A case of recurrent multiple myeloma showing clinical features similar to medication-related osteonecrosis of the jaw (MRONJ)

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Case Report

A case of recurrent multiple myeloma showing clinical features similar to medication-related osteonecrosis of the jaw (MRONJ) Koji Tsunematsu a,b , Takahiro Kanno b , Joji Sekine b,∗ a b

Division of Oral and Maxillofacial Surgery, National Hospital Organization Hamada Medical Center, Asaimachi 777-12, Hamada, Shimane 697-8511, Japan Department of Oral and Maxillofacial Surgery, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan

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Article history: Received 16 December 2015 Received in revised form 1 April 2016 Accepted 12 April 2016 Available online xxx Keywords: Multiple myeloma Bisphosphonate Medication-related osteonecrosis of the jaw

a b s t r a c t We report a case of recurrent multiple myeloma in the mandibular ramus showing clinical features similar to those of medication-related osteonecrosis of the jaw (MRONJ) at the initial visit. A 53-year-old man was referred to our department for suspected MRONJ following repeated intravenous bisphosphonate administration, with the chief complaint of hypaesthesia in the mandible. The patient had been treated with bortezomib and cyclophosphamide plus dexamethasone for multiple myeloma as well as intravenous bisphosphonate (zoledronic acid). Radiographic examination revealed sclerotic bone and resorptive lesions in the mandibular angle and ramus. Given the history of myeloma, biopsy was performed for histopathological diagnosis. Biopsy results indicated a diagnosis of recurrent multiple myeloma and not MRONJ, and the patient was treated with lenalidomide and dexamethasone. Consequently, the hypaesthesia in the mandible improved without further growth of the lesion, and the tumor has remained under control so far during the follow-up of about 1 year. © 2016 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Published by Elsevier Ltd. All rights reserved.夽

1. Introduction Myeloma is often accompanied by systemic changes such as nodular proliferation of plasma cells in the bone marrow, bone destruction caused by abnormal monoclonal immunoglobulin elevation, major organ failure, and hematopoietic disorders [1]. Although multiple myeloma can affect various parts of the body, the oral region is rarely affected at the initial onset of the primary or recurrent lesion. Furthermore, clinical reports concerning multiple myeloma have rarely described primary manifestations in the mandible [2]. Recently, the efficacy of bisphosphonate for multiple myelomas has been well documented [3]. In 2010, the International Myeloma Working Group proposed guidelines for bisphosphonate preparations and treatment for multiple myeloma. However, the use of bisphosphonates for the treatment of multiple myeloma has been reported to cause a medication-related osteonecrosis of the jaw (MRONJ) [4]. Therefore, the treatment of multiple myeloma

夽 Asian AOMS: Asian Association of Oral and Maxillofacial Surgeons; ASOMP: Asian Society of Oral and Maxillofacial Pathology; JSOP: Japanese Society of Oral Pathology; JSOMS: Japanese Society of Oral and Maxillofacial Surgeons; JSOM: Japanese Society of Oral Medicine; JAMI: Japanese Academy of Maxillofacial Implants. ∗ Corresponding author. Tel.: +81 853 20 2301; fax: +81 853 20 2299. E-mail address: [email protected] (J. Sekine).

necessitates close cooperation between medical and dental departments to provide interdisciplinary treatment and care. This is particularly pertinent, since lesions of multiple myeloma in the mandible are difficult to distinguish from MRONJ in terms of diagnostic imaging and clinical symptoms [5]. Here, we report an unusual case of recurrent multiple myeloma that manifested in the mandible with clinical features similar to those of MRONJ.

2. Case report In December 2014, a 53-year-old Japanese man was referred to our department with the chief complaint of hypaesthesia in the left mental region. The patient had multiple myeloma involving the left sixth and eighth ribs, right second and seventh ribs, left clavicle, and left humeral head, for which he had been treated with bortezomib (1.3 mg/m2 ), cyclophosphamide (500 mg/m2 ), and dexamethasone (40 mg) in the Department of Hematology since January 2013. He had received bisphosphonate therapy (zoledronic acid, 4 mg every 28 days) from June 2013 onward for 19 months. The progress of multiple myeloma was halted following chemotherapy and administration of bisphosphonates for 1.5 years. However, the patient experienced paresthesia of the left mental area and mandible, and radiography revealed a radiolucent area in the mandible possibly indicative of osteonecrosis or osteomyelitis. The patient was

http://dx.doi.org/10.1016/j.ajoms.2016.04.006 2212-5558/© 2016 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Published by Elsevier Ltd. All rights reserved.夽

Please cite this article in press as: Tsunematsu K, et al. A case of recurrent multiple myeloma showing clinical features similar to medication-related osteonecrosis of the jaw (MRONJ). J Oral Maxillofac Surg Med Pathol (2016), http://dx.doi.org/10.1016/j.ajoms.2016.04.006

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therefore strongly suspected to have developed MRONJ caused by the administration of bisphosphonates, and he was referred to our Department of Oral and Maxillofacial Surgery. At the initial examination at our division, gum bleeding was observed in the left mandibular first molar alveolar region with possibly a fistula in which the mandibular bone was probed through it. Radiographic findings by panoramic radiograph show a radiolucent lesion in the left premolar area to mandibular angle possibly indicative of osteonecrosis or osteomyelitis (Fig. 1A). Also, the border of the lesion was unclear. Computed tomography (CT) values in the mandibular first and second molar surrounding the bone were higher than another region (Fig. 1B). We thus made a possible preliminary diagnosis of MRONJ based on the clinical symptoms and his treatment history of medication course. We here suspected stage 2 MRONJ according

to the classification of American Association of Oral and Maxillofacial Surgeons position paper described in 2014 [4]. Subsequently, precise examinations to confirm the diagnosis were performed. Magnetic resonance imaging (MRI) finding showed, on the other hand, the loss of the signal intensity within the marrow on the T1-weighted in the mandibular first molar surrounding the bone, and a soft tissue formation, measuring 26 mm, continuous with the bone cortex in the mandibular notch in the T2-weighted image. A T1-weighted image showed low intensity, meanwhile T2-weighted image showed moderate high intensity in the soft tissue mass (Fig. 1C and D). Fludeoxyglucose (18 F)-positron emission tomography–computed tomography (18 F-FDG PET/CT) revealed increased uptake in the left 6–8 ribs (SUVmax = 3.49), sternum (SUVmax = 4.02), left clavicle (SUVmax = 5.28), upper left humerus head (SUVmax = 2.71), and left mandibular ramus (SUVmax = 8.19)

Fig. 1. Image findings. (A) Panoramic radiography of the mandible at the first examination (the arrow shows a radiolucent lesion in the left mandible possibly indicative of osteonecrosis or osteomyelitis). (B) Computed tomography values in the mandibular first and second molar surrounding the bone were higher than another region. (C) Magnetic resonance image showing infection of left side mandible bone on T1-weighted coronal images. (D) Magnetic resonance image showing a soft tissue formation measuring 26 mm, continuous with the bone cortex in the left mandibular notch on T2-weighted coronal images. (E) Fludeoxyglucose (18 F)-positron emission tomography–computed tomography (the arrow shows left mandibular notch image). Left side mandibular notch; SUVmax: 8.19.

Please cite this article in press as: Tsunematsu K, et al. A case of recurrent multiple myeloma showing clinical features similar to medication-related osteonecrosis of the jaw (MRONJ). J Oral Maxillofac Surg Med Pathol (2016), http://dx.doi.org/10.1016/j.ajoms.2016.04.006

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(Fig. 1E). Laboratory examinations showed that the C-reactive protein and lactate dehydrogenase levels were slightly increased, while ␤2 -microglobulin and immunoglobulin G levels were also elevated (Table 1). While the radiographic images could indicate infectious osteomyelitis lesions with MRONJ, the MRI and 18 F-FDG PET/CT suggested the possibility of recurrent multiple myeloma in the mandible. Since discriminating between MRONJ and multiple myeloma was difficult based on imaging findings alone, we decided to perform tissue biopsy of the mandibular ramus via the oral cavity under intravenous sedation. Histopathological examination of the biopsied tissue revealed features of multiple myeloma. Hematoxylin and eosin staining of the biopsied tissue revealed diffuse proliferation of plasma cells. With regard to the immunohistochemical profile of the tumor, it was positive for kappa and negative for lambda (Fig. 2A–C). The patient was referred back to the Division of Hematology where he received therapy with lenalidomide (25 mg on days 1–21 with repeated administration every 28 days) and dexamethasone (40 mg on days 1, 8, 15, and 22 with repeated administration every 28 days) from January 2015 for 1 year. Consequently, the hypaesthesia in the left mental region improved without further growth of the lesion, and the tumor has remained under control thus far with close follow-up for a period of about 1 year up to December 2015. 3. Discussion The incidence of multiple myeloma in the oral region is typically lower than 20–30% [6]. Relapse of primary multiple myeloma may be overlooked in cases with symptoms of MRONJ subsequent to the administration of bisphosphonates. Common clinical symptoms and signs of multiple myeloma include bony pain, fatigue, anemia, and increased occurrence of infectious diseases [7]. More than 80% of patients with multiple myeloma have osteolytic bone disease, which increases the risk of skeletal-related events such as pathological fractures, spinal cord compression, and the need for radiotherapy or surgery. Bone disease is primarily due to increased osteoclastic activity and impaired osteoblast activity [8]. Distinguishing multiple myeloma from multiple metastatic lesions necessitates extensive clinical, diagnostic imaging, and laboratory evaluations, including histopathological examination [4]. Bisphosphonates are pyrophosphate analogues with high bone affinity that can inhibit osteoclastic activity. Zoledronic acid is the most commonly used bisphosphonate for treating multiple myeloma. Bisphosphonate therapy, which was approved for medical insurance in July 1997 in Japan, is used as supportive therapy for

Table 1 Laboratory findings. Hematological findings

Immunoglobulin findings

WBC RBC Hb Ht AST ALT Na K Ca BUN CRE CRP TP ALb

IgG IgA IgM ␤2 -MG

7010/␮l 429 × 104 /␮l 13.5 g/dl ↓ 38.4% ↓ 35 IU/l 14 IU/l 139 mEq/l 4.4 mEq/l 8.7 mEq/l 14.6 mg/dl 0.80 mg/dl 0.9 mg/dl ↑ 8.3 g/dl 4.0 g/dl

4148 mg/dl ↑ 39 mg/dl ↓ 35 mg/dl ↑ 2.8 mg/dl ↑

Fig. 2. Histopathological findings. (A) Biopsied tissue revealing diffuse proliferation of plasma cells (original magnification, 400×; hematoxylin and eosin stain). (B) With regard to the immunohistochemical profile of the tumor, it was positive for kappa (original magnification, 100×; in situ hybridization). (C) With regard to the immunohistochemical profile of the tumor, it was negative for lambda (original magnification, 100×; in situ hybridization).

multiple myeloma. A widely reported side effect of bisphosphonate therapy is MRONJ, with a cumulative incidence of 0.8–12% [9]. The initial symptoms of multiple myeloma in the mandible are often the same as those of MRONJ. Maxillofacial involvement in patients with multiple myeloma is not uncommon, but the diagnosis of multiple myeloma is often overlooked in these sites. The earliest MRONJ lesions could be identifiable with MRI imagings

Please cite this article in press as: Tsunematsu K, et al. A case of recurrent multiple myeloma showing clinical features similar to medication-related osteonecrosis of the jaw (MRONJ). J Oral Maxillofac Surg Med Pathol (2016), http://dx.doi.org/10.1016/j.ajoms.2016.04.006

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as areas of decreased fat and signal intensity within the marrow on T1-weighted images [10]. Similarly, MRI finding of multiple myeloma is the loss of the T1 hyperintensity of fatty marrow in some cases [11]. However, MRONJ and multiple myeloma are reported to be difficult to identify the other imaging findings from common characteristic of cortical bone breaking or loss without histopathological diagnoses [10,11]. Furthermore, if the lesions are infected in the oral sits, the imaging findings of MRI could be even more difficult. Therefore, it is difficult to identify patients previously treated for multiple myeloma who are at high risk of relapse of the primary disease as well as developing MRONJ as reported here. In such cases, it is important to distinguish MRONJ from multiple myeloma. The histopathological findings of MRONJ include bone necrosis with devitalized trabecular bone and empty lacunae without inflammatory infiltrate or metastasis [12]. On the other hand, multiple myeloma is a malignant B cell tumor originating from pre-switched, follicle center B lymphocytes which differentiate into plasma cells that accumulate in the bone marrow. Therefore, immunohistochemistry is an important tool used for diagnosis and prognosis of multiple myeloma [13]. Based on our experience, histopathological examination via tissue biopsy of the affected mandible is recommended for distinguishing MRONJ from recurrent multiple myeloma. Considering the increased risk of developing MRONJ and relapse of primary disease in the survivors of multiple myeloma, oral health care professionals play a critical role in the long-term surveillance of these patients. An interdisciplinary approach that brings together medical and dental departments is recommended for treating such patients [11]. In conclusion, in a patient with a history of bisphosphonate therapy for multiple myeloma, the differential diagnosis for radiolucent lesions in maxillofacial bones, particularly in the mandible, should include MRONJ and recurrent multiple myeloma. Accurate diagnosis requires extensive clinical, diagnostic imaging, and laboratory evaluations, including histopathological examination of tissue biopsy. Interdisciplinary cooperation between medical and dental departments is important for the management of such patients. Ethical approval Not required. This clinical report complies with the Declaration of Helsinki.

Conflict of interest None. Acknowledgement The authors would like to thank Dr. Makoto Nagasaki (Chief, Division of Clinical Laboratory, National Hospital Organization Hamada Medical Center) for providing his expert technical and valuable advice regarding immunochemical and histopathological diagnosis. References [1] Ohtsuru H, Tanabe Y, Takaku Y, Kakizawa T, Saitou M, Yamaguchi M, et al. Multiple myeloma with sensory paralysis after extraction of mandibular wisdom tooth as initial symptom. Shikwa Gakuho 2006;106:38–42. [2] Kamada S, Ono M, Kuribayashi K, Kudoh A, Tei K. A case of multiple myeloma with initial symptoms of paresthesia of the mental region. Hokkaido J Dent Sci 2014;35:62–9. [3] Wang X, Yan X, Li Y. A meta-analysis of the antitumor effect and safety of bisphosphonates in the treatment of multiple myeloma. Int J Clin Exp Med 2015;8:6743–54. [4] Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, et al., American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on medicationrelated osteonecrosis of the jaw – 2014 update. J Oral Maxillofac Surg 2014;72:1938–56. [5] Miller CD, Goltry RR, Shenasky JH. Multiple myeloma involving the mandible. Report of a case. Oral Surg Oral Med Oral Pathol 1969;28:603–9. [6] Shah A, Ali A, Latoo S, Ahmad I. Multiple myeloma presenting as gingival mass. J Maxillofac Oral Surg 2010;9:209–12, http://dx.doi.org/10.1007/ s12663-010-0050-7. [7] Harle L, Chan C. A healthy young man presenting with multiple rib fractures. Clin Chem 2010;56:1390–2. [8] Mozaffari E, Mupparapu M, Otis L. Undiagnosed multiple myeloma causing extensive dental bleeding: report of a case and review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;94:448–53. [9] Mawardi H, Cutler C, Treister N. Management update: non-Hodgkin lymphoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;107:19–33. [10] Krishnan A, Arslanoglu A, Yildirm N, Silbergleit R, Aygun N. Imaging findings of bisphosphonate-related osteonecrosis of the jaw with emphasis on early magnetic resonance imaging findings. J Comput Assist Tomogr 2009;33: 298–304. [11] Libshitz HI, Malthouse SR, Cunningham D, MacVicar AD, Husband JE. Multiple myeloma: appearance at MR imaging. Radiology 1992;182:833–7. [12] Elias FP, Maikel P, Andrey M, Oscar M, Juan G. Bisphosphonate-induced osteonecrosis of the jaws: clinical, imaging, and histopathology findings. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2014;118:408–17. [13] Santra M, Shaughnessy Jr JD, Bellamy WT. Expression of multiple myeloma associated markers in bone marrow spicules using a novel immunohistochemical technique. Biotech Histochem 2011;86:119–23.

Please cite this article in press as: Tsunematsu K, et al. A case of recurrent multiple myeloma showing clinical features similar to medication-related osteonecrosis of the jaw (MRONJ). J Oral Maxillofac Surg Med Pathol (2016), http://dx.doi.org/10.1016/j.ajoms.2016.04.006