimentin, and, kappa/lambda chains. In situ hybridization is negative for kappa and lambda immunoglobulin (IG) light chains.
Very rarely osteosarcoma may develop in several bones. This variant “CCO multicentric osteosarcoma” may have two distinct presentations: synchronous and metachronous.
Specific histological features have resulted in the need to subclassify CCOs (see Table 11.1). However, no relationship exists:
Between histologic subtypes (varieties), treatment, and prognosis.
These histologic variants of CCO account of no more than 10–15 % of all CCO.
It reproduces the histologic subtypes (variants) of a primary CCO, with osteoblastic (sclerotic) type, fibroblastic (MFH-like), and chondroblastic high-grade varieties.
The most common histologic subtype of Paget’s sarcoma is an osteosarcoma, although fibrosarcoma, chondrosarcoma, and malignant fibrous histiocytoma can also occur. The osteosarcoma may have an osteoblastic, fibroblastic, and/or chondroblastic appearance in decreasing order of frequency. Variants, such as telangiectatic or small-cell osteosarcomas, have been reported.
Osteosarcomas associated with benign lesions, such as osteomyelitis, have rarely been reported, but it is imperative that it be recognized because it is much more malignant than the other malignancies associated with osteomyelitis, such as secondary squamous carcinoma.
Sarcomas in fibrous dysplasia have frequently been associated with radiotherapy, but a small percentage of patients had not undergone this treatment, so the tumors could not be considered postradiation sarcomas. Osteoblastic, fibroblastic, and chondroblastic types of osteosarcoma have been reported to be associated with fibrous dysplasia in patients who have not undergone radiotherapy. All were high-grade highly malignant lesions, with a poor prognosis.
The bone infarct-sarcoma risk is very low and is difficult to assess, as many bone infarcts are asymptomatic. The microscopic features are related to malignant fibrous histiocytoma and rarely to high- and low-grade CCO. Peripheral areas of bone infarct are sometimes identified adjacent to a CCO. Dead bone trabeculae, granulation tissue, and fat necrosis with dystrophic calcifications and with highly malignant cell-producing bone are the feature of these secondary osteosarcomas.
Postradiation-induced sarcomas include osteosarcomas, chondrosarcomas, and malignant fibrous histiocytomas; these sarcomas do not differ from their conventional primary counterparts. They are high-grade sarcomas which are frequently associated histologically with radiation osteitis with the necrotic bone and reparative changes and with elevated cellular proliferation of fibroblastic tissue and reactive new bone. Atypical mesenchymal cells, with pleomorphic and hyperchromatic nuclei, characterize the reparative changes in close proximity with the high-grade induced osteosarcomas.
Sarcomas have been reported to arise at the site of metallic implants; however, this phenomenon is very rare. The most frequent type is high-grade osteosarcoma which does not differ from its conventional primary counterpart.
Pathologic Differential Diagnosis
Fracture callus, hypertrophic callus, stress, and/or insufficiency fracture
Benign parosteal osteocartilaginous proliferations (Nora’s disease)
Aneurysmal bone cyst
Fibrosarcoma (malignant fibrous histiocytoma)
Some rare conditions such as osteogenesis imperfecta or osteopetrosis are predisposing factors for the development of exuberant callus.
The early and later stages of hyperplastic callus may be present as continuity among various microscopic elements, namely, hypercellular areas containing spindle cells with early osteoid formation and an interconnecting network of reactive bone with prominent osteoblastic rimming, juxtaposed hyaline cartilage and trabecular bone.
It usually presents brisk mitotic figures without atypia, but in unusual sclerotic cases, the differential diagnosis with malignancy may be very complicated.
Stress Fracture, Insufficiency Fracture, Avulsion Fracture
An unnoticed stress fracture and/or insufficiency fracture in adulthood, or an avulsion fracture in a young athlete, may pose problems for differential diagnosis between reactive lesion and osteosarcoma.
Florid Reactive Periostitis and Bizarre Parosteal Osteochondromatous Proliferation
Less-frequent surface lesions such as florid reactive periostitis and bizarre parosteal osteochondromatous proliferations (Nora’s disease) may be mistaken for a surface or central osteosarcoma in acral parts or in the long bones.
Nora’s lesion, a cup-shaped cartilaginous exostotic lesion in which disorganized islands of hyaline cartilage blends with the woven bone and basophilic blue bone in a fibrous back ground are helpful features in the diagnosis of this lesion.
On X-ray, the periphery of the lesion is mineralized both grossly and histologically, whereas there is a lack of mineralization at the center (zonation).
On histology the center of the lesion has a fasciitis-like appearance, mitoses rich.
No atypia or necrosis.
The well-organized architecture of myositis ossificans is completely lost in osteosarcomas, and prominent bone production is present in the center of an osteosarcoma.
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