Comments on the pathogenesis and medical treatment of central giant cell granulomas

Abstract

To the Editor:—The potential to medically control central giant cell granulomas (CGCGs) of the jaws, as presented in the recent article by Pogrel (J Oral Maxillofac Surg 61:649–653, 2003)1Pogrel M.A. Calcitonin therapy for central giant cell granuloma.J Oral Maxillofac Surg. 2003; 61: 649Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar with the corresponding Discussion by Kaban and Dodson (J Oral Maxillofac Surg 61:653–654, 2003), is an innovative and promising approach to the treatment of problematic tumors. We would like to expand the discussion on the pathogenesis and treatment of these lesions and include the relevant information in the literature on the tumor counterparts found in long bones and small bones of the hands and feet. Comparison of the literature on CGCG of the jaws2O’Malley M. Pogrel M.A. Stewart J.C.B. et al.Central giant cell granulomas of the jaws Phenotype and proliferation markers.J Oral Pathol Med. 1997; 26: 159Crossref PubMed Scopus (78) Google Scholar, 3Liu B. Yu S.F. Li T.J. Multinucleated giant cells in various forms of giant cell containing lesions of the jaws express features of osteoclasts.J Oral Pathol Med. 2003; 32: 367Crossref PubMed Scopus (142) Google Scholar with giant cell tumor of long bones (GCT),4Joyner C.J. Quinn J.M. Triffitt J.T. et al.Phenotypic characterization of mononuclear and multinucleated cells of giant cell tumor of bone.Bone Miner. 1992; 16: 37Abstract Full Text PDF PubMed Scopus (63) Google Scholar, 5Miyamoto N. Higuchi Y. Tajima M. et al.Spindle-shaped cells derived from giant-cell tumor of bone support differentiation of blood monocytes to osteoclast-like cells.J Orthop Res. 2000; 18: 647Crossref PubMed Scopus (41) Google Scholar, 6Robinson D. Einhorn T.A. Giant cell tumor of bone A unique paradigm of stromal-hematopoietic cellular interactions.J Cell Biochem. 1994; 55: 300Crossref PubMed Scopus (36) Google Scholar, 7Zheng M.H. Robbins P. Xu J. et al.The histogenesis of giant cell tumor of bone A model of interaction between neoplastic cells and osteoclasts.Histol Histopathol. 2001; 16: 297PubMed Google Scholar and giant cell reparative granuloma of small bones (GCRG)8Itonaga I. Schulze E. Burge P.D. et al.Phenotypic characterization of mononuclear and multinucleated cells of giant cell reparative granuloma of small bones.J Pathol. 2002; 198: 30Crossref PubMed Scopus (17) Google Scholar indicates that these lesions are histologically and pathogenetically similar. All are composed of large numbers of monocyte-derived multinucleated giant cell osteoclasts in a mononuclear stroma of spindle mesenchymal cells (fibroblast-related) and round monocyte-macrophages. While the giant cell is the most prominent feature of these lesions, it is the mononuclear spindle cell, that is the proliferating cell (in cell cycle). It is believed that this spindle cell recruits monocytes and induces them to differentiate into osteoclastic giant cells through release of cytokines. While the histopathogenesis of CGCG, GCT, and GCRG appears to be nearly identical, the biologic behavior of CGCG of the jaws is more closely aligned with CGRC of small bones than with the more aggressive GCT of long bone. The reason for this difference is unknown. Although red cell extravasation can be extensive in some CGCGs, these tumors are not fundamentally vascular tumors; that is, the proliferating cells are not endothelial cells. Only a small percentage of cells in these lesions are endothelial cells, and these are found lining supporting tumor capillaries.2O’Malley M. Pogrel M.A. Stewart J.C.B. et al.Central giant cell granulomas of the jaws Phenotype and proliferation markers.J Oral Pathol Med. 1997; 26: 159Crossref PubMed Scopus (78) Google Scholar Explanation for red cell extravasation is likely related to vascular permeability associated with cytokine release by the mononuclear spindle cells. Interestingly, some GCTs of long bone may exhibit hypervascularity, a feature attributed to the expression of vascular endothelial growth factor (VEGF).9Zheng M.H. Xu J. Robbins P. et al.Gene expression of vascular endothelial growth factor in giant cell tumors of bone.Hum Pathol. 2000; 31: 804Abstract Full Text PDF PubMed Scopus (42) Google Scholar In GCTs, VEGF expression is believed to be related not only to neoangiogenesis, but also to osteoclastogenesis. VEGF has not been assessed in CGCGs. The cause of CGCGs continues to be a mystery. These lesions do not fit neatly into our concept of either reactive or neoplastic disease, and as a group exhibit features of both. Perhaps there is a reactive form and a neoplastic form and we do not yet have the skills to separate them. Alternatively, one could speculate that the subset of tumors that behave as neoplasms develop from a reactive (reparative) lesion through an epigenetic event occurring in spindle mesenchymal cells of bone resulting in escape from cell cycle controls and in expression of proteins capable of monocyte recruitment and differentiation into osteoclasts (Fig 1). Molecular studies should provide significant information about the basic defect that initiates these lesions. Understanding the molecular mechanisms of CGCGs is important for the development of therapeutic compounds that can target key tumor proteins. Theoretically, gaining control over the proliferation of mononuclear spindle cells that appear to be driving this tumor, would provide the greatest therapeutic benefit. A potential target for the control of the proliferating spindle cells might be MDM2 protein/gene, which may be overexpressed in GCTs10Evdokiou A. Atkins G.J. Bouralexis S. et al.Expression of alternatively-spliced MDM2 transcripts in giant cell tumors of bone.Int J Oncol. 2001; 19: 625PubMed Google Scholar and CGCGs.11de Souza P.E. Paim J.F. Carvalhais J.N. et al.Immunohistochemical expression of p53, MDM2, Ki-67, and PCNA in central giant cell granuloma and giant cell tumor.J Oral Pathol Med. 1999; 28: 54Crossref PubMed Scopus (44) Google Scholar To date, this protein, which promotes proliferation through p53 binding, is the only cell cycle-associated protein determined to be overexpressed. The p53 gene does not appear to be mutated in these lesions. Realistically, control of tumor growth is more likely to be related to inhibition of osteoclastogenesis, because more is known about this process. Also, agents that have the potential to block the action of osteoclasts are currently available. One of these agents, calcitonin, has a rational basis for CGCG medical therapy. Osteoclasts express calcitonin receptors and can be inhibited by calcitonin.12Kudo O. Sabokbar A. Pocock A. et al.Isolation of human osteoclasts formed in vitro Hormonal effects on the bone-resorbing activity of human osteoclasts.Calcif Tissue Int. 2002; 71: 539Crossref PubMed Scopus (18) Google Scholar, 13Zaidi M. Inzerillo A.M. Moonga B.S. et al.Forty years of calcitonin—where are we now?.Bone. 2002; 30: 655Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar In GCTs and CGCGs, tumor giant cells and their precursors, also express calcitonin receptors making them a reasonable therapeutic target.14Miyamoto N. Higuchi Y. Tajima M. et al.Spindle-shaped cells derived from giant cell tumor of bone support differentiation of blood monocytes to osteoclast-like cells.J Orthop Res. 2000; 18: 647Crossref PubMed Google Scholar, 15Pogrel M.A. Regezi J.A. Harris S.T. et al.Calcitonin treatment for central giant cell granulomas of the mandible Report of two cases.J Oral Maxillofac Surg. 1999; 57: 848Abstract Full Text PDF PubMed Scopus (71) Google Scholar How this impacts on the proliferating spindle cells is undetermined. Nonetheless, clinical studies on treatment of CGCGs with calcitonin have shown positive results probably through control of osteoclastogenesis.15Pogrel M.A. Regezi J.A. Harris S.T. et al.Calcitonin treatment for central giant cell granulomas of the mandible Report of two cases.J Oral Maxillofac Surg. 1999; 57: 848Abstract Full Text PDF PubMed Scopus (71) Google Scholar Recently, it has been shown that osteoclastogenesis is under the influence of osteoprotegrin (inhibition of resorption) and its antagonist osteoprotegrin ligand (initiation of resorption) via an osteoclast receptor protein known as RANK (Receptor Activator of Nuclear Factor-kB).16Bolon B. Shalhoub V. Kostenuik P.J. et al.Osteoprotegrin, an endogenous antiosteoclast factor for protecting bone in rheumatoid arthritis.Arthritis Rheum. 2002; 46: 3121Crossref PubMed Scopus (50) Google Scholar, 17Buckley K.A. Hipskind A. Gartland A. et al.Adenosine triphosphate stimulates human osteoclast activity via upregulation of osteoblast-expressed receptor activator of nuclear factor-kappa B ligand.Bone. 2002; 31: 582Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 18Nagasawa T. Kobayashi H. Kiji M. et al.LPS-stimulated human gingival fibroblasts inhibit the differentiation of monocytes into osteoclasts through production of osteoprotegrin.Clin Exp Immunol. 2002; 130: 338Crossref PubMed Scopus (78) Google Scholar Because these proteins have been demonstrated in GCTs19Atkins G.J. Haynes D.R. Graves S.E. et al.Expression of osteoclast differentiation signals by stromal elements of giant cell tumors.J Bone Miner Res. 2000; 15: 640Crossref PubMed Scopus (155) Google Scholar, 20Hu Y. Yu S. Gene expression of osteoprotegrin and osteoclast differentiation factor in giant cell tumor.Zhonghua Bing Li Xue Za Zhi. 2002; 31: 128PubMed Google Scholar, 21Huang L. Xu J. Wood D. et al.Gene expression of osteoprotegrin ligand, osteoprotegrin, and receptor activator of NF-kappaB in giant cell tumor of bone.Am J Pathol. 2000; 156: 761Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar, 22Roux S. Amazit L. Meduri G. et al.RANK (receptor activator in nuclear factor kappa B) and RANK ligand are expressed in giant cell tumors of bone.Am J Clin Pathol. 2002; 117: 210Crossref PubMed Scopus (133) Google Scholar and more recently in CGCGs3Liu B. Yu S.F. Li T.J. Multinucleated giant cells in various forms of giant cell containing lesions of the jaws express features of osteoclasts.J Oral Pathol Med. 2003; 32: 367Crossref PubMed Scopus (142) Google Scholar (J.A. Regezi, unpublished data), control over these proteins may provide another strategy for medical treatment of these tumors. The rationale for treatment with osteoprotegrin (inhibition bone resorption) is similar to the rationale for treatment with calcitonin. However, the utility of osteoprotegrin is untested, and the systemic effects have not been evaluated. Other proteins that have been identified in GCT of long bone may have a role in the control of osteoclastogenesis. These include TNF-alpha,23Rao V.H. Singh R.K. Delimont D.C. et al.Transcriptional regulation of MMP-9 expression in stromal cells of human giant cell tumor of bone by tumor necrosis factor-alpha.Int J Oncol. 1999; 14: 291PubMed Google Scholar MMP-9,3Liu B. Yu S.F. Li T.J. Multinucleated giant cells in various forms of giant cell containing lesions of the jaws express features of osteoclasts.J Oral Pathol Med. 2003; 32: 367Crossref PubMed Scopus (142) Google Scholar, 23Rao V.H. Singh R.K. Delimont D.C. et al.Transcriptional regulation of MMP-9 expression in stromal cells of human giant cell tumor of bone by tumor necrosis factor-alpha.Int J Oncol. 1999; 14: 291PubMed Google Scholar cathepsin K,3Liu B. Yu S.F. Li T.J. Multinucleated giant cells in various forms of giant cell containing lesions of the jaws express features of osteoclasts.J Oral Pathol Med. 2003; 32: 367Crossref PubMed Scopus (142) Google Scholar, 24Dodds R.A. James I.E. Rieman D. et al.Human osteoclast cathepsin K is processed intracellularly prior to attachment and bone resorption.J Bone Miner Res. 2001; 16: 478Crossref PubMed Scopus (70) Google Scholar and VEGF.9Zheng M.H. Xu J. Robbins P. et al.Gene expression of vascular endothelial growth factor in giant cell tumors of bone.Hum Pathol. 2000; 31: 804Abstract Full Text PDF PubMed Scopus (42) Google Scholar These proteins, which may be part of CGCG pathogenesis as well, make potential therapeutic targets. Other agents, such as bisphosphonates25Hortobagyi G.N. Novel approaches to the management of bone metastases in patients with breast cancer.Semin Oncol. 2002; 29: 134Abstract Full Text Full Text PDF PubMed Google Scholar, 26Terpos E. Palermos J. Viniou N. et al.Pamidronate increases markers of bone formation in patients with multiple myeloma in plateau phase under interferon-alpha treatment.Calcif Tissue Int. 2001; 68: 285Crossref PubMed Scopus (20) Google Scholar and TGF-beta,27Yan T. Riggs B.L. Boyle W.J. et al.Regulation of osteoclastogenesis and RANK expression by TGF-beta1.J Cell Biochem. 2001; 83: 320Crossref PubMed Scopus (90) Google Scholar that are associated with bone metabolism (not yet studied in giant cell lesions) also deserve assessment. Anti-angiogenic drugs (eg, monoclonal antibodies) may have a role in the treatment of CGCGs, especially those that target VEGF and its receptors.28Zhu Z. Bohlen P. Witte L. Clinical development of angiogenesis inhibitors to vascular endothelial growth factor and its receptors as cancer therapeutics.Curr Cancer Drug Targets. 2002; 2: 135Crossref PubMed Scopus (60) Google Scholar, 29Pegram M.D. Reese D.M. Combined biological therapy of breast cancer using monoclonal antibodies directed against HER2/neu protein and vascular endothelial growth factor.Semin Oncol. 2002; 29: 29Abstract Full Text Full Text PDF PubMed Google Scholar However, because CGCGs are not of endothelial origin, it is not clear that VEGF or other angiogenic factors, such as basic fibroblastic growth factor, will prove to be suitable therapeutic targets. As CGCGs are generally slow growing and focally expansile (due to osteoclastogenesis) lesions of probable fibroblastic origin, and do not have the capacity to metastasize, the role of anti-angiogenesis in CGCG would be less significant than in malignant neoplasms. In a retrospective uncontrolled study, alpha-interferon injections were used as an adjunct to surgical curettage of CGCGs.30Kaban L.B. Troulis M.J. Ebb D. et al.Antiangiogenic therapy with interferon alpha for giant cell lesions of the jaws.J Oral Maxillofac Surg. 2002; 60: 1103Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar Success was reported in this small series of patients. The reported therapeutic advantage of the adjunctive alpha-interferon injections was attributed to the drug’s antiangiogenic effect, although the other powerful biologic effects of alpha-interferon including inhibition of bone resorption were not apparently considered.31Brassard D.L. Grace M.J. Bordens R.W. Interferon-alpha as an immunotherapeutic protein.J Leuko Biol. 2002; 71: 565PubMed Google Scholar, 32Corssmit E.P.M. De Metz J. Sauerwein H.P. et al.Biologic responses to IFN-alpha administration in humans.J Interferon & Cytokine Res. 2000; 20: 1039Crossref PubMed Scopus (50) Google Scholar Also, the effect if alpha interferon alone (no surgery) on CGCGs was not tested. Until curettage and alpha-interferon are used in separate protocols, the combined regimen can not be declared advantageous because clinical improvement could have simply been the effect of curettage interrupting the natural history of CGCG. Corticosteroids have been used to treat CGCGs, but the rationale is somewhat tenuous, as corticosteroids are known to effect bone resorption and osteoporosis. In the anecdotal cases in which it has appeared beneficial, the effect may have been related to reduction of monocytes in the lesions. Another explanation of the occasional successes reported could be related to a seemingly contradictory affect of corticosteroids in which there is both inhibition of bone resorption and proliferation and differentiation of osteoclasts.33Hirayama T. Sabokbar A. Athanasou N.A. Effect of corticosteroids on human osteoclast formation and activity.J Endocrinol. 2002; 175: 155Crossref PubMed Scopus (77) Google Scholar Initial studies now indicate that a medical approach to the treatment CGCGs is feasible. Important to further development of a rational therapy is research in both the laboratory and the clinic. In the laboratory, a focus on gene and protein expression of these tumors can lead to identification of therapeutic targets. Measuring the effects of potential drugs in tissue culture of CGCG could give invaluable preliminary information. In the clinic, controlled studies with significant numbers of subjects need to be designed. Ideally, there should be a consortium of OMFS surgical centers working with the same protocols, because of the relatively uncommon occurrence of CGCGs. A standard rational regimen with predictable results could be achieved.