A 24-Year-Old Woman with Neck Pain

The patient was diagnosed with residual or recurrent stromal tumor cells of a giant cell tumor of bone.

Reference: Zhang Y, Ilaslan H, Krishnaney AA, Bauer TW. Morphological transformation of giant-cell tumor of bone after treatment with denosumab: a case report. JBJS Case Connect. 2016 Sep 14;6(3):e74.

Giant-cell tumor of bone (GCTB) is a benign, locally aggressive lytic neoplasm that accounts for approximately 4% to 5% of all primary bone tumors. Histologically, it is composed of a proliferation of oval, or spindled, mononuclear cells admixed with uniformly distributed osteoclast-type giant cells. It is now thought that the mononuclear cells are neoplastic and clonal, exhibiting specific H3F3A driver mutations. These clonal mononuclear cells may show phenotypic markers of osteoblasts such as RUNX2 (runt-related transcription factor 2) and SATB2 (special AT-rich sequence-binding protein 2) and express RANKL (receptor activator of nuclear factor κ-B ligand), which recruits the osteoclast precursor cells and induces the differentiation of osteoclast-type multinucleated giant cells in GCTB. The abundant osteoclastic giant cells lead to bone reabsorption and allow growth of the tumor. In June 2013, the U.S. Food and Drug Administration (FDA) approved the use of denosumab, a monoclonal antibody antagonist of RANKL, for the management of patients who have unresectable GCTB or those in whom resection would likely result in severe morbidity. By binding to RANKL, denosumab prevents the RANK-RANKL interaction and thus the formation of osteoclastic giant cells in the region of the tumor. A spectrum of histological changes after denosumab treatment has been described recently, with the main features including a reduction or depletion of osteoclastic giant cells and an increase in woven-bone formation.

This case confirms the findings of previous studies that denosumab treatment can induce radiographic and histological changes in GCTB. As described in those reports, the resection specimen was notable for the absence of osteoclastic giant cells but a marked increase in bone formation in the mononuclear component of the tumor that progressed. A spectrum of histological changes has been described after treatment with denosumab. Several reports have described a storiform growth pattern of spindled cells with a morphological appearance similar to that of benign fibrous histiocytoma. Others have suggested an aggressive appearance of osteoid similar to the morphology of an osteosarcoma. Wojcik et al. recently suggested that the histological appearance may relate to the length of denosumab treatment, with early lesions showing a cellular spindled stroma and with lesions excised later showing more prominent bone formation reminiscent of fibrous dysplasia or low-grade central osteosarcoma. In the case of this patient, the multinuclear osteoclastic giant cells were depleted and replaced by newly formed woven bone, deposited in interconnected strands with prominent osteoblastic rimming and intervening loose fibrovascular stroma, features similar to those of an osteoblastoma. Areas of spindled stromal cells resembling a benign fibro-osseous lesion were simultaneously present.

While denosumab has proven to be effective for reducing the number of osteoclastic giant cells by interfering with osteoclastic differentiation, it does not necessarily eliminate neoplastic stromal cells. For example, Girolami et al. demonstrated the same H3F3A-mutated mononuclear cell populations both before and after treatment of a GCTB with denosumab. Previous in vitro experiments also showed that stromal cells continued to proliferate once the tumor was no longer exposed to denosumab. It has been suggested that these neoplastic stromal cells are osteoblast-lineage cells, which express osteoblast and preosteoblast markers, a concept supported by the increased osteoid matrix and woven-bone formation noted in this patient. However, it is unclear whether denosumab induces a partial maturation of neoplastic stromal cells toward osteoblastic maturation, leading to osteoid matrix deposition and woven-bone formation, as suggested by Girolami et al., or whether the increased bone formation reflects a shift in the balance away from resorption and toward bone formation by depleting the osteoclastic giant cells in the GCTB. It is difficult to make strong treatment recommendations on the basis of a case report, but this case, as well as a growing understanding of the mechanism of action of denosumab, suggest that this treatment may be effective for reducing the osteoclastic giant cells and limiting tumor size but should not necessarily be expected to result in necrosis of the entire GCTB. Continued proliferation of the neoplastic component of the GCTB may continue, so close follow-up of patients who have been managed with denosumab seems appropriate. Pathologists, radiologists, and surgeons need to be aware of this post-treatment effect to avoid misdiagnosis of recurrent GCTB as an osteoblastoma or other fibro-osseous lesion. In addition, it appears that treatment with denosumab alone may only partially address the therapeutic need of the patient.

Reference: Zhang Y, Ilaslan H, Krishnaney AA, Bauer TW. Morphological transformation of giant-cell tumor of bone after treatment with denosumab: a case report. JBJS Case Connect. 2016 Sep 14;6(3):e74.