Accepted Manuscript Management of Central Giant Cell Granuloma with Subcutaneous Denosumab Therapy Aparna Naidu, DDS, MS Michael P. Malmquist, DMD Claude A. Denham, MD Sterling R. Schow, DMD PII:
S0278-2391(14)01115-X
DOI:
10.1016/j.joms.2014.06.456
Reference:
YJOMS 56396
To appear in:
Journal of Oral and Maxillofacial Surgery
Received Date: 2 May 2014 Revised Date:
13 June 2014
Accepted Date: 30 June 2014
Please cite this article as: Naidu A, , Malmquist MP, Denham CA, Schow SR, Management of Central Giant Cell Granuloma with Subcutaneous Denosumab Therapy, Journal of Oral and Maxillofacial Surgery (2014), doi: 10.1016/j.joms.2014.06.456. 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.
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Management of Central Giant Cell Granuloma with Subcutaneous Denosumab Therapy
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Aparna Naidu DDS, MS Assistant Professor, Department of Diagnostic Sciences Texas A&M University, Baylor College of Dentistry Dallas, Texas
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Michael P. Malmquist DMD Resident, Department of Oral and Maxillofacial Surgery Texas A&M University, Baylor College of Dentistry Baylor University Medical Center Dallas, Texas
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Claude A. Denham MD Department of Medical Oncology - Hematology Baylor Charles A. Sammons Cancer Center Baylor University Medical Center Dallas, Texas
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Sterling R. Schow DMD Professor, Department of Oral and Maxillofacial Surgery Texas A&M University, Baylor College of Dentistry Baylor University Medical Center Dallas, Texas
Corresponding author: Aparna Naidu, DDS, MS Department of Diagnostic Sciences Texas A&M University – Baylor College of Dentistry 3302 Gaston Ave. Rm 213D Dallas, TX 75246 [email protected] Phone: 214-828-8197 Fax: 214-828-8306
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Management of Central Giant Cell Granuloma with Subcutaneous Denosumab Therapy
ABSTRACT
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Purpose
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In recent years, the treatment of central giant cell granuloma has become focused on the inhibition of osteoclast differentiation and proliferation. Medications that were developed for the treatment of giant cell tumor of bone and bone resorption from metastatic skeletal disease have shown some success in the treatment of central giant cell granuloma. We report two cases of central giant cell granuloma of the mandible that were treated effectively with subcutaneous denosumab. Materials and Methods
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Two cases of histologically diagnosed central giant cell granuloma of the mandible were treated with monthly subcutaneous injections of 120 mg denosumab primarily or following intralesional corticosteroid therapy. Clinical and radiographic follow-up was recorded over a period of 24 months (Case #1) and 15 months (Case #2). Results
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In both cases, progressive radiodensity and osseous regeneration was noted 4-6 months after denosumab therapy was initiated. Decreased size of the lesion and improvement in bone contour and facial symmetry was seen in both cases. Conclusion
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The significant radiographic, clinical, and histologic response seen in these two cases suggests that denosumab may represent a viable alternative or adjunctive procedure to eliminate or reduce the extent of surgical intervention and morbidity in the treatment of CGCG. Future prospective studies with a larger sample size would provide more comprehensive information about the long-term effects, and possible adverse side effects of treating CGCG of the jaws with denosumab.
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INTRODUCTION
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Central giant cell granuloma of the jaws was first documented as “giant-cell reparative granuloma” by Jaffe in 1953 1. Jaffe sought to differentiate between these lesions and giant cell tumors that are seen mainly in the long bones of the skeleton. Giant cell tumors demonstrate relatively aggressive clinical behavior, high rates of recurrence and a potential for metastasis 2,3. While central giant cell granulomas (CGCGs) of the jaws have no significant malignant potential, they may be locally aggressive with a high recurrence rate, and produce cortical expansion, displacement of teeth, root resorption and sensory alteration 4,5. The term giant-cell reparative granuloma is seldom used today because it remains questionable that it represents a reparative process.
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Most cases of CGCG arise as a painless expansion of the alveolar bone, and may be first recognized as radiolucencies found on routine radiographic examination. Occasionally, pain, paresthesia or tooth displacement may be reported. Radiographically CGCG can be unilocular or multilocular, with a potential to reach 10cm or more, resorb adjacent tooth roots, and perforate cortical bone 6. A classification of aggressive and non-aggressive giant cell lesions, based on clinical and radiographic parameters, characterizes aggressive lesions as being greater than 5cm in size, showing rapid growth, tooth displacement, root resorption, recurrence and cortical perforation 7,8. Histologically, CGCG may resemble the aforementioned giant cell tumor of bone, aneurysmal bone cyst, brown tumor of hyperparathyroidism, and giant cell lesions of cherubism, which all contain multinucleated giant cells that are virtually identical to the multinucleated cells of CGCG. The multinucleated cells of giant cell tumor of bone contain antigenic properties and phenotypic markers that are similar to the mononuclear precursor cells that differentiate into osteoclasts 9,10,11. Giant cell tumor of bone is thought to have two cell populations, including both osteoclast-like giant cells and background stromal cells of osteoblastic origin 12. The tumor cells in CGCG and other giant cell lesions express immunohistochemical markers for macrophages and osteoclasts, which suggests they arise from mononuclear precursor cells of the granulocyte/macrophage lineage13,14,15.
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The most frequent treatment of CGCG is surgical curettage, which results in a recurrence rate of 11 to 49% 16,17,18,19. Surgical resection with 0.5cm margins is much more effective, resulting in a recurrence rate of 6% in one clinical study 18. However, complete surgical resection may significantly compromise esthetics and function in some cases. The overall recurrence rate was found to be 26.3% in the largest review of CGCG in the literature 5. The highest rates of recurrence are seen in tumors demonstrating aggressive clinical behavior, producing pain, paresthesia and root resorption 5. Intralesional corticosteroid injections were first introduced as a non-surgical alternative treatment for CGCG in 1988 20. Weekly corticosteroid injections resulted in complete resolution in 3 of 4 lesions over a period of 6 weeks in the first documented series of reported cases of CGCG treated in this manner 21. Steroids inhibit bone resorption and induce apoptosis of osteoclasts 22,23,24. While some cases of CGCG respond well to corticosteroid therapy, the results are inconsistent and highly variable. Marx and Stern reported that, in their experience, 65% of cases of CGCG treated with intralesional
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corticosteroids showed complete resolution, while 35% of cases either did not respond at all or behaved more aggressively, requiring either further curettage or resection 25. Recurrence most often was noted within 12-18 months after the initial treatment, and was correlated with the size of the lesion 25.
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The multinucleated giant cells in CGCG and giant cell tumor of bone are known to express calcitonin receptors, which is the basis for calcitonin therapy of CGCG 26,27. Calcitonin has been theorized to inhibit osteoclast function. Eight out of nine patients treated with subcutaneous calcitonin injections showed no reduction in lesion size after 6 months of therapy, but showed complete resolution after 18 months 28. There appears to be a variable number of calcitonin receptors on the giant cells of CGCG, with only 56% of lesions showing immunohistochemical positivity for calcitonin receptors, which explains why calcitonin therapy is not always effective 29.
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Interferon therapy is utilized in a number of conditions, including viral infections, neoplastic processes,and vascular proliferations. The efficacy of interferon is related to its suppression of fibroblast growth factors, which may slow angiogenesis in tumors. The idea that giant cell lesions of the jaws are proliferative vascular lesions that may respond to antiangiogenetic therapy was first proposed by Kaban et al 8. In this initial study, subcutaneous interferon-alpha was administered in patients with surgically treated aggressive giant cell lesions of the maxilla and mandible. Seven patients out of eight showed no recurrence after a mean follow-up period of 1.9 years. In a follow-up study of 26 cases, Kaban suggests that enucleation with preservation of vital structures and adjuvant interferon therapy is an effective strategy in managing aggressive giant cell lesions 30. Interferon also affects bone turnover by enhancing differentiation of mesenchymal stem cells into osteoblasts, and inhibiting osteoclast differentiation 31,32,33 . Interferon injections have led to slowing down growth of CGCG and decreasing tumor size, but total remission is not frequently seen, unless the interferon therapy is combined with surgical debulking of the tumor. Although there has been some degree of success in treating CGCG with interferon, there are potentially serious complications of interferon therapy, including the possibility of developing druginduced lupus erythematosus and pancreatitis 32.
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In recent years, treatment of giant cell tumor of bone and CGCG has become focused on the inhibition of osteoclast differentiation and proliferation. Medications that were developed for the treatment of bone resorption from metastatic skeletal disease have shown some success in the treatment of CGCG and giant cell tumor of bone 34,35. Bisphosphonates are known to affect bone resorption by their direct effect on osteoclasts. Once bound to bone mineral, bisphosphonates are released when the environment becomes acidic, such as in areas of osteoclastic resorption 36. Bisphosphonates have been fairly effective in reducing growth of CGCG and giant cell tumor of bone, significantly reducing the morbidity that may result from surgical treatment 34,35. More recently, denosumab (Xgeva®,Prolia®), a human monoclonal antibody directed at nuclear factor‑κB ligand (RANKL), has been utilized. RANKL is expressed on the surface of osteoblasts and stromal cells and binds to RANK on the surface of osteoclasts, contributing to osteoclast formation, differentiation and proliferation 37,38. The stromal cells of giant cell tumor have demonstrated the ability to secrete RANKL and upregulate osteoclast development 39. Denosumab binds to RANKL and inhibits this process, resulting in decreased differentiation and resorptive function of osteoclasts 37,38. A possible
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complication is the development of osteonecrosis of the jaws, which has been seen in 1.1-10.0 % of cancer patients treated with either bisphosphonates or denosumab 40,41,42.
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Recent phase II clinical trials showed that denosumab reduced the need for morbid surgery in patients with giant cell tumor of bone and may represent a viable new treatment option 43,44. We report two cases of CGCG of the mandible that were treated with subcutaneous denosumab and discuss the potential benefits and possible complications of this recently recognized therapeutic agent. MATERIALS AND METHODS
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Case #1
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A 9-year-old female was referred to the Department of Oral and Maxillofacial Surgery at Texas A&M University, Baylor College of Dentistry for evaluation of an expansile lesion of the anterior mandible. The duration of the lesion was unknown, but was first noted by her parents two months prior to seeking evaluation. The lesion was not tender to palpation and no lymphadenopathy was detected. The overlying mucosa was within normal limits and there were no signs of ulceration. The anterior mandible was grossly expanded bucco-lingually from the inferior border to the alveolar crest, producing notable facial asymmetry and displacement of the chin to the right side (Figure 1). Gross mobility, displacement of the anterior mandibular dentition and malocclusion were noted (Figure 2). A conebeam computerized tomography (CBCT) scan was acquired, which demonstrated a 10 cm x 4 cm multilocular radiolucency extending from the left first mandibular premolar to the developing right second mandibular premolar (Figures 3A and 3B). Superior-inferior and buccal-lingual expansion was seen.
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An incisional biopsy was performed of the right mandible and submitted for histopathologic evaluation, resulting in a diagnosis of central giant cell granuloma (Figure 4). Subsequent serum testing showed that serum calcium, alkaline phosphatase, phosphorus, and parathyroid hormone levels were within normal ranges. A pediatric oncologist and pediatric endocrinologist were also consulted, and it was agreed that medical therapy might be beneficial to avoid or minimize the extent of a surgical procedure to treat the lesion. Medical therapy with calcitonin, bisphosphonates, interferon, and denosumab were all considered and informed consent was obtained to begin denosumab therapy. Initially, loading doses of Denosumab (Xgeva®) were administered subcutaneously on the 8th and 15th of the first month of treatment. This was followed by monthly doses of 120 mg, based on findings of the phase-II clinical trial by Thomas et al (2010) 43.
Case #2 A 42-year –old female presented to her general dentist with sporadic pain and paresthesia of the left posterior mandible. Her past medical history was significant for type II diabetes mellitus, essential hypertension and gastroesophageal reflux disease. She was taking metformin and lisinopril.
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She noticed swelling of the left mandible that had developed 1 week prior to seeking treatment. Her general dentist noted a large radiolucency of the left posterior mandible and she was referred to the Department of Oral and Maxillofacial Surgery at Texas A&M University, Baylor College of Dentistry for evaluation. A CBCT scan demonstrated a 4cm x 5cm x 5cm multilocular expansile radiolucency of the mandibular angle and ramus extending to the sigmoid notch and condyle (Figures 5A and 5B). The margins were thin and scalloped with internal septae and calcifications noted within the lesion. The left second mandibular molar was displaced mesially and superiorly and facial asymmetry was noted. An incisional biopsy revealed a central giant cell lesion, compatible with central giant cell granuloma or brown tumor of parathyroidism (Figure 6). Laboratory values for calcium, albumin, and parathyroid hormone were within a normal range, and a diagnosis of central giant cell granuloma was made.
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The patient was presented with options for treatment, including surgical resection, curettage, and medical therapy with intralesional steroids, bisphosphonates, calcitonin, interferon, or denosumab. A medical oncologist was also consulted. In order to avoid a resection with disarticulation of the left mandible, intralesional steroid injections were initiated and subcutaneous denosumab therapy was planned. Sixty milligrams of triamcinolone (Kenalog®-10 Injection) were diluted into 6mL, and multiple areas of lesion were entered and injected. The patient received 4 doses of intralesional triamcinolone in 5 weeks. On week 6, the surgeon was unable to inject intralesionally because of resistance to needle penetration. Monthly subcutaneous injections of 120mg denosumab (Xgeva®) were concurrently initiated and triamcinolone injections were discontinued. The patient was given calcium and vitamin D supplementation and laboratory testing was performed at each monthly treatment.
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This retrospective report of two cases was approved by the corresponding institution as being exempt from review by the Institutional Review Board.
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Case #1
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RESULTS
After 6 months of denosumab therapy, a CBCT scan was repeated and the internal characteristics of the lesion had changed from mostly radiolucent to a diffuse radiopacity, when compared to the previous CBCT (Figures 7A and 7B). After 10 monthly doses of denosumab, the facial asymmetry had significantly decreased and the teeth in the area showed decreased mobility. The size of the lesion and associated buccal and lingual cortical expansion had decreased. At each visit, a complete blood count (CBC) was performed and a basic metabolic panel was performed. She was given calcium and vitamin D supplementation throughout her treatment. After 18 months of denosumab treatment, a CBCT scan showed markedly increased radiodensity of the right anterior mandible (Figure 8). The teeth had become stabilized, and the alignment had
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improved. Denosumab therapy was discontinued at that time due to the development of hypercalcemia. Her serum calcium had risen to 10.7 mg/dL towards the end of her treatment, but subsequently decreased to 10.3 mg/dL within 6 months. An incisional biopsy was performed, and it was noted intraoperatively that the lesional area was filled with new spongy bone. There was no clinical evidence of granulation tissue or residual soft tissue pathology. Histopathologic evaluation revealed viable bone and fatty marrow with mild chronic inflammation (Figure 9). No residual central giant cell granuloma was seen.
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A CBCT scan was repeated in six months (2 years after the initial diagnosis), which demonstrated improving radiodensity of most of the lesion, with one focal area of decreased density near the facial cortical border inferior to the incisors (Figure 10). An incisional biopsy revealed residual central giant cell granuloma in this area. A CBCT 4 months later showed evidence of osseous regeneration and the lesion appeared to remain stable. Her mandibular asymmetry had continued to resolve and the stability and alignment of the teeth had improved (Figure 11A and 11B). Orthodontic treatment is being considered for the future and follow-up CBCT scans are planned at 6 month intervals.
Case #2
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After 4 months of denosumab therapy, a CBCT scan revealed considerable shrinkage in size of the lesion and a dramatic increase in radiodensity (Figure 12). The patient no longer complained of pain or paresthesia and her facial asymmetry had improved. The radiodensity continued to improve at 6 months. After 9 months of denosumab therapy, external asymmetry was no longer present and an incisional biopsy was performed to evaluate for osseous regeneration and possible residual lesion. Histopathologic evaluation revealed viable bone and marrow fibrosis with no residual giant cell granuloma (Figure 13). At that time the denosumab treatment was discontinued. A CBCT scan was taken 6 months later (15 months after the initial diagnosis), which showed continued resolution with decrease in size of the lesion and improvement in contour of the left mandible (Figure 14A and 14B). The patient had no functional limitations at that time. She will continue to be followed at 6 month intervals.
DISCUSSION
Denosumab was initially developed for use in patients with early and advanced-stage cancer, as well as for the treatment of osteoporosis. The goals of denosumab therapy are to prevent progressive bone loss and reduce fragility fractures. Inhibition of RANKL both reduces the rate of osteoclastic
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resorption and inhibits the development of osteolytic bone metastases 38,45. Multiple Phase III studies have suggested that denosumab is more effective than the bisphosphonate, zoledronic acid, in treating patients with skeletal metastases from breast cancer, prostate cancer and multiple myeloma 46,47,48. These studies compared the effects of 120mg subcutaneous denosumab to 4mg intravenous zoledronate administered every 4 weeks, and showed that denosumab suppressed bone resorption more significantly than zoledronic acid.
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The antiresorptive effects of bisphosphonates and denosumab result in a decrease in bone resorption and subsequent decrease in bone turnover markers, such as cross-linked C-telopeptide of type I collagen (CTX), cross-linked N-telopeptide of type I collagen (NTX) and bone alkaline phosphatase 49 . The result is increased bone mineral density, which occurs more rapidly and to a greater extent with denosumab when compared to bisphosphonates 50. In contrast to bisphosphonates, which bind to mineralized bone matrix, denosumab blocks the receptor-mediated activation of osteoclasts and has no affinity for bone matrix. A major difference between denosumab and bisphosphonates is that most of the antiresorptive effects of denosumab should dissipate within 6 months of stopping the drug 51. Bisphosphonates are deposited in bone and accumulate with a potential half-life greater than ten years.
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After 6 months of denosumab treatment, bone turnover markers start to increase and return to baseline 52. The inhibition of osteoclast mediated bone resorption by denosumab is based on the reversible binding of the drug to RANKL on osteoblasts and precursor stromal cells 53. A recent position paper published by the American Academy of Oral and Maxillofacial Surgeons specifically addressing medication-related osteonecrosis of the jaws (MRONJ) emphasizes that, in contrast to bisphosphonates, RANK ligand inhibitors like denosumab do not bind to bone and their effects on bone remodeling are mostly diminished within 6 months of treatment cessation 51.
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Some of the adverse effects of denosumab therapy include urinary tract infection, upper respiratory tract infection, dyspnea, sciatica, cataracts, constipation diarrhea, rash, hyperhidrosis, pain in extremities, hypocalcemia, hypophosphatemia, and osteonecrosis of the jaw. The aforementioned Phase III studies of skeletal metastases indicated an average incidence of osteonecrosis of the jaw was 1.8% with denosumab and 1.3% with zoledronic acid 46,47,48,54. Twenty percent of patients treated with zoledronic acid develop acute-phase reactions resulting in fever, myalgia, and bone pain within the first 3 days of treatment, and only 8.7% of patients treated with denosumab experienced such reactions. Hypocalcemia was more frequent with denosumab (9.6%) than with zoledronic acid (5.0%). When bisphosphonates have been utilized in the medical management of giant cell tumor of bone, the local recurrence rate was 4.2% compared to 30% in a control group in a case controlled study 55 . As an alternative to bisphosphonates, and because denosumab is known to inhibit osteoclast function via the RANK/RANKL pathway, its inhibition of the osteoclast-like giant cells in giant cell tumor of bone has been evaluated in two Phase II clinical studies funded by Amgen 43,44. In the first open-label study, a single group of 37 individuals with unresectable giant cell tumor received 120 mg subcutaneous denosumab every 4 weeks with loading doses on days 8 and 15 of the first month 43. Tumor response was assessed through radiographic evaluation and histologic analysis and defined to be the elimination of either 90% or more of giant cells or no radiological progression of the lesion up to week 25. Eighty-six
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percent of cases resulted in a positive tumor response. The most common adverse event reported was pain in an extremity (18%), followed by back pain (11%) and headache (11%). The authors of the study acknowledged that the therapeutic effects of denosumab could have been confounded by previous treatments with chemotherapy, radiation therapy, bisphosphonate therapy, or surgery 43.
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In the second open-label study, 282 patients in parallel groups with giant cell tumors in long bones were studied over a period of 6 months 44. The cohorts included both surgically unsalvageable giant cell tumors and those determined to be salvageable with surgery, but that would result in severe morbidity 44. Patients received 120 mg of subcutaneous denosumab every 4 weeks with initial loading doses on days 8 and 15 of the first cycle. The investigators reported that 96% of patients with surgically unsalvageable giant cell tumors had no disease progression after a median follow-up time of 13 months. In cases of giant cell tumor that were surgically salvageable, 74% of patients required no surgery and 62% of patients who had surgery underwent a less morbid procedure than planned. The median followup in cohort 2 was 9.2 months. Adverse events during the course of therapy included osteonecrosis of the jaws (1%), hypocalcemia (5%), hypophosphatemia (3%), and anemia, back pain, and pain in extremities, each of which occurred in 1% of patients 44.
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To date, there have been no published prospective clinical studies of denosumab therapy in patients with CGCG of the jaws. Because the neoplastic cells of giant cell tumor and CGCG have shown similar antigenic and phenotypic characteristics, equivalent therapeutic alternatives to surgical intervention have been developed for both lesions. Both cases of CGCG we are reporting had aggressive clinical and radiographic characteristics with respect to size, rapid growth, symptoms and tooth displacement (Chuong 1986). Clinical follow-up information was available for 24 months (Case #1) and 15 months (Case #2) and is ongoing at this time. In both cases, progressive radiodensity and osseous regeneration was noted after denosumab therapy was initiated, even in the presence of an adjacent focus of residual CGCG seen in Case #1. The dramatic response to denosumab therapy in Case #2 may have been potentiated by the previous intralesional injections of triamcinolone. The patient continued to have acute symptoms and compliance problems with the initial intralesional steroid injections. Prolonged and overall effective results were seen after subcutaneous denosumab injections were initiated and the patient was able to continue without complications.
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The significant radiographic, clinical, and histologic response seen in these two cases suggests that denosumab may represent a viable alternative or adjunctive procedure to eliminate or reduce the extent of surgical intervention and morbidity in the treatment of CGCG. Future prospective studies with a larger sample size would provide more comprehensive information about the long-term effects, and possible adverse side effects of treating CGCG of the jaws with denosumab.
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36. Van Beek ER, Lowik CW, Ebetino FH, Papapoulos SE. Binding and antiresorptive properties of heterocycle-containing bisphosphonate analogs: structureactivity relationships. Bone 1998; 23: 437-442. 37. Castellano D, Sepulveda JM, García-Escobar I, et al. The role of RANK-ligand inhibition in cancer: the story of denosumab. Oncologist. 2011;16(2):136-45. 38. Brown JE, Coleman RE. Denosumab in patients with cancer—a surgical strike against the osteoclast. Nat Rev Clin Oncol 2012;9, 110–118. 39. Huang L, Xu J, Wood DJ, et al. Gene expression of osteoprotegerin ligand, osteoprotegerin, and receptor activator of NF-κB in giant cell tumor of bone: Possible involvement in tumor cellinduced osteoclast-like cell formation. Am J Pathol 2000;156(3): 761-767. 40. Stopeck A, Body JJ, Fujiwara Y, et al. Denosumab versus zoledronic acid for the treatment of breast cancer patients with bone metastases: results of a randomized phase 3 study. Eur J Cancer Suppl 2009; 7: 2–3. 41. Henry D, von Moos R, Vadhan-Raj S, et al. A double-blind, randomized study of denosumab versus zoledronic acid for the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. Eur J Cancer Suppl 2009; 7: 12. 42. Khosla S, Burr D, Cauley J, et al. Bisphosphonate-Associated Osteonecrosis of the Jaw: Report of a Task Force of the American Society for Bone and Mineral Research Bone Miner Res 2007;22:1479–1491. 43. Thomas D, Henshaw R, Skubitz K, et al. Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study. Lancet Oncol 2010; 11: 275–80. 44. Chawla S, Henshaw R, Seeger L, et al. Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallelgroup, phase 2 study. Lancet Oncol. 2013 Aug;14(9):901-8. 45. Kitazawa S, Kitazawa R. RANK ligand is a prerequisite for cancer-associated osteolytic lesions. J Pathol 2002;198:228–236. 46. Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, doubleblind study. J Clin Oncol 2010;28:5132–9. 47. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, doubleblind study. Lancet 2011;377: 813–22. 48. Henry DH, Costa L, Goldwasser F, et al. Randomized, doubleblind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 2011;29:1125–32. 49. Miller PD, Bolognese MA, Lewiecki EM, et al. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone. 2008 Aug;43(2):222-9. 50. Brown JP, Prince RL, Deal C, et al. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res. 2009 Jan;24(1):153-61.
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51. American Association of Oral and Maxillofacial Surgeons. Medication-Related Osteonecrosis of the Jaw – 2014 Update. http://www.aaoms.org/docs/position_papers/mronj_position_paper.pdf?pdf=MRONJ-PositionPaper. Accessed April 21, 2014. 52. Papapoulos S, Chapurlat R, Libanati C, et al. Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension. J Bone Miner Res. 2012 Mar;27(3):694-701. 53. Delmas PD. Clinical potential of RANKL inhibition for the management of postmenopausal osteoporosis and other metabolic bone diseases. J Clin Densitom. 2008 Apr-Jun;11(2):325-38. 54. Lipton A, Siena S, Rader M, et al. Comparison of denosumab versus zoledronic acid (za) for treatment of bone metastases in advanced cancer patients: an integrated analysis of 3 pivotal trials [abstract 1249P]. Ann Oncol 2010;21(suppl 8):viii380. 55. Tse LF, Wong KC, Kumta SM, et al. Bisphosphonates reduce local recurrence in extremity giant cell tumor of bone: a case–control study. Bone 2008;42:68–73.
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FIGURE LEGENDS Figure 1: Case #1: Patient photograph at initial presentation. Frontal view shows the facial asymmetry and chin displacement to the right side.
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Figure 2: Case #1: Intraoral photograph showing labial and lingual expansion and displacement of the anterior mandibular teeth. Figure 3A: Case #1: Cone beam computerized tomographic (CBCT) image of a multilocular radiolucency extending from the left first mandibular premolar to the developing right second mandibular premolar.
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Figure 3B: Case #1: Axial computed tomograph showing the multilocular lesion. Significant superior-inferior and buccal-lingual expansion was noted.
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Figure 4: Case #1: High power photomicrograph of a proliferation of multinucleated giant cells in a cellular background stroma containing numerous extravasated erythrocytes. Hematoxylin and eosin stain. 200x original magnification. Figure 5A: Case #2: CBCT image of a multilocular expansile radiolucency of the mandibular angle and ramus extending to the sigmoid notch and condyle.
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Figure 5B: Case #2: Axial computed tomograph showing buccal and lingual cortical expansion. The margins of the lesion were thin and scalloped with internal septae and calcifications noted centrally. Figure 6: Case #2: High power photomicrograph of a central giant cell lesion. Hematoxylin and eosin stain. 200x original magnification. Figure 7A: Case #1: CBCT image after 6 months subcutaneous denosumab therapy.
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Figure 7B: Case #1: Axial computed tomograph after 6 months subcutaneous denosumab therapy demonstrating a diffuse radiopacity within the lesion.
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Figure 8: Case #1: CBCT image 18 months of denosumab therapy showing increased radiodensity of the anterior mandibular lesion. Figure 9: Case #1: Low power photomicrograph shows new viable trabecular bone formation with fatty marrow. Numerous osteocytes are present. Hematoxylin and eosin stain. 100x original magnification. Figure 10: Case #1: Axial computed tomograph 24 months after the initial diagnosis demonstrating increased radiodensity throughout most of the lesion, with one focal area of decreased density near the facial cortical border inferior to the incisors. Figure 11A: Case #1: Patient photograph 28 months after initial diagnosis. Frontal view shows siginificant resolution of the mandibular asymmetry.
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Figure 11B: Case #1: Intraoral photograph 28 months after initial diagnosis showing improved alignment of the mandibular teeth and diminished bucco-lingual expansion. Figure 12: Case #2: After 4 months of denosumab therapy, CBCT image shows dramatic increase in radiodensity and decreased size of the lesion.
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Figure 13: Case #2: Low power photomicrograph after 9 months of denosumab therapy demonstrates mature lamellar bone with osteocytes present in the lacunae. Hematoxylin and eosin stain. 100x original magnification.
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Figure 14A and 14B: Case #2: 15 months after the initial diagnosis, CBCT images show continued resolution with decrease in size of the lesion and improvement in contour of the left mandible.
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S0278-2391(14)01115-X
DOI:
10.1016/j.joms.2014.06.456
Reference:
YJOMS 56396
To appear in:
Journal of Oral and Maxillofacial Surgery
Received Date: 2 May 2014 Revised Date:
13 June 2014
Accepted Date: 30 June 2014
Please cite this article as: Naidu A, , Malmquist MP, Denham CA, Schow SR, Management of Central Giant Cell Granuloma with Subcutaneous Denosumab Therapy, Journal of Oral and Maxillofacial Surgery (2014), doi: 10.1016/j.joms.2014.06.456. 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.
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Management of Central Giant Cell Granuloma with Subcutaneous Denosumab Therapy
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Aparna Naidu DDS, MS Assistant Professor, Department of Diagnostic Sciences Texas A&M University, Baylor College of Dentistry Dallas, Texas
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Michael P. Malmquist DMD Resident, Department of Oral and Maxillofacial Surgery Texas A&M University, Baylor College of Dentistry Baylor University Medical Center Dallas, Texas
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Claude A. Denham MD Department of Medical Oncology - Hematology Baylor Charles A. Sammons Cancer Center Baylor University Medical Center Dallas, Texas
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Sterling R. Schow DMD Professor, Department of Oral and Maxillofacial Surgery Texas A&M University, Baylor College of Dentistry Baylor University Medical Center Dallas, Texas
Corresponding author: Aparna Naidu, DDS, MS Department of Diagnostic Sciences Texas A&M University – Baylor College of Dentistry 3302 Gaston Ave. Rm 213D Dallas, TX 75246 [email protected] Phone: 214-828-8197 Fax: 214-828-8306
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Management of Central Giant Cell Granuloma with Subcutaneous Denosumab Therapy
ABSTRACT
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Purpose
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In recent years, the treatment of central giant cell granuloma has become focused on the inhibition of osteoclast differentiation and proliferation. Medications that were developed for the treatment of giant cell tumor of bone and bone resorption from metastatic skeletal disease have shown some success in the treatment of central giant cell granuloma. We report two cases of central giant cell granuloma of the mandible that were treated effectively with subcutaneous denosumab. Materials and Methods
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Two cases of histologically diagnosed central giant cell granuloma of the mandible were treated with monthly subcutaneous injections of 120 mg denosumab primarily or following intralesional corticosteroid therapy. Clinical and radiographic follow-up was recorded over a period of 24 months (Case #1) and 15 months (Case #2). Results
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In both cases, progressive radiodensity and osseous regeneration was noted 4-6 months after denosumab therapy was initiated. Decreased size of the lesion and improvement in bone contour and facial symmetry was seen in both cases. Conclusion
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The significant radiographic, clinical, and histologic response seen in these two cases suggests that denosumab may represent a viable alternative or adjunctive procedure to eliminate or reduce the extent of surgical intervention and morbidity in the treatment of CGCG. Future prospective studies with a larger sample size would provide more comprehensive information about the long-term effects, and possible adverse side effects of treating CGCG of the jaws with denosumab.
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INTRODUCTION
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Central giant cell granuloma of the jaws was first documented as “giant-cell reparative granuloma” by Jaffe in 1953 1. Jaffe sought to differentiate between these lesions and giant cell tumors that are seen mainly in the long bones of the skeleton. Giant cell tumors demonstrate relatively aggressive clinical behavior, high rates of recurrence and a potential for metastasis 2,3. While central giant cell granulomas (CGCGs) of the jaws have no significant malignant potential, they may be locally aggressive with a high recurrence rate, and produce cortical expansion, displacement of teeth, root resorption and sensory alteration 4,5. The term giant-cell reparative granuloma is seldom used today because it remains questionable that it represents a reparative process.
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Most cases of CGCG arise as a painless expansion of the alveolar bone, and may be first recognized as radiolucencies found on routine radiographic examination. Occasionally, pain, paresthesia or tooth displacement may be reported. Radiographically CGCG can be unilocular or multilocular, with a potential to reach 10cm or more, resorb adjacent tooth roots, and perforate cortical bone 6. A classification of aggressive and non-aggressive giant cell lesions, based on clinical and radiographic parameters, characterizes aggressive lesions as being greater than 5cm in size, showing rapid growth, tooth displacement, root resorption, recurrence and cortical perforation 7,8. Histologically, CGCG may resemble the aforementioned giant cell tumor of bone, aneurysmal bone cyst, brown tumor of hyperparathyroidism, and giant cell lesions of cherubism, which all contain multinucleated giant cells that are virtually identical to the multinucleated cells of CGCG. The multinucleated cells of giant cell tumor of bone contain antigenic properties and phenotypic markers that are similar to the mononuclear precursor cells that differentiate into osteoclasts 9,10,11. Giant cell tumor of bone is thought to have two cell populations, including both osteoclast-like giant cells and background stromal cells of osteoblastic origin 12. The tumor cells in CGCG and other giant cell lesions express immunohistochemical markers for macrophages and osteoclasts, which suggests they arise from mononuclear precursor cells of the granulocyte/macrophage lineage13,14,15.
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The most frequent treatment of CGCG is surgical curettage, which results in a recurrence rate of 11 to 49% 16,17,18,19. Surgical resection with 0.5cm margins is much more effective, resulting in a recurrence rate of 6% in one clinical study 18. However, complete surgical resection may significantly compromise esthetics and function in some cases. The overall recurrence rate was found to be 26.3% in the largest review of CGCG in the literature 5. The highest rates of recurrence are seen in tumors demonstrating aggressive clinical behavior, producing pain, paresthesia and root resorption 5. Intralesional corticosteroid injections were first introduced as a non-surgical alternative treatment for CGCG in 1988 20. Weekly corticosteroid injections resulted in complete resolution in 3 of 4 lesions over a period of 6 weeks in the first documented series of reported cases of CGCG treated in this manner 21. Steroids inhibit bone resorption and induce apoptosis of osteoclasts 22,23,24. While some cases of CGCG respond well to corticosteroid therapy, the results are inconsistent and highly variable. Marx and Stern reported that, in their experience, 65% of cases of CGCG treated with intralesional
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corticosteroids showed complete resolution, while 35% of cases either did not respond at all or behaved more aggressively, requiring either further curettage or resection 25. Recurrence most often was noted within 12-18 months after the initial treatment, and was correlated with the size of the lesion 25.
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The multinucleated giant cells in CGCG and giant cell tumor of bone are known to express calcitonin receptors, which is the basis for calcitonin therapy of CGCG 26,27. Calcitonin has been theorized to inhibit osteoclast function. Eight out of nine patients treated with subcutaneous calcitonin injections showed no reduction in lesion size after 6 months of therapy, but showed complete resolution after 18 months 28. There appears to be a variable number of calcitonin receptors on the giant cells of CGCG, with only 56% of lesions showing immunohistochemical positivity for calcitonin receptors, which explains why calcitonin therapy is not always effective 29.
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Interferon therapy is utilized in a number of conditions, including viral infections, neoplastic processes,and vascular proliferations. The efficacy of interferon is related to its suppression of fibroblast growth factors, which may slow angiogenesis in tumors. The idea that giant cell lesions of the jaws are proliferative vascular lesions that may respond to antiangiogenetic therapy was first proposed by Kaban et al 8. In this initial study, subcutaneous interferon-alpha was administered in patients with surgically treated aggressive giant cell lesions of the maxilla and mandible. Seven patients out of eight showed no recurrence after a mean follow-up period of 1.9 years. In a follow-up study of 26 cases, Kaban suggests that enucleation with preservation of vital structures and adjuvant interferon therapy is an effective strategy in managing aggressive giant cell lesions 30. Interferon also affects bone turnover by enhancing differentiation of mesenchymal stem cells into osteoblasts, and inhibiting osteoclast differentiation 31,32,33 . Interferon injections have led to slowing down growth of CGCG and decreasing tumor size, but total remission is not frequently seen, unless the interferon therapy is combined with surgical debulking of the tumor. Although there has been some degree of success in treating CGCG with interferon, there are potentially serious complications of interferon therapy, including the possibility of developing druginduced lupus erythematosus and pancreatitis 32.
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In recent years, treatment of giant cell tumor of bone and CGCG has become focused on the inhibition of osteoclast differentiation and proliferation. Medications that were developed for the treatment of bone resorption from metastatic skeletal disease have shown some success in the treatment of CGCG and giant cell tumor of bone 34,35. Bisphosphonates are known to affect bone resorption by their direct effect on osteoclasts. Once bound to bone mineral, bisphosphonates are released when the environment becomes acidic, such as in areas of osteoclastic resorption 36. Bisphosphonates have been fairly effective in reducing growth of CGCG and giant cell tumor of bone, significantly reducing the morbidity that may result from surgical treatment 34,35. More recently, denosumab (Xgeva®,Prolia®), a human monoclonal antibody directed at nuclear factor‑κB ligand (RANKL), has been utilized. RANKL is expressed on the surface of osteoblasts and stromal cells and binds to RANK on the surface of osteoclasts, contributing to osteoclast formation, differentiation and proliferation 37,38. The stromal cells of giant cell tumor have demonstrated the ability to secrete RANKL and upregulate osteoclast development 39. Denosumab binds to RANKL and inhibits this process, resulting in decreased differentiation and resorptive function of osteoclasts 37,38. A possible
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complication is the development of osteonecrosis of the jaws, which has been seen in 1.1-10.0 % of cancer patients treated with either bisphosphonates or denosumab 40,41,42.
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Recent phase II clinical trials showed that denosumab reduced the need for morbid surgery in patients with giant cell tumor of bone and may represent a viable new treatment option 43,44. We report two cases of CGCG of the mandible that were treated with subcutaneous denosumab and discuss the potential benefits and possible complications of this recently recognized therapeutic agent. MATERIALS AND METHODS
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Case #1
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A 9-year-old female was referred to the Department of Oral and Maxillofacial Surgery at Texas A&M University, Baylor College of Dentistry for evaluation of an expansile lesion of the anterior mandible. The duration of the lesion was unknown, but was first noted by her parents two months prior to seeking evaluation. The lesion was not tender to palpation and no lymphadenopathy was detected. The overlying mucosa was within normal limits and there were no signs of ulceration. The anterior mandible was grossly expanded bucco-lingually from the inferior border to the alveolar crest, producing notable facial asymmetry and displacement of the chin to the right side (Figure 1). Gross mobility, displacement of the anterior mandibular dentition and malocclusion were noted (Figure 2). A conebeam computerized tomography (CBCT) scan was acquired, which demonstrated a 10 cm x 4 cm multilocular radiolucency extending from the left first mandibular premolar to the developing right second mandibular premolar (Figures 3A and 3B). Superior-inferior and buccal-lingual expansion was seen.
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An incisional biopsy was performed of the right mandible and submitted for histopathologic evaluation, resulting in a diagnosis of central giant cell granuloma (Figure 4). Subsequent serum testing showed that serum calcium, alkaline phosphatase, phosphorus, and parathyroid hormone levels were within normal ranges. A pediatric oncologist and pediatric endocrinologist were also consulted, and it was agreed that medical therapy might be beneficial to avoid or minimize the extent of a surgical procedure to treat the lesion. Medical therapy with calcitonin, bisphosphonates, interferon, and denosumab were all considered and informed consent was obtained to begin denosumab therapy. Initially, loading doses of Denosumab (Xgeva®) were administered subcutaneously on the 8th and 15th of the first month of treatment. This was followed by monthly doses of 120 mg, based on findings of the phase-II clinical trial by Thomas et al (2010) 43.
Case #2 A 42-year –old female presented to her general dentist with sporadic pain and paresthesia of the left posterior mandible. Her past medical history was significant for type II diabetes mellitus, essential hypertension and gastroesophageal reflux disease. She was taking metformin and lisinopril.
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She noticed swelling of the left mandible that had developed 1 week prior to seeking treatment. Her general dentist noted a large radiolucency of the left posterior mandible and she was referred to the Department of Oral and Maxillofacial Surgery at Texas A&M University, Baylor College of Dentistry for evaluation. A CBCT scan demonstrated a 4cm x 5cm x 5cm multilocular expansile radiolucency of the mandibular angle and ramus extending to the sigmoid notch and condyle (Figures 5A and 5B). The margins were thin and scalloped with internal septae and calcifications noted within the lesion. The left second mandibular molar was displaced mesially and superiorly and facial asymmetry was noted. An incisional biopsy revealed a central giant cell lesion, compatible with central giant cell granuloma or brown tumor of parathyroidism (Figure 6). Laboratory values for calcium, albumin, and parathyroid hormone were within a normal range, and a diagnosis of central giant cell granuloma was made.
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The patient was presented with options for treatment, including surgical resection, curettage, and medical therapy with intralesional steroids, bisphosphonates, calcitonin, interferon, or denosumab. A medical oncologist was also consulted. In order to avoid a resection with disarticulation of the left mandible, intralesional steroid injections were initiated and subcutaneous denosumab therapy was planned. Sixty milligrams of triamcinolone (Kenalog®-10 Injection) were diluted into 6mL, and multiple areas of lesion were entered and injected. The patient received 4 doses of intralesional triamcinolone in 5 weeks. On week 6, the surgeon was unable to inject intralesionally because of resistance to needle penetration. Monthly subcutaneous injections of 120mg denosumab (Xgeva®) were concurrently initiated and triamcinolone injections were discontinued. The patient was given calcium and vitamin D supplementation and laboratory testing was performed at each monthly treatment.
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This retrospective report of two cases was approved by the corresponding institution as being exempt from review by the Institutional Review Board.
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RESULTS
After 6 months of denosumab therapy, a CBCT scan was repeated and the internal characteristics of the lesion had changed from mostly radiolucent to a diffuse radiopacity, when compared to the previous CBCT (Figures 7A and 7B). After 10 monthly doses of denosumab, the facial asymmetry had significantly decreased and the teeth in the area showed decreased mobility. The size of the lesion and associated buccal and lingual cortical expansion had decreased. At each visit, a complete blood count (CBC) was performed and a basic metabolic panel was performed. She was given calcium and vitamin D supplementation throughout her treatment. After 18 months of denosumab treatment, a CBCT scan showed markedly increased radiodensity of the right anterior mandible (Figure 8). The teeth had become stabilized, and the alignment had
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improved. Denosumab therapy was discontinued at that time due to the development of hypercalcemia. Her serum calcium had risen to 10.7 mg/dL towards the end of her treatment, but subsequently decreased to 10.3 mg/dL within 6 months. An incisional biopsy was performed, and it was noted intraoperatively that the lesional area was filled with new spongy bone. There was no clinical evidence of granulation tissue or residual soft tissue pathology. Histopathologic evaluation revealed viable bone and fatty marrow with mild chronic inflammation (Figure 9). No residual central giant cell granuloma was seen.
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A CBCT scan was repeated in six months (2 years after the initial diagnosis), which demonstrated improving radiodensity of most of the lesion, with one focal area of decreased density near the facial cortical border inferior to the incisors (Figure 10). An incisional biopsy revealed residual central giant cell granuloma in this area. A CBCT 4 months later showed evidence of osseous regeneration and the lesion appeared to remain stable. Her mandibular asymmetry had continued to resolve and the stability and alignment of the teeth had improved (Figure 11A and 11B). Orthodontic treatment is being considered for the future and follow-up CBCT scans are planned at 6 month intervals.
Case #2
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After 4 months of denosumab therapy, a CBCT scan revealed considerable shrinkage in size of the lesion and a dramatic increase in radiodensity (Figure 12). The patient no longer complained of pain or paresthesia and her facial asymmetry had improved. The radiodensity continued to improve at 6 months. After 9 months of denosumab therapy, external asymmetry was no longer present and an incisional biopsy was performed to evaluate for osseous regeneration and possible residual lesion. Histopathologic evaluation revealed viable bone and marrow fibrosis with no residual giant cell granuloma (Figure 13). At that time the denosumab treatment was discontinued. A CBCT scan was taken 6 months later (15 months after the initial diagnosis), which showed continued resolution with decrease in size of the lesion and improvement in contour of the left mandible (Figure 14A and 14B). The patient had no functional limitations at that time. She will continue to be followed at 6 month intervals.
DISCUSSION
Denosumab was initially developed for use in patients with early and advanced-stage cancer, as well as for the treatment of osteoporosis. The goals of denosumab therapy are to prevent progressive bone loss and reduce fragility fractures. Inhibition of RANKL both reduces the rate of osteoclastic
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resorption and inhibits the development of osteolytic bone metastases 38,45. Multiple Phase III studies have suggested that denosumab is more effective than the bisphosphonate, zoledronic acid, in treating patients with skeletal metastases from breast cancer, prostate cancer and multiple myeloma 46,47,48. These studies compared the effects of 120mg subcutaneous denosumab to 4mg intravenous zoledronate administered every 4 weeks, and showed that denosumab suppressed bone resorption more significantly than zoledronic acid.
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The antiresorptive effects of bisphosphonates and denosumab result in a decrease in bone resorption and subsequent decrease in bone turnover markers, such as cross-linked C-telopeptide of type I collagen (CTX), cross-linked N-telopeptide of type I collagen (NTX) and bone alkaline phosphatase 49 . The result is increased bone mineral density, which occurs more rapidly and to a greater extent with denosumab when compared to bisphosphonates 50. In contrast to bisphosphonates, which bind to mineralized bone matrix, denosumab blocks the receptor-mediated activation of osteoclasts and has no affinity for bone matrix. A major difference between denosumab and bisphosphonates is that most of the antiresorptive effects of denosumab should dissipate within 6 months of stopping the drug 51. Bisphosphonates are deposited in bone and accumulate with a potential half-life greater than ten years.
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After 6 months of denosumab treatment, bone turnover markers start to increase and return to baseline 52. The inhibition of osteoclast mediated bone resorption by denosumab is based on the reversible binding of the drug to RANKL on osteoblasts and precursor stromal cells 53. A recent position paper published by the American Academy of Oral and Maxillofacial Surgeons specifically addressing medication-related osteonecrosis of the jaws (MRONJ) emphasizes that, in contrast to bisphosphonates, RANK ligand inhibitors like denosumab do not bind to bone and their effects on bone remodeling are mostly diminished within 6 months of treatment cessation 51.
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Some of the adverse effects of denosumab therapy include urinary tract infection, upper respiratory tract infection, dyspnea, sciatica, cataracts, constipation diarrhea, rash, hyperhidrosis, pain in extremities, hypocalcemia, hypophosphatemia, and osteonecrosis of the jaw. The aforementioned Phase III studies of skeletal metastases indicated an average incidence of osteonecrosis of the jaw was 1.8% with denosumab and 1.3% with zoledronic acid 46,47,48,54. Twenty percent of patients treated with zoledronic acid develop acute-phase reactions resulting in fever, myalgia, and bone pain within the first 3 days of treatment, and only 8.7% of patients treated with denosumab experienced such reactions. Hypocalcemia was more frequent with denosumab (9.6%) than with zoledronic acid (5.0%). When bisphosphonates have been utilized in the medical management of giant cell tumor of bone, the local recurrence rate was 4.2% compared to 30% in a control group in a case controlled study 55 . As an alternative to bisphosphonates, and because denosumab is known to inhibit osteoclast function via the RANK/RANKL pathway, its inhibition of the osteoclast-like giant cells in giant cell tumor of bone has been evaluated in two Phase II clinical studies funded by Amgen 43,44. In the first open-label study, a single group of 37 individuals with unresectable giant cell tumor received 120 mg subcutaneous denosumab every 4 weeks with loading doses on days 8 and 15 of the first month 43. Tumor response was assessed through radiographic evaluation and histologic analysis and defined to be the elimination of either 90% or more of giant cells or no radiological progression of the lesion up to week 25. Eighty-six
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percent of cases resulted in a positive tumor response. The most common adverse event reported was pain in an extremity (18%), followed by back pain (11%) and headache (11%). The authors of the study acknowledged that the therapeutic effects of denosumab could have been confounded by previous treatments with chemotherapy, radiation therapy, bisphosphonate therapy, or surgery 43.
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In the second open-label study, 282 patients in parallel groups with giant cell tumors in long bones were studied over a period of 6 months 44. The cohorts included both surgically unsalvageable giant cell tumors and those determined to be salvageable with surgery, but that would result in severe morbidity 44. Patients received 120 mg of subcutaneous denosumab every 4 weeks with initial loading doses on days 8 and 15 of the first cycle. The investigators reported that 96% of patients with surgically unsalvageable giant cell tumors had no disease progression after a median follow-up time of 13 months. In cases of giant cell tumor that were surgically salvageable, 74% of patients required no surgery and 62% of patients who had surgery underwent a less morbid procedure than planned. The median followup in cohort 2 was 9.2 months. Adverse events during the course of therapy included osteonecrosis of the jaws (1%), hypocalcemia (5%), hypophosphatemia (3%), and anemia, back pain, and pain in extremities, each of which occurred in 1% of patients 44.
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To date, there have been no published prospective clinical studies of denosumab therapy in patients with CGCG of the jaws. Because the neoplastic cells of giant cell tumor and CGCG have shown similar antigenic and phenotypic characteristics, equivalent therapeutic alternatives to surgical intervention have been developed for both lesions. Both cases of CGCG we are reporting had aggressive clinical and radiographic characteristics with respect to size, rapid growth, symptoms and tooth displacement (Chuong 1986). Clinical follow-up information was available for 24 months (Case #1) and 15 months (Case #2) and is ongoing at this time. In both cases, progressive radiodensity and osseous regeneration was noted after denosumab therapy was initiated, even in the presence of an adjacent focus of residual CGCG seen in Case #1. The dramatic response to denosumab therapy in Case #2 may have been potentiated by the previous intralesional injections of triamcinolone. The patient continued to have acute symptoms and compliance problems with the initial intralesional steroid injections. Prolonged and overall effective results were seen after subcutaneous denosumab injections were initiated and the patient was able to continue without complications.
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The significant radiographic, clinical, and histologic response seen in these two cases suggests that denosumab may represent a viable alternative or adjunctive procedure to eliminate or reduce the extent of surgical intervention and morbidity in the treatment of CGCG. Future prospective studies with a larger sample size would provide more comprehensive information about the long-term effects, and possible adverse side effects of treating CGCG of the jaws with denosumab.
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FIGURE LEGENDS Figure 1: Case #1: Patient photograph at initial presentation. Frontal view shows the facial asymmetry and chin displacement to the right side.
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Figure 2: Case #1: Intraoral photograph showing labial and lingual expansion and displacement of the anterior mandibular teeth. Figure 3A: Case #1: Cone beam computerized tomographic (CBCT) image of a multilocular radiolucency extending from the left first mandibular premolar to the developing right second mandibular premolar.
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Figure 3B: Case #1: Axial computed tomograph showing the multilocular lesion. Significant superior-inferior and buccal-lingual expansion was noted.
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Figure 4: Case #1: High power photomicrograph of a proliferation of multinucleated giant cells in a cellular background stroma containing numerous extravasated erythrocytes. Hematoxylin and eosin stain. 200x original magnification. Figure 5A: Case #2: CBCT image of a multilocular expansile radiolucency of the mandibular angle and ramus extending to the sigmoid notch and condyle.
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Figure 5B: Case #2: Axial computed tomograph showing buccal and lingual cortical expansion. The margins of the lesion were thin and scalloped with internal septae and calcifications noted centrally. Figure 6: Case #2: High power photomicrograph of a central giant cell lesion. Hematoxylin and eosin stain. 200x original magnification. Figure 7A: Case #1: CBCT image after 6 months subcutaneous denosumab therapy.
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Figure 7B: Case #1: Axial computed tomograph after 6 months subcutaneous denosumab therapy demonstrating a diffuse radiopacity within the lesion.
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Figure 8: Case #1: CBCT image 18 months of denosumab therapy showing increased radiodensity of the anterior mandibular lesion. Figure 9: Case #1: Low power photomicrograph shows new viable trabecular bone formation with fatty marrow. Numerous osteocytes are present. Hematoxylin and eosin stain. 100x original magnification. Figure 10: Case #1: Axial computed tomograph 24 months after the initial diagnosis demonstrating increased radiodensity throughout most of the lesion, with one focal area of decreased density near the facial cortical border inferior to the incisors. Figure 11A: Case #1: Patient photograph 28 months after initial diagnosis. Frontal view shows siginificant resolution of the mandibular asymmetry.
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Figure 11B: Case #1: Intraoral photograph 28 months after initial diagnosis showing improved alignment of the mandibular teeth and diminished bucco-lingual expansion. Figure 12: Case #2: After 4 months of denosumab therapy, CBCT image shows dramatic increase in radiodensity and decreased size of the lesion.
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Figure 13: Case #2: Low power photomicrograph after 9 months of denosumab therapy demonstrates mature lamellar bone with osteocytes present in the lacunae. Hematoxylin and eosin stain. 100x original magnification.
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Figure 14A and 14B: Case #2: 15 months after the initial diagnosis, CBCT images show continued resolution with decrease in size of the lesion and improvement in contour of the left mandible.
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