Sites of Involvement
It has a major preference for the epiphysis of the long bones, about half of the cases occurring about the knee: distal femur, proximal tibia, and proximal fibula.
After the knee, the distal radius and upper humerus are frequent locations.
It also occurs in apophyses like the greater trochanter of the femur.
In the rare occasions where GCT is seen in a skeleton with open physis, it is seen in the metaphysis or the shaft of the bone.
About 15 % of the cases affect flat bones, pelvis, sacrum, vertebrae, etc.
It is exceptional in the scapula, ribs, skull, and mandibula.
Hands and feet are also rare locations.
Exceptionally, GCT is seen in multiple sites, and, in this instance, it may be difficult to distinguish multicentricity from metastatization.
Clinical Symptoms and Signs
Local pain and the presence of a tender mass is the usual presentation.
Limitation of movements of the adjacent joint is seen in large tumors.
Pathological fracture occurs in an average of 5 % of the cases at presentation.
More than in any other tumor, the joint analyses of clinical data, especially patient’s age, imaging, and pathologic findings are extremely important to achieve a correct diagnosis.
Conventional radiograph typically shows an epiphyseal, eccentric, lytic lesion with no peripheral sclerosis, extending to the subchondral bone, in a patient with closed physes.
Trabeculation is sometimes seen, and it seems to be related to less aggressive lesions.
The margins of the lesions may or may not be well defined.
GCT can present signs of aggressiveness, like a broad transition zone, cortical thinning, cortical destruction, and soft tissue mass.
Pathological fracture in load-bearing bones is commonly associated with telescoping of the bone fragments.
Non-load-bearing bones, like the radius and humerus, usually host larger tumors.
CT complements the study with important details, such as better defining the limits of the lesion, eventual mineralization, characteristic eccentric position, limits with the articular cartilage, and absence of peripheral sclerosis. Pseudotrabeculation, represented by osseous ridges, is emphasized by this image method.
MRI shows, in T1-weighted images, an intermediary or attenuated signal intensity; in sequences for fluid there is an intense signal and heterogeneous enhancement with contrast media.
Fluid-fluid levels, either on CT or MRI, suggest the formation of secondary aneurysmal bone cyst, reported in 14 % of cases.
Image Differential Diagnosis
Aneurysmal Bone Cyst
When located in an epiphysis, this is the more common image differential diagnosis to consider; except for the usual metaphyseal location, it may be impossible to differentiate ABC from a GCT with predominant secondary ABC-like changes; imaging is fundamental to spot non-cystic areas to orient biopsy.
It has a similar preference for epiphyseal localization, but the presence of calcifications, peripheral sclerosis, and younger age can suggest the diagnosis before the biopsy.
Clear Cell Chondrosarcoma
Also for its epiphyseal localization, CCCS can be considered in the differential diagnosis; more frequent mineral deposits and the identification of some chondroid matrix by MRI, present in a third of the cases, may help in the diagnosis.
Giant Cell-Rich Osteosarcoma and Telangiectatic Osteosarcoma
Like GCT with secondary ABC-like changes, both these OS variants can present fluid-fluid levels and are the most important confusions to avoid. Close attention to clinical data, as age and site, is essential in getting important clues to consider before the biopsy.
It may be difficult to differentiate from a GCT of the sacrum, but chordoma is more frequently located in the midline than GCT.
The cut surface of a whole specimen will show an epiphyseal eccentrical lesion, with somewhat circumscribed but ill-defined limits.
The tumor may press the articular cartilage, rarely trespassing it; invasion of the adjacent joint, when it occurs, is preferentially by way of destruction of the lateral bone cortex and through the synovial capsule.
Larger tumors are seen to extend and involve the metaphysis.
The tumor tissue itself has a heterogeneous appearance, is fleshy or friable, and has dark brown with yellowish areas of degeneration or necrosis and hemorrhagic areas.
Extensive, solid, whitish-pink, fleshy areas in a large tumor may suggest aggressiveness or malignization.
The bone cortex may be destroyed by the tumor, which may expand to the adjacent soft parts and produce a thin periosteal reactive bony shell.
Fragments obtained by curettage are irregular, reddish-brown membranous, or friable.
Efforts have to be made to select those areas unaffected by secondary changes for examination.
At the microscopic level, the classical picture includes the presence of a great number of multinucleated giant cells more or less uniformly distributed among a variable number of plump, round or spindle, mononucleated stromal cells.
Giant cells can be very large, sometimes with more than 100 nuclei.
The mononuclear cells of the stroma have abundant eosinophilic cytoplasm, and nuclei are traditionally compared to those of the giant cells, which are large with little chromatin and one or two inconspicuous nucleoli.
Stromal cells may predominate in some areas.
A variable number of typical mitotic pictures can be seen.
Atypical mitoses suggest malignancy.
Fibrous tissue and collections of foamy macrophages may be present as well as areas of hemorrhage and hemosiderin deposits due to a rich vascular network.
Reactive-like immature bone can be seen focally and may be due to the possible preosteoblastic phenotype of the stromal cells. It can be more frequent in cases of pathological fracture.
The margins of the tumor can show permeation, including occasional vascular permeation, but the cells will preserve their benign, typical appearance.
The same can be said of the histology of the metastatic nodules.
These two last findings, by themselves, have no prognostic value.
The lesion sometimes penetrates into the marrow spaces between trabeculae, where there is no reactive bone formation or fibrous membrane. This feature explains the frequency of recurrences after curettage made without chemical cauterization.
Pathology Differential Diagnosis
Aneurysmal Bone Cyst
GCT frequently presents small ABC-like areas that, when abundant, prompt this differential diagnosis. GCT, however, contains at least some solid component representing the neoplasia which must be located to target a biopsy. In ABC eventual solid areas are histologically constituted by secondary changes.
Giant Cell-Rich Osteosarcoma and Telangiectatic Osteosarcoma
Attention to clinical data, as age and site, is paramount.
These osteosarcoma variants have very atypical cells as well as atypical mitoses. Adequate sampling has to be made in order to find bone production by the neoplastic cells, which define the diagnosis.
Giant Cell Reparative Granuloma
This is a lesion more frequently affecting the long bones of hands and feet, where GCT is rare, and presents a reactive tissue aspect, where osteoid production can be seen, and frequent foci of hemorrhage, where the giant cells tend to concentrate.
“Brown Tumor” of Hyperparathyroidism
Multinucleated giant cells, usually smaller than in GCT, can be very frequent in a “brown tumor,” and its stroma is more fibrogenic, with a greater tendency to spindling of the mononuclear cells; hemosiderin deposits are abundant; tunneling bone resorption or “cutting cones” of cortex or bone trabeculae are suggestive of this lesion. Clinical and laboratory data confirm the diagnosis.
Benign Fibrous Histiocytoma
Clusters of giant cells, usually smaller than in GCT, are seen in this lesion among a spindle cell stroma with a storiform arrangement; lipid and hemosiderin-laden histiocytes are usually present.
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Giant cells are positive for CD68, CD45, and CD33.
Telomeric association is found in stromal cells in 50–70 % of the cases and can be of help in a differential diagnosis. This is not yet known to be related to prognosis.
Histone H3.3 alterations, specifically in H3F3A, leading to p.Gly34Trp changes were found, were restricted to the stroma cell population of GCT, and were not detected in osteoclasts or their precursors.
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