Modern Interpretation of Giant Cell Tumor of Bone: Predominantly Osteoclastogenic Stromal Tumor (original) (raw)
Related papers
Expression of Osteoclast Differentiation Signals by Stromal Elements of Giant Cell Tumors
Journal of Bone and Mineral Research, 2000
The mechanisms by which primary tumors of the bone cause bone destruction have not been elucidated. Unlike most other lytic bone tumors, osteoclastomas, otherwise known as giant cell tumors (GCT), contain osteoclast-like cells within the tumor stroma. A new member of the TNF-ligand superfamily member, osteoclast differentiation factor (ODF/OPGL/RANKL/TRANCE), was recently identified. ODF was shown to directly stimulate osteoclastogenesis, in the presence of M-CSF. In this study, the expression of ODF was examined in a number of tumor samples associated with bone lysis in vivo. In addition, we investigated expression of the ODF receptor on osteoclast precursors, RANK, as well as the ODF inhibitor osteoprotegerin (OPG), and another TNF-ligand superfamily member, TRAIL, previously shown to abrogate the inhibitory effects of OPG. We report here the novel finding that GCT stromal cells contain abundant ODF mRNA, whereas the giant cell population exclusively expresses RANK mRNA. These results are consistent with the osteoclast-mediated bone destruction by these tumors. We also report the expression of OPG and TRAIL mRNA in GCT samples. A comparison with other lytic and nonlytic tumors of bone showed that GCT express more ODF and TRAIL mRNA relative to OPG mRNA. In addition, GCT were found to express a number of cytokines previously reported to play central roles in osteoclastogenesis, namely, IL-1, −6, −11, −17, as well as TNF-α. Importantly, GCT were also found to express high levels of M-CSF mRNA, a cytokine shown to be an essential cofactor of ODF, and a survival factor for mature and developing osteoclasts. Furthermore, expression of these molecules by stromal cells isolated from GCT continued in vitro. Thus GCT constitutively express all of the signals that are currently understood to be necessary for the differentiation of osteoclasts from precursor cells.
Giant cell tumor of bone: A unique paradigm of stromal-hematopoietic cellular interactions
Journal of Cellular Biochemistry, 1994
Giant cell tumor of bone is a progressive, potentially malignant process which destroys skeletal tissue by virtue of its osteoclast complement. As a biological entity it provides a unique natural model of bone resorption by osteoclasts whose recruitment and development is controlled by a neoplastic population of fibroblast-like cells. Understanding of the etiopathogenesis of this tumor could provide new insights into the mechanisms underlying osteoblast-osteoclast interactions in normal and diseased bone. Recent studies have shown that the stromal cell component in giant cell tumors is the only proliferating subpopulation of cells, and the giant cells themselves are nonproliferative and reactive. These stromal cells express several genes associated with the osteoblastic phenotype, synthesize, to a limited degree, certain matrix proteins associated with bone, and express several factors which are presumably involved in the recruitment of osteoclasts. In culture, giant cell tumor-associated stromal cells promote the fusion of monocytes and the proliferation of osteoblasts either by the secretion of factors or cell-cell contact. Hence, giant cell tumor of bone is a self-contained biosystem in which cells of both the stromal and hematopoietic lineages interact in a fashion similar to that observed in normal skeletal remodeling. The neoplastic nature of the stromal component, however, drives the hematopoietic precursors to undergo fusion, produces aggressive bone resorption, and results in extensive skeletal destruction. Examination of the various components of this system could lead to new directions for investigations aimed at a better understanding of osteoblast-osteoclast interactions. 0 I 994 Wiley-Liss, Inc.
Phenotypic and molecular studies of giant-cell tumors of bone and soft tissue
Human pathology, 2005
Giant-cell tumor of bone (GCTB) and giant-cell tumor of soft tissue (GCTST) are tumors that contain a prominent osteoclastlike giant-cell component. The precise relationship between these morphologically similar tumors is unclear, and the cellular mechanism whereby giant cells accumulate within these and other locally aggressive tumors is uncertain. In this study, we have examined the cytochemical, functional, and molecular phenotype of the mononuclear and multinucleated components of GCTB and GCTST. Giant cells in GCTB and GCTST exhibited an osteoclast phenotype expressing tartrate-resistant acid phosphatase and vitronectin receptor and being capable of lacunar resorption. The mononuclear stromal cells derived from GCTB and GCTST exhibited an osteoblast phenotype, expressing alkaline phosphatase, and the receptor activator for nuclear factor jB ligand (RANKL), a factor that is essential for osteoclast formation. These cells also expressed osteoprotegerin (OPG), an inhibitor of osteoclastogenesis, and TRAIL, a receptor that binds OPG. Lacunar resorption by giant cells isolated from GCTB and GCTST was inhibited by OPG, zoledronate, and calcitonin. These findings indicate that the mononuclear and giant-cell components of GCTB and GCTST have similar phenotypic features and that the accumulation of osteoclasts in these giant-cell-rich tumors occurs by a RANKLdependent process. RANKL expression by osteoblastlike mononuclear stromal cells in these tumors stimulates osteoclast formation and resorption; this would account for the osteolysis associated with these giant-cell-rich tumors. Inhibitors of osteoclast formation and activity are likely to be effective in controlling the osteolysis associated with GCTB and possibly other giant-cell-rich lesions. D Human Pathology (2005) 36, 945 -954 www.elsevier.com/locate/humpath
Giant cell tumor of bone: a neoplasm or a reactive condition?
International journal of clinical and experimental pathology, 2008
Giant cell tumor of bone (GCTB) is a benign but locally aggressive bone tumor of young adults. It typically presents as a large lytic mass at the end of the epiphysis of long bones. Grossly it is comprised of cystic and hemorrhagic areas with little or no periosteal reaction. Microscopically areas of frank hemorrhage, numerous multinucleated giant cells and spindly stromal cells are present. Telomeric fusions, increased telomerase activity and karyotypic aberrations have been advanced as a proof of its neoplastic nature. However such findings are not universal and can be seen in rapidly proliferating normal cells as well as in several osseous lesions of developmental and/or reactive nature, and the true neoplastic nature of GCTB remains controversial. The ancillary studies have generally not reached to the point where these alone can be taken as sole diagnostic and discriminatory criteria. While giant cells and stromal cells have been extensively studied, little attention has been p...
American Journal of Pathology, 2005
cause bony destruction, are thought to be recruited from normal monocytic pre-osteoclasts by stromal cell expression of the ligand for receptor activator of nuclear factor B (RANKL). This model forms the foundation for clinical trials in GCTs of novel cancer therapeutics targeting RANKL. Using expression profiling, we identified both osteoblast and osteoclast signatures within GCTs, including key regulators of osteoclast differentiation and function such as RANKL, a C-type lectin, osteoprotegerin, and the wnt inhibitor SFRP4. After ex vivo generation of stromaland osteoclast-enriched cultures, we unexpectedly found that RANKL mRNA and protein were more highly expressed in osteoclasts than in stromal cells, as determined by expression profiling, flow cytometry, immunohistochemistry, and reverse transcriptase-polymerase chain reaction. The expression patterns of molecules implicated in signaling between stromal cells and monocytic osteoclast precursors were analyzed in both primary and fractionated GCTs. Finally, using array-based comparative genomic hybridization, neither GCTs nor the derived stromal cells demonstrated significant genomic gains or losses. These data raise questions regarding the role of RANKL in GCTs that may be relevant to the development of molecularly targeted therapeutics for this disease.
The Clinical Approach Toward Giant Cell Tumor of Bone
The Oncologist
Here we provide an overview of imaging, histopathology, genetics and multidisciplinary treatment of giant cell tumor of bone (GCTB), an intermediate, locally aggressive but rarely metastasizing tumor. Overexpression of receptor activator of nuclear factor kappa-B ligand (RANKL) by mononuclear neoplastic stromal cells promotes recruitment of numerous reactive multinucleated giant cells. Conventional radiographs show a typical eccentric lytic lesion, mostly located in meta-epiphyseal area of long bones. GCTB may also arise in axial skeleton and very occasionally in small bones of hands and feet. Magnetic resonance imaging is necessary to evaluate the extent of GCTB within bone and surrounding soft tissues in order to plan a surgical approach. Curettage with local adjuvants is the preferred treatment. Recurrence rates after curettage with phenol and polymethylmethacrylate (PMMA; 8-27%) or cryosurgery and PMMA (0-20%) are comparable. Resection is indicated when joint salvage is not feas...
Journal of Bone and Mineral Research, 2009
Giant cell tumor of bone (GCTB) is a benign bone tumor with a shown clinical behavior of local recurrences and rare distant metastases. GCTB is composed of uniformly distributed osteoclastic giant cells, thought to originate from the fusion of monocyte-macrophage lineage cells, in a background consisting of mononuclear rounded cells and spindle-shaped cells. Several reports showed the specific expression of markers, such as CD14 on the mononuclear rounded cell population, however, lacking osteoclastic giant cells. Blood monocytes that were CD14+, CD33+, or CD14+/CD33+ have also been shown to be programmed as pre-osteoclasts. The macrophage marker CD33 is expressed earlier than CD14 in macrophage maturation, whereas CD14 is expressed longer than CD33. The aim of this study was to investigate CD14/CD33 expression profiles in GCTB. Nineteen GCTB tumor samples of 19 patients were studied. Immunofluorescent analyses were performed with monoclonal antibodies against CD14, CD33, RANK, and CD51. To unambiguously further prove the expression of these molecules, quantitative RT-PCR was used with subsequent sequencing of its products. All samples showed similar immunoreactivity profiles. The mononuclear rounded cell population was positive for RANK, CD51, CD14, and CD33. The osteoclastic giant cell population expressed RANK and CD51, as well as CD33, but was consistently negative for CD14 expression. The CD14 and CD33 profiles were confirmed by quantitative RT-PCR. These RT-PCR products were sequence verified. Osteoclasts in GCTB are the result of fusion of CD33-expressing pre-osteoclasts that further fuse with CD14+ mononuclear cells. Although these results reflect a static rather than a dynamic spectrum, we strongly believe that osteoclastogenesis seems not to be the exclusive result of fusion of intratumoral CD14+ mononuclear cells. Moreover, CD33-modulated osteoclastogenesis opens up the possibility for novel therapeutic directions.
Giant cell tumor of bone is an osseous neoplasm that is histologically benign but clinically shows local aggression and high rate of recurrence. The histogenesis of this lesion remains unclear. The histological appearance does not predict the clinical outcome and there are still many unanswered questions with regard to both its treatment and prognosis. In order to further clarify this lesion, we examined ultrastructurally and immunohistochemically the tumor mononuclear cells in ten patients operated on in our hospital for matrix metalloproteinase-9. Positive reaction was detected in the spindle-like stromal cells of giant cell tumor of bone and these cells had the ultrastructural characteristics of fibroblastic cells. The other mononuclear cells did not express matrix metalloproteinase-9 and showed ultrastuctural characteristics of macrophage-like cells. The positive reaction for matrix metalloproteinase-9 in all patients clearly shows that this protease may play a key role in the pathophysiology of giant cell tumor of bone. Key words: giant cell tumor of bone, ultrastructural study, matrix metalloproteinase-9
2018
Introduction: Osteoclastic bone resorption and osteolysis with tendency for local recurrence and pulmonary metastases are a common complication of stage III Campanacci giant cell tumour of the bone (GCTB). Studies have shown RANKL highly stimulates osteoclastogenesis through nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1), which regulates a number of osteoclast-specific genes. Osteoclastogenesis is retarded in NFATc1 suppression and knock-out embryonic stem cells in vitro. To our knowledge, the regulation of NFATc1 in osteoclastic resorption in GCTB has not been studied in stage III GCTB. It is important to fully understand the osteoclast-associated GCTB pathogenesis to identify a new therapeutic approach by targeting NFATc1 in GCTB treatment. We analyzed NFATc1 expression immuno-histochemistry of 31 consecutive cases of stage III giant cell tumour of the bone to determine the clinico-pathological correlation. Methodology: This observational cross-...