Giant Cell Tumor Of Bone

Not clinically relevant

Conventional giant cell tumor: There is evidence that the neoplastic stromal cells in giant cell tumor are of osteoblastic lineage: when treated with denosumab, a RANK ligand inhibitor, the mutant cells mature and form bone, a process reversed on withdrawal of treatment. In addition, the stromal cells express (pre)osteoblast markers, including alkaline phosphatase, RUNX2, SP7 transcription factor (osterix), and SATB2. Depletion of osteoclast-like cells implies that an osteoclast-like growth factor suppresses stromal cell differentiation and results in proliferation.

At least 95% of giant cell tumors harbor pathogenic H3-3A (H3F3A) gene mutations, approximately 90% of which are H3.3 p.Gly34Trp, with the next most common being p.Gly34Leu; rarer variants (p.Gly34Met, p.Gly34Arg, and p.Gly34Val) have also been reported. Copy-number and rearrangement analysis showed that tumors are diploid overall, with a paucity of structural changes. The mechanism by which the mutant H3.3 drives the neoplasm is not defined.

Malignancy in giant cell tumor: The mechanism by which malignant transformation occurs is unknown. TP53 and HRAS mutations have been identified in malignant giant cell tumor not associated with prior irradiation. Strong expression of p53 has been demonstrated in some (but not all) secondary malignant giant cell tumors.

Conventional giant cell tumor is well defined and often lies eccentrically within the end of a long bone, which is typically asymmetrically expanded. The surrounding cortex is often thinned and in areas may be destroyed completely, but it is generally contained by the periosteum. The subchondral bone plate can be focally eroded, but the tumor seldom penetrates the articular cavity. Viable tumor is characterized by a soft, friable, tan-red and hemorrhagic appearance, but cream-yellow and firm white areas corresponding to xanthomatous change and fibrous tissue are commonly seen. Areas of hemorrhage and blood-filled cystic spaces corresponding to aneurysmal changes may be seen. In contrast to conventional giant cell tumor, the texture of a malignant giant cell tumor is typically firm and fleshy.

Giant cell tumor is a highly cellular lesion typically dominated by large numbers of non-neoplastic osteoclast-like giant cells, between which mononuclear cells are embedded. The giant cells have a variable number of nuclei, some with > 50 per cell. Mononuclear cells in giant cell tumor exhibit a variety of morphological appearances, including round to oval cells in a non-fibrotic background and spindled cells associated with fibrous matrix. The neoplastic cells have an ill-defined cell membrane with pale eosinophilic cytoplasm; their nuclei exhibit an open chromatin pattern and contain one or two small nucleoli. However, it is difficult to distinguish the neoplastic cells from macrophages (CD68-positive cells) without immunolabeling; the former show a variable (occasionally high) mitotic count. The presence of atypical mitotic figures should raise suspicion for malignancy.

The typical features of a giant cell tumor can be obscured by extensive necrosis, recent hemorrhage, hemosiderin deposition, aneurysmal change, collections of foamy macrophages, and reactive/reparative non-mutant fibrous tissue. In addition, areas of stromal overgrowth of the neoplastic mononuclear cells are uncommon. The presence of substantial deposition of bone is not common, although reactive/metaplastic bone formation can occasionally be striking and can be prominent when associated with a fracture. Exceptionally, otherwise typical giant cell tumor contains benign-appearing hyaline cartilaginous nodules, and the differential diagnosis then includes dedifferentiated chondrosarcoma and chondroblastoma.

Small numbers of otherwise typical giant cell tumors may contain scattered mononuclear cells with marked nuclear pleomorphism, enlarged hyperchromatic nuclei, irregular nuclear contours, smudged nuclear chromatin, and nuclear pseudoinclusions. The nature of these cells is uncertain and probably represents degenerative change, because their scattered distribution/pattern is not suggestive of malignancy. Nevertheless, these cases can be challenging to classify, particularly on a biopsy specimen.
The cortical bone surrounding the giant cell tumor is often severely eroded by osteoclasts and is commonly replaced by a reactive eggshell-like rim of new bone at the tumor periphery. In areas, the cortical bone can be completely destroyed but is generally contained by a band of fibrous tissue, which is likely to represent reactive periosteum; it is uncommon to see convincing soft tissue invasion. Focal incipient entrapment of host bone can be seen at the leading edge of the tumor. Vascular invasion may be present, especially after previous curettage.

Giant cell tumor may metastasize to the lung, and in these cases, the histological appearance is similar to that at the primary site. Peripheral reactive bone formation can also be seen in these tumor nodules.
Malignant giant cell tumor: Primary malignancy in a giant cell tumor is uncommon and is typically represented by a nodule of highly pleomorphic, neoplastic mononuclear cells in an otherwise conventional giant cell tumor. Malignant transformation in a giant cell tumor is more common than the primary subtype and occurs after treatment of a conventional giant cell tumor, including with radiotherapy. The conventional giant cell tumor may or may not be detectable in these cases. The ratio of the conventional to malignant components varies considerably. Some use the term “dedifferentiated giant cell tumor” to describe malignant giant cell tumors that exhibit a sharp delineation between the conventional and the malignant components.

Not clinically relevant

Between 15% and 50% of conventional giant cell tumors recur locally after curettage and usually within 2 years. Between 3% and 7% of patients develop metastatic lung disease with histological features of conventional giant cell tumor. Predictors of metastatic disease include local recurrence, but also possibly surgical manipulation. Vascular invasion is commonly seen in cases that metastasize to the lung.
The median interval between metastasis and local recurrence is approximately 2 years. Patients with malignant giant cell tumors typically have a worse prognosis, with reported 5-year survival rates of 50% or less. Factors associated with poor prognosis include high-grade histology, presence of necrosis, and metastasis at diagnosis.

Not clinically relevant

Essential: predominant neoplastic mononuclear cells; numerous osteoclast-like giant cells; presence of atypical mitotic figures may suggest malignancy.

Desirable: features of local aggressiveness; presence of necrosis; evidence of vascular invasion or metastasis.