Giant cell tumor in a case of Paget's disease of bone: an aggressive benign tumor exhibiting a quick response to an innovative therapeutic agent.
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ABSTRACT:
SUBMITTER: Cosso R
PROVIDER: S-EPMC3004463 | biostudies-literature | 2010 May
REPOSITORIES: biostudies-literature
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Giant cell tumor in a case of Paget's disease of bone: an aggressive benign tumor exhibiting a quick response to an innovative therapeutic agent.
Cosso Roberta R Nuzzo Vincenzo V Zuccoli Alfonso A Brandi Maria Luisa ML Falchetti Alberto A
Clinical cases in mineral and bone metabolism : the official journal of the Italian Society of Osteoporosis, Mineral Metabolism, and Skeletal Diseases 20100501 2
Giant cell tumor of bone, also called osteoclastoma, is a rare skeletal complication of Paget's disease of bone. We here report a patient from Southern Italy who developed a GCT infiltrating the neighboring tissues. We will focus on either a review on this rare bone tumor, including some genetic aspects, or the current established therapies. Since this case has been published in International literature, here we report the updated clinical findings on it. Finally, we will describe the therapeuti ...[more]
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Project description:BackgroundQuantifying the incidence of giant cell tumor (GCT) of bone is challenging because it is a rare, histologically benign bone tumor for which population-level statistics are unavailable in most countries. We estimated the 2017 incidence of GCT in China using a direct (registry-based) approach with available population-based data.Materials and methodsThe most recent age- and sex-specific incidence rates of GCT recorded in the Bone Tumor Registry in Japan (2015) were applied to 2017 age- and sex-matched populations projected by the United Nations for China in order to estimate 2017 incidence. An adjustment factor calculated using registry data suggesting that GCT may represent a greater proportion of bone tumors in China than in Japan (Guo, 1999) was applied to provide secondary estimates.ResultsAnnual GCT incidence was estimated to be 1.49 per million population or 2094 new cases in China for 2017. A comparison of this estimated incidence with Japan (1.25 per million) and the United States (1.38 per million) indicates that the incidence is somewhat higher in China using identical methods. Secondary estimates suggest that GCT incidence in China may be as high as 2.57 per million or 3625 new cases in 2017. The corresponding 3-year limited-duration prevalence of GCT in China using a registry-based approach and general age-specific mortality is 6276 (secondary estimate: 10,876).ConclusionsLeveraging unique population-based registry data, we estimated that GCT is a rare disease in the Chinese population with an incidence ranging between 1.49 and 2.57 cases per million persons per year. Possible differences in diagnostic classification of GCT, urban-rural demographics, and the younger demographic distribution of the Chinese population may underlie observations that GCT, a condition that primarily affects young individuals (20-40 years of age), accounts for a higher proportion of skeletal tumors in China than in other regions.
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Project description:Paget's disease of bone (PDB) is a common metabolic bone disease characterised by focal areas of increased bone turnover, which primarily affects people over the age of 55 years. Genetic factors have a fundamental role in the pathogenesis of PDB and are probably the main predisposing factor for the disease. The genetic contribution to PDB susceptibility ranges from rare pathogenic mutations in the single gene SQSTM1 to more common, small effect variants in at least seven genetic loci that predispose to the disease. These loci have additive effects on disease susceptibility and interact with SQSTM1 mutations to affect disease severity, making them a potentially useful tool in predicting disease risk and complication and in managing treatments. Many of these loci harbour genes that have important function in osteoclast differentiation such as CSF1, DCSTAMP and TNFRSF11A. Other susceptibility loci have highlighted new molecular pathways that have not been previously implicated in regulation of bone metabolism such as OPTN, which was recently found to negatively regulate osteoclast differentiation. PDB-susceptibility variants exert their effect either by affecting the protein coding sequence such as variants found in SQSTM1 and RIN3 or by influencing gene expression such as those found in OPTN and DCSTAMP. Epidemiological studies indicate that environmental triggers also have a key role in PDB and interact with genetic factors to influence manifestation and severity of the disease; however, further studies are needed to identify these triggers.
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Project description:The unpredictable behavior of giant cell tumor (GCT) parallels its controversial histogenesis. Multinucleated giant cells, stromal cells, and CD68(+) monocytes/macrophages are the three elements that interact in GCT. We compared the ability of stromal cells and normal mesenchymal stromal cells to differentiate into osteoblasts. Stromal cells and mesenchymal cells had similar proliferation rates and lifespans. Although stromal cells expressed early osteogenic markers, they were unable to differentiate into osteoblasts but they did express intracellular adhesion molecule-1, a marker of bone-lining cells. They were unable to form clones in a semisolid medium and unable to promote osteoclast differentiation, although they exerted a strong chemotactic effect on osteoclast precursors. Stromal cells may be either immature proliferating osteogenic elements or specialized osteoblast-like cells that fail to show neoplastic features but can induce the differentiation of osteoclast precursors. They might be secondarily induced to proliferate by a paracrine effect induced by monocyte-macrophages and/or giant cells. The increased number of giant cells in GCT may be secondary to an autocrine circuit mediated by the receptor activator of nuclear factor kB.
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Project description:Genetic studies including chromosome analysis, telomere reduction and telomere activity, DNA microsatellites and loss of heterozygosity (LOH) studies have been performed on giant cell tumor (GCT) of bone however whether this primary skeletal neoplasm represents a monoclonal or polyclonal proliferation is unknown. Utilizing a new assay to study the polymorphic human androgen receptor locus (HUMARA), the ratio of maternal inactive X-chromosome to the paternal inactive X (Lyon hypothesis) is determined via a methylation--specific polymerase chain reaction (PCR) technique to detect X-chromosome polymorphisms. Characterization of the genetic tumorigenesis of this unpredictable neoplasm may lend insight into its biological behavior and offer improvements in therapeutic intervention, as new information emerges regarding osteoclastic bone resorption. Seventeen female patients with giant cell tumor of bone had their DNA harvested and their X-chromosome inactivation pattern and polymorphisms determined and compared to control. A polyclonal proliferation pattern was identified in all informative samples studied.
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Project description:Purpose of reviewGiant cell tumor of bone (GCTB) is an uncommon benign primary bone tumor, consisting of receptor activator of nuclear factor kappa-B (RANK) expressing reactive osteoclast-like giant cells and neoplastic spindle-shaped cells. Denosumab was approved by FDA in 2013 and by EMA in 2014 to treat adults and skeletally mature adolescents with unresectable GCTB or when resection is likely to result in severe morbidity. However, there is much discussion regarding the optimal applied treatment strategy.Recent findingsNeoadjuvant treatment of GCTB with denosumab can effectively downstage tumors to facilitate less morbid surgery or completely avoid the need for resection, but there is concern about local recurrence postsurgery. Definitive treatment of unresectable GTCB improves symptoms and halts tumor progression. The optimal treatment duration is unclear and long-term treatment is associated with adverse events like osteonecrosis of the jaw (ONJ) and atypical femoral fractures. Denosumab maintenance dose interval is currently being investigated.SummaryFor the related but heterogenous group of giant cell rich tumors of bone, like aneurysmal bone cysts (ABC) and central giant cell granuloma (CGCG), denosumab is a new treatment modality under investigation. Given the effectiveness in GCTB, this could be a promising treatment option for selected patients with advanced disease.
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