Accepted Manuscript Alternative Pharmacological Therapy for the Aggressive Central Giant Cell Granuloma: Denosumab Wh Schreuder, MD DDS Aw Coumou, MD Pahw Kessler, MD DDS PhD J. De Lange, MD DDS PhD PII:
S0278-2391(14)00228-6
DOI:
10.1016/j.joms.2014.02.017
Reference:
YJOMS 56225
To appear in:
Journal of Oral and Maxillofacial Surgery
Received Date: 20 October 2013 Revised Date:
27 January 2014
Accepted Date: 1 February 2014
Please cite this article as: Schreuder W, Coumou A, Kessler P, De Lange J, Alternative Pharmacological Therapy for the Aggressive Central Giant Cell Granuloma: Denosumab, Journal of Oral and Maxillofacial Surgery (2014), doi: 10.1016/j.joms.2014.02.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Alternative Pharmacological Therapy for the Aggressive Central Giant Cell Granuloma: Denosumab
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WH SCHREUDER1 MD DDS, AW COUMOU2 MD, PAHW KESSLER3 MD DDS PhD, J DE LANGE1 MD
DDS PhD
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1) Department of Oral and Maxillofacial Surgery, Academic Medical Center / Academic Center Dentistry Amsterdam, University of Amsterdam, The Netherlands
Netherlands
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2) Department of Medical Oncology, Academic Medical Center, University of Amsterdam, The
3) Department of Cranio-Maxillo-Facial Surgery, University Hospital Maastricht, Maastricht
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University, The Netherlands
Keywords: Giant Cell Granuloma, Receptor Activator of Nuclear Factor-kappa B, RANK Ligand,
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Maxilla
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Correspondence Address: W.H. Schreuder
Department of Oral and Maxillofacial Surgery Academic Medical Center, University of Amsterdam P.O. Box 22660, 1100 DD Amsterdam-Zuidoost Phone: +31-20-5663899 Fax: +31-20-5669032 Email: [email protected]
ACCEPTED MANUSCRIPT ABSTRACT In the search for new pharmacological therapies for the central giant cell granuloma (CGCG), proteins that are essential to osteoclastogenesis are intriguing potential targets. In this case report, we describe a 25-year old patient with an aggressive central giant cell granuloma of the maxilla, who was
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successfully treated with the antiresorptive agent denosumab, after other pharmacological treatment failed to achieve a regression or stabilisation of the tumour. Denosumab may be a promising
alternative to potentially mutilating surgery in this disease. However, more research is needed before
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SC
definite conclusions can be drawn about the potential role of this agent in the treatment of CGCG.
ACCEPTED MANUSCRIPT INTRODUCTION
Central giant cell granuloma (CGCG) is a rare benign osteolytic lesion of the jawbone. A 5-year population based study estimates its incidence at 0,00011%.1 It was first described by Jaffe as a
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reactive-reparative process.2 However, it is now considered to be a true neoplasm.3 The most common treatment is surgical curettage. However, recurrence rates ranging from 11-72% have been reported in literature, especially for the so-called aggressive lesions.4 In the last two decades a number of pharmacologic therapies have been described.4 Pharmacologic treatment offers the
SC
advantage of preventing or at least minimizing extensive and mutilating surgical procedures,
characterized by detrimental functional outcomes and an inevitable loss of teeth, nerve function and
M AN U
altered facial contours. Until now, the most common and successful applied pharmacological agents are the intralesional corticosteroid injections and the systemic treatment with calcitonin or interferon alpha-2a.5,6,7 Proteins that play a role in osteoclastogenesis are hypothesized to be a possible target in the systemic treatment of CGCG.4 The discovery and subsequent understanding of the essential role of
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the RANK/RANKL/OPG pathway in bone biology, has opened the door to new potential therapeutic targets.
Denosumab is a monoclonal antibody against RANKL, and was developed as a treatment for
EP
osteoporosis. It is an effective antiresorptive agent, and could be useful in the treatment of other skeletal diseases with excessive osteoclast activity, such as CGCG. In this paper, a patient is described
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with an aggressive central giant cell granuloma, who was treated with denosumab after other pharmacological treatments failed to achieve a regression or stabilisation of the tumour.
ACCEPTED MANUSCRIPT CASE REPORT A 25-year-old woman with a history of type I diabetes was referred with a progressive swelling of her anterior maxilla. Histopathological examination of a biopsy confirmed the diagnosis of central giant cell granuloma (Figure 4A). Hyperparathyroidism was excluded by laboratory investigations.
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Clinical examination showed severe protrusion of the upper lip and flattening the nasolabial folds (Figure 2A). On intra-oral examination there was a firm swelling at the buccal and palatal sides of the anterior maxilla extending from the left maxillary first molar to the right maxillary first molar. The
SC
alveolar ridges were swollen with a bluish-brown aspect of the overlying mucosa on the palatal side (Figure 2B). An orthodontic splint had to be applied to stabilize the mobile and displaced anterior
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maxillary teeth. There was extension of the tumour mass into the nasal cavity with partial obstruction of the nasal airway. Computer tomography (CT) confirmed an expansive growing lesion in the maxilla with destruction of the nasal floor and extension into the nasal cavity (Figure 1A). There were radiological features of an aggressive lesion, e.g. perforation of the cortex, tooth displacement and root resorption. Routine haematological investigations were normal.
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Shortly after initial diagnosis, pharmacological treatment was initiated by the referring hospital with daily calcitonin administration. Calcitonin was administered initially by daily nasal spray of 200 IU (Miacalcin, Novartis Pharma, Basel, Switzerland), and later followed by subcutaneous injections of
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calcitonin 100 IU (Miacalcin, Novartis Pharma, Basel, Switzerland). After 4 months of treatment, the lesion had grown considerably. The following 8 months, the patient was treated with a combination of
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daily subcutaneous calcitonin 100 IU and weekly pegylated-interferon-alpha-2a (Pegasys, Roche, Basel, Switzerland) 180 ug. The dosage of this pegylated form of interferon was comparable to the recommended dosage for the treatment of hepatitis C. This treatment regimen was also unsuccessful. Because the patient suffered from side effects, e.g. flu-like symptoms, palpitations and periods of severe hypotension, the interferon administration was terminated. While the patient was scheduled for a subtotal maxillectomy, she was referred to our clinic for a second opinion. Because of the aggressive features of the lesion, the large dimensions of the tumour and the mutilation associated with surgery in this young individual, we suggested an alternative
ACCEPTED MANUSCRIPT treatment regimen: off-label use of denosumab. The local Medical Ethical Committee approved the treatment regimen. Over the course of 12 months the patient received monthly, subcutaneous injections of denosumab 120 mg (Prolia, Amgen, Thousand Oaks, United States of America), with additional loading doses of 120
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mg on days 8 and 15 of month 1. Daily supplements of calcium 500 mg and vitamin D 400 IU were prescribed. Disease status was radiologically assessed by CT on day 1, after 6 months, upon cessation of the therapy (12 months) and during further follow-up (15 months and 24 months). Histological response to the treatment was assessed by way of a post-treatment biopsy that was obtained 1 month
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after the last injection.
Two months after commencing therapy the patient noticed less mobility of the anterior maxillary
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teeth. The CT scan after 6 months of therapy demonstrated regression of the tumour, reformation of cortex along the periphery and islands of intralesional bone formation (Figure 1B). The follow-up CT scans at cessation of therapy and 1 year after completion of therapy were more or less stable with some further regression (Figure 1C and 1D). Histopathological analysis of the post-treatment
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incisional biopsy showed elimination of the giant cells along with granulation and fibrous tissue, with no residue of the earlier diagnosed CGCG (Figure 5B). In order to monitor adverse events and the effects on bone and calcium metabolism, physical
EP
examination and blood samples were performed monthly throughout the course of treatment. Reported adverse events were mild, namely fatigue, myalgia, dizziness, constipation and cramps. Initial (mid-
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winter) laboratory samples showed a lowered 25-hydroxycholecalciferol, which soon improved to normal levels with the suppletion with colecalciferol 400 IU/dose (10 micrograms). Calcium and albumin levels were normal.
Long-term follow up is indicated. Any corrective surgical procedures will only be considered, if there are no signs of recurrent disease at least two years after cessation of pharmacological treatment.
ACCEPTED MANUSCRIPT DISCUSSION
Denosumab is a fully human monoclonal IgG2 antibody with a high affinity and specificity for RANKL. RANKL is an essential cytokine in osteoclastogenesis; it also stimulates the survival and
against bone diseases characterized by excessive osteoclastic activity.
RI PT
activation of readily formed osteoclasts.8 Therefore, it may be a possible target for novel therapies
There are three key components to RANKL signalling (Figure 6A).8 The receptor, receptor activator
SC
of nuclear factor κB (RANK), is expressed by a variety of cells, but primarily by osteoclasts and mononuclear pre-osteoclasts. The ligand, receptor activator of nuclear factor κB ligand (RANKL), is a
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member of the TNF family and is highly expressed by osteoblasts, periosteal cells and osteocytes. A soluble decoy receptor, osteoprotegerin (OPG), is also expressed by osteoblasts and acts as a natural negative regulator of RANKL. Denosumab mimics the effect of OPG, inhibiting the RANK-RANKL interaction and subsequently the formation, activation and survival of osteoclasts (Figure 6B). Although the fundamental understanding of the biological behaviour of CGCG is still lacking, the
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histological features are well described. Histopathologic biopsies demonstrate spindle-shaped stromal cells and characteristic multinucleated giant cells arranged in a fibroblastic stroma with foci of hemorrhage. Recently, the key components of RANKL signalling have been demonstrated in CGCG.9
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The spindle-shaped mononuclear cells are osteoblast-like cells and support osteoclast formation through expression of RANKL. The multinucleated giant cells in CGCG have an osteoclastic
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phenotype and may be formed by the fusion of precursors, which come from the monocyte/macrophage lineage. Both the osteoclast-like giant cells and their precursors express RANK. These features of CGCG tissue suggest that the recruitment of osteoclast-like giant cells is related to stromal expression of RANKL, and the giant cells are responsible for the osteolytic destructive behaviour of the tumour. If this is the case, therapeutic agents that inhibit this RANK/RANKL interaction, such as denosumab, could theoretically control CGCG. Denosumab was first developed and is currently still being studied for the treatment of osteoporosis. Later studies focused on the increase of bone mass in patients with a high risk of fractures receiving
ACCEPTED MANUSCRIPT androgen deprivation therapy for prostate cancer, aromatase inhibitor therapy for breast cancer and prevention of skeletal related events in patients with bone metastases from solid tumours. The outcome of these studies led to the approval by the U.S. Food and Drug Administration (FDA) for clinical application in these aforementioned indications. Although the hypothetical basis of the role for
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denosumab in the treatment of giant cell-rich disorders, such as central giant cell granuloma, seems promising, the evidence is currently lacking. However, a recent proof-of-principle phase II study of 35 patients with recurrent or unresectable giant cell tumour of long bones (GCT) showed encouraging results.10 Thirty of thirty-five evaluable patients experienced a tumour response: twenty out of twenty
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assessed by histology, demonstrated near complete elimination of giant cells after repeat biopsy
following treatment, and ten out of fifteen showed radiographic stabilization of disease at 6 months.
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Although in the literature CGT and CGCG are delineated as distinct entities, in both tumours the interplay between the stromal population of osteoblastic origin and a distinctive osteoclast-like population of multinucleated giant cells is critical in the pathogenesis.
As with other cytokines, RANKL has known and unknown effects on extraskeletal systems and cells.
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This may lead to possible unanticipated adverse effects such as infections or malignancies. RANKL is expressed on subsets of T and B cells, and RANKL-deficient mice show a lack of normal lymph node development along with inhibition of early T and B lymphocyte development.11 No study published to
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date has reported an increased incidence of malignancy and in clinical trials no statistically significant or clinically meaningful effect on the immune system has been observed. The systematic review
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published by Peddi et al.12 on the efficacy and safety of denosumab compared to bisphosphonates in patients with bone metastasis, analyzing 6 controlled trials with 6142 patients, confirmed this finding demonstrating no increased rates for infections or occurrence of new cancers. While there was an increased risk of hypocalcaemia, no cardiac and neurologic complications were documented in the trials included in the review. Osteonecrosis of the jaw (ONJ) seems to be the most serious adverse event. A recent meta-analysis by Qi et al13, that pooled 8963 patients from 7 RCTs in which the incidence of denosumab osteonecrosis of the jaw (DONJ) ranged from 0-4,6%, showed a calculated summary incidence of patients receiving denosumab of 1,7 % (95% CI: 0.9-3.1%) using a randomeffect model. Denosumab treatment significantly increased the risk of developing DONJ in cancer
ACCEPTED MANUSCRIPT patients with a RR of 1.613 (95% CI: 1.050-2.478, P=0.029). Although this review has limitations, including heterogeneity of the included studies, it underlines that physicians should be aware of this adverse effect. Furthermore, the drug has not been studied in a paediatric population. It may be concluded that if currently available pharmacological treatment options fail to achieve a
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tumour response in aggressive CGCG, denosumab might offer a promising alternative before mutilating surgery is initiated. There is a strong need for more data on optimal dosage, duration of treatment, long-term safety issues and tumour control after cessation of therapy. Only after these data become available, can definite conclusions be drawn about the potential role of denosumab in the
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treatment of CGCG. Solely then is further clinical use for this specific indication justified.
ACCEPTED MANUSCRIPT ACKNOWLEDGEMENTS
The authors would like to thank Dr. V.C. Harris for editing the manuscript. The authors would like to thank Dr. T.J.J. Maal for his support and assistance in the 3D images and
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volumetric measurements in this manuscript. The authors would like to thank Dr. R.R. Jurhill and Dr. J. Bras from the department of Pathology for their support and expertise during the treatment of this patient and assistance in preparation of this
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manuscript.
ACCEPTED MANUSCRIPT FIGURE 1
Figure 1: The 3D reconstructed images of the computed tomogram show the destructive expansive osteolytic lesion in the anterior maxilla before treatment (A). Futhermore, these images also show the
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bony demarcation of the lesion due to reformation of the cortex after 6 months of treatment (B) and at cessation of therapy (C). This result has proven to remain stable for one year after treatment with even little further regression (D).
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FIGURE 2
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Figure 2: These clinical photographs show the flattening of the nasolabial folds and protrusion of the upper lip (A) with a bluish-brown mucosal swelling on the palate (B). The clinical photographs after treatment show the preservation of the teeth and occlusion (C) and restoration of the palatal vault without any surgical intervention (D).
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FIGURE 3
Figure 3: Volumetric measurements of the lesion (shown in green) before treatment (A; volume 35848 mm3) and three months after cessation of therapy (shown in orange) (B; volume 18114 mm3)
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FIGURE 4
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demonstrate regression of the lesion (C).
Figure 4A: The orthopantomogram before the start of treatment, showing the large osseous defect in the anterior maxilla.
Figure 4B: The orthopantomogram after 6 months of treatment, showing bone formation in the anterior maxilla.
ACCEPTED MANUSCRIPT FIGURE 5
Figure 5A: Histopathological appearance before treatment: Haematoxylin-eosin stained section demonstrating a highly cellular lesion with mononuclear macrophage-like cells and spindle-shaped fibroblastic cells. Multinuclear osteoclast-like giant cells are dispersed throughout the lesion (indicated
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by arrow). There are extravasated erythrocytes (indicated by double arrow) and areas of hemosiderin deposits (not shown in this picture).
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Figure 5B: Histopathological appearance after treatment: Haematoxylin-eosin stained section demonstrating fibrotic tissue (indicated by asterix) with signs of mild chronic infection and old
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hemorrhage (hemosiderin deposits) (indicated by arrow). There are no signs of the earlier diagnosed central giant cell granuloma.
FIGURE 6
Figure 6A: A simplified diagram of the RANK-RANKL pathway. In CGCG, it is hypothesized that
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the formation of osteolytic osteoclast like giant cells from its precursors is related to spindle shaped mononuclear cell expression of RANKL. Both the multinucleated giant cell and its precursors express
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RANK.
Figure 6B: The same diagram showing graphically the site of interaction of denosumab. By binding to
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RANKL, denosumab inhibits osteoclast formation, function and survival. Thereby, it decreases bone resorption and increases bone mass and strength in cortical and trabecular bone.
ACCEPTED MANUSCRIPT REFERENCES
1. de Lange J, van den Akker HP, Klip H. Incidence and disease free survival after surgical therapy of central giant-cell granulomas of the jaw in The Netherlands: 1990-1995. Head Neck 26:792, 2004.
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2. Jaffe HL. Giant-cell reparative granuloma, traumatic bone cyst, and fibrous (fibro-osseous) dysplasia of the jawbones. Oral Surg 6:159, 1953.
3. Whitaker SB, Waldron CA. Central giant cell lesions of the jaws. Oral Surg Oral Med Oral Pathol 95:199, 1993.
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4. de Lange, van den Akker HP, van den Berg H. Central giant cell granuloma of the jaw: a review of the literature with emphasis on therapy options. Oral Surg Oral Med Oral Pathol Endod 104:603, 2007.
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5. Terry BC, Jacoway JR. Management of central giant cell lesions: An alternative to surgical therapy. Oral Maxillofac Surg Clin N Am 6:579, 1994.
6. Harris M. Central giant cell granulomas of the jaws regress with calcitonin therapy. Br J Oral Maxillofac Surg 31:89, 1993.
7. Kaban LB, Troulis MJ, Wilkinson MS, Ebb D, Dodson TB. Adjuvant antiangiogenic therapy for giant
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cell tumors of the jaws. J Oral Maxillofac 65:2018, 2007.
8. Sinningen K, Tsourdi E, Rauner M, Rachner TD, Hamann C, Hofbauer LC. Skeletal and extraskeletal actions of Denosumab. Endocrine 42:52, 2012.
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9. Bo Lui, Shi-Feng Yu, Tie-Jun Li. Multinucleated giant cells in various forms of giant cell containing lesions of the jaws express features of osteoclasts. J Oral Pathol Med 32:367, 2003.
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10. Thomas D, Henshaw R, Skubitz K, Chawla S, Staddon A, Blay JY, Roudier M, Smith J, Ye Z, Sohn W, Dansey R, Jun S. Denosumab in patients with giant-cell tmour of bone: an open-label, phase 2 study. Lancet Oncol 11:275, 2010. 11. Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A, Khoo W, Wakeham A, Dunstan CR, Lacey DL, Mak TW, Boyle WJ, Penninger JM. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymphnode organogenesis. Nature 397:315, 1999. 12. Peddi P, Lopez-Olivo MA, Pratt GF, Suarez-Almazor ME. Denosumab in patients with cancer and skeletal metastases: A systematic review and meta-analysis. Cancer Treat Rev 39:97, 2013.
ACCEPTED MANUSCRIPT 13. Qi WX, Tang LN, He AN, Yao Y, Shen Z. Risk of osteonecrosis of the jaw in cancer patients receiving denosumab: a meta-analysis of seven randomized controlled trials. Int J Clin Oncol 2013 [Epub ahead
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S0278-2391(14)00228-6
DOI:
10.1016/j.joms.2014.02.017
Reference:
YJOMS 56225
To appear in:
Journal of Oral and Maxillofacial Surgery
Received Date: 20 October 2013 Revised Date:
27 January 2014
Accepted Date: 1 February 2014
Please cite this article as: Schreuder W, Coumou A, Kessler P, De Lange J, Alternative Pharmacological Therapy for the Aggressive Central Giant Cell Granuloma: Denosumab, Journal of Oral and Maxillofacial Surgery (2014), doi: 10.1016/j.joms.2014.02.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Alternative Pharmacological Therapy for the Aggressive Central Giant Cell Granuloma: Denosumab
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WH SCHREUDER1 MD DDS, AW COUMOU2 MD, PAHW KESSLER3 MD DDS PhD, J DE LANGE1 MD
DDS PhD
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1) Department of Oral and Maxillofacial Surgery, Academic Medical Center / Academic Center Dentistry Amsterdam, University of Amsterdam, The Netherlands
Netherlands
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2) Department of Medical Oncology, Academic Medical Center, University of Amsterdam, The
3) Department of Cranio-Maxillo-Facial Surgery, University Hospital Maastricht, Maastricht
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University, The Netherlands
Keywords: Giant Cell Granuloma, Receptor Activator of Nuclear Factor-kappa B, RANK Ligand,
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Maxilla
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Correspondence Address: W.H. Schreuder
Department of Oral and Maxillofacial Surgery Academic Medical Center, University of Amsterdam P.O. Box 22660, 1100 DD Amsterdam-Zuidoost Phone: +31-20-5663899 Fax: +31-20-5669032 Email: [email protected]
ACCEPTED MANUSCRIPT ABSTRACT In the search for new pharmacological therapies for the central giant cell granuloma (CGCG), proteins that are essential to osteoclastogenesis are intriguing potential targets. In this case report, we describe a 25-year old patient with an aggressive central giant cell granuloma of the maxilla, who was
RI PT
successfully treated with the antiresorptive agent denosumab, after other pharmacological treatment failed to achieve a regression or stabilisation of the tumour. Denosumab may be a promising
alternative to potentially mutilating surgery in this disease. However, more research is needed before
AC C
EP
TE D
M AN U
SC
definite conclusions can be drawn about the potential role of this agent in the treatment of CGCG.
ACCEPTED MANUSCRIPT INTRODUCTION
Central giant cell granuloma (CGCG) is a rare benign osteolytic lesion of the jawbone. A 5-year population based study estimates its incidence at 0,00011%.1 It was first described by Jaffe as a
RI PT
reactive-reparative process.2 However, it is now considered to be a true neoplasm.3 The most common treatment is surgical curettage. However, recurrence rates ranging from 11-72% have been reported in literature, especially for the so-called aggressive lesions.4 In the last two decades a number of pharmacologic therapies have been described.4 Pharmacologic treatment offers the
SC
advantage of preventing or at least minimizing extensive and mutilating surgical procedures,
characterized by detrimental functional outcomes and an inevitable loss of teeth, nerve function and
M AN U
altered facial contours. Until now, the most common and successful applied pharmacological agents are the intralesional corticosteroid injections and the systemic treatment with calcitonin or interferon alpha-2a.5,6,7 Proteins that play a role in osteoclastogenesis are hypothesized to be a possible target in the systemic treatment of CGCG.4 The discovery and subsequent understanding of the essential role of
TE D
the RANK/RANKL/OPG pathway in bone biology, has opened the door to new potential therapeutic targets.
Denosumab is a monoclonal antibody against RANKL, and was developed as a treatment for
EP
osteoporosis. It is an effective antiresorptive agent, and could be useful in the treatment of other skeletal diseases with excessive osteoclast activity, such as CGCG. In this paper, a patient is described
AC C
with an aggressive central giant cell granuloma, who was treated with denosumab after other pharmacological treatments failed to achieve a regression or stabilisation of the tumour.
ACCEPTED MANUSCRIPT CASE REPORT A 25-year-old woman with a history of type I diabetes was referred with a progressive swelling of her anterior maxilla. Histopathological examination of a biopsy confirmed the diagnosis of central giant cell granuloma (Figure 4A). Hyperparathyroidism was excluded by laboratory investigations.
RI PT
Clinical examination showed severe protrusion of the upper lip and flattening the nasolabial folds (Figure 2A). On intra-oral examination there was a firm swelling at the buccal and palatal sides of the anterior maxilla extending from the left maxillary first molar to the right maxillary first molar. The
SC
alveolar ridges were swollen with a bluish-brown aspect of the overlying mucosa on the palatal side (Figure 2B). An orthodontic splint had to be applied to stabilize the mobile and displaced anterior
M AN U
maxillary teeth. There was extension of the tumour mass into the nasal cavity with partial obstruction of the nasal airway. Computer tomography (CT) confirmed an expansive growing lesion in the maxilla with destruction of the nasal floor and extension into the nasal cavity (Figure 1A). There were radiological features of an aggressive lesion, e.g. perforation of the cortex, tooth displacement and root resorption. Routine haematological investigations were normal.
TE D
Shortly after initial diagnosis, pharmacological treatment was initiated by the referring hospital with daily calcitonin administration. Calcitonin was administered initially by daily nasal spray of 200 IU (Miacalcin, Novartis Pharma, Basel, Switzerland), and later followed by subcutaneous injections of
EP
calcitonin 100 IU (Miacalcin, Novartis Pharma, Basel, Switzerland). After 4 months of treatment, the lesion had grown considerably. The following 8 months, the patient was treated with a combination of
AC C
daily subcutaneous calcitonin 100 IU and weekly pegylated-interferon-alpha-2a (Pegasys, Roche, Basel, Switzerland) 180 ug. The dosage of this pegylated form of interferon was comparable to the recommended dosage for the treatment of hepatitis C. This treatment regimen was also unsuccessful. Because the patient suffered from side effects, e.g. flu-like symptoms, palpitations and periods of severe hypotension, the interferon administration was terminated. While the patient was scheduled for a subtotal maxillectomy, she was referred to our clinic for a second opinion. Because of the aggressive features of the lesion, the large dimensions of the tumour and the mutilation associated with surgery in this young individual, we suggested an alternative
ACCEPTED MANUSCRIPT treatment regimen: off-label use of denosumab. The local Medical Ethical Committee approved the treatment regimen. Over the course of 12 months the patient received monthly, subcutaneous injections of denosumab 120 mg (Prolia, Amgen, Thousand Oaks, United States of America), with additional loading doses of 120
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mg on days 8 and 15 of month 1. Daily supplements of calcium 500 mg and vitamin D 400 IU were prescribed. Disease status was radiologically assessed by CT on day 1, after 6 months, upon cessation of the therapy (12 months) and during further follow-up (15 months and 24 months). Histological response to the treatment was assessed by way of a post-treatment biopsy that was obtained 1 month
SC
after the last injection.
Two months after commencing therapy the patient noticed less mobility of the anterior maxillary
M AN U
teeth. The CT scan after 6 months of therapy demonstrated regression of the tumour, reformation of cortex along the periphery and islands of intralesional bone formation (Figure 1B). The follow-up CT scans at cessation of therapy and 1 year after completion of therapy were more or less stable with some further regression (Figure 1C and 1D). Histopathological analysis of the post-treatment
TE D
incisional biopsy showed elimination of the giant cells along with granulation and fibrous tissue, with no residue of the earlier diagnosed CGCG (Figure 5B). In order to monitor adverse events and the effects on bone and calcium metabolism, physical
EP
examination and blood samples were performed monthly throughout the course of treatment. Reported adverse events were mild, namely fatigue, myalgia, dizziness, constipation and cramps. Initial (mid-
AC C
winter) laboratory samples showed a lowered 25-hydroxycholecalciferol, which soon improved to normal levels with the suppletion with colecalciferol 400 IU/dose (10 micrograms). Calcium and albumin levels were normal.
Long-term follow up is indicated. Any corrective surgical procedures will only be considered, if there are no signs of recurrent disease at least two years after cessation of pharmacological treatment.
ACCEPTED MANUSCRIPT DISCUSSION
Denosumab is a fully human monoclonal IgG2 antibody with a high affinity and specificity for RANKL. RANKL is an essential cytokine in osteoclastogenesis; it also stimulates the survival and
against bone diseases characterized by excessive osteoclastic activity.
RI PT
activation of readily formed osteoclasts.8 Therefore, it may be a possible target for novel therapies
There are three key components to RANKL signalling (Figure 6A).8 The receptor, receptor activator
SC
of nuclear factor κB (RANK), is expressed by a variety of cells, but primarily by osteoclasts and mononuclear pre-osteoclasts. The ligand, receptor activator of nuclear factor κB ligand (RANKL), is a
M AN U
member of the TNF family and is highly expressed by osteoblasts, periosteal cells and osteocytes. A soluble decoy receptor, osteoprotegerin (OPG), is also expressed by osteoblasts and acts as a natural negative regulator of RANKL. Denosumab mimics the effect of OPG, inhibiting the RANK-RANKL interaction and subsequently the formation, activation and survival of osteoclasts (Figure 6B). Although the fundamental understanding of the biological behaviour of CGCG is still lacking, the
TE D
histological features are well described. Histopathologic biopsies demonstrate spindle-shaped stromal cells and characteristic multinucleated giant cells arranged in a fibroblastic stroma with foci of hemorrhage. Recently, the key components of RANKL signalling have been demonstrated in CGCG.9
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The spindle-shaped mononuclear cells are osteoblast-like cells and support osteoclast formation through expression of RANKL. The multinucleated giant cells in CGCG have an osteoclastic
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phenotype and may be formed by the fusion of precursors, which come from the monocyte/macrophage lineage. Both the osteoclast-like giant cells and their precursors express RANK. These features of CGCG tissue suggest that the recruitment of osteoclast-like giant cells is related to stromal expression of RANKL, and the giant cells are responsible for the osteolytic destructive behaviour of the tumour. If this is the case, therapeutic agents that inhibit this RANK/RANKL interaction, such as denosumab, could theoretically control CGCG. Denosumab was first developed and is currently still being studied for the treatment of osteoporosis. Later studies focused on the increase of bone mass in patients with a high risk of fractures receiving
ACCEPTED MANUSCRIPT androgen deprivation therapy for prostate cancer, aromatase inhibitor therapy for breast cancer and prevention of skeletal related events in patients with bone metastases from solid tumours. The outcome of these studies led to the approval by the U.S. Food and Drug Administration (FDA) for clinical application in these aforementioned indications. Although the hypothetical basis of the role for
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denosumab in the treatment of giant cell-rich disorders, such as central giant cell granuloma, seems promising, the evidence is currently lacking. However, a recent proof-of-principle phase II study of 35 patients with recurrent or unresectable giant cell tumour of long bones (GCT) showed encouraging results.10 Thirty of thirty-five evaluable patients experienced a tumour response: twenty out of twenty
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assessed by histology, demonstrated near complete elimination of giant cells after repeat biopsy
following treatment, and ten out of fifteen showed radiographic stabilization of disease at 6 months.
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Although in the literature CGT and CGCG are delineated as distinct entities, in both tumours the interplay between the stromal population of osteoblastic origin and a distinctive osteoclast-like population of multinucleated giant cells is critical in the pathogenesis.
As with other cytokines, RANKL has known and unknown effects on extraskeletal systems and cells.
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This may lead to possible unanticipated adverse effects such as infections or malignancies. RANKL is expressed on subsets of T and B cells, and RANKL-deficient mice show a lack of normal lymph node development along with inhibition of early T and B lymphocyte development.11 No study published to
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date has reported an increased incidence of malignancy and in clinical trials no statistically significant or clinically meaningful effect on the immune system has been observed. The systematic review
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published by Peddi et al.12 on the efficacy and safety of denosumab compared to bisphosphonates in patients with bone metastasis, analyzing 6 controlled trials with 6142 patients, confirmed this finding demonstrating no increased rates for infections or occurrence of new cancers. While there was an increased risk of hypocalcaemia, no cardiac and neurologic complications were documented in the trials included in the review. Osteonecrosis of the jaw (ONJ) seems to be the most serious adverse event. A recent meta-analysis by Qi et al13, that pooled 8963 patients from 7 RCTs in which the incidence of denosumab osteonecrosis of the jaw (DONJ) ranged from 0-4,6%, showed a calculated summary incidence of patients receiving denosumab of 1,7 % (95% CI: 0.9-3.1%) using a randomeffect model. Denosumab treatment significantly increased the risk of developing DONJ in cancer
ACCEPTED MANUSCRIPT patients with a RR of 1.613 (95% CI: 1.050-2.478, P=0.029). Although this review has limitations, including heterogeneity of the included studies, it underlines that physicians should be aware of this adverse effect. Furthermore, the drug has not been studied in a paediatric population. It may be concluded that if currently available pharmacological treatment options fail to achieve a
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tumour response in aggressive CGCG, denosumab might offer a promising alternative before mutilating surgery is initiated. There is a strong need for more data on optimal dosage, duration of treatment, long-term safety issues and tumour control after cessation of therapy. Only after these data become available, can definite conclusions be drawn about the potential role of denosumab in the
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treatment of CGCG. Solely then is further clinical use for this specific indication justified.
ACCEPTED MANUSCRIPT ACKNOWLEDGEMENTS
The authors would like to thank Dr. V.C. Harris for editing the manuscript. The authors would like to thank Dr. T.J.J. Maal for his support and assistance in the 3D images and
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volumetric measurements in this manuscript. The authors would like to thank Dr. R.R. Jurhill and Dr. J. Bras from the department of Pathology for their support and expertise during the treatment of this patient and assistance in preparation of this
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manuscript.
ACCEPTED MANUSCRIPT FIGURE 1
Figure 1: The 3D reconstructed images of the computed tomogram show the destructive expansive osteolytic lesion in the anterior maxilla before treatment (A). Futhermore, these images also show the
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bony demarcation of the lesion due to reformation of the cortex after 6 months of treatment (B) and at cessation of therapy (C). This result has proven to remain stable for one year after treatment with even little further regression (D).
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FIGURE 2
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Figure 2: These clinical photographs show the flattening of the nasolabial folds and protrusion of the upper lip (A) with a bluish-brown mucosal swelling on the palate (B). The clinical photographs after treatment show the preservation of the teeth and occlusion (C) and restoration of the palatal vault without any surgical intervention (D).
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FIGURE 3
Figure 3: Volumetric measurements of the lesion (shown in green) before treatment (A; volume 35848 mm3) and three months after cessation of therapy (shown in orange) (B; volume 18114 mm3)
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FIGURE 4
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demonstrate regression of the lesion (C).
Figure 4A: The orthopantomogram before the start of treatment, showing the large osseous defect in the anterior maxilla.
Figure 4B: The orthopantomogram after 6 months of treatment, showing bone formation in the anterior maxilla.
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Figure 5A: Histopathological appearance before treatment: Haematoxylin-eosin stained section demonstrating a highly cellular lesion with mononuclear macrophage-like cells and spindle-shaped fibroblastic cells. Multinuclear osteoclast-like giant cells are dispersed throughout the lesion (indicated
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by arrow). There are extravasated erythrocytes (indicated by double arrow) and areas of hemosiderin deposits (not shown in this picture).
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Figure 5B: Histopathological appearance after treatment: Haematoxylin-eosin stained section demonstrating fibrotic tissue (indicated by asterix) with signs of mild chronic infection and old
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hemorrhage (hemosiderin deposits) (indicated by arrow). There are no signs of the earlier diagnosed central giant cell granuloma.
FIGURE 6
Figure 6A: A simplified diagram of the RANK-RANKL pathway. In CGCG, it is hypothesized that
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the formation of osteolytic osteoclast like giant cells from its precursors is related to spindle shaped mononuclear cell expression of RANKL. Both the multinucleated giant cell and its precursors express
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RANK.
Figure 6B: The same diagram showing graphically the site of interaction of denosumab. By binding to
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RANKL, denosumab inhibits osteoclast formation, function and survival. Thereby, it decreases bone resorption and increases bone mass and strength in cortical and trabecular bone.
ACCEPTED MANUSCRIPT REFERENCES
1. de Lange J, van den Akker HP, Klip H. Incidence and disease free survival after surgical therapy of central giant-cell granulomas of the jaw in The Netherlands: 1990-1995. Head Neck 26:792, 2004.
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2. Jaffe HL. Giant-cell reparative granuloma, traumatic bone cyst, and fibrous (fibro-osseous) dysplasia of the jawbones. Oral Surg 6:159, 1953.
3. Whitaker SB, Waldron CA. Central giant cell lesions of the jaws. Oral Surg Oral Med Oral Pathol 95:199, 1993.
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4. de Lange, van den Akker HP, van den Berg H. Central giant cell granuloma of the jaw: a review of the literature with emphasis on therapy options. Oral Surg Oral Med Oral Pathol Endod 104:603, 2007.
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5. Terry BC, Jacoway JR. Management of central giant cell lesions: An alternative to surgical therapy. Oral Maxillofac Surg Clin N Am 6:579, 1994.
6. Harris M. Central giant cell granulomas of the jaws regress with calcitonin therapy. Br J Oral Maxillofac Surg 31:89, 1993.
7. Kaban LB, Troulis MJ, Wilkinson MS, Ebb D, Dodson TB. Adjuvant antiangiogenic therapy for giant
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cell tumors of the jaws. J Oral Maxillofac 65:2018, 2007.
8. Sinningen K, Tsourdi E, Rauner M, Rachner TD, Hamann C, Hofbauer LC. Skeletal and extraskeletal actions of Denosumab. Endocrine 42:52, 2012.
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9. Bo Lui, Shi-Feng Yu, Tie-Jun Li. Multinucleated giant cells in various forms of giant cell containing lesions of the jaws express features of osteoclasts. J Oral Pathol Med 32:367, 2003.
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10. Thomas D, Henshaw R, Skubitz K, Chawla S, Staddon A, Blay JY, Roudier M, Smith J, Ye Z, Sohn W, Dansey R, Jun S. Denosumab in patients with giant-cell tmour of bone: an open-label, phase 2 study. Lancet Oncol 11:275, 2010. 11. Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A, Khoo W, Wakeham A, Dunstan CR, Lacey DL, Mak TW, Boyle WJ, Penninger JM. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymphnode organogenesis. Nature 397:315, 1999. 12. Peddi P, Lopez-Olivo MA, Pratt GF, Suarez-Almazor ME. Denosumab in patients with cancer and skeletal metastases: A systematic review and meta-analysis. Cancer Treat Rev 39:97, 2013.
ACCEPTED MANUSCRIPT 13. Qi WX, Tang LN, He AN, Yao Y, Shen Z. Risk of osteonecrosis of the jaw in cancer patients receiving denosumab: a meta-analysis of seven randomized controlled trials. Int J Clin Oncol 2013 [Epub ahead
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